condition found tbRes List
NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱
Source: TCGA
Type: Antiapoptotic
Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱
236- AL,    Allicin: Chemistry and Biological Properties
- Analysis, NA, NA
GSH↓, allicin reacts with GSH
Bacteria↓, Antimicrobial
LDL↓, reduction without altering HDL
ROS↑, antioxidant at low doses
NRF2↑,
cognitive↑, by activating the Nrf2-system
memory↑, by activating the Nrf2-system
BP↓, via H2S generation
RNS↓,

256- AL,  doxoR,    Allicin Overcomes Doxorubicin Resistance of Breast Cancer Cells by Targeting the Nrf2 Pathway
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
NRF2↓,
HO-1↓,
p‑Akt↓,

254- AL,    Allicin and Cancer Hallmarks
- Review, Var, NA
NRF2⇅, 40 nM
BAX↑,
Bcl-2↓,
Fas↑,
MMP↓,
Bax:Bcl2↑,
Cyt‑c↑,
Casp3↑,
Casp12↑,
GSH↓, Allicin can easily penetrate the cell membrane and react with the cellular thiol to transiently deplete the intracellular GSH level, inducing the inhibition of cell cycle progression and growth arrest [98].
TumCCA↑,
ROS↑, An in vitro study indicated that allicin encourages oxidative stress and autophagy in Saos-2 and U2OS (osteosarcoma cells) by modulating the MALATI-miR-376a-Wnt and β-catenin pathway [99].
antiOx↓, As an antioxidant phytochemical, it scavenges reactive oxygen species (ROS) and protects cells from oxidative DNA damage [34].

2657- AL,    Allicin pharmacology: Common molecular mechanisms against neuroinflammation and cardiovascular diseases
- Review, CardioV, NA - Review, AD, NA
*Inflam↓, allicin integrate a broad spectrum of properties (e.g., anti-inflammatory, immunomodulatory, antibiotic, antifungal, antiparasitic, antioxidant, nephroprotective, neuroprotective, cardioprotective, and anti-tumoral activities, among others).
*antiOx↑, improving the antioxidant system
*neuroP↑,
*cardioP↑,
*AntiTum↑,
*mtDam↑, Indeed, the current evidence suggests that allicin improves mitochondrial function by enhancing the expression of HSP70 and NRF2, decreasing RAAS activation, and promoting mitochondrial fusion processes.
*HSP70/HSPA5↑, llicin improves mitochondrial function by enhancing the expression of HSP70 and decreasing RAAS activation
*NRF2↑,
*RAAS↓,
*cognitive↑, Allicin enhances the cognitive function of APP (amyloid precursor protein)/PS1 (presenilin 1) double transgenic mice by decreasing the expression levels of Aβ, oxidative stress, and improving mitochondrial function.
*SOD↑, positive effects on cognition in an AD mouse model by administrating a preventive dose of allicin. These effects might be mediated by an increase of SOD and reduction of ROS
*ROS↓,
*NRF2↑, Chronic treatment with allicin increased the expression of NRF2 and targeted downstream of NRF2, such as NADPH, quinone oxidoreductase 1 (NQO1), and γ-glutamyl cysteine synthetase (γ-GCS), in the hippocampus of aged mice
*ER Stress↓, protective effects of 16 weeks of allicin treatment in a rat model of endoplasmic reticulum stress-related cognitive deficits.
*neuroP↑, allicin was able to ameliorate depressive-like behaviors by decreasing neuroinflammation, oxidative stress iron aberrant accumulation,
*memory↑, allicin improved lead acetate-caused learning and memory deficits and decreased the ROS level
*TBARS↓, Oral administration of allicin was able to reduce thiobarbituric reactive substances (TBARS) and myeloperoxidase (MPO) levels, and concurrently increased (SOD) activity, glutathione S-transferase (GST) and glutathione (GSH) levels in a rat model of
*MPO↓,
*SOD↑,
*GSH↑,
*iNOS↓, decreasing the expression of iNOS and increased the phosphorylation of endothelial NOS (eNOS)
*p‑eNOS↑,
*HO-1↑, OSCs upregulate the endogenous antioxidant NRF2 and heme oxygenase-1 (HO-1)

2660- AL,    Allicin: A review of its important pharmacological activities
- Review, AD, NA - Review, Var, NA - Review, Park, NA - Review, Stroke, NA
*Inflam↓, It showed neuroprotective effects, exhibited anti-inflammatory properties, demonstrated anticancer activity, acted as an antioxidant, provided cardioprotection, exerted antidiabetic effects, and offered hepatoprotection.
AntiCan↑,
*antiOx↑,
*cardioP↑, This vasodilatory effect helps protect against cardiovascular diseases by reducing the risk of hypertension and atherosclerosis.
*hepatoP↑,
*BBB↑, This allows allicin to easily traverse phospholipid bilayers and the blood-brain barrier
*Half-Life↝, biological half-life of allicin is estimated to be approximately one year at 4°C. However, it should be noted that its half-life may differ when it is dissolved in different solvents, such as vegetable oil
*H2S↑, allicin undergoes metabolism in the body, leading to the release of hydrogen sulfide (H2S)
*BP↓, H2S acts as a vasodilator, meaning it relaxes and widens blood vessels, promoting blood flow and reducing blood pressure.
*neuroP↑, It acts as a neuromodulator, regulating synaptic transmission and neuronal excitability.
*cognitive↑, Studies have suggested that H2S may enhance cognitive function and protect against neurodegenerative diseases like Alzheimer's and Parkinson's by promoting neuronal survival and reducing oxidative stress.
*neuroP↑, various research studies suggest that the neuroprotective mechanisms of allicin can be attributed to its antioxidant and anti-inflammatory properties
*ROS↓,
*GutMicro↑, may contribute to the overall health of the gut microbiota.
*LDH↓, Liu et al. found that allicin treatment led to a significant decrease in the release of lactate dehydrogenase (LDH),
*ROS↓, allicin's capacity to lower the production of reactive oxygen species (ROS), decrease lipid peroxidation, and maintain the activities of antioxidant enzymes
*lipid-P↓,
*antiOx↑,
*other↑, allicin was found to enhance the expression of sphingosine kinases 2 (Sphk2), which is considered a neuroprotective mechanism in ischemic stroke
*PI3K↓, allicin downregulated the PI3K/Akt/nuclear factor-kappa B (NF-κB) pathway, inhibiting the overproduction of NO, iNOS, prostaglandin E2, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-alpha induced by interleukin-1 (IL-1)
*Akt↓,
*NF-kB↓,
*NO↓,
*iNOS↓,
*PGE2↓,
*COX2↓,
*IL6↓,
*TNF-α↓, Allicin has been found to regulate the immune system and reduce the levels of TNF-α and IL-8.
*MPO↓, Furthermore, allicin significantly decreased tumor necrosis factor-alpha (TNF-α) levels and myeloperoxidase (MPO) activity, indicating its neuroprotective effect against brain ischemia via an anti-inflammatory pathway
*eff↑, Allicin, in combination with melatonin, demonstrated a marked reduction in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), Kelch-like ECH-associated protein 1 (Keap-1), and NF-κB genes in rats with brain damage induced by acryl
*NRF2↑, Allicin treatment decreased oxidative stress by upregulating Nrf2 protein and downregulating Keap-1 expression.
*Keap1↓,
*TBARS↓, It significantly reduced myeloperoxidase (MPO) and thiobarbituric acid reactive substances (TBARS) levels,
*creat↓, and decreased blood urea nitrogen (BUN), creatinine, LDH, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) levels.
*LDH↓,
*AST↓,
*ALAT↓,
*MDA↓,
*SOD↑, Allicin also increased the activity of superoxide dismutase (SOD) as well as the levels of glutathione S-transferase (GST) and glutathione (GSH) in the liver, kidneys, and brain
*GSH↑,
*GSTs↑,
*memory↑, Allicin has demonstrated its ability to improve learning and memory deficits caused by lead acetate injury by promoting hippocampal astrocyte differentiation.
chemoP↑, Allicin safeguards mitochondria from damage, prevents the release of cytochrome c, and decreases the expression of pro-apoptotic factors (Bax, cleaved caspase-9, cleaved caspase-3, and p53) typically activated by cisplatin
IL8↓, Allicin has been found to regulate the immune system and reduce the levels of TNF-α and IL-8.
Cyt‑c↑, In addition, allicin was reported to induce cytochrome c, increase expression of caspase 3 [86], caspase 8, 9 [82,87], caspase 12 [80] along with enhanced p38 protein expression levels [81], Fas expression levels [82].
Casp3↑,
Casp8↑,
Casp9↑,
Casp12↑,
p38↑,
Fas↑,
P53↑, Also, significantly increased p53, p21, and CHK1 expression levels decreased cyclin B after allicin treatment.
P21↑,
CHK1↓,
CycB↓,
GSH↓, Depletion of GSH and alterations in intracellular redox status have been found to trigger activation of the mitochondrial apoptotic pathway was the antiproliferative function of allicin
ROS↑, Hepatocellular carcinoma (HCC) cells were sensitised by allicin to the mitochondrial ROS-mediated apoptosis induced by 5-fluorouracil
TumCCA↑, According to research findings, allicin has been shown to decrease the percentage of cells in the G0/G1 and S phases [87], while causing cell cycle arrest at the G2/M phase
Hif1a↓, Allicin treatment was found to effectively reduce HIF-1α protein levels, leading to decreased expression of Bcl-2 and VEGF, and suppressing the colony formation capacity and cell migration rate of cancer cells
Bcl-2↓,
VEGF↓,
TumCMig↓,
STAT3↓, antitumor properties of allicin have been attributed to various mechanisms, including promotion of apoptosis, inhibition of STAT3 signaling
VEGFR2↓, suppression of VEGFR2 and FAK phosphorylation
p‑FAK↓,

1235- ALA,  Cisplatin,    α-Lipoic acid prevents against cisplatin cytotoxicity via activation of the NRF2/HO-1 antioxidant pathway
- in-vitro, Nor, HEI-OC1 - ex-vivo, NA, NA
ROS↑, production of reactive oxygen species (ROS) by cisplatin is one of the major mechanisms of cisplatin-induced cytotoxicity
HO-1↓, due to Cisplatin only
*toxicity↓, LA was safe at concentrations up to 0.5 mM in HEI-OC1 cells (normal)
chemoP↑, had a protective effect against cisplatin-induced cytotoxicity
*ROS↓, Intracellular ROS production in HEI-OC1(normal) cells was rapidly increased by cisplatin for up to 48 h. However, treatment with LA significantly reduced the production of ROS
*HO-1↑, and increased the expression of the antioxidant proteins HO-1 and SOD1
*SOD1↑,
*NRF2↑, antioxidant activity of LA was through the activation of the NRF2/HO-1 antioxidant pathway

278- ALA,    The Multifaceted Role of Alpha-Lipoic Acid in Cancer Prevention, Occurrence, and Treatment
- Review, NA, NA
ROS↑, direct anticancer effect of the antioxidant ALA is manifested as an increase in intracellular ROS levels in cancer cells
NRF2↑, enhance the activity of the anti-inflammatory protein nuclear factor erythroid 2–related factor 2 (Nrf2), thereby reducing tissue damage
Inflam↓,
frataxin↑,
*BioAv↓, Oral ALA has a bioavailability of approximately 30% due to issues such as poor stability in the stomach, low solubility, and hepatic degradation.
ChemoSen↑, ALA can enhance the functionality of various other anticancer drugs, including 5-fluorouracil in colon cancer cells and cisplatin in MCF-7 breast cancer cells
Hif1a↓, it is inferred that lipoic acid may inhibit the expression of HIF-1α
eff↑, act as a synergistic agent with natural polyphenolic substances such as apigenin and genistein
FAK↓, ALA inhibits FAK activation by downregulating β1-integrin expression and reduces the levels of MMP-9 and MMP-2
ITGB1↓,
MMP2↓,
MMP9↓,
EMT↓, ALA inhibits the expression of EMT markers, including Snail, vimentin, and Zeb1
Snail↓,
Vim↓,
Zeb1↓,
P53↑, ALA also stimulates the mutant p53 protein and depletes MGMT
MGMT↓, depletes MGMT by inhibiting NF-κB signalling, thereby inducing apoptosis
Mcl-1↓,
Bcl-xL↓,
Bcl-2↓,
survivin↓,
Casp3↑,
Casp9↑,
BAX↑,
p‑Akt↓, ALA inhibits the activation of tumour stem cells by reducing Akt phosphorylation.
GSK‐3β↓, phosphorylation and inactivation of GSK3β
*antiOx↑, indirect antioxidant protection through metal chelation (ALA primarily binds Cu2+ and Zn2+, while DHLA can bind Cu2+, Zn2+, Pb2+, Hg2+, and Fe3+) and the regeneration of certain endogenous antioxidants, such as vitamin E, vitamin C, and glutathione
*ROS↓, ALA can directly quench various reactive species, including ROS, reactive nitrogen species, hydroxyl radicals (HO•), hypochlorous acid (HclO), and singlet oxygen (1O2);
selectivity↑, In normal cells, ALA acts as an antioxidant by clearing ROS. However, in cancer cells, it can exert pro-oxidative effects, inducing pathways that restrict cancer progression.
angioG↓, Combining these two hypotheses, it can be hypothesized that ALA may regulate copper and HIF-2α to limit tumor angiogenesis.
MMPs↓, ALA was shown to inhibit invasion by decreasing the mRNA levels of key matrix metalloproteinases (MMPs), specifically MMP2 and MMP9, which are crucial for the metastatic process
NF-kB↓, ALA has been shown to enhance the efficacy of the chemotherapeutic drug paclitaxel in breast and lung cancer cells by inhibiting the NF-κB signalling pathway and the functions of integrin β1/β3 [138,139]
ITGB3↓,
NADPH↓, ALA has been shown to inhibit NADPH oxidase, a key enzyme closely associated with NP, including NOX4

267- ALA,    α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells
- vitro+vivo, Lung, A549 - vitro+vivo, Lung, PC9
Apoptosis↑,
ROS↑, mitochondrial ROS(remarkably increased)
PDK1↓,
NRF2↓,
PDK1↓,
Bcl-2↓,
Casp9↑,
Dose∅, 1.5 mM LA for 24 h

265- ALA,    Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
ROS↓, ALA decreased ROS production, SOD1 and GSTP1 protein expression
SOD↓, SOD1, DU145
GSTP1/GSTπ↓,
NRF2↓, significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2
p62↓, du145
p62↑, LNCaP
SOD↑, LNCaP
p‑mTOR↑, revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3.
Beclin-1↓,
ROS↑, Interestingly, in LNCaP cells, we observed an almost significant increase in ROS content (p = 0.06) after ALA compared to the control, concomitantly with a significant upregulation of the antioxidant enzyme SOD1 after 48 h.
SOD1↑,

3438- ALA,    The Potent Antioxidant Alpha Lipoic Acid
- Review, NA, NA - Review, AD, NA
*antiOx↑, Both of alpha lipoic acid and its reduced form have been shown to possess anti-oxidant, cardiovascular, cognitive, anti-ageing, detoxifying, anti-inflammatory, anti-cancer, and neuroprotective pharmacological properties
*cardioP↑,
*cognitive↑, Alpha lipoic acid has the ability to decrease cognitive impairment and may be a successful therapy for Alzheimer’s disease and any disease related dementias
*AntiAge↑,
*Inflam↓,
*AntiCan↑,
*neuroP↑, ALA has neuroprotective effects in experimental brain injury caused by trauma and subarachnoid hemorrhage
*IronCh↑, Also, the ability of ALA to chelate metals can produce an antioxidant effect
*ROS↑, DHLA can exert a pro-oxidant effect of donating its electrons for the reduction of iron, which can then break down peroxide to the prooxidant hydroxyl radical via the Fenton reaction [10]. So, ALA and its reduced form DHLA, can promote antioxidant pr
*Weight↓, α-lipoic acid supplementation at a dose of 300 mg/day might help to could help to promote weight loss and fat mass reduction in healthy overweight/obese women following an energy-restricted balanced diet
*Ach↑, Alpha lipoic acid increases the production of Acetylcholine (Ach) via activating choline acetyl transferase and increases glucose uptake, hence, supplying more acetyl-CoA for the production of Ach of each
*ROS↓, also scavenges reactive oxygen species, thereby increasing the concentration levels of reduced Glutathione (GSH).
*GSH↑,
*lipid-P↓, Alpha lipoic acid can scavenge lipid peroxidation products as hydroxynonenal and acrolein.
*memory↑, learning and memory in the passive avoidance test partially through its antioxidant activity.
*NRF2↑, α-LA treatment has been shown to increase Nrf2 nuclear localization
*ChAT↑, Alpha lipoic acid increases the production of Acetylcholine (Ach) via activating choline acetyl transferase and increases glucose uptake, hence, supplying more acetyl-CoA for the production of Ach of each
*GlucoseCon↑,
*Acetyl-CoA↑,

3449- ALA,    Alpha-Lipoic Acid Downregulates IL-1β and IL-6 by DNA Hypermethylation in SK-N-BE Neuroblastoma Cells
- in-vitro, AD, SK-N-BE
*antiOx↑, ability to maintain its antioxidant properties both in its oxidised and reduced form
*NRF2↑, Antioxidant action of ALA is mediated by two essential nuclear factors: nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light chain-enhancer of activated B cells (NF-kB) [5,6,7,8,9,10]
*NF-kB↓,
*IL1β↓, ALA-dependent down-regulation of IL-1β and IL-6 in neuronal cells.
*IL6↓,
neuroP↑, ALA was already indicated as a potential therapeutic agent in aging-associated neurodegenerative disorders

3456- ALA,    Renal-Protective Roles of Lipoic Acid in Kidney Disease
- Review, NA, NA
*RenoP↑, We focus on various animal models of kidney injury by which the underlying renoprotective mechanisms of ALA have been unraveled
*ROS↓, ALA’s renal protective actions that include decreasing oxidative damage, increasing antioxidant capacities, counteracting inflammation, mitigating renal fibrosis, and attenuating nephron cell death.
*antiOx↑,
*Inflam↓,
*Sepsis↓, figure 1
*IronCh↑, ALA can also chelate metals such as zinc, iron, and copper and regenerate endogenous antioxidants—such as glutathione—and exogenous vitamin antioxidants—such as vitamins C and E—with minimal side effects
*BUN↓, ALA can decrease acute kidney injury by lowering serum blood urea nitrogen, creatinine levels, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), thereby decreasing endothelin-1 vasoconstriction, neutrophil dif
*creat↓,
*TNF-α↓,
*IL6↓,
*IL1β↓,
*MDA↓, pretreatment with ALA decreased MDA content and ameliorated renal oxidative stress
*NRF2↑, activate the Nrf2 signaling pathway, leading to upregulation of the second-phase cytoprotective proteins such as heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1)
*HO-1↑,
*NQO1↑,
*chemoP↑, ALA has also been shown to lower plasma creatinine levels and urine output, increase creatinine clearance and urine osmolality, and normalize sodium excretion in cisplatin kidney injury
*eff↑, ALA can also minimize renal toxicity induced by gold nanoparticles, which are often used as drug carriers
*NF-kB↓, Enhancing autophagy, inhibiting NF-KB, attenuating mitochondrial oxidative stress

3539- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*ROS↓, scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age.
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑,
*antiOx↑, LA has long been touted as an antioxidant
*NRF2↑, activate Phase II detoxification via the transcription factor Nrf2
*MMP9↓, lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*VCAM-1↓,
*NF-kB↓,
*cognitive↑, it has been used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits, and has been implicated as a modulator of various inflammatory signaling pathways
*Inflam↓,
*BioAv↝, LA bioavailability may be dependent on multiple carrier proteins.
*BioAv↝, observed that approximately 20-40% was absorbed [
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies
*H2O2∅, Neither species is active against hydrogen peroxide
*neuroP↑, chelation of iron and copper in the brain had a positive effect in the pathobiology of Alzheimer’s Disease by lowering free radical damage
*PKCδ↑, In addition to PKCδ, LA activates Erk1/2 [92, 93], p38 MAPK [94], PI3 kinase [94], and Akt [94-97].
*ERK↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, In skeletal muscle, LA is proposed to recruit GLUT4 from its storage site in the Golgi to the sarcolemma, so that glucose uptake is stimulated by the local increase in transporter abundance.
*GlucoseCon↑,
*BP↝, Feeding LA to hypertensive rats normalized systolic blood pressure and cytosolic free Ca2+
*eff↑, Clinically, LA administration (in combination with acetyl-L-carnitine) showed some promise as an antihypertensive therapy by decreasing systolic pressure in high blood pressure patients and subjects with the metabolic syndrome
*ICAM-1↓, decreased demyelination and spinal cord expression of adhesion molecules (ICAM-1 and VCAM-1)
*VCAM-1↓,
*Dose↝, Considering the transient cellular accumulation of LA following an oral dose, which does not exceed low micromolar levels, it is entirely possible that some of the cellular effects of LA when given at supraphysiological concentrations may be not be c

3541- ALA,    Insights on alpha lipoic and dihydrolipoic acids as promising scavengers of oxidative stress and possible chelators in mercury toxicology
- Review, Var, NA
*antiOx↑, α-LA has been widely used as an antioxidant compound in many multivitamin formulations, food supplements, anti-aging formulas, and even in human and pet food recipes
*IronCh↑, potential role in the chelation of metals and in restoring normal levels of intracellular glutathione (GSH) after depletion caused by toxicants,
*GSH↑,
*BBB?, ALA, which can pass through the blood-brain barrier (BBB
Apoptosis↑, increased level of apoptosis, mitochondrial membrane depolarization, ROS production, lipid peroxidation, poly-(ADP)-ribose polymerase 1 (PARP1), caspase 3 and 9 expression levels in simultaneous ALA (0.05 mM) and cisplatin(0.025 mM)-treated MCF7
MMP↓,
ROS↑,
lipid-P↑,
PARP1↑,
Casp3↑,
Casp9↑,
*NRF2↑, ALA's ability to activate Nfr2 in GSH production
*GSH↑,
*ROS↓, administration of ALA has been shown to reduce oxidative stress
RenoP↑, ALA also reduced lipid peroxidation in the kidneys caused by the anticancer drug cisplatin,
ChemoSen↑, ALA enhances the functions of various anticancer drugs such as 5-fluorouracil in CRC [146] and cisplatin in MCF-7 cells
*BG↓, ALA was shown to lower the blood glucose levels in patients with type 2 diabetes

3272- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*antiOx↑, LA has long been touted as an antioxidant,
*glucose↑, improve glucose and ascorbate handling,
*eNOS↑, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*NRF2↑,
*MMP9↓,
*VCAM-1↓,
*NF-kB↓,
*cardioP↑, used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits,
*cognitive↑,
*eff↓, The efficiency of LA uptake was also lowered by its administration in food,
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies;
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑, LA markedly increases intracellular glutathione (GSH),
*PKCδ↑, PKCδ, LA activates Erk1/2 [92,93], p38 MAPK [94], PI3 kinase [94], and Akt
*ERK↑,
*p38↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN [95],
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, stimulate GLUT4 translocation
*GLUT1↑, LA-stimulated translocation of GLUT1 and GLUT4.
*Inflam↓, LA as an anti-inflammatory agent

3271- ALA,    Decrypting the potential role of α-lipoic acid in Alzheimer's disease
- Review, AD, NA
*antiOx↑, Alpha-lipoic acid (α-LA), a natural antioxidant
*memory↑, multiple preclinical studies indicating beneficial effects of α-LA in memory functioning, and pointing to its neuroprotective effects
*neuroP↑, α-LA could be considered neuroprotective
*Inflam↓, α-LA shows antioxidant, antiapoptotic, anti-inflammatory, glioprotective, metal chelating properties in both in vivo and in vitro studies.
*IronCh↑, α-LA leads to a marked downregulation in iron absorption and active iron reserve inside the neuron
*NRF2↑, α-LA induces the activity of the nuclear factor erythroid-2-related factor (Nrf2), a transcription factor.
*BBB↑, capable of penetrating the BBB
*GlucoseCon↑, Fig 2, α-LA mediated regulation of glucose uptake
*Ach↑, α-LA may show its action on the activity of the ChAT enzyme, which is an essential enzyme in acetylcholine metabolism
*ROS↓,
*p‑tau↓, decreased degree of tau phosphorylation following treatment with α-LA
*Aβ↓, α-LA possibly induce the solubilization of Aß plaques in the frontal cortex
*cognitive↑, cognitive reservation of α-LA served AD model was markedly upgraded in additional review
*Hif1a↑, α-LA treatment efficaciously induces the translocation and activity of hypoxia-inducible factor-1α (HIF-1α),
*Ca+2↓, research found that α-LA therapy remarkably declines Ca2+ concentration and calpain signaling
*GLUT3↑, inducing the downstream target genes expression, such as GLUT3, GLUT4, HO-1, and VEGF.
*GLUT4↑,
*HO-1↑,
*VEGF↑,
*PDKs↓, α-LA also ameliorates survival in mutant mice of Huntington's disease [150–151], possibly due to the inhibition of the activity of pyruvate dehydrogenase kinase
*PDH↑, α-LA administration enhances PDH expression in mitochondrial hepatocytes by inhibiting the pyruvate dehydrogenase kinase (PDK),
*VCAM-1↓, α-LA inhibits the expression of cell-cell adhesion molecule-1 and VCAM-1 in spinal cords and TNF-α induced neuronal endothelial cells injury
*GSH↑, α-LA may enhance glutathione production in old-aged models
*NRF2↑, activation of the Nrf2 signaling by α-LA
*hepatoP↑, α-LA also protected the liver against oxidative stress-mediated hepatotoxicity
*ChAT↑, α-LA in mice models may prevent neuronal injury possibly due to an increase in ChAT in the hippocampus of animal models

3550- ALA,    Mitochondrial Dysfunction and Alpha-Lipoic Acid: Beneficial or Harmful in Alzheimer's Disease?
- Review, AD, NA
*antiOx↑, antioxidant and anti-inflammatory properties
*Inflam↓,
*PGE2↓, α-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-α, IL-1β, and IL-6
*COX2↓,
*iNOS↓,
*TNF-α↓,
*IL1β↓,
*IL6↓,
*BioAv↓, α-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic
*Ach↑, α-LA increases the production of acetylcholine [30], inhibits the production of free radicals [31], and promotes the downregulation of inflammatory processes
*ROS↓,
*cognitive↑, Studies have shown that patients with mild AD who were treated with α-LA showed a slower progression of cognitive impairment
*neuroP↑, α-LA is classified as an ideal neuroprotective antioxidant because of its ability to cross the blood-brain barrier and its uniform uptake profile throughout the central and peripheral nervous systems
*BBB↑,
*Half-Life↓, α-LA presented a mean time to reach the maximum plasma concentration (tmax) of 15 minutes and a mean plasma half-life (t1/2) of 14 minutes
*BioAv↑, LA consumption is recommended 30 minutes before or 2 hours after food intake
*Casp3↓, α-LA had an effect on caspases-3 and -9, reducing the activity of these apoptosis-promoting molecules to basal levels
*Casp9↓,
*ChAT↑, α-LA increased the expression of M2 muscarinic receptors in the hippocampus and M1 and M2 in the amygdala, in addition to ChaT expression in both regions.
*cognitive↑, α-LA acts on these apoptotic signalling pathways, leading to improved cognitive function and attenuation of neurodegeneration.
*eff↑, Based on their results, the authors suggest that treatment with α-LA would be a successful neuroprotective option in AD, at least as an adjuvant to standard treatment with acetylcholinesterase inhibitors.
*cAMP↑, The increase of cAMP caused by α-LA inhibits the release of proinflammatory cytokines, such as IL-2, IFN-γ, and TNF-α.
*IL2↓,
*INF-γ↓,
*TNF-α↓,
*SIRT1↑, Protein expression encoded by SIRT1 showed higher levels after α-LA treatment, especially in liver cells.
*SOD↑, antioxidant enzymes (SOD and GSH-Px) and malondialdehyde (MDA) were analysed by ELISA after 24 h of MCAO, which showed that the enzymatic activities were recovered and MDA was reduced in the α-LA-treated groups i
*GPx↑,
*MDA↓,
*NRF2↑, The ratio of nucleus/cytoplasmic Nrf2 was higher in the α-LA group 40 mg/kg, indicating that the activation of this factor also occurred in a dose-dependent manner

1159- And,    Andrographolide, an Anti-Inflammatory Multitarget Drug: All Roads Lead to Cellular Metabolism
- Review, NA, NA
NRF2↑,
COX2↓,
IL6↓,
IL8↓,
IL1↓, IL-1β
iNOS↓,
MPO↓,
TNF-α↓,
VEGF↓,
Hif1a↓,
p‑AMPK↑,

2586- Api,  doxoR,    Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway
- in-vitro, HCC, Bel-7402
NRF2↓, APG dramatically reduced Nrf2 expression at both the messenger RNA and protein levels through downregulation of PI3K/Akt pathway, leading to a reduction of Nrf2-downstream genes.
ChemoSen↑, APG can be used as an effective adjuvant sensitizer to prevent chemoresistance by downregulating Nrf2 signaling pathway.

2593- Api,    Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo
- in-vivo, BC, 4T1
TumCP↓, API suppresses 4T1 cells proliferation
TumCMig↓, API restraints 4T1 cells migration and invasion
TumCI↓,
Apoptosis↑, API triggers 4T1 apoptosis and modulates the expression levels of apoptotic-associated proteins in 4T1 cells
MMP↑, API triggers the depolarization of ΔΨm in 4T1 cells
ROS↑, API induces ROS generation
p‑PI3K↓, The results revealed a significant downregulation of p-PI3K/PI3K, p-AKT/AKT, and Nrf2 in 4T1 cells following API treatment
PI3K↓,
Akt↓,
NRF2↓,
AntiTum↑, API exhibits anti-tumor activity in mice
OS↑, results of animal survival experiments show that API can appropriately prolong the survival of mice with mammary gland tumors

2594- Api,  docx,    Targeted hyaluronic acid-based lipid nanoparticle for apigenin delivery to induce Nrf2-dependent apoptosis in lung cancer cells
- in-vitro, Lung, A549
NRF2↓, Apigenin (4,5,7-trihydroxyflavone; APG), as a typically dietary flavonoid, is a potent small molecule inhibitor of Nrf2 that has been studied for its Nrf2 and anticancer activity in different cancers
ChemoSen↑, overcome limitations of the clinical use of APG and improve the efficacy of DTX in lung cancer.

2596- Api,  LT,    Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment
- Review, Var, NA
NRF2↓, In addition, natural compounds such as apigenin, luteolin, chrysin and brusatol have been shown to be potent Nrf2 inhibitors.
chemoP↑, These findings suggest that natural Nrf2 inhibitors could be utilized as chemopreventive and chemotherapeutic agents, as well as tumor sensitizers for conventional radiotherapy and chemotherapy.

2639- Api,    Plant flavone apigenin: An emerging anticancer agent
- Review, Var, NA
*antiOx↑, Apigenin (4′, 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties
*Inflam↓,
AntiCan↑,
ChemoSen↑, Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers.
BioEnh↑, Apigenin’s anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies.
chemoP↑, apigenin highlighting its potential activity as a chemopreventive and therapeutic agent.
IL6↓, In taxol-resistant ovarian cancer cells, apigenin caused down regulation of TAM family of tyrosine kinase receptors and also caused inhibition of IL-6/STAT3 axis, thereby attenuating proliferation.
STAT3↓,
NF-kB↓, apigenin treatment effectively inhibited NF-κB activation, scavenged free radicals, and stimulated MUC-2 secretion
IL8↓, interleukin (IL)-6, and IL-8
eff↝, The anti-proliferative effects of apigenin was significantly higher in breast cancer cells over-expressing HER2/neu but was much less efficacious in restricting the growth of cell lines expressing HER2/neu at basal levels
Akt↓, Apigenin interferes in the cell survival pathway by inhibiting Akt function by directly blocking PI3K activity
PI3K↓,
HER2/EBBR2↓, apigenin administration led to the depletion of HER2/neu protein in vivo
cycD1↓, Apigenin treatment in breast cancer cells also results in decreased expression of cyclin D1, D3, and cdk4 and increased quantities of p27 protein
CycD3↓,
p27↑,
FOXO3↑, In triple-negative breast cancer cells, apigenin induces apoptosis by inhibiting the PI3K/Akt pathway thereby increasing FOXO3a expression
STAT3↓, In addition, apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion of breast cancer cells [
MMP2↓,
MMP9↓,
VEGF↓, Apigenin acts on the HIF-1 binding site, which decreases HIF-1α, but not the HIF-1β subunit, thereby inhibiting VEGF.
Twist↓,
MMP↓, Apigenin treatment of HGC-27 and SGC-7901 gastric cancer cells resulted in the inhibition of proliferation followed by mitochondrial depolarization resulting in apoptosis
ROS↑, Further studies revealed apigenin-induced apoptosis in hepatoma tumor cells by utilizing ROS generated through the activation of the NADPH oxidase
NADPH↑,
NRF2↓, Apigenin significantly sensitized doxorubicin-resistant BEL-7402 (BEL-7402/ADM) cells to doxorubicin (ADM) and increased the intracellular concentration of ADM by reducing Nrf2-
SOD↓, In human cervical epithelial carcinoma HeLa cells combination of apigenin and paclitaxel significantly increased inhibition of cell proliferation, suppressing the activity of SOD, inducing ROS accumulation leading to apoptosis by activation of caspas
COX2↓, melanoma skin cancer model where apigenin inhibited COX-2 that promotes proliferation and tumorigenesis
p38↑, Additionally, it was shown that apigenin treatment in a late phase involves the activation of p38 and PKCδ to modulate Hsp27, thus leading to apoptosis
Telomerase↓, apigenin inhibits cell growth and diminishes telomerase activity in human-derived leukemia cells
HDAC↓, demonstrated the role of apigenin as a histone deacetylase inhibitor. As such, apigenin acts on HDAC1 and HDAC3
HDAC1↓,
HDAC3↓,
Hif1a↓, Apigenin acts on the HIF-1 binding site, which decreases HIF-1α, but not the HIF-1β subunit, thereby inhibiting VEGF.
angioG↓, Moreover, apigenin was found to inhibit angiogenesis, as suggested by decreased HIF-1α and VEGF expression in cancer cells
uPA↓, Furthermore, apigenin intake resulted in marked inhibition of p-Akt, p-ERK1/2, VEGF, uPA, MMP-2 and MMP-9, corresponding with tumor growth and metastasis inhibition in TRAMP mice
Ca+2↑, Neuroblastoma SH-SY5Y cells treated with apigenin led to induction of apoptosis, accompanied by higher levels of intracellular free [Ca(2+)] and shift in Bax:Bcl-2 ratio in favor of apoptosis, cytochrome c release, followed by activation casp-9, 12
Bax:Bcl2↑,
Cyt‑c↑,
Casp9↑,
Casp12↑,
Casp3↑, Apigenin also augmented caspase-3 activity and PARP cleavage
cl‑PARP↑,
E-cadherin↑, Apigenin treatment resulted in higher levels of E-cadherin and reduced levels of nuclear β-catenin, c-Myc, and cyclin D1 in the prostates of TRAMP mice.
β-catenin/ZEB1↓,
cMyc↓,
CDK4↓, apigenin exposure led to decreased levels of cell cycle regulatory proteins including cyclin D1, D2 and E and their regulatory partners CDK2, 4, and 6
CDK2↓,
CDK6↓,
IGF-1↓, A reduction in the IGF-1 and increase in IGFBP-3 levels in the serum and the dorsolateral prostate was observed in apigenin-treated mice.
CK2↓, benefits of apigenin as a CK2 inhibitor in the treatment of human cervical cancer by targeting cancer stem cells
CSCs↓,
FAK↓, Apigenin inhibited the tobacco-derived carcinogen-mediated cell proliferation and migration involving the β-AR and its downstream signals FAK and ERK activation
Gli↓, Apigenin inhibited the self-renewal capacity of SKOV3 sphere-forming cells (SFC) by downregulating Gli1 regulated by CK2α
GLUT1↓, Apigenin induces apoptosis and slows cell growth through metabolic and oxidative stress as a consequence of the down-regulation of glucose transporter 1 (GLUT1).

2318- Api,    Apigenin as a multifaceted antifibrotic agent: Therapeutic potential across organ systems
- Review, Nor, NA
*ROS↓, Apigenin reduces fibrosis by targeting oxidative stress, fibroblast activation, and ECM buildup across organs
*PKM2↓, PKM2-HIF-1α pathway inhibited
*Hif1a↓,
*TGF-β↓, apigenin suppresses the PKM2-HIF-1α and TGF-β signaling pathways to prevent fibrosis
*AMPK↑, In the kidneys, it activates AMPK to suppress TGF-β1-induced fibroblast transformation
*Inflam↓, For the brain, apigenin reduces inflammation and oxidative stress through the PI3K/Akt/Nrf2 pathway.
*PI3K↓, Apigenin exerts neuroprotective effects in neonatal hypoxic-ischemic (HI) brain injury by activating the PI3K/Akt/Nrf2 signaling pathway, which is critical in defending neurons from oxidative stress and inflammation.
*Akt↑,
*NRF2↑, apigenin reduces oxidative damage through Nrf2 and NF-κB pathway modulation
*NF-kB↓, downregulates critical TGF-β and NF-κB pathways.

1547- Api,    Apigenin: Molecular Mechanisms and Therapeutic Potential against Cancer Spreading
- Review, NA, NA
angioG↓,
EMT↓,
CSCs↓,
TumCCA↑,
Dose∅, Dried parsley 45,035ug/g: Dried chamomille flower 3000–5000ug/g: Parsley 2154.6ug/g:
ROS↑, activity of Apigenin has been linked to the induction of oxidative stress in cancer cells
MMP↓, triggering intracellular ROS accumulation and loss of mitochondrial integrity
Catalase↓, catalase and glutathione (GSH), molecules involved in alleviating oxidative stress, were downregulated after Apigenin
GSH↓,
PI3K↓, suppression of the PI3K/Akt and NF-κB
Akt↓,
NF-kB↓,
OCT4↓, glycosylated form of Apigenin (i.e., Vitexin) was able to suppress stemness features of human endometrial cancer, as documented by the downregulation of Oct4 and Nanog
Nanog↓,
SIRT3↓, inhibition of sirtuin-3 (SIRT3) and sirtuin-6 (SIRT6) protein levels
SIRT6↓,
eff↑, ability of Apigenin to interfere with CSC features is often enhanced by the co-administration of other flavonoids, such as chrysin
eff↑, Apigenin combined with a chemotherapy agent, temozolomide (TMZ), was used on glioblastoma cells and showed better performance in cell arrest at the G2 phase compared with Apigenin or TMZ alone,
Cyt‑c↑, release of cytochrome c (Cyt c)
Bax:Bcl2↑, Apigenin has been shown to induce the apoptosis death pathway by increasing the Bax/Bcl-2 ratio
p‑GSK‐3β↓, Apigenin has been shown to prevent activation of phosphorylation of glycogen synthase kinase-3 beta (GSK-3β)
FOXO3↑, Apigenin administration increased the expression of forkhead box O3 (FOXO3)
p‑STAT3↓, Apigenin can induce apoptosis via inhibition of STAT3 phosphorylation
MMP2↓, downregulation of the expression of MMP-2 and MMP-9
MMP9↓,
COX2↓, downregulation of PI3K/Akt in leukemia HL60 cells [156,157] and of COX2, iNOS, and reactive oxygen species (ROS) accumulation in breast cancer cells
MMPs↓, triggering intracellular ROS accumulation and loss of mitochondrial integrity, as proved by low MMP in Apigenin-treated cells
NRF2↓, suppressed the nuclear factor erythroid 2-related factor 2 (Nrf2)
HDAC↓, inhibition of histone deacetylases (HDACs) is the mechanism through which Apigenin induces apoptosis in prostate cancer cells
Telomerase↓, Apigenin has been shown to downregulate telomerase activity
eff↑, Indeed, co-administration with 5-fluorouracil (5-FU) increased the efficacy of Apigenin in human colon cancer through p53 upregulation and ROS accumulation
eff↑, Apigenin synergistically enhances the cytotoxic effects of Sorafenib
eff↑, pretreatment of pancreatic BxPC-3 cells for 24 h with a low concentration of Apigenin and gemcitabine caused the inhibition of the GSK-3β/NF-κB signaling pathway, leading to the induction of apoptosis
eff↑, In NSCLC cells, compared to monotherapy, co-treatment with Apigenin and naringenin increased the apoptotic rate through ROS accumulation, Bax/Bcl-2 increase, caspase-3 activation, and mitochondrial dysfunction
eff↑, Several studies have shown that Apigenin-induced autophagy may play a pro-survival role in cancer therapy; in fact, inhibition of autophagy has been shown to exacerbate the toxicity of Apigenin
XIAP↓,
survivin↓,
CK2↓,
HSP90↓,
Hif1a↓,
FAK↓,
EMT↓,

1561- Api,    Apigenin Reactivates Nrf2 Anti-oxidative Stress Signaling in Mouse Skin Epidermal JB6 P + Cells Through Epigenetics Modifications
- in-vivo, Nor, JB6
*NRF2↑, API enhanced the nuclear translocation of Nrf2
*DNMT1↓, API reduced the expression of the DNMT1, DNMT3a, and DNMT3b epigenetic proteins as well as the expression of some HDACs (1–8).
*DNMT3A↓,
*HDAC↓,
*AntiCan↑, results may provide new therapeutic insights into the prevention of skin cancer by dietary phytochemicals.

1562- Api,    Apigenin protects human melanocytes against oxidative damage by activation of the Nrf2 pathway
- in-vitro, Vit, NA
*SOD↑,
*Catalase↑,
*GPx↑, GSH-Px
*MDA↓,
*NRF2↑, Nrf2 transcription factor, an important regulator oxidative stress and its downstream target genes, was significantly increased by apigenin treatment
*toxicity∅, Apigenin’s non-toxicity

1076- ART/DHA,    The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer
- Review, NA, NA
Ferroptosis↑,
ROS↑, interaction between heme-derived iron and ART will result in the production of ROS
ER Stress↑,
i-Iron↓, DHA can cause intracellular iron depletion in a time- and dose-dependent manner
TumAuto↑,
AMPK↑,
mTOR↑,
P70S6K↑,
Fenton↑,
lipid-P↑,
ROS↑,
ChemoSen↑, combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.
NRF2↑, Liu et al. discovered that ART covalently targets Keap1 at Cys151 to activate the Nrf2-dependent pathway [94

567- ART/DHA,    An Untargeted Proteomics and Systems-based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells
- in-vitro, Lung, BEAS-2B
NRF2↑, artesunate is Nrf2 regulator
AP-1↑,
NFAT↑,

3389- ART/DHA,    Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers
- Review, Var, NA
GSH↓, decreasing cellular GSH levels and the presence of iron-induced ROS generation
ROS↑,
NRF2↑, However, ART-mediated killing of cisplatin-resistant HNC cells can simultaneously activate the NRF2-antioxidant response element (ARE) pathway, which contributes to ferroptosis resistance
eff↑, Therefore, the combination of ART with NRF2 genetic silencing or trigonelline may provide a preferable efficacy

3387- ART/DHA,    Ferroptosis: A New Research Direction of Artemisinin and Its Derivatives in Anti-Cancer Treatment
- Review, Var, NA
BioAv↓, Artemisinin, extracted from Artemisia annua L., is a poorly water-soluble antimalarial drug
lipid-P↑, promote the accumulation of intracellular lipid peroxides to induce cancer cell ferroptosis, alleviating cancer development and resulting in strong anti-cancer effects in vitro and in vivo.
Ferroptosis↑,
Iron↑, Artemisinin and Its Derivatives Upregulate Fe2+ Levels in Cancer Cells
GPx4↓, GPX4-dependent defense system is significantly inhibited
GSH↓, , leading to a significant decrease in GSH, GPX4, and SLC7A11 protein expression
P53↑, ARTEs can upregulate p53 protein expression in multiple cancer cells
ER Stress↑, ARTEs can trigger ERS in cancer cells to activate the PERK-ATF4 pathway and upregulate GRP78 expression
PERK↑,
ATF4↑,
GRP78/BiP↑,
CHOP↑, which activates CHOP
ROS↑, promoting the accumulation of intracellular ROS, and leading to ferroptosis
NRF2↑, ARTEs can activate the nuclear factor erythroid-derived 2-like 2 (Nrf2) -γ-glutamyl-peptide pathway in cancer cells, resulting in cancer cell ferroptosis resistance

3388- ART/DHA,    Keap1 Cystenine 151 as a Potential Target for Artemisitene-Induced Nrf2 Activation
- in-vitro, Lung, A549 - in-vitro, Nor, GP-293 - in-vitro, BC, MDA-MB-231
NRF2↑, ATT upregulated Nrf2 in the MB231 cells . ATT increased Nrf2 levels at low doses ranging from 1 to 5 μM
ROS∅, ATT does not increase ROS production and cannot active Nrf2 by inducing oxidative stress

1358- Ash,    Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms
- Review, Var, NA
TumCCA↑,
Apoptosis↑,
TumAuto↑,
Ferroptosis↑,
TumCP↓,
CSCs↓,
TumMeta↓,
EMT↓,
angioG↓,
Vim↓,
HSP90↓,
annexin II↓, annexin II proteins directly bind to WA
m-FAM72A↓,
BCR-ABL↓,
Mortalin↓,
NRF2↓,
cMYB↓,
ROS↑, WA inhibits proliferation through ROS-mediated intrinsic apoptosis
ChemoSen↑, WA and cisplatin, WA produced ROS, while cisplatin caused DNA damage, suggesting that lower doses of cisplatin combined with suboptimal doses of WA could achieve the same effect
eff↑, sulforaphane and WA showed synergistic effects on epigenetic modifiers and cell proliferation in breast cancer cells
ChemoSen↑, WA and sorafenib caused G2/M arrest in anaplastic and papillary thyroid cancer cells
ChemoSen↑, combination of WA and 5-FU executed PERK axis-mediated endoplasmic reticulum (ER) stress-induced autophagy and apoptosis
eff↑, WA and carnosol also exhibit a synergistic effect on pancreatic cancer
*BioAv↓, Saurabh by Saurabh et al and Tianming et al reported oral bioavailability values 1.8% and 32.4 ± 4.8%, respectively, in male rats.
ROCK1↓, In another study, WA reduces macrophage infiltration and inhibits the expression of protein tyrosine kinase-2 (Pyk2), rho-associated kinase 1 (ROCK1), and VEGF in a hepatocellular carcinoma xenograft model, thereby suppressing tumor invasion and angi
TumCI↓,
Sp1/3/4↓, Furthermore, WA exerts potent anti-angiogenic activity in vivo.174 In the Ehrlich ascites tumor model, WA exerts its anti-angiogenic activity by reducing the binding of the transcription factor specificity protein 1 (Sp1) to VEGF
VEGF↓, n another study, WA reduces macrophage infiltration and inhibits the expression of protein tyrosine kinase-2 (Pyk2), rho-associated kinase 1 (ROCK1), and VEGF in a hepatocellular carcinoma xenograft model, thereby suppressing tumor invasion and angio
Hif1a↓, Furthermore, WA suppresses the AK4-HIF-1α signaling axis and acts as a potent antimetastatic agent in lung cancer.Citation79
EGFR↓, WA synergistically inhibited wild-type epidermal growth factor receptor (EGFR) lung cancer cell viability

3156- Ash,    Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug
- Review, Var, NA
MAPK↑, Figure 3
p38↑,
BAX↑,
BIM↑,
CHOP↑,
ROS↑,
DR5↑,
Apoptosis↑,
Ferroptosis↑,
GPx4↓,
BioAv↝, WA has a rapid oral absorption and reaches to peak plasma concentration of around 16.69 ± 4.02 ng/ml within 10 min after oral administration of Withania somnifera aqueous extract at dose of 1000 mg/kg, which is equivalent to 0.458 mg/kg of WA
HSP90↓, table 1 10uM) were found to inhibit the chaperone activity of HSP90
RET↓,
E6↓,
E7↓,
Akt↓,
cMET↓,
Glycolysis↓, by suppressing the glycolysis and tricarboxylic (TCA) cycle
TCA↓,
NOTCH1↓,
STAT3↓,
AP-1↓,
PI3K↓,
eIF2α↓,
HO-1↑,
TumCCA↑, WA (1--3 uM) have been reported to inhibit cell proliferation by inducing G2 and M phase cycle arrest inovarian, breast, prostate, gastric and myelodysplastic/leukemic cancer cells and osteosarcoma
CDK1↓, WA is able to decrease the cyclin-dependent kinase 1 (Cdk1) activity and prevent Cdk1/cyclin B1 complex formation, which are key steps in cell cycle progression
*hepatoP↑, A treatment (40 mg/kg) reduces acetaminophen-induced liver injury (AILI) in mouse models and decreases H 2O 2-induced glutathione (GSH) depletion and necrosis in hepatocyte
*GSH↑,
*NRF2↑, WA triggers an anti-oxidant response after acetaminophen overdose by enhancing hepatic transcription of the nuclear factor erythroid 2–related factor 2 (NRF2)-responsive gene
Wnt↓, indirectly inhibit Wnt
EMT↓, WA can also block tumor metastasis through reduced expression of epithelial mesenchymal transition (EMT) markers.
uPA↓, WA (700 nM) exert anti-meta-static activities in breast cancer cells through inhibition of the urokinase-type plasminogen activator (uPA) protease
CSCs↓, s WA (125-500 nM) suppress tumor sphere formation indicating that the self-renewal of CSC is abolished
Nanog↓, loss of these CSC-specific characteristics is reflected in the loss of typical stem cell markers such as ALDH1A, Nanog, Sox2, CD44 and CD24
SOX2↓,
CD44↓,
lactateProd↓, drop in lactate levels compared to control mice.
Iron↑, Furthermore, we found that WA elevates the levels of intracellular labile ferrous iron (Fe +2 ) through excessive activation of heme oxygenase-1 (HMOX1), which independently causes accumulation of toxic lipid radicals and ensuing ferroptosis
NF-kB↓, nhibition of NF-kB kinase signaling pathway

3160- Ash,    Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal
- Review, Var, NA
TumCCA↑, withaferin A suppressed cell proliferation in prostate, ovarian, breast, gastric, leukemic, and melanoma cancer cells and osteosarcomas by stimulating the inhibition of the cell cycle at several stages, including G0/G1 [86], G2, and M phase
H3↑, via the upregulation of phosphorylated Aurora B, H3, p21, and Wee-1, and the downregulation of A2, B1, and E2 cyclins, Cdc2 (Tyr15), phosphorylated Chk1, and Chk2 in DU-145 and PC-3 prostate cancer cells.
P21↑,
cycA1↓,
CycB↓,
cycE↓,
CDC2↓,
CHK1↓,
Chk2↓,
p38↑, nitiated cell death in the leukemia cells by increasing the expression of p38 mitogen-activated protein kinases (MAPK)
MAPK↑,
E6↓, educed the expression of human papillomavirus E6/E7 oncogenes in cervical cancer cells
E7↓,
P53↑, restored the p53 pathway causing the apoptosis of cervical cancer cells.
Akt↓, oral dose of 3–5 mg/kg withaferin A attenuated the activation of Akt and stimulated Forkhead Box-O3a (FOXO3a)-mediated prostate apoptotic response-4 (Par-4) activation,
FOXO3↑,
ROS↑, the generation of reactive oxygen species, histone H2AX phosphorylation, and mitochondrial membrane depolarization, indicating that withaferin A can cause the oxidative stress-mediated killing of oral cancer cells [
γH2AX↑,
MMP↓,
mitResp↓, withaferin A inhibited the expansion of MCF-7 and MDA-MB-231 human breast cancer cells by ROS production, owing to mitochondrial respiration inhibition
eff↑, combination treatment of withaferin A and hyperthermia induced the death of HeLa cells via a decrease in the mitochondrial transmembrane potential and the downregulation of the antiapoptotic protein myeloid-cell leukemia 1 (MCL-1)
TumCD↑,
Mcl-1↓,
ER Stress↑, . Withaferin A also attenuated the development of glioblastoma multiforme (GBM), both in vitro and in vivo, by inducing endoplasmic reticulum stress via activating the transcription factor 4-ATF3-C/EBP homologous protein (ATF4-ATF3-CHOP)
ATF4↑,
ATF3↑,
CHOP↑,
NOTCH↓, modulating the Notch-1 signaling pathway and the downregulation of Akt/NF-κB/Bcl-2 . withaferin A inhibited the Notch signaling pathway
NF-kB↓,
Bcl-2↓,
STAT3↓, Withaferin A also constitutively inhibited interleukin-6-induced phosphorylation of STAT3,
CDK1↓, lowering the levels of cyclin-dependent Cdk1, Cdc25C, and Cdc25B proteins,
β-catenin/ZEB1↓, downregulation of p-Akt expression, β-catenin, N-cadherin and epithelial to the mesenchymal transition (EMT) markers
N-cadherin↓,
EMT↓,
Cyt‑c↑, depolarization and production of ROS, which led to the release of cytochrome c into the cytosol,
eff↑, combinatorial effect of withaferin A and sulforaphane was also observed in MDA-MB-231 and MCF-7 breast cancer cells, with a dramatic reduction of the expression of the antiapoptotic protein Bcl-2 and an increase in the pro-apoptotic Bax level, thus p
CDK4↓, downregulates the levels of cyclin D1, CDK4, and pRB, and upregulates the levels of E2F mRNA and tumor suppressor p21, independently of p53
p‑RB1↓,
PARP↑, upregulation of Bax and cytochrome c, downregulation of Bcl-2, and activation of PARP, caspase-3, and caspase-9 cleavage
cl‑Casp3↑,
cl‑Casp9↑,
NRF2↑, withaferin A binding with Keap1 causes an increase in the nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels, which in turn, regulates the expression of antioxidant proteins that can protect the cells from oxidative stress.
ER-α36↓, Decreased ER-α
LDHA↓, inhibited growth, LDHA activity, and apoptotic induction
lipid-P↑, induction of oxidative stress, increased lipid peroxidation,
AP-1↓, anti-inflammatory qualities of withaferin A are specifically attributed to its inhibition of pro-inflammatory molecules, α-2 macroglobulin, NF-κB, activator protein 1 (AP-1), and cyclooxygenase-2 (COX-2) inhibition,
COX2↓,
RenoP↑, showing strong evidence of the renoprotective potential of withaferin A due to its anti-inflammatory activity
PDGFR-BB↓, attenuating the BB-(PDGF-BB) platelet growth factor
SIRT3↑, by increasing the sirtuin3 (SIRT3) expression
MMP2↓, withaferin A inhibits matrix metalloproteinase-2 (MMP-2) and MMP-9,
MMP9↓,
NADPH↑, but also provokes mRNA stimulation for a set of antioxidant genes, such as NADPH quinone dehydrogenase 1 (NQO1), glutathione-disulfide reductase (GSR), Nrf2, heme oxygenase 1 (HMOX1),
NQO1↑,
GSR↑,
HO-1↑,
*SOD2↑, cardiac ischemia-reperfusion injury model. Withaferin A triggered the upregulation of superoxide dismutase SOD2, SOD3, and peroxiredoxin 1(Prdx-1).
*Prx↑,
*Casp3?, and ameliorated cardiomyocyte caspase-3 activity
eff↑, combination with doxorubicin (DOX), is also responsible for the excessive generation of ROS
Snail↓, inhibition of EMT markers, such as Snail, Slug, β-catenin, and vimentin.
Slug↓,
Vim↓,
CSCs↓, highly effective in eliminating cancer stem cells (CSC) that expressed cell surface markers, such as CD24, CD34, CD44, CD117, and Oct4 while downregulating Notch1, Hes1, and Hey1 genes;
HEY1↓,
MMPs↓, downregulate the expression of MMPs and VEGF, as well as reduce vimentin, N-cadherin cytoskeleton proteins,
VEGF↓,
uPA↓, and protease u-PA involved in the cancer cell metastasis
*toxicity↓, A was orally administered to Wistar rats at a dose of 2000 mg/kg/day and had no adverse effects on the animals
CDK2↓, downregulated the activation of Bcl-2, CDK2, and cyclin D1
CDK4↓, Another study also demonstrated the inhibition of Hsp90 by withaferin A in a pancreatic cancer cell line through the degradation of Akt, cyclin-dependent kinase 4 Cdk4,
HSP90↓,

3161- Ash,    Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage
- in-vivo, Stroke, NA
*neuroP↑, Withaferin A (WFA), a natural compound, exhibits a positive effect on a number of neurological diseases
*MDA↓, WFA markedly decreased the level of malondialdehyde, an oxidative stress marker,
*ROS↓,
*SOD↑, and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase
*GPx↑,
*NRF2↑, results demonstrated that WFA activated the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, promoted translocation of Nrf2 from the cytoplasm to nucleus, and increased HO-1 expression.
*HO-1↑, WFA induces HO-1 expression to attenuate oxidative damage in vitro

3163- Ash,  Rad,    Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis
*radioP↑, Withaferin A (WA) protected only normal lymphocytes, but not cancer cells, against IR-induced apoptosis
selectivity↑,
*Casp3↓, WA treatment led to significant inhibition of IR-induced caspase-3 activation and decreased IR-induced DNA damage to lymphocytes and bone-marrow cells.
*DNAdam↓,
*ROS↓, WA reduced intracellular ROS and GSH levels
*GSH↓,
*NRF2↑, WA induced pro-survival transcription factor, Nrf-2, and expression of cytoprotective genes HO-1, catalase, SOD, peroxiredoxin-2 via ERK.
*HO-1↑,
*Catalase↑,
*SOD↑,
*Prx↑,
*ERK↑, Activated ERK promotes the nuclear translocation and activity of Nrf2

3164- Ash,    Withaferin A alleviates fulminant hepatitis by targeting macrophage and NLRP3
*hepatoP↑, Withania Somnifera, is a hepatoprotective agent
*IKKα↓, WA also inhibits inflammation by directly inhibiting IκκB activity46,47 or NLRP3 inflammasome activation in vitro in immune cells
*NLRP3↓,
*NRF2↑, WA probably protects against FH by targeting the macrophage and/or hepatocyte stress via activating NRF2, AMPKα
*AMPK↑,
*Inflam↓, Thus, WA potently protects against GalN/LPS-induced hepatotoxicity and inflammation
*Apoptosis↓, WA suppressed hepatic apoptosis in vivo
*cl‑Casp3↓, attenuate the increase of cleaved CASP3 and cleaved PARP1
*cl‑PARP1↓,
*NLRP3↓, WA prevented GalN/LPS-induced FH partially by inhibiting activation of the NLRP3 inflammasome
*ROS↓, fig 7
*ALAT↓,
*AST↓,
*GSH↑, (GSH) levels were significantly depleted by ~50% 6 h after GalN/LPS administration and were recovered to levels comparable with that of control mice by WA treatment

3174- Ash,    Withaferin A Acts as a Novel Regulator of Liver X Receptor-α in HCC
- in-vitro, HCC, HepG2 - in-vitro, HCC, Hep3B - in-vitro, HCC, HUH7
NF-kB↓, We found that many of Nuclear factor kappa B (NF-κB), angiogenesis and inflammation associated proteins secretion is downregulated upon Withaferin A treatment.
angioG↓,
Inflam↓,
TumCP↓, uppressed the proliferation, migration, invasion, and anchorage-independent growth of these HCC cells.
TumCMig↓,
TumCI↓,
Sp1/3/4↓, Withaferin A inhibits NF-κB, Specificity protein 1 (Sp1) transcription factors, and downregulates Vascular Endothelial Growth Factor (VEGF) gene expression
VEGF↓,
angioG↓, Withaferin A (2.5 µM) treatment decreased the secretion of various angiogenesis-related markers, growth factors, and cytokines (Serpin F1(PEDF), uPA, PDGF-AA, Angiogenin, Endothelin-1, Macrophage migration inhibitory factor (MIF), PAI-1, MCP1, ICAM-1
uPA↓,
PDGF↓,
MCP1↓,
ICAM-1↓,
*NRF2↑, It also upregulates the Nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor and protects from Acetaminophen-induced hepatotoxicity and liver injury
*hepatoP↑,

3173- Ash,    Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma
- in-vitro, neuroblastoma, NA
GPx4↓, WA drops the protein level and activity of GPX4
HO-1↑, WA induces a novel noncanonical ferroptosis pathway by increasing the labile Fe(II) pool upon excessive activation of heme oxygenase 1 (HMOX1) through direct targeting of Kelch-like ECH-associated protein 1 (KEAP1), which is sufficient to induce lipi
lipid-P↑, which is sufficient to induce lipid peroxidation
Keap1↓, In line with this, we observed decreased levels of KEAP1 along with increased levels of NRF2 in conditions in which HMOX1 is upregulated
NRF2↑,
Ferroptosis↑, WA increases intracellular labile Fe(II) upon excessive activation of HMOX1, which is sufficient to induce ferroptosis

3166- Ash,    Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives
- Review, Var, NA
*p‑PPARγ↓, preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ)
*cardioP↑, cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis.
*AMPK↑,
*BioAv↝, The oral bioavailability was found to be 32.4 ± 4.8% after 5 mg/kg intravenous and 10 mg/kg oral WA administration.
*Half-Life↝, The stability studies of WA in gastric fluid, liver microsomes, and intestinal microflora solution showed similar results in male rats and humans with a half-life of 5.6 min.
*Half-Life↝, WA reduced quickly, and 27.1% left within 1 h
*Dose↑, WA showed that formulation at dose 4800 mg having equivalent to 216 mg of WA, was tolerated well without showing any dose-limiting toxicity.
*chemoP↑, Here, we discuss the chemo-preventive effects of WA on multiple organs.
IL6↓, attenuates IL-6 in inducible (MCF-7 and MDA-MB-231)
STAT3↓, WA displayed downregulation of STAT3 transcriptional activity
ROS↓, associated with reactive oxygen species (ROS) generation, resulted in apoptosis of cells. The WA treatment decreases the oxidative phosphorylation
OXPHOS↓,
PCNA↓, uppresses human breast cells’ proliferation by decreasing the proliferating cell nuclear antigen (PCNA) expression
LDH↓, WA treatment decreases the lactate dehydrogenase (LDH) expression, increases AMP protein kinase activation, and reduces adenosine triphosphate
AMPK↑,
TumCCA↑, (SKOV3 andCaOV3), WA arrest the G2/M phase cell cycle
NOTCH3↓, It downregulated the Notch-3/Akt/Bcl-2 signaling mediated cell survival, thereby causing caspase-3 stimulation, which induces apoptosis.
Akt↓,
Bcl-2↓,
Casp3↑,
Apoptosis↑,
eff↑, Withaferin-A, combined with doxorubicin, and cisplatin at suboptimal dose generates ROS and causes cell death
NF-kB↓, reduces the cytosolic and nuclear levels of NF-κB-related phospho-p65 cytokines in xenografted tumors
CSCs↓, WA can be used as a pharmaceutical agent that effectively kills cancer stem cells (CSCs).
HSP90↓, WA inhibit Hsp90 chaperone activity, disrupting Hsp90 client proteins, thus showing antiproliferative effects
PI3K↓, WA inhibited PI3K/AKT pathway.
FOXO3↑, Par-4 and FOXO3A proapoptotic proteins were increased in Pten-KO mice supplemented with WA.
β-catenin/ZEB1↓, decreased pAKT expression and the β-catenin and N-cadherin epithelial-to-mesenchymal transition markers in WA-treated tumors control
N-cadherin↓,
EMT↓,
FASN↓, WA intraperitoneal administration (0.1 mg) resulted in significant suppression of circulatory free fatty acid and fatty acid synthase expression, ATP citrate lyase,
ACLY↓,
ROS↑, WA generates ROS followed by the activation of Nrf2, HO-1, NQO1 pathways, and upregulating the expression of the c-Jun-N-terminal kinase (JNK)
NRF2↑,
HO-1↑,
NQO1↑,
JNK↑,
mTOR↓, suppressing the mTOR/STAT3 pathway
neuroP↑, neuroprotective ability of WA (50 mg/kg b.w)
*TNF-α↓, WA attenuate the levels of neuroinflammatory mediators (TNF-α, IL-1β, and IL-6)
*IL1β↓,
*IL6↓,
*IL8↓, WA decreases the pro-inflammatory cytokines (IL-6, TNFα, IL-8, IL-18)
*IL18↓,
RadioS↑, radiosensitizing combination effect of WA and hyperthermia (HT) or radiotherapy (RT)
eff↑, WA and cisplatin at suboptimal dose generates ROS and causes cell death [41]. The actions of this combination is attributed by eradicating cells, revealing markers of cancer stem cells like CD34, CD44, Oct4, CD24, and CD117

3172- Ash,    Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis
- in-vitro, HCC, HepG2 - in-vitro, Nor, HL7702
Keap1↑, Notably, Withaferin A elevated Keap1 expression to mitigate Nrf2 signaling activation-mediated epithelial to mesenchymal transition (EMT) and ferroptosis-related protein xCT expression
NRF2↓,
EMT↓, Withaferin A suppresses epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer
TumCP↓, Withaferin A restrains proliferation, invasion, and VM of hepatoma cells while preserving normal hepatocytes
TumCI↓,
selectivity↑, , treatment with Withaferin A ranging from 1 to 100 μM had little effect on cell viability of human normal liver cells (HL-7702 cells), indicating the little cytotoxicity on normal hepatocytes.
*toxicity↓,
ROS↑, Withaferin A strikingly enhanced ROS () and MDA levels (), but reduced the GSH levels (), indicating the induction of ferroptosis by Withaferin A
MDA↑,
GSH↓,
Ferroptosis↑,

2292- Ba,  BA,    Baicalin and baicalein in modulating tumor microenvironment for cancer treatment: A comprehensive review with future perspectives
- Review, Var, NA
AntiCan↑, Baicalin and baicalein exhibit anticancer activities against multiple cancers with extremely low toxicity to normal cells.
*toxicity↓,
BioAv↝, Baicalein permeates easily through the epithelium from the gut lumen to the blood underneath due to its low molecular mass and high lipophilicity, albeit a low presence of its transporters.
BioAv↓, In contrast, baicalin has limited permeability partly due to its larger molecular mass and higher hydrophilicity [24]. The overall low water solubility of baicalin and baicalein contributes to their poor bioavailability.
*ROS↓, baicalin protected macrophages against mycoplasma gallisepticum (MG)-induced ROS production and NLRP3 inflammasome activation by upregulating autophagy and TLR2-NFκB pathway
*TLR2↓,
*NF-kB↓,
*NRF2↑, Therefore, baicalin exerts strong antioxidant activity by activating NRF2 antioxidant program.
*antiOx↑,
*Inflam↓, These data suggest that by attenuating ROS and inflammation baicalein inhibits tumor formation and metastasis.
HDAC1↓, baicalein reduced CTCLs by inhibiting HDAC1 and HDAC8 and its effect on tumor inhibition was better than traditional HDAC inhibitors
HDAC8↓,
Wnt↓, Baicalein also reduced the proliferation of acute T-lymphoblastic leukemia (TLL) Jurkat cells by inhibiting the Wnt/β-catenin signaling pathway
β-catenin/ZEB1↓,
PD-L1↓, baicalein and baicalin promoted antitumor immune response by suppressing PD-L1 expression of HCC cells, thus increasing tumor regression
Sepsis↓, Baicalein can also attenuate severe sepsis via ameliorating immune dysfunction of T lymphocytes.
NF-kB↓, downregulation of NFκB and CD74/CD44 signaling in EBV-transformed B cells
LOX1↓, baicalein is considered to be an inhibitor of lipoxygenases (LOXs)
COX2↓, inhibits the expression of NF-κB/p65 and COX-2
VEGF↑, Baicalin was shown to suppress the expression of VEGF, resulting in the inhibition of PI3K/AKT/mTOR pathway and reduction of proliferation and migration of human mesothelioma cells
PI3K↓,
Akt↓,
mTOR↓,
MMP2↓, baicalin suppressed expression of MMP-2 and MMP-9 via restriction of p38MAPK signaling, resulting in reduced breast cancer cell growth, invasion
MMP9↓,
SIRT1↑, The inhibition of MMP-2 and MMP-9 expression in NSCLC cells is mediated by activating the SIRT1/AMPK signaling pathway.
AMPK↑,

2296- Ba,    The most recent progress of baicalein in its anti-neoplastic effects and mechanisms
- Review, Var, NA
CDK1↓, graphical abstract
Cyc↓,
p27↑,
P21↑,
P53↑,
TumCCA↑, Cell cycle arrest
TumCI↓, Inhibit invastion
MMP2↓,
MMP9↓,
E-cadherin↑,
N-cadherin↓,
Vim↓,
LC3A↑,
p62↓,
p‑mTOR↓,
PD-L1↓,
CAFs/TAFs↓,
VEGF↓,
ROCK1↓,
Bcl-2↓,
Bcl-xL↓,
BAX↑,
ROS↑,
cl‑PARP↑,
Casp3↑,
Casp9↑,
PTEN↑, A549, H460
MMP↓, ↓mitochondrial transmembrane potential, redistribution of cytochrome c,
Cyt‑c↑,
Ca+2↑, ↑Ca2+
PERK↑, ↑PERK, ↑IRE1α, ↑CHOP,
IRE1↑,
CHOP↑,
Copper↑, ↑Cu+2
Snail↓, ↓Snail, ↓vimentin, ↓Twist1,
Vim↓,
Twist↓,
GSH↓, ↑ROS, ↓GSH, ↑MDA, ↓MMP, ↓NRF2, ↓HO-1, ↓GPX4, ↓FTH1, ↑TFR1, ↓p-JAK2, ↓p-STAT3
NRF2↓,
HO-1↓,
GPx4↓,
XIAP↓, ↓Bcl-2, ↓Bcl-xL, ↓XIAP, ↓surviving
survivin↓,
DR5↑, ↑ROS, ↑DR5

2623- Ba,    Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of baicalein against oxidative stress-induced DNA damage and apoptosis in HEI193 Schwann cells
- in-vitro, Nor, HEI193
*DNAdam↓, Our results showed that baicalein effectively inhibited H2O2-induced cytotoxicity and DNA damage associated with the inhibition of reactive oxygen species (ROS) accumulation.
*ROS↓,
*Bax:Bcl2↓, increased the Bax/Bcl-2 ratio
*p‑NRF2↑, baicalein increased not only the expression but also the phosphorylation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and promoted the expression of heme oxygenase-1 (HO-1)
*HO-1↑, it is well known that the antioxidant efficacy of baicalein is related to the activation of the Nrf2/HO-1 signaling pathway
*neuroP↑, suggested that baicalein may have a beneficial effect on the prevention and treatment of peripheral neuropathy induced by oxidative stress.
*MMP↑, inhibitory effect of baicalein on MMP reduction

2625- Ba,  LT,    Baicalein and luteolin inhibit ischemia/reperfusion-induced ferroptosis in rat cardiomyocyte
- in-vivo, Stroke, NA
*lipid-P↓, Baicalein and luteolin prevented the Fe-SP-induced lipid peroxidation in rat neonatal cardiomyocytes.
*ACSL4∅, Baicalein and luteolin can reduce the protein levels of ACSL4 and Nrf2, and enhance the protein levels of GPX4 in ischemia/reperfusion-treated rat hearts.
*NRF2∅, Our results suggest that BAI and Lut prevented the I/R-induced increased of ACSL4, NRF2, and HO-1 protein
*GPx4∅, BAI and Lut prevented the I/R-induced increased of ACSL4, NRF2, and HO-1 protein, and the I/R-decreased GPX4 protein levels
*Ferroptosis↓, BAI was found to suppress ferroptosis in cancer cells via reducing reactive oxygen species (ROS) generation.
*ROS↓,
*MDA↓, Moreover, both BAI and Lut decreased ROS and malondialdehyde (MDA) generation and the protein levels of ferroptosis markers, and restored Glutathione peroxidase 4 (GPX4) protein levels in cardiomyocytes reduced by ferroptosis inducers
*eff↑, BAI and Lut reduced the I/R-induced myocardium infarction
*HO-1∅, Our results suggest that BAI and Lut prevented the I/R-induced increased of ACSL4, NRF2, and HO-1 protein

2626- Ba,    Molecular targets and therapeutic potential of baicalein: a review
- Review, Var, NA - Review, AD, NA - Review, Stroke, NA
AntiCan↓, anticancer, antidiabetic, antimicrobial, antiaging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects
*neuroP↑,
*cardioP↑, Cardioprotective action of baicalein
*hepatoP↑,
*RenoP↑, baicalein’s capacity to lessen cisplatin-induced nephrotoxicity is probably due, at least in part, to the attenuation of renal oxidative and/or nitrative stress
TumCCA↑, Baicalein induces G1/S arrest in lung squamous carcinoma (CH27) cells by downregulating CDK4 and cyclin D1, as well as upregulating cyclin E
CDK4↓,
cycD1↓,
cycE↑,
BAX↑, SGC-7901 cells showed that when baicalein was administered, Bcl-2 was downregulated and Bax was increased
Bcl-2↓,
VEGF↓, Baicalein inhibits the synthesis of vascular endothelial growth factor (VEGF), HIF-1, c-Myc, and nuclear factor kappa B (NF-κB) in the G1 and S phases of ovarian cancer cell
Hif1a↓,
cMyc↓,
NF-kB↓,
ROS↑, Baicalein produced intracellular reactive oxygen species (ROS) and activated BNIP3 to slow down the development and hasten the apoptosis of MG-63,OS cell
BNIP3↑,
*neuroP↑, Baicalein exhibits neuroprotective qualities against amyloid (AN) functions by preventing AN from aggregating in PC12 neuronal cells to cause A𝛽-induced cytotoxicity
*cognitive↑, baicalein encourages non-amyloidogenic processing of APP, which lowers the generation of A𝛽 and enhances cognitive function
*NO↓, baicalein effectively reduced NO generation and iNOS gene expression
*iNOS↓,
*COX2↓, Baicalein therapy significantly decreased the expression of COX-2 and iNOS, as well as PGE2 and NF-κB, indicating a protective effect against cerebral I/R injury.
*PGE2↓,
*NRF2↑, Baicalein therapy markedly elevated nuclear Nrf2 expression and AMPK phosphorylation in the ischemic cerebral cortex
*p‑AMPK↑,
*Ferroptosis↓, Baicalein suppressed ferroptosis associated with 12/15-LOX, hence lessening the severity of post-traumatic epileptic episodes generated by FeCl3
*lipid-P↓, HT22 cells were damaged by ferroptosis, which is mitigated by baicalein may be due to its lipid peroxidation inhibitor
*ALAT↓, Baicalin lowers the raised levels of hepatic markers alanine transaminase (ALT), aspartate aminotransferase (AST)
*AST↓,
*Fas↓, Baicalin has also been shown to suppress apoptosis, decrease FAS protein expression, block the caspase-8 pathway, and decrease Bax protein production
*BAX↓,
*Apoptosis↓,

2627- Ba,  Cisplatin,    Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways
RenoP↑, Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function
*iNOS↑, Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear tra
*TNF-α↓,
*IL6↓,
*NF-kB↓,
*MAPK↓, baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys
*ERK↓,
*JNK↓,
*antiOx↑, Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys.
*NRF2↓,
*HO-1↑,
*Cyt‑c∅, inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP
*Casp3∅,
*Casp9∅,
*PARP∅,

2617- Ba,    Potential of baicalein in the prevention and treatment of cancer: A scientometric analyses based review
- Review, Var, NA
Ca+2↑, MDA-MB-231 ↑Ca2+
MMP2↓, MDA-MB-231 ↓MMP-2/9
MMP9↓,
Vim↓, ↓Vimentin, ↓SNAIL, ↑E-cadherin, ↓Wnt1, ↓β-catenin
Snail↓,
E-cadherin↑,
Wnt↓,
β-catenin/ZEB1↓,
p‑Akt↓, MCF-7 ↓p-Akt, ↓p-mTOR, ↓NF-κB
p‑mTOR↓,
NF-kB↓,
i-ROS↑, MCF-7 ↑Intracellular ROS, ↓Bcl-2, ↑Bax, ↑cytochrome c, ↑caspase-3/9
Bcl-2↓,
BAX↑,
Cyt‑c↑,
Casp3↑,
Casp9↑,
STAT3↓, 4T1, MDA-MB-231 ↓STAT3, ↓ IL-6
IL6↓,
MMP2↓, HeLa ↓MMP-2, ↓MMP-9
MMP9↓,
NOTCH↓, ↓Notch 1
PPARγ↓, ↓PPARγ
p‑NRF2↓, HCT-116 ↓p-Nrf2
HK2↓, ↓HK2, ↓LDH-A, ↓PDK1, ↓glycolysis, PTEN/Akt/HIF-1α regulation
LDHA↓,
PDK1↓,
Glycolysis↓,
PTEN↑, Furthermore, baicalein inhibited hypoxia-induced Akt phosphorylation by promoting PTEN accumulation, thereby attenuating hypoxia-inducible factor-alpha ( HIF-1a) expression in AGS cells.
Akt↓,
Hif1a↓,
MMP↓, SGC-7901 ↓ΔΨm
VEGF↓, ↓VEGF, ↓VEGFR2
VEGFR2↓,
TOP2↓, ↓Topoisomerase II
uPA↓, ↓u-PA, ↓TIMP1, ↓TIMP2
TIMP1↓,
TIMP2↓,
cMyc↓, ↓β-catenin, ↓c-Myc, ↓cyclin D1, ↓Axin-2
TrxR↓, EL4 ↓Thioredoxin reductase, ↑ASK1,
ASK1↑,
Vim↓, ↓vimentin
ZO-1↑, ↑ZO-1
E-cadherin↑, ↑E-cadherin
SOX2↓, PANC-1, BxPC-3, SW1990 ↓Sox-2, ↓Oct-4, ↓SHH, ↓SMO, ↓Gli-2
OCT4↓,
Shh↓,
Smo↓,
Gli1↓,
N-cadherin↓, ↓N-cadherin
XIAP↓, ↓XIAP

1527- Ba,    Baicalein Alleviates Arsenic-induced Oxidative Stress through Activation of the Keap1/Nrf2 Signalling Pathway in Normal Human Liver Cells
- in-vitro, Nor, MIHA
*p‑NRF2↑, Baicalein upregulated the protein expression levels of phosphorylated Nrf2 (p-Nrf2) and nuclear Nrf2, inhibited the downregulation of Nrf2 target genes induced by arsenic
*ROS↓, decreased the production of ROS and MDA (normal cells)
*MDA↓,
*antiOx↑, thereby enhancing the antioxidant capacity of cells and reducing oxidative stress

1530- Ba,    Baicalein Decreases Hydrogen Peroxide‐Induced Damage to NG108‐15 Cells via Upregulation of Nrf2
- in-vitro, Nor, NG108-15
*12LOX↓, baicalein, a 12 LOX inhibitor,
*ROS↓, ROS levels in cells treated with H2O2 for 2 h were higher than those in buffer-treated control cells (left panel), whereas levels in baicalein plus H2O2 treated cells were indistinguishable from those in control cells
*NRF2↑, upregulating Nrf2 expression
*eff↑, N-acetylcysteine (10uM) or sulforaphane (1uM) was as effective as baicalein in blocking the harmful effects induced by H2O2

2021- BBR,    Berberine: An Important Emphasis on Its Anticancer Effects through Modulation of Various Cell Signaling Pathways
- Review, NA, NA
*antiOx?, Berberine has been noted as a potential therapeutic candidate for liver fibrosis due to its antioxidant and anti-inflammatory activities
*Inflam↓,
Apoptosis↑, Apoptosis induced by berberine in liver cancer cells caused cell cycle arrest at the M/G1 phase and increased the Bax expression
TumCCA↑,
BAX↑,
eff↑, mixture of curcumin and berberine effectively decreases growth in breast cancer cell lines
VEGF↓, berberine also prevented the expression of VEGF
PI3K↓, berberine plays an important role in cancer management through inhibition of the PI3K/AKT/mTOR pathway
Akt↓,
mTOR↓,
Telomerase↓, Berberine decreased the telomerase activity and level of the colorectal cancer cell line,
β-catenin/ZEB1↓, berberine and its derivatives have the ability to inhibit β-catenin/Wnt signaling in tumorigenesis
Wnt↓,
EGFR↓, berberine treatment decreased cell proliferation and epidermal growth factor receptor expression levels in the xenograft model.
AP-1↓, Berberine efficiently targets both the host and the viral factors accountable for cervical cancer development via inhibition of activating protein-1
NF-kB↓, berberine inhibited lung cancer cell growth by concurrently targeting NF-κB/COX-2, PI3K/AKT, and cytochrome-c/caspase signaling pathways
COX2↑,
NRF2↓, Berberine suppresses the Nrf2 signaling-related protein expression in HepG2 and Huh7 cells,
RadioS↑, suggesting that berberine supports radiosensitivity through suppressing the Nrf2 signaling pathway in hepatocellular carcinoma cells
STAT3↓, regulating the JAK–STAT3 signaling pathway
ERK↓, berberine prevented the metastatic potential of melanoma cells via a reduction in ERK activity, and the protein levels of cyclooxygenase-2 by a berberine-caused AMPK activation
AR↓, Berberine reduced the androgen receptor transcriptional activity
ROS↑, In a study on renal cancer, berberine raised the levels of autophagy and reactive oxygen species in human renal tubular epithelial cells derived from the normal kidney HK-2 cell line, in addition to human cell lines ACHN and 786-O cell line.
eff↑, berberine showed a greater apoptotic effect than gemcitabine in cancer cells
selectivity↑, After berberine treatment, it was noticed that berberine showed privileged selectivity towards cancer cells as compared to normal ones.
selectivity↑, expression of caspase-1 and its downstream target Interleukin-1β (IL-1β) was higher in osteosarcoma cells as compared to normal cells
BioAv↓, several studies have been undertaken to overcome the difficulties of low absorption and poor bioavailability through nanotechnology-based strategies.
DNMT1↓, In human multiple melanoma cell U266, berberine can inhibit the expression of DNMT1 and DNMT3B, which leads to hypomethylation of TP53 by altering the DNA methylation level and the p53-dependent signal pathway
cMyc↓, Moreover, berberine suppresses SLC1A5, Na+ dependent transporter expression through preventing c-Myc

1392- BBR,    Based on network pharmacology and experimental validation, berberine can inhibit the progression of gastric cancer by modulating oxidative stress
- in-vitro, GC, AGS - in-vitro, GC, MKN45
TumCG↓,
TumCMig↓,
ROS↑, intracellular
MDA↑, intracellular
SOD↓, intracellular
NRF2↓,
HO-1↓,
Hif1a↓,
EMT↓,
Snail↓,
Vim↓,

1385- BBR,  5-FU,    Low-Dose Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents via Induction of Autophagy and Antioxidation
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
eff↓, Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents
ROS↑, LDB mildly while HDB greatly stimulated ROS generation BBR-induced ROS generation may activate the antioxidant response therefore to promote cancer cell proliferation.
TumCP↑,
NRF2↑,
ChemoSen↓, These findings revealed a potential negative impact of BBR on its adjuvant anti-breast cancer therapy

1389- BBR,  Lap,    Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS
- in-vitro, BC, BT474 - in-vitro, BC, AU-565
ChemoSen↑, combination therapy of berberine with lapatinib overcame lapatinib resistance.
Apoptosis↑,
ROS↑,
NRF2↓, Berberine reverses lapatinib resistance by inhibiting the Nrf2 signaling pathway

1380- BBR,  doxoR,    treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358.
- in-vivo, Nor, NA
*ROS↓, Ber effectively rescued the DOX-induced production of reactive oxygen species (ROS) and MDA, mitochondrial morphological damage and membrane potential loss in neonatal rat cardiac myocytes and fibroblasts.
*MDA↓, Pretreatment with Ber inhibited ROS and MDA production and increased SOD activity and the mitochondrial membrane potential in DOX-challenged CFs.
*SOD↑,
*NRF2↑,
*HO-1↑,

2756- BetA,    Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway
- in-vitro, HCC, HUH7 - in-vitro, HCC, H1299
TumCP↓, betulinic acid could suppress proliferation and migration of hepatoma cells, raised ROS level and inhibited antioxidation level in cells
ROS↓,
antiOx↓,
TumCG↓, These findings indicate that betulinic acid has the capacity to significantly impede hepatoma cells growth and migration
TumCMig↓,
NRF2↓, The expression of antioxidant proteins Nrf2, GPX4 and HO-1 was also considerably lower in the BETM and BETH groups than in the Control group
GPx4↓,
HO-1↓,
NCOA4↑, suggesting that betulinic acid activates ferritinophagy by boosting NCOA4 expression and FTH1 degradation.
FTH1↓, betulinic acid groups (10 mg/kg, 20 mg/kg, and 40 mg/kg) greatly boosted LC3II and NCOA4 expressions and suppressed FTH1
Ferritin↑, In summation, betulinic acid decreases antioxidation in tumour tissues from nude mice, inhibits ferritin expression, enhances the expression of ferritinophagy-associated protein, activates ferritinophagy, and initiates ferroptosis in tumour cells.
Ferroptosis↑,
GSH↓, In comparison to the Control group, the betulinic acid groups (10 mg/kg, 20 mg/kg and 40 mg/kg) reduced dramatically GSH and hydroxyl radical inhibition capacity in serum, considerably increased serum Fe2+), and decreased dramatically serum MDA
MDA↓,

2757- BetA,    Betulinic Acid Inhibits Glioma Progression by Inducing Ferroptosis Through the PI3K/Akt and NRF2/HO-1 Pathways
- in-vitro, GBM, U251
tumCV↓, BA reduced viability; inhibited colony formation, migration, and invasion; and triggered apoptosis.
TumCMig↓,
TumCI↓,
Apoptosis↑,
p‑PI3K↓, BA administration decreased the levels of phosphorylated PI3K and AKT.
p‑Akt↓,
Ferroptosis↑, BA-induced ferroptosis and HO-1 and NRF2 levels were increased
HO-1↑,
NRF2↑,

2758- BetA,    Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway
- in-vivo, Nor, NA
*ROS↓, protective effects and mechanisms of BA in blocking oxidative stress caused by acute exposure to T-2 toxin in the thymus of mice was studied.
*MDA↓, BA pretreatment reduced ROS production, decreased the MDA content, and increased the content of IgG in serum and the levels of SOD and GSH in the thymus.
*SOD↑,
*GSH↑,
*p‑p38↓, BA downregulated the phosphorylation of the p38, JNK, and ERK proteins, while it upregulated the expression of the Nrf2 and HO-1 proteins in thymus tissues.
*p‑JNK↓,
*p‑ERK↓,
*NRF2↑,
*HO-1↑,
*MAPK↓, suppressing the MAPK signaling pathway.
*heparanase↑, BA also showed protective activities against alcohol-induced liver damage and dexamethasone-induced spleen and thymus oxidative damage, and these protective effects were related to the antioxidant capacity of BA
*antiOx↑, BA Increased T-2 Toxin-Induced Thymus Antioxidative Capacity

2759- BetA,    Chemopreventive and Chemotherapeutic Potential of Betulin and Betulinic Acid: Mechanistic Insights From In Vitro, In Vivo and Clinical Studies
- Review, Var, NA
chemoP↑, chemopreventive and chemotherapeutic effects of betulin and betulinic acid by presenting in vitro, in vivo
ChemoSen↑,
*Inflam↓, right side depicts anti-inflammatory effect by suppressing proinflammatory mediators
*NRF2↑, boosting NRF2 (antioxidant/anti-inflammatory).
*NF-kB↓, suppressing proinflammatory mediators (NF-κB and COX)
*COX2↓,
ROS↑, By rapidly increasing the generation of reactive oxidative species and concurrently dissipating mitochondrial membrane potential in a dose- and time-dependent manner, betulinic acid also has an anticancer effect on melanoma cells
MMP↓,
Sp1/3/4↓, nude mice bearing LNCaP cell xenografts has been observed by betulinic acid treatment and this result was associated with reduction in the expression of Sp1, Sp3, and Sp4 proteins and vascular endothelial growth factor (VEGF)
VEGF↓,

2725- BetA,    Betulinic acid protects against renal damage by attenuation of oxidative stress and inflammation via Nrf2 signaling pathway in T-2 toxin-induced mice
- in-vivo, Nor, NA
*RenoP↑, BA pretreatment alleviated excessive glomerular hemorrhage and inflammatory cell infiltration in kidneys caused by T-2 toxin.
*SOD?, Moreover, pretreatment with BA mitigated T-2 toxin-induced renal oxidative damage by up-regulating the activities of SOD and CAT, and the content of GSH, while down-regulating the accumulation of ROS and MDA
*Catalase↑,
*GSH↑,
*ROS↓,
*MDA↓,
*IL1β↓, decreasing the mRNA expression of IL-1β, TNF-α and IL-10, and increasing IL-6 mRNA expression
*TNF-α↓,
*IL10↓,
*IL6↑,
*NRF2↑, pretreatment with BA could activate Nrf2 signaling pathway.

726- Bor,    Redox Mechanisms Underlying the Cytostatic Effects of Boric Acid on Cancer Cells—An Issue Still Open
- Review, NA, NA
NAD↝, high affinity for the ribose moieties of NAD+
SAM-e↝, high affinity for S-adenosylmethione
PSA↓,
IGF-1↓,
Cyc↓, reduction in cyclins A–E
P21↓,
p‑MEK↓,
p‑ERK↓, ERK (P-ERK1/2)
ROS↑, induce oxidative stress by decreasing superoxide dismutase (SOD) and catalase (CAT)
SOD↓,
Catalase↓,
MDA↑,
GSH↓,
IL1↓, IL-1α
IL6↓,
TNF-α↓,
BRAF↝,
MAPK↝,
PTEN↝,
PI3K/Akt↝,
eIF2α↑,
ATF4↑,
ATF6↑,
NRF2↑,
BAX↑,
BID↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
Bcl-xL↓,

738- Bor,    Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways
- in-vitro, GBM, U251 - in-vitro, GBM, A172 - in-vitro, Nor, SVGp12
TumCP↓,
GPx4↓, borax treatment decreased GPx4, GSH, HSPA5 and NRF2 levels in U251 and A172 cells while increasing MDA levels and caspase‐3/7 activity.
GSH↓,
HSP70/HSPA5↓,
NRF2↓,
MDA↑,
Casp3↑,
Casp7↑,
Ferroptosis↑, Consequently, borax may induce ferroptosis in GBM cells
selectivity↑, Treating SVG cells with borax concentrations ranging from 0 to 800 μM for 24 h did not result in a significant reduction in viability compared to the control group

3517- Bor,  Se,    The protective effects of selenium and boron on cyclophosphamide-induced hepatic oxidative stress, inflammation, and apoptosis in rats
- in-vivo, Nor, NA
*hepatoP↑, However, it was found that Se protects the liver slightly better against CP damage than B
*ALAT↓, statistically significant difference was observed in the serum levels of ALT, AST, ALP, TAS, TOS and OSI.
*AST↓,
*ALP↓,
*NF-kB↓, A statistically significant difference was observed in serum levels of NF-kB, TNF-α, IL -1β, IL -6 and IL -10 when the Se + CP and B + CP-treated groups were compared with the CP-treated group
*TNF-α↓, fig 9
*IL1β↓,
*IL6↓,
*IL10↑,
*SOD↑, A statistically remarkable change in serum levels of SOD, CAT, GPx, MDA and GSH was observed in the group receiving only CP compared to groups Se, B and the control.
*Catalase↑,
*MDA↓, Fig 10
*GSH↑,
*GPx↑,
*antiOx↑, suggests that B and Se increase intracellular antioxidant status.
*NRF2↑, Se and B treatment can protect rat liver tissue from CP-induced oxidative stress, inflammation, and apoptosis by regulating Bax/Bcl-2 and Nrf2-Keap-1 signaling pathways.
*Keap1↓,

3513- Bor,    Boric Acid Activation of eIF2α and Nrf2 Is PERK Dependent: a Mechanism that Explains How Boron Prevents DNA Damage and Enhances Antioxidant Status
- in-vitro, Pca, DU145 - in-vitro, Nor, MEF
NRF2↑, Cytoplasmic Nrf2 was translocated to the nucleus at 1.5–2 h in DU-145 and MEF WT cells, but not MEF PERK −/− cells. BA treatment demonstrating BA-activated Nrf2
selectivity↑, but not MEF PERK −/− cells.
NQO1↑, , NQO1, GCLC, and HMOX-1. DU-145 cells treated with BA increased the expression of all three gene
GCLC↑,
HO-1↑,
TumCP↓, BA activates Nrf2 and ARE explains how BA slows proliferation of DU-145 cells but does not cause apoptosis

3511- Bor,    Boron
- Review, NA, NA
*memory↑, In boron-deprived humans, boron supplementation improved mental alertness, attention, short-term memory, and motor speed and dexterity.
*motorD↑,
*neuroP↑,
Ca+2↓, human prostate cells, boric acid acts as a reversible noncompetitive inhibitor of cADPR leading to decreased endoplasmic reticulum Ca2+
ATF4↑, The decreased Ca2+ results in the E74 like ETS transcription factor 2α activating transcription factor 4 (ATF4) and nuclear factor erythroid 2 like 2 (Nrf2),
NRF2↑,
*Inflam↓, a dietary boron intake >0.4 mg/d may be useful for bone and brain health and in modulating inflammatory and oxidative stress
*ROS↓,

3510- Bor,    Boron Affects the Development of the Kidney Through Modulation of Apoptosis, Antioxidant Capacity, and Nrf2 Pathway in the African Ostrich Chicks
- in-vivo, Nor, NA
*RenoP↑, Our results revealed that low doses of boron (up to 160 mg) had positive effect, while high doses (especially 640 mg) caused negative effect on the development of the kidney
*ROS↓, The low doses regulate the oxidative and enzyme activity in the kidney.
*antiOx↑, boron at low doses upregulated the expression of genes involved in the antioxidant pathway
*Apoptosis↓, low levels of boron (up to 160 mg) inhibited the cell apoptosis, regulate the enzyme activity, and improved the antioxidant system, thus may encourage the development of the ostrich chick's kidney
*NRF2↑, maximum localization of Nrf2 in 80 mg/L BA dose group
*HO-1↑, As the boron concentration increased, the expression of Nrf2, GCLc, and HO-1 genes upregulated
*MDA↓, In comparison to those of the group 1, MDA content (lipid peroxidation marker) was significantly decreased by 26.02 and 48.12% in the 40 and 80 mg/L BA groups
*lipid-P↓,
*GPx↓, GSH-PX activity of ostrich chick kidney tissue was slightly increased in the 40 and 80 mg/L BA groups,
*Catalase↑, supplementation of low doses of boron in the ostrich drinking water has resulted in stimulation of antioxidant capacity of GR, CAT, and SOD significantly.
*SOD↑,
*ALAT↓, boron supply in low doses (especially 80 mg/L BA) showed decrease levels in the activity of ALT, AST, and ALP.
*AST↓,
*ALP↓,

3524- Bor,    Boric Acid Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice
*Inflam↓, Furthermore, BA exhibited anti-inflammatory properties by suppressing inflammatory cytokines within the lung tissue.
*SOD↑, BA ingestion caused upregulation in SOD and a decrease in MDA contents in lung tissue homogenates.
*MDA↓,
*GRP78/BiP↓, BA downregulated the levels of GRP78 and CHOP compared to the LPS group.
*CHOP↓,
*NRF2↑, Remarkably, BA also upregulated transcription and protein expression of Nrf2 and HO-1 compared to the LPS group.
*HO-1↑,

2775- Bos,    The journey of boswellic acids from synthesis to pharmacological activities
- Review, Var, NA - Review, AD, NA - Review, PSA, NA
ROS↑, modulation of reactive oxygen species (ROS) formation and the resulting endoplasmic reticulum stress is central to BA’s molecular and cellular anticancer activities
ER Stress↑,
TumCG↓, Cell cycle arrest, growth inhibition, apoptosis induction, and control of inflammation are all the effects of BA’s altered gene expression
Apoptosis↑,
Inflam↓,
ChemoSen↑, BA has additional synergistic effects, increasing both the sensitivity and cytotoxicity of doxorubicin and cisplatin
Casp↑, BA decreases viability and induces apoptosis by activat- ing the caspase-dependent pathway in human pancreatic cancer (PC) cell lines
ERK↓, BA might inhibit the activation of Ak strain transforming (Akt) and extracellular signal–regulated kinase (ERK)1/2,
cl‑PARP↑, initiation of cleavage of PARP were prompted by the treatment with AKBA
AR↓, AKBA affects the androgen receptor by reducing its expression,
cycD1↓, decrease in cyclin D1, which inhibits cellular proliferation
VEGFR2↓, In prostate cancer, the downregulation of vascular endothelial growth factor receptor 2–mediated angiogenesis caused by BA
CXCR4↓, Figure 6
radioP↑,
NF-kB↓,
VEGF↓,
P21↑,
Wnt↓,
β-catenin/ZEB1↓,
Cyt‑c↑,
MMP2↓,
MMP1↓,
MMP9↓,
PI3K↓,
MAPK↓,
JNK↑,
*5LO↓, Table 1 (non cancer)
*NRF2↑,
*HO-1↑,
*MDA↓,
*SOD↑,
*hepatoP↑, Preclinical studies demonstrated hepatoprotective impact for BA against different models of hepatotoxicity via tackling oxidative stress, and inflammatory and apoptotic indices
*ALAT↓,
*AST↓,
*LDH↑,
*CRP↓,
*COX2↓,
*GSH↑,
*ROS↓,
*Imm↑, oral administration of biopolymeric fraction (BOS 200) from B. serrata in mice led to immunostimulatory effects
*Dose↝, BA at low concentration tend to stimulate an immune response, as those utilized in the study of Beghelli et al. (2017) however, utilizing higher concentration suppressed the immune response
*eff↑, Useful actions on skin and psoriasis
*neuroP↑, AKBA has substantially diminished the levels of inflammatory markers such as 5-LOX, TNF-, IL-6, and meliorated cognition in lipopolysaccharide-induced neuroinflammation rodent models
*cognitive↑,
*IL6↓,
*TNF-α↓,

2772- Bos,    Mechanistic role of boswellic acids in Alzheimer’s disease: Emphasis on anti-inflammatory properties
- Review, AD, NA
*neuroP↑, (AKBA) that possess potent anti-inflammatory and neuroprotective properties in AD
*Inflam↓,
*AChE↓, inhibiting the acetylcholinesterase (AChE) activity in the cholinergic pathway and improve choline levels
*Choline↑,
*NRF2↑, BAs modulate key molecular targets and signalling pathways like 5-lipoxygenase/cyclooxygenase, Nrf2, NF-kB, cholinergic, amyloid-beta (Aβ), and neurofibrillary tangles formation (NFTs) that are involved in AD
*NF-kB↑,
*BBB↑, AKBA has efficiently abled to cross the blood brain barrier (BBB)
*BioAv↑, bioavailability of AKBA was significantly higher in case of sublingual route when compared to intranasal administration, as demonstrated by area under curves (AUCs) analysis
*Half-Life↓, half-life of the drug was about six hours and peak plasma levels of the drug reach 30 hrs after oral administration of 333 mg of BSE.
*Dose↝, drug needs to be administered at a dosing interval of 6 hrs
*PGE2↓, BAs possessed anti-inflammatory activity by inhibiting microsomal prostaglandin E2 synthase-1 (mPGES1)
*ROS↓, prevented oxidative stress-induced neuronal damage and cognitive impairment because of the antioxidant, anti-inflammatory and anti-glutamatergic effects
*cognitive↑,
*antiOx↑,
5LO↓, AKBA significantly reduced pro-inflammatory mediators such as 5-LOX, TNF-α, IL-6 levels and improve cognition
*TNF-α↓,
*IL6↓,
*HO-1↑, AKBA shows neuroprotective effects against ischaemic injury via nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade activation

2768- Bos,    Boswellic acids as promising agents for the management of brain diseases
- Review, Var, NA - Review, AD, NA - Review, Park, NA
*neuroP↑, BAs-induced neuroprotection is proposed to be associated with the ability to reduce neurotoxic aggregates, decrease oxidative stress, and improve cognitive dysfunction.
*ROS↓,
*cognitive↓,
TumCP↓, BAs have been suggested as potential agents for the treatment of brain tumors due to their potential to attenuate cell proliferation, migration, metastasis, angiogenesis, and promote apoptosis during both in vitro and in vivo studies
TumCMig↓,
TumMeta↓,
angioG↓,
Apoptosis↑,
*Inflam↓, The anti-inflammatory activities of BAs have been investigated in many preclinical and clinical trials
IL1↓, BAs inhibit the production of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α) in several experimental studies.
IL2↓,
IL4↓,
IL6↓,
TNF-α↓,
P53↑, AKBA has been reported to induce apoptosis in pancreatic and gastric cancers, through tumor suppressor protein 53 (p53)-independent pathway, while reducing expression of protein kinase (PK) B and NF-kb
Akt↓,
NF-kB↓,
DNAdam↑, DNA fragmentation, and activation of caspase cascade
Casp↑,
COX2↓, regulated genes such as cyclooxygenase-2 (COX-2), matrix metallopeptidase-9 (MMP-9), C-X-C motif chemokine receptor 4 (CXCR4), and vascular endothelial growth factor (VEGF)
MMP9↓,
CXCR4↓,
VEGF↓,
*SOD↑, BAs against oxidative injury has been shown in several cell lines and animal models [12], [13], [21]. BAs exert protective effects through the normalization of antioxidant enzyme levels, such as superoxide dismutase (SOD), catalase, and glutathione p
*Catalase↑,
*GPx↑,
*NRF2↑, Moreover, it can activate nuclear factor erythroid 2-related factor-2 (Nrf2)/antioxidant response element-regulated pathways

1425- Bos,    Protective Effect of Boswellic Acids against Doxorubicin-Induced Hepatotoxicity: Impact on Nrf2/HO-1 Defense Pathway
- in-vivo, Nor, NA
*ChemoSen↑, BAs significantly improved the altered liver enzyme activities and oxidative stress markers.
*NRF2↑, BAs increased the Nrf2 and HO-1 expression, which provided protection against DOX-induced oxidative insult
*HO-1↑,
*ROS↓, appear to scavenge ROS and inhibit lipid peroxidation and DNA damage of DOX-induced hepatotoxicity
*lipid-P↓,
*DNAdam↓,

2394- CAP,    Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction
- in-vitro, Nor, GES-1
*mtDam↓, CAP ameliorated mitochondrial damage, facilitated the nuclear translocation of NRF2, thereby promoting the expression of downstream antioxidant response elements, HO-1, Trx, GSS and NQO1 in GES-1 cells.
*NRF2↑,
*HO-1↑,
*Trx↑,
*GSS↑,
*NQO1↑,
*Keap1↓, CAP could directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2.
*ROS↓, Capsaicin protects GES-1 from oxidative stress
*PKM2↓, Previous studies have demonstrated that CAP can directly bind to and inhibit the activity of PKM2 and LDHA, subsequently attenuating inflammatory response
*LDHA↓,
*Inflam↓,

2392- Cela,    The role of natural products targeting macrophage polarization in sepsis-induced lung injury
- Review, Sepsis, NA
TNF-α↓, Celastrol suppresses the release of the proinflammatory cytokines TNF-α, IL-1β, and IL-6; inhibits the PKM2-dependent Warburg effec
IL1β↓,
IL6↓,
Warburg↓,
PKM2↓,
NRF2↑, Additionally, celastrol activates the NRF2/HO-1 pathway, inhibits the activation of NF-κB, and reduces the expression of TNF-α, IL-6, IL-1β, and iNOS, further suppressing M1 polarization
HO-1↑,
NF-kB↓,
iNOS↓,
M1↓, further suppressing M1 polarization

2794- CHr,    An updated review on the versatile role of chrysin in neurological diseases: Chemistry, pharmacology, and drug delivery approaches
- Review, Park, NA - Review, Stroke, NA
*neuroP↑, chrysin has protective effects against neurological conditions by modulating oxidative stress, inflammation, and apoptosis in animal models.
*ROS↓,
*Inflam↓,
*Apoptosis↓,
*IL1β↓, attenuated IL-1β and TNF-α, COX-2, iNOS, and NF-kB expression, activated JNK
*TNF-α↓,
*COX2↓,
*iNOS↓,
*NF-kB↓,
*JNK↓,
*HDAC↓, alleviated histone deacetylase (HDCA) activity, GSK-3β levels, IFNγ, IL-17,
*GSK‐3β↓,
*IFN-γ↓,
*IL17↓,
*GSH↑, increased GSH levels
*NRF2↑, Park's: Increased Nrf2, modulated HO-1, SOD, CAT, decreased MDA, inhibited NF-κB and iNOS
*HO-1↑, upregulated expression of hallmark antioxidant enzymes, including HO-1, SOD, and CAT; and decreased levels of MDA
*SOD↑,
*MDA↓,
*NO↓, Attenuated NO, increased GPx
*GPx↑,
*TBARS↓, decreased levels of TBARS, AChE, restored activities of GR, GSH, SOD, CAT and Vitamin C
*AChE↓,
*GR↑,
*Catalase↑,
*VitC↑,
*memory↑, attenuated memory impairment
*lipid-P↓, attenuated lipid peroxidation
*ROS↓, attenuated ROS

2781- CHr,  PBG,    Chrysin a promising anticancer agent: recent perspectives
- Review, Var, NA
PI3K↓, It can block Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling in different animals against various cancers
Akt↓,
mTOR↓,
MMP9↑, Chrysin strongly suppresses Matrix metalloproteinase-9 (MMP-9), Urokinase plasminogen activator (uPA) and Vascular endothelial growth factor (VEGF), i.e. factors that can cause cancer
uPA↓,
VEGF↓,
AR↓, Chrysin has the ability to suppress the androgen receptor (AR), a protein necessary for prostate cancer development and metastasis
Casp↑, starts the caspase cascade and blocks protein synthesis to kill lung cancer cells
TumMeta↓, Chrysin significantly decreased lung cancer metastasis i
TumCCA↑, Chrysin induces apoptosis and stops colon cancer cells in the G2/M cell cycle phase
angioG↓, Chrysin prevents tumor growth and cancer spread by blocking blood vessel expansion
BioAv↓, Chrysin’s solubility, accessibility and bioavailability may limit its medical use.
*hepatoP↑, As chrysin reduced oxidative stress and lipid peroxidation in rat liver cells exposed to a toxic chemical agent.
*neuroP↑, Protecting the brain against oxidative stress (GPx) may be aided by increasing levels of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx).
*SOD↑,
*GPx↑,
*ROS↓, A decrease in oxidative stress and an increase in antioxidant capacity may result from chrysin’s anti-inflammatory properties
*Inflam↓,
*Catalase↑, Supplementation with chrysin increased the activity of antioxidant enzymes like SOD and catalase and reduced the levels of oxidative stress markers like malondialdehyde (MDA) in the colon tissue of the rats.
*MDA↓, Antioxidant enzyme activity (SOD, CAT) and oxidative stress marker (MDA) levels were both enhanced by chrysin supplementation in mouse liver tissue
ROS↓, reduction of reactive oxygen species (ROS) and oxidative stress markers in the cancer cells further indicated the antioxidant activity of chrysin
BBB↑, After crossing the blood-brain barrier, it has been shown to accumulate there
Half-Life↓, The half-life of chrysin in rats is predicted to be close to 2 hours.
BioAv↑, Taking chrysin with food may increase the effectiveness of the supplement: increased by a factor of 1.8 when taken with a high-fat meal
ROS↑, In contrast to 5-FU/oxaliplatin, chrysin increases the production of reactive oxygen species (ROS), which in turn causes autophagy by stopping Akt and mTOR from doing their jobs
eff↑, mixture of chrysin and cisplatin caused the SCC-25 and CAL-27 cell lines to make more oxygen free radicals. After treatment with chrysin, cisplatin, or both, the amount of reactive oxygen species (ROS) was found to have gone up.
ROS↑, When reactive oxygen species (ROS) and calcium levels in the cytoplasm rise because of chrysin, OC cells die.
ROS↑, chrysin is the cause of death in both types of prostate cancer cells. It does this by depolarizing mitochondrial membrane potential (MMP), making reactive oxygen species (ROS), and starting lipid peroxidation.
lipid-P↑,
ER Stress↑, when chrysin is present in DU145 and PC-3 cells, the expression of a group of proteins that control ER stress goes up
NOTCH1↑, Chrysin increased the production of Notch 1 and hairy/enhancer of split 1 at the protein and mRNA levels, which stopped cells from dividing
NRF2↓, Not only did chrysin stop Nrf2 and the genes it controls from working, but it also caused MCF-7 breast cancer cells to die via apoptosis.
p‑FAK↓, After 48 hours of treatment with chrysin at amounts between 5 and 15 millimoles, p-FAK and RhoA were greatly lowered
Rho↓,
PCNA↓, Lung histology and immunoblotting studies of PCNA, COX-2, and NF-B showed that adding chrysin stopped the production of these proteins and maintained the balance of cells
COX2↓,
NF-kB↓,
PDK1↓, After the chrysin was injected, the genes PDK1, PDK3, and GLUT1 that are involved in glycolysis had less expression
PDK3↑,
GLUT1↓,
Glycolysis↓, chrysin stops glycolysis
mt-ATP↓, chrysin inhibits complex II and ATPases in the mitochondria of cancer cells
Ki-67↓, the amounts of Ki-67, which is a sign of growth, and c-Myc in the tumor tissues went down
cMyc↓,
ROCK1↓, (ROCK1), transgelin 2 (TAGLN2), and FCH and Mu domain containing endocytic adaptor 2 (FCHO2) were much lower.
TOP1↓, DNA topoisomerases and histone deacetylase were inhibited, along with the synthesis of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and (IL-1 beta), while the activity of protective signaling pathways was increased
TNF-α↓,
IL1β↓,
CycB↓, Chrysin suppressed cyclin B1 and CDK2 production in order to stop cancerous growth.
CDK2↓,
EMT↓, chrysin treatment can also stop EMT
STAT3↓, chrysin block the STAT3 and NF-B pathways, but it also greatly reduced PD-L1 production both in vivo and in vitro.
PD-L1↓,
IL2↑, chrysin increases both the rate of T cell growth and the amount of IL-2

2807- CHr,    Evidence-based mechanistic role of chrysin towards protection of cardiac hypertrophy and fibrosis in rats
- in-vivo, Nor, NA
*antiOx↑, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic
Inflam↓,
*cardioP↑, Pre-treatment with chrysin of 60 mg/kg reversed the ISO-induced damage to myocardium and prevent cardiac hypertrophy and fibrosis through various anti-inflammatory, anti-apoptotic, antioxidant and anti-fibrotic pathways
*GSH↑, CHY at the highest dose (60 mg/kg) significantly bolstered the antioxidant status :GSH, SOD and CAT
*SOD↑,
*Catalase↑,
*GAPDH↑, significant increase in GAPDH levels was observed in CHYP group in comparison with normal group
*BAX↓, Decrease in apoptotic (Bax), increase in anti-apoptotic (Bcl-2)
*Bcl-2↑,
*PARP↓, expression of downstream signalling proteins, that is, PARP, cytochrome-C and caspase-3 were following the similar pattern. however at CHY 60 mg/kg treatment group, the levels were remarkably (P < 0·001) reduced.
*Cyt‑c↓,
*Casp3↓,
*NOX4↓, Whereas, lower levels of Nox-4 and higher levels of Nrf-2, HO-1 and HSP-70 were observed in CHYP group
*NRF2↑,
*HO-1↑,
*HSP70/HSPA5↑,

2782- CHr,    Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives
- Review, Var, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, antioxidant, anti-inflammatory, hepatoprotective, neuroprotective
*Inflam↓, inhibitory effect of chrysin on inflammation and oxidative stress is also important in Parkinson’s disease
*hepatoP↑,
*neuroP↑,
*BioAv↓, Accumulating data demonstrates that poor absorption, rapid metabolism, and systemic elimination are responsible for poor bioavailability of chrysin in humans that, subsequently, restrict its therapeutic effects
*cardioP↑, cardioprotective [69], lipid-lowering effect [70]
*lipidLev↓,
*RenoP↑, Renoprotective
*TNF-α↓, chrysin reduces levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2).
*IL2↓,
*PI3K↓, induction of the PI3K/Akt signaling pathway by chrysin contributes to a reduction in oxidative stress and inflammation during cerebral I/R injury
*Akt↓,
*ROS↓,
*cognitive↑, Chrysin (25, 50, and 100 mg/kg) improves cognitive capacity, inflammation, and apoptosis to ameliorate traumatic brain injury
eff↑, chrysin and silibinin is beneficial in suppressing breast cancer malignancy via decreasing cancer proliferation
cycD1↓, chrysin and silibinin induced cell cycle arrest via down-regulation of cyclin D1 and hTERT
hTERT↓,
VEGF↓, Administration of chrysin is associated with the disruption of hypoxia-induced VEGF gene expression
p‑STAT3↓, chrysin is capable of reducing STAT3 phosphorylation in hypoxic conditions without affecting the HIF-1α protein level.
TumMeta↓, chrysin is a potent agent in suppressing metastasis and proliferation of breast cancer cells during hypoxic conditions
TumCP↓,
eff↑, combination therapy of breast cancer cells using chrysin and metformin exerts a synergistic effect and is more efficient compared to chrysin alone
eff↑, combination of quercetin and chrysin reduced levels of pro-inflammatory factors, such as IL-1β, Il-6, TNF-α, and IL-10, via NF-κB down-regulation.
IL1β↓,
IL6↓,
NF-kB↓,
ROS↑, after chrysin administration, an increase occurs in levels of ROS that, subsequently, impairs the integrity of the mitochondrial membrane, leading to cytochrome C release and apoptosis induction
MMP↓,
Cyt‑c↑,
Apoptosis↑,
ER Stress↑, in addition to mitochondria, ER can also participate in apoptosis
Ca+2↑, Upon chrysin administration, an increase occurs in levels of ROS and cytoplasmic Ca2+ that mediate apoptosis induction in OC cells
TET1↑, In MKN45 cells, chrysin promotes the expression of TET1
Let-7↑, Chrysin is capable of promoting the expression of miR-9 and Let-7a as onco-suppressor factors in cancer to inhibit the proliferation of GC cells
Twist↓, Down-regulation of NF-κB, and subsequent decrease in Twist/EMT are mediated by chrysin administration, negatively affecting cervical cancer metastasis
EMT↓,
TumCCA↑, nduction of cell cycle arrest and apoptosis via up-regulation of caspase-3, caspase-9, and Bax are mediated by chrysin
Casp3↑,
Casp9↑,
BAX↑,
HK2↓, Chrysin administration (15, 30, and 60 mM) reduces the expression of HK-2 in hepatocellular carcinoma (HCC) cells to impair glucose uptake and lactate production.
GlucoseCon↓,
lactateProd↓,
Glycolysis↓, In addition to glycolysis metabolism impairment, the inhibitory effect of chrysin on HK-2 leads to apoptosis
SHP1↑, upstream modulator of STAT3 known as SHP-1 is up-regulated by chrysin
N-cadherin↓, Furthermore, N-cadherin and E-cadherin are respectively down-regulated and up-regulated upon chrysin administration in inhibiting melanoma invasion
E-cadherin↑,
UPR↑, chrysin substantially diminishes survival by ER stress induction via stimulating UPR, PERK, ATF4, and elF2α
PERK↑,
ATF4↑,
eIF2α↑,
RadioS↑, Irradiation combined with chrysin exerts a synergistic effect
NOTCH1↑, Irradiation combined with chrysin exerts a synergistic effect
NRF2↓, in reducing Nrf2 expression, chrysin down-regulates the expression of ERK and PI3K/Akt pathways—leading to an increase in the efficiency of doxorubicin in chemotherapy
BioAv↑, chrysin at the tumor site by polymeric nanoparticles leads to enhanced anti-tumor activity, due to enhanced cellular uptake
eff↑, Chrysin- and curcumin-loaded nanoparticles significantly promote the expression of TIMP-1 and TIMP-2 to exert a reduction in melanoma invasion

2785- CHr,    Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin
- Review, Var, NA
*NF-kB↓, suppressed pro-inflammatory cytokine expression and histamine release, downregulated nuclear factor kappa B (NF-kB), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS)
*COX2↓,
*iNOS↓,
angioG↓, upregulated apoptotic pathways [28], inhibited angiogenesis [29] and metastasis formation
TOP1↓, suppressed DNA topoisomerases [31] and histone deacetylase [32], downregulated tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)
HDAC↓,
TNF-α↓,
IL1β↓,
cardioP↑, promoted protective signaling pathways in the heart [34], kidney [35] and brain [8], decreased cholesterol level
RenoP↑,
neuroP↑,
LDL↓,
BioAv↑, bioavailability of chrysin in the oral route of administration was appraised to be 0.003–0.02% [55], the maximum plasma concentration—12–64 nM
eff↑, Chrysin alone and potentially in combination with metformin decreased cyclin D1 and hTERT gene expression in the T47D breast cancer cell line
cycD1↓,
hTERT↓,
MMP-10↓, Chrysin pretreatment inhibited MMP-10 and Akt signaling pathways
Akt↓,
STAT3↓, Chrysin declined hypoxic survival, inhibited activation of STAT3, and reduced VEGF expression in hypoxic cancer cells
VEGF↓,
EGFR↓, chrysin to inhibit EGFR was reported in a breast cancer stem cell model [
Snail↓, chrysin downregulated MMP-10, reduced snail, slug, and vimentin expressions increased E-cadherin expression, and inhibited Akt signaling pathway in TNBC cells, proposing that chrysin possessed a reversal activity on EMT
Slug↓,
Vim↓,
E-cadherin↑,
eff↑, Fabrication of chrysin-attached to silver and gold nanoparticles crossbred reduced graphene oxide nanocomposites led to augmentation of the generation of ROS-induced apoptosis in breast cancer
TET1↑, Chrysin induced augmentation in TET1
ROS↑, Pretreatment with chrysin induced ROS formation, and consecutively, inhibited Akt phosphorylation and mTOR.
mTOR↓,
PPARα↓, Chrysin inhibited mRNA expression of PPARα
ER Stress↑, ROS production by chrysin was the critical mediator behind induction of ER stress, leading to JNK phosphorylation, intracellular Ca2+ release, and activation of the mitochondrial apoptosis pathway
Ca+2↑,
ERK↓, reduced protein expression of p-ERK/ERK
MMP↑, Chrysin pretreatment led to an increase in mitochondrial ROS creation, swelling in isolated mitochondria from hepatocytes, collapse in MMP, and release cytochrome c.
Cyt‑c↑,
Casp3↑, Chrysin could elevate caspase-3 activity in the HCC rats group
HK2↓, chrysin declined HK-2 combined with VDAC-1 on mitochondria
NRF2↓, chrysin inhibited the Nrf2 expression and its downstream genes comprising AKR1B10, HO-1, and MRP5 by quenching ERK and PI3K-Akt pathway
HO-1↓,
MMP2↓, Chrysin pretreatment also downregulated MMP2, MMP9, fibronectin, and snail expression
MMP9↓,
Fibronectin↓,
GRP78/BiP↑, chrysin induced GRP78 overexpression, spliced XBP-1, and eIF2-α phosphorylation
XBP-1↓,
p‑eIF2α↑,
*AST↓, Chrysin administration significantly reduced AST, ALT, ALP, LDH and γGT serum activities
ALAT↓,
ALP↓,
LDH↓,
COX2↑, chrysin attenuated COX-2 and NFkB p65 expression, and Bcl-xL and β-arrestin levels
Bcl-xL↓,
IL6↓, Reduction in IL-6 and TNF-α and augmentation in caspases-9 and 3 were observed due to chrysin supplementation.
PGE2↓, Chrysin induced entire suppression NF-kB, COX-2, PG-E2, iNOS as well.
iNOS↓,
DNAdam↑, Chrysin induced apoptosis of cells by causing DNA fragmentation and increasing the proportions of DU145 and PC-3 cells
UPR↑, Also, it induced ER stress via activation of UPR proteins comprising PERK, eIF2α, and GRP78 in DU145 and PC-3 cells.
Hif1a↓, Chrysin increased the ubiquitination and degradation of HIF-1α by increasing its prolyl hydroxylation
EMT↓, chrysin was effective in HeLa cell by inhibiting EMT and CSLC properties, NF-κBp65, and Twist1 expression
Twist↓,
lipid-P↑, Chrysin disrupted intracellular homeostasis by altering MMP, cytosolic Ca (2+) levels, ROS generation, and lipid peroxidation, which plays a role in the death of choriocarcinoma cells.
CLDN1↓, Chrysin decreased CLDN1 and CLDN11 expression in human lung SCC
PDK1↓, Chrysin alleviated p-Akt and inhibited PDK1 and Akt
IL10↓, Chrysin inhibited cytokines release, TNF-α, IL-1β, IL-10, and IL-6 induced by Ni in A549 cells.
TLR4↓, Chrysin suppressed TLR4 and Myd88 mRNA and protein expression.
NOTCH1↑, Chrysin inhibited tumor growth in ATC both in vitro and in vivo through inducing Notch1
PARP↑, Pretreating cells with chrysin increased cleaved PARP, cleaved caspase-3, and declined cyclin D1, Mcl-1, and XIAP.
Mcl-1↓,
XIAP↓,

2786- CHr,    Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives
- Review, Var, NA
Apoptosis↑, chrysin inhibits cancer growth through induction of apoptosis, alteration of cell cycle and inhibition of angiogenesis, invasion and metastasis without causing any toxicity and undesirable side effects to normal cells
TumCCA↑,
angioG↓,
TumCI↓,
TumMeta↑,
*toxicity↓,
selectivity↑,
chemoP↑, Induction of phase II detoxification enzymes, such as glutathione S-transferase (GST) or NAD(P)H:quinone oxidoreductase (QR) is one of the major mechanism of protection against initiation of carcinogenesis
*GSTs↑,
*NADPH↑,
*GSH↑, upregulation of antioxidant and carcinogen detoxification enzymes (glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), GST and QR)
HDAC8↓, inhibits of HDAC8 enzymatic activity
Hif1a↓, Prostate DU145: Inhibits HIF-1a expression through Akt signaling and abrogation of VEGF expression
*ROS↓, chrysin (20 and 40 mg/kg) was shown to exhibit chemopreventive activity by ameliorating oxidative stress and inflammation via NF-kB pathway
*NF-kB↓,
SCF↓, Chrysin has also been reported to have the ability to abolish the stem cell factor (SCF)/c-Kit signaling in human myeloid leukemia cells by preventing the PI3 K pathway
cl‑PARP↑, (PARP) and caspase-3 and concurrently decreasing pro-survival proteins survivin and XIAP
survivin↓,
XIAP↓,
Casp3↑, activation of caspase-3 and -9.
Casp9↑,
GSH↓, chrysin sustains a significant depletion of intracellular GSH concentrations in human NSCLC cells
ChemoSen↑, chrysin potentiates cisplatin toxicity, in part, via synergizing pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and by depleting cellular GSH, an important antioxidant defense
Fenton↑, ability to participate in a fenton type chemical reaction
P21↑, upregulation of p21 independent of p53 status and decrease in cyclin D1, CDK2 protein levels
P53↑,
cycD1↓,
CDK2↓,
STAT3↓, chrysin inhibits angiogenesis through inhibition of STAT3 and VEGF release mediated by hypoxia through Akt signaling pathway
VEGF↓,
Akt↓,
NRF2↓, Chrysin treatment significantly reduced nrf2 expression in cells at both the mRNA and protein levels through down-regulation of PI3K-Akt and ERK pathways.

2591- CHr,  doxoR,    Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway
- in-vitro, HCC, Bel-7402
NRF2↓, chrysin is a potent Nrf2 inhibitor which sensitizes BEL-7402/ADM cells to ADM
ChemoSen↑, chrysin may be an effective adjuvant sensitizer to reduce anticancer drug resistance by down-regulating Nrf2 signaling pathway.
HO-1↓, Consequently, expression of Nrf2-downstream genes HO-1, AKR1B10, and MRP5 were reduced

2590- CHr,    Chrysin suppresses proliferation, migration, and invasion in glioblastoma cell lines via mediating the ERK/Nrf2 signaling pathway
- in-vitro, GBM, T98G - in-vitro, GBM, U251 - in-vitro, GBM, U87MG
TumCP↓, Chrysin inhibited the proliferation, migration, and invasion capacity of glioblastoma cells in dose- and time-dependent manners.
TumCMig↓,
TumCI↓,
NRF2↓, chrysin deactivated the Nrf2 signaling pathway by decreasing the translocation of Nrf2 into the nucleus
HO-1↓, suppressing the expression of hemeoxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1
NADPH↓,
ERK↓, Chrysin treatment downregulates the Nrf2 pathway via inhibition of ERK signaling

1510- CUR,  Chemo,    Combination therapy in combating cancer
- Review, NA, NA
*NRF2↑, Curcuminoids are linear diarylheptanoids that upregulate Nrf2 expression and induce Nrf2 translocation to the nucleus to elicit its antioxidant effects
*GSH↑, curcuminoids upregulate glutathione levels which have been shown to reduce ROS levels and remove carcinogens, aiding in chemoprevention
*ROS↓,
ChemoSideEff↓, aiding in chemoprevention
eff↑, Curcuminoids in combination with chemotherapy have demonstrated an overall positive outcome, and have also shown to increase the survival rate in some patients
OS↓, shown to increase the survival rate in some patients
chemoP↑, have been shown to reduce ROS levels and remove carcinogens, aiding in chemoprevention

1485- CUR,  Chemo,  Rad,    Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs
- Review, Var, NA
ChemoSen↑, Such effects of curcumin were due to its ability to sensitize cancer cells for increased production of ROS
NF-kB↓, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-κB, STAT3, COX2, Akt
*STAT3↓, curcumin acts as a chemosensitizer and radiosensitizer has also been studied extensively. For example, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-kB, STAT3, COX2, Akt,
*COX2↓,
*Akt↓,
*NRF2↑, The protective effects of curcumin appear to be mediated through its ability to induce the activation of NRF2 and induce the expression of antioxidant enzymes (e.g., hemeoxygenase-1, glutathione peroxidase
*HO-1↑,
*GPx↑,
*NADPH↑,
*GSH↑, increase glutathione (a product of the modulatory subunit of gamma-glutamyl-cysteine ligase)
*ROS↓, dietary curcumin can inhibit chemotherapy-induced apoptosis via inhibition of ROS generation and blocking JNK signaling
*p300↓, inhibit p300 HAT activity
radioP↑, radioprotector for normal organs
chemoP↑, curcumin has also been shown to protect normal organs such as liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity.
RadioS↑,

1410- CUR,    Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway
- vitro+vivo, OS, MG63
tumCV↓,
Apoptosis↑,
TumCG↓,
NRF2↓, after treatment with curcumin, Nrf2 and GPX4 levels were significantly decreased
GPx4↓,
HO-1↓,
xCT↓, SLC7A11
ROS↑, our results revealed that after treatment with curcumin, ROS and MDA levels were significantly increased while GSH levels were decreased
MDA↑,
GSH↓,

2819- CUR,  Chemo,    Curcumin as a hepatoprotective agent against chemotherapy-induced liver injury
- Review, Var, NA
*hepatoP↑, Several studies have shown that curcumin could prevent and/or palliate chemotherapy-induced liver injury
*Inflam↓, mainly due to its anti-inflammatory, antioxidant, antifibrotic and hypolipidemic properties.
*antiOx↓,
*lipid-P↓, Curcumin can lower lipid peroxidation by increasing the content of GSH, a major endogenous antioxidant,
*GSH↑,
*SOD↑, as well as by enhancing the activity of endogenous antioxidant enzymes, such as SOD, CAT, GPx and GST
*Catalase↑,
*GPx↑,
*GSTs↑,
*ROS↓, elimination of ROS
*ALAT↓, attenuated the increase in serum levels of TNF-α as well as several liver enzymes, including ALT, AST, alkaline phosphatase and MDA which are markers of liver damage caused by MTX or cisplatin.
*AST↓,
*MDA↓,
*NRF2↑, Curcumin also attenuated DILI through activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway
*COX2↑, Curcumin can also inhibit the expression of cyclooxygenase-2 (COX-2)
*NF-kB↓, NF-κB inhibition, which decreased the downstream induction of COX-2, ICAM-1 and MCP-1 pro-inflammatory regulators
*ICAM-1↓,
*MCP1↓,
*HO-1↑, increase in HO-1 and NQO1 expression
CXCc↓, Downregulation of pro-inflammatory chemokines, (CXCL1, CXCL2, and MCP-1)

2818- CUR,    Novel Insight to Neuroprotective Potential of Curcumin: A Mechanistic Review of Possible Involvement of Mitochondrial Biogenesis and PI3/Akt/ GSK3 or PI3/Akt/CREB/BDNF Signaling Pathways
- Review, AD, NA
*neuroP↑, Curcumin's protective functions against neural cell degeneration due to mitochondrial dysfunction and consequent events such as oxidative stress, inflammation, and apoptosis in neural cells have been documented
*ROS↓, studies show that curcumin exerts neuroprotective effects on oxidative stress.
*Inflam↓,
*Apoptosis↓,
*cognitive↑, cognitive performance to receive the title of neuroprotective
*cardioP↑, Studies have shown that curcumin can induce cell regeneration and defense in multiple organs such as the brain, cardiovascular system,
other↑, It has been shown that chronic use of curcumin in patients with neurodegenerative disorder can cause gray matter volume increase
*COX2↓, Curcumin also decreased the brain protein levels and activity of cyclooxygenase 2 (COX-2)
*IL1β↓, inhibition of IL-1β and TNF-α production, and enhancement of Nf-Kβ inhibition
*TNF-α↓,
NF-kB↓,
*PGE2↓, hronic curcumin therapy has shown a significant decrease in lipopolysaccharide (LPS)-induced elevation of brain prostaglandin E2 (PGE2) synthesis in rats
*iNOS↓, curcumin pretreatment decreased NOS activity in the ischemic rat model
*NO↓, curcumin has been shown to decrease NOS expression and NO production in rat brain tissue
*IL2↓, IL-2 is a cytokine that is anti-inflammatory. Numerous studies have shown that curcumin increases the secretion of IL-2
*IL4↓, curcumin reduced levels of IL-4
*IL6↓, Numerous studies have shown that curcumin in neurodegenerative events attenuates IL-6 production
*INF-γ↓, curcumin reduced the production of INF-γ, as pro-inflammatory cytokine
*GSK‐3β↓, Furthermore, previous findings have confirmed that inhibition of GSK-3β or CREB activation by curcumin has reduced the production of pro-inflammatory mediators under different conditions
*STAT↓, Inhibition of GSK-3β by curcumin has been found to result in reduced STAT activation
*GSH↑, chronic curcumin therapy increased glutathione levels in primary cultivated rat cerebral cortical cells
*MDA↓, multiple doses of 5, 10, 40 and 60 mg/kg) in rodents will inhibit neurodegenerative agent malicious effects, and reduce the amount of MDA and lipid peroxidation in brain tissue
*lipid-P↓,
*SOD↑, Curcumin induces increased production of SOD, glutathione peroxidase (GPx), CAT, and glutathione reductase (GR) activating antioxidant defenses
*GPx↑,
*Catalase↑,
*GSR↓,
*LDH↓, Curcumin decreased lactate dehydrogenase, lipoid peroxidation, ROS, H2O2 and inhibited Caspase 3 and 9
*H2O2↓,
*Casp3↓,
*Casp9↓,
*NRF2↑, ncreased mitochondrial uncoupling protein 2 and increased mitochondrial biogenesis. Nuclear factor-erythroid 2-related factor 2 (Nrf2)
*AIF↓, Curcumin treatment decreased the number of AIF positive nuclei 24 h after treatment in the hippocampus,
*ATP↑, curcumin in hippocampal cells induced an increase in mitochondrial mass leading to increased production of ATP with major improvements in mitochondrial efficiency

3576- CUR,    Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease
- Review, AD, NA
*Inflam↓, known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions.
*antiOx↑,
*memory↑,
*Aβ↓, curcumin prevents Aβ aggregation and crosses the blood-brain barrier,
*BBB↑,
*cognitive↑, curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD
*tau↓, curcumin's effect on inhibition of A and tau,copper binding ability, cholesterol lowering ability, anti-inflammatory and modulation of microglia, acetylcholinesterase (AChE) inhibition, antioxidant properties,
*LDL↓,
*AChE↓,
*IL1β↓, Curcumin reduced the levels of oxidized proteins and IL1B in the brains of APP mice
*IronCh↑, Curcumin binds to redox-active metals, iron and copper
*neuroP↑, Curcumin, a neuroprotective agent, has poor brain bioavailability.
*BioAv↝,
*PI3K↑, They found that curcumin significantly upregulates phosphatidylinositol 3-kinase (PI3K), Akt, nuclear factor E2-related factor-2 (Nrf2), heme oxygenase 1, and ferritin expression
*Akt↑,
*NRF2↑,
*HO-1↑,
*Ferritin↑,
*HO-2↓, and that it significantly downregulates heme oxygenase 2, ROS, and A40/42 expression.
*ROS↓,
*Ach↑, significant increase in brain ACh, glutathione, paraoxenase, and BCL2 levels with respect to untreated group associated with significant decrease in brain AChE activity,
*GSH↑,
*Bcl-2↑,
*ChAT↑, nvestigation revealed that the selected treatments caused marked increase in ChAT positive cells.

2821- CUR,    Antioxidant curcumin induces oxidative stress to kill tumor cells (Review)
- Review, Var, NA
*antiOx↑, Curcumin is a plant polyphenol in turmeric root and a potent antioxidant
*NRF2↑, regulation by nuclear factor erythroid 2-related factor 2, thereby suppressing reactive oxygen species (ROS) and exerting anti-inflammatory, anti-infective and other pharmacological effects
*ROS↓,
*Inflam↓,
ROS↑, Of note, curcumin induces oxidative stress in tumors. curcumin-induced accumulation of ROS in tumors to kill tumor cells has been noted in several studies
p‑ERK↑, Curcumin promoted ERK/JNK phosphorylation, causing elevated ROS levels and triggering mitochondria-dependent apoptosis
ER Stress↑, Curcumin triggered disturbances in Ca2+ homeostasis, leading to endoplasmic reticulum stress, mitochondrial damage and apoptosis
mtDam↑,
Apoptosis↑,
Akt↓, Curcumin inhibited the AKT/mTOR/p70S6K signaling pathway
mTOR↓,
HO-1↑, Curcumin-induced HO-1 overexpression led to a disturbed intracellular iron distribution and triggered the Fenton reaction
Fenton↑,
GSH↓, Non-small cell lung cancer: Curcumin induced a decrease in GSH and an increase in ROS levels and iron accumulation
Iron↑,
p‑JNK↑, Curcumin causes mitochondrial damage by promoting phosphorylation of ERK and JNK, resulting in the increased release of ROS and cytochrome c into the cytoplasm, thereby triggering a mitochondrion-dependent pathway of apoptosis
Cyt‑c↑,
ATF6↑, thyroid cancer with curcumin, both activating transcription factor (ATF) 6 and the ER stress marker C/EBP homologous protein (CHOP) were activated by curcumin and Ca2+-ATPase activity was also affected.
CHOP↑,

13- CUR,    Role of curcumin in regulating p53 in breast cancer: an overview of the mechanism of action
- Review, BC, NA
P53↑, upregulated other targets including p53, death receptor (DR-5), JN-kinase, Nrf-2, and peroxisome proliferator-activated receptor γ (PPARγ) factors
DR5↑,
JNK↑,
NRF2↑,
PPARγ↑,
HER2/EBBR2↓, (Her-2, IR, ER-a, and Fas receptor)
IR↓,
ER(estro)↓,
Fas↑,
PDGF↓, (PDGF, TGF, FGF, and EGF)
TGF-β↓,
FGF↓,
EGFR↓,
JAK↓,
PAK↓,
MAPK↓,
ATPase↓, (ATPase, COX-2, and matrix metalloproteinase enzyme [MMP])
COX2↓,
MMPs↓,
IL1↓, inflammatory cytokines (IL-1, IL-2, IL-5, IL-6, IL-8, IL-12, and IL-18)
IL2↓,
IL5↓,
IL6↓,
IL8↓,
IL12↓,
IL18↓,
NF-kB↓,
NOTCH1↓,
STAT1↓,
STAT4↓,
STAT5↓,
STAT3↓,

15- CUR,  UA,    Effects of curcumin and ursolic acid in prostate cancer: A systematic review
NF-kB↝,
Akt↝,
AR↝,
Apoptosis↝,
Bcl-2↝,
Casp3↝,
BAX↝,
P21↝,
ROS↝,
Apoptosis↝,
Bcl-xL↝,
JNK↝,
MMP2↝,
P53↝,
PSA↝,
VEGF↝,
COX2↝,
cycD1↝,
EGFR↝,
IL6↝,
β-catenin/ZEB1↝,
mTOR↝,
NRF2↝,
p‑Akt↝,
AP-1↝,
Cyt‑c↝,
PI3K↝,
PTEN↝,
Cyc↝,
TNF-α↝,

414- CUR,    Transcriptome Investigation and In Vitro Verification of Curcumin-Induced HO-1 as a Feature of Ferroptosis in Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
Ferroptosis↑,
Iron↑,
ROS↑,
lipid-P↑,
MDA↑,
GSH↓,
HO-1↑, Curcumin upregulates a variety of ferroptosis target genes related to redox regulation, especially heme oxygenase-1 (HO-1).
NRF2↑,
GPx↓,
ROS↑,
Iron↑, curcumin caused marked accumulation of intracellular iron
GPx4↓,
HSP70/HSPA5↑,
ATFs↑, ATF4
CHOP↑, DDIT3
MDA↑,
FTL↑, Curcumin upregulated FTL (encoding ferritin light chain), FTH1
FTH1↑,
BACH1↑,
REL↑, v-rel reticuloendotheliosis viral oncogene homolog A
USF1↑,
NFE2L2↑,

410- CUR,    Nrf2 depletion enhanced curcumin therapy effect in gastric cancer by inducing the excessive accumulation of ROS
- vitro+vivo, GC, AGS - vitro+vivo, GC, HGC27
ROS↑,
NRF2↑, add knockdown of NRF2 enchances CUR efficacy

405- CUR,  5-FU,    Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis
- vitro+vivo, CRC, HCT116
Apoptosis↑, more pronounced increase in apoptosis in p53-deficient when compared to p53-proficient cells
TumCMig↓,
NRF2↑,
ROS↑, antioxidant N-acetylcysteine suppressed the induction of apoptosis by curcumin
MET↓,
NA↑,

1844- dietFMD,    Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment
- Review, NA, NA
Risk↓, CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients.
AMPK↑, the increased AMP levels activate AMPK
Akt↓, This activation results in the inhibition of AKT and mTOR pathways
mTOR↓,
SIRT1↑, energy deficit also activates the SIRT pathways, which downregulates HIF1α, and the Nrf2 pathway
Hif1a↓,
NRF2↓,
SOD↑, enhances antioxidant defenses (e.g., superoxide dismutase SOD1 and SOD2)
ROS↑, Additionally, in prostate cancer (PC) [55] and triple-negative breast cancer (TNBC) [56] cell lines glucose restriction (GR) has been shown to trigger an increase in ROS, leading to cell death.
IGF-1↓, CR decreases poor prognosis markers such as IGF1, pAKT, and PI3K
p‑Akt↓,
PI3K↑,
GutMicro↑, induces changes in the gut microbiome linked to anti-tumor effects
OS↑, Incorporating a nutraceutical regimen like CR or KD with CT has reduced tumor growth and relapse and improved the survival rate
eff↝, type of dietary intervention, with FMD being the first option, followed by KD and CR last. FMD has been considered the most cost-effective and applicable because it does not completely restrict food intake.
ROS↑, findings consistently indicating that dietary restrictions render highly proliferative tumor cells more susceptible to oxidative damage
TumCCA↑, CR has been reported to induce cell cycle arrest in the G0/G1 phases , enabling cells to undergo DNA repair more efficiently and diminishing DNA damage by CRT
*DNArepair↑,
DNAdam↑, In contrast, tumoral cells, which have an altered cell cycle, are unable to repair DNA, leading to cell death

2272- dietMet,    Methionine restriction - Association with redox homeostasis and implications on aging and diseases
- Review, Nor, NA
*OS↑, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models
*mt-ROS↓, Mitochondrial ROS reduction by methionine restriction (MR) maintains redox balance
*H2S↑, MR ameliorates oxidative stress by autophagy activation and hepatic H2S generation.
*FGF21↑, MR impact on cognition by upregulation of FGF21 and alterations of gut microbiome.
*cognitive↑,
*GutMicro↑,
*IGF-1↓, long-term, low-fat, whole-food vegan diet may increase life expectancy in humans by down-regulating IGF-I activity
*mTOR↓, Suppression of the mTOR pathway by MR can also lead to increased H2S production,
*GSH↑, 80% MR increases the GSH content in erythrocytes of rats,
*SOD↑, A diet restricting methionine to 80% (0.17% Met) significantly increases plasma SOD and decreases MDA levels while increasing mRNA expression of Nrf2, HO-1, and NQO-1 in the heart of HFD-fed mice with cardiovascular impairment
*MDA↓,
*NRF2↑,
*HO-1↑,
*NQO1↑,
*GLUT4↑, In skeletal muscle, MR improved expression and transport of GLUT4 and glycogen levels and increased the expression of glycolysis-related genes (HK2, PFK, PKM) in HFD-fed mice
*Glycolysis↑,
*HK2↑,
*PFK↑,
*PKM2↑,
*GlucoseCon↑, promoting glucose uptake and glycogen synthesis, glycolysis, and aerobic oxidation in skeletal muscle.
*ATF4↑, MR can increase the expression of hepatic FGF21 by activating GCN2/ATF4/PPARα signaling in liver cells, thereby improving insulin sensitivity, accelerating energy expenditure, and promoting fat oxidation and glucose metabolism
*PPARα↑,
GSH↓, MR was able to decrease GSH in HepG2 cells, thereby regulating the activation state of protein tyrosine phosphatases such as PTEN.
GSTs↑, decrease of GSH by MR also triggers upregulation of glutathione S-transferase
ROS↑, Double deprivation of methionine and cystine both in vitro and in vivo resulted in a decrease in GSH content, an increase in ROS levels, and an induction of autophagy in glioma cells
*neuroP↑, A neuroprotective role of FGF21

20- EGCG,    Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the Most Abundant Catechin in Green Tea, and Its Role in the Therapy of Various Types of Cancer
- in-vivo, Liver, NA - in-vivo, Tong, NA
HH↓,
Gli1↓,
Smo↓,
TNF-α↓,
COX2↓, EGCG inhibits cyclooxygenase-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3
*antiOx↑, EGCG is a well-known antioxidant and it scavenges most free radicals, such as ROS and RNS
Hif1a↓,
NF-kB↓,
VEGF↓,
STAT3↓,
Bcl-2↓,
P53↑, EGCG activates p53 in human prostate cancer cells
Akt↓,
p‑Akt↓,
p‑mTOR↓,
EGFR↓,
AP-1↓,
BAX↑,
ROS↑, apoptosis was convoyed by ROS production and caspase-3 cleavage
Casp3↑,
Apoptosis↑,
NRF2↑, pancreatic cancer cells via inducing cellular reactive oxygen species (ROS) accumulation and activating Nrf2 signaling
*H2O2↓, EGCG plays a role in the inhibition of H2O2 and NO production in human skin [10].
*NO↓, EGCG plays a role in the inhibition of H2O2 and NO production in human skin [10].
*SOD↑, fig 2
*Catalase↑, fig 2
*GPx↑, fig 2
*ROS↓, fig 2

1974- EGCG,    Protective Effect of Epigallocatechin-3-Gallate in Hydrogen Peroxide-Induced Oxidative Damage in Chicken Lymphocytes
- in-vitro, Nor, NA
*ROS↓, suppressed the increase in intracellular reactive oxygen species (ROS), nitric oxide (NO),
*NO↓,
*MMP↑, preincubation of the cells with EGCG increased mitochondrial membrane potential (MMP) and reduced calcium ion ([Ca2+]i) load.
*i-Ca+2↓, EGCC Increased Mitochondrial Membrane Potential and Decreased [Ca2+]i
*HO-1↑, expression of SOD, Heme oxygenase-1 (HO-1), Catalase (CAT), GSH-PX, nuclear factor erythroid 2-related factor 2 (Nrf2), and thioredoxin-1 (Trx-1).
*Catalase↑,
*NRF2↑,
*Trx1↑,
*antiOx↑, EGCC Increased Antioxidant Capacity
*SOD↑, EGCC Decreased ROS and Increased SOD Generation
*Apoptosis↓,

3210- EGCG,    Protective effect of epigallocatechin-3-gallate (EGCG) via Nrf2 pathway against oxalate-induced epithelial mesenchymal transition (EMT) of renal tubular cells
- in-vitro, Nor, NA
*ROS↓, reduced production of intracellular ROS through activation of Nrf2 signaling and increased catalase anti-oxidant enzyme.
*NRF2↓,
*Catalase↑,
*antiOx↑,

3209- EGCG,    Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1
- in-vitro, Diabetic, NA
*NRF2↑, EGCG is known as a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2),

3201- EGCG,    Epigallocatechin Gallate (EGCG): Pharmacological Properties, Biological Activities and Therapeutic Potential
- Review, NA, NA
*AntiCan↑, EGCG’s therapeutic potential in preventing and managing a range of chronic conditions, including cancer, cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes
*cardioP↑,
*neuroP↑,
*BioAv↝, Factors such as fasting, storage conditions, albumin levels, vitamin C, fish oil, and piperine have been shown to affect plasma concentrations and the overall bioavailability of EGCG
*BioAv↓, Conversely, bioavailability is reduced by processes such as air oxidation, sulfation, glucuronidation, gastrointestinal degradation, and interactions with Ca2+, Mg2+, and trace metals,
*BioAv↓, EGCG’s oral bioavailability is generally low, with marked differences observed across species, for example, bioavailability rates of 26.5% in CF-1 mice and just 1.6% in Sprague Dawley rats
*Dose↝, plasma concentrations exceeded 1 μM only when doses of 1 g or higher were administered.
*Half-Life↝, Specifically, a dose of 1600 mg yielded a Cmax of 3392 ng/mL (range: 130–3392 ng/mL), with peak levels observed between 1.3 and 2.2 h, AUC (0–∞) values ranging from 442 to 10,368 ng·h/mL, and a half-life (t1/2z) of 1.9 to 4.6 h.
*BioAv↑, Studies on the distribution of EGCG have revealed that, despite its limited absorption, it is rapidly disseminated throughout the body or quickly converted into metabolites
*BBB↑, Additionally, EGCG can cross the blood–brain barrier, allowing it to reach the brain
*hepatoP↓, Several studies have documented liver damage linked to green tea consumption [48,49,50,51,52,53].
*other↓, EGCG has also been shown to inhibit the intestinal absorption of non-heme iron in a dose-dependent manner in a controlled clinical trial
*Inflam↓, EGCG has been widely recognized for its anti-inflammatory effects
*NF-kB↓, EGCG has been shown to suppress NF-κB activation, inhibit its nuclear translocation, and block AP-1 activity
*AP-1↓,
*iNOS↓, downregulation of pro-inflammatory enzymes like iNOS and COX-2 and scavenging of ROS/RNS, including nitric oxide and peroxynitrite
*COX2↓,
*ROS↓,
*RNS↓,
*IL8↓, EGCG has been shown to suppress airway inflammation by reducing IL-8 release, a cytokine involved in neutrophil aggregation and ROS production.
*JAK↓, EGCG blocks the JAK1/2 signaling pathway
*PDGFR-BB↓, downregulate PDGFR and IGF-1R gene expression
*IGF-1R↓,
*MMP2↓, reduce MMP-2 mRNA expression
*P53↓, downregulation of the p53-p21 signaling pathway and the enhanced expression of Nrf2
*NRF2↑,
*TNF-α↓, 25 to 100 μM reduced the levels of TNF-α, IL-6, and ROS while enhancing the expression of E2F2 and superoxide dismutases (SOD1 and SOD2), enzymes vital for cellular antioxidant defense.
*IL6↓,
*E2Fs↑,
*SOD1↑,
*SOD2↑,
Casp3↑, EGCG has been shown to activate key apoptotic pathways, such as caspase-3 activation, cytochrome c release, and PARP cleavage, in various cell models, including PC12 cells exposed to oxidative stress
Cyt‑c↑,
PARP↑,
DNMTs↓, (1) the inhibition of DNA hypermethylation by blocking DNA methyltransferase (DNMT)
Telomerase↓, (2) the repression of telomerase activity;
Hif1a↓, (3) the suppression of angiogenesis via the inhibition of HIF-1α and NF-κB;
MMPs↓, (4) the prevention of cellular metastasis by inhibiting matrix metalloproteinases (MMPs);
BAX↑, (5) the promotion of apoptosis through the activation of pro-apoptotic proteins like BAX and BAK
Bak↑,
Bcl-2↓, while downregulating anti-apoptotic proteins like BCL-2 and BCL-XL;
Bcl-xL↓,
P53↑, (6) the upregulation of tumor suppressor genes such as p53 and PTEN;
PTEN↑,
TumCP↓, (7) the inhibition of inflammation and proliferation via NF-κB suppression;
MAPK↓, (8) anti-proliferative activity through the modulation of MAPK and IGF1R pathways
HGF/c-Met↓, EGCG inhibits hepatocyte growth factor (HGF), which is involved in tumor migration and invasion
TIMP1↑, EGCG has also been shown to influence the expression of tissue inhibitors of metalloproteinases (TIMPs) and MMPs, which are involved in tumorigenesis
HDAC↓, nhibition of UVB-induced DNA hypomethylation and modulation of DNMT and histone deacetylase (HDAC) activities
MMP9↓, inhibiting MMPs such as MMP-2 and MMP-9
uPA↓, EGCG may block urokinase-like plasminogen activator (uPA), a protease involved in cancer progression
GlutMet↓, EGCG can exert antitumor effects by inhibiting glycolytic enzymes, reducing glucose metabolism, and further suppressing cancer-cell growth
ChemoSen↑, EGCG’s combination with standard chemotherapy drugs may enhance their efficacy through additive or synergistic effects, while also mitigating chemotherapy-related side effects
chemoP↑,

3211- EGCG,    Antioxidation Function of EGCG by Activating Nrf2/HO-1 Pathway in Mice with Coronary Heart Disease
- in-vivo, NA, NA
*cardioP↑, EGCG significantly attenuated myocardial injuries and improved blood lipid levels in mice in a concentration-dependent manner.
*VEGF↓, EGCG significantly decreased the expression of VEGFA and MMP-2 and increased the activity of superoxide dismutase (SOD), when reducing the content of reactive oxygen species (ROS) in the myocardial tissue
*MMP2↓,
*SOD↑,
*ROS↓,
*HO-1↑, and upregulating the expression of HO-1, NQO1, and Nrf2.
*NQO1↑,
*NRF2↑,

3212- EGCG,    EGCG maintained Nrf2-mediated redox homeostasis and minimized etoposide resistance in lung cancer cells
- in-vitro, Lung, A549 - in-vivo, Lung, NCIH23
NRF2⇅, In A549, EGCG downregulated nuclear Nrf2 by upregulating the nuclear localization of Keap1 whereas in NCIH23, EGCG augmented Nrf2 by reducing Keap1.
eff↑, Though the direction of Nrf2 regulation was opposite in two cell lines, optimum level of Nrf2 was maintained which increased responsiveness towards etoposide. EGCG sensitized/potentiated lung adenocarcinoma cells towards chemotherapy by inducing G2/
SOD1↑, n NCIH23, the downstream targets of Nrf2, NQO1 and MRP1 did not show any significant alteration in expression with respect to control, with an exception of SOD1(upregulated by 1.28 times)
SOD1↓, EGCG showed exactly opposite effect in A549. It again effectively fitted in a U-shaped hormetic downregulation for all three downstream targets. EGCG (0.5 μM/12 h) most effectively downregulated SOD-1, NQO1 and MRP1expression
MMP2⇅, However, EGCG (0.5 μM) itself increased the activity of MMP-2 and MMP-9. The lowest dose of EGCG required to inhibit MMP-2 and MMP-9 was reported, 8–13 μM in different cancer cell lines
MMP9⇅,

3213- EGCG,  Rad,    Epigallocatechin-3-gallate Enhances Radiation Sensitivity in Colorectal Cancer Cells Through Nrf2 Activation and Autophagy
- in-vitro, CRC, HCT116
RadioS↑, Combination treatment with EGCG and radiation significantly decreased the growth of HCT-116 cells.
TumCP↓, EGCG increased the sensitivity of colorectal cancer cells to radiation by inhibiting cell proliferation and inducing Nrf2 nuclear translocation and autophagy.
NRF2↑,

3214- EGCG,    EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway
- in-vitro, Nor, MRC-5 - in-vitro, Cerv, HeLa - in-vitro, Nor, HEK293 - in-vitro, BC, MDA-MB-231 - in-vitro, CRC, HCT116
mTOR↓, In contrast, EGCG treatment in HeLa cells led to AMPK-induced mTOR inactivation
AMPK↑, via AMPK activation,
selectivity↑, EGCG was previously reported to differentially induce ROS production in normal and cancer cells, resulting in the preferential perturbation of the redox homeostasis of cancer cells via increased ROS levels, especially H2O2, in cancer cells
ROS↑,
selectivity↑, EGCG-induced selective death of cancer cells is accomplished by the positive and negative regulation of the p62-KEAP1-NRF2-HO-1 antioxidant survival pathway between normal cells and cancer cells, respectively,
HO-1↓, HO-1 expression decreased significantly with increasing EGCG concentration in all six different cancer cells
*NRF2↑, According to our findings, EGCG increased the protein level of NRF2 in normal cells but decreased them in cancer cells even though its mRNA levels were more or less equal in both cell types
NRF2↓,
*HO-1↑, upregulates HO-1 through the prolonged stability of NRF2 in MRC5 cells, whereas it downregulates HO-1 through the increased degradation of NRF2 by ubiquitination in HeLa and HCT116 cells.

3215- EGCG,    Epigallocatechin gallate modulates ferroptosis through downregulation of tsRNA-13502 in non-small cell lung cancer
- in-vitro, NSCLC, A549 - in-vitro, NSCLC, H1299
TumCP↓, EGCG resulted in a notable suppression of cell proliferation, as evidenced by a reduction in Ki67 immunofluorescence staining
Ki-67↓,
GPx4↓, EGCG treatment led to a decrease in the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) while increasing the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4).
ACSL4↑,
Iron↑, accompanied by an increase in intracellular iron, malondialdehyde (MDA), and reactive oxygen species (ROS), alongside ultrastructural alterations characteristic of ferroptosis.
MDA↑,
ROS↑,
Ferroptosis↑,
eff↑, The cooperative effect of metformin and EGCG-activated Nrf2/HO-1 signaling pathway, facilitated by SIRT1-mediated Nrf2 deacetylation, enhances the susceptibility of NSCLC to EGCG modulation by promoting reactive oxygen species (ROS) generation and a
NRF2↑,
HO-1↑,

3216- EGCG,    Epigallocatechin-3-gallate suppresses hemin-aggravated colon carcinogenesis through Nrf2-inhibited mitochondrial reactive oxygen species accumulation
- NA, Colon, Caco-2
NRF2↑, EGCG enhanced hemin-induced Nrf2 and antioxidant gene expression
TumCP↓, EGCG reduced hemin-induced proliferation and colon carcinogenesis through Nrf2-inhibited mitochondrial ROS accumulation.
mt-ROS↓,
Keap1↓, We found that hemin treatment increased Nrf2 expression, but decreased Keap1 expression in a time-dependent manner

3217- EGCG,    Epigallocatechin-3-gallate promotes angiogenesis via up-regulation of Nfr2 signaling pathway in a mouse model of ischemic stroke
- in-vivo, Stroke, NA
*angioG↑, angiogenic and neuroprotective effects of EGCG
*neuroG↑,
*NRF2↑, via upregulation of Nrf2 signaling pathway.

3219- EGCG,    Nano-chemotherapeutic efficacy of (−) -epigallocatechin 3-gallate mediating apoptosis in A549 cells: Involvement of reactive oxygen species mediated Nrf2/Keap1signaling
- in-vitro, Lung, A549
ROS↑, Nano EGCG exhibited increased ROS/RNS levels and decreased mitochondrial membrane potential
RNS↓,
MMP↓,
NRF2↑, EGCG exhibited an increased expression of Nrf2 and Keap1 that could regulate apoptosis in A549 cells.
Keap1↓,

3220- EGCG,    Dual Roles of Nrf2 in Cancer
- in-vitro, Lung, A549
NRF2↑, Examples of potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany
eff↓, A549 is more resistant to cisplatin and EGCG induced cell death than any other lung cancer cell line. This was contributed to the high expression of Nrf2 and HMOX-1

3221- EGCG,    EGCG upregulates phase-2 detoxifying and antioxidant enzymes via the Nrf2 signaling pathway in human breast epithelial cells
- in-vitro, Nor, MCF10
*antiOx↑, EGCG upregulated the expression of other antioxidant enzymes, including manganese superoxide dismutase and glutathione S-transferase π in a concentration- and time-dependent manner.
*GSTA1↑,
*NRF2↑, The nuclear accumulation and ARE/EpRE binding of Nrf2 were increased in EGCG-treated MCF10A cells

2845- FIS,    Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
- Review, Var, NA
PI3K↓, block multiple signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38
Akt↓,
mTOR↓,
p38↓,
*antiOx↑, antioxidant, anti-inflammatory, antiangiogenic, hypolipidemic, neuroprotective, and antitumor effect
*neuroP↑,
Casp3↑, U266 cancer cell line through activation of caspase-3, downregulation of Bcl-2 and Mcl-1L, upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, activation of 5'adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and decreased phosphorylation of AKT and mTOR were also observed
ACC↑,
DNAdam↑, DNA fragmentation, mitochondrial membrane depolarizatio
MMP↓,
eff↑, fisetin in combination with a citrus flavanone, hesperetin mediated apoptosis by mitochondrial membrane depolarization and caspase-3 act
ROS↑, NCI-H460 human non-small cell lung cancer line, fisetin generated reactive oxygen species (ROS), endoplasmic reticulum (ER) stress
cl‑PARP↑, fisetin treatment resulted in PARP cleavage
Cyt‑c↑, release of cyt. c
Diablo↑, release of cyt. c and Smac/DIABLO from mitochondria,
P53↑, increased p53 protein levels
p65↓, reduced phospho-p65 and Myc oncogene expression
Myc↓,
HSP70/HSPA5↓, fisetin causes inhibition of proliferation by the modulation of heat shock protein 70 (HSP70), HSP27
HSP27↓,
COX2↓, anti-proliferative effects of fisetin through the activation of apoptosis via inhibition of cyclooxygenase-2 (COX-2) and Wnt/EGFR/NF-κB signaling pathways
Wnt↓,
EGFR↓,
NF-kB↓,
TumCCA↑, The anti-proliferative effects of fisetin and hesperetin were shown to be occurred through S, G2/M, and G0/G1 phase arrest in K562 cell progression
CDK2↓, decrease in levels of cyclin D1, cyclin A, Cdk-4 and Cdk-2
CDK4↓,
cycD1↓,
cycA1↓,
P21↑, increase in p21 CIP1/WAF1 levels in HT-29 human colon cancer cell
MMP2↓, fisetin has exhibited tumor inhibitory effects by blocking matrix metalloproteinase-2 (MMP- 2) and MMP-9 at mRNA and protein levels,
MMP9↓,
TumMeta↓, Antimetastasis
MMP1↓, fisetin also inhibited the MMP-14, MMP-1, MMP-3, MMP-7, and MMP-9
MMP3↓,
MMP7↓,
MET↓, promotion of mesenchymal to epithelial transition associated with a decrease in mesenchymal markers i.e. N-cadherin, vimentin, snail and fibronectin and an increase in epithelial markers i.e. E-cadherin
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↑,
uPA↓, fisetin suppressed the expression and activity of urokinase plasminogen activator (uPA)
ChemoSen↑, combination treatment of fisetin and sorafenib reduced the migration and invasion of BRAF-mutated melanoma cells both in in-vitro
EMT↓, inhibited epithelial to mesenchymal transition (EMT) as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin
Twist↓, inhibited expression of Snail1, Twist1, Slug, ZEB1 and MMP-2 and MMP-9
Zeb1↓,
cFos↓, significant decrease in NF-κB, c-Fos, and c-Jun levels
cJun↓,
EGF↓, Fisetin inhibited epidermal growth factor (EGF)
angioG↓, Antiangiogenesis
VEGF↓, decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF, EGFR, COX-2
eNOS↓,
*NRF2↑, significantly increased nuclear translocation of Nrf2 and antioxidant response element (ARE) luciferase activity, leading to upregulation of HO-1 expression
HO-1↑,
NRF2↓, Fisetin also triggered the suppression of Nrf2
GSTs↓, declined placental type glutathione S-transferase (GST-p) level in the liver of the fisetin- treated rats with hepatocellular carcinoma (HCC)
ATF4↓, Fisetin also rapidly increased the levels of both Nrf2 and ATF4

2852- FIS,    A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms
- Review, CRC, NA
Risk↓, Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC)
P53↑, increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction
MDM2↓,
COX2↓, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways
Wnt↓,
NF-kB↓,
CDK2↓, regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels
CDK4↓,
p‑RB1↓,
cycE↓,
P21↑,
NRF2↓, Pandey and Trigun revealed that fisetin induces apoptosis in CRC cells by inhibiting autophagy and suppressing Nrf2
ROS↑, Furthermore, fisetin elevated ROS levels and downregulated Nrf2 expression, indicating Nrf2 suppression in fisetin-induced apoptosis in CRC cells.
Casp8↑, fisetin treatment resulted in the upregulation of various molecular pathways, including cleaved caspase-8, Fas ligand, TRAIL, and DR5 levels, in the cancer cells
Fas↑,
TRAIL↑,
DR5↑,
MMP↓, Fisetin also caused mitochondrial membrane depolarization, leading to the release of Smac/DIABLO and cytochrome c
Cyt‑c↑,
selectivity↑, enhanced cellular uptake, and induction of apoptosis in cancer cells
P450↝, Fisetin also affected the activities of cytochrome P450 (CYP450 3A4) and glutathione-S-transferase
GSTs↝,
RadioS↑, fisetin pretreatment heightened the radiosensitivity of p53-mutant HT29 human CRC cells
Inflam↓, Fisetin suppresses inflammation in the colon and CRC
β-catenin/ZEB1↓, fisetin in treating colon cancer, revealing its capability to effectively downregulate β-catenin and COX-2
EGFR↓, fisetin decreased EGFR and NF-κB activation in HT29 cells
TumCCA↑, It induces cell cycle arrest, disrupting the transition from the G1 to the S phase, as well as causing G2/M phase arrest
ChemoSen↑, intervention with fisetin and 5-FU appeared to extend the lifespan of the experimental animals

2858- FIS,    Fisetin inhibits cell migration via inducing HO-1 and reducing MMPs expression in breast cancer cell lines
- in-vitro, BC, 4T1
HO-1↑, fisetin increased HO-1 mRNA and protein expressions
NRF2↑, fisetin also elevated Nrf2 expression in nuclear fraction
MMP2↓, fisetin decreased MMP-2 and MMP-9 enzyme activity and gene expression in both protein and mRNA levels.
MMP9↓,

2861- FIS,    The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
- Review, Nor, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, Fisetin is a flavonoid that exhibits potent antioxidant properties and protects the cells against OS
*ROS↓, The antioxidant properties of this flavonoid diminish oxidative stress, ROS production, neurotoxicity, neuro-inflammation, and neurological disorders.
*neuroP↑,
*NO↑, inhibits NO production.
BioAv↝, oral bioavailability of fisetin was reported 7.8 and 31.7% for oral doses of 100 and 200 mg/kg, respectively
*BBB↑, BBB permeability, fisetin can also affect hippocampal synaptic plasticity indirectly through the peripheral system
*toxicity↑, Furthermore, it did not show signs of toxicity at doses up to 2 g/kg in an acute toxicity study with no toxicity in the histopathological analysis of the heart, lungs, kidneys, liver, stomach, intestines, spleen and reproductive organs
*eff↑, potential benefits against neurological health complications and neurodegenerative diseases like AD, PD. HD, ALS, vascular dementia, schizophrenia, stroke, depression, diabetic neuropathy and traumatic brain injury
*GSH↑, direct antioxidant activity in addition to increasing intracellular antioxidants such as glutathione
*SOD↑, fig 2
*Aβ↓,
*12LOX↓,
*COX2↓,
*Catalase↑, Fisetin treatment prevented behavioral deficits, increased brain antioxidant, superoxide dismutase, catalase, reduced glutathione, and BDNF
*Inflam↓, decreased serum homocysteine, and pro-inflammatory biomarkers (TNF-α, IL-6), lipid peroxidation
*TNF-α↓,
*IL6↑,
*lipid-P↓,
NF-kB↓, suppressed the up-regulation of NF-κB, and IDO-1 genes expression, and decreased the rise of IL-1β levels.
IL1β↓,
NRF2↑, fisetin treatment also restored the downregulation of Nrf-2, HO-1, and ChAT genes expression and BDNF levels in the hippocampus, suggesting its protective effect against oxidative stress
HO-1↑,
GSTs↑, Fisetin also restored the AlCl3-induced reduction in the levels of SOD, CAT, GST, and GSH in a study that analysed the effect of this compound on AlCl3-induced reactive gliosis and neuronal inflammation in the brain of mice
cognitive↑, Fisetin improves neurodegenerative disease-associated dementia, cognitive functions and behavioral abnormalities along with increasing age

2825- FIS,    Exploring the molecular targets of dietary flavonoid fisetin in cancer
- Review, Var, NA
*Inflam↓, present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant
*antiOx↓, fisetin possesses stronger oxidant inhibitory activity than well-known potent antioxidants like morin and myricetin.
*ERK↑, inducing extracellular signal-regulated kinase1/2 (ERK)/c-myc phosphorylation, nuclear NF-E2-related factor-2 (Nrf2), glutamate cystine ligase and glutathione (GSH) levels
*p‑cMyc↑,
*NRF2↑,
*GSH↑,
*HO-1↑, activate Nrf2 mediated induction of hemeoxygenase-1 (HO-1) important for cell survival
mTOR↓, in our studies on fisetin in non-small lung cancer cells, we found that fisetin acts as a dual inhibitor PI3K/Akt and mTOR pathways
PI3K↓,
Akt↓,
TumCCA↑, fisetin treatment to LNCaP cells resulted in G1-phase arrest accompanied with decrease in cyclins D1, D2 and E and their activating partner CDKs 2, 4 and 6 with induction ofWAF1/p21 and KIP1/p27
cycD1↓,
cycE↓,
CDK2↓,
CDK4↓,
CDK6↓,
P21↑,
p27↑,
JNK↑, fisetin could inhibit the metastatic ability of PC-3 cells by suppressing of PI3 K/Akt and JNK signaling pathways with subsequent repression of matrix metalloproteinase-2 (MMP-2) and MMP-9
MMP2↓,
MMP9↓,
uPA↓, fisetin suppressed protein and mRNA levels of MMP-2 and urokinase-type plasminogen activator (uPA) in an ERK-dependent fashion.
NF-kB↓, decrease in the nuclear levels of NF-B, c-Fos, and c-Jun was noted in fisetin treated cells
cFos↓,
cJun↓,
E-cadherin↑, upregulation of E-cadherin and down-regulation of vimentin and N-cadherin.
Vim↓,
N-cadherin↓,
EMT↓, EMT inhibiting potential of fisetin has been reported in melanoma cells
MMP↓, The shift in mitochondrial membrane potential was accompanied by release of cytochrome c and Smac/DIABLO resulting in activation of the caspase cascade and cleavage of PARP
Cyt‑c↑,
Diablo↑,
Casp↑,
cl‑PARP↑,
P53↑, fisetin with induction of p53 protein
COX2↓, Fisetin down-regulated COX-2 and reduced the secretion of prostaglandin E2 without affecting COX-1 protein expression.
PGE2↓,
HSP70/HSPA5↓, It was shown that the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 were inhibited in HCT-116 cells exposed to heat shock at 43 C for 1 h in the presence of fisetin
HSP27↓,
DNAdam↑, DNA fragmentation, an increase in the number of sub-G1 phase cells, mitochondrial membrane depolarization and activation of caspase-9 and caspase-3.
Casp3↑,
Casp9↑,
ROS↑, This was associated with production of intracellular ROS
AMPK↑, Fisetin induced AMPK signaling
NO↑, fisetin induced cytotoxicity and showed that fisetin induced apoptosis of leukemia cells through generation of NO and elevated Ca2+ activating the caspase
Ca+2↑,
mTORC1↓, Fisetin was shown to inhibit the mTORC1 pathway and its downstream components including p70S6 K, eIF4B and eEF2 K.
p70S6↓,
ROS↓, Others have also noted a similar decrease in ROS with fisetin treatment.
ER Stress↑, Induction of ER stress upon fisetin treatment, evident as early as 6 h, and associated with up-regulation of IRE1, XBP1s, ATF4 and GRP78, was followed by autophagy which was not sustained
IRE1↑,
ATF4↑,
GRP78/BiP↑,
eff↑, Combination of fisetin and the BRAF inhibitor sorafenib was found to be extremely effective in inhibiting the growth of BRAF-mutated human melanoma cells
eff↑, synergistic effect of fisetin and sorafenib was observed in human cervical cancer HeLa cells,
eff↑, Similarly, fisetin in combination with hesperetin induced apoptosis
RadioS↑, pretreatment with fisetin enhanced the radio-sensitivity of p53 mutant HT-29 cancer cells,
ChemoSen↑, potential of fisetin in enhancing cisplatin-induced cytotoxicity in various cancer models
Half-Life↝, intraperitoneal (ip) dose of 223 mg/kg body weight the maximum plasma concentration (2.53 ug/ml) of fisetin was reached at 15 min which started to decline with a first rapid alpha half-life of 0.09 h and a longer half-life of 3.12 h.

2827- FIS,    The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
- Review, Var, NA
*antiOx↑, effective antioxidant, anti-inflammatory
*Inflam↓,
neuroP↑, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential.
hepatoP↑,
RenoP↑,
cycD1↓, Figure 3
TumCCA↑,
MMPs↓,
VEGF↓,
MAPK↓,
NF-kB↓,
angioG↓,
Beclin-1↑,
LC3s↑,
ATG5↑,
Bcl-2↓,
BAX↑,
Casp↑,
TNF-α↓,
Half-Life↓, Fisetin was given at an effective dosage of 223 mg/kilogram intraperitoneally in mice. The plasma concentration declined biophysically, with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h,
MMP↓, Fisetin powerfully improved apoptotic cells and caused the depolarization of the mitochondrial membrane.
mt-ROS↑, Fisetin played a role in the induction of apoptosis, independently of p53, and increased mitochondrial ROS generation.
cl‑PARP↑, fisetin-induced sub-G1 population as well as PARP cleavage.
CDK2↓, Moreover, the activities of cyclin-dependent kinases (CDK) 2 as well as CDK4 were decreased by fisetin and also inhibited CDK4 activity in a cell-free system, demonstrating that it might directly inhibit the activity of CDK4
CDK4↓,
Cyt‑c↑, Moreover, release of cytochrome c and Smac/Diablo was induced by fisetin
Diablo↑,
DR5↑, Fisetin caused an increase in the protein levels of cleaved caspase-8, DR5, Fas ligand, and TNF-related apoptosis-inducing ligand
Fas↑,
PCNA↓, Fisetin decreased proliferation-related proteins such as PCNA, Ki67 and phosphorylated histone H3 (p-H3) and decreased the expression of cell growth
Ki-67↓,
p‑H3↓,
chemoP↑, Paclitaxel treatment only showed more toxicity to normal cells than the combination of flavonoids with paclitaxel, suggesting that fisetin might bring some safety against paclitaxel-facilitated cytotoxicity.
Ca+2↑, Fisetin encouraged apoptotic cell death via increased ROS and Ca2+, while it increased caspase-8, -9 and -3 activities and reduced the mitochondrial membrane potential in HSC3 cells.
Dose↝, After fisetin treatment at 40 µM, invasion was reduced by 87.2% and 92.4%, whereas after fisetin treatment at 20 µM, invasion was decreased by 52.4% and 59.4% in SiHa and CaSki cells, respectively
CDC25↓, This study proposes that fisetin caused the arrest of the G2/M cell cycle via deactivating Cdc25c as well Cdc2 via the activation of Chk1, 2 and ATM
CDC2↓,
CHK1↑,
Chk2↑,
ATM↑,
PCK1↓, fisetin decreases the levels of SOS-1, pEGFR, GRB2, PKC, Ras, p-p-38, p-ERK1/2, p-JNK, VEGF, FAK, PI3K, RhoA, p-AKT, uPA, NF-ĸB, MMP-7,-9 and -13, whereas it increases GSK3β as well as E-cadherin in U-2 OS
RAS↓,
p‑p38↓,
Rho↓,
uPA↓,
MMP7↓,
MMP13↓,
GSK‐3β↑,
E-cadherin↑,
survivin↓, whereas those of survivin and BCL-2 were reduced in T98G cells
VEGFR2↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2↓, The downregulation of cIAP-2 by fisetin
STAT3↓, fisetin induced apoptosis in TPC-1 cells via the initiation of oxidative damage and enhanced caspases expression by downregulating STAT3 and JAK 1 signaling
JAK1↓,
mTORC1↓, Fisetin acts as a dual inhibitor of mTORC1/2 signaling,
mTORC2↓,
NRF2↑, Moreover, In JC cells, the Nrf2 expression was gradually increased by fisetin from 8 h to 24 h

2829- FIS,    Fisetin: An anticancer perspective
- Review, Var, NA
TumCP↓, Being a potent anticancer agent, fisetin has been used to inhibit stages in the cancer cells (proliferation, invasion), prevent cell cycle progression, inhibit cell growth, induce apoptosis, cause polymerase (PARP) cleavage
TumCI↓,
TumCCA↑,
TumCG↓,
Apoptosis↑,
cl‑PARP↑,
PKCδ↓, fisetin also suppresses the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways, reduces the NF‐κB activation, and down‐regulates the level of the oncoprotein securin
ROS↓,
ERK↓,
NF-kB↓,
survivin↓,
ROS↑, In human multiple myeloma U266 cells, fisetin stimulated the production of free radical species that led to apoptosis
PI3K↓, Multiple studies also authenticated the anticancer role of fisetin through various signaling pathways such as blocking of mammalian target of rapamycin (PI3K/Akt/mTOR)
Akt↓,
mTOR↓,
MAPK↓, phosphatidylinositol‐3‐kinase/protein kinase B, mitogen‐activated protein kinases (MAPK)‐dependent nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and p38, respectively,
p38↓,
HER2/EBBR2↓, (HER2)/neu‐overexpressing breast cancer cell lines. Fisetin caused induction through inactivating the receptor, inducing the degradation of the proteasomes, reducing its half‐life
EMT↓, In addition, mutation of epithelial‐to‐mesenchymal transition (EMT)
PTEN↑, up‐regulation of expression of PTEN mRNA and protein were reported after fisetin treatment
HO-1↑, In breast cancer cells (4T1 and JC cells), fisetin increased HO‐1 mRNA and protein expressions, elevated Nrf2 expression
NRF2↑,
MMP2↓, fisetin reduced MMP‐2 and MMP‐9 enzyme activity and gene expression for both mRNA levels and protein
MMP9↓,
MMP↓, fisetin treatment further led to permeabilization of mitochondrial membrane, activation of caspase‐8 and caspase‐9, as well as the cleavage of poly(ADP‐ribose) polymerase 1
Casp8↑,
Casp9↑,
TRAILR↑, enhanced the levels of TRAIL‐R1
Cyt‑c↑, mitochondrial releasing of cytochrome c into cytosol, up‐regulation and down‐regulation of X‐linked inhibitor of apoptosis protein
XIAP↓,
P53↑, fisetin also enhanced the protein p53 levels
CDK2↓, lowered cell number, the activities of CDK‐2,4)
CDK4↓,
CDC25↓, it also decreased cell division cycle protein levels (CDC)2 and CDC25C, and CDC2 activity (Lu et al., 2005)
CDC2↓,
VEGF↓, down‐regulating the expressions of p‐ERK1/2, vascular endothelial growth factor receptor 1(VEGFR1), p38, and pJNK, respectively
DNAdam↑, Fisetin (80 microM) showed dose‐dependently caused DNA fragmentation, induced cellular swelling and apoptotic death, and showed characteristics of apoptosis.
TET1↓, lowered the TET1 expression levels
CHOP↑, caused up‐regulation of (C/EBP) homologous protein (CHOP) expression and reactive oxygen species production,
CD44↓, down‐regulation of CD44 and CD133 markers
CD133↓,
uPA↓, down‐regulation of levels of matrix metalloproteinase‐2 (MMP‐2), urokinase‐type plasminogen activator (uPA),

2830- FIS,    Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent
- Review, Var, NA
TumCG↓, suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration.
angioG↓,
*ROS↓,
TumCMig↓,
VEGF↓, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1.
MAPK↑, including the activation of MAPK. activation of MAPK is crucial for mediating cancer cell proliferation, apoptosis, and invasion
NF-kB↓, ability of fisetin to suppress NF-κB activity has been demonstrated in various diseases
PI3K↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT
Akt↓,
mTOR↓, Fisetin has been shown to be effective against PI3K expression, AKT phosphorylation, and mTOR activation in various cancer cells,
NRF2↑, effects of fisetin on the activation of Nrf2 and upregulation of HO-1 have been demonstrated in various diseases
HO-1↑,
ROS↓, Liver cancer Resist proliferation, migration and invasion, induce apoptosis, attenuate ROS and inflammation
Inflam↓,
ER Stress↑, Oral cancer Induce apoptosis and autophagy, promote ER stress and ROS, suppress proliferation
ROS↑, Multiple studies have demonstrated that fisetin has the ability to induce apoptosis in cancer cells, and various mechanisms are involved, including the activation of MAPK, NF-κB, p53, and the generation of reactive oxygen species (ROS)
TumCP↓,
ChemoSen↑, Breast cancer Promote apoptosis and invasion and metastasis, enhance chemotherapeutic effects
PTEN↑,
P53↑, activation of MAPK, NF-κB, p53,
Casp3↑,
Casp8↑,
Casp9↑,
COX2↓, fisetin inhibits COX2 expression
Wnt↓, regulating a number of important angiogenesis-related factors in cancer cells, such as VEGF, MMP2/9, eNOS, wingless and Wnt-signaling.
EGFR↓,
Mcl-1↓,
survivin↓, fisetin interferes with NF-κB signaling, resulting in the reduction of survivin, TRAF1, Bcl-xl, Bcl-2, and IAP1/2 levels, ultimately inhibiting apoptosis
IAP1↓,
IAP2↓,
PGE2↓, fisetin inhibits COX2 expression, leading to the down-regulation of PGE2 secretion and inactivation of β-catenin, thereby inducing apoptosis
β-catenin/ZEB1↓,
DR5↑, fisetin markedly induces apoptosis in renal carcinoma through increased expression of DR5, which is regulated by p53.
MMP2↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT and JNK pathways, resulting in the suppression of MMP-2 and MMP-9 expression
MMP9↓,
FAK↓, fisetin can inhibit cell migration and reduce focal adhesion kinase (FAK) phosphorylation levels
uPA↓, fisetin significantly suppresses the invasion of U-2 cells by decreasing the expression of NF-κB, urokinase-type plasminogen activator (uPA), FAK, and MMP-2/9
EMT↓, Fisetin has been shown to have the ability to reverse EMT, thereby inhibiting the invasion and migration of cancer cells
ERK↓, fisetin has the ability to suppress ERK1/2 activation and activate JNK/p38 pathways
JNK↑,
p38↑,
PKCδ↓, fisetin reduces the expression of MMP-9 by inhibiting PKCα/ROS/ERK1/2 and p38 MAPK activation
BioAv↓, low water solubility of fisetin poses a significant challenge for its administration, which can limit its biological effects
BioAv↑, Compared to free fisetin, fisetin nanoemulsion has demonstrated a 3.9-fold increase in the generation of reactive oxygen species (ROS) and induction of apoptosis, highlighting its enhanced efficacy
BioAv↑, Liposomal encapsulation has shown potential in enhancing the anticancer therapeutic effects of fisetin

2833- FIS,  SNP,    Glucose-capped fisetin silver nanoparticles induced cytotoxicity and ferroptosis in breast cancer cells: A molecular perspective
- in-vitro, BC, MDA-MB-231
MMP↓, MDA-MB-231 cells treated with glucose-capped fisetin silver nanoparticles showed signs of apoptosis, decreased mitochondrial membrane potential, and elevated Reactive oxygen species (ROS) production.
ROS↑,
NRF2↑, upregulation of SLC7A11, SLC40A1, NRF2F, NOX2, and NOX5 genes that are associated with various crucial cellular events
NOX↑,
selectivity↑, Glucose nanoparticles selectively deliver cytotoxic agents to cancer cells by targeting the glucose transporters overexpressed in cancer cells, resulting in minimal toxicity to healthy tissues

2838- FIS,    Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)
cl‑Casp3↑, enhanced signals for the cleaved caspase 3 and nuclear PARP-1 in those fisetin-treated cells
cl‑PARP↑,
MMP↓, This was consistent with the collapse of mitochondrial membrane potential and release of cytochrome c
Cyt‑c↑,
ROS↑, fisetin-treated cells showed increased ROS level
NRF2↓, and a significant decline in nuclear Nrf2 immunosignal versus recovery in nuclear Nrf2 due to the treatment with curcumin and resveratrol (Nrf2 activators) and thus, suggesting a role of Nrf2 suppression in fisetin-mediated apoptosis in SW-480 cells.

2843- FIS,    Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
- Review, Var, NA
NRF2↑, fisetin increased the protein level and accumulation Nrf2 and down regulated the protein levels of Keap1
Keap1↓,
ChemoSen↑, In vitro studies showed that fisetin and quercetin could also act against chemotherapeutic resistance in several cancers
BioAv↓, Fisetin has low aqueous solubility and bioavailability
Cyt‑c↑, release of cytochrome c from mitochondria, caspase-3 and caspase-9 mRNA and protein expression, and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels, were found to be regulated in the fisetin-treated cancer cell line
Casp3↑,
Casp9↑,
BAX↑,
tumCV↓, fisetin at 5–80 µM significantly reduced the viability of A431 human epidermoid carcinoma cells by the release of cytochrome c,
Mcl-1↓, reducing the anti-apoptotic protein expression of Bcl-2, Bcl-xL, and Mcl-1 along with elevation of pro-apoptotic protein expression (Bax, Bak, and Bad) and caspase cleavage and poly-ADP-ribose polymerase (PARP) protein
cl‑PARP↑,
IGF-1↓, fisetin promoted caspase-8 and cytochrome c expression, possibly by impeding the aberrant activation of insulin growth factor receptor 1 and Akt
Akt↓,
CDK6↓, fisetin binds with CDK6, which in turn blocks its activity with an inhibitory concentration (IC50) at a concentration of 0.85 μM
TumCCA↑, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases
P53?, exhibiting elevated levels of p53
cycD1↓, 10–60 μM fisetin concentration, prostate cancer cells PC3, LNCaP, and CWR22Ry1 had decreased cellular viability and decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
cycE↓,
CDK2↓, decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
CDK4↓,
CDK6↓,
MMP2↓, fisetin displayed tumor inhibitory effects by blocking MMP-2 and MMP-9 at mRNA and protein levels in prostate PC-3 cells
MMP9↓,
MMP1↓, Similarly, fisetin can also inhibit MMP-1, MMP-9, MMP-7, MMP-3, and MMP-14 gene expression linked with ECM remodeling in human umbilical vascular endothelial cells (HUVECs) and HT-1080 fibrosarcoma cells [9
MMP7↓,
MMP3↓,
VEGF↓, fisetin in a concentration-dependent manner (10–50 μM concentration) significantly inhibited regular serum, growth-enhancing supplement, and vascular endothelial growth factor (VEGF)
PI3K↓, fisetin inhibited PI3K expression and phosphorylation of Akt
mTOR↓, fisetin treatment activated the apoptotic process through inhibiting both PI3K and mammalian target of rapamycin (mTOR) signaling pathways
COX2↓, fisetin resulted in activation of apoptosis and inhibition of COX-2 and the Wnt/EGFR/NF-kB pathway
Wnt↓,
EGFR↓,
NF-kB↓,
ERK↓, Fisetin is one of the flavonoids that has been found to suppress ERK1/2 signaling in human gastric (SGC7901), hepatic (HepG2), colorectal (Caco-2)
ROS↑, fisetin induced ROS generation and suppressed ERK through its phosphorylation
angioG↓, fisetin-induced anti-angiogenesis led to reduced VEGF and epidermal growth factor receptor (EGFR) expression
TNF-α↓, Fisetin suppressed IL-1β-mediated expression of inducible nitric oxide synthase, nitric oxide, interleukin-6, tumor necrotic factor-α, prostaglandin E2, cyclooxygenase-2 (iNOS, NO, IL-6, TNF-α, PGE2, and COX-2),
PGE2↓,
iNOS↓,
NO↓,
IL6↓,
HSP70/HSPA5↝, fisetin-mediated inhibition of cellular proliferation by HSP70 and HSP27 regulation
HSP27↝,

1188- GB,    The potential of Ginkgo biloba in the treatment of human diseases and the relationship to Nrf2-mediated antioxidant protection
- Review, NA, NA
*NRF2↑, activate several signalling mechanisms in cells, including the Nrf2 pathway, which is the master controller of the antioxidant defence that detoxifies reactive oxygen species (ROS)
*ROS↓,

2508- H2,    Molecular hydrogen is a promising therapeutic agent for pulmonary disease
- Review, Var, NA - Review, Sepsis, NA
*ROS↓, inhalation of 2% molecular hydrogen results in the selective scavenging of hydroxyl free radical (·OH) and peroxynitrite anion (ONOO-), significantly improving oxidative stress injury caused by cerebral ischemia/reperfusion (I/R)
eff↝, Molecular hydrogen can exert biological effects on almost all organs, including the brain, heart, lung, liver, and pancreas.
*Inflam?, including roles in the regulation of oxidative stress and anti-inflammatory and anti-apoptotic effects
*NRF2↑, By stimulating nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the basal and induces expression of many antioxidant enzymes
*HO-1↑, hydrogen can increase the expression of heme oxygenase-1 (HO-1)
*SOD↑, increases the activity of the antioxidant enzymes SOD, CAT, and myeloperoxidase (MPO)
*Catalase↑,
*MPO↑,
*ASK1↓, Molecular hydrogen can block the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway
*NADPH↓, thereby inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and decreasing free radical production
*Sepsis↓, Emerging evidence suggests that hydrogen can prevent sepsis, providing a novel treatment strategy for sepsis-induced ALI.
*HMGB1↓, Hydrogen attenuates tissue injury and dysfunction by inhibiting HMGB-1.
ROS↑, it has been shown that hydrogen pretreatment enhances ROS and the expression of pyroptosis-related proteins, stimulates NLRP3 inflammasome/gasdermin D (GSDMD) activation, and inhibits endometrial cancer
NLRP3↑,
GSDMD↑,
chemoP↑, Hydrogen can alleviate the side effects of conventional anti-cancer therapies, such as chemotherapy and radiotherapy, and improve quality of life
eff↑, It significantly improves the physical status of patients, reduces fatigue, insomnia, anorexia, and pain, and decreases elevated tumor markers.

2521- H2,    Oxyhydrogen Gas: A Promising Therapeutic Approach for Lung, Breast and Colorectal Cancer
- Review, CRC, NA - Review, Lung, NA - Review, BC, NA
Inflam↑, Oxyhydrogen gas, a mixture of 66% molecular hydrogen (H2) and 33% molecular oxygen (O2) has shown exceptional promise as a novel therapeutic agent due to its ability to modulate oxidative stress, inflammation, and apoptosis.
ROS↓, neutralises reactive oxygen and nitrogen species
ChemoSen↑, enhancing existing treatments and reducing harmful oxidative states in cancer cells. boosting the effectiveness of conventional therapies
p‑PI3K↓, inhibiting the PI3K/Akt phosphorylation cascade.
p‑Akt↓,
QoL↑, Similar results have been observed in breast cancer, where patients reported improved quality of life.
GutMicro↑, improves intestinal microflora dysbiosis.
chemoP↑, reduced oxidative stress and mitigated tissue damage, suggesting its potential as a cytoprotective agent in cancer patients undergoing radiation therapy or chemotherapy
radioP↑,
*NRF2↑, documented role in activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
*Catalase↑, consequently, hydrogen can enhance the expression of endogenous antioxidant enzymes, including catalase (CAT), glutathione peroxidase (GPx), haem oxygenase (e.g., HO-1), and superoxide dismutase (SOD) [45]
*GPx↑,
*HO-1↑,
*SOD↑,
*TNF-α↓, reducing the expression of proinflammatory mediators such as chemokines (e.g., CXCL15), cytokines (e.g., TNF-α), interleukins (e.g., IL-4, IL-6)
*IL4↓,
*IL6↓,
ChemoSen↑, further research demonstrates that oxyhydrogen gas enhanced the sensitivity of lung cancer cells to chemotherapy drugs, suggesting its potential as an adjuvant therapy
Appetite↑, inhaled oxyhydrogen gas over a minimum of 3 months. The results indicated substantial improvements in appetite, cognition, fatigue, pain, and sleeplessness
cognitive↑,
Pain↓,
Sleep↑,
other?, It is recommended that hydrogen should not exceed 4.6% in air or 4.1% by volume in pure oxygen gas (explosion risk)

2514- H2,    Hydrogen: A Novel Option in Human Disease Treatment
- Review, NA, NA
*Inflam↓, Anti-Inflammatory Effect of H2
*IL1β↓, decrease the overexpression of early proinflammatory cytokines, such as interleukin- (IL-) 1β, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α
*IL6↓,
*IL8↓,
*IL10↓,
*TNF-α↓,
*ROS↓, . H2 can also downregulate ROS directly or as a regulator of a gas-mediated signal.
*HO-1↓, H2 can enhance the expression of the heme oxygenase-1 (HO-1) antioxidant by activating nuclear factor erythroid 2-related factor 2 (Nrf-2), an upstream regulating molecule of HO-1
*NRF2↑,
*ER Stress↓, hydrogen inhalation significantly reduced the ER stress-related protein and alleviated tissue damage in myocardial I/R injury a
H2O2↑, H2-induced ROS production can also be observed in cancer cells.

2516- H2,    Hydrogen Gas in Cancer Treatment
- Review, Var, NA
*Half-Life↓, Except the thigh muscle required a longer time to saturate, the other organs need 5–10 min to reach Cmax (maximum hydrogen concentration).
*ROS↓, regulate several key players in cancer, including ROS, and certain antioxidant enzymes
*selectivity↑, hydrogen gas could selectively scavenge the most cytotoxic ROS, •OH, as tested in an acute rat model of cerebral ischemia and reperfusion
*SOD↑, the expression of superoxide dismutase (SOD) (48), heme oxyganase-1 (HO-1) (49), as well as nuclear factor erythroid 2-related factor 2 (Nrf2) (50), increased significantly, strengthening its potential in eliminating ROS.
*HO-1↑,
*NRF2↑,
*chemoP↑, reduce the adverse effects in cancer treatment while at the same time doesn't abrogate the cytotoxicity of other therapy, such as radiotherapy and chemotherapy
*radioP↑,
ROS↑, Interestingly, due the over-produced ROS in cancer cells (38), the administration of hydrogen gas may lower the ROS level at the beginning, but it provokes much more ROS production as a result of compensation effect, leading to the killing of cancer
*Inflam↓, By regulating inflammation, hydrogen gas can prevent tumor formation, progression, as well as reduce the side effects caused by chemotherapy/radiotherapy
eff↑, More importantly, hydrogen-rich water didn't impair the overall anti-tumor effects of gefitinib both in vitro and in vivo, while in contrast, it antagonized the weight loss induced by gefitinib and naphthalene, and enhanced the overall survival rate
*TNF-α↓, hydrogen-rich saline treatment exerted its protective effects via inhibiting the inflammatory TNF-α/IL-6 pathway, increasing the cleaved C8 expression and Bcl-2/Bax ratio, and attenuating cell apoptosis in both heart and liver tissue
*IL6↓,
*cl‑Casp8↑,
*Bax:Bcl2↓,
*Apoptosis↓,
*cardioP↑,
*hepatoP↑,
*RenoP↑, Hydrogen-rich water also showed renal protective effect against cisplatin-induced nephrotoxicity in rats.
*chemoP↑, nother study showed that both inhaling hydrogen gas (1% hydrogen in air) and drinking hydrogen-rich water (0.8 mM hydrogen in water) could reverse the mortality, and body-weight loss caused by cisplatin via its anti-oxidant property
eff↝, More importantly, hydrogen didn't impair the anti-tumor activity of cisplatin against cancer cell lines in vitro and in tumor-bearing mice
chemoP↑, hydrogen-rich water combinational treatment group exhibited no differences in liver function during the treatment, probably due to its antioxidant activity, indicating it a promising protective agent to alleviate the mFOLFOX6-related liver injury
radioP↑, consumption of hydrogen-rich water reduced the radiation-induced oxidative stress while at the same time didn't compromise anti-tumor effect of radiotherapy
eff↑, Hydrogen Gas Acts Synergistically With Thermal Therapy
TumCG↓, in vivo study showed that under hydrogen gas treatment, tumor growth was significantly inhibited, as well as the expression of Ki-67, VEGF and SMC3
Ki-67↓,
VEGF↓,
selectivity↑, H2-silica could concentration-dependently inhibit the cell viability of human esophageal squamous cell carcinoma (KYSE-70) cells, while it need higher dose to suppress normal human esophageal epithelial cells (HEEpiCs), indicating its selective profi

1635- HCA,    Hydroxycitric acid prevents hyperoxaluric-induced nephrolithiasis and oxidative stress via activation of the Nrf2/Keap1 signaling pathway
- vitro+vivo, Nor, NA
*other↓, HCA administration significantly reduced crystal deposition and kidney injury induced by glyoxylate
*ROS↓, alleviated oxidative stress via upregulating the antioxidant enzyme activities of superoxide dismutase (SOD) and catalase (CAT) and reducing the malondialdehyde (MDA) content
*SOD↑,
*Catalase↑,
*MDA↓,
*NRF2↑, via activating Nrf2/Keap1

1638- HCAs,    Anticancer potential of hydroxycinnamic acids: mechanisms, bioavailability, and therapeutic applications
- Review, Nor, NA
*BioAv↓, Hydroxycinnamic acids are sensitive compounds to the environment in the gastrointestinal track. They may interact with the components in the digestion system or can be affected by pH differences
Inflam↓, Hydroxycinnamic acids (p-coumaric, CAPE, chlorogenic, caffeic, and ferulic acids) exhibit anti-inflammatory activity both in vitro and in vivo
COX2↓, caffeic acid targets COX-2 and its product prostaglan-din E2
TumCCA↑, These phenolics can cause cell cycle arrest at various phases, including G1, S, S-G2, and G2.
ChemoSen↑, sensitize cancer cells to chemotherapy and radiation therapy.
RadioS↑,
selectivity↑, HCAs exhibit selective toxicity, with a higher propensity to induce cell death in cancerous cells compared to normal cells.
ROS↑, 100uM(CA) and 10mM(metforin) cervical Cancer, also 100uM@24hr in A549cells
DNAdam↑,
antiOx↑, Hydroxy-cinnamic acids have an antioxidant effect by suppressing reactive oxygen/nitrogen species (ROS/RNS) and superoxide dismutases (SODs) production
SOD↑,
Catalase↑,
GPx↑,
GSH↑,
NRF2↑,
NF-kB↓, In the promotion stage, these compounds possess anti-inflammatory effects, particularly by inhibit-ing nuclear factor kappa B (NF-kB)
Cyc↓,
CDK1↑, CDKs
P21↑,
p27↑,
P53↑,
VEGF↓,
MAPK↓,

2894- HNK,    Pharmacological features, health benefits and clinical implications of honokiol
- Review, Var, NA - Review, AD, NA
*BioAv↓, HNK showed poor aqueous solubility due to phenolic hydroxyl groups forming intramolecular hydrogen bonds and poor solubility in water (
*neuroP↑, HNK has the accessibility to reach the neuronal tissue by crossing the BBB and showing neuroprotective effects
*BBB↑,
*ROS↓, fig 2
*Keap1↑,
*NRF2↑,
*Casp3↓,
*SIRT3↑,
*Rho↓,
*ERK↓,
*NF-kB↓,
angioG↓,
RAS↓,
PI3K↓,
Akt↓,
mTOR↓,
*memory↑, oral administration of HNK (1 mg/kg) in senescence-accelerated mice prevents age-related memory and learning deficits
*Aβ↓, in Alzheimer’s disease, HNK significantly reduces neurotoxicity of aggregated Ab
*PPARγ↑, Furthermore, the expression of PPARc and PGC1a was increased by HNK, suggesting its beneficial impact on energy metabolism
*PGC-1α↑,
NF-kB↓, activation of NFjB was suppressed by HNK via suppression of nuclear translocation and phosphorylation of the p65 subunit and further instigated apoptosis by enhancing TNF-a
Hif1a↓, HNK has anti-oxidative properties and can downregulate the HIF-1a protein, inhibiting hypoxia- related signaling pathways
VEGF↓, renal cancer, via decreasing the vascular endothelial growth factor (VEGF) and heme-oxygenase-1 (HO-1)
HO-1↓,
Foxm1↓, HNK interaction with the FOXM1 oncogenic transcription factor inhibits cancer cells
p27↑, HNK treatment upregulates the expression of CDK inhibitor p27 and p21, whereas it downregulates the expression of CDK2/4/6 and cyclin D1/2
P21↑,
CDK2↓,
CDK4↓,
CDK6↓,
cycD1↓,
Twist↓, HNK averted the invasion of urinary bladder cancer cells by downregulating the steroid receptor coactivator, Twist1 and Matrix metalloproteinase-2
MMP2↓,
Rho↑, By activating the RhoA, ROCK and MLC signaling, HNK inhibits the migration of highly metastatic renal cell carcinoma
ROCK1↑,
TumCMig↓,
cFLIP↓, HNK can be used to suppress c-FLIP, the apoptosis inhibitor.
BMPs↑, HNK treatment increases the expression of BMP7 protein
OCR↑, HNK might increase the oxygen consumption rate while decreasing the extracellular acidification rate in breast cancer cells.
ECAR↓,
*AntiAg↑, It also suppresses the platelet aggregation
*cardioP↑, HNK is an attractive cardioprotective agent because of its strong antioxidative properties
*antiOx↑,
*ROS↓, HNK treatment reduced cellular ROS production and decreased mitochondrial damage in neonatal rat cardiomyocytes exposed to hypoxia/reoxygenation
P-gp↓, The expres- sion of P-gp at mRNA and protein levels is reduced in HNK treatment on human MDR and MCF-7/ADR breast cancer cell lines

2864- HNK,    Honokiol: A Review of Its Anticancer Potential and Mechanisms
- Review, Var, NA
TumCCA↑, induction of G0/G1 and G2/M cell cycle arrest
CDK2↓, (via the regulation of cyclin-dependent kinase (CDK) and cyclin proteins),
EMT↓, epithelial–mesenchymal transition inhibition via the downregulation of mesenchymal markers
MMPs↓, honokiol possesses the capability to supress cell migration and invasion via the downregulation of several matrix-metalloproteinases
AMPK↑, (activation of 5′ AMP-activated protein kinase (AMPK) and KISS1/KISS1R signalling)
TumCI↓, inhibiting cell migration, invasion, and metastasis, as well as inducing anti-angiogenesis activity (via the down-regulation of vascular endothelial growth factor (VEGFR) and vascular endothelial growth factor (VEGF)
TumCMig↓,
TumMeta↓,
VEGFR2↓,
*antiOx↑, diverse biological activities, including anti-arrhythmic, anti-inflammatory, anti-oxidative, anti-depressant, anti-thrombocytic, and anxiolytic activities
*Inflam↓,
*BBB↑, Due to its ability to cross the blood–brain barrier
*neuroP↑, beneficial towards neuronal protection through various mechanism, such as the preservation of Na+/K+ ATPase, phosphorylation of pro-survival factors, preservation of mitochondria, prevention of glucose, reactive oxgen species (ROS), and inflammatory
*ROS↓,
Dose↝, Generally, the concentrations used for the in vitro studies are between 0–150 μM
selectivity↑, Interestingly, honokiol has been shown to exhibit minimal cytotoxicity against on normal cell lines, including human fibroblast FB-1, FB-2, Hs68, and NIH-3T3 cells
Casp3↑, ↑ Caspase-3 & caspase-9
Casp9↑,
NOTCH1↓, Inhibition of Notch signalling: ↓ Notch1 & Jagged-1;
cycD1↓, ↓ cyclin D1 & c-Myc;
cMyc↓,
P21?, ↑ p21WAF1 protein
DR5↑, ↑ DR5 & cleaved PARP
cl‑PARP↑,
P53↑, ↑ phosphorylated p53 & p53
Mcl-1↑, ↓ Mcl-1 protein
p65↓, ↓ p65; ↓ NF-κB
NF-kB↓,
ROS↑, ↑ JNK activation ,Increase ROS activity:
JNK↑,
NRF2↑, ↑ Nrf2 & c-Jun protein activation
cJun↑,
EF-1α↓, ↓ EFGR; ↓ MAPK/PI3K pathway activity
MAPK↓,
PI3K↓,
mTORC1↓, ↓ mTORC1 function; ↑ LKB1 & cytosolic localisation
CSCs↓, Inhibit stem-like characteristics: ↓ Oct4, Nanog & Sox4 protein; ↓ STAT3;
OCT4↓,
Nanog↓,
SOX4↓,
STAT3↓,
CDK4↓, ↓ Cdk2, Cdk4 & p-pRbSer780;
p‑RB1↓,
PGE2↓, ↓ PGE2 production ↓ COX-2 ↑ β-catenin
COX2↓,
β-catenin/ZEB1↑,
IKKα↓, ↓ IKKα
HDAC↓, ↓ class I HDAC proteins; ↓ HDAC activity;
HATs↑, ↑ histone acetyltransferase (HAT) activity; ↑ histone H3 & H4
H3↑,
H4↑,
LC3II↑, ↑ LC3-II
c-Raf↓, ↓ c-RAF
SIRT3↑, ↑ Sirt3 mRNA & protein; ↓ Hif-1α protein
Hif1a↓,
ER Stress↑, ↑ ER stress signalling pathway activation; ↑ GRP78,
GRP78/BiP↑,
cl‑CHOP↑, ↑ cleaved caspase-9 & CHOP;
MMP↓, mitochondrial depolarization
PCNA↓, ↓ cyclin B1, cyclin D1, cyclin D2 & PCNA;
Zeb1↓, ↓ ZEB2 Inhibit
NOTCH3↓, ↓ Notch3/Hes1 pathway
CD133↓, ↓ CD133 & Nestin protein
Nestin↓,
ATG5↑, ↑ Atg7 protein activation; ↑ Atg5;
ATG7↑,
survivin↓, ↓ Mcl-1 & survivin protein
ChemoSen↑, honokiol potentiated the apoptotic effect of both doxorubicin and paclitaxel against human liver cancer HepG2 cells.
SOX2↓, Honokiol was shown to downregulate the expression of Oct4, Nanog, and Sox2 which were known to be expressed in osteosarcoma, breast carcinoma and germ cell tumours
OS↑, Lipo-HNK was also shown to prolong survival and induce intra-tumoral apoptosis in vivo.
P-gp↓, Honokiol was shown to downregulate the expression of P-gp at mRNA and protein levels in MCF-7/ADR, a human breast MDR cancer cell line
Half-Life↓, For i.v. administration, it has been found that there was a rapid rate of distribution followed by a slower rate of elimination (elimination half-life t1/2 = 49.22 min and 56.2 min for 5 mg or 10 mg of honokiol, respectively
Half-Life↝, male and female dogs was assessed. The elimination half-life (t1/2 in hours) was found to be 20.13 (female), 9.27 (female), 7.06 (male), 4.70 (male), and 1.89 (male) after administration of doses of 8.8, 19.8, 3.9, 44.4, and 66.7 mg/kg, respectively.
eff↑, Apart from that, epigallocatechin-3-gallate functionalized chitin loaded with honokiol nanoparticles (CE-HK NP), developed by Tang et al. [224], inhibit HepG2
BioAv↓, extensive biotransformation of honokiol may contribute to its low bioavailability.

2868- HNK,    Honokiol: A review of its pharmacological potential and therapeutic insights
- Review, Var, NA - Review, Sepsis, NA
*P-gp↓, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6),
*ROS↓,
*TNF-α↓,
*IL10↓,
*IL6↓,
eIF2α↑, Bcl-2, phosphorylated eIF2α, CHOP,GRP78, Bax, cleaved caspase-9 and phosphorylated PERK
CHOP↑,
GRP78/BiP↑,
BAX↑,
cl‑Casp9↑,
p‑PERK↑,
ER Stress↑, endoplasmic reticulum stress and proteins in apoptosis in 95-D and A549 cells
Apoptosis↑,
MMPs↓, decrease in levels of matrix metal-mloproteinases, P-glycoprotein expression, the formation of mammosphere, H3K27 methyltransferase, c-FLIP, level of CXCR4 receptor,pluripotency-factors, Twist-1, class I histone deacetylases, steroid receptor co
cFLIP↓,
CXCR4↓,
Twist↓,
HDAC↓,
BMPs↑, enhancement in Bax protein, and (BMP7), as well as interference with an activator of transcription 3 (STAT3), (mTOR), (EGFR), (NF-kB) and Shh
p‑STAT3↓, secreased the phosphorylation of STAT3
mTOR↓,
EGFR↓,
NF-kB↓,
Shh↓,
VEGF↓, induce apoptosis, and regulate the vascular endothelial growth factor-A expression (VEGF-A)
tumCV↓, human glioma cell lines (U251 and U-87 MG) through inhibition of colony formation, glioma cell viability, cell migration, invasion, suppression of ERK and AKT signalling cascades, apoptosis induction, and reduction of Bcl-2 expression.
TumCMig↓,
TumCI↓,
ERK↓,
Akt↓,
Bcl-2↓,
Nestin↓, increased the Bax expression, lowered the CD133, EGFR, and Nesti
CD133↓,
p‑cMET↑, HKL through the downregulating the phosphorylation of c-Met phosphorylation and stimulation of Ras,
RAS↑,
chemoP↑, Cheng and coworker determined the chemopreventive role of HKL against the proliferation of renal cell carcinoma (RCC) 786‑0 cells through multiple mechanism
*NRF2↑, , HKL also effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in in vivo and in vitro model
*NADPH↓, (HUVECs) such as inhibition of NADPH oxidase activity, suppression of p22 (phox) protein expression, Rac-1 phosphorylation, reactive oxygen species production, inhibition of degradation of Ikappa-B-alpha, and suppression of activity of of NF-kB
*p‑Rac1↓,
*ROS↓,
*IKKα↑,
*NF-kB↓,
*COX2↓, Furthermore, HKL treatment the inhibited cyclooxygenase (COX-2) upregulation, reduces prostaglandin E2 production, enhanced caspase-3 activity reduction
*PGE2↓,
*Casp3↓,
*hepatoP↑, compound also displayed hepatoprotective action against oxidative injury in tert-butyl hydroperoxide (t-BHP)-injured AML12 liver cells in in vitro model
*antiOx↑, compound reduces the level of acetylation on SOD2 to stimulate its antioxidative action, which results in reduced reactive oxygen species aggregation in AML12 cells
*GSH↑, HKL prevents oxidative damage induced by H2O2 via elevating antioxidant enzymes levels which includes glutathione and catalase and promotes translocation and activation transcription factor Nrf2
*Catalase↑,
*RenoP↑, imilarly, the compound protects renal reperfusion/i-schemia injury (IRI) in adult male albino Wistar rats via reducing theactivities of serum alkaline phosphatase (ALP), aspartate aminotrans- ferase (AST) and alanine aminotransferase (ALT)
*ALP↓,
*AST↓,
*ALAT↓,
*neuroP↑, Several reports and works have shown that HKL displays some neuroprotective properties
*cardioP↑, Cardioprotection
*HO-1↑, the expression level of heme oxygenase-1 (HO-1)was remarkably up-regulated and miR-218-5p was significantly down-regulated in septic mice treated with HKL
*Inflam↓, anti-inflammatory action of HKL at dose of 10 mg/kg in the muscle layer of mice

2872- HNK,    Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis
- in-vivo, ALS, NA - NA, Stroke, NA - NA, AD, NA - NA, Park, NA
*eff↑, Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease
*ROS↓, honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway.
*GSH↑,
*NRF2↑,
*motorD↑, Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function
*OS↑,
*neuroP↑, honokiol exerted neuroprotection in ALS models.
*BBB↑, due to its strong lipophilic property, honokiol can readily permeate the blood–brain barrier and blood–cerebrospinal fluid barrier.
*cognitive↑, honokiol was shown a beneficial effect on the cognitive impairment in APP/PS1 via ameliorating the mitochondrial dysfunction
*eff↑, Furthermore, honokiol was applied for patent (200310121303.0) for ischemic stroke treatment, and the clinical trials would be started soon in China
*antiOx↑, Honokiol showed strong antioxidant capacity in vitro and protected the yeast against H2O2 induced oxidative damage
*Cyt‑c↑, cytoplasmic release of cytochrome c was markedly decreased
*PGC-1α↑, 10 μmol/L and significantly upregulated the PGC-1α, NRF1, and TFAM protein

2873- HNK,    Honokiol Alleviates Oxidative Stress-Induced Neurotoxicity via Activation of Nrf2
- in-vitro, Nor, PC12
*neuroP↑, multiple pharmacological functions, including neuroprotection.
*GSH↑, Hon attenuates the H2O2- or 6-hydroxydopamine (6-OHDA)-induced apoptosis of PC12 cells by increasing the glutathione level
*HO-1↑, and upregulating a multitude of cytoprotective proteins, including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, thioredoxin 1, and thioredoxin reductase 1.
*NADPH↑,
*Trx1↑,
*TrxR1↑,
*NRF2↑, Hon promotes transcription factor Nrf2 nuclear translocation and activation.
*ROS↓, Hon is promising for further development as a therapeutic drug against oxidative stress-related neurodegenerative disorders. Inhibition of ROS accumulation
*antiOx↑, Upregulation of antioxidant species in PC12 cells
*BBB↑, Hon has the ability to cross the BBB
Dose↓, We demonstrated here that Hon, at the concentration as low as 5 μM, significantly rescues the cells from H2O2- or 6-OHDA-induced oxidative damage

2871- HNK,    Antihyperalgesic Properties of Honokiol in Inflammatory Pain Models by Targeting of NF-κB and Nrf2 Signaling
- in-vivo, Nor, NA
*TNF-α↓, honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF).
*IL1β↓,
*IL6↓,
*VEGF↓,
*NRF2↑, honokiol was also found to potentiate the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) levels.
*SOD2↑,
*HO-1↑,
*Inflam↓, honokiol reduced the inflammation
*Pain↓, honokiol might be a promising candidate as a new treatment for pain. results showed that honokiol remarkably reduced pain response throughout the chronic inflammatory pain model
*NO↓, Honokiol significantly reduced NO production after 6 days of treatment
toxicity↓, Treating mice with honokiol for 6 days showed no visible sign of toxicity or ill health. Obtained values, which were used as an indicator of liver and renal function, are shown in the table

2915- LT,    Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells
- in-vitro, Colon, HT29 - in-vitro, CRC, SNU-407 - in-vitro, Nor, FHC
DNMTs↓, luteolin inhibited the expression of DNA methyltransferases, a transcription repressor, and increased the expression and activity of ten-eleven translocation (TET) DNA demethylases,
TET1↑,
NRF2↑, luteolin decreased the methylation of the Nrf2 promoter region, which corresponded to the increased mRNA expression of Nrf2
HDAC↓, Recently, Zao et al. demonstrated that luteolin epigenetically activates the Nrf2 pathway by downregulating DNA methyltransferase (DNMT) and histone deacetylase (HDAC) expression
tumCV↓, Luteolin decreased the viability of all three cell lines in a dose-dependent manner
BAX↑, luteolin upregulated the expression of the apoptotic protein Bax, active caspase-9, and active caspase-3, while it downregulated the expression of the anti-apoptotic protein Bcl-2,
Casp9↑,
Casp3↑,
Bcl-2↓,
ROS↓, Luteolin promotes ROS scavenging by inducing the expression of antioxidant enzymes
GSS↑, luteolin increased the protein expression of the antioxidant enzymes GCLc, GSS, catalase, and HO-1 in a dose- and time-dependent manner
Catalase↑,
HO-1↑,
DNMT1↓, Luteolin markedly decreased the protein expression of DNMT1, DNMT3A, and DNMT3B in a dose- and time-dependent manner
DNMT3A↓,
TET1↑, In contrast, it markedly increased the protein expression of TET1, TET2, and TET3 in a dose- and time-dependent manner
TET3↑,
TET2↓,
P53↑, Luteolin upregulated the expression of p53 and its target p21 in a dose- and time-dependent manner
P21↑,

2916- LT,    Antioxidative and Anticancer Potential of Luteolin: A Comprehensive Approach Against Wide Range of Human Malignancies
- Review, Var, NA - Review, AD, NA - Review, Park, NA
proCasp9↓, , by inactivating proteins; such as procaspase‐9, CDC2 and cyclin B or upregulation of caspase‐9 and caspase‐3, cytochrome C, cyclin A, CDK2, and APAF‐1, in turn inducing cell cycle
CDC2↓,
CycB↓,
Casp9↑,
Casp3↑,
Cyt‑c↑,
cycA1↑,
CDK2↓, inhibit CDK2 activity
APAF1↑,
TumCCA↑,
P53↑, enhances phosphorylation of p53 and expression level of p53‐targeted downstream gene.
BAX↑, Increasing BAX protein expression; decreasing VEGF and Bcl‐2 expression it can initiate cell cycle arrest and apoptosis.
VEGF↓,
Bcl-2↓,
Apoptosis↑,
p‑Akt↓, reduce expression levels of p‐Akt, p‐EGFR, p‐Erk1/2, and p‐STAT3.
p‑EGFR↓,
p‑ERK↓,
p‑STAT3↓,
cardioP↑, Luteolin plays positive role against cardiovascular disorders by improving cardiac function
Catalase↓, It can reduce activity levels of catalase, superoxide dismutase, and GS4
SOD↓,
*BioAv↓, bioavailability of luteolin is very low. Due to the momentous first pass effect, only 4.10% was found to be available from dosage of 50 mg/kg intake of luteolin
*antiOx↓, luteolin classically exhibits antioxidant features
*ROS↓, The antioxidant potential of luteolin and its glycosides is mainly due to scavenging activity against reactive oxygen species (ROS) and nitrogen species
*NO↓,
*GSTs↑, Luteolin may also have a role in protection and enhancement of endogenous antioxidants such as glutathione‐S‐transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT)
*GSR↑,
*SOD↑,
*Catalase↑,
*lipid-P↓, Luteolin supplementation significantly suppressed the lipid peroxidation
PI3K↓, inhibits PI3K/Akt signaling pathway to induce apoptosis
Akt↓,
CDK2↓, inhibit CDK2 activity
BNIP3↑, upregulation of BNIP3 gene
hTERT↓, Suppress hTERT in MDA‐MB‐231 breast cancer cel
DR5↑, Boost DR5 expression
Beclin-1↑, Activate beclin 1
TNF-α↓, Block TNF‐α, NF‐κB, IL‐1, IL‐6,
NF-kB↓,
IL1↓,
IL6↓,
EMT↓, Suppress EMT essentially notable in cancer metastasis
FAK↓, Block EGFR‐signaling pathway and FAK activity
E-cadherin↑, increasing E‐cadherin expression by inhibiting mdm2
MDM2↓,
NOTCH↓, Inhibit NOTCH signaling
MAPK↑, Activate MAPK to inhibit tumor growt
Vim↓, downregulation of vimentin, N‐cadherin, Snail, and induction of E‐cadherin expressions
N-cadherin↓,
Snail↓,
MMP2↓, negatively regulated MMP2 and TWIST1
Twist↓,
MMP9↓, Inhibit matrix metalloproteinase‐9 expressions;
ROS↑, Induce apoptosis, reactive oxygen development, promotion of mitochondrial autophagy, loss of mitochondrial membrane potential
MMP↓,
*AChE↓, Reduce AchE activity to slow down inception of Alzheimer's disease‐like symptoms
*MMP↑, Reverse mitochondrial membrane potential dissipation
*Aβ↓, Inhibit Aβ25‐35
*neuroP↑, reduces neuronal apoptosis; inhibits Aβ generation
Trx1↑, luteolin against human bladder cancer cell line T24 was due to induction cell‐cycle arrest at G2/M, downregulation of p‐S6, suppression of cell survival, upregulation of p21 and TRX1, reduction in ROS levels.
ROS↓,
*NRF2↑, Luteolin reduced renal injury by inhibiting XO activity, modulating uric acid transporters, as well as activating Nrf2 HO‐1/NQO1 antioxidant pathways and renal SIRT1/6 cascade.
NRF2↓, Luteolin exerted anticancer effects in HT29 cells as it inhibits nuclear factor‐erythroid‐2‐related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway
*BBB↑, Luteolin can be used to treat brain cancer due to ability of this molecule to easily cross the blood–brain barrier
ChemoSen↑, In ovarian cancer cells, luteolin chemosensitizes the cells through repressing the epithelial‐mesenchymal transition markers
GutMicro↑, Luteolin was also observed to modulate gut microbiota which reduce the number of tumors in case of colorectal cancer by enhancing the number of health‐related microbiota and reduced the microbiota related to inflammation

2919- LT,    Luteolin as a potential therapeutic candidate for lung cancer: Emerging preclinical evidence
- Review, Var, NA
RadioS↑, it can be used as an adjuvant to radio-chemotherapy and helps to ameliorate cancer complications
ChemoSen↑,
chemoP↑,
*lipid-P↓, ↓LPO, ↑CAT, ↑SOD, ↑GPx, ↑GST, ↑GSH, ↓TNF-α, ↓IL-1β, ↓Caspase-3, ↑IL-10
*Catalase↑,
*SOD↑,
*GPx↑,
*GSTs↑,
*GSH↑,
*TNF-α↓,
*IL1β↓,
*Casp3↓,
*IL10↑,
NRF2↓, Lung cancer model ↓Nrf2, ↓HO-1, ↓NQO1, ↓GSH
HO-1↓,
NQO1↓,
GSH↓,
MET↓, Lung cancer model ↓MET, ↓p-MET, ↓p-Akt, ↓HGF
p‑MET↓,
p‑Akt↓,
HGF/c-Met↓,
NF-kB↓, Lung cancer model ↓NF-κB, ↓Bcl-XL, ↓MnSOD, ↑Caspase-8, ↑Caspase-3, ↑PARP
Bcl-2↓,
SOD2↓,
Casp8↑,
Casp3↑,
PARP↑,
MAPK↓, LLC-induced BCP mouse model ↓p38 MAPK, ↓GFAP, ↓IBA1, ↓NLRP3, ↓ASC, ↓Caspase1, ↓IL-1β
NLRP3↓,
ASC↓,
Casp1↓,
IL6↓, Lung cancer model ↓TNF‑α, ↓IL‑6, ↓MuRF1, ↓Atrogin-1, ↓IKKβ, ↓p‑p65, ↓p-p38
IKKα↓,
p‑p65↓,
p‑p38↑,
MMP2↓, Lung cancer model ↓MMP-2, ↓ICAM-1, ↓EGFR, ↓p-PI3K, ↓p-Akt
ICAM-1↓,
EGFR↑,
p‑PI3K↓,
E-cadherin↓, Lung cancer model ↑E-cadherin, ↑ZO-1, ↓N-cadherin, ↓Claudin-1, ↓β-Catenin, ↓Snail, ↓Vimentin, ↓Integrin β1, ↓FAK
ZO-1↑,
N-cadherin↓,
CLDN1↓,
β-catenin/ZEB1↓,
Snail↓,
Vim↑,
ITGB1↓,
FAK↓,
p‑Src↓, Lung cancer model ↓p-FAK, ↓p-Src, ↓Rac1, ↓Cdc42, ↓RhoA
Rac1↓,
Cdc42↓,
Rho↓,
PCNA↓, Lung cancer model ↓Cyclin B1, ↑p21, ↑p-Cdc2, ↓Vimentin, ↓MMP9, ↑E-cadherin, ↓AIM2, ↓Pro-caspase-1, ↓Caspase-1 p10, ↓Pro-IL-1β, ↓IL-1β, ↓PCNA
Tyro3↓, Lung cancer model ↓TAM RTKs, ↓Tyro3, ↓Axl, ↓MerTK, ↑p21
AXL↓,
CEA↓, B(a)P induced lung carcinogenesis ↓CEA, ↓NSE, ↑SOD, ↑CAT, ↑GPx, ↑GR, ↑GST, ↑GSH, ↑Vitamin E, ↑Vitamin C, ↓PCNA, ↓CYP1A1, ↓NF-kB
NSE↓,
SOD↓,
Catalase↓,
GPx↓,
GSR↓,
GSTs↓,
GSH↓,
VitE↓,
VitC↓,
CYP1A1↓,
cFos↑, Lung cancer model ↓Claudin-2, ↑p-ERK1/2, ↑c-Fos
AR↓, ↓Androgen receptor
AIF↑, Lung cancer model ↑Apoptosis-inducing factor protein
p‑STAT6↓, ↓p-STAT6, ↓Arginase-1, ↓MRC1, ↓CCL2
p‑MDM2↓, Lung cancer model ↓p-PI3K, ↓p-Akt, ↓p-MDM2, ↑p-P53, ↓Bcl-2, ↑Bax
NOTCH1↓, Lung cancer model ↑Bax, ↑Cleaved-caspase 3, ↓Bcl2, ↑circ_0000190, ↓miR-130a-3p, ↓Notch-1, ↓Hes-1, ↓VEGF
VEGF↓,
H3↓, Lung cancer model ↑Caspase 3, ↑Caspase 7, ↓H3 and H4 HDAC activities
H4↓,
HDAC↓,
SIRT1↓, Lung cancer model ↑Bax/Bcl-2, ↓Sirt1
ROS↑, Lung cancer model ↓NF-kB, ↑JNK, ↑Caspase 3, ↑PARP, ↑ROS, ↓SOD
DR5↑, Lung cancer model ↑Caspase-8, ↑Caspase-3, ↑Caspase-9, ↑DR5, ↑p-Drp1, ↑Cytochrome c, ↑p-JNK
Cyt‑c↑,
p‑JNK↑,
PTEN↓, Lung cancer model 1/5/10/30/50/80/100 μmol/L ↑Cleaved caspase-3, ↑PARP, ↑Bax, ↓Bcl-2, ↓EGFR, ↓PI3K/Akt/PTEN/mTOR, ↓CD34, ↓PCNA
mTOR↓,
CD34↓,
FasL↑, Lung cancer model ↑DR 4, ↑FasL, ↑Fas receptor, ↑Bax, ↑Bad, ↓Bcl-2, ↑Cytochrome c, ↓XIAP, ↑p-eIF2α, ↑CHOP, ↑p-JNK, ↑LC3II
Fas↑,
XIAP↓,
p‑eIF2α↑,
CHOP↑,
LC3II↑,
PD-1↓, Lung cancer model ↓PD-L1, ↓STAT3, ↑IL-2
STAT3↓,
IL2↑,
EMT↓, Luteolin exerts anticancer activity by inhibiting EMT, and the possible mechanisms include the inhibition of the EGFR-PI3K-AKT and integrin β1-FAK/Src signaling pathways
cachexia↓, luteolin could be a potential safe and efficient alternative therapy for the treatment of cancer cachexi
BioAv↑, A low-energy blend of castor oil, kolliphor and polyethylene glycol 200 increases the solubility of luteolin by a factor of approximately 83
*Half-Life↝, ats administered an intraperitoneal injection of luteolin (60 mg/kg) absorbed it rapidly as well, with peak levels reached at 0.083 h (71.99 ± 11.04 μg/mL) and a prolonged half-life (3.2 ± 0.7 h)
*eff↑, Luteolin chitosan-encapsulated nano-emulsions increase trans-nasal mucosal permeation nearly 6-fold, drug half-life 10-fold, and biodistribution of luteolin in brain tissue 4.4-fold after nasal administration

2921- LT,    Luteolin as a potential hepatoprotective drug: Molecular mechanisms and treatment strategies
- Review, Nor, NA
*hepatoP↑, Due to its excellent liver protective effect, luteolin is an attractive molecule for the development of highly promising liver protective drugs.
*AMPK↑, fig2
*SIRT1↑,
*ROS↑,
STAT3↓,
TNF-α↓,
NF-kB↓,
*IL2↓,
*IFN-γ↓,
*GSH↑,
*SREBP1↓,
*ZO-1↑,
*TLR4↓,
BAX↑, anti cancer
Bcl-2↓,
XIAP↓,
Fas↑,
Casp8↑,
Beclin-1↑,
*TXNIP↓, luteolin inhibited TXNIP, caspase-1, interleukin-1β (IL-1β) and IL-18 to prevent the activation of NLRP3 inflammasome, thereby alleviating liver injury.
*Casp1↓,
*IL1β↓,
*IL18↓,
*NLRP3↓,
*MDA↓, inhibiting oxidative stress and regulating the level of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH)
*SOD↑,
*NRF2↑, luteolin promoted the activation of the Nrf2/ antioxidant response element (ARE) pathway and NF-κB cell apoptosis pathway, thereby reversing the decrease in Nrf2 levels(lead induced liver injury)
*ER Stress↓, down regulate the formation of nitrotyrosine (NT) and endoplasmic reticulum (ER) stress induced by acetaminophen, and alleviate liver injury
*ALAT↓, ↓ALT, AST, MDA, iNOS, NLRP3 ↑GSH, SOD, Nrf2
*AST↓,
*iNOS↓,
*IL6↓, ↓TXNIP, NLRP3, TNF-α, IL-6 ↑HO-1, NQO1
*HO-1↑,
*NQO1↑,
*PPARα↑, ↓TNF-α, IL-6 IL-1β, Bax ↑PPARα
*ATF4↓, ↓ALT, AST, TNF-α, IL-6, MDA, ATF-4, CHOP ↑GSH, SOD
*CHOP↓,
*Inflam↓, Luteolin ameliorates MAFLD through anti-inflammatory and antioxidant effects
*antiOx↑,
*GutMicro↑, luteolin could significantly enrich more than 10% of intestinal bacterial species, thereby increasing the abundance of ZO-1, down regulating intestinal permeability and plasma lipopolysaccharide

2930- LT,    Luteolin confers renoprotection against ischemia–reperfusion injury via involving Nrf2 pathway and regulating miR320
- in-vitro, Nor, NA
*RenoP↑, luteolin protects the kidney against I/R injury via reducing oxidative stress, increasing antioxidant enzymes and reducing expression of Nrf2 and miR320.
*ROS↓,
*antiOx↑,
*NRF2↓,

2914- LT,    Therapeutic Potential of Luteolin on Cancer
- Review, Var, NA
*antiOx↑, As an antioxidant, Luteolin and its glycosides can scavenge free radicals caused by oxidative damage and chelate metal ions
*IronCh↑,
*toxicity↓, The safety profile of Luteolin has been proven by its non-toxic side effects, as the oral median lethal dose (LD50) was found to be higher than 2500 and 5000 mg/kg in mice and rats, respectively, equal to approximately 219.8−793.7 mg/kg in humans
*BioAv↓, One major problem related to the use of flavonoids for therapeutic purposes is their low bioavailability.
*BioAv↑, Resveratrol, which functions as the inhibitor of UGT1A1 and UGT1A9, significantly improved the bioavailability of Luteolin by decreasing the major glucuronidation metabolite in rats
DNAdam↑, Luteolin’s anticancer properties, which involve DNA damage, regulation of redox, and protein kinases in inhibiting cancer cell proliferation
TumCP↓,
DR5↑, Luteolin was discovered to promote apoptosis of different cancer cells by increasing Death receptors, p53, JNK, Bax, Cleaved Caspase-3/-8-/-9, and PARP expressions
P53↑,
JNK↑,
BAX↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↑,
survivin↓, downregulating proteins involved in cell cycle progression, including Survivin, Cyclin D1, Cyclin B, and CDC2, and upregulating p21
cycD1↓,
CycB↓,
CDC2↓,
P21↑,
angioG↓, suppress angiogenesis in cancer cells by inhibiting the expression of some angiogenic factors, such as MMP-2, AEG-1, VEGF, and VEGFR2
MMP2↓,
AEG1↓,
VEGF↓,
VEGFR2↓,
MMP9↓, inhibit metastasis by inhibiting several proteins that function in metastasis, such as MMP-2/-9, CXCR4, PI3K/Akt, ERK1/2
CXCR4↓,
PI3K↓,
Akt↓,
ERK↓,
TumAuto↑, can promote the conversion of LC3B I to LC3B II and upregulate Beclin1 expression, thereby causing autophagy
LC3B-II↑,
EMT↓, Luteolin was identified to suppress the epithelial to mesenchymal transition by upregulating E-cadherin and downregulating N-cadherin and Wnt3 expressions.
E-cadherin↑,
N-cadherin↓,
Wnt↓,
ROS↑, DNA damage that is induced by reactive oxygen species (ROS),
NICD↓, Luteolin can block the Notch intracellular domain (NICD) that is created by the activation of the Not
p‑GSK‐3β↓, Luteolin can inhibit the phosphorylation of the GSK3β induced by Wnt, resulting in the prevention of GSK3β inhibition
iNOS↓, Luteolin in colon cancer and the complications associated with it, particularly the decreasing effect on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)
COX2↓,
NRF2↑, Luteolin has been identified to increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which is a crucial transcription factor with anticarcinogenic properties related
Ca+2↑, caused loss of the mitochondrial membrane action potential, enhanced levels of mitochondrial calcium (Ca2+),
ChemoSen↑, Luteolin enhanced the effect of one of the most effective chemotherapy drugs, cisplatin, on CRC cells
ChemoSen↓, high dose of Luteolin application negatively affected the oxaliplatin-based chemotherapy in a p53-dependent manner [52]. They suggested that the flavonoids with Nrf2-activating ability might interfere with the chemotherapeutic efficacy of anticancer
IFN-γ↓, decreased the expression of interferon-gamma-(IFN-γ)
RadioS↑, suggested that Luteolin can act as a radiosensitizer, promoting apoptosis by inducing p38/ROS/caspase cascade
MDM2↓, Luteolin treatment was associated with increased p53 and p21 and decreased MDM4 expressions both in vitro and in vivo.
NOTCH1↓, Luteolin suppressed the growth of lung cancer cells, metastasis, and Notch-1 signaling pathway
AR↓, downregulating the androgen receptor (AR) expression
TIMP1↑, Luteolin inhibits the migration of U251MG and U87MG human glioblastoma cell lines by downregulating MMP-2 and MMP-9 and upregulating the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2.
TIMP2↑,
ER Stress↑, Luteolin caused oxidative stress and ER stress in the Hep3B cells,
CDK2↓, Luteolin’s ability to decrease Akt, polo-like kinase 1 (PLK1), cyclin B1, cyclin A, CDC2, cyclin-dependent kinase 2 (CDK2) and Bcl-xL
Telomerase↓, Luteolin dose-dependently inhibited the telomerase levels and caused the phosphorylation of NF-κB and the target gene of NF-κB, c-Myc to suppress the human telomerase reverse transcriptase (hTERT)
p‑NF-kB↑,
p‑cMyc↑,
hTERT↓,
RAS↓, Luteolin was found to suppress the expressions of K-Ras, H-Ras, and N-Ras, which are the activators of PI3K
YAP/TEAD↓, Luteolin caused significant inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)
TAZ↓,
NF-kB↓, Luteolin was found to have a strong inhibitory effect on the NF-κB
NRF2↓, Luteolin-loaded nanoparticles resulted in a significant reduction in the Nrf2 levels compared to Luteolin alone.
HO-1↓, The expressions of the downstream genes of Nrf2, Ho1, and MDR1 were also reduced, where inhibition of Nrf2 expression significantly increased the cell death of breast cancer cells
MDR1↓,

2595- LT,    Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?
- Review, Var, NA
*NRF2↑, Nrf2/ARE Activation in Non-Cancer Experimental Model - (luteolin, baicalin and apigenin) are more prominent in upregulating Nrf2 protein expression in both in vitro
NRF2↓, , luteolin, apigenin and chrysin, were found to be effective in inhibiting the Nrf2/ARE pathway in different cancer cell lines [60,61,62,63,68,209].
NRF2⇅, luteolin exhibits dual roles in cancer cell growth in vitro and cancer promotion in vivo

2589- LT,  Chemo,    Luteolin Inhibits Breast Cancer Stemness and Enhances Chemosensitivity through the Nrf2-Mediated Pathway
- in-vitro, BC, MDA-MB-231
NRF2↓, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features
HO-1↓,
ChemoSen↑, combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells.
CSCs↓, Luteolin Inhibited Cancer Stemness Capacity in MDA-MB-231 Cells
SIRT1↓, luteolin suppressed Nrf2, HO-1, Sirt3, and Cripto-1 expression in MDA-MB-231 cells.

2588- LT,  Chemo,    Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway
- in-vitro, CRC, HCT116
NRF2↓, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner.
NQO1↓, Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and GSTα1/2] expression and decreased reduced glutathione in wild type mouse small intestinal cells.
HO-1↓,
GSH↓,
ChemoSen↑, uteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect.

2587- LT,    Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs
- in-vitro, Lung, A549
NRF2↓, luteolin elicited a dramatic reduction in Nrf2 at both the mRNA and the protein levels, leading to decreased Nrf2 binding to AREs, down-regulation of ARE-driven genes, and depletion of reduced glutathione.
GSH↓,
ChemoSen↑, luteolin significantly sensitized A549 cells to the anticancer drugs oxaliplatin, bleomycin, and doxorubicin.
HO-1↓, ↓HO-1

1709- Lyco,    Lycopene prevents carcinogen-induced cutaneous tumor by enhancing activation of the Nrf2 pathway through p62-triggered autophagic Keap1 degradation
- in-vitro, Nor, JB6
*antiOx↑, Lycopene stimulated the activation of antioxidant enzymes and the translocation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) that predominantly maintained intracellular redox equilibrium
*NRF2↑, Lycopene activated the Nrf2 pathway in the presence of carcinogens in vivo and in vitro
*GSH/GSSG↓, Lycopene also rebalanced the GSH/GSSG ratio, partly representing the cellular redox condition commendably
*Catalase↝, catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), and glutathione peroxidase (GPx), lower activities of these enzymes were reversed by this compound
*GR↝,
*SOD↝,
*GPx↝,
*GSH↑, mRNA levels of GSH and these antioxidant substances were also up-regulated significantly by lycopene pretreatment
*Keap1↓, Lycopene induced activation of Nrf2 by reducing Keap1 protein
*p62↑, lycopene induced p62 binding to Keap1, so Keap1 degradation was mediated by p62

1708- Lyco,    The Anti-Cancer Activity of Lycopene: A Systematic Review of Human and Animal Studies
- Review, Var, NA
OS↑, reduced prostate cancer-specific mortality in men at high risk for prostate cancer
ChemoSen↑, improved the response to docetaxel chemotherapy in advanced castrate-resistant prostate cancer
QoL↑, lycopene improved the quality of life, and provided relief from bone pain and control of lower urinary tract symptoms
PSA∅, PSA stabilisation in prostate cancer
eff↑, Lycopene co-supplementation with vitamin E also showed an improvement in the results of prostate cancer treatment
AntiCan↑, lycopene intake showed a strong protective effect against stomach cancer, regardless of H. pylori status
AntiCan↑, A lycopene-rich diet was shown to reduce the incidence of pancreatic cancer in humans by 31%
angioG↓,
VEGF↓,
Hif1a↓,
SOD↑,
Catalase↑,
GPx↑,
GSH↑,
GPx↑,
GR↑,
MDA↓,
NRF2↑,
HO-1↑,
COX2↓,
PGE2↓,
NF-kB↓,
IL4↑,
IL10↑,
IL6↓,
TNF-α↓,
PPARγ↑,
TumCCA↑, G(0)/G(1) phase
FOXO3↓,
Casp3↑,
IGF-1↓, breast cancer,crc
p27↑,
STAT3↓,
CDK2↓,
CDK4↓,
P21↑,
PCNA↓,
MMP7↓,
MMP9↓,

3528- Lyco,    The Importance of Antioxidant Activity for the Health-Promoting Effect of Lycopene
- Review, Nor, NA - Review, AD, NA - Review, Park, NA
*antiOx↑, the antioxidant effect of lycopene
*ROS↓, Lycopene has the ability to reduce reactive oxygen species (ROS) and eliminate singlet oxygen, nitrogen dioxide, hydroxyl radicals, and hydrogen peroxide
*BioAv↝, human body cannot synthesize lycopene. It must be supplied with the diet
*Half-Life↑, half-life of lycopene in human plasma is 12–33 days
*BioAv↓, bioavailability decreases with age and in the case of certain diseases
*BioAv↑, heat treatment process of food increases the bioavailability of lycopene
*cardioP↑, positive effect on cardiovascular diseases, including the regulation of blood lipid levels
*neuroP↑, beneficial effects in nervous system disorders, including neurodegenerative diseases such as Parkinson′s disease and Alzheimer′s disease
*H2O2↓, Lycopene has the ability to reduce reactive oxygen species (ROS) and eliminate singlet oxygen, nitrogen dioxide, hydroxyl radicals, and hydrogen peroxide
*VitC↑, ability to regenerate non-enzymatic antioxidants such as vitamin C and E.
*VitE↑,
*GPx↑, increase in cardiac GSH-Px activity and an increase in cardiac GSH levels
*GSH↑,
*MPO↓, also a decrease in the level of cardiac myeloperoxidase (MPO), cardiac H2O2, and a decrease in cardiac glutathione S transferase (GSH-ST) activity.
*GSTs↓,
*SOD↑, increasing the activity of GSH-Px and SOD in the liver
*NF-kB↓, reducing the expression of NF-κB mRNA in the heart
*IL1β↓, decreased the level of IL-1β and IL-6 and increased the level of anti-inflammatory IL-10 in the heart
*IL6↓,
*IL10↑,
*MAPK↓, inhibited the activation of the ROS-dependent pro-hypertrophic mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways.
*Akt↓,
*COX2↓, decrease in the levels of pro-inflammatory mediators in heart: COX-2, TNF-α, IL-6, and IL-1β and an increase in the anti-inflammatory cardiac TGF-β1.
*TNF-α↓,
*TGF-β1↑,
*NO↓, reduced NO levels in heart and cardiac NOS activity
*GSR↑, increase in the level of cardiac and hepatic SOD, CAT, GSH, GPx, and glutathione reductase (GR)
*NRF2↑, It also activated nuclear factor-erythroid 2 related factor 2 (Nrf2). This affected the downstream expression of HO-1 [97].
*HO-1↑,
*TAC↑, Researchers observed an increase in the liver in TAC and GSH levels and an increase in GSH-Px and SOD activity
*Inflam↓, study showed that lycopene was anti-inflammatory
*BBB↑, Lycopene is a lipophilic compound, which makes it easier to penetrate the blood–brain barrier.
*neuroP↑, Lycopene had also a neuroprotective effect by restoring the balance of the NF-κB/Nrf2 pathway.
*memory↑, lycopene on LPS-induced neuroinflammation and oxidative stress in C57BL/6J mice. The tested carotenoid prevented memory loss

3531- Lyco,    Lycopene attenuates the inflammation and apoptosis in aristolochic acid nephropathy by targeting the Nrf2 antioxidant system
- in-vivo, Nor, NA
*NRF2↑, After LYC intervened in the body, it activated Nrf2 nuclear translocation and its downstream HO-1 and NQO1 antioxidant signaling pathways
*HO-1↑, Lycopene activates Nrf2-HO-1 antioxidant pathway to inhibit oxidative stress injury induced by AAI exposure in NRK52E cells
*NQO1↑,
*ROS↓, LYC inhibited ROS production by renal tubular epithelial cells, and alleviated mitochondrial damage.
*mtDam↓,
*Bcl-2↑, LYC was able to up-regulate the expression of Bcl-2, down-regulate Bax expression and inhibit the activation of cleaved forms of Caspase-9 and Caspase-3, which finally attenuated the apoptosis
*BAX↓,
*Casp9↓,
*Casp3↓,
*Apoptosis↓,
*RenoP↑, Interestingly, there was a significant improvement in damaged renal tissue in mice with AAN after lycopene intervention
*lipid-P↓, lycopene significantly decreased the expression of AAI-induced lipid peroxidation product (MDA), and increased the expression of antioxidant enzyme systems (T-AOC, SOD, and GSH-PX)
*SOD↑,
*GPx↑,
*Inflam↓, Lycopene improves inflammatory responses in the kidneys of AAN mice
*TNF-α↓, TNF-α, IL-6, IL-10, was increased and the expression of IL-12 was decreased in the kidneys of model mice compared with the control group. However, LYC intervention reversed the expression of these genes in a dose-dependent manner
*IL6↓,
*IL10↓,

3532- Lyco,    Lycopene alleviates oxidative stress via the PI3K/Akt/Nrf2pathway in a cell model of Alzheimer’s disease
- in-vitro, AD, NA
*ROS↓, Lycopene alleviated OS and apoptosis, activated the PI3K/Akt/Nrf2 signaling pathway, upregulated antioxidant and antiapoptotic proteins and downregulated proapoptotic proteins.
*PI3K↑,
*Akt↑,
*NRF2↑,
*antiOx↑,
*Aβ↓, Lycopene possibly prevents Aβ-induced damage by activating the PI3K/Akt/Nrf2 signaling pathway and reducing the expression of BACE in M146L cells.
*Apoptosis↓, Lycopene alleviates apoptosis in M146L cells
*neuroP↑, lycopene shows the neuroprotective effects of antioxidative damage and antiapoptotic by reducing the phosphorylation of PI3K/Akt

3275- Lyco,    Multifaceted Effects of Lycopene: A Boulevard to the Multitarget-Based Treatment for Cancer
- Review, Var, NA
TumCCA↑, lycopene impedes the progress of the cell cycle from the G1 to the S phase, primarily by diminishing the cyclin D and cyclin E levels.
cycD1↓,
cycE↓,
CDK2↓, causes a subsequent inactivation of CDK4 and CDK2 through a reduced phosphorylation of Rb
CDK4↓,
P21↑, lycopene elevates CDK inhibitor, p21, and p53 (tumor suppressor) levels
P53↑,
GSK‐3β↓, Finally, GSK3β, p21, p27, Bad, caspase 9, and p53 (via Mdm2) are inactivated
p27↓,
Akt↓, lycopene inhibits AKT (protein kinase B) and mTOR
mTOR↓,
ROS↓, ability of lycopene to minimize ROS formation and mitigate oxidative stress
MMPs↓, lycopene may decrease the activity of metalloproteinases of the matrix and prevent SK-Hep1 cellular adhesion, invasion, and migration
TumCI↓,
TumCMig↓,
NF-kB↓, well-documented that lycopene inhibits NF-kB binding activity
*iNOS↓, They also claimed that the lycopene caused a decline in the LPS-induced protein and mRNA expression of iNOS,
*COX2↓, Lycopene can therefore decrease the gene expression of iNOS and COX-2 as a non-toxic agent via controlling pro-inflammatory genes
lipid-P↓, suppress gastric cancer by multimodal mechanisms of reduction in lipid peroxidation, elevation in the levels of antioxidants, and enhanced GSH
GSH↑,
NRF2↑, Reportedly, lycopene is known to “upregulate” this ARE system via Nrf2 in vitro (HepG2 and MCF-7 cells)

3268- Lyco,    Lycopene as a Natural Antioxidant Used to Prevent Human Health Disorders
- Review, AD, NA
*BioAv↓, Lycopene bioavailability can be decreased by ageing, and some of the pathological states, such as cardiovascular diseases (CVDs)
*AntiCan↑, For instance, it has been shown that a higher dietary intake and circulating concentration of lycopene have protective effects against prostate cancer (PCa), in a dose-dependent way
*ROCK1↓, It remarkably lessened the expression of ROCK1, Ki-67, ICAM-1 and ROCK2,
*Ki-67↓,
*ICAM-1↓,
*cardioP↑, Lycopene is a cardioprotective nutraceutical.
*antiOx↑, Lycopene is a well-known antioxidant.
*NQO1↑, Furthermore, lycopene supplementation improves mRNA expressions of the NQO-1 and HO-1 as antioxidant enzymes.
*HO-1↑,
*TNF-α↓, downregulate inflammatory cytokines (i.e., TNF-α, and IL-1β) in the hippocampus of the mice.
*IL22↓,
*NRF2↑, Lycopene decreased neuronal oxidative damage by activating Nrf2, as well as by inactivating NF-κB translocation in H2O2-related SH-SY5Y cell model
*NF-kB↓,
*MDA↓, significantly reduced the malondialdehyde (MDA)
*Catalase↑, Furthermore, it improved the catalase (CAT), superoxide dismutase (SOD), and GSH levels, and antioxidant capacity [109].
*SOD↑,
*GSH↑,
*cognitive↑, Lycopene administration considerably improved cognitive defects, noticeably reduced MDA levels and elevated GSH-Px activity, and remarkably reduced tau
*tau↓,
*hepatoP↑, Lycopene was also found to be effective against hepatotoxicity by acting as an antioxidant, regulating total glutathione (tGSH) and CAT concentrations
*MMP2↑, It also elevated MMP-2 down-regulation
*AST↓, lowering the liver enzymes levels, like aspartate transaminase (AST), alanine transaminase (ALT), LDL, free fatty acid, and MDA.
*ALAT↓,
*P450↑, Moreover, tomato powder has been shown to have a protective agent against alcohol-induced hepatic injury by inducing cytochrome p450 2E1
*DNAdam↓, lycopene decreased DNA damage
*ROS↓, It has been revealed that they inhibited ROS production, protected antioxidant enzymes, and reversed hepatotoxicity in rats’ liver
*neuroP↑, lycopene consumption relieved cognitive defects, age-related memory loss, neuronal damage, and synaptic dysfunction of the brain.
*memory↑,
*Ca+2↓, Lycopene suppressed the 4-AP-invoked release of glutamate and elevated intra-synaptosomal Ca2+ level.
*Dose↝, an in vivo study revealed that lycopene (6.5 mg/day) was effective against cancer in men [147]. However, lycopene dose should be increased up to 10 mg/day, in the case of advanced PCa.
*Dose↑, lycopene supplementation (15 mg/day, for 12 weeks) in an old aged population improved immune function through increasing natural killer cell activity by 28%
*Dose↝, Finally, according to different epidemiological studies, daily lycopene intake can be suggested to be 2 to 20 mg per day
*toxicity∅, A toxicological study on rats showed the no-observed-adverse-effect level at the highest examined dose (i.e., 1.0% in the diet)
PGE2↓, Lycopene doses of 0, 10, 20, and 30 µM were used to treat human colorectal cancer cell. Prostaglandin E2 (PGE2), and NO levels declined after lycopene administration,
CDK2↓, Treatment with lycopene reduced cell hyperproliferation induced by UVB and ultimately promoted apoptosis and reduced CDK2 and CDK4 complex in SKH-1 hairless mice
CDK4↓,
STAT3↓, lycopene reduced the STAT3 expression in ovarian tissues
NOX↓, (SK-Hep-1) cells and indicated a substantial reduction in NOX activity. Moreover, it inhibits the protein expression of NOX4, NOX4 mRNA and ROS intracellular amounts
NOX4↓,
ROS↓,
*SREBP1↓, Lycopene decreases the fatty acid synthase (FAS), sterol regulatory element-binding protein 1c (SREBP-1c), and Acetyl-CoA carboxylase (ACC1) expression in HFD mice.
*FASN↓,
*ACC↓,

3264- Lyco,    Pharmacological potentials of lycopene against aging and aging‐related disorders: A review
- Review, Var, NA - Review, AD, NA - Review, Stroke, NA
*antiOx↑, Anti‐oxidative mechanism of lycopene
*ROS↓, Lycopene inhibits ROS generation and subsequent oxidative stress by inducing antioxidant enzymes (SOD, CAT, GSH, GSH‐Px, and GST) and limiting MDA level and lipid peroxidation (LPO).
*SOD↑,
*Catalase↑,
*GSH↑,
*GSTs↑,
*MDA↓,
*lipid-P↓,
*NRF2↑, Lycopene also prevents ROS release by upregulating Nrf2‐mediated HO‐1 levels and inhibiting iNOS‐activated NO generation
*HO-1↑,
*iNOS↓,
*NO↓,
*TAC↑, upregulating total antioxidant capacity (TAC) and direct inhibition of 8‐OHdG, NOX4.
*NOX4↓,
*Inflam↓, Anti‐inflammatory mechanism of lycopene.
*IL1↓, IL‐1, IL‐6, IL‐8, IL‐1β, and TNF‐α release.
*IL6↓,
*IL8↓,
*IL1β↓,
*TNF-α↓,
*TLR2↓, prevents inflammation by inhibiting toll‐like receptors TLR2 and TLR4 and endothelial adhesion molecules VCAM1 and ICAM‐1.
*TLR4↓,
*VCAM-1↓,
*ICAM-1↓,
*STAT3↓, inhibiting STAT3, NF‐κB, ERK pathway, and IL‐6 and TNF‐α release.
*NF-kB↓,
*ERK↓,
*BP↓, Another clinical study demonstrated that consumption of raw tomato (200 g/day) could prevent type 2 diabetes‐associated cardiovascular diseases by lowering systolic and diastolic blood pressure, upregulating ApoA1, and downregulating ApoB levels
ROS↓, lycopene suppresses the metastasis of the SK‐HEP‐1 cell line by NOX‐4 mRNA expression inhibition and the reactive ROS intracellular activity inhibition
PGE2↓, Lycopene is also used to treat colorectal cancer cells in humans, and the introduction of lycopene decreases the prostaglandin E2 and nitric oxide levels
cardioP↑, Lycopene‐rich foods can be highly beneficial in preventing cardiovascular diseases as lycopene is a potential source of antioxidants
*neuroP↑, beneficial role of lycopene on aging‐related neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been confirmed in both experimental and clinical trials
*creat↓, Several pre‐clinical studies reported that lycopene treatment significantly reduced serum urea and serum creatinine, as well as reversed various toxic chemical‐induced nephrotoxicity and oxidative damage by exhibiting excellent antioxidative properti
*RenoP↑,

1780- MEL,    Utilizing Melatonin to Alleviate Side Effects of Chemotherapy: A Potentially Good Partner for Treating Cancer with Ageing
- Review, Var, NA
*antiOx↑, Melatonin is a potent antioxidant and antiageing molecule, is nontoxic, and enhances the efficacy and reduces the side effects of chemotherapy.
*toxicity↓,
ChemoSen↑,
*eff↑, melatonin was superior in preventing free radical destruction compared to other antioxidants, vitamin E, β-carotene, vitamin C, and garlic oil
*mitResp↑, increasing the expression and activity of the mitochondrial respiration chain complexes
*ATP↑, increasing the expression and activity of the mitochondrial respiration chain complexes
*ROS↓, most attractive property of melatonin is that its metabolites also regulate the mitochondrial redox status by scavenging ROS and RNS
*CardioT↓, melatonin has a protective effect on the heart without affecting DOX's antitumor activity,
*GSH↑, improving the de novo synthesis of glutathione (GSH) by promoting the activity of gamma-glutamylcysteine synthetase
*NOS2↓, melatonin inhibits the production of nitric oxide synthase (NOS)
*lipid-P↓, lipid peroxidation was reduced after melatonin treatment (role in induces organ failure)
eff↑, but it also enhances its antitumor activity more than vitamin E
*HO-1↑, melatonin upregulates heme oxygenase-1 (HO-1) (role in induces organ failure)
*NRF2↑, decreased bladder injury and apoptosis due to the upregulation of Nrf2 and nuclear transcription factor NF-κB expression
*NF-kB↑,
TumCP↓, significantly reduced cell proliferation
eff↑, Pretreatment with melatonin effectively preserved the ovaries from cisplatin-induced injury
neuroP↑, Melatonin has neuroprotective roles in oxaliplatin-induced peripheral neuropathy

1204- MET,    Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer
- in-vitro, Lung, A549 - in-vitro, Lung, H1299
MDA↑,
ROS↑,
Iron↑, iron ions
GSH↓,
T-SOD↓,
Catalase↓,
GPx4↓,
xCT↓,
NRF2↓,
HO-1↓,

3457- MF,    Cellular stress response to extremely low‐frequency electromagnetic fields (ELF‐EMF): An explanation for controversial effects of ELF‐EMF on apoptosis
- Review, Var, NA
Apoptosis↑, Ding et al., 8 it was demonstrated that 24‐h exposure to 60 Hz, 5 mT ELF‐EMF could potentiate apoptosis induced by H2O2 in HL‐60 leukaemia cell lines.
H2O2↑,
ROS↑, One of the main mechanisms proposed for defining anticancer effects of ELF‐EMF is induction of apoptosis through upregulation of reactive oxygen species (ROS) which has also been confirmed by different experimental studies.
eff↑, intermittent 100 Hz, 0.7 mT EMF significantly enhanced rate of apoptosis in human hepatoma cell lines pretreated with low‐dose X‐ray radiation.
eff↑, 50 Hz, 45 ± 5 mT pulsed EMF, significantly potentiated rate of apoptosis induced by cyclophosphamide and colchicine
Ca+2↑, Over the past few years, lots of data have shown that ELF‐EMF exposure regulates intracellular Ca2+ level
MAPK↑, Mitogen‐activated protein kinase (MAPK) cascades are among the other important signalling cascades which are stimulated upon exposure to ELF‐EMF in several types of examined cells
*Catalase↑, ELF‐EMF exposure can upregulate expression of different antioxidant target genes including CAT, SOD1, SOD2, GPx1 and GPx4.
*SOD1↑,
*GPx1↑,
*GPx4↑,
*NRF2↑, Activation and upregulation of Nrf2 expression, the master redox‐sensing transcription factor may be the most prominent example in this regard which has been confirmed in a Huntington's disease‐like rat model.
TumAuto↑, Activation of autophagy, ER stress, heat‐shock response and sirtuin 3 expression are among the other identified cellular stress responses to ELF‐EMF exposure
ER Stress↑,
HSPs↑,
SIRT3↑,
ChemoSen↑, Contrarily, when chemotherapy and ELF‐EMF exposure are performed simultaneously, this increase in ROS levels potentiates the oxidative stress induced by chemotherapeutic agents
UPR↑, In consequence of ER stress, cells begin to initiate UPR to counteract stressful condition.
other↑, Since the only proven effects of ELF‐EMF exposure on cells are cellular adaptive responses, ROS overproduction and intracellular calcium overload
PI3K↓, figure 3
JNK↑,
p38↑,
eff↓, ontrarily, when cells are exposed to ELF‐EMF, a new source of ROS production is introduced in cells which can at least partially reverse anticancer effects observed with cell's treatment with melatonin.
*toxicity?, More importantly, ELF‐EMF exposure to normal cells in most cases has shown to be safe and un‐harmful.

3462- MF,    The Effect of a Static Magnetic Field on microRNA in Relation to the Regulation of the Nrf2 Signaling Pathway in a Fibroblast Cell Line That Had Been Treated with Fluoride Ions
- in-vitro, Nor, NA
*NRF2↑, Moreover, the static magnetic field had a beneficial effect on the cells with fluoride-induced oxidative stress due to stimulating the antioxidant defense.
*Keap1↓, exposure to an SMF induced a significant reduction in the level of KEAP1 mRNA compared to the untreated cells
*SOD↑, also increased activity of the antioxidant enzymes (superoxide dismutase—SOD and glutathione peroxidase—GPx) compared to the cells that had only been treated with fluoride
*GPx↑,
*ROS↓, SMF resulted in a decrease in the production of intracellular ROS and a decrease in the MDA concentration, as was shown in our previous report
*MDA↓,
*SOD1↑, SOD1, SOD2 and GSR (glutathione reductase) a significant increase in their expression was revealed in the cells that had been co-exposed to fluoride and an SMF with a 0.65 T flux density
*SOD2↑,
*GSR↑,

1273- Myr,    Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4
- vitro+vivo, GC, NA
Ferroptosis↑, (iron and ROS are critical for ferroptosis)
MDA↑,
Iron↑,
GSH↓,
NOX4↑, increased NOX4 expression in tumor tissue (is an enzyme that produces reactive oxygen species (ROS), particularly hydrogen peroxide (H₂O₂).)
NRF2↓,
GPx4↓,

1987- Part,  Rad,    A NADPH oxidase dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells
- in-vitro, Pca, PC3 - in-vitro, Nor, PrEC
selectivity↑, parthenolide (PN), a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells.
RadioS↑,
ROS↑, oxidative stress in PC3 cells but not in PrEC cells
*ROS∅, oxidative stress in PC3 cells but not in PrEC cells
NADPH↑, In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, MnSOD, CAT
Trx↓,
PI3K↑,
Akt↑,
p‑FOXO3↓, downregulation of FOXO3a targets, antioxidant enzyme manganese superoxide dismutase (MnSOD) and catalase
SOD2↓, MnSOD
Catalase↓,
radioP↑, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells
*NADPH∅, Parthenolide activates NADPH oxidase in PC3 cells but not in PrEC cells
*GSH↑, increases glutathione (GSH) in PrEC cells(normal cells)
*GSH/GSSG↑, GSH/GSSG ratio is not significantly changed by parthenolide in PC3 cells but is increased 2.4 fold in PrEC cells (normal cells)
*NRF2↑, The induction of GSH may be due to the activation of the Nrf2/ARE (antioxidant/electrophile response element) pathway

1985- Part,    KEAP1 Is a Redox Sensitive Target That Arbitrates the Opposing Radiosensitive Effects of Parthenolide in Normal and Cancer Cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145 - in-vitro, Nor, PrEC - in-vivo, NA, NA
ROS↑, parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase
NADPH↑,
RadioS↑, In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury
radioP↑, DMAPT, the water soluble prodrug of parthenolide, is a promising agent for selectively enhancing the sensitivity of prostate cancer cells to radiation while protecting normal tissues from damage caused by radiation.
Trx↓, causes oxidation of thioredoxin (TrX) in prostate cancer cells
*ox-Keap1↑, three normal cell lines, parthenolide increased the oxidized form of Keap1 but decreased the reduced form of Keap1
ox-Keap1↓, results from the three cancer cell lines appeared to be completely opposite to results observed in normal cells treated with parthenolide
rd-Keap1↑, in vivo results show that parthenolide decreased the oxidized form of Keap1 but increased the reduced form of Keap1 in the tumors
*NRF2↑, Oxidization of Keap1 leads to activation of the Nrf2 pro-survival pathway in normal cells. Nrf2 pathway is a major mechanism by which parthenolide protects normal cells against radiation injury
NRF2∅, but no changes were observed in the three cancer cell lines.
NF-kB↓, It has been reported that parthenolide is a potent inhibitor of NF-κB

1680- PBG,    Protection against Ultraviolet A-Induced Skin Apoptosis and Carcinogenesis through the Oxidative Stress Reduction Effects of N-(4-bromophenethyl) Caffeamide, a Propolis Derivative
- in-vitro, Nor, HS68
*ROS↓, K36H reduced UVA-induced intracellular reactive oxygen species generation
*NRF2↑, increased nuclear factor erythroid 2–related factor 2 translocation into the nucleus to upregulate the expression of heme oxygenase-1, an intrinsic antioxidant enzyme.
*HO-1↑,
*cJun↓, K36H inhibited UVA-induced activation of extracellular-signal-regulated kinases and c-Jun N-terminal kinases,
*MMP1↓, reduced the overexpression of matrix metalloproteinase (MMP)-1 and MMP-2
*MMP2↓,
*p‑cJun↓, K36H inhibited the phosphorylation of c-Jun and downregulated c-Fos expression
*cFos↓,
*BAX↓, K36H attenuated UVA-induced Bax and caspase-3 expression and upregulated antiapoptotic protein B-cell lymphoma 2 expression.
*Casp3↓,
*DNAdam↓, K36H reduced UVA-induced DNA damage.
*iNOS↓, K36H also downregulated inducible nitric oxide synthase, cyclooxygenase-2 and interleukin-6 expression as well as the subsequent generation of prostaglandin E2 and nitric oxide.
*COX2↓,
*IL6↓,
*PGE2↓,
*NO↓,

3251- PBG,    The Antioxidant and Anti-Inflammatory Effects of Flavonoids from Propolis via Nrf2 and NF-κB Pathways
- Review, AD, NA - Review, Diabetic, NA - Review, Var, NA - in-vitro, Nor, H9c2
*antiOx↑, In this study, the antioxidant and anti-inflammatory effects of the main flavonoids of propolis (chrysin, pinocembrin, galangin, and pinobanksin) and propolis extract were researched.
*Inflam↓,
*ROS↓, ROS levels were decreased; SOD and CAT activities were increased; and the expression of HO-1 protein was increased by chrysin.
*SOD↑,
*Catalase↑,
*HO-1↑,
*NO↓, The results demonstrated that NO (Nitric Oxide), NOS (Nitric Oxide Synthase), and the activation of the NF-κB signaling pathway were inhibited in a dose-dependent manner
*NOS2↓,
*NF-kB↓,
*NRF2↑, it is possible that phytochemicals activate the Nrf2 pathway and inhibited the NF-κB (Nuclear factor kappa B) pathway.
*hepatoP↑, propolis has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, and hepatoprotective properties.
*MDA↓, chrysin reduced the cytotoxicity, MDA levels, and lysosomal and mitochondrial damage induced by AlP in a dose-dependent manner and increased the GSH activity induced by AlP i
*mtDam↓,
*GSH↑,
*p65↓, Similarly, galangin at 15, 30, and 60 mg/kg inhibited the expression of NF-κB p65, NOS, TNF-α, and IL-1β in a dose-dependent manner
*TNF-α↓,
*IL1β↓,
*NRF2↑, Nrf2 translocation from the cytoplasm to the nucleus was up-regulated (chrysin range of 5 μM–10 μM, pinocembrin range of 5 μM–40 μM, and propolis-extract range of 5 μg/mL–40 μg/mL)
*NRF2↓, and then down-regulated (chrysin range of 15 μM–25 μM, pinocembrin range of 40 μM–60 μM, and propolis-extract range of 40 μg/mL–100 μg/mL) following treatments with chrysin, pinocembrin, and propolis extract
*ROS⇅, Secondly, chrysin, pinocembrin, galangin, pinobanksin, and propolis extract exhibited antioxidant and pro-oxidant effects in a dose-dependent manner.
*BioAv↓, bioavailability values of galangin and chrysin in propolis extracts were determined in a study, and they were at 7.8% and 7.5%, respectively
*BioAv↑, Moreover, propolis extract has a higher bioavailability than single-flavonoid standards

3252- PBG,    Propolis Extract and Its Bioactive Compounds—From Traditional to Modern Extraction Technologies
- Review, NA, NA
*Inflam↓, extracts act by suppressing similar targets, from pro-inflammatory TNF/NF-κB to the pro-proliferative MAPK/ERK pathway.
*TNF-α↓,
*NF-kB↓,
*MAPK↓,
*ERK↓,
*antiOx↑, they activate similar antioxidant mechanisms of action, like Nrf2-ARE intracellular antioxidant pathway,
*NRF2↑,
*cardioP↑, pinocembrin was shown to be cardioprotective by enhancing glycolysis in the myocardium, which is an essential mechanism of action against ischemic injury of the heart
*Glycolysis↑,
*Ca+2↓, Reducing the content of Ca2+ in mitochondria prevents mitochondrial membrane swelling,
*HO-1↑, CAPE is beneficial as an antioxidant and the inductor of heme oxygenase-1 (HO), Nrf2-regulated gene
*NRF2↑,
*neuroP↑, HO-1 induction results in cardioprotective effects in diabetes [80], neuroprotective in microglial cells

3253- PBG,    Brazilian red propolis extract enhances expression of antioxidant enzyme genes in vitro and in vivo
- in-vitro, Nor, HEK293 - in-vivo, Nor, NA
*NRF2↑, enhanced the expression of Nrf2-regulated genes in HEK293 cells. It also increased Nrf2 protein in the nucleus, which was partially inhibited by kinase inhibitors.
*ROS↓, EERP suppressed ROS generation and cytotoxicity induced by tert-butyl hydroperoxide.

3254- PBG,    Brazilian green propolis water extract up-regulates the early expression level of HO-1 and accelerates Nrf2 after UVA irradiation
- in-vitro, Nor, NA
*HO-1↑, WEP acts as an early inducer of HO-1 and rapid activator of Nrf2 to protect against UVA-induced oxidative stress.
*NRF2↑,

3255- PBG,    Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2
- in-vivo, Nor, NA
*IGF-1↓, propolis downregulated IGF1 expression
*MMP2↑, Propolis also increased MMP-2 and decreased MMP-12 expression, favoring the process of tissue repair.
*ROS↓, propolis recruited leukocytes, including macrophages, without ROS release.
*Inflam↓, thus increasing the number of arginase-positive cells and IL-10 levels and favoring an anti-inflammatory microenvironment
*IL10↓,
*NRF2∅, Proteins and enzymes related to Nrf2 were not altered,

3257- PBG,    The Potential Use of Propolis as a Primary or an Adjunctive Therapy in Respiratory Tract-Related Diseases and Disorders: A Systematic Scoping Review
- Review, Var, NA
CDK4↓, CAPE also induces G1 phase cell arrest by lowering the expression of CDK4, CDK6, Rb, and p-Rb. M
CDK6↓,
pRB↓,
ROS↓, Artepillin C, a bioactive component of Brazilian green propolis, reduces oxidative damage markers, namely 4-HNE-modified proteins, 8-OHdG, malonaldehyde, and thiobarbituric acid reactive substances in lung tissues with pulmonary adenocarcinoma
TumCCA↑, Propolin, a novel component of prenylflavanones in Taiwanese propolis, was demonstrated to have anti-cancer properties. Propolin H induces cell arrest at G1 phase and upregulates the expression of p21
P21↑,
PI3K↓, Propolin C also inhibits PI3K/Akt and ERK-mediated epithelial-to-mesenchymal transition by upregulating E-cadherin (epithelial cell marker) and downregulating vimentin
Akt↓,
EMT↓,
E-cadherin↑,
Vim↓,
*COX2↓, bioactive compounds such as CAPE, galangin significantly reduce the activity of lung cyclooxygenase (COX) and myeloperoxidase (MPO), and malonaldehyde (MDA), TNF-α, and IL-6 levels, while increasing the activity of catalase (CAT) and SOD
*MPO↓,
*MDA↓,
*TNF-α↓,
*IL6↓,
*Catalase↑,
*SOD↑,
*AST↓, Chrysin also reduces the expression of oxidative and inflammatory markers such as aspartate transaminase (AST), alanine aminotransferase (ALT), IL-1β, IL-10, TNF-α, and MDA levels and increases the antioxidant parameters such as SOD, CAT, and GPx
*ALAT↓,
*IL1β↓,
*IL10↓,
*GPx↓,
*TLR4↓, propolis also inhibits the expression of Toll-like receptor 4 (TLR4), macrophage infiltration, MPO activity, and apoptosis of lung tissues in septic animals
*Sepsis↓,
*IFN-γ↑, CAPE also significantly increases IFN-γ
*GSH↑, propolis significantly increased the level of GSH and the histological appearances of propolis-treated bleomycin-induced pulmonary fibrosis rats.
*NRF2↑, CAPE significantly increases the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2)
*α-SMA↓, propolis significantly inhibits the expression of α- SMA, collagen fibers, and TGF-1β.
*TGF-β↓,
*IL5↓, Propolis also inhibits the expression of inflammatory cytokines and chemokines such as TNF-α, IL-5, IL-6, IL-8, IL-10, NF-kB, IFN-γ, PGF2a, and PGE2.
*IL6↓,
*IL8↓,
*PGE2↓,
*NF-kB↓,
*MMP9↓, downregulating the expression of TGF-1β, ICAM-1, α-SMA, MMP-9, IgE, and IgG1.

2962- PL,    Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents
- in-vitro, Nor, PC12
*GSH↑, compounds 4 and 5 remarkably elevats GSH level and antioxidant enzymes activity (NQO1, Trx, and TrxR).
*NQO1↑,
*Trx↑,
*TrxR↑,
*NRF2↑, revealed that the total Nrf2 expression was slightly upregulated. 4 and 5, have been identified as potent Nrf2 activators with minimal cytotoxicity.
*NRF2⇅, Notably, the cytosolic Nrf2 decreased gradually (Figure 9, middle panel). Coincidently, the amount of Nrf2 in nuclei increased.
*eff↑, Induction of transcription of antioxidant genes via the Nrf2-dependent cytoprotective pathway requires translocation of Nrf2 from cytosol to nucleus.
*BioAv↑, PL could cross the BBB after oral administration
*ROS↓, The elevation of cellular endogenous antioxidant system prevents the accumulation of ROS and thus confers protection against oxidative insults to the cells.

2961- PL,    Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis
- in-vitro, ESCC, KYSE-30
Pyro↑, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells
TumCP↓,
TumCMig↓,
TumCI↓,
ASC↑, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS.
cl‑Casp1↑,
NLRP3↑,
GSDMD↑,
ROS↑,
NRF2↓, PL inhibited the malignant behavior of ESCC cells in vitro and tumorigenesis of ESCC in vivo by inhibiting NRF2 and promoting ROS-TXNIP-NLRP3-mediated pyroptosis.
TXNIP↑,

2960- PL,    Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents
- Analysis, Nor, NA
NRF2↑, Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor
neuroP↑,

2955- PL,    Heme Oxygenase-1 Determines the Differential Response of Breast Cancer and Normal Cells to Piperlongumine
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
ROS?, Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells.
*ROS∅,
other⇅, opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1)
HO-1↑, Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells.
*HO-1↑,
NRF2↑, piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species.
Keap1↓, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1)
cl‑PARP↑, Following piperlongumine treatment, cleaved PARP levels increased in time- (Fig. 1D) and dose-dependent
selectivity↑, These data clearly show that piperlongumine has a cancer cell-selective killing effect
GSH↓, piperlongumine can selectively decrease the level of reduced GSH and increase the level of oxidized GSSG, leading to ROS accumulation and subsequent apoptosis in cancer cells
GSSG↑, we observed piperlongumine-mediated depletion of GSH, a reduction in the GSH/GSSG ratio and accumulation of intracellular ROS in MCF-7 cells but not in MCF-10A cells

2954- PL,    The metabolites from traditional Chinese medicine targeting ferroptosis for cancer therapy
- Review, Var, NA
NRF2↑, PL significantly increased ROS levels and protein glutathionylation with a concomitant elevation in Nrf-2 expression
ROS↑, PL selectively destroyed hepatocellular carcinoma cells rather than normal hepatocytes via ROS–endoplasmic reticulum (ER)–MAPK–CHOP axis,
ER Stress↑,
MAPK↑,
CHOP↑,
selectivity↑, PL selectively killed human breast cancer MCF-7 cells instead of human MCF-10A breast epithelial cells
Keap1↝, PL directly interacted with Kelch-like ECH-associated protein-1 (Keap1), which resulted in Nrf-2-mediated HO-1 expression
HO-1↑,
Ferroptosis↑, pancreatic cancer cell death mainly via the induction of ROS-mediated ferroptosis

2948- PL,    The promising potential of piperlongumine as an emerging therapeutics for cancer
- Review, Var, NA
tumCV↓, inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases,
TumCP↓,
TumCI↓,
angioG↓,
EMT↓,
TumMeta↓,
*hepatoP↑, A study demonstrated the hepatoprotective effects of P. longum via decreasing the rate of lipid peroxidation and increasing glutathione (GSH) levels
*lipid-P↓,
*GSH↑,
cardioP↑, cardioprotective effect
CycB↓, downregulated the mRNA expression of the cell cycle regulatory genes such as cyclin B1, cyclin D1, cyclin-dependent kinases (CDK)-1, CDK4, CDK6, and proliferating cell nuclear antigen (PCNA)
cycD1↓,
CDK2↓,
CDK1↓,
CDK4↓,
CDK6↓,
PCNA↓,
Akt↓, suppression of the Akt/mTOR pathway by PL was also associated with the partial inhibition of glycolysis
mTOR↓,
Glycolysis↓,
NF-kB↓, Suppression of the NF-κB signaling pathway and its related genes by PL was reported in different cancers
IKKα↓, inactivation of the inhibitor of NF-κB kinase subunit beta (IKKβ)
JAK1↓, PL efficiently inhibited cell proliferation, invasion, and migration by blocking the JAK1,2/STAT3 signaling pathway
JAK2↓,
STAT3↓,
ERK↓, PL also negatively regulates ERK1/2 signaling pathways, thereby suppressing the level of c-Fos in CRC cells
cFos↓,
Slug↓, PL was found to downregulate slug and upregulate E-cadherin and inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells
E-cadherin↑,
TOP2↓, ↓topoisomerase II, ↑p53, ↑p21, ↓Bcl-2, ↑Bax, ↑Cyt C, ↑caspase-3, ↑caspase-7, ↑caspase-8
P53↑,
P21↑,
Bcl-2↓,
BAX↑,
Casp3↑,
Casp7↑,
Casp8↑,
p‑HER2/EBBR2↓, ↓p-HER1, ↓p-HER2, ↓p-HER3
HO-1↑, ↑Apoptosis, ↑HO-1, ↑Nrf2
NRF2↑,
BIM↑, ↑BIM, ↑cleaved caspase-9 and caspase-3, ↓p-FOXO3A, ↓p-Akt
p‑FOXO3↓,
NA↓,
Sp1/3/4↓, ↑apoptosis, ↑ROS, ↓Sp1, ↓Sp3, ↓Sp4, ↓cMyc, ↓EGFR, ↓survivin, ↓cMET
cMyc↓,
EGFR↓,
survivin↓,
cMET↓,
NQO1↑, G2/M phase arrest, ↑apoptosis, ↑ROS, ↓p-Akt, ↑Bad, ↓Bcl-2, ↑NQO1, ↑HO-1, ↑SOD2, ↑p21, ↑p-ERK, ↑p-JNK,
SOD2↑,
TrxR↓, G2/M cell cycle arrest, ↑apoptosis, ↑ROS, ↓GSH, ↓TrxR
MDM2↓, ↑ROS, ↓MDM-2, ↓cyclin B1, ↓Cdc2, G2/M phase arrest, ↑p-eIF2α, ↑ATF4, KATO III ↑CHOP, ↑apoptosis
p‑eIF2α↑,
ATF4↑,
CHOP↑,
MDA↑, ↑ROS, ↓TrxR1, ↑cleaved caspase-3, ↑CHOP, ↑MDA
Ki-67↓, ↓Ki-67, ↓MMP-9, ↓Twist,
MMP9↓,
Twist↓,
SOX2↓, ↓SOX2, ↓NANOG, ↓Oct-4, ↑E-cadherin, ↑CK18, ↓N-cadherin, ↓vimentin, ↓snail, ↓slug
Nanog↓,
OCT4↓,
N-cadherin↓,
Vim↓,
Snail↓,
TumW↓, ↓Tumor weight, ↓tumor growth
TumCG↓,
HK2↓, ↓HK2
RB1↓, ↓Rb
IL6↓, ↓IL-6, ↓IL-8,
IL8↓,
SOD1↑, ↑SOD1
RadioS↑, ombination with PL, very low intensity of radiation is found to be effective in cancer cells
ChemoSen↑, PL as a chemosensitizer which sensitized the cancer cells towards the commercially available chemotherapeutics
toxicity↓, PL does not have any adverse effect on the normal functioning of the liver and kidney.
Sp1/3/4↓, In vitro SKBR3 ↓Sp1, ↓Sp3, ↓Sp4
GSH↓, In vitro MCF-7 ↓CDK1, G2/M phase arrest ↓CDK4, ↓CDK6, ↓PCNA, ↓p-CDK1, ↑cyclin B1, ↑ROS, ↓GSH, ↓p-IκBα,
SOD↑, In vitro PANC-1, MIA PaCa-2 ↑ROS, ↑SOD1, ↑GSTP1, ↑HO-1

2946- PL,    Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent
- Review, Var, NA
ROS↑, piperlongumine inhibits cancer growth by resulting in the accumulation of intracellular reactive oxygen species, decreasing glutathione and chromosomal damage, or modulating key regulatory proteins, including PI3K, AKT, mTOR, NF-kβ, STATs, and cycD
GSH↓, reduced glutathione (GSH) levels in mouse colon cancer cells
DNAdam↑,
ChemoSen↑, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy
RadioS↑, piperlongumine treatment enhances ROS production via decreasing GSH levels and causing thioredoxin reductase inhibition
BioEnh↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine
selectivity↑, It shows selectivity toward human cancer cells over normal cells and has minimal side effects
BioAv↓, ts low aqueous solubility affects its anti-cancer activity by limiting its bioavailability during oral administration
eff↑, encapsulation of piperlongumine in another biocompatible natural polymer, chitosan, has been found to result in pH-dependent piperlongumine release and to enhance cytotoxicity via efficient intracellular ROS accumulation against human gastric carcin
p‑Akt↓, Fig 2
mTOR↓,
GSK‐3β↓,
β-catenin/ZEB1↓,
HK2↓, iperlongumine treatment decreases cell proliferation, single-cell colony-formation ability, and HK2-mediated glycolysis in NSCLC cells via inhibiting the interaction between HK2 and voltage-dependent anion channel 1 (VDAC1)
Glycolysis↓,
Cyt‑c↑,
Casp9↑,
Casp3↑,
Casp7↑,
cl‑PARP↑,
TrxR↓, piperlongumine (4 or 12 mg/kg/day for 15 days) administration significantly inhibits increase in tumor weight and volume with less TrxR1 activity in SGC-7901 cell
ER Stress↑,
ATF4↝,
CHOP↑, activating the downstream ER-MAPK-C/EBP homologous protein (CHOP) signaling pathway
Prx4↑, piperlongumine kills high-grade glioma cells via oxidative inactivation of PRDX4 mediated ROS induction, thereby inducing intracellular ER stress
NF-kB↓, piperlongumine treatment (2.5–5 mg/ kg body weight) decreases the growth of lung tumors via inhibition of NF-κB
cycD1↓, decreases expression of cyclin D1, cyclin- dependent kinase (CDK)-4, CDK-6, p- retinoblastoma (p-Rb)
CDK4↓,
CDK6↓,
p‑RB1↓,
RAS↓, piperlongumine downregulates the expression of Ras protein
cMyc↓, inhibiting the activity of other related proteins, such as Akt/NF-κB, c-Myc, and cyclin D1 in DMH + DSS induced colon tumor cells
TumCCA↑, by arresting colon tumor cells in the G2/M phase of the cell cycle
selectivity↑, hows more selective cytotoxicity against human breast cancer MCF-7 cells than human breast epithelial MCF-10A cells
STAT3↓, thus inducing inhibition of the STAT3 signaling pathway in multiple myeloma cells
NRF2↑, Nrf2) activation has been found to mediate the upregulation of heme oxygenase-1 (HO-1) in piperlongumine treated MCF-7 and MCF-10A cells
HO-1↑,
PTEN↑, stimulates ROS accumulation; p53, p27, and PTEN overexpression
P-gp↓, P-gp, MDR1, MRP1, survivin, p-Akt, NF-κB, and Twist downregulation;
MDR1↓,
MRP1↓,
survivin↓,
Twist↓,
AP-1↓, iperlongumine significantly suppresses the expression of transcription factors, such as AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6, and YY1.
Sp1/3/4↓,
STAT1↓,
STAT6↓,
SOX4↑, increased expression of p21, SOX4, and XBP in B-ALL cells
XBP-1↑,
P21↑,
eff↑, combined use of piperlongumine with cisplatin enhances the sensitivity toward cisplatin by inhibiting Akt phosphorylation
Inflam↓, inflammation (COX-2, IL6); invasion and metastasis, such as ICAM-1, MMP-9, CXCR-4, VEGF;
COX2↓,
IL6↓,
MMP9↓,
TumMeta↓,
TumCI↓,
ICAM-1↓,
CXCR4↓,
VEGF↓,
angioG↓,
Half-Life↝, The analysis of the plasma of piperlongumine treated mice (50 mg/kg) after intraperitoneal administration, 1511.9 ng/ml, 418.2 ng/ml, and 41.9 ng/ml concentrations ofplasma piperlongumine were found at 30 minutes, 3 hours, and 24 hours, respecti
BioAv↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine

39- QC,    A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells
- Analysis, NA, NA
ROS↑, production of ROS in both cancer, and cancer stem cells,
GSH↓, By directly reducing the intracellular pool of glutathione (GSH), QC can influence ROS metabolism
IL6↓, QC is its ability to inhibit inflammatory mediators including IFN-γ, IL-6, COX-2, IL-8, iNOS, TNF-α, and many other cancer inflammatory mechanisms
COX2↓,
IL8↓,
iNOS↓,
TNF-α↓,
MAPK↑, quercetin-3-methyl ether stopped the growth of cancer in the esophagus by blocking the Akt/mTOR/P70S6k and MAPK pathways, which are important for the growth of cancer
ERK↑,
SOD↑,
ATP↓,
Casp↑,
PI3K/Akt↓,
mTOR↓,
NOTCH1↓,
Bcl-2↓,
BAX↑,
IFN-γ↓,
TumCP↓, QC directly involves inducing apoptosis and/or the cell cycle arrest process, and also inhibits the propagation of rapidly proliferating cells
TumCCA↑,
Akt↓, quercetin-3-methyl ether stopped the growth of cancer in the esophagus by blocking the Akt/mTOR/P70S6k and MAPK pathways, which are important for the growth of cancer
P70S6K↓,
*Keap1↓,
*GPx↑, inhibiting its negative regulator, Keap1, resulting in Nrf-2 nuclear translocation [86]. This results in the production and activation of enzymes namely GPX, CAT, heme oxygenase 1 (HO-1), peroxiredoxin (PRX)
*Catalase↑,
*HO-1↑,
*NRF2↑,
NRF2↑, The effect of QC on nuclear translocation of Nrf-2 in a time-dependent manner, and increased expression level in HepG2, MgM (malignant mesothelioma) MSTO-211H, and H2452 cells at mRNA and protein quantity has been reported recently
eff↑, quercetin coupled with gold nanoparticles promoted apoptosis by inhibiting the EGFR/P13K/Akt-mediated pathway
HIF-1↓, Quercetin has been shown to suppress the Akt-mTOR pathway and hypoxia-induced factor 1 signaling pathway in gastric cancer cells, resulting in preventative autophagy

923- QC,    Quercetin as an innovative therapeutic tool for cancer chemoprevention: Molecular mechanisms and implications in human health
- Review, Var, NA
ROS↑, decided by the availability of intracellular reduced glutathione (GSH),
GSH↓, extended exposure with high concentration of quercetin causes a substantial decline in GSH levels
Ca+2↝,
MMP↓,
Casp3↑, activation of caspase-3, -8, and -9
Casp8↑,
Casp9↑,
other↓, when p53 is inhibited, cancer cells become vulnerable to quercetin-induced apoptosis
*ROS↓, Quercetin (QC), a plant-derived bioflavonoid, is known for its ROS scavenging properties and was recently discovered to have various antitumor properties in a variety of solid tumors.
*NRF2↑, Moreover, the therapeutic efficacy of QC has also been defined in rat models through the activation of Nrf-2/HO-1 against high glucose-induced damage
HO-1↑,
TumCCA↑, QC increases cell cycle arrest via regulating p21WAF1, cyclin B, and p27KIP1
Inflam↓, QC-mediated anti-inflammatory and anti-apoptotic properties play a key role in cancer prevention by modulating the TLR-2 (toll-like receptor-2) and JAK-2/STAT-3 pathways and significantly inhibit STAT-3 tyrosine phosphorylation within inflammatory ce
STAT3↓,
DR5↑, several studies showed that QC upregulated the death receptor (DR)
P450↓, it hinders the activity of cytochrome P450 (CYP) enzymes in hepatocytes
MMPs↓, QC has also been shown to suppress metastatic protein expression such as MMPs (matrix metalloproteases)
IFN-γ↓, QC is its ability to inhibit inflammatory mediators including IFN-γ, IL-6, COX-2, IL-8, iNOS, TNF-α,
IL6↓,
COX2↓,
IL8↓,
iNOS↓,
TNF-α↓,
cl‑PARP↑, Induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, mitochondrial membrane depolarization,
Apoptosis↑, increased apoptosis and p53 expression
P53↑,
Sp1/3/4↓, HT-29 colon cancer cells: decreased the expression of Sp1, Sp3, Sp4 mrna, and survivin,
survivin↓,
TRAILR↑, H460 Increased the expression of TRAILR, caspase-10, DFF45, TNFR 1, FAS, and decreased the expression of NF-κb, ikkα
Casp10↑,
DFF45↑,
TNFR 1↑,
Fas↑,
NF-kB↓,
IKKα↓,
cycD1↓, SKOV3 Reduction in cyclin D1 level
Bcl-2↓, MCF-7, HCC1937, SK-Br3, 4T1, MDA-MB-231 Decreased Bcl-2 expression, increasedBax expression, inhibition of PI3K-Akt pathway
BAX↑,
PI3K↓,
Akt↓,
E-cadherin↓, MDA-MB-231 Induced the expression of E-cadherin and downregulated vimentin levels, modulation of β-catenin target genes such as cyclin D1 and c-Myc
Vim↓,
β-catenin/ZEB1↓,
cMyc↓,
EMT↓, MCF-7 Suppressed the epithelial–mesenchymal transition process, upregulated E-cadherin expression, downregulated vimentin and MMP-2 expression, decreased Notch1 expression
MMP2↓,
NOTCH1↓,
MMP7↓, PANC-1, PATU-8988 Decreased the secretion of MMP and MMP7, blocked the STAT3 signaling pathway
angioG↓, PC-3, HUVECs Reduced angiogenesis, increased TSP-1 protein and mrna expression
TSP-1↑,
CSCs↓, PC-3 and LNCaP cells Activated capase-3/7 and inhibit the expression of Bcl-2, surviving and XIAP in CSCs.
XIAP↓,
Snail↓, inhibiting the expression of vimentin, slug, snail and nuclear β-catenin, and the activity of LEF-1/TCF responsive reporter
Slug↓,
LEF1↓,
P-gp↓, MCF-7 and MCF-7/dox cell lines Downregulation of P-gp expression
EGFR↓, MCF-7 and MDA-MB-231 cells Suppressed EGFR signaling and inhibited PI3K/Akt/mTOR/GSK-3β
GSK‐3β↓,
mTOR↓,
RAGE↓, IA Paca-2, BxPC3, AsPC-1, HPAC and PANC1 Silencing RAGE expression
HSP27↓, Breast cancer In vivo NOD/SCID mice Inhibited the overexpression of Hsp27
VEGF↓, QC significantly reversed an elevation in profibrotic markers (VEGF, IL-6, TGF, COL-1, and COL-3)
TGF-β↓,
COL1↓,
COL3A1↓,

3354- QC,    Quercetin: Its Main Pharmacological Activity and Potential Application in Clinical Medicine
- Review, Var, NA
*ROS↓, quercetin is the most effective free radical scavenger in the flavonoid family
*IronCh↓, Chelating metal ions: related studies have confirmed that quercetin can induce Cu2+ and Fe2+ to play an antioxidant role through catechol in its structure.
*lipid-P↓, quercetin could inhibit Fe2+-induced lipid peroxidation by binding Fe2+ a
*GSH↑, regulation of glutathione levels to enhance antioxidant capacity.
*NRF2↑, quercetin upregulates the expression of Nrf2 and nuclear transfer by activating the intracellular p38 MAPK pathway, increasing the level of intracellular GSH
TumCCA↑, human leukaemia U937 cells, quercetin induces cell cycle arrest at G2 (late DNA synthesis phase)
ER Stress↑, quercetin can induce ER stress and promote the release of p53, thereby inhibiting the activities of CDK2, cyclin A, and cyclin B, thereby causing MCF-7 breast cancer cells to stagnate in the S phase.
P53↑,
CDK2↓,
cycA1↓,
CycB↓,
cycE↓, downregulation of cyclins E and D, PNCA, and Cdk-2 protein expression and increased expressions of p21 and p27
cycD1↓,
PCNA↓,
P21↑,
p27↑,
PI3K↓, quercetin inhibited the PI3K/AKT/mTOR and STAT3 pathways in PEL, which downregulated the expression of survival cell proteins such as c-FLIP, cyclin D1, and cMyc.
Akt↓,
mTOR↓,
STAT3↓, in excess of 20 μM by inhibiting STAT3 signalling
cFLIP↓,
cMyc↓,
survivin↓, Lung cancer [27] ↓ Survivin ↑DR5
DR5↓,
*Inflam↓, Quercetin has been confirmed to be a long-acting anti-inflammatory substance in flavonoids
*IL6↓, inhibit IL-8 is stronger and can inhibit IL-6 and increase cytosolic calcium levels
*IL8↓,
COX2↓, inhibit the enzymes that produce inflammation (cyclooxygenase (COX) and lipoxygenase (LOX))
5LO↓,
*cardioP↑, The protective mechanism of quercetin on the cardiovascular system
*FASN↓, 25 μM, within 30 minutes could inhibit the synthesis of fatty acids.
*AntiAg↑, quercetin helps reduce lipid peroxidation, platelet aggregation, and capillary permeability
*MDA↓, quercetin can decrease the levels of malondialdehyde (MDA)

3350- QC,    Quercetin and the mitochondria: A mechanistic view
- Review, NA, NA
*antiOx↑, antioxidant and anti-inflammatory properties
*Inflam↓,
*NRF2↑, Quercetin is able to activate the master regulator nuclear factor erythroid 2-related factor 2 (Nrf2)
ROS⇅, That is, as a free radical-scavenging antioxidant, quercetin protects cells against DNA damage induced by reactiveoxygen species (ROS), but the oxidized quercetin intermediates (see above) can then react with glutathione (GSH) thereby lowering GSH
*NRF2↑, 10uM (24 h) Mouse primary hepatocytes Activation of Nrf2; ↑HO-1 levels; ↑expression of PPARα and PGC-1α
*HO-1↑,
*PPARα↑,
*PGC-1α↑,
*SIRT1↑, Rat hippocampus ↑ SIRT1, PGC-1α, NRF-1, and TFAM levels; ATP levels;
*ATP↑,
ATP↓, L1210 and P388 leukemia cells (Suolinna et al., 1975). At least in part, the authors attributed the pro-apoptotic effect of quercetin in these cell lines to its capacity to inhibit ATP synthase, causing a decrease in ATP content.
ERK↓, downregulation of ERK1/2 by quercetin (50-100 uM for 24 or 48 h, combined or not with resveratrol
cl‑PARP↑, NCaP cells ↑PARP cleavage ↑ Caspase-9, caspase-8, and caspase-3 activities
Casp9↑,
Casp8↑,
BAX↑, MDA-MB-231 cells ↑Bax levels, ↓MMP, ↑cytochrome c release, ↑caspase-9 and caspase-3 activities
MMP↓,
Cyt‑c↑,
Casp3↑,
HSP27↓, T98G cells: ↓Hsp27 and Hsp72 contents, ↓Ras and Raf level
HSP72↓,
RAS↓,
Raf↓,

3347- QC,    Recent Advances in Potential Health Benefits of Quercetin
- Review, Var, NA - Review, AD, NA
*antiOx↑, Its strong antioxidant properties enable it to scavenge free radicals, reduce oxidative stress, and protect against cellular damage.
*ROS↓,
*Inflam?, Quercetin’s anti-inflammatory properties involve inhibiting the production of inflammatory cytokines and enzymes,
TumCP↓, exhibits anticancer effects by inhibiting cancer cell proliferation and inducing apoptosis.
Apoptosis↑,
*cardioP↑, cardiovascular benefits such as lowering blood pressure, reducing cholesterol levels, and improving endothelial function
*BP↓, Quercetin‘s ability to reduce blood pressure was also supported by a different investigation
TumMeta↓, The most important impact of quercetin is its ability to inhibit the spread of certain cancers including those of the breast, cervical, lung, colon, prostate, and liver
MDR1↓, quercetin decreased the expression of genes multidrug resistance protein 1 and NAD(P)H quinone oxidoreductase 1 and sensitized MCF-7 cells to the chemotherapy medication doxorubicin
NADPH↓,
ChemoSen↑,
MMPs↓, Inhibiting CT26 cells’ migration and invasion abilities by inhibiting their expression of tissue inhibitors of metalloproteinases (TIMPs) inhibits their invasion and migration abilities
TIMP2↑,
*NLRP3↓, inhibited NLRP3 by acting on this inflammasome
*IFN-γ↑, quercetin significantly upregulates the gene expression and production of interferon-γ (IFN-γ), which is obtained from T helper cell 1 (Th1), and downregulates IL-4, which is obtained from Th2.
*COX2↓, quercetin is known to decrease the production of inflammatory molecules COX-2, nuclear factor-kappa B (NF-κB), activator protein 1 (AP-1), mitogen-activated protein kinase (MAPK), reactive nitric oxide synthase (NOS), and reactive C-protein (CRP)
*NF-kB↓,
*MAPK↓,
*CRP↓,
*IL6↓, Quercetin suppressed the production of inflammatory cytokines such as IL-6, TNF-α, and IL-1β via upregulating TLR4.
*TNF-α↓,
*IL1β↓,
*TLR4↑,
*PKCδ↓, Quercetin employed suppression on the phosphorylation of PKCδ to control the PKCδ–JNK1/2–c-Jun pathway.
*AP-1↓, This pathway arrested the accumulation of AP-1 transcription factor in the target genes, thereby resulting in reduced ICAM-1 and inflammatory inhabitation
*ICAM-1↓,
*NRF2↑, Quercetin overexpressed Nrf2 and targeted its downstream gene, contributing to increased HO-1 levels responsible for the down-regulation of TNF-α, iNOS, and IL-6
*HO-1↑,
*lipid-P↓, Quercetin acts as a potent antioxidant by scavenging ROS, inhibiting lipid peroxidation, and enhancing the activity of antioxidant enzymes
*neuroP↑, This helps to counteract oxidative stress and protect against neurodegenerative processes that contribute to AD
*eff↑, rats treated with chronic rotenone or 3-nitropropionic acid showed enhanced neuroprotection when quercetin and fish oil were taken orally
*memory↑, Both memory and learning abilities in the test animals increased
*cognitive↑,
*AChE↓, The increase in AChE activity brought on by diabetes was prevented in the cerebral cortex and hippocampus by quercetin at a level of 50 mg/kg body weight.
*BioAv↑, consumption of fried onions compared to black tea, suggesting that the form of quercetin present in onions is better absorbed than that in tea
*BioAv↑, This suggests that dietary fat can increase the absorption of quercetin [180]
*BioAv↑, potential of liposomes to enhance the bioactivity and bioavailability of quercetin has been the subject of several investigations
*BioAv↑, several emulsion types that may be employed to encapsulate quercetin, but oil-in-water (O/W) emulsions are the most widely utilized.
*BioAv↑, the kind of oil (triglyceride oils made up of either long-chain or medium-chain fatty acids) affected the bioaccessibility of quercetin and gastrointestinal stability, emphasizing the significance of picking a suitable oil phase

3343- QC,    Quercetin, a Flavonoid with Great Pharmacological Capacity
- Review, Var, NA - Review, AD, NA - Review, Arthritis, NA
*antiOx↑, Quercetin has a potent antioxidant capacity, being able to capture reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive chlorine species (ROC),which act as reducing agents by chelating transition-metal ions.
*ROS↓, Quercetin is a potent scavenger of reactive oxygen species (ROS), protecting the organism against oxidative stress
*angioG↓,
*Inflam↓, anti-inflammatory properties; the ability to protect low-density lipoprotein (LDL) oxidation, and the ability to inhibit angiogenesis;
*BioAv↓, It is known that the bioavailability of quercetin is usually relatively low (0.17–7 μg/mL), less than 10% of what is consumed, due to its poor water solubility (hydrophobicity), chemical stability, and absorption profile.
*Half-Life↑, their slow elimination since their half-life ranges from 11 to 48 h, which could favor their accumulation in plasma after repeated intakes
*GSH↑, Animal and cell studies have demonstrated that quercetin induces the synthesis of GSH
*SOD↑, increase in the expression of superoxide dismutase (SOD), catalase (CAT), and GSH with quercetin pretreatment
*Catalase↑,
*Nrf1↑, quercetin accomplishes this process involves increasing the activity of the nuclear factor erythroid 2-related factor 2 (NRF2), enhancing its binding to the ARE, reducing its degradation
*BP↓, quercetin has been shown to inhibit ACE activity, reducing blood pressure
*cardioP↑, quercetin has positive effects on cardiovascular diseases
*IL10↓, Under the influence of quercetin, the levels of interleukin 10 (IL-10), IL-1β, and TNF-α were reduced.
*TNF-α↓,
*Aβ↓, quercetin’s ability to modulate the enzyme activity in clearing amyloid-beta (Aβ) plaques, a hallmark of AD pathology.
*GSK‐3β↓, quercetin can inhibit the activity of glycogen synthase kinase 3β,
*tau↓, thus reducing tau aggregation and neurofibrillary tangles in the brain
*neuroP↑,
*Pain↓, quercetin reduces pain and inflammation associated with arthritis
*COX2↓, quercetin included the inhibition of oxidative stress, production of cytokines such as cyclooxygenase-2 (COX-2) and proteoglycan degradation, and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) (Nrf2/HO-1)
*NRF2↑,
*HO-1↑,
*IL1β↓, Mechanisms included decreased levels of TNF-α, IL-1β, IL-17, and monocyte chemoattractant protein-1 (MCP-1)
*IL17↓,
*MCP1↓,
PKCδ↓, studies with human leukemia 60 (HL-60) cells report that concentrations between 20 and 30 µM are sufficient to exert an inhibitory effect on cytosolic PKC activity and membrane tyrosine protein kinase (TPK) activity.
ERK↓, 50 µM resulted in the blockade of the extracellular signal-regulated kinases (ERK1/2) pathway
BAX↓, higher doses (75–100 µM) were used, as these doses reduced the expression of proapoptotic factors such as Bcl-2-associated X protein (Bax) and caspases 3 and 9
cMyc↓, induce apoptosis at concentrations of 80 µM and also causes a downregulation of cellular myelocytomatosis (c-myc) and Kirsten RAt sarcoma (K-ras) oncogenes
KRAS↓,
ROS↓, compound’s antioxidative effect changes entirely to a prooxidant effect at high concentrations, which induces selective cytotoxicity
selectivity↑, On the other hand, when noncancerous cells are exposed to quercetin, it exerts cytoprotective effects;
tumCV↓, decrease cell viability in human glioma cultures of the U-118 MG cell line as well as an increase in death by apoptosis and cell arrest at the G2 checkpoint of the cell cycle.
Apoptosis↑,
TumCCA↑,
eff↑, quercetin combined with doxorubicin can induce multinucleation of invasive tumor cells, downregulate P-glycoprotein (P-gp) expression, increase cell sensitivity to doxorubicin,
P-gp↓,
eff↑, resveratrol, quercetin, and catechin can effectively block the cell cycle and reduce cell proliferation in vivo
eff↑, cotreatment with epigallocatechin gallate (EGCG) inhibited catechol-O-methyltransferase (COMT) activity, decreasing COMT protein content and thereby arresting the cell cycle of PC-3 human prostate cancer cells
eff↑, synergistic treatment of tamoxifen and quercetin was also able to inhibit prostate tumor formation by regulating angiogenesis
eff↑, coadministration of 2.5 μM of EGCG, genistein, and quercetin suppressed the cell proliferation of a prostate cancer cell line (CWR22Rv1) by controlling androgen receptor and NAD (P)H: quinone oxidoreductase 1 (NQO1) expression
CycB↓, It can also downregulate cyclin B1 and cyclin-dependent kinase-1 (CDK-1),
CDK1↓,
CDK4↓, quercetin causes a decrease in cyclins D1/Cdk4 and E/Cdk2 and an increase in p21 in vascular smooth muscle cells
CDK2↓,
TOP2↓, quercetin is known to be a potent inhibitor of topoisomerase II (TopoII), a cell cycle-associated enzyme necessary for DNA replication
Cyt‑c↑, quercetin can induce apoptosis (cell death) through caspase-3 and caspase-9 activation, cytochrome c release, and poly ADP ribose polymerase (PARP) cleavage
cl‑PARP↑,
MMP↓, quercetin induces the loss of mitochondrial membrane potential, leading to the activation of the caspase cascade and cleavage of PARP.
HSP70/HSPA5↓, apoptotic effects of quercetin may result from the inhibition of HSP kinases, followed by the downregulation of HSP-70 and HSP-90 protein expression
HSP90↓,
MDM2↓, (MDM2), an onco-protein that promotes p53 destruction, can be inhibited by quercetin
RAS↓, quercetin can prevent Ras proteins from being expressed. In one study, quercetin was found to inhibit the expression of Harvey rat sarcoma (H-Ras), K-Ras, and neuroblastoma rat sarcoma (N-Ras) in human breast cancer cells,
eff↑, there was a substantial difference in EMT markers such as vimentin, N-cadherin, Snail, Slug, Twist, and E-cadherin protein expression in response to AuNPs-Qu-5, inhibiting the migration and invasion of MCF-7 and MDA-MB cells

3342- QC,    Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells — up regulation of Nrf2 expression and down regulation of NF-κB and COX-2
- in-vitro, Nor, HepG2
*ROS↓, Pre-treatment with quercetin ameliorated ROS and calcium release as well as NF-κB induction and expression
*Ca+2↓,
*NF-kB↓,
*NRF2↑, Quercetin induced Nrf-2 nuclear translocation and expression.
*COX2↓, Quercetin's anti-inflammatory property was exhibited as it down regulated COX-2.
*Inflam↓,

3369- QC,    Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects
- Review, Pca, NA
FAK↓, Quercetin can inhibit HGF-induced melanoma cell migration by inhibiting the activation of c-Met and its downstream Gabl, FAK and PAK [84]
TumCCA↑, stimulation of cell cycle arrest at the G1 stage
p‑pRB↓, mediated through regulation of p21 CDK inhibitor and suppression of pRb phosphorylation resulting in E2F1 sequestering.
CDK2↑, low dose of quercetin has brought minor DNA injury and Chk2 induction
CycB↓, quercetin has a role in the reduction of cyclin B1 and CDK1 levels,
CDK1↓,
EMT↓, quercetin suppresses epithelial to mesenchymal transition (EMT) and cell proliferation through modulation of Sonic Hedgehog signaling pathway
PI3K↓, quercetin on other pathways such as PI3K, MAPK and WNT pathways have also been validated in cervical cancer
MAPK↓,
Wnt↓,
ROS↑, colorectal cancer, quercetin has been shown to suppress carcinogenesis through various mechanisms including affecting cell proliferation, production of reactive oxygen species and expression of miR-21
miR-21↑,
Akt↓, Figure 1 anti-cancer mechanisms
NF-kB↓,
FasL↑,
Bak↑,
BAX↑,
Bcl-2↓,
Casp3↓,
Casp9↑,
P53↑,
p38↑,
MAPK↑,
Cyt‑c↑,
PARP↓,
CHOP↑,
ROS↓,
LDH↑,
GRP78/BiP↑,
ERK↑,
MDA↓,
SOD↑,
GSH↑,
NRF2↑,
VEGF↓,
PDGF↓,
EGF↓,
FGF↓,
TNF-α↓,
TGF-β↓,
VEGFR2↓,
EGFR↓,
FGFR1↓,
mTOR↓,
cMyc↓,
MMPs↓,
LC3B-II↑,
Beclin-1↑,
IL1β↓,
CRP↓,
IL10↓,
COX2↓,
IL6↓,
TLR4↓,
Shh↓,
HER2/EBBR2↓,
NOTCH↓,
DR5↑, quercetin has enhanced DR5 expression in prostate cancer cells
HSP70/HSPA5↓, Quercetin has also suppressed the upsurge of hsp70 expression in prostate cancer cells following heat treatment and enhanced the quantity of subG1 cells
CSCs↓, Quercetin could also suppress cancer stem cell attributes and metastatic aptitude of isolated prostate cancer cells through modulating JNK signaling pathway
angioG↓, Quercetin inhibits angiogenesis-mediated of human prostate cancer cells through negatively modulating angiogenic factors (TGF-β, VEGF, PDGF, EGF, bFGF, Ang-1, Ang-2, MMP-2, and MMP-9)
MMP2↓,
MMP9↓,
IGFBP3↑, Quercetin via increasing the level of IGFBP-3 could induce apoptosis in PC-3 cells
uPA↓, Quercetin through decreasing uPA and uPAR expression and suppressing cell survival protein and Ras/Raf signaling molecules could decrease prostate cancer progression
uPAR↓,
RAS↓,
Raf↓,
TSP-1↑, Quercetin through TSP-1 enhancement could effectively inhibit angiogenesis

3367- QC,    Targeting Nrf2 signaling pathway by quercetin in the prevention and treatment of neurological disorders: An overview and update on new developments
- Review, Stroke, NA - Review, AD, NA
*NRF2↑, Que enhanced the expression of Nrf2 and inhibited alterations in the shape and death of neurons in the hippocampus.
*neuroP↑,
*motorD↑, Que protected the blood-brain barrier via stimulating Nrf2 in animal stroke, which alleviated ischemic reperfusion and motor dysfunction.
*Inflam↓, (2) By triggering the Nrf2 pathway, Que reduced the neuroinflammation and oxidative damage brought on by TBI in the cortex
*cognitive↑, (3) In an experimental model of AD, Que enhanced cognitive function by decreasing A1-4, antioxidant activity, and Nrf2 levels in the brain.

3363- QC,    The Protective Effect of Quercetin on Endothelial Cells Injured by Hypoxia and Reoxygenation
- in-vitro, Nor, HBMECs
*Apoptosis↓, Quercetin can promote the viability, migration and angiogenesis of HBMECs, and inhibit the apoptosis.
*angioG↑,
*NRF2↑, quercetin can also activate Keap1/Nrf2 signaling pathway, reduce ATF6/GRP78 protein expression.
*Keap1↓,
*ATF6↓,
*GRP78/BiP↓,
*CLDN5↑, quercetin could increase the expression of Claudin-5 and Zonula occludens-1.
*ZO-1↑,
*MMP↑, reducing mitochondrial membrane potential damage and inhibiting cell apoptosis.
*BBB↑, quercetin can increase the level of BBB connexin, suggesting that quercetin can maintain BBB integrity.
*ROS↓, Quercetin Could Inhibit Oxidative Stress
*ER Stress↓, In our study, ER stress was activated by H/R, and the levels of ATF6 and GRP78 were increased. Quercetin at 1 μmol/L was able to significantly reduce the protein levels of both, inhibit ER stress, and protect HBMECs from H/R injury

882- RES,    Resveratrol: A Double-Edged Sword in Health Benefits
- Review, NA, NA
AntiTum↑,
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↓,
Bcl-xL↓,
P53↑,
NAF1↓,
NRF2↑,
ROS↑,
Apoptosis↑,
HDAC↓, Resveratrol is also an Histone deacetylase inhibitors
TumCCA↑,
TumAuto↑,
angioG↓,
iNOS↓, inhibit iNOS expression in colon cancer cells

1511- RES,  Chemo,    Combination therapy in combating cancer
- Review, NA, NA
eff↑, Our studies, as well as others, have shown the effectiveness of resveratrol in combination therapy in vitro and in vivo
*NRF2↓, chemopreventive effects through the activation of Nrf2 and consequently GSH expression
*GSH↑,
*ROS↓, In addition, curcuminoids upregulate glutathione levels which have been shown to reduce ROS levels and remove carcinogens, aiding in chemoprevention
chemoP↑,
ChemoSideEff↓, Our lab showed that this antioxidant compound has cytoprotective properties against the side effects of chemotherapy

2650- RES,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
ROS↑, Several molecular mechanisms have been proposed for the anticancer activity of resveratrol, including ROS induction
Dose↝, ROS, the effect of resveratrol appears to be concentration dependent; at low concentrations, it exerts antioxidant effects, whereas at high concentrations (50–100 µM), resveratrol induces ROS production
NRF2↑, Cheng et al. [27] reported that resveratrol-induced ROS activate the Nrf2 signaling pathway, which subsequently suppresses NAF1 and induces apoptosis in pancreatic cancer cells.
NAF1↓,
ChemoSen↑, This also increased their sensitivity to gemcitabine.
BioAv↓, Despite the promising potential of resveratrol, its unstable pharmacokinetics due to its high metabolism and poor bioavailability limit its clinical application.

2566- RES,    A comprehensive review on the neuroprotective potential of resveratrol in ischemic stroke
- Review, Stroke, NA
*neuroP↑, comprehensive overview of resveratrol's neuroprotective role in IS
*NRF2↑, Findings from previous studies suggest that Nrf2 activation can significantly reduce brain injury following IS and lead to better outcomes
*SIRT1↑, neuroprotective effects by activating nuclear factor erythroid 2-related factor 2 (NRF2) and sirtuin 1 (SIRT1) pathways.
*PGC-1α↑, IRT1 activation by resveratrol triggers the deacetylation and activation of downstream targets like peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and forkhead box protein O (FOXO)
*FOXO↑,
*HO-1↑, ctivation of NRF2 through resveratrol enhances the expression of antioxidant enzymes, like heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), which neutralize reactive oxygen species and mitigate oxidative stress in the ischemic bra
*NQO1↑,
*ROS↓,
*BP↓, Multiple studies have demonstrated that resveratrol presented protective effects in IS, it can mediate blood pressure and lipid profiles which are the main key factors in managing and preventing stroke
*BioAv↓, The residual quantity of resveratrol undergoes metabolism, with the maximum reported concentration of free resveratrol being 1.7–1.9 %
*Half-Life↝, The levels of resveratrol peak 60 min following ingestion. Another study found that within 6 h, there was a further rise in resveratrol levels. This increase can be attributed to intestinal recirculation of metabolites
*AMPK↑, Resveratrol also increases AMPK and inhibits GSK-3β (glycogen synthase kinase 3 beta) activity in astrocytes, which release energy, makes ATP available to neurons and reduces ROS
*GSK‐3β↓,
*eff↑, Furthermore, oligodendrocyte survival is boosted by resveratrol, which may help to preserve brain homeostasis following a stroke
*AntiAg↑, resveratrol may suppress platelet activation and aggregation caused by collagen, adenosine diphosphate, and thrombin
*BBB↓, Although resveratrol is a highly hydrophobic molecule, it is exceedingly difficult to penetrate a membrane like the BBB. However, an alternate administration is through the nasal cavity in the olfactory area, which results in a more pleasant route
*Inflam↓, Resveratrol's anti-inflammatory effects have been demonstrated in many studies
*MPO↓, Resveratrol dramatically lowered the amounts of cerebral infarcts, neuronal damage, MPO activity, and evans blue (EB) content in addition to neurological impairment scores.
*TLR4↓, TLR4, NF-κB p65, COX-2, MMP-9, TNF-α, and IL-1β all had greater levels of expression after cerebral ischemia, whereas resveratrol decreased these amounts
*NF-kB↓,
*p65↓,
*MMP9↓,
*TNF-α↓,
*IL1β↓,
*PPARγ↑, Previous studies have shown that resveratrol activates the PPAR -γ coactivator 1α (PGC-1 α), which has free radical scavenging properties
*MMP↑, Resveratrol can prevent mitochondrial membrane depolarization, preserve adenosine triphosphate (ATP) production, and inhibit the release of cytochrome c
*ATP↑,
*Cyt‑c∅,
*mt-lipid-P↓, mitochondrial lipid peroxidation (LPO), protein carbonyl, and intracellular hydrogen peroxide (H2O2) content were significantly reduced in the resveratrol treatment group, while the expression of HSP70 and metallothionein were restored
*H2O2↓,
*HSP70/HSPA5↝,
*Mets↝,
*eff↑, Shin et al. showed that 5 mg/kg intravenous (IV) resveratrol reduced infarction volume by 36 % in an MCAO mouse model.
*eff↑, This study indicates that resveratrol holds the potential to improve stroke outcomes before ischemia as a pre-treatment strategy
*motorD↑, resveratrol treatment significantly reduced infarct volume and prevented motor impairment, increased glutathione, and decreased MDA levels compared to the control group,
*MDA↓,
*NADH:NAD↑, Resveratrol treatment significantly enhanced the intracellular NAD+/NADH ratio
eff↑, Pretreatment with resveratrol (20 or 40 mg/kg) significantly lowered the cerebral edema, infarct volume, lipid peroxidation products, and inflammatory markers
eff↑, Intraperitoneal administration of resveratrol at a dose of 50 mg/kg reduced cerebral ischemia reperfusion damage, brain edema, and BBB malfunction

2441- RES,    Anti-Cancer Properties of Resveratrol: A Focus on Its Impact on Mitochondrial Functions
- Review, Var, NA
*toxicity↓, Although resveratrol at high doses up to 5 g has been reported to be non-toxic [34], in some clinical trials, resveratrol at daily doses of 2.5–5 g induced mild-to-moderate gastrointestinal symptoms [
*BioAv↝, After an oral dose of 25 mg in healthy human subjects, the concentrations of native resveratrol (40 nM) and total resveratrol (about 2 µM) in plasma suggested significantly greater bioavailability of resveratrol metabolites than native resveratrol
*Dose↝, The total plasma concentration of resveratrol did not exceed 10 µM following high oral doses of 2–5 g
*hepatoP↑, hepatoprotective effects
*neuroP↑, neuroprotective properties
*AntiAg↑, Resveratrol possesses the ability to impede platelet aggregation
*COX2↓, suppresses promotion by inhibiting cyclooxygenase-2 activity
*antiOx↑, It is widely recognized that resveratrol has antioxidant properties at concentrations ranging from 5 to 10 μM.
*ROS↓, antioxidant properties at concentrations ranging from 5 to 10 μM.
*ROS↑, pro-oxidant properties when present in doses ranging from 10 to 40 μM
PI3K↓, It is known that resveratrol suppresses PI3-kinase, AKT, and NF-κB signaling pathways [75] and may affect tumor growth via other mechanisms as well
Akt↓,
NF-kB↓,
Wnt↓, esveratrol inhibited breast cancer stem-like cells in vitro and in vivo by suppressing Wnt/β-catenin signaling pathway
β-catenin/ZEB1↓,
NRF2↑, Resveratrol activated the Nrf2 signaling pathway, causing separation of the Nrf2–Keap1 complex [84], leading to enhanced transcription of antioxidant enzymes, such as glutathione peroxidase-2 [85] and heme-oxygenase (HO-1)
GPx↑,
HO-1↑,
BioEnh?, Resveratrol was demonstrated to have an impact on drug bioavailability,
PTEN↑, Resveratrol could suppress leukemia cell proliferation and induce apoptosis due to increased expression of PTEN
ChemoSen↑, Resveratrol enhances the sensitivity of cancer cells to chemotherapeutic agents through various mechanisms, such as promoting drug absorption by tumor cells
eff↑, it can also be used in nanomedicines in combination with various compounds or drugs, such as curcumin [101], quercetin [102], paclitaxel [103], docetaxel [104], 5-fluorouracil [105], and small interfering ribonucleic acids (siRNAs)
mt-ROS↑, enhancing the oxidative stress within the mitochondria of these cells, leading to cell damage and death.
Warburg↓, Resveratrol Counteracts Warburg Effect
Glycolysis↓, demonstrated in several studies that resveratrol inhibits glycolysis through the PI3K/Akt/mTOR signaling pathway in human cancer cells
GlucoseCon↓, resveratrol reduced glucose uptake by cancer cells due to targeting carrier Glut1
GLUT1↓,
lactateProd↓, therefore, less lactate was produced
HK2↓, Resveratrol (100 µM for 48–72 h) had a negative impact on hexokinase II (HK2)-mediated glycolysis
EGFR↓, activation of EGFR and downstream kinases Akt and ERK1/2 was observed to diminish upon exposure to resveratrol
cMyc↓, resveratrol suppressed the expression of leptin and c-Myc while increasing the level of vascular endothelial growth factor.
ROS↝, it acts as an antioxidant in regular conditions but as a strong pro-oxidant in cancer cells,
MMPs↓, Main targets of resveratrol in tumor cells. COX-2—cyclooxygenase-2, SIRT-1—sirtuin 1, MMPs—matrix metalloproteinases,
MMP7↓, Resveratrol was shown to exert an inhibitory effect on the expression of β-catenins and also target genes c-Myc, MMP-7, and survivin in multiple myeloma cells, thus reducing the proliferation, migration, and invasion of cancer cells
survivin↓,
TumCP↓,
TumCMig↓,
TumCI↓,

3071- RES,    Resveratrol and Its Anticancer Effects
- Review, Var, NA
chemoP↑, In this review, the effects of resveratrol are emphasized on chemopreventive, therapeutic, and anticancer.
SIRT1↑, RSV can directly activate Sirt1 expression and induce autophagy independently or dependently on the mammalian target of rapamycin (mTOR)
Hif1a↓, RSV suppresses tumor angiogenesis by inhibiting HIF-1a and VEGF protein
VEGF↓,
STAT3↓, RSV effectively prevents cancer by inhibiting STAT3 expression
NF-kB↓, also has an inhibitory effect on antiapoptotic mediators such as NF-kB, COX-2, phosphatidylinositol 3-kinase (PI3K), and mTOR (52).
COX2↓,
PI3K↓,
mTOR↓,
NRF2↑, Activation of the Nrf2/antioxidant response element (ARE) pathway by endogenous or exogenous stimuli under normal physiological conditions has the potential to inhibit cancer and/or cancer cell survival, growth, and proliferation
NLRP3↓, RSV downregulates the NLRP3 gene by activating the Sirt1 protein, thereby inducing autophagy
H2O2↑, RSV mediates cytotoxicity in cancer cells by increasing intracellular hydrogen peroxide (H2O2) and oxidative stress levels that will cause cell death
ROS↑,
P53↑, RSV activates p53, increases the expression of PUMA and BAX
PUMA↑,
BAX↑,

3052- RES,    Resveratrol-Induced Downregulation of NAF-1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways
- in-vitro, PC, PANC1 - in-vitro, PC, MIA PaCa-2 - in-vitro, PC, Bxpc-3
NAF1↓, resveratrol suppresses the expression of NAF-1 in pancreatic cancer cells by inducing cellular reactive oxygen species (ROS) accumulation and activating Nrf2 signaling.
ROS↑,
NRF2↑,
eff↑, may enhance the efficacy of gemcitabine in pancreatic cancer therapy.
TumCG↓, Resveratrol decreased the growth of the cancer cells in a dose- and time-dependent manner.

3062- RES,    Resveratrol enhances post-injury muscle regeneration by regulating antioxidant and mitochondrial biogenesis
- in-vivo, Nor, NA
*antiOx↑, RES enhanced antioxidant capacity via the Kelch-like ECH-associated protein 1 (KEAP-1)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway
*Keap1↓,
*NRF2↑,
*HO-1↑,
*GPx↑, as indicated by elevated activities of total antioxidant capacity, Glutathione peroxidase (GSH-PX), and superoxidase dismutase (SOD).
*SOD↑,

3061- RES,    The Anticancer Effects of Resveratrol: Modulation of Transcription Factors
- Review, Var, NA
AhR↓, Several reports demonstrate the inhibitory effects of resveratrol on AhR-mediated activation of phase I enzymes.
NRF2↑, Bishayee et al. (18) demonstrated that attenuation of DENA (diethyl nitrosamine)-induced liver carcinogenesis by resveratrol was mediated by increased Nrf2 expression.
*NQO1↑, Induction of Nrf2 signaling by resveratrol resulted in increased expression of NQO1, heme-oxygenase 1 (HO-1), and glutamate cysteine ligase catalytic subunit in cigarette smoke extract-treated bronchial epithelial cells
*HO-1↑,
*GSH↑, observed restored glutathione levels in cigarette smoke extract-treated A549 lung alveolar epithelial cancer cells by resveratrol;
P53↑, we highlight reported resveratrol-induced, p53-mediated anticancer mechanisms.
Cyt‑c↑, release of mitochondria proteins (e.g. cytochrome c, Smac/DIABLO, etc.) to the cytosol, thus triggering suppression of inhibitors of apoptosis proteins (e.g. Bcl2, Bcl-XL, survivin, XIAP, etc.) and caspase activation in several cancers
Diablo↑,
Bcl-2↓,
Bcl-xL↓,
survivin↓,
XIAP↓,
FOXO↑, activation of FoxO transcription factors is implicated in the observed anticancer activities of resveratrol.
p‑PI3K↓, resveratrol's ability to inhibit the phosphorylation of PI3K/Akt (
p‑Akt↓,
BIM↑, Bim/TRAIL/DR4/DR5/p27KIP1 induction and cyclin D1 inhibition) of resveratrol on prostate cancer cells
DR4↑,
DR5↑,
p27↑,
cycD1↓,
SIRT1↑, resveratrol is considered a SIRT1 agonist
NF-kB↓, resveratrol not only curbs expression of NF-κB, but also impedes the phosphorylation of IκBα thereby keeping the constitutive NF-κB subunit in an inactive state, resulting in suppression of the inflammatory
ATF3↑, Furthermore, increased ATF3 expression by resveratrol facilitated induction of apoptosis

3060- RES,    Resveratrol targeting NRF2 disrupts the binding between KEAP1 and NRF2-DLG motif to ameliorate oxidative stress damage in mice pulmonary infection
- in-vitro, Nor, RAW264.7 - in-vivo, NA, NA
*NRF2↑, RES triggers the activation of NRF2, resulting in an anti-oxidative effect
*antiOx↑,
*ROS↓, RES ameliorates oxidative stress damage in the lung tissue of mice with pathogenic condition.

3059- RES,    Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury
- in-vivo, Nor, HK-2
*RenoP↑, Resveratrol improved renal function, proteinuria, histological changes and inflammation in aging mice
*Inflam↓,
*NRF2↑, expression of Nrf2-HO-1-NOQ-1 signaling and SIRT1-AMPK-PGC-1α signaling was increased in the RSV group
*HO-1↑,
*SIRT1↑,
*ROS↓, Activation of the Nrf2 and SIRT1 signaling pathways ameliorated oxidative stress and mitochondrial dysfunction.
AntiAge↑, Pharmacological targeting of Nrf2 signaling molecules may reduce the pathologic changes of aging in the kidney

3057- RES,    The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway
- Review, Var, NA - Review, AD, NA - Review, Stroke, NA
*NRF2↑, Resveratrol stimulates the Nrf2 signaling through blockage of Keap1
*Keap1↓,
*ROS↓, Res ameliorates oxidative stress, apotosis and inflammatory indexes in several tissues.
*Apoptosis↓,
*Inflam↓,
*antiOx↑, Beneficial effects such as anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, cardioprotective, renoprotective, anti-obesity, anti-diabetic, and anti-cancer
*hepatoP↑,
*neuroP↑, neuroprotective Res-associated effect resulting in the activation of Nrf2 signaling pathway.
*cardioP↑,
*RenoP↑,
*AntiCan↑,
*memory↑, Res could ameliorate the spatial memory in the experimental animals via increasing the SOD, glutathione peroxidase (GPx) and CAT expression and activity.
*SOD↑,
*GPx↑,
*Catalase↑,
*MDA↓, Res decreased malondialdehyde (MDA) brain levels in these mice activating the Nrf2/HO-1, indicating its potential to decrease the cell oxidative damage.
*NRF2↑,
*HO-1↑,
*ROS↓,
*Aβ↓, Res improved AD by reducing Aβ protein expression in the brain of treated mice
*iNOS↓, Res ameliorated Aβ-induced increase of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)(pro-inflammatory enzymes), reversed and decreased the mRNA expression levels of antioxidative genes (GPx1, SOD-1, Nrf2, CAT, glutathione, and
*COX2↓,
*GSH↑, Res, significantly reduced NSCs death and the MDA levels, raising proliferation, SOD activity, and GSH content after OGD/R damage
*HO-1⇅, through marked the Nrf2/HO-1 upregulation in hypoxia-ischemia pups
*SIRT1↑, restored activity and expression of SIRT1 mediated by Nrf2.

3054- RES,    Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line
- in-vitro, Melanoma, A375
TumCG↓, Treating A375SM cells with resveratrol resulted in a decrease in cell growth.
P21↑, resveratrol was observed to increase the gene expression levels of p21 and p27, as well as decrease the gene expression of cyclin B.
p27↑,
CycB↓,
ROS↑, generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress were confirmed at the cellular and protein levels
ER Stress↑,
p‑p38↑, Resveratrol induced the ROS-p38-p53 pathway by increasing the gene expression of phosphorylated p38 mitogen-activated protein kinase
P53↑, while it induced the p53 and ER stress pathway by increasing the gene expression levels of phosphorylated eukaryotic initiation factor 2α and C/EBP homologous protein.
p‑eIF2α↑,
EP4↑,
CHOP↑,
Bcl-2↓, downregulating B-cell lymphoma-2 (Bcl-2) expression and upregulating Bcl-2-associated X protein expression
BAX↓,
TumCCA↑, Resveratrol induced cell cycle arrest of melanoma cell line
NRF2↓, the decrease in Nrf2 expression caused by resveratrol may prevent the development of such resistance and thereby increase the sensitivity of melanoma cells to chemotherapy.
ChemoSen↑,
GSH↓, (GSH/GSSG) ratio was not measured, it can easily be assumed that the increased ROS generation by resveratrol reduced the GSH/GSSG ratio compared with the control

3053- RES,    Resveratrol represses estrogen-induced mammary carcinogenesis through NRF2-UGT1A8-estrogen metabolic axis activation
- in-vitro, NA, NA
NRF2↑, whereas treatment with resveratrol could upregulate the expression of NRF2 and UGT1A8, accelerate metabolic elimination of catechol estrogens, inhibit estrogen-induced DNA damage and suppress the pathological development of breast cancer.
DNAdam↓, esveratrol attenuates mammary carcinogenesis through inhibiting estrogen-induced DNA damage

3100- RES,    Neuroprotective effects of resveratrol in Alzheimer disease pathology
- Review, AD, NA
*neuroP↑, several studies have reported interesting insights about the neuroprotective properties of the polyphenolic compound resveratrol
*BioAv↓, However, resveratrol’s low bioavailability originating from its poor water solubility and resulting from its short biological half-life
*Half-Life↓,
*BioAv↑, encapsulation in liposomal formulations
*BBB↑, Resveratrol being a lipophilic compound can readily cross the BBB via transmembrane diffusion
*NRF2↑, resveratrol into aged cells leading to the activation of cellular Nrf2-mediated antioxidant defense systems
*BioAv↓, An oral dose of 25 mg results in less than 5 μg/mL in the serum following absorption through the gastrointestinal tract, corresponding to approximately a 1000-fold decrease in bioavailability.
*BioAv↑, Treatment with pterostilbene also produced a sevenfold rise in its oral bioavailability than the parent resveratrol
*SIRT1↑, Amongst all the naturally occurring activators of SIRT 1, resveratrol is considered to be the most effective SIRT 1 activator.
*cognitive↑, Pterostilbene has shown to be a potent modulator of cognition and cellular oxidative stress associated with AD
*lipid-P↓, Figure 2
*HO-1↑,
*SOD↑,
*GSH↑,
*GPx↑,
*G6PD↑,
*PPARγ↑,
*AMPK↑,
*Aβ↓, Lowered Aβ levels by activating AMPK pathway

3092- RES,    Resveratrol in breast cancer treatment: from cellular effects to molecular mechanisms of action
- Review, BC, MDA-MB-231 - Review, BC, MCF-7
TumCP↓, The anticancer mechanisms of RES in regard to breast cancer include the inhibition of cell proliferation, and reduction of cell viability, invasion, and metastasis.
tumCV↓,
TumCI↓,
TumMeta↓,
*antiOx↑, antioxidative, cardioprotective, estrogenic, antiestrogenic, anti-inflammatory, and antitumor properties it has been used against several diseases, including diabetes, neurodegenerative diseases, coronary diseases, pulmonary diseases, arthritis, and
*cardioP↑,
*Inflam↑,
*neuroP↑,
*Keap1↓, RES administration resulted in a downregulation of Keap1 expression, therefore, inducing Nrf2 signaling, and leading to a decrease in oxidative damage
*NRF2↑,
*ROS↓,
p62↓, decrease the severity of rheumatoid arthritis by inducing autophagy via p62 downregulation, decreasing the levels of interleukin-1β (IL-1β) and C-reactive protein as well as mitigating angiopoietin-1 and vascular endothelial growth factor (VEGF) path
IL1β↓,
CRP↓,
VEGF↓,
Bcl-2↓, RES downregulates the levels of Bcl-2, MMP-2, and MMP-9, and induces the phosphorylation of extracellular-signal-regulated kinase (ERK)/p-38 and FOXO4
MMP2↓,
MMP9↓,
FOXO4↓,
POLD1↓, The in vivo experiment involving a xenograft model confirmed the ability of RES to reduce tumor growth via POLD1 downregulation
CK2↓, RES reduces the expression of casein kinase 2 (CK2) and diminishes the viability of MCF-7 cells.
MMP↓, Furthermore, RES impairs mitochondrial membrane potential, enhances ROS generation, and induces apoptosis, impairing BC progression
ROS↑,
Apoptosis↑,
TumCCA↑, RES has the capability of triggering cell cycle arrest at S phase and reducing the number of 4T1 BC cells in G0/G1 phase
Beclin-1↓, RES administration promotes cytotoxicity of DOX against BC cells by downregulating Beclin-1 and subsequently inhibiting autophagy
Ki-67↓, Reducing the Ki-67
ATP↓, RES’s administration is responsible for decreasing ATP production and glucose metabolism in MCF-7 cells.
GlutMet↓,
PFK↓, RES decreased PFK activity, preventing glycolysis and glucose metabolism in BC cells and decreasing cellular growth rate
TGF-β↓, RES (12.5–100 µM) inhibited TGF-β signaling and reduced the expression levels of its downstream targets that include Smad2 and Smad3 and as a result impaired the progression of BC cells.
SMAD2↓,
SMAD3↓,
Vim?, a significant decrease in the levels of vimentin, Snail1 and Slug occurred, while E-cadherin levels increased to suppress EMT and metastasis of BC cells.
Snail↓,
Slug↓,
E-cadherin↑,
EMT↓,
Zeb1↓, a significant decrease in the levels of vimentin, Snail1 and Slug occurred, while E-cadherin levels increased to suppress EMT and metastasis of BC cells.
Fibronectin↓,
IGF-1↓, RES administration (10 and 20 µM) impaired the migration and invasion of BC cells via inhibiting PI3K/Akt and therefore decreasing IGF-1 expression and preventing the upregulation of MMP-2
PI3K↓,
Akt↓,
HO-1↑, The activation of heme oxygenase-1 (HO-1) signaling by RES reduced MMP-9 expression and prevented metastasis of BC cells
eff↑, RES-loaded gold nanoparticles were found to enhance RES’s ability to reduce MMP-9 expression as compared to RES alone
PD-1↓, RES inhibited PD-1 expression to promote CD8+ T cell activity and enhance Th1 immune responses.
CD8+↑,
Th1 response↑,
CSCs↓, RES has the ability to target CSCs in various tumors
RadioS↑, RES in reversing drug resistance and radio resistance.
SIRT1↑, RES administration (12.5–200 µmol/L) promotes sensitivity of BC cells to DOX by increasing Sirtuin 1 (SIRT1) expression
Hif1a↓, downregulating HIF-1α expression, an important factor in enhancing radiosensitivity
mTOR↓, mTOR suppression

3030- RosA,    Anticancer Activity of Rosmarinus officinalis L.: Mechanisms of Action and Therapeutic Potentials
- Review, Var, NA
ROS⇅, could defend against their oxidative damage of DNA, proteins, and lipids [15], although, as subsequently observed, the derivatives of rosemary are, in some conditions, capable of inducing a cytotoxic effect precisely through the release of ROS
*NRF2↑, scavenging action, RE has also been stated to control intracellular antioxidant systems, by stimulating the activation of nuclear transcription factor (Nrf)2 target genes
*GSH↑, augmenting the glutathione level, with an increase in its reduced form (GSH) compared with that of its oxidized form (GSSG)
HDAC2↓, Similar to the effects of SAHA, RA reduced cell growth and blocked cancer spheroid formation, caused the apoptosis of tumor cells, and blocked the expression of HDAC2

3018- RosA,    Rosemary (Rosmarinus officinalis L.) polyphenols and inflammatory bowel diseases: Major phytochemicals, functional properties, and health effects
- Review, IBD, NA
*Inflam↓, rosemary polyphenols have the potential to decrease the severity of intestinal inflammation.
*GutMicro↑, including improved gut barrier (increased mucus secretion and tight junction), increased antioxidant enzymes,
*antiOx↑,
*NF-kB↓, inhibiting inflammatory pathways and cytokines (downregulation of NF-κB, NLRP3 inflammasomes, STAT3 and activation of Nrf2), and modulating gut microbiota community
*NLRP3↓,
*STAT3↓,
*NRF2↑,

3001- RosA,    Therapeutic Potential of Rosmarinic Acid: A Comprehensive Review
- Review, Var, NA
TumCP↓, including in tumor cell proliferation, apoptosis, metastasis, and inflammation
Apoptosis↑,
TumMeta↓,
Inflam↓,
*antiOx↑, RA is therefore considered to be the strongest antioxidant of all hydroxycinnamic acid derivatives
*AntiAge↑, , it also exerts powerful antimicrobial, anti-inflammatory, antioxidant and even antidepressant, anti-aging effects
*ROS↓, RA and its metabolites can directly neutralize reactive oxygen species (ROS) [10] and thereby reduce the formation of oxidative damage products.
BioAv↑, RA is water-soluble, and according to literature data, the efficacy of secretion of this compound in infusions is about 90%
Dose↝, Accordingly, it is possible to consume approximately 110 mg RA daily, i.e., approximately 1.6 mg/kg for adult men weighing 70 kg.
NRF2↑, liver cancer cell line, HepG2, transfected with plasmid containing ARE-luciferin gene, RA predominantly enhances ARE-luciferin activity and promotes nuclear factor E2-related factor-2 (Nrf2) translocation from cytoplasm to the nucleus
P-gp↑, and also increases MRP2 and P-gp efflux activity along with intercellular ATP level
ATP↑,
MMPs↓, RA concurrently induced necrosis and apoptosis and stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis.
cl‑PARP↓,
Hif1a↓, inhibits transcription factor hypoxia-inducible factor-1α (HIF-1α) expression
GlucoseCon↓, it also suppressed glucose consumption and lactate production in colorectal cells
lactateProd↓,
Warburg↓, may suppress the Warburg effects through an inflammatory pathway involving activator of transcription-3 (STAT3) and signal transducer of interleukin (IL)-6
TNF-α↓, RA supplementation also reduced tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and IL-6 levels, and modulated p65 expression [
COX2↓,
IL6↓,
HDAC2↓, RA induced the cell cycle arrest and apoptosis in prostate cancer cell lines (PCa, PC-3, and DU145) [31]. These effects were mediated through modulation of histone deacetylases expression (HDACs), specifically HDAC2;
GSH↑, RA can also inhibit adhesion, invasion, and migration of Ls 174-T human colon carcinoma cells through enhancing GSH levels and decreasing ROS levels
ROS↓,
ChemoSen↑, RA also enhances chemosensitivity of human resistant gastric carcinoma SGC7901 cells
*BG↓, RA significantly increased insulin index sensitivity and reduced blood glucose, advanced glycation end-products, HbA1c, IL-1β, TNFα, IL-6, p-JNK, P38 mitogen-activated protein kinase (MAPK), and NF-κB levels
*IL1β↓,
*TNF-α↓,
*IL6↓,
*p‑JNK↓,
*p38↓,
*Catalase↑, The reduced activities of CAT, SOD, glutathione S-transferases (GST), and glutathione peroxidase (GPx) and the reduced levels of vitamins C and E, ceruloplasmin, and GSH in plasma of diabetic rats were also significantly recovered by RA application
*SOD↑,
*GSTs↑,
*VitC↑,
*VitE↑,
*GSH↑,
*GutMicro↑, protective effects of RA (30 mg/kg) against hypoglycemia, hyperlipidemia, oxidative stress, and an imbalanced gut microbiota architecture was studied in diabetic rats.
*cardioP↑, Cardioprotective Activity: RA also reduced fasting serum levels of vascular cell adhesion molecule 1 (VCAM-1), inter-cellular adhesion molecule 1 (ICAM-1), plasminogen-activator-inhibitor-1 (PAI-1), and increased GPX and SOD levels
*ROS↓, Finally, in H9c2 cardiac muscle cells, RA inhibited apoptosis by decreasing intracellular ROS generation and recovering mitochondria membrane potential
*MMP↓,
*lipid-P↓, At once, RA suppresses lipid peroxidation (LPO) and ROS generation, whereas in HSC-T6 cells it increases cellular GSH.
*NRF2↑, Additionally, it significantly increases Nrf2 translocation
*hepatoP↑, Hepatoprotective Activity
*neuroP↑, Nephroprotective Activity
*P450↑, RA also reduced CP-produced oxidative stress and amplified cytochrome P450 2E1 (CYP2E1), HO-1, and renal-4-hydroxynonenal expression.
*HO-1↑,
*AntiAge↑, Anti-Aging Activity
*motorD↓, A significantly delays motor neuron dysfunction in paw grip endurance tests,

3002- RosA,    Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols
- Review, Var, NA
TumCG↓, SW480 colon cancer cells and found RE to significantly decrease cell growth at a concentration of 31.25 µg/mL (48 h),
TumCP↓, Cell proliferation was dramatically decreased and cell cycle arrest was induced in HT-29 and SW480 c
TumCCA↑,
ChemoSen↑, RE enhanced the inhibitory effects of the chemotherapeutic drug 5-fluorouracil (5-FU) on proliferation and sensitized 5-FU resistant cells
NRF2↑, HCT116 ↑ Nrf2, ↑ PERK, ↑ sestrin-2, ↑ HO-1, ↑ cleaved-casp 3
PERK↑,
SESN2↑,
HO-1↑,
cl‑Casp3↑,
ROS↑, HT-29 ↑ ROS accumulation, ↑ UPR, ↑ ER-stress
UPR↑,
ER Stress↑,
CHOP↑, HT-29: ↑ ROS levels, ↑ HO-1 and CHOP
HER2/EBBR2↓, SK-BR-3: ↑ FOS levels, ↑ PARP cleavage, ↓ HER2, ↓ ERBB2, ↓ ERα receptor.
ER-α36↓,
PSA↓, LNCaP : ↑ CHOP, ↓ PSA production, ↑ Bax, ↑ cleaved-casp 3, ↓ androgen receptor expression
BAX↑,
AR↓,
P-gp↓, A2780: ↓ P-glyco protein, ↑ cytochrome c gene, ↑ hsp70 gene
Cyt‑c↑,
HSP70/HSPA5↑,
eff↑, This study noted that the rosemary essential oil was more potent than its individual components (α-pinene, β-pinene, 1,8-cineole) when tested alone at the same concentrations.
p‑Akt↓, A549: ↓ p-Akt, ↓ p-mTOR, ↓ p-P70S6K, ↑ PARP cleavage
p‑mTOR↓,
p‑P70S6K↓,
cl‑PARP↑,
eff↑, RE containing 10 µM equivalent of CA, or 10 µM CA alone (96 h) potentiated the ability of vitamin D derivatives to inhibit cell viability and proliferation, induce apoptosis and cell cycle arrest and increase differentiation of WEHI-3BD murine leukem

3004- RosA,    Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: Involvement of Nrf2 antioxidant system
- in-vitro, Nor, HSC-T6
*GSH↓, increasing the synthesis of glutathione (GSH) involved in nuclear factor kappa B (NF-κB)-dependent inhibition of MMP-2 activity
*MMP2↓,
*ROS↓, RA suppresses ROS generation and lipid peroxidation (LPO) whereas increases cellular GSH in HSC-T6 cells.
*lipid-P↓,
*NRF2↑, RA significantly increased antioxidant response element (ARE)-mediated luciferase activity, nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2)

1748- RosA,    The Role of Rosmarinic Acid in Cancer Prevention and Therapy: Mechanisms of Antioxidant and Anticancer Activity
- Review, Var, NA
AntiCan↑, RA exhibits significant potential as a natural agent for cancer prevention and treatment
*BioAv↝, Various factors, including its lipophilic nature, stability in the gastrointestinal tract, and interactions with food, can significantly influence its absorption
*CardioT↓, RA attenuated these effects by reducing ROS levels, indicating its potential role as a cardioprotective agent during chemotherapy.
*Iron↓, Another significant mechanism antioxidant activity of RA is its capacity to chelate transition metal ions, particularly iron (Fe2+) and copper (Cu2+), which can catalyze the formation of highly reactive hydroxyl radicals through the Fenton reaction.
*ROS↓, forming stable complexes with Fe2+ and Cu2+, thus inhibiting their pro-oxidant activity.
*SOD↑, SOD, CAT, and GPx, play crucial roles in neutralizing ROS and maintaining cellular redox homeostasis. RA upregulates the expression and activity of these enzymes
*Catalase↑,
*GPx↑,
*NRF2↑, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a primary regulator of the antioxidant response
MARK4↓, Anwar’s study demonstrated that RA inhibited MARK4 activity in MDA-MB-231 breast cancer cells, resulting in dose-dependent apoptosis
MMP9↓, RA effectively inhibited cancer cell invasion and migration by reducing matrix metalloproteinase-9 (MMP-9) activity
TumCCA↑, caused cell cycle arrest
Bcl-2↓, RA downregulates Bcl-2 expression and upregulates Bax, thereby promoting apoptosis
BAX↑,
Apoptosis↑,
E-cadherin↑, promoting E-cadherin expression, while downregulating N-cadherin and vimentin
N-cadherin↓,
Vim↓,
Gli1↓, induced apoptosis by downregulating Gli1, a key component of the Hedgehog signaling pathway,
HDAC2↓, RA induced apoptosis by modulating histone deacetylase 2 (HDAC2) expression
Warburg↓, anti-Warburg effect of RA in colorectal carcinoma
Hif1a↓, RA inhibits hypoxia-inducible factor-1 alpha (HIF-1α) and downregulates miR-155
miR-155↓,
p‑PI3K↑, RA has been shown to upregulate p-PI3K, protecting cells through the PI3K/Akt pathway,
ROS↑, RA, induces significant ROS generation in A549 cells, which triggers both apoptosis and autophagy.
*IronCh↑, RA’s dual nature as both a phenolic acid and a flavonoid-related compound enables it to chelate metal ions and prevent the formation of free radicals,

1688- Se,    Potential Role of Selenium in the Treatment of Cancer and Viral Infections
- Review, Var, NA
IL2↑, in mice promoted T cell receptor signaling that pushed T cell differentiation toward a Th1 phenotype by increasing interleukin -2 (IL-2) and interferon gamma (INF-γ) production
INF-γ↑,
Th1 response↑, 18 human subjects treated with 200 μg selenium-enriched broccoli daily for three days showed that selenium supplementation resulted in substantially higher levels of both Th1 and Th2 cytokines secreted by peripheral blood mononuclear cells
Th2↑,
Dose↑, Wang et al. on hens supplemented selenium (5 mg/kg, 10 mg/kg, and 15 mg/kg) orally for three time periods (15, 30, and 45 days) found that excessive selenium intake leads to a substantial reduction in the amount of IFN-γ and IL-2 cytokines
AntiCan∅, after 5.5 years, the results of this study revealed no relationship between selenium supplementation and prostate cancer risk reduction in men with low selenium levels
Risk↑, instead, they discovered that taking selenium supplements raised the high-grade prostate cancer risk in men who had high selenium levels
chemoP↑, selenium provided protection of normal tissues from drug-induced toxicity
Hif1a↓, Selenium down-regulates HIFs,
VEGF↓, leading to the subsequent down-regulation in expression of several genes including those involved in angiogenesis such as vascular endothelial growth factor (VEGF)
selectivity↑, Selenium also helps with DNA repair in response to DNA-damaging agents, which improves the effectiveness of chemotherapeutic agents by protecting normal cells from their toxicity.
*GADD45A↑, selenium protected WT-MEF from DNA damage in a p53-dependent manner by increasing the expression of p53-dependent DNA repair proteins such as XPC, XPE, and Gadd45a. Thus, cells lacking p53, such as tumor cells, did not receive the same protection
NRF2↓, a defined dose and schedule of selenium down-regulates and up-regulates Nrf2 in tumor tissue and normal tissue, respectively
*NRF2↑, a defined dose and schedule of selenium up-regulates Nrf2 in normal tissue
ChemoSen↑, These differential effects were associated with selective sensitization of tumor tissues to subsequent treatment with chemotherapy. Overactivation of Nrf2 increases the expression of MRPs, consequently decreasing the effectiveness of chemotherapy .
angioG↓, The inhibition of hypoxia-induced activation of HIF-1α and VEGF by knocking down Nrf2 suppresses angiogenesis, demonstrating a crosstalk mechanism between Nrf2 and HIF-1α in angiogenesis
PrxI↓, Selenium was shown to reduce drug detoxification and increase cytotoxic effects of anti-cancer drugs in tumor cells through suppression of the Nrf2/Prx1 pathway,
ChemoSideEff↓, showed that selenium supplementation attenuated the cardiotoxic effects of doxorubicin by decreasing oxidative stress and inflammation through Nrf2 pathway activation
eff↑, combination of niacin and selenium reduced the reactive oxygen species generated by sepsis and diminished the resultant lung injury by upregulating Nrf2 signaling

2552- SFN,  Chemo,    Chemopreventive activity of sulforaphane
- Review, Var, NA
chemoP↑, chemopreventive activity of SFN
TumCG↓, SFN can inhibit the initiation of tumor development or halt the progression of cancer
*ROS↓, SFN can also exhibit chemopreventive behavior by interfering with various signaling pathways that regulate oxidative stress, inflammation, cell proliferation, differentiation, and apoptosis
*Inflam↓,
*Dose↝, In rats, the pharmacokinetics of SFN was assessed following an oral dose of 50 μmol of SFN. The plasma concentration of SFN can be detected at 1 hour and it peaks at 20 μM at 4 hours.
*NRF2↑, epigenetic reactivation of Nrf2 and subsequent induction of downstream target genes HO-1, NQO1, and UGT1A1
*HO-1↑,
*NQO1↑,
NF-kB↓, inactivation of NF-κB is an important chemopreventive mechanism of SFN
ROS↑, It was demonstrated that SFN-induced apoptosis is mediated by reactive oxygen species (ROS)-mediated activation of AMPK in human gastric cancer cells.

2553- SFN,    Mechanistic review of sulforaphane as a chemoprotective agent in bladder cancer
- Review, Bladder, NA
antiOx↓, SFN is a bioactive compound with both antioxidant and anti-inflammatory properties.
Inflam↓,
ChemoSen↑, SFN also improves the efficacy of certain traditional chemotherapeutic regimens
ROS⇅, A lesser established mechanism proposed by Li, et al. is that SFN induces mild increases ROS, leading to transcription factor EB (TFEB) activation. TFEB plays a role in activating antioxidant response elements and...ultimately reducing overall oxidat
*NRF2↑, SFN treatment increased Nrf2 and, therefore, glutathione levels
*GSH↑,
Catalase↑, Cancer cells treated with SFN showed higher catalase levels, heme oxygenase 1, and NAD(P)
HO-1↑,
NAD↑,
chemoP↑, Taken together, these studies provide strong evidence for the chemoprotective nature of SFN in various human epithelial cancers, including those of the bladder.

2555- SFN,    Chemopreventive functions of sulforaphane: A potent inducer of antioxidant enzymes and apoptosis
- Review, Var, NA
chemoP↑, induction of Metallothioneins MT by sulforaphane as a strategy for achieving chemoprevention and chemoprotection.
HDAC↓, sulforaphane supplementation resulted in slower tumor growth and significant histone deacetylase (HDAC) inhibition in the xenografts,
TumCCA↑, HDAC inhibition represents a novel chemoprevention mechanism by which sulforaphane can promote cell cycle arrest and apoptosis.
Apoptosis↑,
Mets↑, induction of Metallothioneins MT by sulforaphane
*NRF2↑, We have shown that sulforaphane can activate Nrf2 ...suggesting that increased expression of Nrf2 protein may play a key role in sulforaphane-induced MT gene activation.
ROS⇅, exposure to high concentrations of sulforaphane might generate an oxidant signal to stimulate caspase 3 pathway activation and DNA fragmentation, leading to cell death.

3180- SFN,    Exploring the therapeutic effects of sulforaphane: an in-depth review on endoplasmic reticulum stress modulation across different disease contexts
- Review, Var, NA
*cardioP↑, broad range of protective functions of sulforaphane, improving various diseases, such as cardiovascular, central nervous system, liver, eye, and reproductive diseases, as well as diabetes, cancer, gastroenteritis, and osteoarthritis,
*ER Stress↓, through the amelioration of ER stress in both in vivo and in vitro studies.
GRP78/BiP↑, Sulforaphane significantly increased the level of Bip/GRP78, and XBP-1 protein expression and enhanced the rate of HepG2 cells apoptosis.
XBP-1↑,
Apoptosis↑,
*NRF2↑, Mitigates oxidative stress and ER stress in vascular cells, contributing to cardioprotection
UPR↑, SFN can drive the UPR into an overactivated state(ai)

3193- SFN,    Epigenetic Therapeutics Targeting NRF2/KEAP1 Signaling in Cancer Oxidative Stress
- Review, Var, NA
DNMTs↓, SFN, a natural phytochemical, primarily attenuates both DNMTs and HDACs, individually suppressing DNA hypermethylation and histones deacetylation, ultimately upregulating NRF2.
HDAC↑,
NRF2↑,
DNMT1↓, significant attenuation of DNMT1 and DNMT3a contributed to a decrease in the methylated CpG ratio in the NFE2L2 promoter region in an SFN dose- and time-dependent manner, thus increasing NRF2
DNMT3A↓,
NQO1↑, consequently increasing the transcription of its target genes such as NQO1 and catechol-O-methyltransferase (COMT)
COMT↑,
TumCG↓, SFN may prevent or slow the growth of recurrent prostate cancer, essentially without severe adverse events.
*toxicity↓,

3192- SFN,    Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention
- in-vitro, Pca, PC3
Sp1/3/4↓, Sp1 protein was significantly decreased by SFN treatment in prostate cancer cells . Because SFN decreased the expression of Sp1, and to a lesser extent Sp3
selectivity↑, SFN alters gene expression differentially in normal and cancer cells with key targets in chemopreventive processes, making it a promising dietary anti-cancer agent.
NRF2↑, through the induction of phase 2 enzymes via Keap1-Nrf2 signaling
HDAC↓, SFN also inhibits the activity and/or expression of genes that regulate epigenetic mechanisms including histone deactylases (HDACs) and DNA methyltransferases (DNMTs) in cancer cells
DNMTs↓,
TumCCA↑, 15 μM SFN treatment induces cell cycle arrest at the G1 phase and only modestly increases apoptosis
selectivity↑, Normal prostate epithelial cells (PREC) do not undergo cell cycle arrest or apoptosis in response to this SFN treatment
HO-1↑, In all cell lines and time points, HO1 and NQO1 were identified as significantly upregulated by SFN
NQO1↑,
CDK2↓, MX non-receptor tyrosine kinase (BMX), cyclin-dependent kinase 2 (CDK2), and polo-like kinase 1 (PLK1) had decreased expression with SFN treatment
TumCP↓, suppression of Sp1 expression decreased prostate cancer cells proliferation.
BID↑, SFN treatment produced a significant increase in the expression of the apoptosis related genes Bid, Smac/Diablo, and ICAD only in PC-3 cells (
Smad1↑,
Diablo↑,
ICAD↑,
Cyt‑c↑, It also increased the expression of cytochrome c, c-IAP1, and HSP27 in PC-3 cells while it decreased expression in PREC cells.
IAP1↑,
HSP27↑,
*Cyt‑c↓,
*IAP1↓,
*HSP27↓,
survivin↓, In these studies, inhibition of Sp1 is associated with inhibition of the cancer promoting genes survivin, CDK4, VEGF and the androgen receptor.
CDK4↓,
VEGF↓,
AR↓,

3184- SFN,    The Integrative Role of Sulforaphane in Preventing Inflammation, Oxidative Stress and Fatigue: A Review of a Potential Protective Phytochemical
- Review, Nor, NA
*NRF2↑, SFN treatment modulates redox balance via activating redox regulator nuclear factor E2 factor-related factor (Nrf2).
*Inflam↓, SFN reduces inflammation by suppressing centrally involved inflammatory regulator nuclear factor-kappa B (NF-κB),
*NF-kB↓,
*ROS↓, SFN in preventing fatigue, inflammation, and oxidative stress,
*BioAv↝, It was identified that the lowest oral dose of SFN (2.8 µmol/kg or 0.5 mg/kg) has an absolute bioavailability of more than 80%, whilst with the highest dose (28 µmol/kg or 5 mg/kg) had only 20% bioavailability
*BioAv↝, For example, quickly steaming broccoli sprouts, followed by myrosinase treatment, contains the highest amount SFN, which is approximately 11 and 5 times higher than freeze dried and untreated steamed broccoli sprouts, respectively
*BioAv↝, The peak concentration of SFN metabolites (1.91 ± 0.24 µM) was identified in urine after 1 h of oral dose (200 µmol) of broccoli sprout ITCs to four healthy human volunteers
*BioAv↝, study with 20 participants, providing 200 µmol of SFN in capsule form revealed a peak of SFN equivalence (0.7 ± 0.2 µM) at 3 h
*cardioP↑, FN actives signaling pathways and phosphorylates Nrf2, which further increases the expression and activity of phase 2 enzymes, such as GR, GST, TR, NQO1, to minimize cardiac cell arrest,
*GPx↑, 200 mg of dried broccoli sprouts increased glutathione content, decreased levels of oxidized glutathione, increased the activity of GR and glutathione peroxidase (GPx), which are associated with decreasing oxidative stress in the cardiovascular syst
*SOD↑, SFN treatment activates Nrf2, which translocates into the nucleus to induce production of cellular defense enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase (HO) 1, NADPH quinone oxidoreductase
*Catalase↑,
*GPx↑,
*HO-1↑,
*NADPH↑,
*NQO1↑,
*LDH↓, Furthermore, creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH) (two enzymatic markers to assess muscle damage) were significantly lower after SFN treatment compared to a placebo
*hepatoP↑, protects exercise-induced liver damage, evidenced by reducing blood levels of enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), via inducing antioxidant defense response
*ALAT↓,
*AST↓,
*IL6↓, fresh broccoli sprouts (30 g/day) daily for 10 weeks. After the intervention period, plasma IL-6 concentrations were significantly lower

2448- SFN,    Sulforaphane and bladder cancer: a potential novel antitumor compound
- Review, Bladder, NA
Apoptosis↑, Recent studies have demonstrated that Sulforaphane not only induces apoptosis and cell cycle arrest in BC cells, but also inhibits the growth, invasion, and metastasis of BC cells
TumCG↓,
TumCI↓,
TumMeta↓,
glucoNG↓, Additionally, it can inhibit BC gluconeogenesis
ChemoSen↑, demonstrate definite effects when combined with chemotherapeutic drugs/carcinogens.
TumCCA↑, SFN can block the cell cycle in G2/M phase, upregulate the expression of Caspase3/7 and PARP cleavage, and downregulate the expression of Survivin, EGFR and HER2/neu
Casp3↑,
Casp7↑,
cl‑PARP↑,
survivin↓,
EGFR↓,
HER2/EBBR2↓,
ATP↓, SFN inhibits the production of ATP by inhibiting glycolysis and mitochondrial oxidative phosphorylation in BC cells in a dose-dependent manner
Glycolysis↓,
mt-OXPHOS↓,
AKT1↓, dysregulation of glucose metabolism by inhibiting the AKT1-HK2 axis
HK2↓,
Hif1a↓, Sulforaphane inhibits glycolysis by down-regulating hypoxia-induced HIF-1α
ROS↑, SFN can upregulate ROS production and Nrf2 activity
NRF2↑,
EMT↓, inhibiting EMT process through Cox-2/MMP-2, 9/ ZEB1 and Snail and miR-200c/ZEB1 pathways
COX2↓,
MMP2↓,
MMP9↓,
Zeb1↓,
Snail↓,
HDAC↓, FN modulates the histone status in BC cells by regulating specific HDAC and HATs,
HATs↓,
MMP↓, SFN upregulates ROS production, induces mitochondrial oxidative damage, mitochondrial membrane potential depolarization, cytochrome c release
Cyt‑c↓,
Shh↓, SFN significantly lowers the expression of key components of the SHH pathway (Shh, Smo, and Gli1) and inhibits tumor sphere formation, thereby suppressing the stemness of cancer cells
Smo↓,
Gli1↓,
BioAv↝, SFN is unstable in aqueous solutions and at high temperatures, sensitive to oxygen, heat and alkaline conditions, with a decrease in quantity of 20% after cooking, 36% after frying, and 88% after boiling
BioAv↝, It has been reported that the ability of individuals to use gut myrosinase to convert glucoraphanin into SFN varies widely
Dose↝, Excitingly, it has been reported that daily oral administration of 200 μM SFN in melanoma patients can achieve plasma levels of 655 ng/mL with good tolerance

2444- SFN,    Sulforaphane Delays Fibroblast Senescence by Curbing Cellular Glucose Uptake, Increased Glycolysis, and Oxidative Damage
- in-vitro, Nor, MRC-5
*GlucoseCon↓, SFN delayed senescence by decreasing glucose metabolism on the approach to senescence, exhibiting a caloric restriction mimetic-like activity
*ROS↓, and thereby decreased oxidative damage to cell protein and DNA
*Trx↓, This was associated with increased expression of thioredoxin-interacting protein, curbing entry of glucose into cells;
*HK2↓, decreased hexokinase-2
*NRF2↑, SFN is an activator of transcription factor Nrf2 [14] which regulates antioxidant response element- (ARE-) linked gene expression.
*Catalase↓, CAT, PDRX1, and GCLM, expression was increased in senescence and treatment with SFN increased the expression further
*TXNIP↑, increased expression of TXNIP, curbing the entry of glucose into cells
*PFKFB2↓, decreased PFKFB2 and increased G6PD, downregulating glycolysis.
*G6PD↑,

1725- SFN,    Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway
- Review, Var, NA
*toxicity∅, Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects
AntiCan↑, such as anticancer and antioxidant activities.
antiOx↑,
NRF2↑, FN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress;
DNMTs↓, SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs)
HDAC↓,
Hif1a↓, By suppressing the expression and activity of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), SFN inhibited the angiogenesis and metastasis of ovarian and colon cancers
VEGF↓,
P21↑, 15 μM SFN treatment caused reexpression of p21WAF1/CIP1 due to reduced expression of class I and II HDACs
TumCCA↑, resulted in cell cycle arrest
ac‑H3↑, upregulation of acetylated histone H3 and H4
ac‑H4↑,
DNAdam↑, SFN induced DNA damage
Dose↝, To achieve the effective inhibition of HDAC activity, it was reported that the concentration of SFN used in vitro experiments was from 3 to 15 μM, a single oral dose of 10 μmol in mice, and 68 g broccoli sprouts in human

1730- SFN,    Sulforaphane: An emergent anti-cancer stem cell agent
- Review, Var, NA
BioAv↓, When exposed to high temperatures during meal preparation, myrosinase can be degraded, lose its function, and subsequently compromise the synthesis of SFN.
BioAv↑, eating raw cruciferous vegetables, instead of heating them can significantly improve the biodisponibility of SFN and its subsequent beneficial effects.
GSTA1↑, induction of Phase II enzymes [glutathione S-transferase (GST)
P450↓, (cytochrome P450, CYP) inhibition
TumCCA↑, herb-derived agent can also promote cell cycle arrest and apoptosis by regulating different signaling pathways including Nuclear Factor erythroid Related Factor 2 (Nrf2)-Keap1 and NF-κB.
HDAC↓, modulate the activity of some epigenetic factors, such as histone deacetylases (HDAC),
P21↑, upregulation of p21 and p27,
p27↑,
DNMT1↓, SFN was able to decrease the expression of DNMT1 and DNMT3 in LnCap prostate cancer cells
DNMT3A↓,
cycD1↑, reduce methylation in Cyclin D2 promoter, thus inducing Cyclin D2 gene expression in those cells
DNAdam↑, SFN induced DNA damage, enhanced Bax expression and the release of cytochrome C followed by apoptosis
BAX↑,
Cyt‑c↑,
Apoptosis↑,
ROS↑, SFN increased reactive oxygen species (ROS), apoptosis-inducing factor (AIF)
AIF↑,
CDK1↑,
Casp3↑, activation of caspase-3, -8, and -9
Casp8↑,
Casp9↑,
NRF2↑, SFN significantly activated the major antioxidant marker Nrf2 and decreased NFκB, TNF-α, IL-1β
NF-kB↓,
TNF-α↓,
IL1β↓,
CSCs↓, SFN, have attracted attention due to their anti-CSC effect
CD133↓,
CD44↓,
ALDH↓,
Nanog↓,
OCT4↓,
hTERT↓,
MMP2↓,
EMT↓, SFN was reported to inhibit EMT and metastasis in the NSCLC, the cell lines H1299
ALDH1A1↓, ALDH1A1), Wnt3, and Notch4, other CSC-related genes inhibited by SFN treatment
Wnt↓,
NOTCH↓, SFN can inhibit aberrantly activated embryonic pathways in CSCs, including Sonic Hedgehog (SHH), Wnt/β-catenin, Cripto-1 (CR-1), and Notch.
ChemoSen↑, These results suggest that the antioxidant properties of SFN do not impact the cytotoxicity of antineoplastic drugs, but on the contrary, seems to improve it.
*Ki-67↓, Ki-67 and HDAC3 levels significantly decreased in benign breast tissues, and there was also a reduction in HDAC activity in blood cells
*HDAC3↓,
*HDAC↓,

1724- SFN,    Sulforaphane: A review of its therapeutic potentials, advances in its nanodelivery, recent patents, and clinical trials
- Review, Var, NA
antiOx↑, management of various diseases mainly due to its potent antioxidant properties.
NRF2↑, SFN achieves the activation of Nrf2 through the modification of cysteines of Kelch-like ECH-associated protein-1 (Keap1) resulting in the induction of phase-II (carcinogen-detoxifying) enzyme in cells
HDAC↓, SFN is known to inhibit the Histone deacetylases (HDACs) as well as Topoisomerases I and II enzymes, which play important roles during DNA replication.
neuroP↑, SFN upregulates the Nrf2 expression, thereby shows the neuroprotective efficacy.

1723- SFN,    Sulforaphane as a potential remedy against cancer: Comprehensive mechanistic review
- Review, Var, NA
*NRF2↑, activation of nuclear factor erythroid 2-related factor 2 (Nrf2). In this way, the oxidative stress and other toxicants are diminished
ROS↑, Cytotoxic effects of SFN are delivered via complex mechanisms where ROS generation results in improving apoptosis
MMP↓, ROS generation is also followed by mitochondrial membrane potential disruption that results in cytochrome c cytosolic release cleaving the poly-ADP-ribose polymerase and apoptosi
Cyt‑c↑,
cl‑PARP↑,
Apoptosis↑,
AMPK↑, AMPK signaling activated by SFN, high concentrations of ROS are produced
GSH↓, SFN-induced ROS generation also results in depletion of GSH levels

1494- SFN,  doxoR,    Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model
- in-vivo, BC, NA - in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
CardioT↓, SFN (4 mg/kg, 5 days/week) protected against mortality and cardiac dysfunction induced by DOX
*GSH↑, Rats Hearts: SFN and DOX co-treatment reduced MDA and 4-HNE adduct formation and also prevented DOX-induced depletion of GSH levels
*ROS↓, SFN reduces DOX-induced oxidative stress in the heart of non-tumor bearing rats.
*NRF2↑, activates Nrf2 in rat hearts during DOX treatment
NRF2∅, SFN does not interfere with DOX toxicity or Nrf2 activity in breast cancer cell lines
HDAC↓, SFN acts synergistically with DOX to inhibit HDAC and DNMT activity, decrease ERα detection and increase caspase-3 activity
DNMTs↓,
Casp3↑,
ER-α36↓, ERα levels in MCF-7, MDA-MB-231
Remission↑, SFN+DOX treatment (with a total DOX dose of 20 mg/kg) was able to eradicate the tumors in all rats by day 35 after tumor implantation
eff↑, SFN (4 mg/kg oral; 5 days/week for 5 weeks) with DOX (total of 10 or 20 mg/kg i.p. administered over 4 weeks) and showed that in combination with SFN, the dosage of DOX could be < by 50% while still eliciting the same anti-cancer effects as DOX alone
ROS↑, Increased generation of reactive oxygen species (ROS), an altered redox status, and aerobic glycolysis for energy production distinguish highly proliferative cancer cells from normal healthy cells
selectivity?, ROS production... distinguish highly proliferative cancer cells from normal healthy cells

1482- SFN,    Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway
- in-vitro, Bladder, T24
tumCV↓,
Apoptosis↑,
Cyt‑c↑,
Bax:Bcl2↑, Bcl-2/Bax dysregulation
Casp9↑,
Casp3↑,
Casp8∅,
cl‑PARP↑,
ROS↑, sulforaphane triggered reactive oxygen species (ROS) generation
MMP↓,
eff↓, blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine.
ER Stress↑,
p‑NRF2↑, accumulation of phosphorylated Nrf2 proteins in the nucleus
HO-1↑, induction of heme oxygenase-1 expression

1484- SFN,    Sulforaphane’s Multifaceted Potential: From Neuroprotection to Anticancer Action
- Review, Var, NA - Review, AD, NA
neuroP↑, current evidence supporting the neuroprotective and anticancer effects of SFN
AntiCan↑,
NRF2↑, neuroprotective effects through the activation of the Nrf2 pathway
HDAC↓, histone deacetylase was inhibited after human subjects ingested 68 g of broccoli sprouts
eff↑, sensitize cancer cells to chemotherapy
*ROS↓, protecting neurons [14] and microglia [15] against oxidative stress
neuroP↑, neuroprotective effects in Alzheimer’s disease (AD)
HDAC↓, capacity as a histone deacetylase (HDAC) inhibitor
*toxicity∅, normal cells are relatively resistant to SFN-induced cell death
BioAv↑, SFN has good bioavailability; it can reach high intracellular and plasma concentrations
eff↓, However, it is important to consider that at lower doses, specifically 2.5 μM, SFN resulted in a slight increase in cell proliferation by 5.18–11.84% within a 6 to 48 h treatment window
cycD1↓, in breast cancer
CDK4↓, in breast cancer
p‑RB1↓, in breast cancer
Glycolysis↓, in prostate cancer
miR-30a-5p↑, ovarian cancer
TumCCA↑, gastric cancer
TumCG↓,
TumMeta↓,
eff↑, SFN emerged as a critical enhancer of ST’s efficacy by suppressing resistance in RCC cells, offering a potent approach to overcome ST monotherapy limitations.
ChemoSen↑, SFN may improve the effectiveness of chemotherapy by increasing cancer cell sensitivity to the drugs used to treat them
RadioS↑, SFN may help protect healthy cells and tissues from the harmful effects of radiation
CardioT↓, Several studies have demonstrated the protective role of SFN in cardiotoxicity
angioG↓, In colon cancers, SFN blocks cells’ progression and angiogenesis by inhibiting HIF-1α and VEGF expression
Hif1a↓,
VEGF↓,
*BioAv?, SFN is well absorbed in the intestine, with an absolute bioavailability of approximately 82%.
*Half-Life∅, In rats, after an oral dose of 50 μmol of SFN, the plasma concentration of SFN can peak at 20 μM at 4 h and decline with a half-life of about 2.2 h

1428- SFN,    Broccoli or Sulforaphane: Is It the Source or Dose That Matters?
- Review, NA, NA
HDAC↓, >100 µmol/kg
NRF2↑, sulforaphane is the most cited natural product activator of Nrf2 signaling

1495- SFN,  doxoR,    Sulforaphane protection against the development of doxorubicin-induced chronic heart failure is associated with Nrf2 Upregulation
- in-vivo, Nor, NA
*CardioT↓, SFN significantly prevented DOX-induced progressive cardiac dysfunction between 2-6 weeks and prevented DOX-induced cardiac function deterioration.
*NRF2↑, SFN upregulated NF-E2-related factor 2 (Nrf2)
*eff↓, protective effect of SFN against DOX-induced fibrotic and inflammatory responses was abolished by Nrf2 silencing.
*ROS↓, prevented DOX-induced cardiac oxidative stress

1501- SFN,    The Inhibitory Effect of Sulforaphane on Bladder Cancer Cell Depends on GSH Depletion-Induced by Nrf2 Translocation
- in-vitro, CRC, T24
Dose↝, SFN (2.5 µM) was shown to promote cell proliferation (5.18–11.84%) and migration in T24 cells, whilst high doses of SFN (>10 µM) inhibited cell growth significantly.
NRF2↑, induction effect of SFN on Nrf2 expression at both low (2.5 µM) and high dose (10 µM) was characterized by a bell-shaped curve.
GSH↓, highly dependent on Nrf2-mediated GSH depletion and following production. These findings suggested that a higher dose of SFN is required for the prevention and treatment of bladder cancer.
eff↑, GSH-depleting agent L-Buthionine-sulfoximine abolished the effect of SFN on cell proliferation.

1437- SFN,    Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition
- Review, NA, NA
HDAC↓, 15 μM
HDAC1↓,
HDAC2↓,
HDAC3↓,
HDAC8↓,
eff↑, this evidence suggests that sulforaphane may also compromise DNA repair mechanisms in cancer cells with selectivity.
ac‑HSP90↑,
DNMT1↓, 10 μM sulforaphane in 6 days inhibited DNMT1 and DNMT3a expression by 48% and 78%, respectively
DNMT3A↓,
hTERT↓,
NRF2↑, enhance nuclear translocation of Nrf2 and increase expression of Nrf2-target antioxidant genes, including HO-1, NQO1, and UGT1A1
HO-1↑,
NQO1↑,
miR-155↓,
miR-200c↑,
SOX9↓,
*toxicity↓, broccoli sprout-infused beverage containing 400 μM glucoraphanin nightly for 2 weeks causing no adverse effects and being well tolerated in 200 subjects

1458- SFN,    Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma
- Review, Bladder, NA
HDAC↓, SFN’s role as a natural HDAC-inhibitor is highly relevant
eff↓, SFN exerts stronger anti-proliferative effects on bladder cancer cell lines under hypoxia, compared to normoxic conditions
TumW↓, mice, SFN (52 mg/kg body weight) for 2 weeks reduced tumor weight by 42%
TumW↓, In another study a 63% inhibition was noted when tumor bearing mice were treated with SFN (12 mg/kg body weight) for 5 weeks
angioG↓,
*toxicity↓, In both investigations, the administration of SFN did not evoke apparent toxicity
GutMicro↝, SFN may protect against chemical-induced bladder cancer by normalizing the composition of gut microbiota and repairing pathophysiological destruction of the gut barrier,
AntiCan↑, A prospective study involving nearly 50,000 men indicated that high cruciferous vegetable consumption may reduce bladder cancer risk
ROS↑, Evidence shows that SFN upregulates the ROS level in T24 bladder cancer cells to induce apoptosis
MMP↓,
Cyt‑c↑,
Bax:Bcl2↑,
Casp3↑,
Casp9↑,
Casp8∅,
cl‑PARP↑,
TRAIL↑, ROS generation promotes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity
DR5↑,
eff↓, Blockade of ROS generation inhibited apoptotic activity and prevented Nrf2 activation in cells treated with SFN, pointing to a direct effect of ROS on apoptosis
NRF2↑, SFN potently inhibits carcinogenesis via activation of the Nrf2 pathway
ER Stress↑, endoplasmic reticulum stress evoked by SFN
COX2↓, downregulates COX-2 in T24 cells
EGFR↓, downregulation of both the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2/neu
HER2/EBBR2↓,
ChemoSen↑, gemcitabine/cisplatin and SFN triggered pathway alterations in bladder cancer may open new therapeutic strategies, including a combined treatment regimen to cause additive effects.
NF-kB↓,
TumCCA?, cell cycle at the G2/M phase
p‑Akt↓,
p‑mTOR↓,
p70S6↓,
p19↑, p19 and p21, are elevated under SFN
P21↑,
CD44↓, CD44s expression correlates with induced intracellular levels of ROS in bladder cancer cells variants v3–v7 on bladder cancer cells following SFN exposure

1465- SFN,    TRAIL attenuates sulforaphane-mediated Nrf2 and sustains ROS generation, leading to apoptosis of TRAIL-resistant human bladder cancer cells
- NA, Bladder, NA
eff↑, Combined treatment with SFN and TRAIL (SFN/TRAIL) significantly induced apoptosis
Apoptosis↑,
Casp↑,
MMP↓,
BID↑,
DR5↑,
ROS↑, SFN increased both the generation of reactive oxygen species (ROS) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is an anti-oxidant enzyme.
NRF2↑,
eff↑, Interestingly, TRAIL effectively suppressed SFN-mediated nuclear translocation of Nrf2, and the period of ROS generation was more extended compared to that of treatment with SFN alone.
eff↓, blockade of ROS generation inhibited apoptotic activity

2168- SFN,    Amelioration of Alzheimer's disease by neuroprotective effect of sulforaphane in animal model
- in-vivo, AD, NA
*NRF2↑, previously been found to stimulate the Nrf2-ARE pathway
*cognitive↑, ameliorated cognitive function of Aβ-induced AD acute mouse models
other↓, inhibition of Aβ aggregation

1508- SFN,    Nrf2 targeting by sulforaphane: A potential therapy for cancer treatment
- Review, Var, NA
*BioAv↑, RAW: higher amounts were detected when broccoli were eaten raw (bioavailability equal to 37%), compared to the cooked broccoli (bioavailability 3.4%)
HDAC↓, Sulforaphane is able to down-regulate HDAC activity and induce histone hyper-acetylation in tumor cell
TumCCA↓, Sulforaphane induces cell cycle arrest in G1, S and G2/M phases,
eff↓, in leukemia stem cells, sulforaphane potentiates imatinib effect through inhibition of the Wnt/β-catenin functions
Wnt↓,
β-catenin/ZEB1↓,
Casp12?, inducing caspases activation
Bcl-2↓,
cl‑PARP↑,
Bax:Bcl2↑, unbalancing the ratio Bax/Bcl-2
IAP1↓, down-regulating IAP family proteins
Casp3↑,
Casp9↑,
Telomerase↓, In Hep3B cells, sulforaphane reduces telomerase activity
hTERT↓, inhibition of hTERT expression;
ROS?, increment of ROS, induced by this compound, is essential for the downregulation of transcription and of post-translational modification of hTERT in suppression of telomerase activity
DNMTs↓, (2.5 - 10 μM) represses hTERT by impacting epigenetic pathways, in particular through decreased DNA methyltransferases activity (DNMTs)
angioG↓, inhibit tumor development through regulation of angiogenesis
VEGF↓,
Hif1a↓,
cMYB↓,
MMP1↓, inhibition of migration and invasion activities induced by sulforaphane in oral carcinoma cell lines has been associated to the inhibition of MMP-1 and MMP-2
MMP2↓,
MMP9↓,
ERK↑, inhibits invasion by activating ERK1/2, with consequent upregulation of E-cadherin (an invasion inhibitor)
E-cadherin↑,
CD44↓, downregulation of CD44v6 and MMP-2 (invasion promoters)
MMP2↓,
eff↑, ombination of sulforaphane and quercetin synergistically reduces the proliferation and migration of melanoma (B16F10) cells
IL2↑, induces upregulation of IL-2 and IFN-γ
IFN-γ↑,
IL1β↓, downregulation of IL-1beta, IL-6, TNF-α, and GM-CSF
IL6↓,
TNF-α↓,
NF-kB↓, sulforaphane inhibits the phorbol ester induction of NF-κB, inhibiting two pathways, ERK1/2 and NF-κB
ERK↓,
NRF2↑, At molecular level, sulforaphane modulates cellular homeostasis via the activation of the transcription factor Nrf2.
RadioS↑, sulforaphane could be used as a radio-sensitizing agent in prostate cancer if clinical trials will confirm the pre-clinical results.
ChemoSideEff↓, chemopreventive effects of sulforaphane

1513- SFN,  acetaz,    Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis
- in-vitro, BrCC, H720 - in-vivo, BrCC, NA - in-vitro, BrCC, H727
eff↑, Combining AZ+SFN reduced tumor cell survival compared to each agent alone, both in vitro and in vivo xenograft tissues.
tumCV↓,
Apoptosis↑,
P21↑,
PI3K↓,
Akt↓,
mTOR↓,
5HT↓, significantly reducing 5-HT secretion in carcinoid syndrome.
NRF2↑, AZ and SFN increased the expression of Nrf2 by 61% and 104%, respectively. Combination treatment further increased expression by 127%

1509- SFN,    Combination therapy in combating cancer
- Review, NA, NA
NRF2↑, chemopreventive properties that are thought to be due to potent upregulation of Nrf2
ChemoSideEff↓, chemopreventive properties
eff↑, combined SFN with taxol in treatment of prostate cancer cell line DU145, and observed that SFN potentiated the effects of low doses of taxol
TumCP↓,
Apoptosis↑,
TumCCA↑, induce G2/M cell cycle arrest in vitro and in vivo
eff↑, SFN positively enhanced bortezomib, lenalidomide, and conventional drugs, such as dexamethasone, doxorubicin, and melphalan in a synergistic manner
PSA↓, SFN has shown to significantly reduce levels of prostate-specific antigen (PSA) (44.4% SFN group vs. 71.8% in placebo)
P53↑, SFN activates various anti-cancer responses such as p53, ARE, IRF-1, Pax-6 and XRE while suppressing proteins involved in tumorigenesis and progression, such as HIF1α, AP-1 and CA IX
Hif1a↓, while suppressing proteins involved in tumorigenesis and progression, such as HIF1α, AP-1 and CA IX
CAIX↓,
chemoR↓, SFN has thus shown to reduce chemoresistance and may be a potential agent to be used in conjunction with chemotherapeutics
5HT↓, SFN downregulates 5-HT receptor expression in Caco-2 cells

3302- SIL,    Protective effects of silymarin in glioblastoma cancer cells through redox system regulation
- in-vitro, GBM, U87MG
NRF2↑, The expression level of Nrf2 and HO-1 and glutaredoxin and thioredoxin enzymes were checked by real-time PCR method, and the expression level increased significantly after treatment.
HO-1↑,
Trx↑,
antiOx↑, Our findings suggest that silymarin may exert its cytotoxic and anticancer effects by enhancing the Nrf2/HO-1 pathway through antioxidant mechanisms in U-87 MG cells.

3307- SIL,    Flavolignans from Silymarin as Nrf2 Bioactivators and Their Therapeutic Applications
- Review, Var, NA
*NRF2↑, antioxidant and protective activities, which are probably related to the activation of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), known as a master regulator of the cytoprotector response.
*antiOx↑, many studies have been conducted in order to identify its different biological activities, such as antioxidant, chemoprotective, anti-inflammatory,
*chemoP↑,
*Inflam↓,
*BioAv↑, The design of silybinnano-emulsions using oil, surfactants, and co-surfactants (sefsol-218/Tween 80/ethanol) in oral administration was more capable of improving the SM hepatoprotective effect than SM alone [138].
eff↑, ↑ Induction of UGT1A7 with propolis, artichoke and SM (7.3, 5 and 4.5-fold respectively
*NQO1↑, ↑ activity of NQO1
TNF-α↓, ↑ SOD and GPx activity ↓ gastric inflammation: TNF- α, IL-6 and myeloperoxidase activity,
IL6↓,
*GSH↑, PC12 cells (normal) ↑ intracellular levels of GSH ↓ levels of ROS and MDA
*ROS↓,
*MDA↓,
eff↑, combination of SM with vitamin E and/or curcumin can be a good option for the treatment of liver injury induced by toxic substances
*hepatoP↑,
*GPx↑, 50 mg/kg of SM inhibits the synthesis of lipid peroxides, promotes the upregulation of Nrf2, and the enhancement of the activity of GPx and SOD enzymes, increasing antioxidant and cytoprotective defense, thus preventing gastric oxidative stress.
*SOD↑,
*Catalase↑, treatment with SM at 200 mg/kg for 3 days improved oxidative stress by reducing MDA and increasing the activity of SOD, Cat, and GPx in lung tissue
*HO-1↑, These results were related to the upregulation of Nrf2, HO-1, and NQO1 in male Sprague-Dawley rats.
*neuroP↑, SM can exert neuroprotection against acrylamide-induced damage

3308- SIL,    Structural basis of Nrf2 activation by flavonolignans from silymarin
- Analysis, NA, NA
*antiOx↑, Experimental findings have suggested that the antioxidative and protective activities of these compounds could be due to their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2)
*chemoP↑,
*NRF2↑,

3309- SIL,    Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives
- Review, NA, NA
*ROS↓, (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut.
*IronCh↑,
*MMP↑, (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance.
*NRF2↑, (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation
*Inflam↓, (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases.
*hepatoP↑,
*HSPs↑, (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins
*Trx↑,
*SIRT2↑, increased expression of protective molecules (GSH, Thioredoxins, heat shock proteins (HSPs), sirtuins, etc.)
*GSH↑,
*ROS↑, Similarly, production of O2− and NO in isolated rat Kupffer cells were inhibited by silibinin in a dose-dependent manner, with IC50 80 μM
*NADPH↓, It also decreased the NADPH oxidase, iNOS and NF-κB over expression by As and upregulated the Nrf2 expression in the renal tissue.
*iNOS↓,
*NF-kB↓,
*BioAv↓, active free silibinin concentration in plasma after oral consumption of SM, depending on dose of supplementation, could be in the range 0.2–2.0 μM.
*Dose↝, healthy volunteers, after an oral administration of SM (equivalent to 120 mg silibinin), total (unconjugated + conjugated) silibinin concentration in plasma was 1.1–1.3 μg/mL
*BioAv↑, For example, silibinin concentration in the gut could reach 800 μM

3310- SIL,    Silymarin attenuates paraquat-induced lung injury via Nrf2-mediated pathway in vivo and in vitro
- in-vitro, Lung, A549
Inflam↓, silymarin administration abated PQ-induced lung histopathologic changes, decreased inflammatory cell infiltration
MPO↓, suppressed myeloperoxidase (MPO) activity and nitric oxide (NO)/inducible nitric oxide synthases (iNOS) expression,
NO↓,
iNOS↓,
ROS↓, improved oxidative stress (malondialdehyde, MDA; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GSH-Px) in lung tissue and serum.
MDA↑,
SOD↑,
Catalase↑,
GPx↑,
NRF2↑, silymarin upregulated the levels of nuclear factor-erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1(NQO1).
HO-1↑,
NADPH↑,

3311- SIL,    Silymarin protects against acrylamide-induced neurotoxicity via Nrf2 signalling in PC12 cells
- in-vitro, Nor, PC12
*antiOx↑, Silymarin (SM) is a well-known antioxidant, anti-inflammatory and anti-cancer compound extracted from the milk thistle.
*Inflam↓,
AntiCan↑,
*ROS↓, SM could reduce ROS and MDA levels and increase GSH levels in AA-induced PC12 cells.
*MDA↓,
*GSH↓,
*NRF2↑, SM could activate Nrf2 signalling and increase the expression of Nrf2, Gpx, GCLC and GCLM in AA-treated PC12 cells.
*GPx↑,
*GCLC↑,
*GCLM↑,

3315- SIL,    Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats
- in-vivo, Nor, NA
neuroP↑, Silymarin protects against the brain and sciatic nerve injuries induced by docetaxel.
*NRF2↑, Silymarin activates Nrf2/HO-1, and suppresses Bax/Bcl2 signaling.
*HO-1↑,
*lipid-P↓, SLM significantly decreased brain lipid peroxidation level and ameliorated brain glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in DTX-administered rats
*GSH↑,
*SOD↑,
*Catalase↑,
*GPx↑,
*NF-kB↓, SLM attenuated levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α),
*TNF-α↓,
*JNK↓, decreased the expression of c-Jun N-terminal kinase (JNK) in the sciatic nerve
*Bcl-2↑, SLM markedly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) and downregulated the expression of Bcl-2 associated X protein (Bax) in the brain
*BAX↑,

3324- SIL,    Silymarin prevents NLRP3 inflammasome activation and protects against intracerebral hemorrhage
*ROS↓, Silymarin (200 mg/kg) treatment 30 mins post ICH injury prevented increase in oxidative stress markers and up-regulated antioxidant status.
*TAC↑,
*NF-kB↓, Silymarin treatment significantly down regulated the inflammatory responses by suppressing NF-κB-p65 levels and inflammasome-mediated caspase-1/IL-1β expressions.
*IL2↓,
*NRF2↑, treatment with silymarin post ICH injury increased Nrf-2/HO-1 and thereby improved overall cytoprotection.
*HO-1↑,
*neuroP↑, silymarin acts as neuroprotective compound by preventing inflammatory activation and up regulating Nrf-2/HO-1 signaling post ICH injury.
*Inflam↓,
*NLRP3↓, The NLRP3 mediated inflammatory responses were down regulated during silymarin treatment post ICH injury compared to ICH group

3312- SIL,    Silymarin Alleviates Oxidative Stress and Inflammation Induced by UV and Air Pollution in Human Epidermis and Activates β-Endorphin Release through Cannabinoid Receptor Type 2
- Human, Nor, NA
*antiOx↑, silymarin (SM), an antioxidant and anti-inflammatory complex of flavonoids,
*Inflam↓,
*ROS↓, SM decreased morphological alterations, ROS, and IL-1a in UV+urban-dust-stressed RHE.
*IL1α↓,
*AhR↑, AHR- and Nrf2-related genes were upregulated, which control the antioxidant effector and barrier function.
*NRF2↑,
*IL8↓, Interleukin 8 gene expression was decreased.

3319- SIL,    Silymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms
- Review, AD, NA - Review, Park, NA - Review, Stroke, NA
*neuroP↑, Silymarin can be used as a neuroprotective therapy against AD, PD and CI
*ROS↓, Silymarin prohibit oxidative stress, pathologic protein aggregation.
*Inflam↓, Silymarin inhibit neuroinflammation, apoptosis, and estrogenic receptor modulation.
*Apoptosis↓,
*BBB?, Silymarin, as a polyphenolic complex, can cross the blood-brain barrier (BBB)
*tau↓, inhibitory action of Silibinin on tau protein phosphorylation in the hippocampus and cortical region of the brain could describe an important neuro-protective effect against AD progression
*NF-kB↓, inhibiting the NF-κB pathway leading to attenuating the activity of NF-κB (
*IL1β↓, inhibition of inflammatory responses such as IL-1β and TNF-α mRNA gene
*TNF-α↓,
*IL4↓, enhance the production of IL-4 in the hippocampal region
*MAPK↓, down-regulation of MAPK activation
*memory↑, Silibinin exhibited its beneficial effect on improvement of memory impairment in rats
*cognitive↑, Silymarin was able to alleviated the impairment in cognitive, learning and memory ability caused by Aβ aggravation through making a reduction in oxidative stress in the hippocampal region
*Aβ↓,
*ROS↓,
*lipid-P↓, eduction in lipid peroxidation, controlling the GSH levels and then cellular anti-oxidant status improvement,
*GSH↑,
*MDA↓, Silymarin could reduce MDA content and significantly increased the reduced activity level of antioxidant enzyme, including SOD, CAT and GSH in the brain tissue induced by aluminum
*SOD↑,
*Catalase↑,
*AChE↓, Silibinin/ Silymarin, as a strong suppressor of AChE and BChE activity, exerted a positive effect against AD symptoms via increasing the ACh level in the brain
*BChE↓,
*p‑ERK↓, Silibinin could inhibit increased level of phosphorylated ERK, JNK and p38 (p-ERK, p-JNK and p-p38, respectively
*p‑JNK↓,
*p‑p38↓,
*GutMicro↑, demonstrated in APP/PS1 transgenic mice model of AD which was associated with controlling of the gut microbiota by both Silymarin and Silibinin
*COX2↓, Inhibition of the NF-κB pathway/ expression, Inhibition of IL-1β, TNF-α, COX_2 and iNOS level/ expression
*iNOS↓,
*TLR4↓, suppress TLR4 pathways and then subsequently diminished elevated level of TNF-α and up-regulated percentage of NF-κB mRNA expression
*neuroP↑, neuro-protective mechanisms on cerebral ischemia (CI)
*Strength↑, Silymarin decreased the loss of grip strength in the experimental rats
*AMPK↑, In SH-SY5Y cells, Silibinin blocked OGD/re-oxygenation- induced neuronal degeneration via AMPK activation as well as suppression in both ROS production and MMP reduction and even reduced neuronal apoptosis and necrosis.
*MMP↑,
*necrosis↓,
*NRF2↑, Silymarin up-regulated Nrf-2/HO-1 signaling (Yuan et al., 2017
*HO-1↑,

3318- SIL,    Pharmaceutical prospects of Silymarin for the treatment of neurological patients: an updated insight
- Review, AD, NA - Review, Park, NA
*hepatoP↑, widely studied as a hepatoprotective drug for various liver disorders.
*neuroP↑, research studies have shown its putative neuroprotective nature against various brain disorders, including psychiatric, neurodegenerative, cognitive, metabolic and other neurological disorders
*TLR4↓, Silymarin treatment has shown anti-inflammatory action in AD models by suppressing toll-like receptor 4 (TLR4) pathways and decreasing the increased mRNA levels of TNF-α, IL-1β and NF-κB
*TNF-α↓,
*IL1β↓,
*NF-kB↓,
*memory↑, improvement in memory los
*cognitive↑, finally leading to normal cognitive functions
*NRF2↑, upregulating the Nrf-2/HO-1 signaling in mice model
*HO-1↑,
*ROS↓, inhibition of oxidative stress in the brain
*Akt↑, Figure 4
*mTOR↑,
*SOD↑,
*Catalase↑,
*GSH↑,
*IL10↑,
*IL6↑,
*NO↓,
*MDA↓,
*AChE↓,
*MAPK↓,

3316- SIL,  Chemo,    Silymarin Nanoparticles Counteract Cognitive Impairment Induced by Doxorubicin and Cyclophosphamide in Rats; Insights into Mitochondrial Dysfunction and Nrf2/HO-1 Axis
Inflam↓, Silymarin was reported to possess anti-inflammatory, antioxidant, and neuroprotective impacts.
antiOx↓,
neuroP↑,
cognitive↑, recent study shed light on the neuroprotective attributes of silymarin against cognitive dysfunction instigated in rats with doxorubicin/cyclophosphamide combination
NRF2↑, additionally, caspase-3 augmentation and of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) pathway disturbance were found following chemotherapy treatment.
HO-1↑,
memory↑, Silymarin treatment opposed such effects via enhancing memory function, preserving brain architecture, and reducing acetylcholinesterase activity and caspase-3 level.
AChE↓,
Casp3↓,

3313- SIL,    Silymarin attenuates post-weaning bisphenol A-induced renal injury by suppressing ferroptosis and amyloidosis through Kim-1/Nrf2/HO-1 signaling modulation in male Wistar rats
- in-vivo, NA, NA
*NRF2↑, silymarin activates the Nrf2/HO-1 pathway, thus providing cellular defense
*HO-1↑,
*creat↓, Silymarin diminished BPA-induced rise in serum urea, creatinine, BUN, and plasma kim-1 levels.
*BUN↓,
*RenoP↑, improved renal histoarchitecture in BPA-exposed rats.
*MDA↓, suppression of BPA-induced rise in renal iron, MDA, TNF-α, IL-1β, and cytochrome c levels, and myeloperoxidase and caspase 3 activities by silymarin therapy.
*TNF-α↓,
*IL1β↓,
*Cyt‑c↓,
*Casp3↓,
*GSTs↓, silymarin attenuated BPA-induced downregulation of Nrf2 and GSH levels, and HO-1, GPX4, SOD, catalase, GST, and GR activities.
*GSH↑,
*GPx4↑,
*SOD↑,
*GSR↓,
*Ferroptosis↓, silymarin mitigated post-weaning BPA-induced renal toxicity by suppressing ferroptosis and amyloidosis through Kim-1/Nrf2/HO-1 modulation.

2217- SK,    Shikonin Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis to Attenuate Renal Ischemia/Reperfusion Injury by Activating the Sirt1/Nrf2/HO-1 Pathway
- in-vivo, Nor, NA - in-vitro, Nor, HK-2
*ER Stress↓, shikonin alleviated ER stress-induced apoptosis in I/R mice
*SIRT1↑, shikonin activated Sirt1/Nrf2/HO-1 signaling post-I/R
*NRF2↑,
*HO-1↑,
*eff↓, inhibition of Sirt1 limited shikonin-mediated protection against ER stress-stimulated apoptosis in both animal and cellular models.
*RenoP↑, Shikonin pretreatment alleviates renal I/R injury through activating Sirt1/Nrf2/HO-1 signaling to inhibit ER stress-mediated apoptosis.
*GRP78/BiP↓, The current study revealed that shikonin significantly downregulated GRP78, CHOP, caspase-12, Bax, and cleaved caspase-3 proteins levels in renal tissues of I/R mice and H/R-challenged HK-2 cells
*CHOP↓,
*Casp12↓,
*BAX↓,
*cl‑Casp3↓,

2225- SK,    Shikonin protects skin cells against oxidative stress and cellular dysfunction induced by fine particulate matter
- in-vitro, Nor, HaCaT
*antiOx↑, antioxidant capabilities of shikonin and its ability to protect human keratinocytes from oxidative stress induced by fine particulate matter
*ROS↓, 3 µM was nontoxic to human keratinocytes and effectively scavenged reactive oxygen species (ROS) while increasing the production of reduced glutathione (GSH).
*GSH↑,
*GCLC↑, Shikonin increased the expression of GCLC and GSS via AKT and NRF2 activation
*GSS↑,
*Akt↑,
*NRF2↑,

2220- SK,    Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades
- in-vivo, Nor, NA
*RenoP↑, Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture.
*ROS↓, Shikonin Defended against Renal Oxidative Stress and Activated the SIRT1/Nrf2/HO-1 Cascades in Rats with Gentamicin-Induced Renal Damage
*SIRT1↓,
*NRF2↑,
*HO-1↑,
*GSH↑, significant rise in GSH, TAC levels, and SOD activity, as well as SIRT1, Nrf2, and HO-1 protein levels
*TAC↑,
*SOD↑,
*MDA↓, significant decrease in the renal MDA, NO, and iNOS
*NO↓,
*iNOS↓,
*NHE3↑, shikonin treatment significantly and dose-dependently enhanced the reduced NHE3 level and mRNA expression induced by repeated gentamicin injections,
*PI3K↑, in the current study, shikonin treatment of the gentamicin-injected groups increased PI3K

2218- SK,    Shikonin Alleviates Endothelial Cell Injury Induced by ox-LDL via AMPK/Nrf2/HO-1 Signaling Pathway
- in-vitro, Nor, HUVECs
*Dose↝, When the shikonin concentration was >0.1 μmol/L, the cell viability increased significantly.
*Apoptosis↓, SKN Reduces ox-LDL-Induced Endothelial Cell Apoptosis
*Casp3↓, SKN pretreatment downregulated the cleaved caspase-3 protein levels and upregulated Bcl-2 protein levels in a concentration-dependent manner.
*Bcl-2↑,
*Inflam↓, SKN Downregulates the Expression of Inflammatory Factors Induced by ox-LDL
*VCAM-1↓, SKN pretreatment significantly downregulates the levels of VCAM1, ICAM1, and E-selectin proteins.
*ICAM-1↓,
*E-sel↓,
*ROS↓, SKN pretreatment significantly decreases the generation of ROS and increases the SOD activity induced by ox-LDL.
*SOD↑,
*AMPK↑, SKN Inhibits Oxidative Stress Damage by Activating the AMPK-Nrf2-HO-1 Pathway
*NRF2↑,
*HO-1↑,
*TNF-α↓, TNF-α, IL-1β, IL-6, VCAM1, ICAM1, and E-selectin in endothelial cells, while SKN treatment significantly downregulated the expression of these proteins mentioned above
*IL1β↓,
*IL6↓,

2216- SK,    Shikonin upregulates the expression of drug-metabolizing enzymes and drug transporters in primary rat hepatocytes
- in-vivo, Nor, NA
*NRF2↑, Shikonin effectively upregulates the transcription of CYP isozymes, phase II detoxification enzymes, and phase III membrane transporters and this function is at least partially through activation of AhR and Nrf2
*AhR↑,
*CYP1A1↑, shikonin dose-dependently increased the protein expression of CYP1A1, CYP1A2, CYP2C6, CYP2D1, and CYP3A2.
*CYP1A2↑,
*CYP2C6↑,
*CYP2D1↑,
*CYP3A2↑,
*NQO1↑, Compared with the controls, cells treated with 2 uM shikonin had 5.5-, 3.0-, and 2.0-fold higher UGT1A1, NQO1, and PGST protein levels

3042- SK,    The protective effects of Shikonin on lipopolysaccharide/D -galactosamine-induced acute liver injury via inhibiting MAPK and NF-kB and activating Nrf2/HO-1 signaling pathways
- in-vivo, Nor, NA
*TNF-α↓, Our results showed that SHK treatment distinctly decreased serum TNF-a, IL-1b, IL-6 and IFN-g inflammatory cytokine production
*IL1β↓,
*IL6↓,
*IFN-γ↓,
*ALAT↓, , reduced serum ALT, AST, hepatic MPO and ROS production levels,
*AST↓,
*MPO↓,
*ROS↓,
*JNK↓, inhibited JNK1/2, ERK1/2, p38 and NF-kB (p65) phosphorylation, and suppressed IkBa phosphorylation and degradation.
*ERK↓,
*p38↓,
*NF-kB↓,
*p‑IKKα↓,
*SOD↑, SHK could dramatically increase SOD and GSH production, as well as reduce ROS production,
*GSH↑,
*HO-1↑, through up-regulating the protein expression of HO-1, Nqo1, Gclc and Gclm, which was related to the induction of Nrf2 nuclear translocation.
*NRF2↑,
*hepatoP↑,

1280- SK,    Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells
- in-vitro, GC, AGS
ROS↑, shikonin induced the generation of ROS as well as caspase 3-dependent apoptosis.
Casp3↑,
P53↑, shikonin induced p53 expression but repressed Nrf2 expression
NRF2↓, Nrf2/ARE signaling pathway may be inhibited by shikonin treatment, especially at high concentration of 250 nM

1346- SK,    An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683
NRF2↓, ROS production by shikonin resulted in the inhibition of nuclear translocation of Nrf2
ROS↑, ROS generation from mitochondrial complex II
Apoptosis↑,
Cyt‑c↑, release cytochrome c to the cytosol
GSH↓,
MMP↓,
P53↑,
HO-1⇅, In Hs683 cells, the expressions of γ-GCS and HO-1 were slightly inhibited by shikonin at 3 h. However, shikonin increased the expressions of γ-GCS, catalase, SOD-1 and HO-1 at 24 h.

2011- SK,    Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling
- in-vitro, Nor, HL7702 - in-vivo, Nor, NA
*NRF2↑, Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells.
*hepatoP↑, SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) le
*ALAT↓, reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST)
*AST↓,
*MPO↓,
*ROS↓, neutralized oxidative stress in APAP-treated human normal liver L-02 cells
*GSH↑, enhanced the liver glutathione (GSH) level in APAP-treated mice

2009- SK,    Necroptosis inhibits autophagy by regulating the formation of RIP3/p62/Keap1 complex in shikonin-induced ROS dependent cell death of human bladder cancer
- in-vitro, Bladder, NA
TumCG↓, shikonin has a selective inhibitory effect on bladder cancer cells
selectivity↑, and has no toxicity on normal bladder epithelial cells
*toxicity∅,
Necroptosis↑, shikonin induced necroptosis and impaired autophagic flux via ROS generation
ROS↑,
p62↑, accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS
Keap1↑,
*NRF2↑, activated the Nrf2 signaling pathway to fight against ROS
eff↑, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect.

2201- SK,    Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice
- in-vitro, PSA, HaCaT - in-vivo, NA, NA
*eff↑, SHK treatment significantly improved imiquimod (IMQ)-induced psoriasis symptoms in mice
*IL6↓, attenuated the production of inflammatory cytokines, including interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (i.e., TNF-α)
*IL17↓,
*TNF-α↓,
*lipid-P↑, enhancing intracellular and mitochondrial ferrous and lipid peroxidation levels
*NRF2↓, by regulating expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear receptor coactivator 4 (NCOA4) and glutathione peroxidase 4 (GPX4)
*HO-1↝,
*NCOA4↝,
*GPx4↓, low dose SHK on LPS inhibited GPX4 and Nrf2 expression
*Ferroptosis↓, inhibited ferroptosis in psoriatic skin by reducing inflammation, ameliorating oxidative stress and iron accumulation.
*Inflam↓,
*ROS↓,
*Iron↓,

2214- SK,    Shikonin Attenuates Cochlear Spiral Ganglion Neuron Degeneration by Activating Nrf2-ARE Signaling Pathway
- in-vitro, Nor, NA
*NRF2↑, shikonin can increase the expression of Nrf2 and its downstream molecules HO-1 and NQO1, thereby enhancing the antioxidant capacity of SGNs and SGSs
*HO-1↑,
*NQO1↑,
*antiOx↑,
*neuroP↑, shikonin pretreatment has a defensive effect on auditory nerve damage.
*ROS↓, shikonin pretreatment can also significantly reduce the high levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in SGNs caused by ouabain, and increase the levels of superoxide dismutase (SOD) and reduced glutathione (GSH) expression
*MDA↓,
*SOD↑,
GSH↑,

2215- SK,  doxoR,    Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice
- in-vivo, Nor, NA
*cardioP↑, Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration
*ROS↓, Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis.
*Inflam↓,
*Mst1↓, Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
*NRF2↑,
*eff↓, Nrf2 knockdown counteracted the protective effects of shikonin on cardiac injury and dysfunction caused by DOX in mice
*antiOx↑, Previous studies have shown that shikonin possesses direct and indirect antioxidant properties, as evidenced by its ability to restore SOD expression and GSH levels, as well as block oxidative stress
*SOD↑,
*GSH↑,
*TNF-α↓, shikonin decreased the elevlated cardiac TNF-α induced by DOX
BAX↓, Shikonin attenuated DOX-induced upregulation of Bax and the down-regulation of Bcl-2
Bcl-2↑,

2198- SK,    Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis
- in-vitro, OS, MG63 - in-vitro, OS, 143B
TumCP↓, shikonin significantly suppressed OS cells proliferation and blocked the cell cycle progression in vitro.
TumCCA↑,
Ferroptosis↑, ferroptosis in OS cells by promoting the Fe2+ accumulation, reactive oxygen species and lipid peroxidation formation, malondialdehyde production and mitochondrial damage
Iron↑,
ROS↑,
lipid-P↑,
MDA↑,
mtDam↑,
NRF2↓, influenced Nrf2 stability via inducing ubiquitin degradation, which suppressed the expression of Nrf2 downstream targets xCT and GPX4, and led to stimulating ferroptosis. Promoted Nrf2 degradation
xCT↓,
GPx4↓,
GSH/GSSG↓, GSH/GSSG ratio declined after shikonin (1.5 uM) treatment
Keap1↑, shikonin (1.5 uM) significantly downregulated the expression of Nrf2 and upregulated the expression of Keap1

2197- SK,    Shikonin derivatives for cancer prevention and therapy
- Review, Var, NA
ROS↑, This compound accumulates in the mitochondria, which leads to the generation of reactive oxygen species (ROS), and deregulates intracellular Ca2+ levels.
Ca+2↑,
BAX↑, shikonin alone by increasing the expression of the pro-apoptotic Bax protein and decreasing the expression of the anti-apoptotic Bcl2 protein
Bcl-2↓,
MMP9↓, This treatment also inhibited metastasis by decreasing the expression of MMP-9 and NF-kB p65 without affecting MMP-2 expression.
NF-kB↓,
PKM2↓, Figure 4
Hif1a↓,
NRF2↓,
P53↑,
DNMT1↓,
MDR1↓,
COX2↓,
VEGF↓,
EMT↓,
MMP7↓,
MMP13↓,
uPA↓,
RIP1↑,
RIP3↑,
Casp3↑,
Casp7↑,
Casp9↑,
P21↓,
DFF45↓,
TRAIL↑,
PTEN↑,
mTOR↓,
AR↓,
FAK↓,
Src↓,
Myc↓,
RadioS↑, shikonin acted as a radiosensitizer because of the high ROS production it induced.

1193- SM,    Cryptotanshinone from the Salvia miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways
- in-vivo, Alcohol, NA - in-vitro, Liver, HepG2
*p‑AMPK↑,
*SIRT1↑,
*NRF2↑,
*CYP2E1↓,
*lipoGen↓,
*ROS↓,
*Inflam↓,

365- SNP,    Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species
- in-vitro, Hepat, HepG2
ROS↑,
GlucoseCon↓,
TumCD↑,
NRF2↓, Decreased mRNA levels of Nrf2

372- SNP,    Investigating oxidative stress and inflammatory responses elicited by silver nanoparticles using high-throughput reporter genes in HepG2 cells: effect of size, surface coating, and intracellular uptake
- in-vitro, Hepat, HepG2
NRF2↑,
GSH↓,

1052- TQ,    Thymoquinone Anticancer Effects Through the Upregulation of NRF2 and the Downregulation of PD-L1 in MDA-MB-231 Triple-Negative Breast Cancer Cells
- in-vitro, BC, MDA-MB-231
NRF2↑, TQ had the ability to elicit more than 2-fold increase in Nrf2 expression in IFN-γ stimulated MDA-MB-231 cells.
PD-L1↓,
Apoptosis↑,

2126- TQ,    Biological and therapeutic activities of thymoquinone: Focus on the Nrf2 signaling pathway
- Review, Nor, NA
*antiOx↑, several biological effects, including antioxidant, antibacterial, antineoplastic, nephroprotective, hepatoprotective, gastroprotective, neuroprotective, anti-nociceptive, and anti-inflammatory activities.
*Bacteria↓,
*RenoP↑,
*hepatoP↑,
*neuroP↑,
*Inflam↓,
*Keap1↓, beneficial effects are mostly related to modulation of the Nrf2 signaling pathway by blockage of Keap1, stimulating the expression of the Nrf2 gene, and inducing the nuclear translocation of Nrf2
*NRF2↑,
*other↝, lots of references for normal cell reactions

2130- TQ,    Thymoquinone Attenuates Brain Injury via an Anti-oxidative Pathway in a Status Epilepticus Rat Model
- in-vivo, Nor, NA
*eff↑, Latency to SE increased in the TQ-pretreated group compared with rats in the model group, while the total power was significantly lower.
*memory↑, TQ may also have a protective effect on learning and memory function.
*NRF2↑, TQ-pretreatment significantly increased the expression of Nrf2, HO-1 proteins and SOD in the hippocampus.
*HO-1↑,
*SOD↑,
*ROS↓, mechanism may be mediated by modulation of an antioxidative pathway.

2131- TQ,    Therapeutic impact of thymoquninone to alleviate ischemic brain injury via Nrf2/HO-1 pathway
- in-vitro, Stroke, NA - in-vivo, Nor, NA
*eff↑, TQ significantly mitigates brain damage and motor dysfunction after ischemic stroke.
*OS↑, observations coincided with curtailed cell death, inflammation, oxidative stress, apoptosis, and autophagy
*Inflam↓,
*ROS↓,
*NRF2↑, Most importantly, Nrf2/HO-1 signaling pathway activation by TQ was vital in the modulation of the above processes
*HO-1↑,

2132- TQ,    Thymoquinone treatment modulates the Nrf2/HO-1 signaling pathway and abrogates the inflammatory response in an animal model of lung fibrosis
- in-vivo, Nor, NA
*Weight∅, BM administration resulted in a significant weight loss, which was ameliorated by TQ treatment.
*antiOx↑, BMILF was associated with a reduction in the antioxidant mechanisms and increased lipid peroxidation (abnormalities were diminished with TQ treatment)
*lipid-P↓,
*MMP7↓, elevated levels of inflammatory cytokines, MMP-7 expression, apoptotic markers (caspase 3, Bax, and Bcl-2), and fibrotic changes including TGF-β and hydroxyproline levels in lung tissues were evident. These abnormalities were diminished with TQ
*Casp3↓,
*BAX↓,
*TGF-β↓,
*Diff↑, differential cell count in BALF was significantly improved in rats treated with TQ
*NRF2↓, TQ also produced a dose-dependent reduction in the expressions of Nrf2, Ho-1 and TGF-β
*HO-1↓,
*NF-kB↓, NF-jB protein expression has been significantly and dose dependently decreased in TQ treated groups (10 and 20 mg/kg bw)
*IκB↑, IkBa has been significantly and dose dependently increase in TQ treated groups (10 and 20 mg/kg bw).

2133- TQ,  CUR,  Cisplatin,    Thymoquinone and curcumin combination protects cisplatin-induced kidney injury, nephrotoxicity by attenuating NFκB, KIM-1 and ameliorating Nrf2/HO-1 signalling
- in-vitro, Nor, HEK293 - in-vivo, NA, NA
*creat↓, BUN, creatinine, CK and pro-inflammatory cytokines like TNF-α, IL-6 and MRP-1 to be elevated in the cisplatin-treated group while reducing glomerular filtration rate. Tq + Cur treatment significantly improved these conditions.
*TNF-α↓,
*IL6↓,
*MRP↓,
*GFR↑,
*mt-ATPase↑, antioxidant enzyme levels and mitochondrial ATPases were restored upon treatment,
*p‑Akt↑, Tq + Cur treatment increased the expressions of phosphorylated Akt, Nrf2 and HO-1 proteins while decreasing the levels of cleaved caspase 3 and NFκB in kidney homogenates.
*NRF2↑,
*HO-1↑,
*Casp3↓,
*NF-kB↓,
*RenoP↑, In summary, Tq + Cur had protective effects on cisplatin-induced nephrotoxicity and renal injury

2134- TQ,    Modulation of Nrf2/HO1 Pathway by Thymoquinone to Exert Protection Against Diazinon-induced Myocardial Infarction in Rats
- in-vivo, Nor, NA
*ALAT↓, CK-MB, ALT, and AST) were shown. DN-treated rats showed significantly elevated enzyme activities as compared with control rats (147.33 ± 20.85, 110.67 ± 9.65, and 407.5 ± 31.3, respectively), and these abnormalities were alleviated in the TQ treatmen
*AST↓,
*MDA↓, TQ treatment to DN intoxicated rats significantly decreased MDA levels when compared with the DN alone group of rats, recommending the protective antioxidant role of TQ
*ROS↓,
*GSSG↓, GSSG that exhibit significant elevation in DN intoxication and normalized levels during TQ treatment.
*GSH↑, Administration of TQ with DN during the experimental period significantly increased GSH (heart and serum), vit-E and vit-C contents to near normal levels in the heart tissues and serum
*VitE↑,
*VitC↑,
*NRF2↑, TQ, significantly increased Nrf2, HO-1, NQO1, and SOD were noticed (22.2 ± 1.41, 37.2 ± 2.6, 33.37 ± 4.28, and 52.7 ± 3.05, respectively), when compared to the DN intoxicated group.
*HO-1↑,
*NQO1↑,
*SOD↑,
*cardioP↑, Restoration of body weight and improvement in heart weight in TQ treatment showed beneficial effects of TQ treatment.
*GSH/GSSG↑, TQ has a significant efficacy to control the levels of oxidized and reduced glutathione pools and able to decrease the GSSG/GSH ratio.
*GPx↑, TQ enhances GSH and GPx activities in DN-intoxicated rats by a beneficial mechanism.

2135- TQ,    Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKα as upstream targets
- in-vitro, Nor, HaCaT
*HO-1↑, TQ induced the expression of HO-1 in HaCaT/ Cells treated with TQ (1, 5, 10, 20 lM) for 6 h induced the expression of HO-1 protein. maximal induction observed until 12 h and then returned to basal level time thereafter
*NRF2↑, Treatment with TQ increased the localization of nuclear factor (NF)-erythroid2-(E2)-related factor-2 (Nrf2) in the nucleus and elevated the antioxidant response element (ARE)-reporter gene activity.
*e-ERK↑, TQ induced the phosphorylation of extracellular signal-regulated kinase (ERK), Akt and cyclic AMP-activated protein kinase-α (AMPKα).
*e-Akt↑,
*AMPKα↑,
*ROS↑, Treatment of HaCaT cells with TQ resulted in a concentration-dependent increase in the intracellular accumulation of ROS (most occurs at 20uM concentration -see figure 5A)
*eff↓, pretreatment with N-acetyl cysteine (NAC) abrogated TQ-induced ROS accumulation, Akt and AMPKα activation, Nrf2 nuclear localization, the ARE-luciferase activity, and HO-1 expression in HaCaT cells
*tumCV∅, does not change much 1-20uM of TQ (normal cells) see figure 1A

2106- TQ,    Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy
- Review, Var, NA
Apoptosis↑, The anticancer power of TQ is accomplished by several aspects; including promotion of apoptosis, arrest of cell cycle and ROS generation.
TumCCA↑,
ROS↑,
*Catalase↑, activation of antioxidant cytoprotective enzymes including, CAT, SOD, glutathione reductase (GR) [80], glutathione-S-transferase (GST) [81] and glutathione peroxidase (GPx) - scavenging H2O2 and superoxide radicals and preventing lipid peroxidation
*SOD↑,
*GR↑,
*GSTA1↓,
*GPx↑,
*H2O2↓,
*ROS↓,
*lipid-P↓,
*HO-1↑, application of TQ to HaCaT (normal) cells promoted the expression of HO-1 in a concentration and time-dependent pattern
p‑Akt↓, TQ could induce ROS which provoked phosphorylation and activation of Akt and AMPK-α
AMPKα↑,
NK cell↑, TQ was outlined to enhance natural killer (NK) cells activity
selectivity↑, Many researchers have noticed that the growth inhibitory potential of TQ is particular to cancer cells
Dose↝, Moreover, TQ has a dual effect in which it can acts as both pro-oxidant and antioxidant in a dose-dependent manner; it acts as an antioxidant at low concentration whereas, at higher concentrations it possess pro-oxidant property
eff↑, Pro-oxidant property of TQ occurs in the presence of metal ions including copper and iron which induce conversion of TQ into semiquinone. This leads to generation of reactive oxygen species (ROS) causing DNA damage and induction of cellular apoptosis
GSH↓, TQ for one hour resulted in three-fold increase of ROS while reduced GSH level by 60%
eff↓, pre-treatment of cells with N-acetylcysteine, counteracted TQ-induced ROS production and alleviated growth inhibition
P53↑, TQ provokes apoptosis in MCF-7 cancer cells by up regulating the expression of P53 by time-dependent manner.
p‑STAT3↓, TQ inhibited the phosphorylation of STAT3
PI3K↑, via up regulation of PI3K and MPAK signalling pathway
MAPK↑,
GSK‐3β↑, TQ produced apoptosis in cancer cells and modulated Wnt signaling by activating GSK-3β, translocating β-catenin
ChemoSen↑, Co-administration of TQ and chemotherapeutic agents possess greater cytotoxic influence on cancer cells.
RadioS↑, Treatment of cells with both TQ and IR enhanced the antiproliferative power of TQ as observed by shifting the IC50 values for MCF7 and T47D cells from ∼104 and 37 μM to 72 and 18 μM, respectively.
BioAv↓, TQ cannot be used as the primary therapeutic agent because of its poor bioavailability [177,178] and lower efficacy
NRF2↑, TQ to HaCaT cells promoted the expression of HO-1 in a concentration and time-dependent pattern. This was achieved via increasing stabilization of Nrf2

3402- TQ,    Enhanced Apoptosis in Pancreatic Cancer Cells through Thymoquinone-rich Nigella sativa L. Methanol Extract: Targeting NRF2/HO-1 and TNF-α Pathways
- in-vitro, PC, PANC1 - in-vitro, PC, MIA PaCa-2
tumCV↓, TQ significantly decreased viability at 20 μM
NRF2↑, TQ enhances the expression of NRF2 and its downstream target HO-1, promoting antioxidant responses and cellular protection.
HO-1↑,
TNF-α↓,

3401- TQ,    Molecular mechanisms and signaling pathways of black cumin (Nigella sativa) and its active constituent, thymoquinone: a review
- Review, Var, NA
TumCP↓, thymoquinone can inhibit cancer cell proliferation through disruption of the PI3K/AKT pathway by upregulating phosphatase and tensin homolog
*antiOx↑, thymoquinone improve antioxidant enzyme activities, effectively scavenges free radicals, and thus protect cells from oxidative stress.
*ROS↓, modulate reactive oxygen species levels in tumor cells,
NRF2↑, regulate responses to oxidative stress and inflammation via Nrf2 and NF-κB pathways
NF-kB↓, Inhibits inflammatory response
TumCCA↑, arrest the cell cycle in the G2/M phase
*GABA↑, N. sativa and thymoquinone can elevate brain GABA content, and thus it may ameliorate epilepsy
P53↑,
P21↑,
AMPK↑,
neuroP↑, thymoquinone, exhibit various pharmacological activities, including neuroprotective, nephroprotective, cardioprotective, gastroprotective, hepatoprotective, and anti-cancer effects.
cardioP↑,
hepatoP↑,

3400- TQ,  Chemo,    Thymoquinone Ameliorates Carfilzomib-Induced Renal Impairment by Modulating Oxidative Stress Markers, Inflammatory/Apoptotic Mediators, and Augmenting Nrf2 in Rats
- in-vitro, Nor, NA
*GSH↑, 10 and 20 mg/kg TQ significantly decreased serum markers and increased antioxidant enzymes.
*SOD↑, TQ treatment (10 mg/kg) resulted in a significant rise in GSH (p < 0.001), CAT (p < 0.0001), and SOD
*lipid-P↓, highest doses of TQ (20 mg/kg) resulted in a significant reduction in lipid peroxidation compared to the CFZ group
*IL1β↑, TQ treatment considerably reduced IL-1β, IL-6, TNF-α, and caspase-3 concentrations.
*IL6↓,
*TNF-α↓,
*Casp3↓,
*Catalase↑,
*NRF2↑, TQ enhanced Nrf2 expression (p < 0.001), and this effect was only seen with 20 mg/kg
*RenoP↑, Degenerative kidney alterations caused by CFZ were reduced with TQ treatment (10 and 20 mg/kg

3399- TQ,    Anticancer Effects of Thymoquinone through the Antioxidant Activity, Upregulation of Nrf2, and Downregulation of PD-L1 in Triple-Negative Breast Cancer Cells
- in-vitro, BC, MDA-MB-231 - NA, BC, MDA-MB-468
ROS↓, The results show that TQ exhibits considerable antioxidant activity and decreases the generation of H2O2,
H2O2↓,
Catalase↑, at the same time increasing catalase (CAT) activity, superoxide dismutase (SOD) enzyme, and glutathione (GSH
SOD↑,
GSH↑,
NQO1↑, TQ treatment increased the levels of the different genes involved in the oxidative stress-antioxidant defense system PRNP, NQO1, and GCLM in both cell lines
GCLM↑,
NRF2↑, Nrf2 mRNA and protein expression were also significantly increased in TQ-treated TNBC cells
PD-L1↓, increased mRNA levels while decreasing PD-L1 protein expression in both cell lines
GSSG↑, Interestingly, a significant increase in GSSG was only found at 5 µM (p < 0.01), followed by a 50% significant reduction (p > 0.001) in GSSG at 15 µM of TQ.
GPx1⇅, TQ boosted GPX1 in MDA-MB-468 cells while decreasing GPX1 in MDA-MB-231 TNBC cells
GPx4↓, mda-mb-231

3398- TQ,  5-FU,    Impact of thymoquinone on the Nrf2/HO-1 and MAPK/NF-κB axis in mitigating 5-fluorouracil-induced acute kidney injury in vivo
- in-vivo, Nor, NA
*RenoP↑, Pre-, post-, and cotreatment with TQ alleviated kidney injury
*TAC↑, by replenishing antioxidant reserves, reducing serum toxicity, decreasing ROS generation and lipid peroxidation, downregulating p38 MAPK/NF-κB axis/pathway proteins, and upregulating Nrf2 and HO-1,
*ROS↓, high-dose TQ alleviated ROS and H2O2 levels in groups III and IV
*lipid-P↓,
*p38↓,
*MAPK↓,
*NF-kB↓,
*NRF2↑,
*HO-1↑,
*MDA↓, TQ diminishes MDA levels
*GPx↑, GPx, GR, and CAT : restoration of GSH reserves and the abovementioned antioxidant enzymes
*GSR↑,
*Catalase↑,
*BUN↓, noticeable inhibition was observed in BUN, Cr, LDH, and KIM-1 at both doses
*LDH↓,
*IL1β↓, downregulation of IL-1β, diminishing inflammation

3410- TQ,    Anti-inflammatory effects of thymoquinone and its protective effects against several diseases
- Review, Arthritis, NA
*Inflam↓, anti-inflammatory, anti-oxidant, and anti-apoptotic properties in several disorders such as asthma, hypertension, diabetes, inflammation, bronchitis, headache, eczema, fever, dizziness and influenza
*antiOx↑, anti-inflammatory and anti-oxidant effects via several molecular pathways
*COX2↓, TQ has been shown to suppress COX2 expression and the ensuing generation of prostaglandins
*NRF2↑, TQ also attenuates inflammation via the Nrf2 pathway [28]. Heme-oxygenase 1 (HO-1) has been shown to be stimulated by TQ
*HO-1↑,
*IL1β↓, oral TQ treatment caused a decrease in several pro-inflammatory regulators, such as interleukin 1 beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor (TNFα), interferon γ (IFNγ) and prostaglandin E2 PGE(2)
*IL6↓,
*TNF-α↓,
*IFN-γ↓,
*PGE2↓,
*cardioP↑, Cardioprotective activity of TQ through anti-inflammation
*Catalase↑, LPS diminished anti-oxidant enzymes including catalase (CAT) and superoxide dismutase (SOD) and the total thiol group. TQ treatment reduced these effects, restoring many of the LPS effects to basal levels
*SOD↑,
*Thiols↑,
*neuroP↑, Neuroprotective activity of TQ through anti-inflammation
*IL12↓, TQ diminished the levels of several cytokines such as IL-6, IL-1β, IL-12p40/70, chemokine C-C motif ligand 12 (CCL12)/monocyte chemotactic protein 5 (MCP-5), CCL2/MCP-1, granulocyte colony-stimulating factor (GCSF), and C-X-C motif chemokine 10 (Cxcl
*MCP1↓,
*CXCc↓,
*ROS↓, consistent with TQ’s efficacy in reducing ROS generation and the ensuing inflammation

3404- TQ,    The Neuroprotective Effects of Thymoquinone: A Review
- Review, Var, NA - Review, AD, NA - Review, Park, NA - Review, Stroke, NA
*Inflam↓, anti-inflammatory, antioxidant, antimicrobial, antiparasitic, anticancer, hypoglycemic, antihypertensive, and antiasthmatic effects.
AntiCan↑,
*TNF-α↓, TQ treatment (2.5, 5, and 10 μM) inhibited the release of TNF-α, IL-6, and IL-1β.
*IL6↓,
*IL1β↓,
*NF-kB↓, TQ treatment (2.5, 5 and 10 μM) inhibited NF-κB-dependent neuroinflammation in BV2 microglia via decreasing iNOS protein levels, κB inhibitor phosphorylation, and binding of NF-κB to the DNA
*iNOS↓,
*NRF2↑, activation of the Nrf2/ARE signaling pathway by TQ resulted in the inhibition of NF-κB-mediated neuroinflammation.
*neuroP↑, TQ has neuroprotection potential against Aβ1-42 in rat hippocampal by ameliorating oxidative stress.
*MMP↑, Thymoquinone ameliorated Aβ1-42-induced neurotoxicity and prevented the mitochondrial membrane potential depolarization and finally reduced the oxidative stress.
*ROS↓,
*MDA↓, Thymoquinone decreased the neuronal cell death in the hippocampal CA1 region and MDA level and increased glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities after forebrain ischemia.
*GSH↑,
*Catalase↑,
*SOD↑,
*IL12↓, Thymoquinone exhibited anti-inflammatory effects by decreasing several cytokines, including TNF-α, NF-κB, IL-6, IL-1β, IL-12p40/70, (CCL12)/MCP-5, (CCL2)/MCP-1, GCSF, and Cxcl 10/IP-10 of, NO, PGE2, and iNOS.
*MCP1↓,
*IP-10/CXCL-10↓,
*PGE2↓,

3405- TQ,  doxoR,    Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism
- vitro+vivo, NA, NA
*cardioP↑, thymoquinone can alleviate doxorubicin-induced cardiac toxicity in mice.
*NRF2↑, alleviate iron death in mouse cardiomyocytes by activating the Nrf2/HO-1 signaling pathway
*HO-1↑,
*ROS↓, Thymoquinone can also alleviate oxidative stress in mouse cardiomyocytes
*NQO1↑, similar effects on the expression levels of NQO1, COX-2, and NOX4
*COX2↓, implied
*NOX4↓, implied
*GPx4↑,
*FTH1↑, Reduces free iron, limiting ferroptosis
*p‑mTOR↓,
*TGF-β↓,

3406- TQ,  Se,    A study to determine the effect of nano-selenium and thymoquinone on the Nrf2 gene expression in Alzheimer’s disease
- in-vivo, AD, NA
*NRF2↑, Nrf2 mean expression levels in the nano-selenium-treated rats, the thymoquinone-treated rats, and the rats that were given both treatments all increased significantly compared to AD rats with no treatment.
*GSH↑, TQ and SeNPs demonstrated improvement in the levels of different biomarkers (Nrf2, Aβ-42, TNF-α, GSH & MDA) reversing them toward the normal levels.
*MDA↓, the mean brain tissue MDA levels in groups 3, 4, and 5 (27.37 ± 9.42, 29.23 ± 12.18, and 23.28 ± 4.89 nmol/mg protein, respectively) were significantly lower than those in group 2
*TNF-α↓, mean serum levels of TNF-α in groups 3, 4, and 5 (63.03 ± 11.07, 66.05 ± 9.96, and 36.41 ± 10.53 pg/ml) were found to be considerably lower than those in group 2

3409- TQ,    Thymoquinone therapy remediates elevated brain tissue inflammatory mediators induced by chronic administration of food preservatives
- in-vivo, Nor, NA
*MDA↓, increased levels of malondialdehyde, TGF-β, CRP, NF-κB, TNF-α, IL-1β and caspase-3 associated with reduced levels of GSH, cyt-c oxidase, Nrf2 and IL-10. However, exposure of rats’ brain tissues to thymoquinone resulted ameliorated all these ef
*TGF-β↓,
*CRP↓,
*NF-kB↓,
*TNF-α↓,
*IL1β↓,
*Casp3↓,
*GSH↑,
*NRF2↑,
*IL10↑,
*neuroP↑, thymoquinone remediates sodium nitrite-induced brain impairment through several mechanisms including attenuation of oxidative stress
*ROS↓,
*Apoptosis↓,
*Inflam↓, TQ activates the Nrf2/ARE antioxidant mechanisms in its anti-inflammatory activity

3415- TQ,    The anti-neoplastic impact of thymoquinone from Nigella sativa on small cell lung cancer: In vitro and in vivo investigations
- in-vitro, Lung, H446
tumCV↓, TQ reduced cell viability, induced apoptosis and cell cycle arrest, depleted ROS, and altered protein expression in associated signaling pathways.
TumCCA↑,
ROS↓, With regards to ROS in the current study, TQ dose-dependently decreased intracellular ROS levels in all SCLC cells except H446 cells upon 24-hour treatment with TQ.
CycB↑, TQ induced upregulation of cyclin B1 and cyclin D3 in H69-adherent and H446 cells, respectively. Cyclins A2, E1, and cdc2 were downregulated, while cyclin D3 was upregulated in H841-adherent cells
CycD3↑,
cycA1↓,
cycE↓,
cDC2↓,
antiOx↑, TQ acted as an antioxidant.
PARP↓, TQ downregulated intratumoral PARP
NRF2↓, TQ exerts its antioxidative effect by upregulating nuclear protein nuclear factor-erythroid 2 related factor 2 (Nrf2), hence amplifying antioxidant response element (ARE) expression.
ARE/EpRE↑,
eff↑, To confirm that the antioxidative action of TQ is anti-survival for cells, H841 cells were employed as a model and treated with NAC. NAC confirmed that ROS depletion led to a decrease in the cell viability of SCLC cells.

3559- TQ,    Molecular signaling pathway targeted therapeutic potential of thymoquinone in Alzheimer’s disease
- Review, AD, NA - Review, Var, NA
*antiOx↑, promising potential in the prevention and treatment of AD due to its significant antioxidative, anti-inflammatory,
*Inflam↑, anti-inflammatory activity of TQ is mediated through the Toll-like receptors (TLRs)
*AChE↓, In addition, it shows anticholinesterase activity and prevents α-synuclein induced synaptic damage.
AntiCan↑, NS plant, has been proven to have a wide range of pharmacological interventions, including antidiabetic, anticancer, cardioprotective, retinoprotective, renoprotective, neuroprotective, hepatoprotective and antihypertensive effects
*cardioP↑,
*RenoP↑,
*neuroP↑,
*hepatoP↑,
TumCG↓, potential ability to inhibit tumor growth by stimulating apoptosis as well as by suppression of the P13K/Akt pathways, cell cycle arrest and by inhibition of angiogenesis
Apoptosis↑,
PI3K↓,
Akt↑,
TumCCA↑,
angioG↓,
*NF-kB↓, TQ inhibits nuclear translocation of NF-kB which subsequently blocks the production of NF-kB mediated neuroinflammatory cytokines
*TLR2↓, TQ administration at different doses (10, 20, 40 mg/kg) significantly down-regulated the mRNA expression of TLR-2, TLR-4, MyD88, TRIF and their downstream effectors Interferon regulatory factor 3 (IRF-3)
*TLR4↓,
*MyD88↓,
*TRIF↓,
*IRF3↓,
*IL1β↓, TQ also inhibits LPS induced pro-inflammatory cytokine release like IL-1B, IL-6 and IL-12 p40/70 via its interaction with NF-kB
*IL6↓,
*IL12↓,
*NRF2↑, Nuclear erythroid-2 related factor/antioxidant response element (Nrf 2/ARE) being an upstream signaling pathway of NF-kB signaling pathway, its activation by TQ
*COX2↓, TQ also inhibits the expression of all genes regulated by NF-kB, i.e., COX-2, VEGF, MMP-9, c-Myc, and cyclin D1 which distinctively lowers NF-kB activation making it a potentially effective inhibitor of inflammation, proliferation and invasion
*VEGF↓,
*MMP9↓,
*cMyc↓,
*cycD1↓,
*TumCP↓,
*TumCI↓,
*MDA↓, it prevents the rise of malondialdehyde (MDA), transforming growth factor beta (TGF-β), c-reactive protein, IL1-β, caspase-3 and concomitantly upregulates glutathione (GSH), cytochrome c oxidase, and IL-10 levels [92].
*TGF-β↓,
*CRP↓,
*Casp3↓,
*GSH↑,
*IL10↑,
*iNOS↑, decline of inducible nitric oxide synthase (iNOS) protein expression
*lipid-P↓, TQ prominently mitigated hippocampal lipid peroxidation and improved SOD activity
*SOD↑,
*H2O2↓, TQ is a strong hydrogen peroxide, hydroxyl scavenger and lipid peroxidation inhibitor
*ROS↓, TQ (0.1 and 1 μM) ensured the inhibition of free radical generation, lowering of the release of lactate dehydrogenase (LDH)
*LDH↓,
*Catalase↑, upsurge the levels of GSH, SOD, catalase (CAT) and glutathione peroxidase (GPX)
*GPx↑,
*AChE↓, TQ exhibited the highest AChEI activity of 53.7 g/mL in which NS extract overall exhibited 84.7 g/mL, which suggests a significant AChE inhibition.
*cognitive↑, Most prominently, TQ has been found to regulate neurite maintenance for cognitive benefits by phosphorylating and thereby activating the MAPK protein, particularly the JNK proteins for embryogenesis and also lower the expression levels of BAX
*MAPK↑,
*JNK↑,
*BAX↓,
*memory↑, TQ portrays its potential of spatial memory enhancement by reversing the conditions as observed by MWM task
*Aβ↓, TQ thus, has been shown to ameliorate the Aβ accumulation
*MMP↑, improving the cellular activity, inhibiting mitochondrial membrane depolarization and suppressing ROS

2454- Trip,    Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ
- in-vitro, HNSCC, HaCaT - in-vivo, NA, NA
GSDME-N↑, Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis.
Pyro↑,
cMyc↓, TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells
HK2↓,
BAD↑, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3.
BAX↑,
Casp3↑,
NRF2↓, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis
xCT↓,
ROS↑, and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME.
eff↑, Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model.
Glycolysis↓, TPL treatment repressed c-Myc/HK-II axis and aerobic glycolysis in head and neck cancer cells
GlucoseCon↓, as evidenced by reduced glucose consumption, lactate production and cellular ATP content following TPL treatment
lactateProd↓,
ATP↓,
xCT↓, TPL (50 nM) treatment decreased the protein levels of NRF2 and SLC7A11 (
eff↑, combination of TPL with erastin is a promising strategy for head and neck cancer therapy.

3112- VitC,    Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid
- Review, Nor, NA
*ROS↓, ascorbate as a free radical scavenger but also summarizes its antioxidant action
*antiOx↑,
*SOD↑, activation of antioxidant enzymes, such as superoxide dismutase, catalase, or glutathione peroxidase.
*Catalase↑,
*GPx↑,
*NRF2↑, ascorbate promotes the activity of transcription factors (Nrf2, Ref-1, AP-1), which enables the expression of genes encoding antioxidant proteins
*AP-1↑,
*Inflam↓, Thus, through its antioxidant properties, the molecule prevents inflammation mediated by lipid peroxidation.
*CRP↓, CRP level in human plasma is significantly reduced by ascorbate supplementation
IFN-γ↓,

3110- VitC,    Vitamin C Attenuates Oxidative Stress, Inflammation, and Apoptosis Induced by Acute Hypoxia through the Nrf2/Keap1 Signaling Pathway in Gibel Carp (Carassius gibelio)
- in-vivo, Nor, NA
*IL2↑, Moreover, the levels of the inflammatory cytokines (tnf-α, il-2, il-6, and il-12) were increased by enhancing the Nrf2/Keap1 signaling pathway
*IL6↑,
*IL12↑,
*NRF2↑,
*Catalase↑, Upregulation of the antioxidant enzymes activity (CAT, SOD, and GPx); T-AOC;
*SOD↑,
*GPx↑,
*GRP78/BiP↓, The expression of GRP78 protein in the liver and endoplasmic reticulum stress and apoptosis induced by hypoxia were inhibited by VC.
*ER Stress↓,

3109- VitC,    Vitamin C Inhibited Pulmonary Metastasis through Activating Nrf2/HO-1 Pathway
- in-vitro, Lung, H1299
TumMeta↓, intraperitoneal injection of Vc inhibits pulmonary metastasis through up-regulating the expression of Nrf2, HO-1, cleaved caspases 3 and 9, and causing DNA damage and apoptosis
NRF2↑,
HO-1↑,
cl‑Casp3↑,
cl‑Casp9↑,
DNAdam↑,
Apoptosis↑,
other↑, Meanwhile, oral administration of Vc up-regulates the expression of p53, directly activates Nrf2/HO-1 pathway, increases expression of cleaved caspases 3 and 9, and ultimately inhibits pulmonary metastasis
selectivity↑, has little cytotoxic effects on normal cells.

3108- VitC,  QC,    The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells
- in-vitro, BC, MDA-MB-231 - in-vitro, Lung, A549
NRF2↓, significant decrease in the expression of Nrf2 mRNA and protein levels following the treatment of breast cancer cells with VC and Q
HO-1↓, In the MDA-MB 231 and MCF-7 cell lines, HO1 was significantly suppressed following treatment with VC and Q
ROS↑, It was demonstrated that ROS levels significantly increased in tumor cells treated with VC and Q.
NRF2⇅, it was demonstrated that treatment of MDA-MB 231 cells with 25 µM Q increased the expression of Nrf2, while 50 and 75 µM Q decreased the mRNA levels of Nrf2.

2592- VitC,    Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line
- in-vitro, CLL, NA
NRF2↓, addition of ascorbic acid to KCL22/SR cells resulted in a decrease in Nrf2-DNA binding and decreases in levels of gamma-GCSl mRNA and GSH.
GSH↓,

114- VitC,  QC,    Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress
- in-vitro, Pca, PC3 - in-vitro, NA, DU145
GPx↓,
GSR↓,
NQO1↓,
NRF2↓,
ROS↑,

1741- VitD3,    Vitamin D Deficiency: Effects on Oxidative Stress, Epigenetics, Gene Regulation, and Aging
- Review, Var, NA
*Inflam↓, Vitamin D is one of the key controllers of systemic inflammation, oxidative stress
*antiOx↑, Vitamin D is also a potent anti-oxidant
*eff↑, Excess Sun Exposure Does Not Cause Hypervitaminosis D
*ROS↓, When vitamin D status is adequate, many of the intracellular oxidative stress-related activities are downregulated.
*NRF2↑, The intracellular Nrf2 level is inversely correlated with the accumulation of mitochondrial ROS [51,60] and the consequent escalation of oxidative stress.
*GPx↑, Vitamin D also upregulates the expression of glutathione peroxidase that converts the ROS molecule H2O2 to water
*Dose↝, adequate maintenance doses of vitamin D3 are needed. This can be achieved in approximately 90% of the adult population with vitamin D supplementation between 1000 to 4000 IU/day, 10,000 IU twice a week, or 50,000 IU twice a month
Dose↑, Others, such as persons with obesity, those with gastrointestinal disorders, and during pregnancy and lactation, are likely to require doses of 6,000 IU/day

2276- VitK2,    Vitamin K2 (MK-7) Intercepts Keap-1/Nrf-2/HO-1 Pathway and Hinders Inflammatory/Apoptotic Signaling and Liver Aging in Naturally Aging Rat
- in-vivo, Nor, NA
*Albumin↑, parallel significant restoration of the serum total protein and albumin by 1.1- and 1.13-fold
*AST↓, VK2 administration reversed this situation, as confirmed by the significant decrease in serum ALT and AST by 0.25- and 0.27-fold
*ALAT↓,
*Keap1↓, significant decrease in Keap-1 mRNA by 0.32-fold
*NRF2↑, significant restoration of the Nrf-2 mRNA level
*HO-1↑,
*COX2↓, VK2 administration to aged animals attenuated hepatic inflammation where hepatic sections from aged-treated rats demonstrated a marked downregulation in COX-2, iNOS and TNF-α
*iNOS↓,
*TNF-α↓,
*TIMP1↓, VK2-treated aged rats showed a significant downregulation in both hepatic TIMP-1 concentration and TGF-β immunostaining compared to the aged untreated control
*TGF-β↓,
*ROS↓, Emerging evidence reported Nrf-2 signaling and VK to play a crucial role in counteracting oxidative stress, DNA damage, senescence and inflammation. These events help in quenching ROS
*DNAdam↓,
*Inflam↓,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 294

Results for Effect on Cancer/Diseased Cells:
5HT↓,2,   5LO↓,2,   ACC↑,1,   AChE↓,1,   ACLY↓,1,   ACSL4↑,1,   AEG1↓,1,   AhR↓,1,   AIF↑,2,   Akt↓,35,   Akt↑,2,   Akt↝,1,   p‑Akt↓,14,   p‑Akt↝,1,   AKT1↓,1,   ALAT↓,1,   ALDH↓,1,   ALDH1A1↓,1,   ALP↓,1,   AMPK↑,10,   p‑AMPK↑,1,   AMPKα↑,1,   angioG↓,27,   annexin II↓,1,   AntiAge↑,1,   AntiCan↓,1,   AntiCan↑,12,   AntiCan∅,1,   antiOx↓,4,   antiOx↑,5,   AntiTum↑,2,   AP-1↓,5,   AP-1↑,1,   AP-1↝,1,   APAF1↑,1,   Apoptosis↑,42,   Apoptosis↝,2,   Appetite↑,1,   AR↓,8,   AR↝,1,   ARE/EpRE↑,1,   ASC↓,1,   ASC↑,1,   ASK1↑,1,   ATF3↑,2,   ATF4↓,1,   ATF4↑,7,   ATF4↝,1,   ATF6↑,2,   ATFs↑,1,   ATG5↑,2,   ATG7↑,1,   ATM↑,1,   ATP↓,5,   ATP↑,1,   mt-ATP↓,1,   ATPase↓,1,   AXL↓,1,   BACH1↑,1,   Bacteria↓,1,   BAD↑,2,   Bak↑,2,   BAX↓,3,   BAX↑,31,   BAX↝,1,   Bax:Bcl2↑,6,   BBB↑,1,   Bcl-2↓,30,   Bcl-2↑,1,   Bcl-2↝,1,   Bcl-xL↓,7,   Bcl-xL↝,1,   BCR-ABL↓,1,   Beclin-1↓,2,   Beclin-1↑,4,   BID↑,3,   BIM↑,4,   BioAv↓,11,   BioAv↑,10,   BioAv↝,5,   BioEnh?,1,   BioEnh↑,2,   BMPs↑,2,   BNIP3↑,2,   BP↓,1,   BRAF↝,1,   Ca+2↓,1,   Ca+2↑,10,   Ca+2↝,1,   cachexia↓,1,   CAFs/TAFs↓,1,   CAIX↓,1,   cardioP↑,5,   CardioT↓,2,   Casp↑,7,   Casp1↓,1,   cl‑Casp1↑,1,   Casp10↑,1,   Casp12?,1,   Casp12↑,3,   Casp3↓,2,   Casp3↑,38,   Casp3↝,1,   cl‑Casp3↑,5,   Casp7↑,5,   Casp8↑,10,   Casp8∅,2,   cl‑Casp8↑,1,   Casp9↑,27,   cl‑Casp9↑,4,   proCasp9↓,1,   Catalase↓,6,   Catalase↑,6,   CD133↓,4,   CD34↓,1,   CD44↓,5,   CD8+↑,1,   CDC2↓,5,   cDC2↓,1,   CDC25↓,2,   Cdc42↓,1,   CDK1↓,6,   CDK1↑,2,   CDK2↓,22,   CDK2↑,1,   CDK4↓,21,   CDK6↓,8,   CEA↓,1,   cFLIP↓,3,   cFos↓,3,   cFos↑,1,   chemoP↑,21,   chemoR↓,1,   ChemoSen↓,2,   ChemoSen↑,49,   ChemoSideEff↓,5,   CHK1↓,2,   CHK1↑,1,   Chk2↓,1,   Chk2↑,1,   CHOP↑,15,   cl‑CHOP↑,1,   cJun↓,2,   cJun↑,1,   CK2↓,3,   CLDN1↓,2,   cMET↓,2,   p‑cMET↑,1,   cMYB↓,2,   cMyc↓,14,   p‑cMyc↑,1,   cognitive↑,4,   COL1↓,1,   COL3A1↓,1,   COMT↑,1,   Copper↑,1,   COX2↓,28,   COX2↑,2,   COX2↝,1,   CRP↓,2,   CSCs↓,12,   CXCc↓,1,   CXCR4↓,5,   Cyc↓,3,   Cyc↝,1,   cycA1↓,4,   cycA1↑,1,   CycB↓,10,   CycB↑,1,   cycD1↓,20,   cycD1↑,1,   cycD1↝,1,   CycD3↓,1,   CycD3↑,1,   cycE↓,7,   cycE↑,1,   CYP1A1↓,1,   Cyt‑c↓,1,   Cyt‑c↑,33,   Cyt‑c↝,1,   DFF45↓,1,   DFF45↑,1,   Diablo↑,5,   DNAdam↓,1,   DNAdam↑,12,   DNMT1↓,6,   DNMT3A↓,4,   DNMTs↓,7,   Dose↓,1,   Dose↑,2,   Dose↝,8,   Dose∅,2,   DR4↑,1,   DR5↓,1,   DR5↑,15,   E-cadherin↓,2,   E-cadherin↑,16,   E6↓,2,   E7↓,2,   ECAR↓,1,   EF-1α↓,1,   eff↓,10,   eff↑,77,   eff↝,4,   EGF↓,2,   EGFR↓,16,   EGFR↑,1,   EGFR↝,1,   p‑EGFR↓,1,   eIF2α↓,1,   eIF2α↑,3,   p‑eIF2α↑,4,   EMT↓,28,   eNOS↓,1,   EP4↑,1,   ER Stress↑,21,   ER-α36↓,3,   ER(estro)↓,1,   ERK↓,13,   ERK↑,3,   p‑ERK↓,2,   p‑ERK↑,1,   FAK↓,8,   p‑FAK↓,2,   m-FAM72A↓,1,   Fas↑,8,   FasL↑,2,   FASN↓,1,   Fenton↑,3,   Ferritin↑,1,   Ferroptosis↑,14,   FGF↓,2,   FGFR1↓,1,   Fibronectin↓,3,   Foxm1↓,1,   FOXO↑,1,   FOXO3↓,1,   FOXO3↑,4,   p‑FOXO3↓,2,   FOXO4↓,1,   frataxin↑,1,   FTH1↓,1,   FTH1↑,1,   FTL↑,1,   GCLC↑,1,   GCLM↑,1,   Gli↓,1,   Gli1↓,4,   glucoNG↓,1,   GlucoseCon↓,5,   GLUT1↓,3,   GlutMet↓,2,   Glycolysis↓,10,   GPx↓,3,   GPx↑,5,   GPx1⇅,1,   GPx4↓,13,   GR↑,1,   GRP78/BiP↑,7,   GSDMD↑,2,   GSDME-N↑,1,   GSH↓,34,   GSH↑,7,   GSH/GSSG↓,1,   GSK‐3β↓,4,   GSK‐3β↑,2,   p‑GSK‐3β↓,2,   GSR↓,2,   GSR↑,1,   GSS↑,1,   GSSG↑,2,   GSTA1↑,1,   GSTP1/GSTπ↓,1,   GSTs↓,2,   GSTs↑,2,   GSTs↝,1,   GutMicro↑,3,   GutMicro↝,1,   H2O2↓,1,   H2O2↑,3,   H3↓,1,   H3↑,2,   p‑H3↓,1,   ac‑H3↑,1,   H4↓,1,   H4↑,1,   ac‑H4↑,1,   Half-Life↓,3,   Half-Life↝,3,   HATs↓,1,   HATs↑,1,   HDAC↓,22,   HDAC↑,1,   HDAC1↓,3,   HDAC2↓,4,   HDAC3↓,2,   HDAC8↓,3,   hepatoP↑,2,   HER2/EBBR2↓,7,   p‑HER2/EBBR2↓,1,   HEY1↓,1,   HGF/c-Met↓,2,   HH↓,1,   HIF-1↓,1,   Hif1a↓,28,   HK2↓,8,   HO-1↓,18,   HO-1↑,34,   HO-1⇅,1,   HSP27↓,4,   HSP27↑,1,   HSP27↝,1,   HSP70/HSPA5↓,5,   HSP70/HSPA5↑,2,   HSP70/HSPA5↝,1,   HSP72↓,1,   HSP90↓,6,   ac‑HSP90↑,1,   HSPs↑,1,   hTERT↓,7,   IAP1↓,2,   IAP1↑,1,   IAP2↓,2,   ICAD↑,1,   ICAM-1↓,3,   IFN-γ↓,4,   IFN-γ↑,1,   IGF-1↓,6,   IGFBP3↑,1,   IKKα↓,4,   IL1↓,5,   IL10↓,2,   IL10↑,1,   IL12↓,1,   IL18↓,1,   IL1β↓,9,   IL2↓,2,   IL2↑,4,   IL4↓,1,   IL4↑,1,   IL5↓,1,   IL6↓,22,   IL6↝,1,   IL8↓,7,   INF-γ↑,1,   Inflam↓,13,   Inflam↑,1,   iNOS↓,9,   IR↓,1,   IRE1↑,2,   Iron↑,9,   i-Iron↓,1,   ITGB1↓,2,   ITGB3↓,1,   JAK↓,1,   JAK1↓,2,   JAK2↓,1,   JNK↑,8,   JNK↝,1,   p‑JNK↑,2,   Keap1↓,5,   Keap1↑,3,   Keap1↝,1,   ox-Keap1↓,1,   rd-Keap1↑,1,   Ki-67↓,6,   KRAS↓,1,   lactateProd↓,5,   LC3A↑,1,   LC3B-II↑,2,   LC3II↑,2,   LC3s↑,1,   LDH↓,2,   LDH↑,1,   LDHA↓,2,   LDL↓,2,   LEF1↓,1,   Let-7↑,1,   lipid-P↓,1,   lipid-P↑,9,   LOX1↓,1,   M1↓,1,   MAPK↓,9,   MAPK↑,9,   MAPK↝,1,   MARK4↓,1,   Mcl-1↓,6,   Mcl-1↑,1,   MCP1↓,1,   MDA↓,3,   MDA↑,13,   MDM2↓,5,   p‑MDM2↓,1,   MDR1↓,4,   p‑MEK↓,1,   memory↑,2,   MET↓,3,   p‑MET↓,1,   Mets↑,1,   MGMT↓,1,   miR-155↓,2,   miR-200c↑,1,   miR-21↑,1,   miR-30a-5p↑,1,   mitResp↓,1,   MMP↓,29,   MMP↑,2,   MMP-10↓,1,   MMP1↓,4,   MMP13↓,2,   MMP2↓,27,   MMP2⇅,1,   MMP2↝,1,   MMP3↓,2,   MMP7↓,7,   MMP9↓,29,   MMP9↑,1,   MMP9⇅,1,   MMPs↓,14,   Mortalin↓,1,   MPO↓,2,   MRP1↓,1,   mtDam↑,2,   mTOR↓,27,   mTOR↑,1,   mTOR↝,1,   p‑mTOR↓,5,   p‑mTOR↑,1,   mTORC1↓,3,   mTORC2↓,1,   Myc↓,2,   N-cadherin↓,12,   NA↓,1,   NA↑,1,   NAD↑,1,   NAD↝,1,   NADPH↓,3,   NADPH↑,5,   NAF1↓,3,   Nanog↓,5,   NCOA4↑,1,   Necroptosis↑,1,   Nestin↓,2,   neuroP↑,12,   NF-kB↓,52,   NF-kB↝,1,   p‑NF-kB↑,1,   NFAT↑,1,   NFE2L2↑,1,   NICD↓,1,   NK cell↑,1,   NLRP3↓,2,   NLRP3↑,2,   NO↓,2,   NO↑,1,   NOTCH↓,5,   NOTCH1↓,7,   NOTCH1↑,3,   NOTCH3↓,2,   NOX↓,1,   NOX↑,1,   NOX4↓,1,   NOX4↑,1,   NQO1↓,3,   NQO1↑,8,   NRF2↓,51,   NRF2↑,81,   NRF2⇅,4,   NRF2↝,1,   NRF2∅,2,   p‑NRF2↓,1,   p‑NRF2↑,1,   NSE↓,1,   OCR↑,1,   OCT4↓,5,   OS↓,1,   OS↑,4,   other?,1,   other↓,2,   other↑,3,   other⇅,1,   OXPHOS↓,1,   mt-OXPHOS↓,1,   P-gp↓,6,   P-gp↑,1,   p19↑,1,   P21?,1,   P21↓,2,   P21↑,24,   P21↝,1,   p27↓,1,   p27↑,10,   p38↓,2,   p38↑,7,   p‑p38↓,1,   p‑p38↑,2,   P450↓,2,   P450↝,1,   P53?,1,   P53↑,35,   P53↝,1,   p62↓,3,   p62↑,2,   p65↓,2,   p‑p65↓,1,   p70S6↓,2,   P70S6K↓,1,   P70S6K↑,1,   p‑P70S6K↓,1,   Pain↓,1,   PAK↓,1,   PARP↓,2,   PARP↑,4,   cl‑PARP↓,1,   cl‑PARP↑,23,   PARP1↑,1,   PCK1↓,1,   PCNA↓,8,   PD-1↓,2,   PD-L1↓,5,   PDGF↓,3,   PDGFR-BB↓,1,   PDK1↓,5,   PDK3↑,1,   PERK↑,4,   p‑PERK↑,1,   PFK↓,1,   PGE2↓,8,   PI3K↓,28,   PI3K↑,3,   PI3K↝,1,   p‑PI3K↓,5,   p‑PI3K↑,1,   PI3K/Akt↓,1,   PI3K/Akt↝,1,   PKCδ↓,3,   PKM2↓,2,   POLD1↓,1,   PPARα↓,1,   PPARγ↓,1,   PPARγ↑,2,   pRB↓,1,   p‑pRB↓,1,   Prx4↑,1,   PrxI↓,1,   PSA↓,3,   PSA↝,1,   PSA∅,1,   PTEN↓,1,   PTEN↑,8,   PTEN↝,2,   PUMA↑,1,   Pyro↑,2,   QoL↑,2,   Rac1↓,1,   radioP↑,6,   RadioS↑,19,   Raf↓,2,   c-Raf↓,1,   RAGE↓,1,   RAS↓,7,   RAS↑,1,   RB1↓,1,   p‑RB1↓,5,   REL↑,1,   Remission↑,1,   RenoP↑,5,   RET↓,1,   Rho↓,3,   Rho↑,1,   RIP1↑,1,   RIP3↑,1,   Risk↓,2,   Risk↑,1,   RNS↓,2,   ROCK1↓,3,   ROCK1↑,1,   ROS?,2,   ROS↓,20,   ROS↑,98,   ROS⇅,4,   ROS↝,2,   ROS∅,1,   i-ROS↑,1,   mt-ROS↓,1,   mt-ROS↑,2,   SAM-e↝,1,   SCF↓,1,   selectivity?,1,   selectivity↑,27,   Sepsis↓,1,   SESN2↑,1,   Shh↓,4,   SHP1↑,1,   SIRT1↓,2,   SIRT1↑,5,   SIRT3↓,1,   SIRT3↑,3,   SIRT6↓,1,   Sleep↑,1,   Slug↓,5,   Smad1↑,1,   SMAD2↓,1,   SMAD3↓,1,   Smo↓,3,   Snail↓,13,   SOD↓,6,   SOD↑,9,   SOD1↓,1,   SOD1↑,3,   SOD2↓,2,   SOD2↑,1,   SOX2↓,4,   SOX4↓,1,   SOX4↑,1,   SOX9↓,1,   Sp1/3/4↓,8,   Src↓,1,   p‑Src↓,1,   STAT1↓,2,   STAT3↓,24,   p‑STAT3↓,5,   STAT4↓,1,   STAT5↓,1,   STAT6↓,1,   p‑STAT6↓,1,   survivin↓,17,   T-SOD↓,1,   TAZ↓,1,   TCA↓,1,   Telomerase↓,6,   TET1↓,1,   TET1↑,4,   TET2↓,1,   TET3↑,1,   TGF-β↓,4,   Th1 response↑,2,   Th2↑,1,   TIMP1↓,1,   TIMP1↑,2,   TIMP2↓,1,   TIMP2↑,2,   TLR4↓,2,   TNF-α↓,20,   TNF-α↝,1,   TNFR 1↑,1,   TOP1↓,2,   TOP2↓,3,   toxicity↓,2,   TRAIL↑,3,   TRAILR↑,2,   Trx↓,2,   Trx↑,1,   Trx1↑,1,   TrxR↓,3,   TSP-1↑,2,   TumAuto↑,5,   TumCCA?,1,   TumCCA↓,1,   TumCCA↑,49,   TumCD↑,2,   TumCG↓,17,   TumCI↓,18,   TumCMig↓,16,   TumCP↓,30,   TumCP↑,1,   tumCV↓,12,   TumMeta↓,14,   TumMeta↑,1,   TumW↓,3,   Twist↓,10,   TXNIP↑,1,   Tyro3↓,1,   uPA↓,14,   uPAR↓,1,   UPR↑,5,   USF1↑,1,   VEGF↓,42,   VEGF↑,1,   VEGF↝,1,   VEGFR2↓,7,   Vim?,1,   Vim↓,16,   Vim↑,1,   VitC↓,1,   VitE↓,1,   Warburg↓,4,   Wnt↓,14,   XBP-1↓,1,   XBP-1↑,2,   xCT↓,5,   XIAP↓,10,   YAP/TEAD↓,1,   Zeb1↓,5,   ZO-1↑,2,   β-catenin/ZEB1↓,14,   β-catenin/ZEB1↑,1,   β-catenin/ZEB1↝,1,   γH2AX↑,1,  
Total Targets: 699

Results for Effect on Normal Cells:
12LOX↓,2,   5LO↓,1,   ACC↓,1,   Acetyl-CoA↑,1,   Ach↑,4,   AChE↓,9,   ACSL4∅,1,   AhR↑,2,   AIF↓,1,   Akt↓,4,   Akt↑,7,   p‑Akt↑,1,   e-Akt↑,1,   ALAT↓,16,   Albumin↑,1,   ALP↓,3,   AMPK↑,10,   p‑AMPK↑,2,   AMPKα↑,1,   angioG↓,1,   angioG↑,2,   AntiAg↑,4,   AntiAge↑,3,   AntiCan↑,5,   antiOx?,1,   antiOx↓,3,   antiOx↑,71,   AntiTum↑,1,   AP-1↓,2,   AP-1↑,1,   Apoptosis↓,14,   ASK1↓,1,   AST↓,17,   ATF4↓,1,   ATF4↑,1,   ATF6↓,1,   ATP↑,4,   mt-ATPase↑,1,   Aβ↓,11,   Bacteria↓,1,   BAX↓,7,   BAX↑,1,   Bax:Bcl2↓,2,   BBB?,2,   BBB↓,1,   BBB↑,17,   BChE↓,1,   Bcl-2↑,5,   BG↓,2,   BioAv?,1,   BioAv↓,18,   BioAv↑,17,   BioAv↝,12,   BP↓,5,   BP↝,1,   BUN↓,3,   Ca+2↓,4,   i-Ca+2↓,1,   cAMP↑,1,   cardioP↑,30,   CardioT↓,3,   Casp1↓,1,   Casp12↓,1,   Casp3?,1,   Casp3↓,16,   Casp3∅,1,   cl‑Casp3↓,2,   cl‑Casp8↑,1,   Casp9↓,3,   Casp9∅,1,   Catalase↓,1,   Catalase↑,44,   Catalase↝,1,   cFos↓,1,   ChAT↑,4,   chemoP↑,6,   ChemoSen↑,1,   Choline↑,1,   CHOP↓,3,   cJun↓,1,   p‑cJun↓,1,   CLDN5↑,1,   cMyc↓,1,   p‑cMyc↑,1,   cognitive↓,1,   cognitive↑,24,   COX2↓,26,   COX2↑,1,   creat↓,5,   CRP↓,5,   CXCc↓,1,   cycD1↓,1,   CYP1A1↑,1,   CYP1A2↑,1,   CYP2C6↑,1,   CYP2D1↑,1,   CYP2E1↓,1,   CYP3A2↑,1,   Cyt‑c↓,3,   Cyt‑c↑,1,   Cyt‑c∅,2,   Diff↑,1,   DNAdam↓,6,   DNArepair↑,1,   DNMT1↓,1,   DNMT3A↓,1,   Dose↑,2,   Dose↝,11,   E-sel↓,1,   E2Fs↑,1,   eff↓,5,   eff↑,21,   eNOS↑,1,   p‑eNOS↑,1,   ER Stress↓,7,   ERK↓,5,   ERK↑,4,   p‑ERK↓,2,   e-ERK↑,1,   Fas↓,1,   FASN↓,2,   Ferritin↑,1,   Ferroptosis↓,4,   FGF21↑,1,   FOXO↑,1,   FTH1↑,1,   G6PD↑,2,   GABA↑,1,   GADD45A↑,1,   GAPDH↑,1,   GCLC↑,2,   GCLM↑,1,   GFR↑,1,   glucose↑,1,   GlucoseCon↓,1,   GlucoseCon↑,4,   GLUT1↑,1,   GLUT3↑,1,   GLUT4↑,4,   Glycolysis↑,2,   GPx↓,2,   GPx↑,33,   GPx↝,1,   GPx1↑,1,   GPx4↓,1,   GPx4↑,3,   GPx4∅,1,   GR↑,2,   GR↝,1,   GRP78/BiP↓,4,   GSH↓,3,   GSH↑,67,   GSH/GSSG↓,1,   GSH/GSSG↑,2,   GSK‐3β↓,4,   GSR↓,2,   GSR↑,4,   GSS↑,2,   GSSG↓,1,   GSTA1↓,1,   GSTA1↑,1,   GSTs↓,2,   GSTs↑,7,   GutMicro↑,6,   H2O2↓,6,   H2O2∅,1,   H2S↑,2,   Half-Life↓,4,   Half-Life↑,2,   Half-Life↝,6,   Half-Life∅,1,   HDAC↓,3,   HDAC3↓,1,   heparanase↑,1,   hepatoP↓,1,   hepatoP↑,28,   Hif1a↓,1,   Hif1a↑,1,   HK2↓,1,   HK2↑,1,   HMGB1↓,1,   HO-1↓,2,   HO-1↑,77,   HO-1⇅,1,   HO-1↝,1,   HO-1∅,1,   HO-2↓,1,   HSP27↓,1,   HSP70/HSPA5↑,2,   HSP70/HSPA5↝,1,   HSPs↑,1,   IAP1↓,1,   ICAM-1↓,6,   IFN-γ↓,4,   IFN-γ↑,2,   IGF-1↓,2,   IGF-1R↓,1,   IKKα↓,1,   IKKα↑,1,   p‑IKKα↓,1,   IL1↓,1,   IL10↓,7,   IL10↑,6,   IL12↓,3,   IL12↑,1,   IL17↓,3,   IL18↓,2,   IL1α↓,1,   IL1β↓,31,   IL1β↑,1,   IL2↓,5,   IL2↑,1,   IL22↓,1,   IL4↓,3,   IL5↓,1,   IL6↓,35,   IL6↑,4,   IL8↓,7,   Imm↑,1,   INF-γ↓,2,   Inflam?,2,   Inflam↓,71,   Inflam↑,2,   iNOS↓,18,   iNOS↑,2,   IP-10/CXCL-10↓,1,   IRF3↓,1,   Iron↓,2,   IronCh↓,1,   IronCh↑,10,   IκB↑,1,   JAK↓,1,   JNK↓,4,   JNK↑,1,   p‑JNK↓,3,   Keap1↓,12,   Keap1↑,1,   ox-Keap1↑,1,   Ki-67↓,2,   LDH↓,6,   LDH↑,1,   LDHA↓,1,   LDL↓,1,   lipid-P↓,28,   lipid-P↑,1,   mt-lipid-P↓,1,   lipidLev↓,1,   lipoGen↓,1,   MAPK↓,8,   MAPK↑,3,   MCP1↓,4,   MDA↓,42,   memory↑,16,   Mets↝,1,   mitResp↑,1,   MMP↓,1,   MMP↑,9,   MMP1↓,1,   MMP2↓,4,   MMP2↑,2,   MMP7↓,1,   MMP9↓,5,   motorD↓,1,   motorD↑,4,   MPO↓,7,   MPO↑,1,   MRP↓,1,   Mst1↓,1,   mtDam↓,3,   mtDam↑,1,   mTOR↓,1,   mTOR↑,1,   p‑mTOR↓,1,   MyD88↓,1,   NADH:NAD↑,1,   NADPH↓,3,   NADPH↑,4,   NADPH∅,1,   NCOA4↝,1,   necrosis↓,1,   neuroG↑,1,   neuroP↑,57,   NF-kB↓,40,   NF-kB↑,2,   NHE3↑,1,   NLRP3↓,6,   NO↓,14,   NO↑,1,   NOS2↓,2,   NOX4↓,3,   NQO1↑,17,   Nrf1↑,1,   NRF2↓,7,   NRF2↑,161,   NRF2⇅,1,   NRF2∅,2,   p‑NRF2↑,2,   OS↑,3,   other↓,2,   other↑,1,   other↝,1,   P-gp↓,1,   p300↓,1,   p38↓,3,   p38↑,1,   p‑p38↓,2,   P450↑,2,   P53↓,1,   p62↑,1,   p65↓,2,   Pain↓,2,   PARP↓,1,   PARP∅,1,   cl‑PARP1↓,1,   PDGFR-BB↓,1,   PDH↑,1,   PDKs↓,1,   PFK↑,1,   PFKFB2↓,1,   PGC-1α↑,4,   PGE2↓,10,   PI3K↓,3,   PI3K↑,5,   PKCδ↓,1,   PKCδ↑,2,   PKM2↓,2,   PKM2↑,1,   PPARα↑,3,   PPARγ↑,3,   p‑PPARγ↓,1,   Prx↑,2,   PTEN↓,2,   RAAS↓,1,   p‑Rac1↓,1,   radioP↑,2,   RenoP↑,20,   Rho↓,1,   RNS↓,1,   ROCK1↓,1,   ROS↓,129,   ROS↑,5,   ROS⇅,1,   ROS∅,2,   mt-ROS↓,1,   selectivity↑,1,   Sepsis↓,3,   SIRT1↓,1,   SIRT1↑,9,   SIRT2↑,1,   SIRT3↑,1,   SOD?,1,   SOD↑,64,   SOD↝,1,   SOD1↑,4,   SOD2↑,4,   SREBP1↓,2,   STAT↓,1,   STAT3↓,3,   Strength↑,1,   TAC↑,5,   tau↓,4,   p‑tau↓,1,   TBARS↓,3,   TGF-β↓,7,   TGF-β1↑,1,   Thiols↑,1,   TIMP1↓,1,   TLR2↓,3,   TLR4↓,7,   TLR4↑,1,   TNF-α↓,47,   toxicity?,1,   toxicity↓,11,   toxicity↑,1,   toxicity∅,5,   TRIF↓,1,   Trx↓,1,   Trx↑,3,   Trx1↑,2,   TrxR↑,1,   TrxR1↑,1,   TumCI↓,1,   TumCP↓,1,   tumCV∅,1,   TXNIP↓,1,   TXNIP↑,1,   VCAM-1↓,6,   VEGF↓,3,   VEGF↑,1,   VitC↑,4,   VitE↑,3,   Weight↓,1,   Weight∅,1,   ZO-1↑,2,   α-SMA↓,1,  
Total Targets: 395

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2
26 Sulforaphane (mainly Broccoli)
21 Thymoquinone
16 Resveratrol
15 EGCG (Epigallocatechin Gallate)
15 Shikonin
13 Curcumin
13 Silymarin (Milk Thistle) silibinin
12 Alpha-Lipoic-Acid
12 Luteolin
12 Quercetin
11 Fisetin
10 Ashwagandha
9 Apigenin (mainly Parsley)
9 Baicalein
9 Chemotherapy
8 doxorubicin
8 Chrysin
8 Propolis -bee glue
8 Lycopene
7 Boron
7 Piperlongumine
6 Honokiol
6 Rosmarinic acid
6 Vitamin C (Ascorbic Acid)
5 Allicin (mainly Garlic)
5 Artemisinin
5 Berberine
5 Betulinic acid
4 Radiotherapy/Radiation
4 Boswellia (frankincense)
4 Hydrogen Gas
3 Cisplatin
3 5-fluorouracil
3 Selenium
3 Silver-NanoParticles
2 Magnetic Fields
2 Parthenolide
1 Andrographis
1 Docetaxel
1 Baicalin
1 Lapatinib
1 Capsaicin
1 Celastrol
1 Ursolic acid
1 diet FMD Fasting Mimicking Diet
1 diet Methionine-Restricted Diet
1 Ginkgo biloba
1 HydroxyCitric Acid
1 Hydroxycinnamic-acid
1 Melatonin
1 Metformin
1 Myricetin
1 acetazolamide
1 Salvia miltiorrhiza
1 triptolide
1 Vitamin D3
1 Vitamin K2
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:%  Target#:226  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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