HO-1 Cancer Research Results

HO-1, HMOX1: Click to Expand ⟱
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(Also known as Hsp32 and HMOX1)
HO-1 is the common abbreviation for the protein (heme oxygenase‑1) produced by the HMOX1 gene.
HO-1 is an enzyme that plays a crucial role in various cellular processes, including the breakdown of heme, a toxic molecule. Research has shown that HO-1 is involved in the development and progression of cancer.
-widely regarded as having antioxidant and cytoprotective effects
-The overall activity of HO‑1 helps to reduce the pro‐oxidant load (by degrading free heme, a pro‑oxidant) and to generate molecules (like bilirubin) that can protect cells from oxidative damage

Studies have found that HO-1 is overexpressed in various types of cancer, including lung, breast, colon, and prostate cancer. The overexpression of HO-1 in cancer cells can contribute to their survival and proliferation by:
  Reducing oxidative stress and inflammation
  Promoting angiogenesis (the formation of new blood vessels)
  Inhibiting apoptosis (programmed cell death)
  Enhancing cell migration and invasion
When HO-1 is at a normal level, it mainly exerts an antioxidant effect, and when it is excessively elevated, it causes an accumulation of iron ions.

A proper cellular level of HMOX1 plays an antioxidative function to protect cells from ROS toxicity. However, its overexpression has pro-oxidant effects to induce ferroptosis of cells, which is dependent on intracellular iron accumulation and increased ROS content upon excessive activation of HMOX1.

-Curcumin   Activates the Nrf2 pathway leading to HO‑1 induction; known for its anti‑inflammatory and antioxidant effects.
-Resveratrol  Induces HO‑1 via activation of SIRT1/Nrf2 signaling; exhibits antioxidant and cardioprotective properties.
-Quercetin   Activates Nrf2 and related antioxidant pathways; contributes to anti‑oxidative and anti‑inflammatory responses.
-EGCG     Promotes HO‑1 expression through activation of the Nrf2/ARE pathway; also exhibits anti‑inflammatory and anticancer properties.
-Sulforaphane One of the most potent natural HO‑1 inducers; triggers Nrf2 nuclear translocation and upregulates a battery of phase II detoxifying enzymes.
-Luteolin    Induces HO‑1 via Nrf2 activation; may also exert anti‑inflammatory and neuroprotective effects in various cell models.
-Apigenin   Has been reported to induce HO‑1 expression partly via the MAPK and Nrf2 pathways; also known for anti‑inflammatory and anticancer activities.
Scientific Papers found: Click to Expand⟱
3453- 5-ALA,    The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis
- in-vitro, Lung, A549
OXPHOS↑, A549 exposed to ALA exhibited enhanced oxidative phosphorylation, which was indicated by an increase in COX protein expression and oxygen consumption.
OCR↑,
Warburg↓, These data demonstrate that ALA inhibits the Warburg effect and induces cancer cell death.
ROS↑, ALA significantly increased O2-generation over 4 h
SOD2↑, ALA stimulates MnSOD, catalase and HO-1 protein expression.
Catalase↑,
HO-1↑,
Casp3↑, ALA induced an increase in the protein expression of activated (cleaved) caspase-3.
Apoptosis↑, these data demonstrate that ALA induced caspase- dependent apoptosis in A549 cells.

5977- AgNPs,  CDT,    Silver Nitroprusside as an Efficient Chemodynamic Therapeutic Agent and a Peroxynitrite nanogenerator for Targeted Cancer Therapy
- in-vivo, Ovarian, A2780S - NA, Ovarian, SKOV3
Fenton↑, Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species
ROS↑, can decompose already existing intracellular H2O2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome.
eff↑, Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kills cancer cells by taking advantage of tumor acidic environment without used of any external stimuli
angioG↓, been reported that Ag-based materials are involved in angiogenesis inhibition by blocking Akt phosphorylation
p‑Akt↓,
EPR↑, These results indicate thatin cancer cell lines internalized AgNP, which partially localized inysosomes and could be relocalized to cytoplasm avoiding degradation due to lysosomal acidic pH, which produce ROS.
selectivity↑, While, in normal fibroblast cells over time AgNP colocalization in lysosomes increased due to the difference in lysosomal pH between cancer and normal cells
selectivity↑, results suggest that AgNP specifically produces ROS in cancer cell lines due to high acidity in comparison to the normal cells.
eff↑, This specific ROS production is probably due to tumor acidic environment in which AgNP act as a Fenton reagent
Cyt‑c↑, Cytochrome c release after AgNP treatment
HO-1↑, In A2780 cell line, HO-1 expression levels increased 8.1-fold when treated with AgNP

4434- AgNPs,  SSE,    Sodium Selenite Ameliorates Silver Nanoparticles Induced Vascular Endothelial Cytotoxic Injury by Antioxidative Properties and Suppressing Inflammation Through Activating the Nrf2 Signaling Pathway
- vitro+vivo, Nor, NA
*ROS↓, Se showed the capacity against AgNP with biological functions in guiding the intracellular reactive oxygen species (ROS) scavenging and meanwhile exhibiting anti-inflammation effects
*Inflam↓,
*NLRP3↓, Se supplementation decreased the intracellular ROS release and suppressed NOD-like receptor protein 3 (NLRP3) and nuclear factor kappa-B (NF-κB
*NF-kB↓,
*NRF2↑, by activating the Nrf2 and antioxidant enzyme (HO-1) signal pathway
*HO-1↑,
*toxicity↓, Several studies have reported that Se was capable of protection against the toxicity of heavy metals, including its role against AgNP-induced toxication.

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)

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

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

3441- ALA,    α-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1α Signaling Pathway in P301S Mice
- in-vivo, AD, NA
*tau↓, α-lipoic acid (LA), which is a naturally occurring cofactor in mitochondrial, has been shown to have properties that can inhibit the tau pathology and neuronal damage in our previous research
*GlucoseCon↑, chronic LA administration significantly increased glucose availability by elevating glucose transporter 3 (GLUT3), GLUT4, vascular endothelial growth factor (VEGF) protein and mRNA level, and heme oxygenase-1 (HO-1) protein level in P301S mouse brain
*GLUT3↑,
*GLUT4↑,
*VEGF↑,
*HO-1↑,
*Glycolysis↑, LA also promoted glycolysis by directly upregulating hexokinase (HK) activity, indirectly by increasing proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and DNA repair enzymes (OGG1/2 and MTH1).
*HK1↑, Our results indicated that the activity of HK was significantly increased after 10 mg/kg LA treatment.
*PGC-1α↑,
*Hif1a↑, found the underlying mechanism of restored glucose metabolism might involve in the activation of brain-derived neurotrophic factor (BDNF)/tyrosine Kinase receptor B (TrkB)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway by LA treatment.
*neuroP↑,

3547- ALA,    Potential Therapeutic Effects of Lipoic Acid on Memory Deficits Related to Aging and Neurodegeneration
- Review, AD, NA - Review, Park, NA
*memory↑, a number of preclinical studies showing beneficial effects of LA in memory functioning, and pointing to its neuroprotective potential effect
*neuroP↑,
*motorD↑, Improved motor dysfunction
*VitC↑, elevates the activities of antioxidants such as ascorbate (vitamin C), α-tocoferol (vitamin E) (Arivazhagan and Panneerselvam, 2000), glutathione (GSH)
*VitE↑,
*GSH↑,
*SOD↑, superoxide dismutase (SOD) activity (Arivazhagan et al., 2002; Cui et al., 2006; Militao et al., 2010), catalase (CAT) (Arivazhagan et al., 2002; Militao et al., 2010), glutathione peroxidase (GSH-Px)
*Catalase↑,
*GPx↑,
*5HT↑, ↑levels of neurotransmitters (dopamine, serotonin and norepinephrine) in various brain regions
*lipid-P↓, ↓ level of lipid peroxidation,
*IronCh↑, ↓cerebral iron levels,
*AChE↓, ↓ AChE activity, ↓ inflammation
*Inflam↓,
*GlucoseCon↑, ↑brain glucose uptake; ↑ in the total GLUT3 and GLUT4 in the old mice;
*GLUT3↑,
*GLUT4↑,
NF-kB↓, authors showed that LA inhibited the stimulation of nuclear factor-κB (NF-κB)
*IGF-1↑, LA restored the parameters of total homocysteine (tHcy), insulin, insulin like growth factor-1 (IGF-1), interlukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Mahboob et al. (2016), analyzed the effects of LA in AlCl3- model of neurodegeneration,
*IL1β↓,
*TNF-α↓, Suppression of NF-κβ p65 translocation and production of proinflammatory cytokines (IL-6 and TNF-α) followed inhibition of cleaved caspase-3
*cognitive↑, demonstrating its capacity in ameliorating cognitive functions and enhancing cholinergic system functions
*ChAT↑, LA treatment increased the expression of muscarinic receptor genes M1, M2 and choline acetyltransferase (ChaT) relative to AlCl3-treated group.
*HO-1↑, R-LA and S-LA also enhanced expression of genes related to anti-oxidative response such as heme oxygenase-1 (HO-1) and phase II detoxification enzymes such as NAD(P)H:Quinone Oxidoreductase 1 (NQO1).
*NQO1↑,

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

4280- Api,    Protective effects of apigenin in neurodegeneration: An update on the potential mechanisms
- Review, AD, NA - Review, Park, NA
*neuroP↑, Apigenin, a flavonoid found in various herbs and plants, has garnered significant attention for its neuroprotective properties
*antiOx↑, shown to possess potent antioxidant activity, which is thought to play a crucial role in its neuroprotective effects
*ROS↓, Apigenin has been demonstrated to scavenge ROS, thereby reducing oxidative stress and mitigating the damage to neurons
*Inflam↓, apigenin has been found to possess anti-inflammatory properties.
*TNF-α↓, inhibit the production of pro-inflammatory cytokines, such as TNF-α and IL-1β, which are elevated in neurodegenerative diseases
*IL1β↓,
*PI3K↑, apigenin has been shown to activate the PI3K/Akt signaling pathway, which is involved in promoting neuronal survival and preventing apoptosis.
*Akt↑,
*BBB↑, Apigenin has additional neuroprotective properties due to its ability to cross the BBB and enter the brain
*NRF2↑, figure 1
*SOD↑, pigenin has also been shown to activate various antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx)
*GPx↑,
*MAPK↓, Apigenin inhibits the MAPK signalling system, which significantly reduces oxidative stress-induced damage in the brain
*Catalase↑, , including SOD, catalase, GPx and heme oxygenase-1 (HO-1) [37].
*HO-1↑,
*COX2↓, apigenin has the ability to inhibit the expression and function of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE-2), enzymes that produce inflammatory mediators
*PGE2↓,
*PPARγ↑, apigenin has the ability to inhibit the expression and function of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE-2), enzymes that produce inflammatory mediators
*TLR4↓,
*GSK‐3β↓, Apigenin can inhibit the activity of GSK-3β,
*Aβ↓, Inhibiting GSK-3 can reduce Aβ production and prevent neurofibrillary disorders.
*NLRP3↓, Apigenin suppresses nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation by upregulating PPAR-γ
*BDNF↑, Apigenin causes upregulation of BDNF and TrkB expression in several animal models
*TrkB↑,
*GABA↑, Apigenin enhances GABAergic signaling by increasing the frequency of chloride channel opening, leading to increased inhibitory neurotransmission
*AChE↓, It blocks acetylcholinesterase and increases acetylcholine availability.
*Ach↑,
*5HT↑, Apigenin has been shown to increase 5-HT levels, decrease 5-HT turnover, and prevent dopamine changes.
*cognitive↑, Apigenin increases the availability of acetylcholine in the synapse after inhibiting AChE, thereby enhancing cholinergic neurotransmission and improving cognitive function and memory
*MAOA↓, apigenin acts as a monoamine oxidase (MAO) inhibitor and MAO inhibitors increase the levels of monoamines in the brain

4278- ART/DHA,    Artemisinin Ameliorates the Neurotoxic Effect of 3-Nitropropionic Acid: A Possible Involvement of the ERK/BDNF/Nrf2/HO-1 Signaling Pathway
- in-vivo, NA, NA
*IL6↓, ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression.
*Casp3↓,
*Casp9↓,
*BDNF↑,
*ERK↑,
*NRF2↑,
*HO-1↑,
*neuroP↑, ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.
*antiOx↑,
*Inflam↓,

3687- Ash,    Role of Withaferin A and Its Derivatives in the Management of Alzheimer’s Disease: Recent Trends and Future Perspectives
- Review, AD, NA
*Aβ↓, neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents.
*tau↓,
*HSPs↝, WA inhibited Hsp90 [127] and induced Hsp 27 and Hsp70 expressions
*antiOx↑,
*ROS↓,
*Inflam↓,
*neuroP↑, confirming WA’s neuroprotective potency against AD.
*cognitive↑, In an AD model, cognitive defects induced by ibotenic acid that was significantly reversed by WA isolated from Ashwagandha root
*NF-kB↓, inhibited nuclear factor NF-κB activation
*HO-1↑, WA also increased the neuro-protective protein heme oxygenase-1, which is beneficial to AD prevention
*memory↑, WA additionally enhances memory [133], prevents Aβ production, reconstructs synapses, and regenerates axons
*AChE↓, WA Inhibits AChE and BuChE Activities
*BChE↓,
*ChAT↑, WA has an important role in AD by reversing the reduction in cholinergic markers such as choline acetyltransferase (ChAT) and acetylcholine
*Ach↑, WA increased the level of ACh, the amount of choline acetyltransferase (ChAT)

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

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/CCNA1↓,
CycB/CCNB1↓,
cycE/CCNE↓,
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

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.
*chemoPv↑, 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

1357- Ash,    Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
- in-vitro, GBM, U87MG - in-vitro, GBM, U251 - in-vitro, GBM, GL26
TumCP↓,
TumCCA↑, G2/M cell cycle
Akt↓,
mTOR↓,
p70S6↓,
p85S6K↓,
AMPKα↑,
TSC2↑,
HSP70/HSPA5↑,
HO-1↑,
HSF1↓,
Apoptosis↑,
ROS↑, Withaferin A elevates pro-oxidant potential in GBM cells and induces a cellular oxidative stress response
eff↓, Pre-treatment with a thiol-antioxidant protects GBM cells from the anti-proliferative and cytotoxic effects of withaferin A NAC pretreatment was able to completely prevent cell cycle shift to G2/M arrest following 1µM WA treatment at 24h

5425- ASTX,    Multiple roles of fucoxanthin and astaxanthin against Alzheimer's disease: Their pharmacological potential and therapeutic insights
- in-vivo, AD, NA
*neuroP↑, fucoxanthin and astaxanthin, natural carotenoids abundant in algae, has shown to possess neuroprotective properties through antioxidant, and anti-inflammatory characteristics in modulating the symptoms of AD.
*antiOx↑,
*Inflam↑,
*AChE↓, Fucoxanthin and astaxanthin exhibit anti-AD activities by inhibition of AChE, BuChE, BACE-1, and MAO, suppression of Aβ accumulation.
*BACE↓,
*MAOA↓,
*Aβ↓,
*memory↑, Recently, Che, Li (Che et al., 2018) reported that astaxanthin possessed memory enhancement.
*MDA↓, Astaxanthin, as an antioxidant, helps to reduce oxidative stress by lowering malondialdehyde (MDA) levels and increasing SOD activity by activation of the NrF2/HO-1 pathway
*SOD↑,
*NRF2↑,
*HO-1↑,
*NF-kB↓, astaxanthin showed NFκB inhibitory activity which caused the downregulation of BACE-1 expression, resulting in Aβ reduction
*GSK‐3β↓, astaxanthin dose-dependently attenuated the GSK-3β activity
*ChAT↑, astaxanthin could reduce neuroinflammation via reducing iNOS expression and spine loss on the hippocampal CA1 pyramidal neurons, and restoring the ChAT expression in the medial septal nucleus
*iNOS↓,
*ROS↓, astaxanthin treatment decreased the ROS production and enhanced the cell growth.
*BBB↑, Astaxanthin can attenuate neurological dysfunction because of its unique chemical structure and can cross the BBB to enter the brain tissue

5501- Ba,    Therapeutic effects and mechanisms of action of Baicalein on stomach cancer: a comprehensive systematic literature review
- Review, GC, NA
AntiCan↑, The review demonstrated that BC exerts therapeutic effects on GC through multiple biochemical mechanisms.
Apoptosis↑, BC plays an important role in inducing apoptosis, inhibiting cell proliferation, and suppressing metastasis in GC cells.
TumCP↓,
TumMeta↓,
BAX↑, graphical abstract
TumAuto↑,
ROS↑,
NRF2↝, BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis.
PI3K↓,
Akt↓,
NF-kB↓,
TGF-β↓,
SMAD4↓,
GPx4↓, It induces autophagy and ferroptosis, partly through p53 activation and suppression of SLC7A11/GPX4, and disrupts mitochondrial membrane potential via reactive oxygen species (ROS) generation [31, 37]
MMP↓,
*HO-1↑, BC stabilizes Nrf2, leading to the induction of antioxidant enzymes such as HO-1, GST, and NQO1, which mitigate oxidative stress and contribute to its antitumor effects [38].
*GSTs↑,
*antiOx↑,
*AntiTum↑,
*NRF2↑,
ChemoSen↑, BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis.
Akt↓,
mTOR↓,
FAK↓, reducing FAK expression
Ki-67↓, Immunohistochemical analysis also revealed lower Ki-67 levels, indicating reduced cellular proliferation.

2624- Ba,    Baicalein inhibition of hydrogen peroxide-induced apoptosis via ROS-dependent heme oxygenase 1 gene expression
- in-vitro, Nor, RAW264.7
*HO-1↑, In the present study, baicalein (BE) but not its glycoside, baicalin (BI), induced heme oxygenase-1 (HO-1) gene expression at both the mRNA and protein levels
*ERK↑, BE induction of HO-1 gene expression via activation of ERKs in macrophages
*ROS↓, HO-1 protein indeed participates in BE's protection against H2O2-induced cytotoxicity via reducing ROS production
*eff↑, BE, but not BI, protection of RAW264.7 cells from H2O2-induced apoptosis
*MMP↑, BE inhibits H2O2-induced reduction of the mitochondrial membrane potential in RAW264.7 cell
*Cyt‑c∅, the release of cytochrome c from mitochondria to the cytosol was detected in H2O2-treated macrophages, and this was blocked by the addition of BE but not BI.

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

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∅,

5552- BBM,    Effects of berbamine against myocardial ischemia/reperfusion injury: Activation of the 5' adenosine monophosphate‐activated protein kinase/nuclear factor erythroid 2‐related factor pathway and changes in the mitochondrial state
- in-vivo, Stroke, NA
*eff↑, BA significantly improved post‐ischemic cardiac function, reduced infarct size and apoptotic cell death, decreased oxidative stress, and improved the mitochondrial state.
*ROS↓,
*mtDam↓,
*AMPK↑, Furthermore, BA markedly increased AMPK activation, Nrf2 nuclear translocation, and the levels of NAD(P)H quinone dehydrogenase and heme oxygenase‐1.
*NRF2↑,
*NADPH↑,
*HO-1↑,
*cardioP↑, berbamine (BA)‐induced cardioprotective effects

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↑,

3678- BBR,    Network pharmacology study on the mechanism of berberine in Alzheimer’s disease model
- Review, AD, NA
*APP↓, BBR were decreased in the mRNA and protein expression of APP and presenilin 1 while PPARG was increased with a reduction in the NF-κB pathway.
*PPARγ↑, upregulated PPARG with decreasing its downstream NF-ΚB pathway
*NF-kB↓,
*Aβ↓, BBR played a protective role in the AD mice model via blocking APP processing and amyloid plaque formation.
*cognitive↑, berberine significantly reduced amyloid accumulation and improved cognitive impairment in APP/PS1 mice
*antiOx↑, via anti-oxidative stress, anti-neuroinflammation, inhibition of neuronal cell apoptosis, etc
*Inflam↓,
*Apoptosis↓,
*BioAv↑, BBR was found to be metabolized to dihydro-berberine by intestinal bacteria, whose bioavailability was five times higher than that of BBR
*BioAv↝, oral bioavailability (OB, >30%),
*BBB↑, blood-brain barrier (BBB, >0.3)
*motorD↑, BBR treated 5×FAD mice ameliorated their behavior activity including in locomotor activity and cognitive function compared to control.
*NRF2↑, BBR enhanced cellular antioxidant capacity, regulated antioxidant-related pathways such as Nrf2 and HO-1, and thereby reduced oxidative stress damage
*HO-1↑,
*ROS↓,
*p‑Akt↑, BBR significantly increased the phosphorylation levels of AKT and ERK
*p‑ERK↑,

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

2749- BetA,    Anti-Inflammatory Activities of Betulinic Acid: A Review
- Review, Nor, NA
Inflam↓, betulinic acid as a promissory lead compound with anti-inflammatory activity
*NO↓, BA can inhibit the production of NO, mainly in macrophages cultures stimulated with bacterial lipopolysaccharide (LPS) and/or interferon gamma (IFN-ɣ)
*IL10↑, (BA) has a broad-spectrum anti-inflammatory activity, significantly increasing IL-10 production, decreasing ICAM-1, VCAM-1, and E-selectin expression and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB),
*ICAM-1↓,
*VCAM-1↓,
*E-sel↓,
*NF-kB↓,
*IKKα↓, BA blocks the NF-κB signaling pathway by inhibiting IκB phosphorylation and d
*COX2↓, BA also inhibits cyclooxygenase-2 (COX-2) activity and, therefore, decrease prostaglandin E2 (PGE2) synthesis
*PGE2↓,
*IL1β↓, The production of critical pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, IL-12, and TNF, is also decreased by BA treatment
*IL6↓,
*IL8↓,
*IL12↓,
*TNF-α↑,
*HO-1↑, induction of HO-1 enzyme activity is associated with the anti-inflammatory effect of BA, since SnPP, an inhibitor of HO-1, promoted a partial reversal of BA’s effect on NF-κB activity,
*IL10↑, BA also increased the amount of IL-10, a well-known anti-inflammatory cytokine
*IL2↓, decreasing the production of pro-inflammatory cytokines, such as IL-2, IL-6, IL-17, and IFN-γ
*IL17↓,
*IFN-γ↓,
*SOD↑, BA decreased the production of the inflammatory mediators described above at the inflammation site and increased enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in the liver
*GPx↑,
*GSR↑,
*MDA↓, BA decreased malondialdehyde (MDA) levels, a key mediator of oxidative stress and widely used as a marker of free radical mediated lipid peroxidation injury, at the inflammation site
*MAPK↓, BA downregulates MAPK signaling pathways (ERK1/2, JNK, and p38) in the paw edema tissue, which, in part, explains the inhibition of cytokine production (IL-1β and TNF), COX-2 expression, and PGE2 production (Figure 3).

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↓,

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

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/CCND1↓, 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

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↓,

4263- CA,    Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action
- Review, AD, NA
*neuroP↑, neuroprotective effect of CA on neuronal cells subjected to ischemia/hypoxia injury via the scavenging or reduction of ROS (reactive oxygen species) and NO (nitric oxide) and inhibition of COX-2 and MAPK pathways
*ROS↓,
*NO↓,
*COX2↓,
*MAPK↓,
*NRF2↑, CA is known to activate the Keap1/Nrf2 pathway, thereby resulting in the production of cytoprotective proteins.
*GSH↑, activation of GSH metabolism
*HO-1↑, activation of Nrf2 target genes, including heme oxygenase 1 (HO-1) and thioredoxin reductase 1 (TXNRD1)
*5HT↑, Observations of increased serotonin and BDNF suggest that CA may represent a novel therapeutic avenue for depressive behaviors that should be further explored.
*BDNF↑, 10 μM CA results in a 1.5-fold increase in levels of BDNF
*PI3K↑, CA has been shown to mediate the activation of the PI3K/Akt/NF-κB pathway
*Akt↑,
*NF-kB↑,
*BBB↑, CA was shown to ameliorate brain edema and blood-brain barrier (BBB) disruption
*SIRT1↑, CA was also shown to increase SIRT1
*memory↑, CA was shown to significantly improve short-term and spatial memory attributes in rat models of AD
*Aβ↓, CA also delayed the deposition of Aβ and protected cells against Aβ-induced cholinergic and mitochondrial dysfunction in a Caenorhabditis elegans model of AD
*NLRP3↓, CA also inhibits the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which plays a critical role in the pathogenesis of neurodegenerative disorders, including AD and PD and COVID-19

4264- CA,    HO-1_Pathway">Carnosic Acid Mitigates Depression-Like Behavior in Ovariectomized Mice via Activation of Nrf2HO-1 Pathway
- in-vivo, NA, NA
*NRF2↑, CA treatment alleviated depressive behavior, induced the expression of Nrf2, HO-1, thioredoxin-1, and brain-derived neurotrophic factor, and enhanced serotonin levels.
*HO-1↑,
*Trx1↑,
*BDNF↑,
*5HT↑,
*ROS↓, CA also suppressed oxidative stress, reduced TNF-α, IL-1β, and iNOS mRNA expression, and ameliorated OVX-induced histopathological changes.
*TNF-α↓,
*IL1β↓,
*iNOS↓,

5864- CA,    Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1
- vitro+vivo, Stroke, PC12
*neuroP↑, neuroprotective effects of one such compound, carnosic acid (CA), found in the herb rosemary o
*GSH↑, CA translocates into the brain, increases the level of reduced glutathione in vivo, and protects the brain against middle cerebral artery ischemia/reperfusion,
*HO-1↑, Electrophiles induce the expression of a set of antioxidant enzymes, called ‘phase 2 enzymes,’ including heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase 1 (NQO1
*NQO1↑,
*NRF2↑, arnosic acid activates the Keap1/Nrf2/ARE pathway
*ARE↑,
*ROS↓, These results suggest that CA protects primary CNS neurons against oxidative stress.
*BBB↑, Within 1 h, CA reached significant levels in the brain, suggesting that CA was able to penetrate the blood–brain barrier.

5871- CA,    Carnosic Acid Attenuates an Early Increase in ROS Levels during Adipocyte Differentiation by Suppressing Translation of Nox4 and Inducing Translation of Antioxidant Enzymes
- in-vitro, Nor, NA
*ROS↓, these results indicate that carnosic acid could down-regulate ROS level in an early stage of MPI-induced adipocyte differentiation
*NF-kB↓, attenuating ROS generation through suppression of NF-κB-mediated translation
*Nrf1↑, Carnosic Acid induces Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-Mediated Translation of Phase II Antioxidant Enzymes
*HO-1↑, HO-1 was significantly (p < 0.001) reduced by MDI hormone mixture compared to that of an undifferentiated treatment. However, it was enhanced by carnosic acid at 1–20 μM d
*GSTs↑, HO-1, γ-GCSc, and GST might be induced by carnosic acid, thus contributing to the down-regulation of ROS level

5859- CAP,    Are We Ready to Recommend Capsaicin for Disorders Other Than Neuropathic Pain?
- Review, Var, NA
*TRPV1↑, the absorbed capsaicin activates its receptor TRPV1, which causes the rapid influx of sodium ions (Na+) and calcium (Ca2+) from the extracellular environment to the cell interior.
*Ca+2↑,
*Na+↑,
*UCPs↑, by increasing thermogenic gene expression such as uncoupling protein 1 (UCP-1), Sirtuin 1 (SIRT-1) [25] and peroxisome proliferator-activated receptor -γ (PPARγ) coactivator 1α (PGC-1α)
*SIRT1↑,
*PPARγ↑,
*Inflam↓, suppressing inflammatory responses, increasing lipid oxidation, inhibiting adipogenesis
*lipid-P↑,
*IL6↓, decreasing the expression of inflammatory biomarkers such as IL-6, TNF, and CCL-2, associated with NF-κB inactivation
*TNF-α↓,
*NF-kB↓,
*p‑Akt↑, Phosphorylation of Akt is also described after capsaicin treatment, which results in disruption of the NRF2/Keap complex and release of activated transcription factor NRF2
*NRF2↑,
*HO-1↑, triggers the transcription of heme-oxygenase1 genes, which are essential for heme degradation and prevention of oxidative damage
*ROS↑,
*GutMicro↑, It is suggested that regular treatment with capsaicin increases diversity in the gut microbiota and abundance of short-chain fatty acid (SCFA)-producing bacteria

5847- CAP,    An updated review on molecular mechanisms underlying the anticancer effects of capsaicin
- in-vitro, Liver, HepG2
HO-1↑, capsaicin induced the expression of HO-1 in human hepatoma HepG2 cells through the generation of ROS and subsequent activation of a redox-sensitive transcription factor nuclear factor erythroid related factor-2 (Nrf2)
ROS↑,
NRF2↑,
*lipid-P↓, capsaicin inhibits lipid peroxidation by increasing the activity of a battery of antioxidant enzymes
*SOD↑, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR)
*Catalase↑,
*GPx↑,
*GSR↑,
*PGE2↓, inhibitory effects of capsaicin on the production of prostaglandin E2 (PGE2) in macrophages incubated with LPS or TPA (
*COX2↓, the inhibition of COX-2 and iNOS expression by capsaicin in these cells is mediated in a VR1/TRPV1-independent manner
*iNOS↓,
TumCP↓, anticancer effects of capsaicin are partly mediated through the inhibition of cancer cell proliferation.
TumCCA↑, Capsaicin inhibited the growth of human esophageal epidermoid carcinoma (CE 81T/VGH) cells by arresting the cell cycle at the G1 phase through the downregulation of cyclin E, cyclin dependent kinase (Cdk)-4 and -6,
cycE/CCNE↓,
CDK4↓,
MMP↓, Similarly, the inhibition of Cdk-2,-4 and-6, the generation of ROS, and the loss of mitochondrial membrane potential were associated with reduced proliferation of human bladder cancer cells upon capsaicin treatment
P53↑, capsaicin is mediated through the induction of p53 nd its target gene products such as, p21, and Bax.
P21↑,
BAX↑,
SIRT1↑, The same study also demonstrated that capsaicin induced autophagy in human fetal lung cells by inducing SIRT1
angioG↓, Capsaicin inhibited angiogenesis in the chick chorioallantoic membrane
P-gp↓, Capsaicin inhibited the P-gp activity in human intestinal carcinoma (Caco2) cells in a concentration- and time-dependent manner (
ChemoSen↑, Capsaicin exhibited synergistic growth inhibitory effects with 5-fluorouracil (5FU) in cholangiocarcinoma cells in culture as well as xenograft tumor growth in nude mice

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↓,

5766- CAPE,    A Nano-Liposomal Formulation of Caffeic Acid Phenethyl Ester Modulates Nrf2 and NF-κβ Signaling and Alleviates Experimentally Induced Acute Pancreatitis in a Rat Model
- in-vivo, Nor, NA
*MDA↓, CAPE-loaded-NL significantly counteracted ornithine-induced elevation in serum activities of pancreatic digestive enzymes and pancreatic levels of malondialdehyde, nuclear factor kappa B (NF-κB) p65, tumor necrosis factor-alpha, nitrite/nitrate, clea
*NF-kB↓,
*p65↓,
*TNF-α↓,
*cl‑Casp3↓,
*GSR↑, pretreatment with CAPE-loaded-NL significantly reinstated the ornithine-lowered glutathione reductase activity, glutathione,
*GSH↑,
*NRF2↑, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 levels and ATP/ADP ratio, and potentiated the Bcl-2/Bax ratio in pancreatic tissue.
*HO-1↑,
*Bax:Bcl2↓,
*antiOx↑, displayed superior antioxidant, anti-inflammatory and anti-apoptotic effects compared to free CAPE oral suspension
*Inflam↓,

5757- CAPE,    Caffeic acid phenethyl ester (CAPE): pharmacodynamics and potential for therapeutic application
- Review, Nor, NA
*NF-kB↓, inhibition of the activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)
NF-kB↓, CAPE has been shown to block NF-κB activation in tumor
P53↑, CAPE enhances the expression of the tumor suppressor protein p53 in glioma cells
FOXO↑, CAPE also interferes with FOXO signaling by increasing the levels of the FOXO-1 downstream tumor suppressor in prostate cancer cells
Wnt↓, CAPE suppressed canonical Wnt signaling of prostate cancer cells, reducing their invasiveness
TumCI↓,
*HO-1↑, CAPE exerts its antioxidant effects through increased HO1 expression, mediated by Nrf-2
MMP9↓, CAPE has been shown to selectively inhibit human matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2)
MMP2↓,
COX1↓, CAPE has been shown to inhibit the in vitro activity of the cyclooxygenases COX-1 and COX-2
COX2↓,
5LO↓, CAPE has also been shown to inhibit arachidonate 5-lipoxygenase (5-LOX)

5900- CAR,  TV,    Lights and Shadows of Essential Oil-Derived Compounds: Antimicrobial and Anti-Inflammatory Properties of Eugenol, Thymol, Cinnamaldehyde, and Carvacrol
- Review, Nor, NA
*Bacteria↓, oil-derived compounds against a broad spectrum of Gram-positive and Gram-negative bacteria, including multidrug-resistant (MDR) strains
*Inflam↓, anti-inflammatory activity of these compounds is also highlighted, with emphasis on their modulation of key signaling pathways such as nuclear factor-kappa B (NF-κB)
*cardioP↑, figure 1
*neuroP↑,
*NADPH↓, thymol has been shown to inhibit NADPH production at a concentration of 200 µg/mL
*NRF2↑, thymol has been shown to activate the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway
*HO-1↑,
*IL1β↓, carvacrol has also shown anti-inflammatory properties [107,108], being able to inhibit pro-inflammatory mediators as IL-1β and TNF-α
*TNF-α↓,

5939- Cela,  Chemo,    Celastrol inhibits proliferation and induces chemosensitization through down-regulation of NF-κB and STAT3 regulated gene products in multiple myeloma cells
- in-vitro, Melanoma, U266 - in-vitro, Melanoma, RPMI-8226
TumCP↓, Celastrol inhibited the proliferation of MM cell lines regardless of whether they were sensitive or resistant to bortezomib and other conventional chemotherapeutic drugs.
ChemoSen↑, It also synergistically enhanced the apoptotic effects of thalidomide and bortezomib.
cycD1/CCND1↓, down-regulation of various proliferative and anti-apoptotic gene products including cyclin D1, Bcl-2, Bcl-xL, survivin, XIAP and Mcl-1.
Bcl-2↓,
survivin↓, Bcl-2, Bcl-xL, XIAP and survivin (BIRC5) were decreased with Hsp90 inhibition
XIAP↓,
Mcl-1↓,
NF-kB↓, suppression of constitutively active NF-κB
IL6↓, Celastrol also inhibited both the constitutive and IL6-induced activation of STAT3
STAT3↓,
Apoptosis↑, which induced apoptosis as indicated by an increase in the accumulation of cells in the sub-G1 phase, an increase in the expression of pro-apoptotic proteins and activation of caspase-3
TumCCA↑,
Casp3↑,
HSP90↓, Predictive analysis of HSP90 activity knock-down along with HO-1 induction
HO-1↑,
JAK2↓, Active phosphorylated STAT3, JAK2 and Src were all show reduced
Src↓,
Akt↑, Celastrol suppresses Akt activation and inhibits the expression of anti-apoptotic proteins in MM cells

5948- Cela,    Recent Trends in anti-tumor mechanisms and molecular targets of celastrol
TumCP↓, mechanism of action of celastrol in terms of inhibition of cell proliferation and regulation of the cell cycle, regulation of apoptosis and autophagy, inhibition of cell invasion and metastasis, anti-inflammation, regulation of immunotherapy, and an
TumCCA↑,
Apoptosis↑,
TumAuto↑,
TumCI↓,
TumMeta↓,
Imm↝,
angioG↓,
Cyt‑c↑, release of cytochrome c (CytC)
ROS↑, increasing ROS levels, and activating the mitochondrial apoptosis pathway
BAX↑, upregulating the expression of CytC and the pro-apoptotic protein Bax, activating caspase-3 and caspase-9, and leading to the cleavage of PARP
Casp3↑,
Casp9↑,
cl‑PARP↑,
PrxII↓, binds to peroxiredoxin-2 (Prdx2) and inhibits its enzyme activity,
ER Stress↑, resulting in ROS-dependent endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells
mtDam↑,
CHOP↑, celastrol upregulates the expression of CHOP, Bip, XBP1s, and IRE1 proteins,
Inflam↓, Anti-inflammatory properties of celastrol
NF-kB↓, Celastrol additionally obstructed NF-κB and its downstream gene products, such as CXCR4 and MMP9, and reduced serum IL-6 and TNF-α levels to inhibit cell invasion and migration in vivo
CXCR4↓,
MMP9↓,
IL6↓,
TNF-α↓,
HSP90↓, accumulation may be due to the inhibition of HSP90 and the stress response
neuroP↑, Our mass spectrometry research also showed that celastrol directly binds to HSP90 and HSP70, exerting antitumor and neuroprotective effects
STAT3↓, Celastrol exerts anti-tumor activity by inhibiting STAT3
Prx↓, celastrol binds directly to Prdx1, Prdx2, Prdx4, and Prdx6 via active cysteine sites, inhibiting their antioxidant activity without affecting protein expression
HO-1↑, Celastrol also targeted heme oxygenase-1 (HO-1), increasing its expression in activated hematopoietic stem cells
eff↑, Research has indicated that celastrol, combined with 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), inhibits the toxic stress response of HSP90-targeted proteins, reduces the sensitization of human glioblastomas to celastrol treatment, an
eff↑, celastrol, when combined with EGFR tyrosine kinase inhibitors (EGFR-TKIs), effectively inhibits the growth and invasion of T790M mutant human lung cancer H1975
BioAv↑, nano-delivery systems present a novel pathway for the development and clinical application of celastrol, potentially overcoming existing limitations and maximizing its therapeutic potential.
toxicity↑, several significant challenges, including its pronounced hepatic and renal toxicity and potential for causing immunosuppression
CardioT↑, celastrol, which includes hepatotoxicity, cardiotoxicity, infertility toxicity, hematopoietic system toxicity and nephrotoxicity.
hepatoP↓,

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

6018- CGA,    Chlorogenic acid: a review on its mechanisms of anti-inflammation, disease treatment, and related delivery systems
- Review, Var, NA - Review, RCC, NA
*BioAv↓, Nevertheless, the inherent low bioavailability of chlorogenic acid poses challenges in practical deployments.
*Inflam↓, chlorogenic acid predominantly impedes the synthesis and secretion of inflammatory mediators such as TNF-α, NO, COX-2, and PGE2.
*TNF-α↓,
*NO↓,
*COX2↓,
*PGE2↓,
*NF-kB↓, Inhibition of NF-κB signaling pathway
*IL6↓, downregulates inflammatory mediators including IL-6, TNF-α, IL-1β, and TLR2 by hindering the phosphorylation of NF-κB pathway proteins,
*IL1β↓,
*TLR2↓,
*MAPK↓, Inhibition of MAPK signaling pathway
*NRF2↓, Activation of the Nrf2 signaling pathway
*HO-1↑, concomitant upregulation of HO-1 and NQO-1
*NQO1↑,
*cardioP↑, its cardioprotective attributes are further elucidated through modulating pertinent signaling pathways
*neuroP↑, This neuroprotection appears to correlate with an upregulation in SOD2 expression facilitated by chlorogenic acid
*SOD↑,
*GSH↑, compound bolsters SOD activity, elevates GSH concentrations, curtails ROS and LDH production, reduces MDA accumulation, and ameliorates cerebral ischemia-reperfusion (CI/R) injury sequels
*ROS↓,
*LDH↓,
*MDA↓,
*cognitive↑, Chlorogenic acid ameliorates such cognitive deficits, a process conceivably attributed to its inhibitory action on NF-κB and IL-6 within frontal brain structures (
*eff↑, One pivotal investigation showcased that bovine serum albumin (BSA)-facilitated chlorogenic acid silver nanoparticles (AgNPs-CGA-BSA) exude substantial antioxidant and anti-neoplastic properties across in vivo and in vitro matrices.


Showing Research Papers: 1 to 50 of 205
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* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 205

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ATF3↑, 1,   Catalase↑, 1,   Fenton↑, 1,   Ferroptosis↑, 3,   GCLC↑, 1,   GPx4↓, 3,   GSR↑, 1,   HO-1↓, 1,   HO-1↑, 13,   Iron↑, 1,   Keap1↓, 1,   lipid-P↑, 2,   NQO1↑, 3,   NRF2↑, 7,   NRF2↝, 1,   OXPHOS↓, 1,   OXPHOS↑, 1,   Prx↓, 1,   PrxII↓, 1,   ROS↓, 1,   ROS↑, 11,   SIRT3↑, 1,   SOD2↑, 1,  

Mitochondria & Bioenergetics ⓘ

CDC2↓, 1,   mitResp↓, 1,   MMP↓, 3,   mtDam↑, 1,   OCR↑, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACLY↓, 1,   AMPK↑, 1,   FASN↓, 1,   Glycolysis↓, 1,   lactateProd↓, 1,   LDH↓, 1,   LDHA↓, 1,   NADPH↑, 1,   PKM2↓, 1,   SIRT1↑, 1,   TCA↓, 1,   Warburg↓, 2,  

Cell Death ⓘ

Akt↓, 6,   Akt↑, 1,   p‑Akt↓, 2,   Apoptosis↑, 9,   BAX↑, 4,   Bcl-2↓, 3,   BIM↑, 1,   Casp↑, 1,   Casp3↑, 4,   cl‑Casp3↑, 1,   Casp9↑, 1,   cl‑Casp9↑, 1,   Chk2↓, 1,   Cyt‑c↑, 4,   DR5↑, 1,   Ferroptosis↑, 3,   HEY1↓, 1,   iNOS↓, 1,   JNK↑, 2,   MAPK↓, 1,   MAPK↑, 2,   Mcl-1↓, 2,   p38↑, 2,   survivin↓, 1,   TumCD↑, 1,  

Kinase & Signal Transduction ⓘ

AMPKα↑, 1,   p70S6↓, 1,   RET↓, 1,   TSC2↑, 1,  

Transcription & Epigenetics ⓘ

H3↑, 1,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 3,   eIF2α↓, 1,   ER Stress↑, 3,   HSF1↓, 1,   HSP70/HSPA5↑, 1,   HSP90↓, 5,  

Autophagy & Lysosomes ⓘ

TumAuto↑, 2,  

DNA Damage & Repair ⓘ

CHK1↓, 1,   P53↑, 3,   PARP↑, 1,   cl‑PARP↑, 2,   PCNA↓, 1,   γH2AX↑, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 2,   CDK2↓, 1,   CDK4↓, 3,   cycA1/CCNA1↓, 1,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 2,   cycE/CCNE↓, 2,   P21↑, 3,   p‑RB1↓, 1,   TumCCA↑, 7,  

Proliferation, Differentiation & Cell State ⓘ

CD44↓, 1,   cMET↓, 1,   CSCs↓, 3,   EMT↓, 3,   ERK↓, 1,   FOXO↑, 1,   FOXO3↑, 2,   mTOR↓, 3,   Nanog↓, 1,   NOTCH↓, 1,   NOTCH1↓, 1,   NOTCH3↓, 1,   p85S6K↓, 1,   PI3K↓, 4,   p‑PI3K↓, 1,   SOX2↓, 1,   Src↓, 1,   STAT3↓, 5,   TumCG↓, 1,   Wnt↓, 3,  

Migration ⓘ

5LO↓, 2,   AP-1↓, 2,   ER-α36↓, 1,   FAK↓, 1,   Ki-67↓, 1,   MMP1↓, 1,   MMP2↓, 3,   MMP9↓, 4,   MMPs↓, 1,   N-cadherin↓, 2,   Slug↓, 1,   SMAD4↓, 1,   Snail↓, 1,   TGF-β↓, 1,   TumCI↓, 3,   TumCMig↓, 1,   TumCP↓, 6,   TumMeta↓, 2,   uPA↓, 2,   Vim↓, 1,   β-catenin/ZEB1↓, 3,  

Angiogenesis & Vasculature ⓘ

angioG↓, 3,   ATF4↑, 1,   EPR↑, 1,   PDGFR-BB↓, 1,   VEGF↓, 2,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

P-gp↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX1↓, 1,   COX2↓, 2,   CXCR4↓, 2,   IL1β↓, 1,   IL6↓, 4,   Imm↝, 1,   Inflam↓, 3,   JAK2↓, 1,   M1↓, 1,   NF-kB↓, 10,   TNF-α↓, 2,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   BioAv↝, 1,   ChemoSen↑, 4,   eff↓, 1,   eff↑, 9,   RadioS↑, 1,   selectivity↑, 4,  

Clinical Biomarkers ⓘ

AR↓, 1,   E6↓, 2,   E7↓, 2,   IL6↓, 4,   Ki-67↓, 1,   LDH↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   CardioT↑, 1,   chemoP↑, 1,   hepatoP↓, 1,   neuroP↑, 2,   radioP↑, 1,   RenoP↑, 2,   toxicity↑, 1,  
Total Targets: 176

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 14,   ARE↑, 1,   Catalase↑, 5,   GPx↓, 1,   GPx↑, 5,   GSH↓, 1,   GSH↑, 10,   GSR↑, 3,   GSS↑, 1,   GSTs↑, 2,   HK1↑, 1,   HO-1↑, 37,   Keap1↓, 1,   lipid-P↓, 4,   lipid-P↑, 1,   MDA↓, 11,   MPO↓, 1,   NQO1↑, 5,   Nrf1↑, 1,   NRF2↓, 2,   NRF2↑, 30,   p‑NRF2↑, 1,   Prx↑, 2,   ROS↓, 26,   ROS↑, 1,   SOD↑, 15,   SOD1↑, 1,   SOD2↑, 1,   TBARS↓, 1,   Trx↑, 1,   Trx1↑, 1,   UCPs↑, 1,   VitC↑, 1,   VitE↑, 1,  

Metal & Cofactor Biology ⓘ

IronCh↑, 3,  

Mitochondria & Bioenergetics ⓘ

MMP↑, 2,   mtDam↓, 2,   mtDam↑, 1,   PGC-1α↑, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 2,   AMPK↑, 2,   BUN↓, 1,   GlucoseCon↑, 3,   Glycolysis↑, 1,   LDH↓, 1,   LDH↑, 1,   LDHA↓, 1,   NADPH↓, 1,   NADPH↑, 1,   PDH↑, 1,   PDKs↓, 1,   PKM2↓, 1,   PPARγ↑, 3,   p‑PPARγ↓, 1,   SIRT1↑, 2,  

Cell Death ⓘ

Akt↑, 2,   p‑Akt↑, 2,   Apoptosis↓, 2,   Bax:Bcl2↓, 2,   Casp3?, 1,   Casp3↓, 2,   Casp3∅, 1,   cl‑Casp3↓, 1,   Casp9↓, 1,   Casp9∅, 1,   Cyt‑c∅, 2,   iNOS↓, 4,   iNOS↑, 1,   JNK↓, 1,   p‑JNK↓, 1,   MAPK↓, 6,   p‑p38↓, 1,   TRPV1↑, 1,  

Transcription & Epigenetics ⓘ

Ach↑, 3,  

Protein Folding & ER Stress ⓘ

CHOP↓, 1,   ER Stress↓, 1,   GRP78/BiP↓, 1,   HSP70/HSPA5↑, 1,   HSPs↝, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 3,   PARP∅, 1,  

Proliferation, Differentiation & Cell State ⓘ

Choline↑, 1,   ERK↓, 1,   ERK↑, 3,   p‑ERK↓, 1,   p‑ERK↑, 1,   GSK‐3β↓, 2,   IGF-1↑, 1,   PI3K↑, 2,  

Migration ⓘ

5LO↓, 1,   APP↓, 1,   Ca+2↓, 1,   Ca+2↑, 1,   E-sel↓, 1,   heparanase↑, 1,   Na+↑, 1,   VCAM-1↓, 2,  

Angiogenesis & Vasculature ⓘ

p‑eNOS↑, 1,   Hif1a↑, 2,   NO↓, 3,   VEGF↑, 2,  

Barriers & Transport ⓘ

BBB↑, 7,   GLUT3↑, 3,   GLUT4↑, 3,   Na+↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 6,   CRP↓, 1,   ICAM-1↓, 1,   IFN-γ↓, 1,   IKKα↓, 1,   IL10↑, 2,   IL12↓, 1,   IL17↓, 1,   IL18↓, 1,   IL1β↓, 8,   IL2↓, 1,   IL6↓, 9,   IL8↓, 2,   Imm↑, 1,   Inflam↓, 16,   Inflam↑, 1,   NF-kB↓, 12,   NF-kB↑, 2,   p65↓, 1,   PGE2↓, 5,   TLR2↓, 1,   TLR4↓, 1,   TNF-α↓, 12,   TNF-α↑, 1,  

Synaptic & Neurotransmission ⓘ

5HT↑, 4,   AChE↓, 5,   BChE↓, 1,   BDNF↑, 4,   ChAT↑, 4,   GABA↑, 1,   MAOA↓, 2,   tau↓, 2,   p‑tau↓, 1,   TrkB↑, 1,  

Protein Aggregation ⓘ

Aβ↓, 6,   BACE↓, 1,   NLRP3↓, 3,  

Hormonal & Nuclear Receptors ⓘ

RAAS↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   BioAv↑, 2,   BioAv↝, 2,   ChemoSen↑, 1,   Dose↑, 1,   Dose↝, 2,   eff↑, 5,   Half-Life↓, 1,   Half-Life↝, 2,  

Clinical Biomarkers ⓘ

ALAT↓, 2,   ALP↓, 1,   AST↓, 2,   creat↓, 1,   CRP↓, 1,   GutMicro↑, 1,   IL6↓, 9,   LDH↓, 1,   LDH↑, 1,  

Functional Outcomes ⓘ

AntiTum↑, 2,   cardioP↑, 5,   chemoP↑, 1,   chemoPv↑, 1,   cognitive↑, 9,   hepatoP↑, 3,   memory↑, 6,   motorD↑, 2,   neuroP↑, 17,   radioP↑, 1,   RenoP↑, 2,   toxicity↓, 3,  

Infection & Microbiome ⓘ

Bacteria↓, 1,   Sepsis↓, 1,  
Total Targets: 175

Scientific Paper Hit Count for: HO-1, HMOX1
15 Sulforaphane (mainly Broccoli)
14 Thymoquinone
12 Resveratrol
11 Curcumin
9 Quercetin
9 Silymarin (Milk Thistle) silibinin
8 Ashwagandha(Withaferin A)
7 Shikonin
6 Fisetin
6 Hydrogen Gas
6 Lycopene
5 Alpha-Lipoic-Acid
5 Chemotherapy
5 EGCG (Epigallocatechin Gallate)
5 Ferulic acid
5 Honokiol
5 Propolis -bee glue
4 Baicalein
4 Carnosic acid
4 Chlorogenic acid
4 Luteolin
4 Piperlongumine
4 Pterostilbene
4 Rosmarinic acid
3 Cisplatin
3 Betulinic acid
3 Boron
3 Boswellia (frankincense)
3 Capsaicin
3 Celastrol
2 Silver-NanoParticles
2 Selenite (Sodium)
2 Radiotherapy/Radiation
2 Berberine
2 doxorubicin
2 Caffeic Acid Phenethyl Ester (CAPE)
2 Chrysin
1 5-Aminolevulinic acid
1 chemodynamic therapy
1 Allicin (mainly Garlic)
1 Apigenin (mainly Parsley)
1 Artemisinin
1 Astaxanthin
1 Berbamine
1 Carvacrol
1 Thymol-Thymus vulgaris
1 Copper and Cu NanoParticles
1 diet Methionine-Restricted Diet
1 Emodin
1 Ginger/6-Shogaol/Gingerol
1 γ-linolenic acid (Borage Oil)
1 Graviola
1 Juglone
1 Melatonin
1 Magnetic Fields
1 Methylsulfonylmethane
1 nicotinamide adenine dinucleotide
1 Oleuropein
1 Piperine
1 Sanguinarine
1 Sesame seeds and Oil
1 Spermidine
1 erastin
1 Taurine
1 5-fluorouracil
1 Urolithin
1 Vitamin C (Ascorbic Acid)
1 Vitamin K2
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:%  Target#:597  State#:%  Dir#:2
  wNotes=on  sortOrder:rid,rpid

 

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