ROS Cancer Research Results

ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.
-mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related)
ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2 inhibition: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α inhibition: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1 inhibition:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK activation: regulates energy metabolism and can increase ROS levels when activated.
• mTOR inhibition: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90 inhibition: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Mevalonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day, -Dipyridamole typically 200mg 2x/day Combined effect research
-Lycopene typically 100mg/day range (note debatable as it mainly lowers NRF2)

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy 
ROS-Inducing Interventions in Cancer — Canonical + Mechanistic Reference
-generated from AI and Cancer database
ROS rating:  +++ strong | ++ moderate | + weak | ± mixed | 0 none
NRF2:        ↓ suppressed | ↑ activated | ± mixed | 0 none
Conditions:  [D] dose  [Fe] metal  [M] metabolic  [O₂] oxygen
             [L] light [F] formulation [T] tumor-type [C] combination




Item ROS↑ NRF2 Condition Mechanism Class Remarks 



ROS">Piperlongumine
+++ ↓ [D][T] ROS-dominant






ROS">Shikonin
+++↓/±[D][T]ROS-dominant






ROS">Vitamin K3 (menadione)
+++↓[D]ROS-dominant






ROS">Copper (ionic / nano)
+++↓[Fe][F]ROS-dominant






ROS">Sodium Selenite
+++↓[D]ROS-dominant






ROS">Juglone
+++↓[D]ROS-dominant






ROS">Auranofin
+++↓[D]ROS-dominant






ROS">Photodynamic Therapy (PDT)
+++0[L][O₂]ROS-dominant






ROS">Radiotherapy / Radiation
+++0[O₂]ROS-dominant






ROS">Doxorubicin
+++↓[D]ROS-dominant






ROS">Cisplatin
++↓[D][T]ROS-dominant






ROS">Salinomycin
++↓[D][T]ROS-dominant






ROS">Artemisinin / DHA
++↓[Fe][T]ROS-dominant






ROS">Sulfasalazine
++↓[C][T]ROS-dominant






ROS">FMD / fasting
++↓[M][C][O₂]ROS-dominant






ROS">Vitamin C (pharmacologic)
++↓[Fe][D]ROS-dominant






ROS">Silver nanoparticles
++±[F][D]ROS-dominant






ROS">Gambogic acid
++↓[D][T]ROS-dominant






ROS">Parthenolide
++↓[D][T]ROS-dominant






ROS">Plumbagin
++↓[D]ROS-dominant






ROS">Allicin
++↓[D]ROS-dominant






ROS">Ashwagandha (Withaferin A)
++↓[D][T]ROS-dominant






ROS">Berberine
++↓[D][M]ROS-dominant






ROS">PEITC
++↓[D][C]ROS-dominant






ROS">Methionine restriction
+↓[M][C][T]ROS-secondary






ROS">DCA
+±[M][T]ROS-secondary






ROS">Capsaicin
+±[D][T]ROS-secondary






ROS">Galloflavin
+0[D]ROS-secondary






ROS">Piperine
+±[D][F]ROS-secondary






ROS">Propyl gallate
+↓[D]ROS-secondary






ROS">Scoulerine
+?[D][T]ROS-secondary






ROS">Thymoquinone
±±[D][T]Dual redox






ROS">Emodin
±±[D][T]Dual redox






ROS">Alpha-lipoic acid (ALA)
±↑[D][M]NRF2-dominant






ROS">Curcumin
±↑/↓[D][F]NRF2-dominant






ROS">EGCG
±↑/↓[D][O₂]NRF2-dominant






ROS">Quercetin
±↑/↓[D][Fe]NRF2-dominant






ROS">Resveratrol
±↑[D][M]NRF2-dominant






ROS">Sulforaphane
±↑↑[D]NRF2-dominant






ROS">Lycopene
0↑—Antioxidant






ROS">Rosmarinic acid
0↑—Antioxidant






ROS">Citrate
00—Neutral


Scientific Papers found: Click to Expand⟱
2327- 2DG,    2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents
- Review, Var, NA
Glycolysis↓, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death
HK2↓,
mt-ROS↑, 2-DG-mediated glucose deprivation stimulates reactive oxygen species (ROS) production in mitochondria, also leading to AMPK activation and autophagy stimulation.
AMPK↑,
PPP↓, 2-DG has been shown to block the pentose phosphate shunt
NADPH↓, Decreased levels of NADPH correlate with reduced glutathione levels, one of the major cellular antioxidants.
GSH↓,
Bax:Bcl2↑, Valera et al. also observed that in bladder cancer cells, 2-DG treatment modulates the Bcl-2/Bax protein ratio, driving apoptosis induction
Apoptosis↑,
RadioS↑, 2-DG radiosensitization results from its effect on thiol metabolism
eff↓, (NAC) treatment, downregulated glutamate cysteine ligase activity, or overexpression of ROS scavenging enzymes
Half-Life↓, its plasma half-life was only 48 min [117]) make 2-DG a rather poor drug candidate
other↝, Adverse effects of 2-DG administration in humans include fatigue, sweating, dizziness, and nausea, mimicking the symptoms of hypoglycemia
eff↓, Moreover, 2-DG has to be used at relatively high concentrations (≥5 mmol/L) in order to compete with blood glucose

4429- AgNPs,    Comparative proteomic analysis reveals the different hepatotoxic mechanisms of human hepatocytes exposed to silver nanoparticles
- in-vitro, Liver, HepG2
*toxicity↝, As the liver is one of the largest accumulation and deposition sites of circulatory AgNPs, it is important to evaluate the hepatotoxicity induced by AgNPs
selectivity↑, cancerous liver cells were generally more sensitive than the normal liver cells.
mt-ROS↑, mitochondrial ROS has been identified as one of the causes of AgNPs-induced hepatotoxicity

4433- AgNPs,    Advancements in metal and metal oxide nanoparticles for targeted cancer therapy and imaging: Mechanisms, applications, and safety concerns
- in-vitro, Liver, HepG2 - in-vitro, Nor, L02
selectivity↑, we evaluated the cytotoxicity of different-sized AgNPs and found that the cancerous liver cells were generally more sensitive than the normal liver cells
selectivity↓, HepG2 cells respond to stresses by adapting energy metabolism, upregulating metallothionein expression and increasing the expression of antioxidants, while L02 cells protect themselves by increasing DNA repair and macro-autophagy.
mt-ROS↑, mitochondrial ROS has been identified as one of the causes of AgNPs-induced hepatotoxicity.

2286- AgNPs,    ROS_localization_after_the_silver_nanoparticles_exposure_depending_on_particle_size">Short-term changes in intracellular ROS localisation after the silver nanoparticles exposure depending on particle size
- in-vitro, Nor, 3T3
*eff↑, These results indicate that the smaller silver particles were more cytotoxic and are consistent with the tentative theory that smaller AgNPs are more cytotoxi
*mt-ROS↑, increased mitochondrial ROS production in the presence of smaller AgNPs
*eff↑, smaller AgNPs particles induced higher levels of mitochondrial ROS

281- ALA,    Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation
- in-vitro, Lung, H460
mt-ROS↑, mitochondria are the primary source of ROS production induced by LA and that these ROS are involved in the apoptotic process.
Apoptosis↑,
Casp9↑,
Bcl-2↓,
eff↓, that all the tested antioxidants were able to inhibit apoptosis induced by LA or DHLA indicating that multiple ROS are involved in the apoptotic process.
eff↑, The pro-oxidant role of LA is generally observed under nonoxidative stress conditions, which is also supported by this study
H2O2↑, LA also induced peroxide generation in these cells
Dose↑, 100uM was enough to generate mitochondrial ROS in lung cancer cells

304- ALA,    alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation
- in-vitro, Colon, HT-29
mt-ROS↑, DHLA but not ALA was able to scavenge cytosolic o2- in HT-29 cells whereas both compounds increased O2 -generation inside mitochondria
Apoptosis↑,
Casp3↑, increased caspase-3-like activity (start after 300uM, figure 2A)
DNAdam↑, and was associated with DNA-fragmentation
Bcl-xL↓, down-regulation of the anti-apoptotic protein bcl-X
Dose↝, The margin between these apparent opposing effects of ROS-production and ROS-scavenging seems to be above 100 uM since at lower concentrations of DHLA no apoptosis-induction was observed.

1355- Ash,    Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF7 - in-vitro, Nor, HMEC
eff↑, WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). ****
mt-ROS↑, WA-induced apoptosis in human breast cancer cells is mediated by mitochondria-derived ROS
mitResp↓,
OXPHOS↓, WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity.
compIII↑,
BAX↑,
Bak↑,
other↓, Cu,Zn-Superoxide dismutase (Cu,Zn-SOD) overexpression confers protection against WA-induced ROS production and apoptosis
ATP∅, steady-state levels of ATP were unaffected by WA treatment in either cell line
*ROS∅, but not in a normal human mammary epithelial cell line (HMEC). WA treatment caused ROS production in breast cancer cells, HMEC were resistant to pro-oxidant effect of this agent.

6424- BBR,    Berberine Protects Glomerular Podocytes via Inhibiting Drp1-Mediated Mitochondrial Fission and Dysfunction
- in-vivo, Nor, NA
*mt-ROS↓, BBR inhibits PA-induced mtROS production, mitochondrial dysfunction and fragmentation in podocytes
*DRP1/DNM1L↓, PA-induced overexpression of Drp1 in mRNA and protein were both abolished by BBR treatment.

2727- BetA,    Betulinic acid in the treatment of breast cancer: Application and mechanism progress
- Review, BC, NA
mt-ROS↑, Its mechanisms mainly include inducing mitochondrial oxidative stress, regulating specific protein (Sp) transcription factors, inhibiting breast cancer metastasis, inhibiting glucose metabolism and NF-κB pathway.
Sp1/3/4↓, By triggering the degradation of Sp1, Sp3, and Sp4, betulinic acid reduces the transcriptional activity of these factors
TumMeta↓,
GlucoseCon↓,
NF-kB↓,
ChemoSen↑, BA can also increase the sensitivity of breast cancer cells to other chemotherapy drugs such as paclitaxel and reduce its toxic side effects.
chemoP↑,
m-Apoptosis↑, variety of mechanisms, including inducing mitochondrial apoptosis, inhibiting topoisomerase
TOP1↓, betulinic acid may inhibit the ability of topoisomerase I or II to properly cleave and re-ligate DNA strands.

2729- BetA,    Betulinic acid in the treatment of tumour diseases: Application and research progress
- Review, Var, NA
ChemoSen↑, Betulinic acid can increase the sensitivity of cancer cells to other chemotherapy drugs
mt-ROS↑, BA has antitumour activity, and its mechanisms of action mainly include the induction of mitochondrial oxidative stress
STAT3↓, inhibition of signal transducer and activator of transcription 3 and nuclear factor-κB signalling pathways.
NF-kB↓,
selectivity↑, A main advantage of BA and its derivatives is that they are cytotoxic to different human tumour cells, while cytotoxicity is much lower in normal cells.
*toxicity↓, It can kill cancer cells but has no obvious effect on normal cells and is also nontoxic to other organs in xenograft mice at a dose of 500 mg/kg
eff↑, BA combined with chemotherapy drugs, such as platinum and mithramycin A, can induce apoptosis in tumour cells
GRP78/BiP↑, In animal xenograft tumour models, BA enhanced the expression of glucose-regulated protein 78 (GRP78)
MMP2↓, reduced the levels of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, in lung metastatic lesions of breast cancer, indicating that BA can reduce the invasiveness of breast cancer in vivo and block epithelial mesenchymal transformation (EMT
P90RSK↓,
TumCI↓,
EMT↓,
MALAT1↓, MALAT1, a lncRNA, was downregulated in hepatocellular carcinoma (HCC) cells treated with BA in vivo,
Glycolysis↓, Suppressing aerobic glycolysis of cancer cells by GRP78/β-Catenin/c-Myc signalling pathways
AMPK↑, activating AMPK signaling pathway
Sp1/3/4↓, inhibiting Sp1. BA at 20 mg/kg/d, the tumour volume and weight were significantly reduced, and the expression levels of Sp1, Sp3, and Sp4 in tumour tissues were lower than those in control mouse tissues
Hif1a↓, Suppressing the hypoxia-induced accumulation of HIF-1α and expression of HIF target genes
angioG↓, PC3: Having anti-angiogenesis effect
NF-kB↑, LNCaP, DU145 — Inducing apoptosis and NF-κB pathway
NF-kB↓, U266 — Inhibiting NF-κB pathway.
MMP↓, BA produces ROS and reduces mitochondrial membrane potential; the mitochondrial permeability transition pore of the mitochondrial membrane plays an important role in apoptosis signal transduction.
Cyt‑c↑, Mitochondria release cytochrome C and increase the levels of Caspase-9 and Caspase-3, inducing cell apoptosis.
Casp9↑,
Casp3↑,
RadioS↑, BA could be a promising drug for increasing radiosensitization in oral squamous cell carcinoma radiotherapy.
PERK↑, BA treatment increased the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptosis pathway and decreased the expression of Sp1.
CHOP/DDIT3↑,
*toxicity↓, BA at a concentration of 50 μg/ml did not inhibit the growth of normal peripheral blood lymphocytes, indicating that the toxicity of BA was at least 1000 times less than that of doxorubicin

2739- BetA,    Glycolytic Switch in Response to Betulinic Acid in Non-Cancer Cells
- in-vitro, Nor, HUVECs - in-vitro, Nor, MEF
*Glycolysis↑, BA elevates the rates of cellular glucose uptake and aerobic glycolysis in mouse embryonic fibroblasts with concomitant reduction of glucose oxidation.
*GlucoseCon↑, BA increases cellular glucose uptake
*Apoptosis↓, Without eliciting signs of obvious cell death BA leads to compromised mitochondrial function, increased expression of mitochondrial uncoupling proteins (UCP) 1 and 2, and liver kinase B1 (LKB1)-dependent activation AMP-activated protein kinase.
*UCP1↓,
*AMPK↑, AMPK activation accounts for the increased glucose uptake and glycolysis which in turn are indispensable for cell viability upon BA treatment.
GLUT1↑, The expression of glucose transporter GLUT1 was elevated upon BA treatment for 16 h
mt-ROS↑, We observed increased production of mitochondrial ROS (Fig. 4A) and elevated expression of uncoupling proteins UCP1 and UCP2 in BA-treated MEF

3695- BM,    Bacopa monnieri (L.) wettst. Extract protects against glutamate toxicity and increases the longevity of Caenorhabditis elegans
- in-vitro, AD, HT22
*OS↑, B.monnieri could increase the median and maximal lifespan of wild type C.elegans, maintain a younger appearing phenotype in the aged C.elegans.
*mt-ROS↓, B.monnieri prevents mitochondrial, and oxidative stress in the cultured cells.
*ROS↓,
*neuroP↑, B.monnieri the potential for therapeutic and preventative use in neurodegenerative disease
*ER Stress↓, B.monnieri prevents ER stress, changing the expression s of ER Stress proteins CHOP and ERP57.

5880- CAR,    In vitro and in vivo antitumor potential of carvacrol nanoemulsion against human lung adenocarcinoma A549 cells via mitochondrial mediated apoptosis
- vitro+vivo, Lung, A549 - in-vitro, Nor, BEAS-2B - in-vitro, Lung, PC9
Dose↝, prepare a carvacrol nanoemulsion (CANE) using an ultrasonication technique and further evaluation of its anticancer potential against human lung adenocarcinoma A549 cells. (160nm)
mt-ROS↑, The CANE induced reactive oxygen species (ROS) production in A549 cells,
p‑JNK↑, leading to activation of key regulators of apoptosis such as p-JNK, Bax and Bcl2 as well as release of cytochrome C, and activation of the caspase cascade.
BAX↑,
Cyt‑c↑,
Casp↑,
AntiTum↑, CANE displayed a strong antitumor potential in vivo using an athymic nude mice model.
ER Stress↑, Abnormally high ROS levels create ER stress with the involvement of three major signaling proteins IRE1-α, PERK and ATF-6
LDH↑, higher LDH activity, which is a well-established biomarker released by damaged cells, was observed in CANE-treated cells
selectivity↑, CANE displayed no cytotoxicity up to 100 µg/ml against normal bronchial epithelium cells (BEAS-2B)
Apoptosis↑, Induction of apoptosis and ROS production in the presence of CANE
DNAdam↑, potential role on DNA damage and chromatin condensation
IRE1↑, We observed a higher expression of IRE1-α in CANE treated cells
XBP-1↑, similar expression pattern for XBP-1
CHOP/DDIT3↓, down-regulation of CHOP, p-eIF2α, and GRP78 was observed in CANE-treated cells
p‑eIF2α↓,
GRP78/BiP↓,
Ca+2↑, increase of Ca+2 levels in CANE-treated cells. A 2.5 fold higher Ca+2 was observed at 100 μg/ml CANE treated cells
MMP↓, CANE severely altered mitochondrial membrane potential (Δψm) in a dose-dependent manner.
Bcl-2↓, up- and down-regulation of pro-apoptotic (Bax) and anti-apoptotic (Bcl2) proteins
Casp3↑, higher levels of cleaved caspase-9 and caspase-3 in cells treated with CANE in a dose-dependent manner
Casp9↑,
eff↓, To confirm this, A549 cells were first treated with N-acetyl-L-cysteine NAC (5 mM), a strong scavenger of ROS, prior to CANE (100 µg/ml) treatment and observed a marked reduction in ROS generation
TumW↓, A significant (p < 0.05) 34.2 and 62.1% reduction in tumor weight was observed in the mice treated with 50 and 100 mg/Kg CANE, orally three times in a week
Weight↑, body weights of 100 mg/kg CANE treated mice remained static up to the second week and increased further up to 4 weeks
eff↑, ultrasonication consider as simple, cost-effective, clean and prompt aseptic technique16, wherein large droplets ruptured into small droplets by ultrasound leading to the formation of nano-scale droplets
eff↑, We selected polysorbate 80 as a surfactant (HLB, 15), which is regarded as safe for using in pharmaceutical and food industries1

939- Catechins,  5-FU,    Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil
- vitro+vivo, GC, SNU620
lactateProd↓, Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity
ROS↑, induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells.
tumCV↓,
LDHA↓, CA better than EGCG
mt-ROS↑, CA and 5FU significantly enhanced mitochondrial ROS production
proApCas↑,

6630- CGA,    In Vitro and In Silico Study on the Impact of Chlorogenic Acid in Colorectal Cancer Cells: Proliferation, Apoptosis, and Interaction with β-Catenin and LRP6
- in-vitro, CRC, HT29 - in-vitro, CRC, SW480
tumCV↓, CGA at 2000 µM significantly affects cell viability and causes DNA fragmentation in SW480 cells rather than in HT-29 cells, but in both cell lines, it induces ROS production.
DNAdam↑,
mt-ROS↑, CGA Induces Mitochondrial Reactive Oxygen Species (ROS) Production
MMP↓, Mitochondrial ROS increase can depolarize the mitochondrial membrane, as was observed in the previous results for SW480,
Casp3↑, increased activation of proapoptotic molecules, such as Caspase-3
eff↝, concentrations of CGA required to achieve the desired biological effect in colorectal cancer cells are higher than the concentrations absorbed from food

1571- Cu,    Copper in cancer: From pathogenesis to therapy
- Review, NA, NA
*toxicity↝, The toxicity of Cu overload is known to be due, in part, to the release of ROS via the Fenton or Haber-Weiss reaction, causing lipid, protein, DNA, and RNA damage
ROS↑, Cu-induced ROS can induce lipid peroxidation, which raises hydroxynonenal (HNE) levels and causes lipid peroxidation to become toxic.
lipid-P↓,
HNE↑, raises hydroxynonenal (HNE) levels and causes lipid peroxidation to become toxic
MAPK↑, Cu exposure causes an elevation in intracellular ROS levels, which then stimulates the MAPK signaling pathway, increasing JNK/SAPK and p38 homologous activity and phosphorylation levels
JNK↑, Cu-induced ROS continuously activate JNK, promote the production of the AP-1 transcription factor, increase Beclin 1 and Atg7 production, and cause autophagy and apoptosis in tumor cells
AP-1↑,
Beclin-1↑,
ATG7↑,
TumAuto↑,
Apoptosis↑,
HO-1↑, Fang and colleagues consistently found that Cu activates the ROS/heme oxygenase-1 (HO-1)/NAD(P)H quinone oxidoreductase-1 (NQO1) signaling cascade to induce autophagy
NQO1↑,
mt-ROS↑, Cu NPs induce complete autophagy by enhancing mitochondrial ROS production and inducing autophagy
Fenton↑, generating large amounts of ROS and oxygen via a Fenton-like reaction

7438- CYN,    Cynaropicrin Suppresses Cell Proliferation by Inducing Mitophagy through p38 MAPK-Mediated Mitochondrial ROS Generation in Human Hepatocellular Carcinoma Cells
- in-vitro, HCC, NA
tumCV↓, cynaropicrin significantly induced cytotoxicity and autophagy in HCC cells, but not in immortalized non-cancerous hepatocytes,
TumAuto↑,
selectivity↑,
mt-ROS↑, which was related to the generation of mitochondrial reactive oxygen species (mtROS) and induction of mitochondrial membrane potential loss.
MMP↓,
LC3B↑, Under cynaropicrin treatment, the expression of microtubule-associated protein light chain 3, which is involved in the elongation of the phagophore membrane, was upregulated
Beclin-1↓, whereas the expression of Beclin-1 and p62, which are essential for the formation of autophagosomes, was downregulated.
p62↓,
PINK1↑, expression of mitophagy regulators PTEN-induced kinase 1 (PINK1) and Parkin in the mitochondria increased, suggesting the induction of autophagic flux in the mitochondria.
PARK2↑,
eff↓, However, N-acetyl-l-cysteine(NAC), a ROS scavenger, counteracted cynaropicrin-induced effects.
p‑MAPK↑, cynaropicrin increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK), and the p38 MAPK inhibitor, SB203580, specifically attenuated cynaropicrin-induced cytotoxicity and mtROS production.

5194- DCA,    Metabolic modulation of glioblastoma with dichloroacetate
- vitro+vivo, GBM, NA
MMP↓, Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA.
mt-ROS↑, DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo.
Apoptosis↑,
CSCs↓,
Hif1a↓, DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro.
P53↑,
angioG↓,
toxicity↓, and there was no hematologic, hepatic, renal, or cardiac toxicity.
PDKs↓, sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas.

6697- DFC,    Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS
Inflam↓, Diclofenac is a non-steroidal anti-inflammatory drug that is widely used clinically but side effects associated with the administration of the drug have been reported.
Casp3↑, diclofenac at least activates caspase 3 and both effector caspases 8 and 9.
Casp8↑,
Casp9↑,
MPT↑, nhibitors of MPT, prevented the downstream activation of the caspase cascade, thus showing that diclofenac opened the mitochondrial pore.
mt-ROS↑, antioxidants were able to prevent caspase activation by diclofenac, revealing that oxidative stress at the mitochondrial level is in the root of MPT induction and caspase cascade activation.

6695- DFC,    Inhibition of lactate dehydrogenase A by diclofenac sodium induces apoptosis in HeLa cells through activation of AMPK
- in-vitro, Cerv, HeLa
other↝, Cancer cells exhibit a unique metabolic preference for the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment.
Glycolysis↓, Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, has been shown to exhibit anticancer effects by interfering with the glucose metabolism pathway.
LDHA↓, DCF binds to LDHA adjacent to the substrate binding site and inhibits its activity in a dose-dependent and allosteric manner in HeLa cells.
Hypoxia↓, Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death.
Apoptosis↑,
lactateProd↓, DCF-induced LDHA inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism through which DCF inhibits glucose uptake in cancer cells.
ATP↓, DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death.
mt-ROS↑,
DNAdam↑,
lipid-P↑,
AMPK↑, Reduction in intracellular ATP levels additionally activates the sensor kinase, adenosine monophosphate-activated protein kinase (AMPK), which further downregulates phosphorylated ribosomal S6 kinase (p-S6K), leading to apoptosis-mediated cell death.
p‑S6K↓,
TumCP↓, DCF inhibits proliferation in HeLa cells
Dose↝, HeLa cells with an IC50 dose of 175 ± 4.86 μm on 24 h of incubation
selectivity↑, DCF did not significantly affect the viability of normal cervical cells at 175 μm (IC50 dose in HeLa cells), where the IC50 value was found to be greater than 1 mm concentration of DCF (
i-MDA↑, The result showed that DCF treatment in HeLa cells led to a significant increase in MDA levels, suggesting an increased level of lipid peroxidation
mtDam↑, Many reports suggest that there is a strong correlation between the inhibition of LDHA and the induction of oxidative stress (ROS production) via mitochondrial damage

4456- DFE,    Induction of apoptosis and cell cycle arrest by ethyl acetate fraction of Phoenix dactylifera L. (Ajwa dates) in prostate cancer cells
- in-vitro, Pca, PC3
TumCD↑, MTT assay showed the strong inhibitory effect of EAFAD on PC3 cells.
MMP↓, Loss of mitochondrial membrane potential and increased oxidative stress were observed in EAFAD treated cells, which suggested mitochondrial involvement in apoptosis.
mt-ROS↑,
Apoptosis↑,
TumCCA↑, arrest the cell cycle in S phase.

6745- DHA,    Omega-3 fatty acid DHA induces ferroptosis in colorectal cancer patient-derived organoids and drug-tolerant cells
- in-vitro, CRC, HT29
tumCV↓, DHA treatment markedly reduced CRC cell viability in a time- and concentration-dependent manner without inducing apoptosis.
selectivity↑, whereas organoids from normal colon tissue were less affected.
Ferroptosis↑, DHA induced ferroptosis in both CRC cells and PDTOs, as evidenced by lipid peroxide accumulation
lipid-P↑, Lipid peroxidation levels in cells increased significantly following treatment with 50 µM and 100 µM DHA, reaching levels higher than those induced by Erastin, a well-established ferroptosis inducer
mt-ROS↑, DHA localized predominantly to the endoplasmic reticulum and mitochondria, where it promoted oxidative stress.
ChemoSen↑, DHA impaired the regrowth of oxaliplatin-tolerant persister cells and enhanced oxaliplatin efficacy in sequential treatment models.
*toxicity↓, low-toxicity strategy to enhance chemotherapy efficacy and target drug-tolerant persister cells in colorectal cancer.
TumCG↓, DHA treatment inhibits colorectal cancer cells growth inducing non-apoptotic cell death
eff↑, the administration of DHA together with Erastin markedly enhanced cell death, even at concentrations of 10 µM DHA, usually insufficient to induce any cytotoxic effects.
eff↑, Furthermore, the combined treatment with DHA made Erastin effective at inducing cell death at a concentration as low as 2 µM
Dose↝, lowest concentration of 10 µM, DHA already exerted a significant effect on organoid growth, whereas at the higher concentration (100 µM) the response exceeded that achieved with chemotherapy treatment alone,
mtDam↑, DHA accumulation in the endoplasmic reticulum was accompanied by mitochondrial dysfunction and increased ROS production, likely amplifying lipid peroxidation
*Inflam↓, dietary DHA supplementation has been shown to reduce intestinal inflammation induced by chemotherapy
*chemoP↑,
Dose↑, Moreover, they are compatible with tissue accumulation achieved through sustained dietary supplementation

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

6317- DRE,    The efficacy of dandelion root extract in inducing apoptosis in drug-resistant human melanoma cells
- in-vitro, Melanoma, A375
Apoptosis↑, we show that dandelion root extract (DRE) specifically and effectively induces apoptosis in human melanoma cells without inducing toxicity in noncancerous cells.
selectivity↑,
Casp8↑, DRE-induced apoptosis activates caspase-8 in A375 cells early on, demonstrating employment of an extrinsic apoptotic pathway to kill A375 cells
mt-ROS↑, Reactive Oxygen Species (ROS) generated from DRE-treated isolated mitochondria indicates that natural compounds in DRE can also directly target mitochondria.
eff↑, Interestingly, the relatively resistant G361 human melanoma cell line responded to DRE when combined with the metabolism interfering antitype II diabetic drug metformin.
*toxicity↓, without toxicity to healthy cells. This triterpene is regarded as cytostatic and not cytotoxic.
Diff↑, Taraxacum Officinale was an effective inducer of differentiation in mouse melanoma cells.
TumCP↓, up-regulated melanogenesis and decreased cell proliferation in mouse melanoma [7].
chemoPv↑, taraxasterol (a triterpenoid), is a worthy chemopreventative agent
*ROS↓, ethanolic Taraxacum Officinale extracts and derivative forms thereof reduce levels of reactive oxygen species (ROS) and nitric oxide production (NO) and inhibit COX-2 expression or its antioxidant activity,
*NO↓, Dandelion flower extracts (DFE) were tested on RAW264.7 cells (mouse macrophages) and exhibited inhibition of NO production in these noncancerous cells.
*COX2↓,
*RNS↓, The inhibition of reactive nitrogen species (RNS) as well as ROS by DFE was attributed to its phenolic components
TumCI↓, Inhibition of cell invasion was corroborated by reduced matrix metalloproteinase activity of MMP-2 and -9, as well as reduced phosphorylation levels of src and FAK [2]
MMP2↓,
MMP9↓,
p‑Src↓,
p‑FAK↓,

6318- DRE,    Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways
- vitro+vivo, CRC, HCT116 - NA, Nor, NCM460
TumCD↑, Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment.
Apoptosis↑, Furthermore, the induction of apoptosis is dependent on caspase-8 activation
Casp8↑,
selectivity↑, The selectivity of DRE to cancer cells was once again confirmed, as normal NCM460 cells were DRE refractive and did not lose metabolic activity and cell viability when exposed to the same doses
TumCMig↓, Dandelion root extract selectively impairs the migration of colon cancer cells
selectivity↑, the normal NCM460 cells treated with DRE were able to migrate into the scratch wound area
Dose↝, DRE administration to normal Balb/c mice, at a dose of 40 mg/kg/day, for a period of 75 days.
toxicity↓, these results established that systemic oral intake of the DRE was safe and its anti-cancer efficacy should be further investigated.
TumCG↓, was efficacious in halting the growth of colon tumors in xenograft models.
MMP↓, loss of mitochondrial membrane potential, in HT-29 cells, with no difference between the control and DRE treated samples of NCM460
mt-ROS↑, results showed a significant increase in the levels of ROS produced in the DRE-treated mitochondria of HT-29 cells
*ROS↓, DRE treatment of isolated mitochondria from NCM460 cells did not produce any significant amounts of ROS. being able to scavenge reactive oxygen species in mouse macrophage cells, RAW264.7
BID↑, DRE treatment led to the truncation of Bid in HT-29 cells selectively, with no increase in Bid truncation in NCM460 cells
Bcl-2↓, table 2
PARP↓,
NF-kB↑, +1.1 fold
*NF-kB↓, -2.3 fold
Casp1↑, +12.3 fold
*Casp1↓, -2.5 fold
COX2↑, DRE treatment selectively decreased the expression of COX-2 in colon cancer cells in a dose and time dependent manner, showing its potential as an anti-inflammatory extract.
OXPHOS↓, altered oxidative phosphorylation and reduced flux through the electron transport chain
ETC↓,

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

5529- EP,    Effects of nsPEFs on Electron Transport and Mitochondrial Structures and Functions
- Review, Var, NA
ETC↓, NsPEFs attenuated electron transport (ET) (O2 consumption) in the electron transport chain (ETC) of intact and permeabilized cells
OCR↓,
CellMemb↑,
mt-ROS↑, Effects of nsPEFs on increases in mROS were synergistic with the complex I inhibitor rotenone
MMP↓, dissipating the ΔΨm

5521- EP,    Nanosecond Pulsed Electric Fields (nsPEFs) Modulate Electron Transport in the Plasma Membrane and the Mitochondria
- in-vitro, BC, 4T1 - in-vitro, Nor, H9c2
ETC↓, NsPEFs attenuates ET in the mitochondrial electron transport system (ETS) at Complex I.
ROS↑, NsPEFs increase ROS more in cytosol of cancer cells.
*mt-ROS↑, NsPEFs increase ROS more in mitochondria in non-cancer cells.

6858- FBZ,    Fenbendazole and Diisopropylamine Dichloroacetate Exert Synergistic Anti-cancer Effects by Inducing Apoptosis and Arresting the Cell Cycle in A549 Lung Cancer Cells
- in-vitro, Lung, A549
eff↑, The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells.
mt-ROS↑, After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression.
Apoptosis↑, The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production
Bcl-2↓,
BAX↑,
Casp3↑, The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells
Casp7↑,
PARP↑,
TumCCA↑, The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins.
cycA1/CCNA1↓,
cycE/CCNE↓,

6911- FIS,    New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells
- vitro+vivo, BC, NA
MMP↓, Mito-fisetin, when used at low micromolar concentrations, stimulated the dissipation of mitochondrial membrane potential and oxidative stress, and affected mitochondrial function, resulting in apoptosis induction in senescent breast cancer cells.
mt-ROS↑, Mito-Fisetin mF3 Induces Oxidative Stress in Mitochondria
Apoptosis↑,
p‑AMPK↑, Mito-fisetin-mediated cytotoxicity was due to increased levels of phosphorylated AMPK, decreased levels of AKT and HSP90,
Akt↓,
HSP90↓,
PI3K↓, Fisetin may interfere with the activity of cell survival promoting signaling pathways such as PI3K/AKT/mTOR and mitochondrial function to stimulate anticancer effects by the inhibition of cell proliferation, metastatic potential, and angiogenesis and
Akt↓,
mTOR↓,
TumCP↓,
TumMeta↓,
angioG↓,
TumCD↑,
selectivity↑, Normal cells were less sensitive to mito-fisetin treatment
TumVol↓, Mito-Fisetin mF3 Inhibits Tumor Size and Induces Cytotoxicity In Vivo

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/CCND1↓, 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/KDR/Flk1↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2/BIRC3↓, 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

2842- FIS,    Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells
- in-vitro, GC, AGS
TumCCA↑, Fisetin (25-100 μM) caused significant decrease in the levels of G1 phase cyclins and CDKs, and increased the levels of p53 and its S15 phosphorylation in gastric cancer cells.
CDK2↓,
P53↑,
selectivity↑, observed that growth suppression and death of non-neoplastic human intestinal FHs74int cells were minimally affected by fisetin
MMP↓, Fisetin strongly increased apoptotic cells and showed mitochondrial membrane depolarization in gastric cancer cells
DNAdam↑, DNA damage was observed as early as 3 h after fisetin treatment which was accompanied with gamma-H2A.X(S139) phosphorylation and cleavage of PARP
cl‑PARP↑,
mt-ROS↑, showed an increase in mitochondrial ROS generation in time- and dose-dependent fashion
eff↓, Pre-treatment with N-acetyl cysteine (NAC) inhibited ROS generation and also caused protection from fisetin-induced DNA damage
survivin↓, We observed a decrease in the levels of survivin by fisetin in gastric cancer cells which further strengthens our results that fisetin decreases antiapoptotic proteins to promote apoptosis.

6981- Form,    Formononetin: a review of its source, pharmacology, drug combination, toxicity, derivatives, and drug delivery systems
- Review, Var, NA - Review, AD, NA - Review, PSA, NA
BioAv↝, FMN has only one phenolic hydroxyl group, so it is poorly soluble in water and easily soluble in organic solvents such as methanol, ethyl acetate, and ether.
*memory↑, It had been found that FMN, isolated from Sophora secundiflora, could improve memory problems by restoring the level of oxidative stress in brain tissues and modulating acetylcholinesterase activity. I
*ROS↓, findings suggest that FMN can inhibit oxidative stress in the liver and restore mitochondrial function
*AChE↓,
*NF-kB↓, FMN, the expression levels of the above three decreased and NF-κB activation was inhibited, which may be related to the release of FMN blocking kelch-like ECH-associated protein-1 (Keap1) and activating the nuclear factor erythroid 2-related factor 2
*Keap1↝,
*NRF2↑,
*Inflam↓, FMN exerted anti-neuroinflammatory effects by targeting peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and bidirectionally regulating NF-κB signaling pathway and Nrf2/Heme oxygenase-1 (HO-1) signaling pathway,
*PGC-1α↝,
*HO-1↓,
*p‑tau↓, thereby inhibiting tau protein hyperphosphorylation.
*cognitive↑, Significantly FMN improve cognitive dysfunction in mice caused by high-fat feeding
*BDNF↑, increased BDNF and 5-hydroxytryptamine (5-HT) levels, and mitigated the progression of depression in mice.
*5HT↑,
*Stroke↓, It could significantly reduce the level of inflammatory factors, increase the number of dendritic spines in neurons, and increase the expression of βIII-tubulin, growth-associated protein 43 (GAP-43), nerve growth factor (NGF) and BDNF.
*PARP1↓, FMN significantly reduced PARP1, PARG, apoptosis-inducing factor (AIF), cysteinyl aspartate-specific protease 3 (caspase-3) and p53 protein in rats with cerebral ischemia-reperfusion injury
*AIF↓,
*Casp3↓,
NP/CIPN↓, FMN had a favorable ameliorative effect on oxaliplatin-induced peripheral neuropathy and did not affect the chemotherapeutic function of oxaliplatin.
*neuroP↑, The neuroprotective mechanism of FMN is shown in Figure 2.
*NGF↑,
*TNF-α↓,
*IL1β↓,
*IL18↓,
*IL6↓,
*VCAM-1↓,
*pol-M2 MC↑,
*hepatoP↑, could reduce hepatotoxicity and improve liver function through inflammatory molecular pathways.
*AST↓, reduce serum AST, ALT, TNF-α and IL-1β levels. I
*ALAT↓,
*LC3II↑, the levels of LC3II, Beclin1, p62, cyclooxygenase-2 (COX2), COX4, MMP and adenosine triphosphate (ATP) were increased
*Beclin-1↑,
*p62↑,
*COX2↑,
*MMP↑,
*ATP↑,
*GSH↑, activity of antioxidant proteins glutathione (GSH), catalase (CAT), GSH-PX in the FMN treatment group recovered, and the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) decreased.
*Catalase↑,
*GPx↑,
*MDA↓,
*antiPs↑, it was found that the interferon (IFN) signaling pathway was inhibited, which could effectively reduce the expression of related inflammatory chemokines, and significantly improve the erythema, scales and thickness of skin lesions in the psoriasis m
*AntiDiabetic↑, FMN effectively mitigated alloxan-induced pancreatic β-cell and DNA damage, lowered blood glucose levels, and increased insulin content.
*glucose↓,
*Insulin↑,
*GutMicro↑, FMN could act as a prebiotic to regulate intestinal microbial flora, thereby improving host metabolism and preventing obesity
*Obesity↓,
COX2↓, FMN effectively inhibited the proliferation of KYSE170 and KYSE150 cells by significantly reducing the mRNA and protein expression levels of COX-2 and cyclin D1, while inducing G1 phase arrest.
cycD1/CCND1↓,
TumCCA↑,
EGFR↓, FMN binds to both WT and mutant EGFR, reducing EGFR kinase activity and inhibiting downstream signaling.
GSK‐3β↑, This, in turn, activated GSK-3β and decreased the expression of myeloid leukemia sequence 1 (Mcl-1), without causing significant toxicity to the vital organs of mice.
Mcl-1↓,
*toxicity↓,
TumCP↓, FMN inhibited the proliferation and growth of cervical cancer cells by inhibiting the expression of HIF-1-α and VEGF.
Hif1a↓,
VEGF↓,
ERK↓, can achieve antiproliferative and invasive effects through effective inhibition of the oncogenic ERK1/2 pathway and the Lamin A/C signaling pathway,
LAMs↓,
Cyt‑c↑, FMN, as a candidate anticancer drug, could release cytochrome C (cyto C) directly through the mitochondrial pathway and activate the cascade reaction of caspase-9, caspase-3 and PARP, which ultimately lead to FaDu cell death
Casp9↑,
Casp3↑,
PARP↑,
TumCD↑,
mitA↑, FMN inhibited mitosis by inactivating the BACH1/p53 signaling pathway, promoted the release of cyto C
BACH1↓,
P53↓,
ROS↑, FMN delivered ROS to mitochondria to release cyto C and activated caspase-3 and caspase-9 cascade reactions to induce apoptosis in MCF7 cells
PD-1↓, FMN has the potential to serve as a PD-1/PD-L1 inhibitor for clinical use
NF-kB↓, FMN mainly interfered with PD-L1 activation by inhibiting the STING-NF-κB signaling pathway
*Bacteria↓, possess other pharmacological activities, such as antibacterial, antiviral, and antiallergic
*AntiViral↑,
*mt-ROS?, FMN effectively reduced the accumulation of ROS and mitochondrial damage in hair cells by activating the PI3K/AKT-Nrf2 signaling pathway, restored the balance of GSH/GSSG.
*PI3K↓,
*chemoP↑, FMN was a potential therapeutic agent for cisplatin-induced ototoxicity.
ChemoSen↑, Therefore, combination therapy had better control effects on multiple targets and a lower risk of drug resistance, which had great application prospects for treating cancer.
eff↑, combination of FMN (30 μM) and sulforaphane (20 μM) exhibited a significant synergistic effect
*toxicity↓, Therefore, it was proved that FMN was safe and non-toxic and could be used for pharmacological and therapeutic purposes.
*BioAv↑, water solubility problem of FMN, succinylated FMN using Bacillus amyloliquefaciens FJ18 to form the compound FMN-7-O-β-D (6″-O-succinyl)-D-glucoside (FMP), which compared to FMN, the water solubility was increased more than 106-fold.
*BioAv↑, To solve those problems, structural modification and nano-delivery systems can be used as a promising solution
*eff↑, FMN can be combined with other treatments, such as immunotherapy, to enhance the therapeutic effect and improve the prognosis of patients;

6983- Form,    Formononetin enhances angiogenesis in diabetic wounds by inhibiting ferroptosis through suppression of mtROS-mediated xCT/GPX4 upregulation
- vitro+vivo, Nor, HUVECs - vitro+vivo, Diabetic, NA
*BloodF↑, Formononetin (FMN), a phytoestrogen from Astragalus roots, is traditionally used to enhance blood function and microcirculation; however, its mechanism remains unclear.
*Ferroptosis↓, FMN effectively reduced ferroptosis markers in HG-treated HUVECs,
*eff↓, and Erastin treatment abolished this protective effect.
*mtDam↓, block ferroptosis through two mechanisms: restoration of mitochondrial integrity and reactivation of the xCT/GPX4 antioxidant system
*xCT↑,
*GPx4↑,
*Wound Healing↑, When we tested FMN in diabetic mice, wound closure rates improved substantially, the expression of xCT and GPX4 was increased, and CD31 expression in wound vessels increased, which matched what we observed in vitro.
*CD31↑,
*mt-ROS↓, mitigation of mitochondrial reactive oxygen species (mtROS) accumulation through xCT/GPX4 activation.

7293- GGB,    Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells
- in-vitro, AML, NA
TumCG↓, GRh2 and GRg3 inhibited cell growth and induced apoptosis, and that GRh2 had greater cytotoxicity than GRg3.
Apoptosis↑,
mt-ROS↑, GRh2 induced generation of more mitochondrial ROS compared with GRg3 in Jurkat cells;

2511- H2,    Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation
- in-vivo, GBM, U87MG
TumCG↓, hydrogen inhalation could effectively suppress GBM tumor growth and prolong the survival of mice with GBM
OS↑,
CD133↓, hydrogen treatment markedly downregulated the expression of markers involved in stemness (CD133, Nestin), proliferation (ki67), and angiogenesis (CD34) and also upregulated GFAP expression, a marker of differentiation.
Ki-67↓,
angioG↓,
Diff↑, pregulated GFAP expression, a marker of differentiation
TumCMig↓, Moreover, hydrogen treatment also suppressed the migration, invasion
TumCI↓,
Dose↝, AMS-H-3 hydrogen-oxygen nebulizer machine (Asclepius Meditec Inc., Shanghai, China), which produces 67% H2 and 33% O. inhaled the mixed air for 1 h two times per day
BBB↑, hydrogen gas can easily cross the BBB.
mt-ROS↑, Intriguingly, molecular hydrogen has also been reported to act as a mitohormetic effector by mildly inducing mitochondrial superoxide production [28]. Perhaps hydrogen-induced ROS promoted the differentiation and downregulation of stemness in GSCs.

2520- H2,    The Impact of Molecular Hydrogen on Mitochondrial ROS and Apoptosis in Colorectal Cancer Cells
- in-vitro, CRC, NA
mt-ROS↓, hydrogen-rich medium, we found a significant mitochondrial ROS decrease (∼40%), especially in the aldolase B over-expressed CRC
ChemoSen↑, hydrogen can synergize the apoptotic response of chemotherapy (∼20% improvement).
other↝, However, the decreasing mtROS signal and increasing apoptosis seems to be controversial with our current understanding, and further study in more detail is required to explore the underlying mechanisms of mitochondrial function and related signaling

2509- H2,    Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway
- in-vitro, Endo, AN3CA - in-vivo, Endo, NA
selectivity↑, Hydrogen exerts a biphasic effect on cancer by promoting tumor cell death and protecting normal cells, which might initiate GSDMD pathway-mediated pyroptosis.
mt-ROS↑, We therefore concluded that molecular hydrogen activated ROS and mtROS generation in endometrial cancer cells.
ROS↑,
TumW↓,
GSDMD↑, ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis
Pyro↑,
Dose↝, Hydrogenated water was produced by H2 dissolved in water saturantly under 0.4 MPa pressure for 6 h with a concentration of 1.0 ppm produced by hydrogen water apparatus
eff↓, In contrast, NAC decreased ROS levels in hydrogen-treated endometrial cancer cells
TumVol↓, We demonstrated that drinking hydrogen-rich water reduced the volume of endometrial tumors in a xenograft mouse model.

3770- H2,    Role of Molecular Hydrogen in Ageing and Ageing-Related Diseases
- Review, AD, NA - Review, Park, NA
*antiOx↑, antioxidative properties as it directly neutralizes hydroxyl radicals and reduces peroxynitrite level
*NRF2↑, activates Nrf2 and HO-1, which regulate many antioxidant enzymes and proteasomes.
*HO-1↑,
*Inflam↓, hydrogen may prevent inflammation
*neuroP↑, prevention and treatment of various ageing-related diseases, such as neurodegenerative disorders, cardiovascular disease, pulmonary disease, diabetes, and cancer.
*cardioP↑,
*other↓, It also prevented ischemia-reperfusion (I/R) injury and stroke in a rat model
*ROS↓, H2 has been shown to exert its beneficial effects in various pathological conditions that involve free radicals and oxidative stress
*NADPH↓, figure 2, H2 Inhibits NADPH Oxidase Activity
*Catalase↑,
*GPx1↑,
*NO↓, H2 Indirectly Reduces Nitric Oxide (NO) Production
*mt-ROS↓, H2 Decreases Mitochondrial ROS
*SIRT3↑, In the kidneys, H2 suppressed the downregulated Sirt3 expression, which is the most abundant member of the sirtuin family, by reducing oxidative stress reactions
*SIRT1↑, In the liver, H2 elevated HO-1 to induce Sirt1 expression
*TLR4↓, H2 inhibits TLR4, which involves hyperglycemia in type 2 diabetes mellitus
*mTOR↓, For example, H2 inhibits mTOR, activates autophagy, and alleviates cognitive impairment resulting from sepsis
*cognitive↑,
*Sepsis↓,
*PTEN↓, It inhibits the activation of the PTEN/AKT/mTOR pathway and alleviates peritoneal fibrosis
*Akt↓,
*NLRP3↓, It also facilitates autophagy-mediated NLRP3 inflammasome inactivation and alleviates mitochondrial dysfunction and organ damage
*AntiAg↑, antiageing mechanism of H2 and the influence on ageing hallmarks are summarized in Figure 3.
*IL6↓, significantly suppressed inflammatory cytokines (IL-6, TNF-α, and IL-1β), MDA, and 8-OHdG, and improved memory dysfunction
*TNF-α↓,
*IL1β↓,
*MDA↓,
*memory↑,
*FOXO3↑, HRW can also upregulate Sirt1-Forkhead box protein O3a (FOXO3a
TumCG↓, H2 inhibits lung cancer progression
*LDL↓, Decreases oxidized LDL; improves HDL function

2879- HNK,    Honokiol Inhibits Lung Tumorigenesis through Inhibition of Mitochondrial Function
- in-vitro, Lung, H226 - in-vivo, NA, NA
tumCV↓, honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol treated group (p= 0.01) while protecting normal bronchial histology (present in 20.5%
selectivity↑,
TumCP↓, In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1/S cell cycle checkpoint, while also leading to increased apoptosis.
TumCCA↑,
Apoptosis↑,
mt-ROS↑, interfering with mitochondrial respiration is a novel mechanism by which honokiol increased generation of reactive oxygen species (ROS) in the mitochondria, : mitochondrial ROS generation
Casp3↑, cells treated with honokiol showed a significant increase in caspase 3/7 activity, which occurred in dose- and time-dependent manners
Casp7↑,
OCR↓, Honokiol caused a fast and concentration-dependent decrease in basal oxygen consumption rate (OCR) in both cell lines
Cyt‑c↑, cytochrome c release was increased in honokil treated mouse lung SCC tissue
ATP↓, found a dramatic decrease in cellular ATP content
mitResp↓, Honokiol inhibits mitochondrial respiration and decreases ATP levels in H226 and H520 cells, which may elevate AMP and the intracellular AMP/ATP ratio, leading to activation of the AMPK
AMP↑,
AMPK↑,

2883- HNK,    Honokiol targets mitochondria to halt cancer progression and metastasis
- Review, Var, NA
ChemoSen↑, Combination of HNK with many traditional chemotherapeutic drugs as well as radiation sensitizes cancer cells to apoptotic death
BBB↓, HNK is also capable of crossing the BBB
Ca+2↑, HNK promotes human glioblastoma cancer cell apoptosis via regulation of Ca(2+) channels
Cyt‑c↑, release of mitochondrial cytochrome c and activation of caspase-3
Casp3↑,
chemoPv↑, potent chemopreventive agent against lung SCC development in a carcinogen-induced lung SCC murine model
OCR↓, HNK treatment results in a decreased oxygen consumption rate (OCR) in whole intact cells, rapidly, and persistently inhibiting mitochondrial respiration, which leads to the induction of apoptosis
mitResp↓,
Apoptosis↑,
RadioS↑, Honokiol as a chemo- and radiosensitizer
NF-kB↓, HNK as an anticancer drug is its potential to inhibit multiple important survival pathways, such as NF-B and Akt
Akt↓,
TNF-α↓, by inhibiting TNF-induced nerve growth factor IB expression in breast cancer cells
PGE2↓, reduced prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) secretion levels
VEGF↓,
NO↝, HNK inhibits cancer cell migration by targeting nitric oxide and cyclooxygenase-2 or Ras GTPase-activating-like protein (IQGAP1) [
COX2↓,
RAS↓,
EMT↓, HNK can reverse the epithelial-mesenchymal-transition (EMT) process, which is a key step during embryogenesis, cancer invasion, and metastasis,
Snail↓, HNK reduced the expression levels of Snail, N-cadherin and -catenin, which are mesenchymal markers, but increased E-cadherin,
N-cadherin↓,
β-catenin/ZEB1↓,
E-cadherin↑,
ER Stress↑, induction of ER stress
p‑STAT3↓, HNK inhibited STAT3 phosphorylation
EGFR↓, inhibiting EGFR phosphorylation and its downstream signaling pathways such as the mTOR signaling pathway
mTOR↓,
mt-ROS↑, We demonstrated that HNK treatment suppresses mitochondrial respiration and increases generation of ROS in the mitochondria, leading to the induction of apoptosis in lung cancer cells
PI3K↓, inhibition of PI3K/Akt/ mTOR, EMT, and Wnt signaling pathways.
Wnt↓,

2869- HNK,    Nature's neuroprotector: Honokiol and its promise for Alzheimer's and Parkinson's
- Review, AD, NA - Review, Park, NA
*neuroP↑, neuroprotective, anti-oxidant, anti-apoptotic, neuromodulating, anti-inflammatory, and many more qualities, honokiol,
*Inflam↓,
*motorD↑, degradation of dopaminergic neurons in Parkinson's disease and improving motor function.
*Aβ↓, Alzheimer's disease, honokiol showed promise in lowering the production of amyloid-beta (Aβ) plaques, phosphorylating tau, and enhancing cognitive performance
*p‑tau↓,
*cognitive↑,
*memory↑, prevented Acetylcholinesterase activity from elevation as well as improved acetylcholine levels, and improved learning, and memory deficits via increased ERK1/2 and Akt phosphorylation
*ERK↑,
*p‑Akt↑,
*PPARγ↑, honokiol has been reported to elevate PPARγ levels in APPswe/PS1dE9 mice as PPARγ is related to ani-inflammatory
*PGC-1α↑, honokiol boosted the expression of PGC1α and PPARγ
*MMP↑, as well as reduced elevated mitochondrial membrane potential and mitochondrial ROS
*mt-ROS↓,
*SIRT3↑, Honokiol has been found as a dual SIRT-3 activator and PPAR-γ agonist that reduced oxidative stress markers within cells and changed the AMPK pathway
*IL1β↓, honokiol prevented restraint stress-induced cognitive dysfunction by reducing the hippocampus's production of IL-1β, TNF-α, glucose-regulated protein (GRP78), and C/EBP homologous protein (CHOP)
*TNF-α↓,
*GRP78/BiP↓,
*CHOP/DDIT3↓,
*NF-kB↓, Additionally, the neuroprotective benefits of honokiol in mice with Aβ-induced learning and memory impairment have been attributed to the inactivation of NF-κB
*GSK‐3β↓, Treatment of honokiol in PC12 cells resulted in reduced GSK-3β and induced β-catenin which effectively showed the neuroprotective and anti-oxidant effect in AD therapy
*β-catenin/ZEB1↑,
*Ca+2↓, , anti-apoptotic effect via reduced caspase 3 levels, and protected membrane injury by reduced calcium level has been investigated in PC12 cells of AD models
*AChE↓, protective effects by serving as an antioxidant, reduced AchE levels, repaired neurofibrillary tangles, reduced NF-kB which downregulates Aβ plaque
*SOD↑, fig1
*Catalase↑,
*GPx↑,

2863- HNK,    Honokiol induces paraptosis-like cell death through mitochondrial ROS-dependent endoplasmic reticulum stress in hepatocellular carcinoma Hep3B cells
- in-vitro, Liver, Hep3B
ER Stress↑, Honokiol also enhanced ER stress, increased cellular calcium ion (Ca2+) levels, and caused mitochondrial dysfunction
Ca+2↑,
mtDam↑,
PTEN↑, Honokiol upregulated the expression of mitophagy regulators such as PTEN-induced kinase 1 and Parkin in the mitochondria
PARK2↑,
Alix/AIP‑1↓, whereas the expression of apoptosis-linked gene 2-interacting protein X (Alix), involved in suppressing paraptosis, was downregulated.
ROS↑, honokiol-induced cytotoxicity was accompanied by excessive generation of intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS).
mt-ROS↑,

2895- HNK,    Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity
- in-vitro, Lung, PC9
eff↑, Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation
TumCP↓,
mt-ROS↑, inhibiting mitochondrial complex ǀ, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3
Prx3↑,
mt-STAT3↓,
*toxicity∅, Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers.
selectivity↑,
ChemoSen↑, combination with standard chemotherapeutics.

2071- HNK,    Identification of senescence rejuvenation mechanism of Magnolia officinalis extract including honokiol as a core ingredient
- Review, Nor, HaCaT
*ROS↓, Magnolia officinalis (M. officinalis) extract significantly lowered the levels of ROS in senescent fibroblasts.
*antiOx↑, honokiol was demonstrated as a core ingredient of M. officinalis extract that exhibits antioxidant effects.
*AntiAge↑, new approaches to anti–aging treatments
*MMP↑, increases MMP
*ECAR↓, senescent fibroblasts treated with M. officinalis extract had lower ECAR values than those treated with DMSO, suggesting that M. officinalis treatment lowed glycolysis rate
*Glycolysis↓, honokiol, similar to M. officinalis, reduced the dependence of glycolysis as an energy source, indicating restoration of mitochondrial function by honokiol.
*PAR-2↓, downregulation of PAR–2 expression by M. officinalis may reduce skin pigmentation.
*CXCL12↑, upregulation of SDF–1 expression by M. officinalis may reduce skin pigmentation.
*BMAL1↑, activation of Bmal–1 expression by M. officinalis promote skin turnover.
*mt-ROS↓, compared to M. officinalis extract, honokiol at 1 and 10 μM was more effective in lowering mitochondrial ROS levels
*OXPHOS↓, Inhibition of oxidative phosphorylation and induction of a compensatory shift toward glycolysis resulted in lower compensatory glycolysis in honokiol–treated senescent fibroblasts

4778- Lyco,    Lycopene exerts cytotoxic effects by mitochondrial reactive oxygen species–induced apoptosis in glioblastoma multiforme
- in-vitro, GBM, GBM8401
BBB↑, lycopene penetration across the blood-brain barrier and its induction of apoptosis, inhibiting proliferation in GBM8401 and T98G GBM cells
Apoptosis↑,
TumCP↑,
P53↑, lycopene promoted p53 upregulation and suppressed cyclins B and cyclin D, leading to cell cycle arrest through ROS-activated ERK pathways.
CycB/CCNB1↓,
cycD1/CCND1↓,
TumCCA↓,
mt-ROS↑, Lycopene induced Mito-ROS accumulation in GBM cells
TumCG↓, Lycopene inhibits the cell growth of GBM cells

2245- MF,    Quantum based effects of therapeutic nuclear magnetic resonance persistently reduce glycolysis
- in-vitro, Nor, NIH-3T3
Warburg↓, tNMR might have the potential to counteract the Warburg effect known from many cancer cells which are prone to glycolysis even under aerobic conditions.
Hif1a↓, combined treatment of tNMR and hypoxia (tNMR hypoxia) led to significantly altered HIF-1α protein levels, namely a further overall reduction in protein amounts
*Hif1a∅, Under normoxic conditions we did not find significant differences in Hif-1α mRNA and protein expression
Glycolysis↓, hypoxic tNMR treatment, driving cellular metabolism to a reduced glycolysis while mitochondrial respiration is kept constant even during reoxygenation.
*lactateProd↓, tNMR reduces lactate production and decreases cellular ADP levels under normoxic conditions
*ADP:ATP↓,
Pyruv↓, Intracellular pyruvate, which was as well decreased in hypoxic control cells, appeared to be further decreased after tNMR under hypoxia
ADP:ATP↓, tNMR under hypoxia further decreased the hypoxia induced decrease of the intracellular ADP/ATP ratio
*PPP↓, pentose phosphate pathway (PPP) is throttled after tNMR treatment, while cell proliferation is enhanced
*mt-ROS↑, tNMR under hypoxia increases mitochondrial and extracellular, but reduces cytosolic ROS
*ROS↓, but reduces cytosolic ROS
RPM↑, Because EMFs are known to affect ROS levels via the radical pair mechanism (RPM)
*ECAR↓, tNMR under normoxic conditions reduces the extracellular acidification rate (ECAR)

533- MF,    Effects of extremely low-frequency magnetic fields on human MDA-MB-231 breast cancer cells: proteomic characterization
- in-vitro, BC, MDA-MB-231 - in-vitro, Nor, MCF10
TumCD↑,
necrosis↑, in normal MCF10A cells
mt-ROS↑, ELF-MF significantly increase the mitochondrial reactive oxygen species production in both MCF-10A and MDA-MB-231 cells, compared to the unexposed cell
other↑, ELF-MF exposed MCF-10A cells exhibited 53 upregulated and 189 downregulated proteins compared with control cells while exposed MDA-MB-231 cells showed 242 upregulated and 86 downregulated proteins compared with the control cells.
*STAT3↓, normal cells
STAT3↑, cancer cells

4355- MF,    Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism
- in-vitro, Nor, C2C12
*mt-OCR↑, figure 1
*mt-ROS↑, Exposure to PEMFs stimulated the production of ROS (Fig. 6A, B) and ATP
*ECAR↑, figure 6
*Dose↝, barrages of 20 × 150 μs on and off pulses for 6 ms repeated at a frequency of 15 Hz. The magnetic flux density rose to predetermined maximal level within ∼50 μs (∼17 T/s) when driving field amplitudes between 0.5 and 3 mT.
*Ca+2↑, 10 min) of C2C12 myoblasts to PEMFs (Supplemental Fig. S1A) augmented cytosolic calcium levels [intracellular [Ca2+] concentration ([Ca2+]i), blue] relative to unexposed myoblasts
*ATP↑,
*other↑, PEMF-stimulated proliferation of myoblasts
*eff↓, TRPC1 silencing precludes PEMF sensitivity.
*eff↝, revealed a magnetic efficacy window

186- MFrot,  MF,    Selective induction of rapid cytotoxic effect in glioblastoma cells by oscillating magnetic fields
- in-vitro, GBM, GBM - in-vitro, Lung, NA
mt-ROS↑, Cytotoxic effects of OMF may be caused by an increase in ROS
Casp3↑, Cell death is associated with activation of caspase 3
selectivity↑, OMF induces highly selective cell death of patient derived GBM cells associated with activation of caspase 3, while leaving normal tissue cells undamaged
TumCD↑, Exposure to OMF causes cancer cell death
ETC↓, The underlying mechanism is a marked increase in ROS in the mitochondria, possibly in part through perturbation of the electron flow in the respiratory chain.
H2O2↑, Figure 6A shows rapid increases in the levels of superoxide and H 2 O 2 in GBM cells,
eff↓, we used the potent antioxidant Trolox to counteract it,
GSH↑, We tested whether GSH synthesis was upregulated as a feedback protective effect in response to OMF-induced increase in ROS. An examination of GSH levels showed that there was a 20% elevation in treated cells
MMP↓, underlying mechanism involves a marked increase in ROS, mitochondrial membrane depolarization, fragmentation of mitochondrial network and activation of caspase 3.


Showing Research Papers: 1 to 50 of 64
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* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 64

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

Fenton↑, 1,   Ferroptosis↑, 1,   GSH↓, 2,   GSH↑, 1,   GSTs↑, 1,   H2O2↑, 2,   HNE↑, 1,   HO-1↑, 1,   Keap1↓, 1,   lipid-P↓, 1,   lipid-P↑, 2,   i-MDA↑, 1,   NQO1↑, 1,   NRF2↑, 2,   OXPHOS↓, 2,   PARK2↑, 2,   Prx3↑, 1,   ROS↑, 7,   mt-ROS↓, 2,   mt-ROS↑, 36,   RPM↑, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

ADP:ATP↓, 1,   ATP↓, 2,   ATP∅, 1,   CDC2↓, 1,   CDC25↓, 1,   compIII↑, 1,   ETC↓, 4,   mitResp↓, 3,   MMP↓, 12,   MPT↑, 1,   mtDam↑, 3,   OCR↓, 3,   PINK1↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AMP↑, 1,   AMPK↑, 4,   p‑AMPK↑, 1,   ATG7↑, 1,   GlucoseCon↓, 1,   Glycolysis↓, 4,   HK2↓, 1,   lactateProd↓, 2,   LDH↑, 1,   LDHA↓, 2,   NADPH↓, 1,   PCK1↓, 1,   PDKs↓, 1,   PPP↓, 1,   Pyruv↓, 1,   p‑S6K↓, 1,   Warburg↓, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 3,   Apoptosis↑, 16,   m-Apoptosis↑, 1,   Bak↑, 1,   BAX↑, 4,   Bax:Bcl2↑, 1,   Bcl-2↓, 5,   Bcl-xL↓, 1,   BID↑, 1,   Casp↑, 2,   Casp1↑, 1,   Casp3↑, 10,   Casp7↑, 2,   Casp8↑, 3,   Casp9↑, 5,   Chk2↑, 1,   Cyt‑c↑, 6,   Diablo↑, 1,   DR5↑, 1,   Fas↑, 1,   Ferroptosis↑, 1,   GSDMD↑, 1,   IAP2/BIRC3↓, 1,   JNK↑, 1,   p‑JNK↑, 1,   MAPK↓, 1,   MAPK↑, 1,   p‑MAPK↑, 1,   Mcl-1↓, 1,   necrosis↑, 1,   p‑p38↓, 1,   proApCas↑, 1,   Pyro↑, 1,   survivin↓, 2,   TumCD↑, 6,  

Kinase & Signal Transduction(tgid=6) ⓘ

Sp1/3/4↓, 2,  

Transcription & Epigenetics(tgid=7) ⓘ

p‑H3↓, 1,   other↓, 1,   other↑, 1,   other↝, 3,   tumCV↓, 5,  

Protein Folding & ER Stress(tgid=8) ⓘ

CHOP/DDIT3↓, 1,   CHOP/DDIT3↑, 1,   p‑eIF2α↓, 1,   ER Stress↑, 3,   GRP78/BiP↓, 1,   GRP78/BiP↑, 1,   HSP90↓, 1,   IRE1↑, 1,   PERK↑, 1,   XBP-1↑, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

ATG5↑, 1,   Beclin-1↓, 1,   Beclin-1↑, 2,   LC3B↑, 1,   LC3s↑, 1,   p62↓, 1,   TumAuto↑, 2,  

DNA Damage & Repair(tgid=10) ⓘ

ATM↑, 1,   CHK1↑, 1,   DNAdam↑, 5,   P53↓, 1,   P53↑, 3,   PARP↓, 1,   PARP↑, 2,   cl‑PARP↑, 2,   PCNA↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK2↓, 2,   CDK4↓, 1,   cycA1/CCNA1↓, 1,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 3,   cycE/CCNE↓, 1,   mitA↑, 1,   TumCCA↓, 1,   TumCCA↑, 6,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

CD133↓, 1,   CSCs↓, 1,   Diff↑, 2,   EMT↓, 2,   ERK↓, 1,   GSK‐3β↑, 2,   mTOR↓, 2,   mTORC1↓, 1,   mTORC2↓, 1,   P90RSK↓, 1,   PI3K↓, 2,   PTEN↑, 1,   RAS↓, 2,   p‑Src↓, 1,   STAT3↓, 2,   STAT3↑, 1,   p‑STAT3↓, 1,   mt-STAT3↓, 1,   TOP1↓, 1,   TumCG↓, 6,   Wnt↓, 1,  

Migration(tgid=13) ⓘ

Alix/AIP‑1↓, 1,   AP-1↑, 1,   BACH1↓, 1,   Ca+2↑, 4,   E-cadherin↑, 2,   p‑FAK↓, 1,   Ki-67↓, 2,   LAMs↓, 1,   MALAT1↓, 1,   MMP13↓, 1,   MMP2↓, 2,   MMP7↓, 1,   MMP9↓, 1,   MMPs↓, 1,   N-cadherin↓, 1,   Rho↓, 1,   Snail↓, 1,   TumCI↓, 3,   TumCMig↓, 2,   TumCP↓, 7,   TumCP↑, 1,   TumMeta↓, 2,   uPA↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 5,   EGFR↓, 2,   Hif1a↓, 4,   Hypoxia↓, 1,   NO↝, 1,   VEGF↓, 3,   VEGFR2/KDR/Flk1↓, 1,  

Barriers & Transport(tgid=15) ⓘ

BBB↓, 1,   BBB↑, 2,   CellMemb↑, 1,   GLUT1↑, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2↓, 2,   COX2↑, 1,   Inflam↓, 1,   JAK1↓, 1,   NF-kB↓, 6,   NF-kB↑, 2,   PD-1↓, 1,   PGE2↓, 1,   TNF-α↓, 2,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↝, 1,   ChemoSen↑, 7,   Dose↑, 2,   Dose↝, 8,   eff↓, 8,   eff↑, 11,   eff↝, 1,   Half-Life↓, 2,   RadioS↑, 3,   selectivity↓, 1,   selectivity↑, 16,  

Clinical Biomarkers(tgid=22) ⓘ

EGFR↓, 2,   Ki-67↓, 2,   LDH↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiTum↑, 1,   chemoP↑, 2,   chemoPv↑, 2,   hepatoP↑, 1,   neuroP↑, 1,   NP/CIPN↓, 1,   OS↑, 1,   RenoP↑, 1,   toxicity↓, 2,   TumVol↓, 2,   TumW↓, 2,   Weight↑, 1,  
Total Targets: 218

Pathway results for Effect on Normal Cells:


NA, unassigned(tgid=0) ⓘ

Stroke↓, 1,  

Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 3,   Catalase↑, 3,   Ferroptosis↓, 1,   GPx↑, 2,   GPx1↑, 1,   GPx4↑, 1,   GSH↑, 2,   HO-1↓, 1,   HO-1↑, 2,   Keap1↝, 1,   MDA↓, 3,   NQO1↑, 1,   NRF2↑, 3,   OXPHOS↓, 1,   RNS↓, 1,   ROS↓, 7,   ROS∅, 1,   mt-ROS?, 1,   mt-ROS↓, 7,   mt-ROS↑, 4,   SIRT3↑, 2,   SOD↑, 2,   xCT↑, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

ADP:ATP↓, 1,   AIF↓, 1,   ATP↑, 2,   DRP1/DNM1L↓, 1,   Insulin↑, 1,   MMP↑, 3,   mtDam↓, 1,   mt-OCR↑, 1,   PGC-1α↑, 1,   PGC-1α↝, 1,   UCP1↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ALAT↓, 1,   AMPK↑, 1,   BMAL1↑, 1,   ECAR↓, 2,   ECAR↑, 1,   FGF21↑, 1,   glucose↓, 1,   GlucoseCon↑, 2,   Glycolysis↓, 1,   Glycolysis↑, 2,   H2S↑, 1,   HK2↑, 1,   lactateProd↓, 1,   LDL↓, 1,   NADPH↓, 1,   PFK↑, 1,   PKM2↑, 1,   PPARα↑, 1,   PPARγ↑, 1,   PPP↓, 1,   SIRT1↑, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 1,   p‑Akt↑, 1,   Apoptosis↓, 1,   Casp1↓, 1,   Casp3↓, 1,   Ferroptosis↓, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

other↓, 1,   other↑, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

CHOP/DDIT3↓, 1,   ER Stress↓, 1,   GRP78/BiP↓, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

Beclin-1↑, 1,   LC3II↑, 1,   p62↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

PARP1↓, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

ERK↑, 1,   FOXO3↑, 1,   GSK‐3β↓, 1,   IGF-1↓, 1,   mTOR↓, 2,   PI3K↓, 1,   PTEN↓, 1,   STAT3↓, 1,  

Migration(tgid=13) ⓘ

AntiAg↑, 1,   Ca+2↓, 1,   Ca+2↑, 1,   CD31↑, 1,   CXCL12↑, 1,   VCAM-1↓, 1,   β-catenin/ZEB1↑, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

ATF4↑, 1,   Hif1a∅, 1,   NO↓, 2,  

Barriers & Transport(tgid=15) ⓘ

GLUT4↑, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2↓, 1,   COX2↑, 1,   IL18↓, 1,   IL1β↓, 3,   IL6↓, 2,   Inflam↓, 5,   pol-M2 MC↑, 1,   NF-kB↓, 3,   PAR-2↓, 1,   TLR4↓, 1,   TNF-α↓, 3,  

Synaptic & Neurotransmission(tgid=18) ⓘ

5HT↑, 1,   AChE↓, 2,   BDNF↑, 1,   NGF↑, 1,   p‑tau↓, 2,  

Protein Aggregation(tgid=19) ⓘ

Aβ↓, 1,   NLRP3↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↑, 2,   Dose↝, 1,   eff↓, 2,   eff↑, 3,   eff↝, 1,  

Clinical Biomarkers(tgid=22) ⓘ

ALAT↓, 1,   AST↓, 1,   BloodF↑, 1,   GutMicro↑, 2,   IL6↓, 2,  

Functional Outcomes(tgid=23) ⓘ

AntiAge↑, 1,   AntiDiabetic↑, 1,   antiPs↑, 1,   cardioP↑, 1,   chemoP↑, 2,   cognitive↑, 4,   hepatoP↑, 1,   memory↑, 3,   motorD↑, 1,   neuroP↑, 5,   Obesity↓, 1,   OS↑, 2,   toxicity↓, 6,   toxicity↝, 2,   toxicity∅, 1,   Wound Healing↑, 1,  

Infection & Microbiome(tgid=24) ⓘ

AntiViral↑, 1,   Bacteria↓, 1,   Sepsis↓, 1,  
Total Targets: 137

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
6 Honokiol
4 Hydrogen Gas
4 Magnetic Fields
3 Silver-NanoParticles
3 Betulinic acid
3 Fisetin
2 Alpha-Lipoic-Acid
2 Diclofenac
2 Dandelion Root
2 Electrical Pulses
2 Formononetin
2 Quercetin
2 Terpinen-4-ol / Tea Tree Oil
1 2-DeoxyGlucose
1 Ashwagandha(Withaferin A)
1 Berberine
1 Bacopa monnieri
1 Carvacrol
1 Catechins
1 5-fluorouracil
1 Chlorogenic acid
1 Copper and Cu NanoParticles
1 Cynaropicrin
1 Dichloroacetate
1 Date Fruit Extract
1 Docosahexaenoic Acid
1 diet Methionine-Restricted Diet
1 EGCG (Epigallocatechin Gallate)
1 Fenbendazole
1 Ginkgolide B
1 Lycopene
1 Magnetic Field Rotating
1 Phenylbutyrate
1 Phenethyl isothiocyanate
1 Cisplatin
1 Piperlongumine
1 Plumbagin
1 Psoralidin
1 Resveratrol
1 EMF
1 Silymarin (Milk Thistle) silibinin
1 Spermidine
1 Vitamin C (Ascorbic Acid)
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#:275  State#:10  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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