Keap1 Cancer Research Results

Keap1, Kelch-like ECH-associated protein 1: Click to Expand ⟱
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Kelch-like ECH-associated protein 1 (Keap1) is a key regulator of the transcription factor Nrf2.

-In several tumor types, loss of Keap1 function (either due to gene mutations or low protein expression) results in unrestrained Nrf2 activity.
• Persistent Nrf2 activation is thought to:
 - Provide tumor cells with enhanced protection against oxidative stress.
 - Contribute to chemoresistance and radioresistance.
 - Promote metabolic reprogramming that fuels tumor growth.

• Thus, in many cancers, altered Keap1 status can serve as an indicator of poor prognosis and has been investigated as a potential target for therapeutic intervention.
Scientific Papers found: Click to Expand⟱
2660- AL,    Allicin: A review of its important pharmacological activities
- Review, AD, NA - Review, Var, NA - Review, Park, NA - Review, Stroke, NA
*Inflam↓, It showed neuroprotective effects, exhibited anti-inflammatory properties, demonstrated anticancer activity, acted as an antioxidant, provided cardioprotection, exerted antidiabetic effects, and offered hepatoprotection.
AntiCan↑,
*antiOx↑,
*cardioP↑, This vasodilatory effect helps protect against cardiovascular diseases by reducing the risk of hypertension and atherosclerosis.
*hepatoP↑,
*BBB↑, This allows allicin to easily traverse phospholipid bilayers and the blood-brain barrier
*Half-Life↝, biological half-life of allicin is estimated to be approximately one year at 4°C. However, it should be noted that its half-life may differ when it is dissolved in different solvents, such as vegetable oil
*H2S↑, allicin undergoes metabolism in the body, leading to the release of hydrogen sulfide (H2S)
*BP↓, H2S acts as a vasodilator, meaning it relaxes and widens blood vessels, promoting blood flow and reducing blood pressure.
*neuroP↑, It acts as a neuromodulator, regulating synaptic transmission and neuronal excitability.
*cognitive↑, Studies have suggested that H2S may enhance cognitive function and protect against neurodegenerative diseases like Alzheimer's and Parkinson's by promoting neuronal survival and reducing oxidative stress.
*neuroP↑, various research studies suggest that the neuroprotective mechanisms of allicin can be attributed to its antioxidant and anti-inflammatory properties
*ROS↓,
*GutMicro↑, may contribute to the overall health of the gut microbiota.
*LDH↓, Liu et al. found that allicin treatment led to a significant decrease in the release of lactate dehydrogenase (LDH),
*ROS↓, allicin's capacity to lower the production of reactive oxygen species (ROS), decrease lipid peroxidation, and maintain the activities of antioxidant enzymes
*lipid-P↓,
*antiOx↑,
*other↑, allicin was found to enhance the expression of sphingosine kinases 2 (Sphk2), which is considered a neuroprotective mechanism in ischemic stroke
*PI3K↓, allicin downregulated the PI3K/Akt/nuclear factor-kappa B (NF-κB) pathway, inhibiting the overproduction of NO, iNOS, prostaglandin E2, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-alpha induced by interleukin-1 (IL-1)
*Akt↓,
*NF-kB↓,
*NO↓,
*iNOS↓,
*PGE2↓,
*COX2↓,
*IL6↓,
*TNF-α↓, Allicin has been found to regulate the immune system and reduce the levels of TNF-α and IL-8.
*MPO↓, Furthermore, allicin significantly decreased tumor necrosis factor-alpha (TNF-α) levels and myeloperoxidase (MPO) activity, indicating its neuroprotective effect against brain ischemia via an anti-inflammatory pathway
*eff↑, Allicin, in combination with melatonin, demonstrated a marked reduction in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), Kelch-like ECH-associated protein 1 (Keap-1), and NF-κB genes in rats with brain damage induced by acryl
*NRF2↑, Allicin treatment decreased oxidative stress by upregulating Nrf2 protein and downregulating Keap-1 expression.
*Keap1↓,
*TBARS↓, It significantly reduced myeloperoxidase (MPO) and thiobarbituric acid reactive substances (TBARS) levels,
*creat↓, and decreased blood urea nitrogen (BUN), creatinine, LDH, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) levels.
*LDH↓,
*AST↓,
*ALAT↓,
*MDA↓,
*SOD↑, Allicin also increased the activity of superoxide dismutase (SOD) as well as the levels of glutathione S-transferase (GST) and glutathione (GSH) in the liver, kidneys, and brain
*GSH↑,
*GSTs↑,
*memory↑, Allicin has demonstrated its ability to improve learning and memory deficits caused by lead acetate injury by promoting hippocampal astrocyte differentiation.
chemoP↑, Allicin safeguards mitochondria from damage, prevents the release of cytochrome c, and decreases the expression of pro-apoptotic factors (Bax, cleaved caspase-9, cleaved caspase-3, and p53) typically activated by cisplatin
IL8↓, Allicin has been found to regulate the immune system and reduce the levels of TNF-α and IL-8.
Cyt‑c↑, In addition, allicin was reported to induce cytochrome c, increase expression of caspase 3 [86], caspase 8, 9 [82,87], caspase 12 [80] along with enhanced p38 protein expression levels [81], Fas expression levels [82].
Casp3↑,
Casp8↑,
Casp9↑,
Casp12↑,
p38↑,
Fas↑,
P53↑, Also, significantly increased p53, p21, and CHK1 expression levels decreased cyclin B after allicin treatment.
P21↑,
CHK1↓,
CycB/CCNB1↓,
GSH↓, Depletion of GSH and alterations in intracellular redox status have been found to trigger activation of the mitochondrial apoptotic pathway was the antiproliferative function of allicin
ROS↑, Hepatocellular carcinoma (HCC) cells were sensitised by allicin to the mitochondrial ROS-mediated apoptosis induced by 5-fluorouracil
TumCCA↑, According to research findings, allicin has been shown to decrease the percentage of cells in the G0/G1 and S phases [87], while causing cell cycle arrest at the G2/M phase
Hif1a↓, Allicin treatment was found to effectively reduce HIF-1α protein levels, leading to decreased expression of Bcl-2 and VEGF, and suppressing the colony formation capacity and cell migration rate of cancer cells
Bcl-2↓,
VEGF↓,
TumCMig↓,
STAT3↓, antitumor properties of allicin have been attributed to various mechanisms, including promotion of apoptosis, inhibition of STAT3 signaling
VEGFR2↓, suppression of VEGFR2 and FAK phosphorylation
p‑FAK↓,

4991- ART/DHA,  doxoR,    Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy
- in-vivo, Nor, H9c2
*cardioP↑, In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes.
*ROS↓,
*Ferroptosis↓,
*NRF2↑,
Keap1↓, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

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

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

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↓,

6010- CGA,    The Biological Activity Mechanism of Chlorogenic Acid and Its Applications in Food Industry: A Review
- Review, Nor, NA
*antiOx↑, mainly shown as anti-oxidant, liver and kidney protection, anti-bacterial, anti-tumor, regulation of glucose metabolism and lipid metabolism, anti-inflammatory, protection of the nervous system,
*hepatoP↑,
*RenoP↑,
AntiTum↑,
*glucose↝,
*Inflam↓,
*neuroP↑,
*ROS↓, ↓Active oxygen (ROS) , ↓Keap1,↑Nrf2, ↑SOD, ↑CAT, ↑Glutathione Peroxidase (GSH-Px), ↑Glutathione (GSH), ↓MDA
*Keap1↓,
*NRF2↑,
*SOD↑,
*Catalase↑,
*GPx↑,
*GSH↑,
*MDA↓,
*p‑ERK↑, ↑ERK1/2 phosphorylation
*GRP78/BiP↑, ↑Glucose regulatory protein 78 (GRP78)
*CHOP↑, ↑C/EBP homologous protein (CHOP)
*GRP94↑, ↑Glucose Regulatory Protein 94 (GRP94)
*Casp3↓, ↓Caspase-9/Caspase-3
*Casp9↓,
*HGF/c-Met↑, ↑Hepatocyte Growth Factor (HGF)
*TNF-α↓, ↓Tumor Necrosis Factor-α (TNF-α)/Interferonγ (IFN-γ)
*TLR4↓, ↓TLR4
*MAPK↓, ↓MAPK signal pathway
*IL1β↓, ↓Interleukin 1β (IL-1β)/Interleukin 6 (IL-6)
*iNOS↓, ↓Inducible Nitric Oxide Synthase (iNOS)
TCA↓, ↓Tricarboxylic acid cycle (TCA) ↓Glycolysis
Glycolysis↓,
Bcl-2↓, ↓Anti-apoptotic gene Bcl-2/Bcl-XL
BAX↑, ↑Pro-apoptotic gene Bax/Bcl-XS/Bad
MAPK↑, ↑p38 mitogen-activated protein kinase (p38 MAPK)
JNK↑, ↑c-Jun N-terminal Kinase (JNK)
CSCs↓, ↓Stem cell marker genes Nanog, POU5F1, Sox2, CD44, Oct4
Nanog↓,
SOX2↓,
CD44↓,
OCT4↓,
P53↑, ↑P53
P21↑, ↑p21
*SOD1↑, ↑CuZnSOD (SOD1)/MnSOD (SOD2)
*AGEs↓, ↓Glycosylation end products (AGEs)
*GLUT2↑, ↑Glucose Transporter 2 (GLUT2)
*HDL↑, ↑High-density lipoprotein (HDL)
*Fas↓, ↓Fatty acid synthase (FAS)
*HMG-CoA↓, ↓β-hydroxy-β-methylglutamyl-CoA (HMG-CoA) reductase
*NF-kB↓, ↑NF-κB signaling pathway
*HO-1↓, ↑Nrf2/HO-1 signaling pathway
*COX2↓, ↓Cyclooxygenase-2 (COX-2)
*TLR4↓, ↓Toll-like receptor 4 (TLR4)
*BioAv↑, One route may be immediate absorption in the stomach or upper gastrointestinal tract, and the other route may be slowly absorbed throughout the small intestine.
*BioAv↝, It indicates that the bioavailability of CGA is closely related to the metabolic capacity of the organism's gut flora
TumCP↓, CGA also inhibits the proliferation, migration, and invasion of cancer cells.
TumCMig↓,
TumCI↓,

5008- DSF,  Cu,    Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis
- in-vitro, HCC, NA
selectivity↑, We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells
TumCD↑,
TumCMig↓,
TumCI↓,
angioG↓,
mtDam↑, Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death.
Iron↑,
lipid-P↑,
Ferroptosis↑,
NF-kB↑, Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu.
p‑p62↑, DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2.
Keap1↓,
eff↑, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis
eff↓, Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu.
ChemoSen↑, Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase.

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

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

2843- FIS,    Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
- Review, Var, NA
NRF2↑, fisetin increased the protein level and accumulation Nrf2 and down regulated the protein levels of Keap1
Keap1↓,
ChemoSen↑, In vitro studies showed that fisetin and quercetin could also act against chemotherapeutic resistance in several cancers
BioAv↓, Fisetin has low aqueous solubility and bioavailability
Cyt‑c↑, release of cytochrome c from mitochondria, caspase-3 and caspase-9 mRNA and protein expression, and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels, were found to be regulated in the fisetin-treated cancer cell line
Casp3↑,
Casp9↑,
BAX↑,
tumCV↓, fisetin at 5–80 µM significantly reduced the viability of A431 human epidermoid carcinoma cells by the release of cytochrome c,
Mcl-1↓, reducing the anti-apoptotic protein expression of Bcl-2, Bcl-xL, and Mcl-1 along with elevation of pro-apoptotic protein expression (Bax, Bak, and Bad) and caspase cleavage and poly-ADP-ribose polymerase (PARP) protein
cl‑PARP↑,
IGF-1↓, fisetin promoted caspase-8 and cytochrome c expression, possibly by impeding the aberrant activation of insulin growth factor receptor 1 and Akt
Akt↓,
CDK6↓, fisetin binds with CDK6, which in turn blocks its activity with an inhibitory concentration (IC50) at a concentration of 0.85 μM
TumCCA↑, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases
P53?, exhibiting elevated levels of p53
cycD1/CCND1↓, 10–60 μM fisetin concentration, prostate cancer cells PC3, LNCaP, and CWR22Ry1 had decreased cellular viability and decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
cycE/CCNE↓,
CDK2↓, decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
CDK4↓,
CDK6↓,
MMP2↓, fisetin displayed tumor inhibitory effects by blocking MMP-2 and MMP-9 at mRNA and protein levels in prostate PC-3 cells
MMP9↓,
MMP1↓, Similarly, fisetin can also inhibit MMP-1, MMP-9, MMP-7, MMP-3, and MMP-14 gene expression linked with ECM remodeling in human umbilical vascular endothelial cells (HUVECs) and HT-1080 fibrosarcoma cells [9
MMP7↓,
MMP3↓,
VEGF↓, fisetin in a concentration-dependent manner (10–50 μM concentration) significantly inhibited regular serum, growth-enhancing supplement, and vascular endothelial growth factor (VEGF)
PI3K↓, fisetin inhibited PI3K expression and phosphorylation of Akt
mTOR↓, fisetin treatment activated the apoptotic process through inhibiting both PI3K and mammalian target of rapamycin (mTOR) signaling pathways
COX2↓, fisetin resulted in activation of apoptosis and inhibition of COX-2 and the Wnt/EGFR/NF-kB pathway
Wnt↓,
EGFR↓,
NF-kB↓,
ERK↓, Fisetin is one of the flavonoids that has been found to suppress ERK1/2 signaling in human gastric (SGC7901), hepatic (HepG2), colorectal (Caco-2)
ROS↑, fisetin induced ROS generation and suppressed ERK through its phosphorylation
angioG↓, fisetin-induced anti-angiogenesis led to reduced VEGF and epidermal growth factor receptor (EGFR) expression
TNF-α↓, Fisetin suppressed IL-1β-mediated expression of inducible nitric oxide synthase, nitric oxide, interleukin-6, tumor necrotic factor-α, prostaglandin E2, cyclooxygenase-2 (iNOS, NO, IL-6, TNF-α, PGE2, and COX-2),
PGE2↓,
iNOS↓,
NO↓,
IL6↓,
HSP70/HSPA5↝, fisetin-mediated inhibition of cellular proliferation by HSP70 and HSP27 regulation
HSP27↝,

4029- FulvicA,  Chemo,    Shilajit mitigates chemotherapeutic drug-induced testicular toxicity: Study on testicular germ cell dynamics, steroidogenesis modulation, and Nrf-2/Keap-1 signaling
- in-vivo, Var, NA
*other↑, Shilajit improves testicular daily production and sperm quality by promoting the conversion of spermatogonia (2C) into spermatids (1C)
*PCNA↑, , stimulating germ cell proliferation (PCNA)
*SOD↑, Shilajit also reduces testicular oxidative stress by increasing antioxidant enzyme activity (SOD) and decreasing lipid peroxidation (LPO)
*lipid-P↓,
*NRF2↑, effects are mediated by upregulation of the antioxidant protein Nrf-2 and downregulation of Keap-1.
*Keap1↓,
*chemoP↑, enhance fertility in cases of testicular damage caused by chemotherapeutic drugs.

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

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

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

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

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

5028- QC,    Quercetin inhibited LPS-induced cytokine storm by interacting with the AKT1-FoxO1 and Keap1-Nrf2 signaling pathway in macrophages
- vitro+vivo, Nor, RAW264.7
*ROS↓, quercetin can reduce ROS through the Keap1-Nrf2 signaling pathway
*Keap1↓,
*NRF2↑,

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

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

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

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

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

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


Showing Research Papers: 1 to 23 of 23

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 23

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 2,   GPx4↓, 1,   GSH↓, 3,   GSSG↑, 1,   HO-1↑, 3,   Iron↑, 1,   Keap1↓, 7,   ox-Keap1↓, 1,   rd-Keap1↑, 1,   lipid-P↑, 2,   NRF2↑, 6,   NRF2∅, 1,   RNS↓, 1,   ROS?, 1,   ROS↑, 6,   mt-ROS↓, 1,   SOD↑, 1,   Trx↓, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 2,   MMP↓, 2,   mtDam↑, 1,  

Core Metabolism/Glycolysis ⓘ

GlutMet↓, 1,   Glycolysis↓, 1,   NADPH↑, 1,   PFK↓, 1,   PI3K/Akt↓, 1,   POLD1↓, 1,   SIRT1↑, 1,   TCA↓, 1,  

Cell Death ⓘ

Akt↓, 3,   Apoptosis↑, 1,   BAX↑, 3,   Bcl-2↓, 4,   Casp↑, 1,   Casp12↑, 1,   Casp3↑, 2,   Casp8↑, 1,   Casp9↑, 2,   CK2↓, 1,   Cyt‑c↑, 2,   Fas↑, 1,   Ferroptosis↑, 2,   iNOS↓, 2,   JNK↑, 1,   MAPK↑, 2,   Mcl-1↓, 1,   p38↑, 1,   TumCD↑, 1,  

Transcription & Epigenetics ⓘ

other⇅, 1,   tumCV↓, 2,  

Protein Folding & ER Stress ⓘ

HSP27↝, 1,   HSP70/HSPA5↝, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↓, 1,   p62↓, 1,   p‑p62↑, 1,  

DNA Damage & Repair ⓘ

CHK1↓, 1,   P53?, 1,   P53↑, 2,   cl‑PARP↑, 2,  

Cell Cycle & Senescence ⓘ

CDK2↓, 1,   CDK4↓, 1,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 1,   cycE/CCNE↓, 1,   P21↑, 2,   TumCCA↑, 4,  

Proliferation, Differentiation & Cell State ⓘ

CD44↓, 1,   CSCs↓, 2,   EMT↓, 1,   ERK↓, 1,   ERK↑, 1,   FOXO4↓, 1,   IGF-1↓, 2,   mTOR↓, 3,   Nanog↓, 1,   NOTCH1↓, 1,   OCT4↓, 1,   P70S6K↓, 1,   PI3K↓, 2,   SOX2↓, 1,   STAT3↓, 1,   Wnt↓, 1,  

Migration ⓘ

E-cadherin↑, 1,   p‑FAK↓, 1,   Fibronectin↓, 1,   Ki-67↓, 1,   MMP1↓, 1,   MMP2↓, 2,   MMP3↓, 1,   MMP7↓, 1,   MMP9↓, 2,   Slug↓, 1,   SMAD2↓, 1,   SMAD3↓, 1,   Snail↓, 1,   TGF-β↓, 1,   TumCI↓, 3,   TumCMig↓, 3,   TumCP↓, 4,   TumMeta↓, 1,   Vim?, 1,   Zeb1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   EGFR↓, 1,   HIF-1↓, 1,   Hif1a↓, 2,   NO↓, 1,   VEGF↓, 3,   VEGFR2↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   CRP↓, 1,   IFN-γ↓, 1,   IL1β↓, 1,   IL6↓, 2,   IL8↓, 2,   NF-kB↓, 2,   NF-kB↑, 1,   PD-1↓, 1,   PGE2↓, 1,   Th1 response↑, 1,   TNF-α↓, 2,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   ChemoSen↑, 2,   eff↓, 1,   eff↑, 3,   RadioS↑, 2,   selectivity↑, 2,  

Clinical Biomarkers ⓘ

CRP↓, 1,   EGFR↓, 1,   IL6↓, 2,   Ki-67↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   AntiTum↑, 1,   chemoP↑, 1,   radioP↑, 1,  

Infection & Microbiome ⓘ

CD8+↑, 1,  
Total Targets: 137

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 9,   Catalase↑, 4,   Catalase↝, 1,   Ferroptosis↓, 1,   GPx↑, 6,   GPx↝, 1,   GSH↑, 5,   GSH/GSSG↓, 1,   GSR↑, 1,   GSS↑, 1,   GSTs↑, 1,   HDL↑, 1,   HO-1↓, 1,   HO-1↑, 6,   HO-1⇅, 1,   Keap1↓, 15,   ox-Keap1↑, 1,   lipid-P↓, 2,   MDA↓, 5,   MPO↓, 1,   NQO1↑, 1,   NRF2↑, 18,   ROS↓, 12,   ROS∅, 1,   SOD↑, 7,   SOD↝, 1,   SOD1↑, 2,   SOD2↑, 1,   TBARS↓, 1,   Trx↑, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↑, 1,   mtDam↓, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 3,   glucose↝, 1,   GLUT2↑, 1,   H2S↑, 1,   HMG-CoA↓, 1,   LDH↓, 2,   LDHA↓, 1,   PKM2↓, 1,   SIRT1↑, 1,  

Cell Death ⓘ

Akt↓, 1,   Apoptosis↓, 2,   Casp3↓, 1,   Casp9↓, 1,   Fas↓, 1,   Ferroptosis↓, 1,   HGF/c-Met↑, 1,   iNOS↓, 4,   MAPK↓, 1,  

Transcription & Epigenetics ⓘ

other↑, 2,   other↝, 1,  

Protein Folding & ER Stress ⓘ

ATF6↓, 1,   CHOP↑, 1,   ER Stress↓, 1,   GRP78/BiP↓, 1,   GRP78/BiP↑, 1,   GRP94↑, 1,  

Autophagy & Lysosomes ⓘ

p62↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 1,   PCNA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↑, 1,   PI3K↓, 1,  

Migration ⓘ

TGF-β↓, 1,   TIMP1↓, 1,   ZO-1↑, 1,  

Angiogenesis & Vasculature ⓘ

angioG↑, 1,   CLDN5↑, 1,   NO↓, 1,  

Barriers & Transport ⓘ

BBB↑, 2,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 4,   IL10↑, 1,   IL1β↓, 2,   IL6↓, 2,   Inflam↓, 7,   NF-kB↓, 3,   PGE2↓, 1,   TLR4↓, 2,   TNF-α↓, 4,  

Protein Aggregation ⓘ

AGEs↓, 1,   Aβ↓, 1,  

Hormonal & Nuclear Receptors ⓘ

GR↝, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   BioAv↝, 1,   eff↑, 1,   Half-Life↝, 1,  

Clinical Biomarkers ⓘ

ALAT↓, 3,   Albumin↑, 1,   ALP↓, 1,   AST↓, 3,   BP↓, 1,   creat↓, 1,   GutMicro↑, 1,   IL6↓, 2,   LDH↓, 2,  

Functional Outcomes ⓘ

AntiCan↑, 1,   cardioP↑, 4,   chemoP↑, 1,   cognitive↑, 1,   hepatoP↑, 5,   memory↑, 2,   neuroP↑, 6,   RenoP↑, 3,  

Infection & Microbiome ⓘ

Bacteria↓, 1,  
Total Targets: 104

Scientific Paper Hit Count for: Keap1, Kelch-like ECH-associated protein 1
3 Quercetin
3 Resveratrol
2 EGCG (Epigallocatechin Gallate)
1 Allicin (mainly Garlic)
1 Artemisinin
1 doxorubicin
1 Ashwagandha(Withaferin A)
1 Boron
1 Selenium
1 Capsaicin
1 Chlorogenic acid
1 Disulfiram
1 Copper and Cu NanoParticles
1 Fisetin
1 Shilajit/Fulvic Acid
1 Chemotherapy
1 Lycopene
1 Magnetic Fields
1 Piperlongumine
1 Parthenolide
1 Thymoquinone
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#:1174  State#:%  Dir#:1
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