Database Query Results : , , NRF2

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

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

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

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

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

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

Scientific Papers found: Click to Expand⟱
365- AgNPs,    Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species
- in-vitro, Hepat, HepG2
ROS↑,
GlucoseCon↓,
TumCD↑,
NRF2↓, Decreased mRNA levels of Nrf2

4428- AgNPs,    p38 MAPK Activation, DNA Damage, Cell Cycle Arrest and Apoptosis As Mechanisms of Toxicity of Silver Nanoparticles in Jurkat T Cells
- in-vitro, AML, Jurkat
toxicity↝, The effect of Ag ions was also investigated and compared with that of AgNPs, as it is anticipated that Ag ions will be released from AgNPs, which may be responsible for their toxicity.
tumCV↓, Cell viability tests indicated high sensitivity of Jurkat T cells when exposed to AgNPs compared to Ag ions
ROS↑, AgNPs and Ag ions induce similar levels of cellular reactive oxygen species during the initial exposure period and; after 24 h, they were increased on exposure to AgNPs compared to Ag ions, which suggest that oxidative stress may be an indirect caus
p38↑, AgNPs exposure activates p38 mitogen-activated protein kinase through nuclear factor-E2-related factor-2 and nuclear factor-kappaB signaling pathways, subsequently inducing DNA damage, cell cycle arrest and apoptosis.
NRF2↓,
NF-kB↝,
DNAdam↑,
Apoptosis↑,

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

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

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

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

2639- Api,    Plant flavone apigenin: An emerging anticancer agent
- Review, Var, NA
*antiOx↑, Apigenin (4′, 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties
*Inflam↓,
AntiCan↑,
ChemoSen↑, Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers.
BioEnh↑, Apigenin’s anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies.
chemoPv↑, apigenin highlighting its potential activity as a chemopreventive and therapeutic agent.
IL6↓, In taxol-resistant ovarian cancer cells, apigenin caused down regulation of TAM family of tyrosine kinase receptors and also caused inhibition of IL-6/STAT3 axis, thereby attenuating proliferation.
STAT3↓,
NF-kB↓, apigenin treatment effectively inhibited NF-κB activation, scavenged free radicals, and stimulated MUC-2 secretion
IL8↓, interleukin (IL)-6, and IL-8
eff↝, The anti-proliferative effects of apigenin was significantly higher in breast cancer cells over-expressing HER2/neu but was much less efficacious in restricting the growth of cell lines expressing HER2/neu at basal levels
Akt↓, Apigenin interferes in the cell survival pathway by inhibiting Akt function by directly blocking PI3K activity
PI3K↓,
HER2/EBBR2↓, apigenin administration led to the depletion of HER2/neu protein in vivo
cycD1/CCND1↓, Apigenin treatment in breast cancer cells also results in decreased expression of cyclin D1, D3, and cdk4 and increased quantities of p27 protein
CycD3↓,
p27↑,
FOXO3↑, In triple-negative breast cancer cells, apigenin induces apoptosis by inhibiting the PI3K/Akt pathway thereby increasing FOXO3a expression
STAT3↓, In addition, apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion of breast cancer cells [
MMP2↓,
MMP9↓,
VEGF↓, Apigenin acts on the HIF-1 binding site, which decreases HIF-1α, but not the HIF-1β subunit, thereby inhibiting VEGF.
Twist↓,
MMP↓, Apigenin treatment of HGC-27 and SGC-7901 gastric cancer cells resulted in the inhibition of proliferation followed by mitochondrial depolarization resulting in apoptosis
ROS↑, Further studies revealed apigenin-induced apoptosis in hepatoma tumor cells by utilizing ROS generated through the activation of the NADPH oxidase
NADPH↑,
NRF2↓, Apigenin significantly sensitized doxorubicin-resistant BEL-7402 (BEL-7402/ADM) cells to doxorubicin (ADM) and increased the intracellular concentration of ADM by reducing Nrf2-
SOD↓, In human cervical epithelial carcinoma HeLa cells combination of apigenin and paclitaxel significantly increased inhibition of cell proliferation, suppressing the activity of SOD, inducing ROS accumulation leading to apoptosis by activation of caspas
COX2↓, melanoma skin cancer model where apigenin inhibited COX-2 that promotes proliferation and tumorigenesis
p38↑, Additionally, it was shown that apigenin treatment in a late phase involves the activation of p38 and PKCδ to modulate Hsp27, thus leading to apoptosis
Telomerase↓, apigenin inhibits cell growth and diminishes telomerase activity in human-derived leukemia cells
HDAC↓, demonstrated the role of apigenin as a histone deacetylase inhibitor. As such, apigenin acts on HDAC1 and HDAC3
HDAC1↓,
HDAC3↓,
Hif1a↓, Apigenin acts on the HIF-1 binding site, which decreases HIF-1α, but not the HIF-1β subunit, thereby inhibiting VEGF.
angioG↓, Moreover, apigenin was found to inhibit angiogenesis, as suggested by decreased HIF-1α and VEGF expression in cancer cells
uPA↓, Furthermore, apigenin intake resulted in marked inhibition of p-Akt, p-ERK1/2, VEGF, uPA, MMP-2 and MMP-9, corresponding with tumor growth and metastasis inhibition in TRAMP mice
Ca+2↑, Neuroblastoma SH-SY5Y cells treated with apigenin led to induction of apoptosis, accompanied by higher levels of intracellular free [Ca(2+)] and shift in Bax:Bcl-2 ratio in favor of apoptosis, cytochrome c release, followed by activation casp-9, 12
Bax:Bcl2↑,
Cyt‑c↑,
Casp9↑,
Casp12↑,
Casp3↑, Apigenin also augmented caspase-3 activity and PARP cleavage
cl‑PARP↑,
E-cadherin↑, Apigenin treatment resulted in higher levels of E-cadherin and reduced levels of nuclear β-catenin, c-Myc, and cyclin D1 in the prostates of TRAMP mice.
β-catenin/ZEB1↓,
cMyc↓,
CDK4↓, apigenin exposure led to decreased levels of cell cycle regulatory proteins including cyclin D1, D2 and E and their regulatory partners CDK2, 4, and 6
CDK2↓,
CDK6↓,
IGF-1↓, A reduction in the IGF-1 and increase in IGFBP-3 levels in the serum and the dorsolateral prostate was observed in apigenin-treated mice.
CK2↓, benefits of apigenin as a CK2 inhibitor in the treatment of human cervical cancer by targeting cancer stem cells
CSCs↓,
FAK↓, Apigenin inhibited the tobacco-derived carcinogen-mediated cell proliferation and migration involving the β-AR and its downstream signals FAK and ERK activation
Gli↓, Apigenin inhibited the self-renewal capacity of SKOV3 sphere-forming cells (SFC) by downregulating Gli1 regulated by CK2α
GLUT1↓, Apigenin induces apoptosis and slows cell growth through metabolic and oxidative stress as a consequence of the down-regulation of glucose transporter 1 (GLUT1).

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

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

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

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

4993- ART/DHA,    Dihydroartemisinin inhibits galectin-1–induced ferroptosis resistance and peritoneal metastasis of gastric cancer via the Nrf2–HO-1 pathway
- vitro+vivo, GC, NA
Ferroptosis↑, DHA suppresses galectin-1-promoted GCPM via the PI3K/Akt/Nrf2/HO-1 pathway in vitro
NRF2↓, DHA promotes ferroptosis by downregulating Nrf2/HO-1
HO-1↓,
PI3K↓, We found that DHA significantly affected galectin-1 expression and inhibited PI3K/Akt activation
Akt↓,
TumMeta↓, DHA inhibits peritoneal metastasis through the PI3K/Akt/Nrf2/HO-1 pathway in vivo

1076- ART/DHA,    The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer
- Review, NA, NA
Ferroptosis↑,
ROS↑, interaction between heme-derived iron and ART will result in the production of ROS
ER Stress↑,
i-Iron↓, DHA can cause intracellular iron depletion in a time- and dose-dependent manner
TumAuto↑,
AMPK↑,
mTOR↑,
P70S6K↑,
Fenton↑,
lipid-P↑,
ROS↑,
ChemoSen↑, combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.
NRF2↑, Liu et al. discovered that ART covalently targets Keap1 at Cys151 to activate the Nrf2-dependent pathway [94
NRF2↓, inhibition of Nrf2-related gene expression accelerated erastin and sorafenib-induced ferroptosis [45]. More importantly, an accumulating body of research suggests that ART may induce ferroptosis in cancer cells by regulating the above molecules.

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

4678- Ash,    Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
- vitro+vivo, NSCLC, H1975
ROS↑, WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects.
AntiTum↑, In vivo research also demonstrated the anti-tumor effect of WA treatment
CSCs↓, We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity
mTOR↓, at least through downregulation of mTOR/STAT3 signaling
STAT3↓,
ChemoSen↑, combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability.
Keap1↑, Interestingly, we found WA treatment gradually increased KEAP1, while it decreased NRF2 in H1975 cells
NRF2↓,

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

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

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

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

5536- BBM,    Regulation of Cell-Signaling Pathways by Berbamine in Different Cancers
- Review, Var, NA
JAK↝, In this review, we comprehensively analyze how berbamine modulates deregulated pathways (JAK/STAT, CAMKII/c-Myc) in various cancers.
STAT3↓, Berbamine physically interacted with STAT3 and inhibited its activation [8].
p‑CaMKII ↓, An orally administered, bioactive small molecule analog of berbamine, tosyl chloride-berbamine (TCB), considerably reduced phosphorylated levels of CaMKIIγ
TGF-β↑, berbamine induces activation of the TGF/SMAD pathway for the effective inhibition of cancer progression.
Smad1↑,
ChemoSen↑, Berbamine enhanced the chemosensitivity of gefitinib against PANC-1 and MIA PaCa-2 cancer cells [8].
RadioS↑, Moreover, berbamine and radiation effectively induced a regression of the tumors in mice subcutaneously injected with FaDu cells [10].
TumCI↓, berbamine-GMO-TPGS nanoparticles showed superior cellular toxicity, as well as an inhibition of migration and invasion in metastatic breast cancer MDA-MB-231,
TumCMig↓,
ROS↑, Berbamine increased the intracellular ROS levels via the downregulation of antioxidative genes such as NRF2, SOD2, GPX-1 and HO-1.
NRF2↓,
SOD2↓,
GPx1↓,
HO-1↓,

5551- BBM,    Berbamine Suppresses the Progression of Bladder Cancer by Modulating the ROS/NF-κB Axis
- vitro+vivo, Bladder, NA
tumCV↓, our results showed that berbamine inhibited cell viability, colony formation, and proliferation.
TumCP↓,
TumCCA↑, Additionally, berbamine induced cell cycle arrest at S phase by a synergistic mechanism involving stimulation of P21 and P27 protein expression
P21↑,
p27↑,
cycD1/CCND1↓, as well as downregulation of CyclinD, CyclinA2, and CDK2 protein expression.
cycA1/CCNA1↓,
CDK2↓,
EMT↓, In addition to suppressing epithelial-mesenchymal transition (EMT), berbamine rearranged the cytoskeleton to inhibit cell metastasis.
TumMeta↓,
p65↓, Mechanistically, the expression of P65, P-P65, and P-IκBα was decreased upon berbamine treatment
p‑p65↓,
IKKα↓,
NF-kB↑, berbamine attenuated the malignant biological activities of BCa cells by inhibiting the NF-κB pathway.
ROS↑, More importantly, berbamine increased the intracellular reactive oxygen species (ROS) level through the downregulation of antioxidative genes such as Nrf2, HO-1, SOD2, and GPX-1.
NRF2↓,
HO-1↓,
SOD2↓,
GPx1↓,
Bax:Bcl2↑, increase in the ratio of Bax/Bcl-2.
TumVol↓, berbamine successfully inhibited tumor growth and blocked the NF-κB pathway in our xenograft model

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

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

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

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

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

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

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

2781- CHr,  PBG,    Chrysin a promising anticancer agent: recent perspectives
- Review, Var, NA
PI3K↓, It can block Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling in different animals against various cancers
Akt↓,
mTOR↓,
MMP9↑, Chrysin strongly suppresses Matrix metalloproteinase-9 (MMP-9), Urokinase plasminogen activator (uPA) and Vascular endothelial growth factor (VEGF), i.e. factors that can cause cancer
uPA↓,
VEGF↓,
AR↓, Chrysin has the ability to suppress the androgen receptor (AR), a protein necessary for prostate cancer development and metastasis
Casp↑, starts the caspase cascade and blocks protein synthesis to kill lung cancer cells
TumMeta↓, Chrysin significantly decreased lung cancer metastasis i
TumCCA↑, Chrysin induces apoptosis and stops colon cancer cells in the G2/M cell cycle phase
angioG↓, Chrysin prevents tumor growth and cancer spread by blocking blood vessel expansion
BioAv↓, Chrysin’s solubility, accessibility and bioavailability may limit its medical use.
*hepatoP↑, As chrysin reduced oxidative stress and lipid peroxidation in rat liver cells exposed to a toxic chemical agent.
*neuroP↑, Protecting the brain against oxidative stress (GPx) may be aided by increasing levels of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx).
*SOD↑,
*GPx↑,
*ROS↓, A decrease in oxidative stress and an increase in antioxidant capacity may result from chrysin’s anti-inflammatory properties
*Inflam↓,
*Catalase↑, Supplementation with chrysin increased the activity of antioxidant enzymes like SOD and catalase and reduced the levels of oxidative stress markers like malondialdehyde (MDA) in the colon tissue of the rats.
*MDA↓, Antioxidant enzyme activity (SOD, CAT) and oxidative stress marker (MDA) levels were both enhanced by chrysin supplementation in mouse liver tissue
ROS↓, reduction of reactive oxygen species (ROS) and oxidative stress markers in the cancer cells further indicated the antioxidant activity of chrysin
BBB↑, After crossing the blood-brain barrier, it has been shown to accumulate there
Half-Life↓, The half-life of chrysin in rats is predicted to be close to 2 hours.
BioAv↑, Taking chrysin with food may increase the effectiveness of the supplement: increased by a factor of 1.8 when taken with a high-fat meal
ROS↑, In contrast to 5-FU/oxaliplatin, chrysin increases the production of reactive oxygen species (ROS), which in turn causes autophagy by stopping Akt and mTOR from doing their jobs
eff↑, mixture of chrysin and cisplatin caused the SCC-25 and CAL-27 cell lines to make more oxygen free radicals. After treatment with chrysin, cisplatin, or both, the amount of reactive oxygen species (ROS) was found to have gone up.
ROS↑, When reactive oxygen species (ROS) and calcium levels in the cytoplasm rise because of chrysin, OC cells die.
ROS↑, chrysin is the cause of death in both types of prostate cancer cells. It does this by depolarizing mitochondrial membrane potential (MMP), making reactive oxygen species (ROS), and starting lipid peroxidation.
lipid-P↑,
ER Stress↑, when chrysin is present in DU145 and PC-3 cells, the expression of a group of proteins that control ER stress goes up
NOTCH1↑, Chrysin increased the production of Notch 1 and hairy/enhancer of split 1 at the protein and mRNA levels, which stopped cells from dividing
NRF2↓, Not only did chrysin stop Nrf2 and the genes it controls from working, but it also caused MCF-7 breast cancer cells to die via apoptosis.
p‑FAK↓, After 48 hours of treatment with chrysin at amounts between 5 and 15 millimoles, p-FAK and RhoA were greatly lowered
Rho↓,
PCNA↓, Lung histology and immunoblotting studies of PCNA, COX-2, and NF-B showed that adding chrysin stopped the production of these proteins and maintained the balance of cells
COX2↓,
NF-kB↓,
PDK1↓, After the chrysin was injected, the genes PDK1, PDK3, and GLUT1 that are involved in glycolysis had less expression
PDK3↑,
GLUT1↓,
Glycolysis↓, chrysin stops glycolysis
mt-ATP↓, chrysin inhibits complex II and ATPases in the mitochondria of cancer cells
Ki-67↓, the amounts of Ki-67, which is a sign of growth, and c-Myc in the tumor tissues went down
cMyc↓,
ROCK1↓, (ROCK1), transgelin 2 (TAGLN2), and FCH and Mu domain containing endocytic adaptor 2 (FCHO2) were much lower.
TOP1↓, DNA topoisomerases and histone deacetylase were inhibited, along with the synthesis of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and (IL-1 beta), while the activity of protective signaling pathways was increased
TNF-α↓,
IL1β↓,
CycB/CCNB1↓, Chrysin suppressed cyclin B1 and CDK2 production in order to stop cancerous growth.
CDK2↓,
EMT↓, chrysin treatment can also stop EMT
STAT3↓, chrysin block the STAT3 and NF-B pathways, but it also greatly reduced PD-L1 production both in vivo and in vitro.
PD-L1↓,
IL2↑, chrysin increases both the rate of T cell growth and the amount of IL-2

2782- CHr,    Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives
- Review, Var, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, antioxidant, anti-inflammatory, hepatoprotective, neuroprotective
*Inflam↓, inhibitory effect of chrysin on inflammation and oxidative stress is also important in Parkinson’s disease
*hepatoP↑,
*neuroP↑,
*BioAv↓, Accumulating data demonstrates that poor absorption, rapid metabolism, and systemic elimination are responsible for poor bioavailability of chrysin in humans that, subsequently, restrict its therapeutic effects
*cardioP↑, cardioprotective [69], lipid-lowering effect [70]
*lipidLev↓,
*RenoP↑, Renoprotective
*TNF-α↓, chrysin reduces levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2).
*IL2↓,
*PI3K↓, induction of the PI3K/Akt signaling pathway by chrysin contributes to a reduction in oxidative stress and inflammation during cerebral I/R injury
*Akt↓,
*ROS↓,
*cognitive↑, Chrysin (25, 50, and 100 mg/kg) improves cognitive capacity, inflammation, and apoptosis to ameliorate traumatic brain injury
eff↑, chrysin and silibinin is beneficial in suppressing breast cancer malignancy via decreasing cancer proliferation
cycD1/CCND1↓, chrysin and silibinin induced cell cycle arrest via down-regulation of cyclin D1 and hTERT
hTERT/TERT↓,
VEGF↓, Administration of chrysin is associated with the disruption of hypoxia-induced VEGF gene expression
p‑STAT3↓, chrysin is capable of reducing STAT3 phosphorylation in hypoxic conditions without affecting the HIF-1α protein level.
TumMeta↓, chrysin is a potent agent in suppressing metastasis and proliferation of breast cancer cells during hypoxic conditions
TumCP↓,
eff↑, combination therapy of breast cancer cells using chrysin and metformin exerts a synergistic effect and is more efficient compared to chrysin alone
eff↑, combination of quercetin and chrysin reduced levels of pro-inflammatory factors, such as IL-1β, Il-6, TNF-α, and IL-10, via NF-κB down-regulation.
IL1β↓,
IL6↓,
NF-kB↓,
ROS↑, after chrysin administration, an increase occurs in levels of ROS that, subsequently, impairs the integrity of the mitochondrial membrane, leading to cytochrome C release and apoptosis induction
MMP↓,
Cyt‑c↑,
Apoptosis↑,
ER Stress↑, in addition to mitochondria, ER can also participate in apoptosis
Ca+2↑, Upon chrysin administration, an increase occurs in levels of ROS and cytoplasmic Ca2+ that mediate apoptosis induction in OC cells
TET1↑, In MKN45 cells, chrysin promotes the expression of TET1
Let-7↑, Chrysin is capable of promoting the expression of miR-9 and Let-7a as onco-suppressor factors in cancer to inhibit the proliferation of GC cells
Twist↓, Down-regulation of NF-κB, and subsequent decrease in Twist/EMT are mediated by chrysin administration, negatively affecting cervical cancer metastasis
EMT↓,
TumCCA↑, nduction of cell cycle arrest and apoptosis via up-regulation of caspase-3, caspase-9, and Bax are mediated by chrysin
Casp3↑,
Casp9↑,
BAX↑,
HK2↓, Chrysin administration (15, 30, and 60 mM) reduces the expression of HK-2 in hepatocellular carcinoma (HCC) cells to impair glucose uptake and lactate production.
GlucoseCon↓,
lactateProd↓,
Glycolysis↓, In addition to glycolysis metabolism impairment, the inhibitory effect of chrysin on HK-2 leads to apoptosis
SHP1↑, upstream modulator of STAT3 known as SHP-1 is up-regulated by chrysin
N-cadherin↓, Furthermore, N-cadherin and E-cadherin are respectively down-regulated and up-regulated upon chrysin administration in inhibiting melanoma invasion
E-cadherin↑,
UPR↑, chrysin substantially diminishes survival by ER stress induction via stimulating UPR, PERK, ATF4, and elF2α
PERK↑,
ATF4↑,
eIF2α↑,
RadioS↑, Irradiation combined with chrysin exerts a synergistic effect
NOTCH1↑, Irradiation combined with chrysin exerts a synergistic effect
NRF2↓, in reducing Nrf2 expression, chrysin down-regulates the expression of ERK and PI3K/Akt pathways—leading to an increase in the efficiency of doxorubicin in chemotherapy
BioAv↑, chrysin at the tumor site by polymeric nanoparticles leads to enhanced anti-tumor activity, due to enhanced cellular uptake
eff↑, Chrysin- and curcumin-loaded nanoparticles significantly promote the expression of TIMP-1 and TIMP-2 to exert a reduction in melanoma invasion

2785- CHr,    Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin
- Review, Var, NA
*NF-kB↓, suppressed pro-inflammatory cytokine expression and histamine release, downregulated nuclear factor kappa B (NF-kB), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS)
*COX2↓,
*iNOS↓,
angioG↓, upregulated apoptotic pathways [28], inhibited angiogenesis [29] and metastasis formation
TOP1↓, suppressed DNA topoisomerases [31] and histone deacetylase [32], downregulated tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)
HDAC↓,
TNF-α↓,
IL1β↓,
cardioP↑, promoted protective signaling pathways in the heart [34], kidney [35] and brain [8], decreased cholesterol level
RenoP↑,
neuroP↑,
LDL↓,
BioAv↑, bioavailability of chrysin in the oral route of administration was appraised to be 0.003–0.02% [55], the maximum plasma concentration—12–64 nM
eff↑, Chrysin alone and potentially in combination with metformin decreased cyclin D1 and hTERT gene expression in the T47D breast cancer cell line
cycD1/CCND1↓,
hTERT/TERT↓,
MMP-10↓, Chrysin pretreatment inhibited MMP-10 and Akt signaling pathways
Akt↓,
STAT3↓, Chrysin declined hypoxic survival, inhibited activation of STAT3, and reduced VEGF expression in hypoxic cancer cells
VEGF↓,
EGFR↓, chrysin to inhibit EGFR was reported in a breast cancer stem cell model [
Snail↓, chrysin downregulated MMP-10, reduced snail, slug, and vimentin expressions increased E-cadherin expression, and inhibited Akt signaling pathway in TNBC cells, proposing that chrysin possessed a reversal activity on EMT
Slug↓,
Vim↓,
E-cadherin↑,
eff↑, Fabrication of chrysin-attached to silver and gold nanoparticles crossbred reduced graphene oxide nanocomposites led to augmentation of the generation of ROS-induced apoptosis in breast cancer
TET1↑, Chrysin induced augmentation in TET1
ROS↑, Pretreatment with chrysin induced ROS formation, and consecutively, inhibited Akt phosphorylation and mTOR.
mTOR↓,
PPARα↓, Chrysin inhibited mRNA expression of PPARα
ER Stress↑, ROS production by chrysin was the critical mediator behind induction of ER stress, leading to JNK phosphorylation, intracellular Ca2+ release, and activation of the mitochondrial apoptosis pathway
Ca+2↑,
ERK↓, reduced protein expression of p-ERK/ERK
MMP↑, Chrysin pretreatment led to an increase in mitochondrial ROS creation, swelling in isolated mitochondria from hepatocytes, collapse in MMP, and release cytochrome c.
Cyt‑c↑,
Casp3↑, Chrysin could elevate caspase-3 activity in the HCC rats group
HK2↓, chrysin declined HK-2 combined with VDAC-1 on mitochondria
NRF2↓, chrysin inhibited the Nrf2 expression and its downstream genes comprising AKR1B10, HO-1, and MRP5 by quenching ERK and PI3K-Akt pathway
HO-1↓,
MMP2↓, Chrysin pretreatment also downregulated MMP2, MMP9, fibronectin, and snail expression
MMP9↓,
Fibronectin↓,
GRP78/BiP↑, chrysin induced GRP78 overexpression, spliced XBP-1, and eIF2-α phosphorylation
XBP-1↓,
p‑eIF2α↑,
*AST↓, Chrysin administration significantly reduced AST, ALT, ALP, LDH and γGT serum activities
ALAT↓,
ALP↓,
LDH↓,
COX2↑, chrysin attenuated COX-2 and NFkB p65 expression, and Bcl-xL and β-arrestin levels
Bcl-xL↓,
IL6↓, Reduction in IL-6 and TNF-α and augmentation in caspases-9 and 3 were observed due to chrysin supplementation.
PGE2↓, Chrysin induced entire suppression NF-kB, COX-2, PG-E2, iNOS as well.
iNOS↓,
DNAdam↑, Chrysin induced apoptosis of cells by causing DNA fragmentation and increasing the proportions of DU145 and PC-3 cells
UPR↑, Also, it induced ER stress via activation of UPR proteins comprising PERK, eIF2α, and GRP78 in DU145 and PC-3 cells.
Hif1a↓, Chrysin increased the ubiquitination and degradation of HIF-1α by increasing its prolyl hydroxylation
EMT↓, chrysin was effective in HeLa cell by inhibiting EMT and CSLC properties, NF-κBp65, and Twist1 expression
Twist↓,
lipid-P↑, Chrysin disrupted intracellular homeostasis by altering MMP, cytosolic Ca (2+) levels, ROS generation, and lipid peroxidation, which plays a role in the death of choriocarcinoma cells.
CLDN1↓, Chrysin decreased CLDN1 and CLDN11 expression in human lung SCC
PDK1↓, Chrysin alleviated p-Akt and inhibited PDK1 and Akt
IL10↓, Chrysin inhibited cytokines release, TNF-α, IL-1β, IL-10, and IL-6 induced by Ni in A549 cells.
TLR4↓, Chrysin suppressed TLR4 and Myd88 mRNA and protein expression.
NOTCH1↑, Chrysin inhibited tumor growth in ATC both in vitro and in vivo through inducing Notch1
PARP↑, Pretreating cells with chrysin increased cleaved PARP, cleaved caspase-3, and declined cyclin D1, Mcl-1, and XIAP.
Mcl-1↓,
XIAP↓,

2786- CHr,    Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives
- Review, Var, NA
Apoptosis↑, chrysin inhibits cancer growth through induction of apoptosis, alteration of cell cycle and inhibition of angiogenesis, invasion and metastasis without causing any toxicity and undesirable side effects to normal cells
TumCCA↑,
angioG↓,
TumCI↓,
TumMeta↑,
*toxicity↓,
selectivity↑,
chemoPv↑, Induction of phase II detoxification enzymes, such as glutathione S-transferase (GST) or NAD(P)H:quinone oxidoreductase (QR) is one of the major mechanism of protection against initiation of carcinogenesis
*GSTs↑,
*NADPH↑,
*GSH↑, upregulation of antioxidant and carcinogen detoxification enzymes (glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), GST and QR)
HDAC8↓, inhibits of HDAC8 enzymatic activity
Hif1a↓, Prostate DU145: Inhibits HIF-1a expression through Akt signaling and abrogation of VEGF expression
*ROS↓, chrysin (20 and 40 mg/kg) was shown to exhibit chemopreventive activity by ameliorating oxidative stress and inflammation via NF-kB pathway
*NF-kB↓,
SCF↓, Chrysin has also been reported to have the ability to abolish the stem cell factor (SCF)/c-Kit signaling in human myeloid leukemia cells by preventing the PI3 K pathway
cl‑PARP↑, (PARP) and caspase-3 and concurrently decreasing pro-survival proteins survivin and XIAP
survivin↓,
XIAP↓,
Casp3↑, activation of caspase-3 and -9.
Casp9↑,
GSH↓, chrysin sustains a significant depletion of intracellular GSH concentrations in human NSCLC cells
ChemoSen↑, chrysin potentiates cisplatin toxicity, in part, via synergizing pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and by depleting cellular GSH, an important antioxidant defense
Fenton↑, ability to participate in a fenton type chemical reaction
P21↑, upregulation of p21 independent of p53 status and decrease in cyclin D1, CDK2 protein levels
P53↑,
cycD1/CCND1↓,
CDK2↓,
STAT3↓, chrysin inhibits angiogenesis through inhibition of STAT3 and VEGF release mediated by hypoxia through Akt signaling pathway
VEGF↓,
Akt↓,
NRF2↓, Chrysin treatment significantly reduced nrf2 expression in cells at both the mRNA and protein levels through down-regulation of PI3K-Akt and ERK pathways.

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

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

5007- DSF,  Cu,    Nrf2/HO-1 Alleviates Disulfiram/Copper-Induced Ferroptosis in Oral Squamous Cell Carcinoma
- vitro+vivo, Oral, NA
AntiTum↑, Accumulating evidence indicates that the disulfiram/copper complex (DSF/Cu) has been shown to have potent antitumor activity against various cancers.
TumCP↓, DSF/Cu reduced the proliferation and clonogenicity of OSCC cells.
Ferroptosis↑, DSF/Cu also induced ferroptosis
Iron↑, Importantly, we confirmed that DSF/Cu could increase the free iron pool, enhance lipid peroxidation, and eventually result in ferroptosis cell death.
lipid-P↑,
NRF2↓, DSF/Cu inhibited the xenograft growth of OSCC cells by suppressing the expression of Nrf2/HO-1.
HO-1↓,

5009- DSF,  Cu,    Activation of Oxidative Stress and Down-Regulation of Nuclear Factor Erythroid 2-Related Factor May Be Responsible for Disulfiram/Copper Complex Induced Apoptosis in Lymphoid Malignancy Cell Lines
- vitro+vivo, lymphoma, NA
AntiTum↑, Disulfiram (DS), an antialcoholism drug, demonstrates strong antitumor activity in a copper (Cu)-dependent manner.
ROS↑, DS/Cu induces reactive oxidative stress (ROS) which activates stress related signaling pathway (c-Jun-amino-terminal kinase, JNK).
JNK↑,
NRF2↓, Nrf2 expression was increased when Raji cells were treated for less than 12h and decreased after 18h or 24h treatment
eff↓, N-acetyl-L-cysteine (NAC), an antioxidant, can partially attenuate DS/Cu complex-induced apoptosis
TumCD↑, Therefore the DS/Cu induced ROS may be higher than that antioxidant factors could protect and thus the Nrf2-mediated cellular survival mechanism was disabled through down regulation of Nrf2 to allow initiation of death process.

5006- DSF,  Cu,    Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition
- vitro+vivo, lymphoma, NA
TumCD↑, n combination with a low concentration (1 μM) of Cu2+, DS induced cytotoxicity in Raji cells with an IC50 of 0.085 ± 0.015 μM and in Molt4 cells with an IC50 of 0.435 ± 0.109 μM.
TumCP↑, DS/Cu inhibits the proliferation of Raji cells in vivo.
Apoptosis↑, After exposure to DS (3.3 μM)/Cu (1 μM) for 24 hours, apoptosis was detected in 81.03 ± 7.91% of Raji cells
NRF2↓, After 24 h exposure, DS/Cu inhibits Nrf2 expression.
ROS↑, DS/Cu induced ROS generation.
p‑JNK↑, DS/Cu induced phosphorylation of JNK and inhibits p65 expression as well as Nrf2 expression both in vitro and in vivo.
p65↓,
eff↓, N-acetyl-L-cysteine (NAC), an antioxidant, can partially attenuate DS/Cu complex-induced apoptosis and block JNK activation in vitro.
NF-kB↓, Moreover, ROS-related activation of JNK pathway and inhibition of NF-κB and Nrf2 may also contribute to the DS/Cu induced apoptosis.

1607- EA,    Exploring the Potential of Ellagic Acid in Gastrointestinal Cancer Prevention: Recent Advances and Future Directions
- Review, GC, NA
STAT3↓, EA inhibits STAT3 signaling
TumCP↓, EA inhibits cell proliferation, induces apoptosis
Apoptosis↑,
NF-kB↓, inhibiting nuclear factor-kappa B
EMT↓, suppressing epithelial–mesenchymal transition
RadioS↑, In liver cancer, EA exhibits radio-sensitizing effects
antiOx↑, As a potential antioxidant agent,
COX1↓, EA suppresses the expression of several factors, including COX1, COX2, c-myc, snail, and twist1
COX2↓,
cMyc↓,
Snail↓,
Twist↓,
MMP2↓, significantly decreased MMP-2 and MMP-9 expression and activity.
P90RSK↓,
CDK8↓, downregulate CDK8 expression and activity
PI3K↓, inactivating PI3K/Akt signaling
Akt↓,
TumCCA↑, promote cell cycle arrest
Casp8↑, ctivating caspase-8, and lowering proliferating cell nuclear antigen (PCNA) expression,
PCNA↓,
TGF-β↓,
Shh↓, suppression of the Akt, Shh, and Notch pathways, EA can prevent the growth, angiogenesis, and metastasis of pancreatic cancer
NOTCH↓,
IL6↓,
ALAT↓, decreasing liver injury biomarkers such as alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST)
ALP↓,
AST↓,
VEGF↓,
P21↑,
*toxicity∅, no toxicity was found for a 50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day
*Inflam↓, ncluding anti-inflammatory [10], anti-oxidant [11], anti-allergic [12], and anti-mutagenic [13] properties, as well as potential health advantages like gastroprotective [14], cardioprotective [15], neuroprotective [16, 17], and hepatoprotective [18,
*cardioP↑,
*neuroP↑,
*hepatoP↑,
ROS↑, Exposure to EAs induced apoptosis, accelerated cell cycle arrest, and elevated the generation of reactive oxygen intermediates [59].
*NRF2↓, As a potential antioxidant agent, it scavenges reactive oxygen species (ROS), and by upregulating of Nrf2,
*GSH↑, Moreover, EA increases reduced glutathione (GSH), which is critical for cellular defense against oxidative stress and liver damage,

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

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

2845- FIS,    Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
- Review, Var, NA
PI3K↓, block multiple signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38
Akt↓,
mTOR↓,
p38↓,
*antiOx↑, antioxidant, anti-inflammatory, antiangiogenic, hypolipidemic, neuroprotective, and antitumor effect
*neuroP↑,
Casp3↑, U266 cancer cell line through activation of caspase-3, downregulation of Bcl-2 and Mcl-1L, upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, activation of 5'adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and decreased phosphorylation of AKT and mTOR were also observed
ACC↑,
DNAdam↑, DNA fragmentation, mitochondrial membrane depolarizatio
MMP↓,
eff↑, fisetin in combination with a citrus flavanone, hesperetin mediated apoptosis by mitochondrial membrane depolarization and caspase-3 act
ROS↑, NCI-H460 human non-small cell lung cancer line, fisetin generated reactive oxygen species (ROS), endoplasmic reticulum (ER) stress
cl‑PARP↑, fisetin treatment resulted in PARP cleavage
Cyt‑c↑, release of cyt. c
Diablo↑, release of cyt. c and Smac/DIABLO from mitochondria,
P53↑, increased p53 protein levels
p65↓, reduced phospho-p65 and Myc oncogene expression
Myc↓,
HSP70/HSPA5↓, fisetin causes inhibition of proliferation by the modulation of heat shock protein 70 (HSP70), HSP27
HSP27↓,
COX2↓, anti-proliferative effects of fisetin through the activation of apoptosis via inhibition of cyclooxygenase-2 (COX-2) and Wnt/EGFR/NF-κB signaling pathways
Wnt↓,
EGFR↓,
NF-kB↓,
TumCCA↑, The anti-proliferative effects of fisetin and hesperetin were shown to be occurred through S, G2/M, and G0/G1 phase arrest in K562 cell progression
CDK2↓, decrease in levels of cyclin D1, cyclin A, Cdk-4 and Cdk-2
CDK4↓,
cycD1/CCND1↓,
cycA1/CCNA1↓,
P21↑, increase in p21 CIP1/WAF1 levels in HT-29 human colon cancer cell
MMP2↓, fisetin has exhibited tumor inhibitory effects by blocking matrix metalloproteinase-2 (MMP- 2) and MMP-9 at mRNA and protein levels,
MMP9↓,
TumMeta↓, Antimetastasis
MMP1↓, fisetin also inhibited the MMP-14, MMP-1, MMP-3, MMP-7, and MMP-9
MMP3↓,
MMP7↓,
MET↓, promotion of mesenchymal to epithelial transition associated with a decrease in mesenchymal markers i.e. N-cadherin, vimentin, snail and fibronectin and an increase in epithelial markers i.e. E-cadherin
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↑,
uPA↓, fisetin suppressed the expression and activity of urokinase plasminogen activator (uPA)
ChemoSen↑, combination treatment of fisetin and sorafenib reduced the migration and invasion of BRAF-mutated melanoma cells both in in-vitro
EMT↓, inhibited epithelial to mesenchymal transition (EMT) as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin
Twist↓, inhibited expression of Snail1, Twist1, Slug, ZEB1 and MMP-2 and MMP-9
Zeb1↓,
cFos↓, significant decrease in NF-κB, c-Fos, and c-Jun levels
cJun↓,
EGF↓, Fisetin inhibited epidermal growth factor (EGF)
angioG↓, Antiangiogenesis
VEGF↓, decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF, EGFR, COX-2
eNOS↓,
*NRF2↑, significantly increased nuclear translocation of Nrf2 and antioxidant response element (ARE) luciferase activity, leading to upregulation of HO-1 expression
HO-1↑,
NRF2↓, Fisetin also triggered the suppression of Nrf2
GSTs↓, declined placental type glutathione S-transferase (GST-p) level in the liver of the fisetin- treated rats with hepatocellular carcinoma (HCC)
ATF4↓, Fisetin also rapidly increased the levels of both Nrf2 and ATF4

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

4641- HT,    Hydroxytyrosol induced ferroptosis through Nrf2 signaling pathway in colorectal cancer cells
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW48
Ferroptosis↑, HT-induced ferroptosis elevates iron levels, lipid peroxidation (LPO) and reactive oxygen species (ROS), while decreasing glutathione (GSH) and mitochondrial membrane potential.
Iron↑,
lipid-P↑, increase in soluble iron pools, which in turn promoted lipid peroxidation
ROS↑,
GSH↓,
MMP↓,
GPx4↓, HT reduced the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) proteins while increasing the expression of Tfr1 protein.
TLR1↑,
eff↓, Additionally, the levels of protein expression of Nrf2 and NQO1 were reversed by two activators of Nrf2, bardoxolone (CDDO) and sulforaphane (SFN)
NRF2↓, HT induces ferroptosis by inhibiting the Nrf2 signaling pathway
ROS↑, Studies have shown that HT not only induces ROS production in tumour cells but also that its antitumor effect may be influenced by its own oxidative properties

5099- JG,    Juglone induces ferroptosis in glioblastoma cells by inhibiting the Nrf2-GPX4 axis through the phosphorylation of p38MAPK
- vitro+vivo, GBM, LN229 - vitro+vivo, GBM, T98G
Ferroptosis↑, Juglone mainly causes cell death by inducing ferroptosis
p‑MAPK↑, juglone can significantly activate the phosphorylation of p38MAPK
NRF2↓, juglone induces the ferroptosis of GBM by activating the phosphorylation of p38MAPK and negatively regulating the Nrf2-GPX4 signaling pathway.
GPx4↓,
TumPF↓, Juglone significantly inhibits the proliferation of GBM cells and induces cell apoptosis
Apoptosis↑,
ROS↑, Juglone can dose-dependently enhance the accumulation of ROS in GBM cells
GSH↓, juglone can reduce the content of GSH
lipid-P↑, lipid peroxidation
Ki-67↓, The results show that juglone significantly inhibits the expression of Ki67, GPX4, and Nrf2
TumCG↓, juglone inhibits tumor growth in vivo by inducing ferroptosis.

4883- LT,  CHr,  BRU,  VitC,    An update of Nrf2 activators and inhibitors in cancer prevention/promotion
- Review, Var, NA
*NRF2↓, figure 3

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

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

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

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

2914- LT,    Therapeutic Potential of Luteolin on Cancer
- Review, Var, NA
*antiOx↑, As an antioxidant, Luteolin and its glycosides can scavenge free radicals caused by oxidative damage and chelate metal ions
*IronCh↑,
*toxicity↓, The safety profile of Luteolin has been proven by its non-toxic side effects, as the oral median lethal dose (LD50) was found to be higher than 2500 and 5000 mg/kg in mice and rats, respectively, equal to approximately 219.8−793.7 mg/kg in humans
*BioAv↓, One major problem related to the use of flavonoids for therapeutic purposes is their low bioavailability.
*BioAv↑, Resveratrol, which functions as the inhibitor of UGT1A1 and UGT1A9, significantly improved the bioavailability of Luteolin by decreasing the major glucuronidation metabolite in rats
DNAdam↑, Luteolin’s anticancer properties, which involve DNA damage, regulation of redox, and protein kinases in inhibiting cancer cell proliferation
TumCP↓,
DR5↑, Luteolin was discovered to promote apoptosis of different cancer cells by increasing Death receptors, p53, JNK, Bax, Cleaved Caspase-3/-8-/-9, and PARP expressions
P53↑,
JNK↑,
BAX↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↑,
survivin↓, downregulating proteins involved in cell cycle progression, including Survivin, Cyclin D1, Cyclin B, and CDC2, and upregulating p21
cycD1/CCND1↓,
CycB/CCNB1↓,
CDC2↓,
P21↑,
angioG↓, suppress angiogenesis in cancer cells by inhibiting the expression of some angiogenic factors, such as MMP-2, AEG-1, VEGF, and VEGFR2
MMP2↓,
AEG1↓,
VEGF↓,
VEGFR2↓,
MMP9↓, inhibit metastasis by inhibiting several proteins that function in metastasis, such as MMP-2/-9, CXCR4, PI3K/Akt, ERK1/2
CXCR4↓,
PI3K↓,
Akt↓,
ERK↓,
TumAuto↑, can promote the conversion of LC3B I to LC3B II and upregulate Beclin1 expression, thereby causing autophagy
LC3B-II↑,
EMT↓, Luteolin was identified to suppress the epithelial to mesenchymal transition by upregulating E-cadherin and downregulating N-cadherin and Wnt3 expressions.
E-cadherin↑,
N-cadherin↓,
Wnt↓,
ROS↑, DNA damage that is induced by reactive oxygen species (ROS),
NICD↓, Luteolin can block the Notch intracellular domain (NICD) that is created by the activation of the Not
p‑GSK‐3β↓, Luteolin can inhibit the phosphorylation of the GSK3β induced by Wnt, resulting in the prevention of GSK3β inhibition
iNOS↓, Luteolin in colon cancer and the complications associated with it, particularly the decreasing effect on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)
COX2↓,
NRF2↑, Luteolin has been identified to increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which is a crucial transcription factor with anticarcinogenic properties related
Ca+2↑, caused loss of the mitochondrial membrane action potential, enhanced levels of mitochondrial calcium (Ca2+),
ChemoSen↑, Luteolin enhanced the effect of one of the most effective chemotherapy drugs, cisplatin, on CRC cells
ChemoSen↓, high dose of Luteolin application negatively affected the oxaliplatin-based chemotherapy in a p53-dependent manner [52]. They suggested that the flavonoids with Nrf2-activating ability might interfere with the chemotherapeutic efficacy of anticancer
IFN-γ↓, decreased the expression of interferon-gamma-(IFN-γ)
RadioS↑, suggested that Luteolin can act as a radiosensitizer, promoting apoptosis by inducing p38/ROS/caspase cascade
MDM2↓, Luteolin treatment was associated with increased p53 and p21 and decreased MDM4 expressions both in vitro and in vivo.
NOTCH1↓, Luteolin suppressed the growth of lung cancer cells, metastasis, and Notch-1 signaling pathway
AR↓, downregulating the androgen receptor (AR) expression
TIMP1↑, Luteolin inhibits the migration of U251MG and U87MG human glioblastoma cell lines by downregulating MMP-2 and MMP-9 and upregulating the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2.
TIMP2↑,
ER Stress↑, Luteolin caused oxidative stress and ER stress in the Hep3B cells,
CDK2↓, Luteolin’s ability to decrease Akt, polo-like kinase 1 (PLK1), cyclin B1, cyclin A, CDC2, cyclin-dependent kinase 2 (CDK2) and Bcl-xL
Telomerase↓, Luteolin dose-dependently inhibited the telomerase levels and caused the phosphorylation of NF-κB and the target gene of NF-κB, c-Myc to suppress the human telomerase reverse transcriptase (hTERT)
p‑NF-kB↑,
p‑cMyc↑,
hTERT/TERT↓,
RAS↓, Luteolin was found to suppress the expressions of K-Ras, H-Ras, and N-Ras, which are the activators of PI3K
YAP/TEAD↓, Luteolin caused significant inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)
TAZ↓,
NF-kB↓, Luteolin was found to have a strong inhibitory effect on the NF-κB
NRF2↓, Luteolin-loaded nanoparticles resulted in a significant reduction in the Nrf2 levels compared to Luteolin alone.
HO-1↓, The expressions of the downstream genes of Nrf2, Ho1, and MDR1 were also reduced, where inhibition of Nrf2 expression significantly increased the cell death of breast cancer cells
MDR1↓,

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

2916- LT,    Antioxidative and Anticancer Potential of Luteolin: A Comprehensive Approach Against Wide Range of Human Malignancies
- Review, Var, NA - Review, AD, NA - Review, Park, NA
proCasp9↓, , by inactivating proteins; such as procaspase‐9, CDC2 and cyclin B or upregulation of caspase‐9 and caspase‐3, cytochrome C, cyclin A, CDK2, and APAF‐1, in turn inducing cell cycle
CDC2↓,
CycB/CCNB1↓,
Casp9↑,
Casp3↑,
Cyt‑c↑,
cycA1/CCNA1↑,
CDK2↓, inhibit CDK2 activity
APAF1↑,
TumCCA↑,
P53↑, enhances phosphorylation of p53 and expression level of p53‐targeted downstream gene.
BAX↑, Increasing BAX protein expression; decreasing VEGF and Bcl‐2 expression it can initiate cell cycle arrest and apoptosis.
VEGF↓,
Bcl-2↓,
Apoptosis↑,
p‑Akt↓, reduce expression levels of p‐Akt, p‐EGFR, p‐Erk1/2, and p‐STAT3.
p‑EGFR↓,
p‑ERK↓,
p‑STAT3↓,
cardioP↑, Luteolin plays positive role against cardiovascular disorders by improving cardiac function
Catalase↓, It can reduce activity levels of catalase, superoxide dismutase, and GS4
SOD↓,
*BioAv↓, bioavailability of luteolin is very low. Due to the momentous first pass effect, only 4.10% was found to be available from dosage of 50 mg/kg intake of luteolin
*antiOx↑, luteolin classically exhibits antioxidant features
*ROS↓, The antioxidant potential of luteolin and its glycosides is mainly due to scavenging activity against reactive oxygen species (ROS) and nitrogen species
*NO↓,
*GSTs↑, Luteolin may also have a role in protection and enhancement of endogenous antioxidants such as glutathione‐S‐transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT)
*GSR↑,
*SOD↑,
*Catalase↑,
*lipid-P↓, Luteolin supplementation significantly suppressed the lipid peroxidation
PI3K↓, inhibits PI3K/Akt signaling pathway to induce apoptosis
Akt↓,
CDK2↓, inhibit CDK2 activity
BNIP3↑, upregulation of BNIP3 gene
hTERT/TERT↓, Suppress hTERT in MDA‐MB‐231 breast cancer cel
DR5↑, Boost DR5 expression
Beclin-1↑, Activate beclin 1
TNF-α↓, Block TNF‐α, NF‐κB, IL‐1, IL‐6,
NF-kB↓,
IL1↓,
IL6↓,
EMT↓, Suppress EMT essentially notable in cancer metastasis
FAK↓, Block EGFR‐signaling pathway and FAK activity
E-cadherin↑, increasing E‐cadherin expression by inhibiting mdm2
MDM2↓,
NOTCH↓, Inhibit NOTCH signaling
MAPK↑, Activate MAPK to inhibit tumor growt
Vim↓, downregulation of vimentin, N‐cadherin, Snail, and induction of E‐cadherin expressions
N-cadherin↓,
Snail↓,
MMP2↓, negatively regulated MMP2 and TWIST1
Twist↓,
MMP9↓, Inhibit matrix metalloproteinase‐9 expressions;
ROS↑, Induce apoptosis, reactive oxygen development, promotion of mitochondrial autophagy, loss of mitochondrial membrane potential
MMP↓,
*AChE↓, Reduce AchE activity to slow down inception of Alzheimer's disease‐like symptoms
*MMP↑, Reverse mitochondrial membrane potential dissipation
*Aβ↓, Inhibit Aβ25‐35
*neuroP↑, reduces neuronal apoptosis; inhibits Aβ generation
Trx1↑, luteolin against human bladder cancer cell line T24 was due to induction cell‐cycle arrest at G2/M, downregulation of p‐S6, suppression of cell survival, upregulation of p21 and TRX1, reduction in ROS levels.
ROS↓,
*NRF2↑, Luteolin reduced renal injury by inhibiting XO activity, modulating uric acid transporters, as well as activating Nrf2 HO‐1/NQO1 antioxidant pathways and renal SIRT1/6 cascade.
NRF2↓, Luteolin exerted anticancer effects in HT29 cells as it inhibits nuclear factor‐erythroid‐2‐related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway
*BBB↑, Luteolin can be used to treat brain cancer due to ability of this molecule to easily cross the blood–brain barrier
ChemoSen↑, In ovarian cancer cells, luteolin chemosensitizes the cells through repressing the epithelial‐mesenchymal transition markers
GutMicro↑, Luteolin was also observed to modulate gut microbiota which reduce the number of tumors in case of colorectal cancer by enhancing the number of health‐related microbiota and reduced the microbiota related to inflammation

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

3828- Lyco,    Lycopene alleviates oxidative stress via the PI3K/Akt/Nrf2pathway in a cell model of Alzheimer's disease
- in-vitro, AD, M146L
*ROS↓, Lycopene alleviated OS and apoptosis, activated the PI3K/Akt/Nrf2 signaling pathway, upregulated antioxidant and antiapoptotic proteins and downregulated proapoptotic proteins.
*PI3K↑,
*Akt↑,
*NRF2↓,
*antiOx↑,
*BACE↓, lycopene inhibited β -secretase (BACE) activity in M146L cells.
*MDA↓,

4780- Lyco,    Potential inhibitory effect of lycopene on prostate cancer
- Review, Pca, NA
TumCP↓, Lycopene suppress the progression and proliferation
TumCCA↑, Lycopene has been found to effectively suppress the progression and proliferation, arrest in-cell cycle, and induce apoptosis of prostate cancer cells in both in-vivo and in-vitro conditions.
Apoptosis↑,
*neuroP↑, the neuro-protective effect of lycopene, mediates the signaling pathways, by inhibiting NF-κB (nuclear factor-κB) and JNK protein (c-Jun N-terminal kinase), and activating Nrf2 (Nuclear factor erythroid 2-related factor 2) and BDNF (
*NF-kB↓,
*JNK↓,
*NRF2↑,
*BDNF↑,
*Ca+2↝, as well as keeping homeostasis by restoring intracellular Ca2+
*antiOx↑, most powerful and natural antioxidants, and its role in preventing prostate cancer.
*AntiCan↑,
*Inflam↓, Anti-inflammatory properties of lycopene depends on time, and it has been found to be through the decrease of inflammatory cytokines (i.e. IL1, IL6, IL8 and tumor necrosis factor-α (TNF-α)
*IL1↓,
*IL6↓,
*IL8↓,
*TNF-α↓,
NF-kB↓, lycopene increased the expression of BCO2 enzyme in an androgen-sensitive cell line that prevented cancer cell proliferation and reduced the NF-κB activity
DNAdam↓, 20 and 50 μM doses of lycopene had an effect on PC3 and DU145 cell lines in inducing apoptosis with DNA damages, and preventing cell growth and colony formation
PSA↓, lycopene twice a day for 3 weeks, showed that lycopene decreases the risk and growth of prostate cancer cells, and also a decrease in the level of PSA,
P53↓, down-regulation of p53, Cyclin-D1, and Nrf-2 have occurred after the incubation of prostate cancer cells with the lycopene received patient’s sera in comparison with placebo
cycD1/CCND1↓,
NRF2↓,
Akt2↓, treatment with lycopene in PC3 cancer cell lines was associated with down-regulation of AKT2 [
PPARγ↓, Another anti-proliferative effect of lycopene was done by increasing PPARγ-LXRα-ABCA1signaling molecules in protein and mRNA level

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

3812- mushLions,    Structural characterization of polysaccharide purified from Hericium erinaceus fermented mycelium and its pharmacological basis for application in Alzheimer's disease: Oxidative stress related calcium homeostasis
- in-vitro, AD, NA
*cognitive↑, Six-week PHEB administration significantly improved the cognitive behavior of mice.
*Aβ↓, Brain injury, amyloid beta deposition and tau hyperphosphorylation were alleviated in PHEB-treated AD mice without changes in other tissues.
*p‑tau↓,
*ROS↓, PHEB alleviated the oxidative stress in brains of AD mice via regulation the Nrf2
*NRF2↓,
*Ca+2↝, PHEB is achieved by regulating calcium homeostasis mediated by oxidative stress

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

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

5217- PG,    Role of redox signaling regulation in propyl gallate-induced apoptosis of human leukemia cells
- in-vitro, AML, THP1 - in-vitro, AML, Jurkat - in-vitro, AML, HL-60
tumCV↓, PG reduced cell viability in THP-1, Jurkat, and HL-60 leukemia cells and induced apoptosis in THP-1 cells.
Casp3↑, PG activated caspases 3, 8, and 9 and increased the levels of p53, Bax, Fas, and Fas ligand
Casp8↑,
Casp9↑,
P53↑,
BAX↑,
Fas↑,
FasL↑,
MAPK↑, PG activated mitogen-activated protein kinases (MAPKs), inhibited nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and induced intracellular glutathione (GSH) depletion.
NRF2↓,
GSH↓,

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

5163- PLB,    Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells
- in-vitro, SCC, SCC25
TumCP↓, PLB inhibited cell proliferation, activated death receptor-mediated apoptotic pathway,
NRF2↓, PLB induces intracellular ROS generation and regulates redox homeostasis via suppressing Nrf2-mediated oxidative signaling pathway in SCC25 cells
TumCCA↑, PLB markedly induced cell cycle arrest at G2/M phase and extrinsic apoptosis
EMT↓, and inhibited epithelial to mesenchymal transition (EMT) and stemness in SCC25 cells.
CSCs↓,
eff↓, Of note, N-acetyl-l-cysteine (NAC) and l-glutathione (GSH) abolished the effects of PLB on cell cycle arrest, apoptosis induction, EMT inhibition, and stemness a
ROS↑, PLB on ROS generation-related molecules
CycB/CCNB1↓, PLB induces G2/M arrest in SCC25 cells via downregulation of cyclin B1, CDK1/cdc2, and cdc25
CDK1↓,
CDK2↓,
CDC25↓,
Vim↓, PLB inhibited the expression of vimentin in a concentration- and time-dependent manner
OCT4↓, PLB significantly decreased the expression level of Oct-4, Sox-2, Nanog, and Bmi-1.
SOX2↓,
Nanog↓,
BMI1↓,
NQO1↓, The expression levels of NQO1, GST, and HSP90 were all markedly decreased
GSTA1↓,
HSP90↓,
toxicity↓, PLB exhibits anticancer activities with minimal side effect in vitro and in vivo,

5032- PTS,    Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism
- in-vivo, Melanoma, NA
TumCG↓, Intravenous administration of Pter decreased human melanoma growth in vivo
NRF2↓, and thereby downregulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing melanomas.
GR↓,
BBB↑, Pter can cross the blood–brain barrier
ACTH↓, Pter inhibits ACTH production in AtT-20 cells
eff↑, combined Pter and GSH depletion treatment chemosensitizes melanoma cells and facilitates their complete elimination.

5034- PTS,    Pterostilbene in Cancer Therapy
- Review, Var, NA
BioAv↓, As it is in general the case for all natural polyphenols, the low systemic bioavailability of PT limits is anticancer potential
Half-Life↓, A key problem directly related to this is its short half-life and low bioavailability under in vivo conditions.
iNOS↓, PT has been shown to downregulate iNOS in both skin [58] and colon cancer [48] models, which leads to the increased apoptosis of the cancer cells.
Apoptosis↑,
STAT3↓, PT has been shown to inhibit STAT3 in lung [59], ovarian [50], pancreatic [57] and endometrial cancer [49]
Akt↓, PT can also function through inhibiting the AKT/mTOR pathway in pancreatic [56] and breast cancers [41,43,44]
mTOR↓,
NF-kB↓, PT can exhibit anticancer activity through the inhibition of NF-κB signaling in colon [48] and skin cancer [58]
NRF2↓, anticancer activity of PT that only works in vivo, when PT indirectly downregulates Nrf2 through the inhibition of glucocorticoid secretion from the pituitary gland, which decreases antioxidant defenses of metastatic melanoma cells and leads to apopt
ChemoSen↑, PT demonstrating synergistic efficacy with cisplatin in ovarian cancer cells . PT showing an additive effect with tamoxifen in breast cancer cells
BBB↑, ability to cross the blood–brain barrier

5031- QC,    Different roles of Nrf2 and NFKB in the antioxidant imbalance produced by esculetin or quercetin on NB4 leukemia cells
- in-vitro, AML, APL NB4
NRF2↓, Quercetin increased the levels of Nrf2 in the cytosol reducing them in the nucleus
ROS↑, AI summary: Suppresses NRF2 activity, Leads to: ↓ antioxidant gene expression, ↑ ROS accumulation, Oxidative stress–driven apoptosis
Apoptosis↑,

5025- QC,    New perspectives on the therapeutic potential of quercetin in non-communicable diseases: Targeting Nrf2 to counteract oxidative stress and inflammation
- Review, Nor, NA
*antiOx↑, Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation.
*Inflam↓,
*NRF2↓,
*ROS↓, Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs.
*cardioP↑, Nrf2 promotes the proliferation and repair of vascular smooth muscle cells, effectively restoring the optimal structure and function of blood vessels to improve cardiovascular health.
*HO-1↑, Que interacts with antioxidant enzymes such as HO-1, CAT, and glutathione peroxidase (GSH-PX), and enhances their free radical scavenging activity
*Catalase↑,
*GPx↑,
*NQO1↑, This process upregulates the expressions of key antioxidant and detoxification genes, such as HO-1 and NQO1, thereby inhibiting excessive intracellular ROS production.
*SIRT1↑, Que mediated by the activation of the Sirt1/Nrf2/HO-1 pathway,

5026- QC,    Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes
- in-vitro, GC, NA
SLC1A5↓, We demonstrated that Quer inhibits SLC1A5 expression
ROS↑, we found that Quer altered the intracellular ROS levels, antioxidant system protein expression levels, and iron content.
Iron↓, Quer increased the intracellular iron content by inhibiting SLC1A5
NRF2↓, Mechanistically, Quer binds to SLC1A5, inhibiting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in decreased xCT/GPX4 expression.
GPx4↓,
Ferroptosis↑, These three changes collectively led to ferroptosis in GC cells

5027- QC,    NRF2 Is Targeted By the Polyphenol Quercetin and Induces Apoptosis, in Part, through up Regulation of Pro Apoptotic Mirs
- in-vivo, AML, NA
HDAC4↓, Qu treatment (50 µM Qu) for 48h downregulated HDAC4, NRF2 and p-NRF2 at protein levels (p<0.05; p<0.005; p<0.005 respectively).
NRF2↓,
p‑NRF2↓,
miR-133a-3p↑, miR-1, miR-133a/b, which target anti-apoptotic genes and miR-206, a pro apoptotic miR, were validated in xenograft model samples, resulting in a significant up-regulation of the expression levels in treated animals
miR-206↑,

3054- RES,    Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line
- in-vitro, Melanoma, A375
TumCG↓, Treating A375SM cells with resveratrol resulted in a decrease in cell growth.
P21↑, resveratrol was observed to increase the gene expression levels of p21 and p27, as well as decrease the gene expression of cyclin B.
p27↑,
CycB/CCNB1↓,
ROS↑, generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress were confirmed at the cellular and protein levels
ER Stress↑,
p‑p38↑, Resveratrol induced the ROS-p38-p53 pathway by increasing the gene expression of phosphorylated p38 mitogen-activated protein kinase
P53↑, while it induced the p53 and ER stress pathway by increasing the gene expression levels of phosphorylated eukaryotic initiation factor 2α and C/EBP homologous protein.
p‑eIF2α↑,
EP4↑,
CHOP↑,
Bcl-2↓, downregulating B-cell lymphoma-2 (Bcl-2) expression and upregulating Bcl-2-associated X protein expression
BAX↓,
TumCCA↑, Resveratrol induced cell cycle arrest of melanoma cell line
NRF2↓, the decrease in Nrf2 expression caused by resveratrol may prevent the development of such resistance and thereby increase the sensitivity of melanoma cells to chemotherapy.
ChemoSen↑,
GSH↓, (GSH/GSSG) ratio was not measured, it can easily be assumed that the increased ROS generation by resveratrol reduced the GSH/GSSG ratio compared with the control

4994- Sal,  Rad,    Salinomycin overcomes radioresistance in nasopharyngeal carcinoma cells by inhibiting Nrf2 level and promoting ROS generation
AntiCan↑, . Salinomycin (SAL) has been identified as a promising anticancer drug during chemical screening
RadioS↓, SAL promoted radiation-induced apoptosis in radioresistant NPC cells.
Apoptosis↑,
NRF2↓, SAL inhibited increased Nrf2 in SUNE1IR cells.
ROS↑, combination treatment of Nrf2-deficient CNE2 cells with SAL and IR markedly increased the level of reactive oxygen species (ROS) and DNA damage.
DNAdam↑,

4908- Sal,    Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145
tumCV↓, salinomycin inhibited the viability and induced the apoptosis of PC-3 and DU145 cells in a dose-dependent manner
ROS↑, salinomycin increased the production of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and the lipid peroxidation.
lipid-P↑,
UPR↑, salinomycin induced the activation of unfolded protein response and endoplasmic reticulum stress in DU145 and PC-3 cells
ER Stress↑,
NRF2↓, salinomycin significantly downregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD(P)H quinone dehydrogenase 1
NADPH↓,
HO-1↓,
SOD↓, and decreased the activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase in PC-3 and DU145 cells.
Catalase↓,
GPx↓,
eff↓, Nrf2 activator, tert-butylhydroquinone, significantly reversed the therapeutic effects of salinomycin by stimulating the Nrf2 pathway and increasing the activity of antioxidant enzymes.
TumCP↓, proliferation of PC-3 and DU145 cells was significantly decreased following treatment with salinomycin (2-50 µM

5139- SAS,    Sulfasalazine induces ferroptosis in osteosarcomas by regulating Nrf2/SLC7A11/GPX4 signaling axis
- in-vitro, OS, MG63 - in-vitro, OS, U2OS
*Inflam↓, Sulfasalazine (SAS), a commonly used anti-inflammatory drug prescribed for nonspecific gastrointestinal diseases, autoimmune rheumatic diseases, ankylosing spondylitis, and various skin conditions
TumCP↓, Our results demonstrate that SAS significantly inhibited the proliferation and migration of OS cells, inducing apoptosis and effectively attenuating their malignant progression.
TumCMig↓,
Apoptosis↑,
Ferroptosis↑, Notably, SAS-treated OS cells displayed hallmarks of ferroptosis, including iron accumulation, elevated levels of malondialdehyde and reactive oxygen species, and reduced levels of glutathione and superoxide dismutase
Iron↑,
MDA↑,
ROS↑,
GSH↓,
SOD↓,
MMP↓, SAS decreased mitochondrial membrane potential in OS cells, potentially indicating mitochondrial damage during ferroptosis.
NRF2↓, Mechanistically, we found that SAS induced ferroptosis by downregulating the expression of NRF2,
xCT↓, subsequently decreasing the expression of the light chain subunit of the cysteine/glutamate transporter system Xc- (SLC7A11) and glutathione peroxidase 4.
GPx4↓,
FTH1↓, SAS treatment decreased FTH1 protein expression

4725- Se,    Targeting the Nrf2-Prx1 Pathway with Selenium to Enhance the Efficacy and Selectivity of Cancer Therapy
- in-vitro, Lung, A549 - in-vitro, CRC, HT29
AntiCan↑, anti-cancer activity of selenium may in part be mediated by suppressing the Nrf2-Prx1 pathway of a tumor.
NRF2↓, Our study showed that seleni-um suppressed Nrf2 activation and reduced the up-regulation of prx1 in tumor tissues obtained from humanlung cancer A549 and colon cancer HT-29
Prx↓,
ChemoSen↑, how selenium modulation of the Nrf2-Prx1 pathway may enhance the efficacy and selectivity of cancer therapy in both pre-clinical and clinical settings.
*Prx↑, Conversely, increased expression of Prx1 and several other Nrf2 target genes was observed in some normal tissues in the tumor-bearing mice.
*NRF2↑,

4726- Se,  Oxy,    Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma
- in-vivo, HCC, NA
eff↝, Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory.
NRF2↓, We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2
p‑p38↑, and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis
Apoptosis↑,
eff↑, These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways
TumVol↓, The results showed that hyperoxia could improve the efficacy of Na2SeO3 and CysSeSeCys in the treatment of HCC, enhance the death rate of HepG2 cells, and further reduce the tumor volume in mice
other↝, These results also suggest that the anticancer mechanism of selenium compounds may be different in different oxygen environments.
toxicity↓, staining results of the liver and kidney of mice showed that the selenium compound combined with oxygen therapy did not show toxicity or side effects on normal organs
Dose↝, therapeutic effect reached the level of the 5 mg/kg selenium compound treatment group
NRF2↝, The results showed that in the 1 % O2 environment, the two selenium compounds promoted the expression of Nrf2, and the Nrf2 level gradually decreased with increasing oxygen concentration.
HO-1↓, The expression of HO-1, CAT and SOD also showed a decreasing trend with increasing oxygen concentration
Catalase↓,
SOD↓,
e-pH↓, The results showed that the extracellular pH value decreased after treatment with selenium compounds for 48 h
pH∅, However, there was no significant change in extracellular pH value in the selenium compound treatment group compared with the oxygen alone group
MAPK↑, Selenium combined with oxygen therapy accelerates cell apoptosis by activating the MAPK signaling pathway
eff↑, In summary, oxygen can significantly enhance the antihepatocellular carcinoma effect of selenium compounds

4737- Se,  Rad,    Nrf2-modulation by seleno-hormetic agents and its potential for radiation protection
- in-vivo, Var, NA
radioP↑, Others and we have shown that seleno-compounds have the potential to protect ionizing radiation-induced toxicities in various tissues and cells both in in vitro and in vivo studies.
*NRF2↑,
NRF2↓, implied

4722- Se,    The Yin and Yang of Nrf2-Regulated Selenoproteins in Carcinogenesis
- Review, Var, NA
Risk↓, Selenium deficiency is associated with a higher cancer risk making also this essential trace element a promising candidate for cancer prevention.
*NRF2↓, Selenium deficiency activates Nrf2 as does a TrxR1 knockout making a synergism between both systems plausible. Although this might hold true for healthy cells, the interplay may turn into the opposite in cancer cells
NRF2↑, The induction of the detoxifying and antioxidant enzymes by Nrf2 will make cancer cells chemoresistant and will protect them against oxidative damage.
*NRF2↓, Selenium exerts its effects mainly as part of selenoproteins with redox functions, and Nrf2 upregulates enzymes of the adaptive response.
OS↑, selenium, vitamin E, and β-carotene, called factor D, significantly reduced total mortality, total cancer mortality, and most significantly mortality from gastric cancer. selenium ... according to subsequent studies it appeared to have the most effic
eff↝, Considering age, the effect of factor D was much stronger in individuals younger than 55 but almost absent in subjects older than 55 years.
eff↝, selenium appears to prevent initiation of cancer in healthy cells at young age, in the elderly it may be harmful and rather support tumor growth of already initiated cells
NRF2↝, “dark” side of Nrf2. Its upregulation in cancer cells provides an advantage for these cells to grow and, in addition, makes them resistant against chemotherapy

4734- SeNPs,  CPT-11,    Cytotoxicity and therapeutic effect of irinotecan combined with selenium nanoparticles
- in-vitro, CRC, HCT8 - in-vivo, NA, NA
chemoP↑, We investigated Nano Se as chemotherapy preventive agent to protect against toxicities of anticancer drug irinotecan and synergistically enhance the anti-tumor treatment effect in vitro and in vivo.
ChemoSen↑,
P53↑, The combination of Nano Se and irinotecan showed increased cytotoxic effect with HCT-8 tumor cells likely by p53 mediated apoptosis.
Apoptosis↑,
TumCG↓, Se inhibited growth of HCT-8 tumor cells partially through caspases mediated apoptosis.tumcg
Casp↑,
Dose↝, In vivo experiment showed Nano Se at a dose of 4 mg/kg/day significantly alleviated adverse effects induced by irinotecan (60 mg/kg) treatment.
NRF2↓, The beneficial effects of Nano Se for tumor therapy were mainly ascribed to selectively regulating Nrf2-ARE (antioxidant responsive elements) pathway in tumor tissues and normal tissues.
selectivity↑,
*NRF2↑,

4735- SeNPs,    Selenium triggers Nrf2-AMPK crosstalk to alleviate cadmium-induced autophagy in rabbit cerebrum
- in-vivo, Nor, NA
*MDA↓, Se decreased the contents of MDA and H2O2 and increased the activities of CAT, SOD, GST, GSH and GSH-Px, alleviating the imbalance of the redox system induced by Cd.
*H2O2↓,
*Catalase↑,
*SOD↑,
*GSTs↑,
*GSH↑,
*NRF2↓, Cd caused the up-regulation of the mRNA levels of autophagy-related genes (ATG3, ATG5, ATG7, ATG12 and p62), AMPK (Prkaa1, Prkaa2, Prkab1, Prkab2, Prkag2, Prkag3) and Nrf2 (Nrf2, HO-1 and NQO
*ATG3↓, which were alleviated by Se, indicated that Se inhibited Cd-induced autophagy and Nrf2 signaling pathway activation
*AMPK↓,
*ROS↓, our study found that Se antagonized Cd-induced oxidative stress and autophagy in the brain by generating crosstalk between AMPK and Nrf2 signaling pathway.

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

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

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

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

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

4723- SSE,    Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4
- in-vitro, CRC, HCT116
TumCP↓, In vitro experiments using HCT116 cells showed that Na₂SeO₃ treatment inhibited proliferation, increased intracellular Fe2⁺, MDA, and ROS levels, and reduced mitochondrial membrane potential.
Iron↑,
MDA↑,
ROS↑,
MMP↓,
NRF2↓, Western blotting further revealed the downregulation of Nrf2 and Gpx4 proteins upon selenium treatment
GPx4↓,
Ferroptosis↑, Our research findings indicate that sodium selenite may induce ferroptosis by regulating the Nrf2/Gpx4 axis, highlighting its potential as a dual nutrient and pharmacological drug for the treatment of CRC.

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

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

3415- TQ,    The anti-neoplastic impact of thymoquinone from Nigella sativa on small cell lung cancer: In vitro and in vivo investigations
- in-vitro, Lung, H446
tumCV↓, TQ reduced cell viability, induced apoptosis and cell cycle arrest, depleted ROS, and altered protein expression in associated signaling pathways.
TumCCA↑,
ROS↓, With regards to ROS in the current study, TQ dose-dependently decreased intracellular ROS levels in all SCLC cells except H446 cells upon 24-hour treatment with TQ.
CycB/CCNB1↑, TQ induced upregulation of cyclin B1 and cyclin D3 in H69-adherent and H446 cells, respectively. Cyclins A2, E1, and cdc2 were downregulated, while cyclin D3 was upregulated in H841-adherent cells
CycD3↑,
cycA1/CCNA1↓,
cycE/CCNE↓,
cDC2↓,
antiOx↑, TQ acted as an antioxidant.
PARP↓, TQ downregulated intratumoral PARP
NRF2↓, TQ exerts its antioxidative effect by upregulating nuclear protein nuclear factor-erythroid 2 related factor 2 (Nrf2), hence amplifying antioxidant response element (ARE) expression.
ARE/EpRE↑,
eff↑, To confirm that the antioxidative action of TQ is anti-survival for cells, H841 cells were employed as a model and treated with NAC. NAC confirmed that ROS depletion led to a decrease in the cell viability of SCLC cells.

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

114- VitC,  QC,    Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145
GPx↓, significant reduction of GPx, GR and NQO1 enzymatic activity
GSR↓,
NQO1↓,
NRF2↓, Our study revealed the significant effects of sequential treatment with VC + Q on Nrf2 suppression in prostate cancer cells
ROS↑, The level of ROS had significant reduction up to 18% (P ¼ 0.046) when DU145 cells treated with dose no.1 of VC þ Q to compare with the control

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

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

5015- Xan,  PEITC,    Comparison of the Impact of Xanthohumol and Phenethyl Isothiocyanate and Their Combination on Nrf2 and NF-κB Pathways in HepG2 Cells In Vitro and Tumor Burden In Vivo
- in-vitro, HCC, HepG2
NRF2↓, Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.
ROS↑, The increased expression of NQO1 (~90%) was associated with increased ROS generation
NF-kB↓, X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression.
COX2↓,
Apoptosis↑, In contrast to single phytochemicals, X + PEITC induced apoptosis.
NRF2↑, All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells
SOD↑,
NQO1↑,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 92

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned ⓘ

ACTH↓, 1,  

Redox & Oxidative Stress ⓘ

antiOx↓, 1,   antiOx↑, 2,   ARE/EpRE↑, 1,   Catalase↓, 6,   Copper↑, 1,   CYP1A1↓, 1,   Fenton↑, 2,   Ferroptosis↑, 14,   GPx↓, 3,   GPx1↓, 2,   GPx4↓, 12,   GSH↓, 20,   GSH/GSSG↓, 1,   GSR↓, 2,   GSTA1↓, 1,   GSTP1/GSTπ↓, 1,   GSTs↓, 2,   GSTs↝, 1,   HO-1↓, 22,   HO-1↑, 1,   HO-1⇅, 1,   Iron↓, 1,   Iron↑, 7,   i-Iron↓, 1,   Keap1↑, 3,   lipid-P↑, 8,   MDA↓, 1,   MDA↑, 9,   NOX4↑, 1,   NQO1↓, 4,   NQO1↑, 1,   NRF2↓, 79,   NRF2↑, 4,   NRF2⇅, 2,   NRF2↝, 2,   p‑NRF2↓, 2,   Prx↓, 1,   PrxI↓, 1,   ROS↓, 4,   ROS↑, 58,   i-ROS↑, 1,   SIRT3↓, 1,   SOD↓, 8,   SOD↑, 3,   SOD1↑, 1,   SOD2↓, 3,   T-SOD↓, 1,   Trx1↑, 1,   TrxR↓, 1,   VitC↓, 1,   VitE↓, 1,   xCT↓, 6,  

Metal & Cofactor Biology ⓘ

Ferritin↑, 1,   FTH1↓, 2,   NCOA4↑, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   ATP↓, 1,   mt-ATP↓, 1,   BCR-ABL↓, 1,   CDC2↓, 2,   CDC25↓, 1,   EGF↓, 1,   MMP↓, 13,   MMP↑, 2,   Mortalin↓, 1,   mtDam↑, 1,   XIAP↓, 6,  

Core Metabolism/Glycolysis ⓘ

ACC↑, 1,   ALAT↓, 2,   AMPK↑, 4,   cMyc↓, 6,   p‑cMyc↑, 1,   GlucoseCon↓, 3,   Glycolysis↓, 4,   HK2↓, 4,   lactateProd↓, 2,   LDH↓, 1,   LDHA↓, 1,   LDL↓, 1,   NADPH↓, 2,   NADPH↑, 1,   PDK1↓, 5,   PDK3↑, 1,   PKM2↓, 1,   PPARα↓, 1,   PPARγ↓, 2,   SIRT1↓, 2,   SIRT1↑, 1,   SLC1A5↓, 1,  

Cell Death ⓘ

Akt↓, 15,   p‑Akt↓, 5,   APAF1↑, 1,   Apoptosis↑, 22,   ASK1↑, 1,   BAD↑, 2,   BAX↓, 1,   BAX↑, 10,   Bax:Bcl2↑, 3,   Bcl-2↓, 8,   Bcl-xL↓, 2,   BIM↑, 1,   Casp↑, 2,   Casp1↓, 1,   cl‑Casp1↑, 1,   Casp12↑, 1,   Casp3↑, 14,   cl‑Casp3↑, 2,   Casp7↑, 2,   Casp8↑, 4,   cl‑Casp8↑, 1,   Casp9↑, 9,   cl‑Casp9↑, 1,   proCasp9↓, 1,   CK2↓, 2,   Cyt‑c↑, 12,   Diablo↑, 1,   DR5↑, 5,   Fas↑, 3,   FasL↑, 2,   Ferroptosis↑, 14,   GSDMD↑, 1,   GSDME-N↑, 1,   HGF/c-Met↓, 1,   hTERT/TERT↓, 4,   iNOS↓, 3,   JNK↑, 2,   p‑JNK↑, 2,   MAPK↓, 1,   MAPK↑, 3,   p‑MAPK↑, 1,   Mcl-1↓, 2,   MDM2↓, 3,   p‑MDM2↓, 1,   Myc↓, 2,   NICD↓, 1,   p27↑, 4,   p38↓, 1,   p38↑, 2,   p‑p38↑, 3,   Pyro↑, 2,   RIP1↑, 1,   survivin↓, 4,   Telomerase↓, 4,   TRAIL↑, 2,   TumCD↑, 3,   YAP/TEAD↓, 1,  

Kinase & Signal Transduction ⓘ

p‑CaMKII ↓, 1,   HER2/EBBR2↓, 1,   Sp1/3/4↓, 1,  

Transcription & Epigenetics ⓘ

cJun↓, 1,   H3↓, 1,   H4↓, 1,   other↝, 1,   tumCV↓, 6,  

Protein Folding & ER Stress ⓘ

CHOP↑, 3,   eIF2α↑, 1,   p‑eIF2α↑, 3,   ER Stress↑, 7,   GRP78/BiP↑, 1,   HSP27↓, 1,   HSP70/HSPA5↓, 2,   HSP90↓, 3,   IRE1↑, 1,   PERK↑, 2,   UPR↑, 3,   XBP-1↓, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↓, 1,   Beclin-1↑, 1,   BNIP3↑, 1,   LC3A↑, 1,   LC3B-II↑, 1,   LC3II↑, 1,   p62↓, 2,   p62↑, 1,   TumAuto↑, 3,  

DNA Damage & Repair ⓘ

DFF45↓, 1,   DNAdam↓, 1,   DNAdam↑, 6,   DNMT1↓, 2,   m-FAM72A↓, 1,   P53↓, 1,   P53↑, 12,   PARP↓, 1,   PARP↑, 2,   cl‑PARP↑, 6,   PCNA↓, 3,   SIRT6↓, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 2,   CDK2↓, 10,   CDK4↓, 3,   Cyc↓, 1,   cycA1/CCNA1↓, 3,   cycA1/CCNA1↑, 1,   CycB/CCNB1↓, 5,   CycB/CCNB1↑, 1,   cycD1/CCND1↓, 8,   CycD3↓, 1,   CycD3↑, 1,   cycE/CCNE↓, 2,   P21↓, 1,   P21↑, 8,   p‑RB1↓, 1,   TumCCA↑, 18,  

Proliferation, Differentiation & Cell State ⓘ

BMI1↓, 1,   CD34↓, 1,   cDC2↓, 1,   CDK8↓, 1,   cFos↓, 1,   cFos↑, 1,   cMYB↓, 1,   CSCs↓, 6,   EMT↓, 16,   EP4↑, 1,   ERK↓, 4,   p‑ERK↓, 1,   FOXO3↑, 2,   Gli↓, 1,   Gli1↓, 1,   p‑GSK‐3β↓, 2,   HDAC↓, 4,   HDAC1↓, 1,   HDAC3↓, 1,   HDAC4↓, 1,   HDAC8↓, 1,   IGF-1↓, 2,   Let-7↑, 1,   mTOR↓, 10,   mTOR↑, 1,   p‑mTOR↓, 2,   p‑mTOR↑, 1,   Nanog↓, 2,   NOTCH↓, 3,   NOTCH1↓, 2,   NOTCH1↑, 3,   OCT4↓, 3,   P70S6K↑, 1,   P90RSK↓, 1,   PI3K↓, 10,   PI3K↑, 1,   p‑PI3K↓, 2,   PTEN↓, 1,   PTEN↑, 3,   RAS↓, 1,   SCF↓, 1,   Shh↓, 2,   SHP1↑, 1,   Smo↓, 1,   SOX2↓, 2,   Src↓, 1,   p‑Src↓, 1,   STAT3↓, 12,   p‑STAT3↓, 3,   p‑STAT6↓, 1,   TAZ↓, 1,   TOP1↓, 2,   TOP2↓, 1,   TumCG↓, 7,   Wnt↓, 5,  

Migration ⓘ

AEG1↓, 1,   Akt2↓, 1,   annexin II↓, 1,   AP-1↓, 1,   AXL↓, 1,   Ca+2↑, 7,   CAFs/TAFs↓, 1,   Cdc42↓, 1,   CEA↓, 1,   CLDN1↓, 2,   E-cadherin↓, 1,   E-cadherin↑, 9,   FAK↓, 5,   p‑FAK↓, 1,   Fibronectin↓, 2,   ITGB1↓, 1,   Ki-67↓, 2,   MET↓, 2,   p‑MET↓, 1,   miR-133a-3p↑, 1,   miR-206↑, 1,   MMP-10↓, 1,   MMP1↓, 1,   MMP13↓, 1,   MMP2↓, 11,   MMP3↓, 1,   MMP7↓, 2,   MMP9↓, 10,   MMP9↑, 1,   MMPs↓, 1,   N-cadherin↓, 7,   Rac1↓, 1,   Rho↓, 2,   RIP3↑, 1,   ROCK1↓, 3,   Slug↓, 1,   Smad1↑, 1,   Snail↓, 8,   TET1↑, 2,   TGF-β↓, 1,   TGF-β↑, 1,   TIMP1↓, 1,   TIMP1↑, 1,   TIMP2↓, 1,   TIMP2↑, 1,   TumCI↓, 8,   TumCMig↓, 7,   TumCP↓, 18,   TumCP↑, 1,   TumMeta↓, 6,   TumMeta↑, 1,   TumPF↓, 1,   Twist↓, 7,   TXNIP↑, 1,   Tyro3↓, 1,   uPA↓, 5,   Vim↓, 10,   Vim↑, 1,   Zeb1↓, 1,   ZO-1↑, 2,   β-catenin/ZEB1↓, 5,  

Angiogenesis & Vasculature ⓘ

angioG↓, 9,   ATF4↓, 1,   ATF4↑, 1,   EGFR↓, 5,   EGFR↑, 1,   p‑EGFR↓, 1,   eNOS↓, 1,   Hif1a↓, 10,   VEGF↓, 16,   VEGFR2↓, 2,  

Barriers & Transport ⓘ

BBB↑, 3,   GLUT1↓, 2,  

Immune & Inflammatory Signaling ⓘ

ASC↓, 1,   ASC↑, 1,   COX1↓, 1,   COX2↓, 9,   COX2↑, 2,   CXCR4↓, 1,   ICAM-1↓, 1,   IFN-γ↓, 1,   IKKα↓, 2,   IL1↓, 1,   IL10↓, 1,   IL1β↓, 3,   IL2↑, 3,   IL6↓, 7,   IL8↓, 1,   INF-γ↑, 1,   Inflam↓, 1,   JAK↝, 1,   NF-kB↓, 17,   NF-kB↑, 1,   NF-kB↝, 1,   p‑NF-kB↑, 1,   p65↓, 3,   p‑p65↓, 2,   PD-1↓, 1,   PD-L1↓, 2,   PGE2↓, 1,   PSA↓, 1,   Th1 response↑, 1,   Th2↑, 1,   TLR1↑, 1,   TLR4↓, 1,   TNF-α↓, 3,  

Cellular Microenvironment ⓘ

pH∅, 1,   e-pH↓, 1,  

Protein Aggregation ⓘ

NLRP3↓, 1,   NLRP3↑, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 5,   CDK6↓, 1,   GR↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 3,   BioAv↑, 4,   BioEnh↑, 1,   ChemoSen↓, 1,   ChemoSen↑, 26,   Dose↑, 1,   Dose↝, 2,   Dose∅, 2,   eff↓, 5,   eff↑, 26,   eff↝, 5,   Half-Life↓, 2,   MDR1↓, 2,   P450↝, 1,   RadioS↓, 1,   RadioS↑, 8,   selectivity↑, 10,  

Clinical Biomarkers ⓘ

ALAT↓, 2,   ALP↓, 2,   AR↓, 5,   AST↓, 1,   CEA↓, 1,   EGFR↓, 5,   EGFR↑, 1,   p‑EGFR↓, 1,   Ferritin↑, 1,   GutMicro↑, 2,   HER2/EBBR2↓, 1,   hTERT/TERT↓, 4,   IL6↓, 7,   Ki-67↓, 2,   LDH↓, 1,   Myc↓, 2,   NSE↓, 1,   PD-L1↓, 2,   PSA↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 3,   AntiCan∅, 1,   AntiTum↑, 4,   cachexia↓, 1,   cardioP↑, 2,   chemoP↑, 3,   chemoPv↑, 3,   ChemoSideEff↓, 1,   neuroP↑, 1,   OS↑, 3,   radioP↑, 1,   RenoP↑, 2,   Risk↓, 3,   Risk↑, 1,   toxicity↓, 2,   toxicity↝, 1,   TumVol↓, 2,  
Total Targets: 425

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx?, 1,   antiOx↑, 12,   Catalase↑, 6,   Ferroptosis↓, 1,   GPx↑, 3,   GPx4↓, 1,   GSH↑, 5,   GSR↑, 1,   GSTs↑, 4,   H2O2↓, 1,   HO-1↓, 1,   HO-1↑, 4,   HO-1↝, 1,   Iron↓, 1,   lipid-P↓, 3,   lipid-P↑, 1,   MDA↓, 4,   NQO1↑, 1,   NRF2↓, 13,   NRF2↑, 11,   Prx↑, 1,   ROS↓, 11,   ROS⇅, 1,   SOD↑, 5,  

Metal & Cofactor Biology ⓘ

IronCh↑, 1,   NCOA4↝, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↑, 1,   mtDam↓, 1,  

Core Metabolism/Glycolysis ⓘ

AMPK↓, 1,   lipidLev↓, 1,   NADPH↑, 1,   SIRT1↑, 1,  

Cell Death ⓘ

Akt↓, 1,   Akt↑, 1,   BAX↓, 1,   Casp3↓, 2,   Casp3∅, 1,   Casp9∅, 1,   Cyt‑c∅, 1,   Ferroptosis↓, 1,   iNOS↓, 1,   iNOS↑, 1,   JNK↓, 2,   MAPK↓, 1,  

Autophagy & Lysosomes ⓘ

ATG3↓, 1,  

DNA Damage & Repair ⓘ

DNArepair↑, 1,   GADD45A↑, 1,   PARP∅, 1,  

Proliferation, Differentiation & Cell State ⓘ

Diff↑, 1,   ERK↓, 1,   PI3K↓, 1,   PI3K↑, 1,  

Migration ⓘ

Ca+2↝, 2,   MMP7↓, 1,   TGF-β↓, 1,  

Angiogenesis & Vasculature ⓘ

NO↓, 2,  

Barriers & Transport ⓘ

BBB↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL1↓, 1,   IL10↑, 1,   IL17↓, 1,   IL1β↓, 2,   IL2↓, 1,   IL6↓, 3,   IL8↓, 1,   Inflam↓, 10,   IκB↑, 1,   NF-kB↓, 6,   p65↓, 1,   TNF-α↓, 6,  

Synaptic & Neurotransmission ⓘ

AChE↓, 1,   BDNF↑, 1,   p‑tau↓, 1,  

Protein Aggregation ⓘ

Aβ↓, 2,   BACE↓, 1,  

Drug Metabolism & Resistance ⓘ

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

Clinical Biomarkers ⓘ

AST↓, 1,   IL6↓, 3,   NOS2↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   cardioP↑, 3,   cognitive↑, 2,   hepatoP↑, 4,   neuroP↑, 6,   RenoP↑, 2,   toxicity↓, 3,   toxicity∅, 1,   Weight∅, 1,  
Total Targets: 91

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2
10 Luteolin
7 Chrysin
6 Apigenin (mainly Parsley)
6 Quercetin
5 Shikonin
4 Vitamin C (Ascorbic Acid)
4 Selenium
3 doxorubicin
3 Ashwagandha(Withaferin A)
3 Baicalein
3 Berberine
3 Disulfiram
3 Copper and Cu NanoParticles
3 Fisetin
2 Silver-NanoParticles
2 Alpha-Lipoic-Acid
2 Artemisinin
2 Berbamine
2 Propolis -bee glue
2 Chemotherapy
2 Lycopene
2 Pterostilbene
2 salinomycin
2 Radiotherapy/Radiation
2 Selenium NanoParticles
2 Selenite (Sodium)
2 Thymoquinone
1 Allicin (mainly Garlic)
1 Docetaxel
1 Cisplatin
1 Lapatinib
1 Betulinic acid
1 Boron
1 Curcumin
1 diet FMD Fasting Mimicking Diet
1 Ellagic acid
1 EGCG (Epigallocatechin Gallate)
1 HydroxyTyrosol
1 Juglone
1 brusatol
1 Metformin
1 Mushroom Lion’s Mane
1 Myricetin
1 Propyl gallate
1 Piperlongumine
1 Plumbagin
1 Resveratrol
1 Sulfasalazine
1 Oxygen, Hyperbaric
1 irinotecan
1 triptolide
1 xanthohumol
1 Phenethyl isothiocyanate
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#:226  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

 

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