Database Query Results : Fisetin, , RenoP

FIS, Fisetin: Click to Expand ⟱
Features:
Fisetin is a plant based flavonoid. Found in strawberries(160ug/g), apples, persimmons, onions, cucumbers, grapes.

-Note half-life 3-4hrs
- Oral BioAv low (40-50%)
Pathways:
- induce ROS production in cancer cells, but also known to reduce it.
Also a claim Fisetin-Induced Reactive Oxygen Species Production Has No Effect on Apoptosis in RCC cells
Also one claim (NAC 10-20mM levels) that NAC enhances ROS/apoptosis
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Does not appear to lower antioxidants in cancer cells
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓,
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, FAK↓, RhoA↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓, TET1↓,
- inhibits HIF-1α↓, cMyc↓, LDH↓, GRP78↑,
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells : CD133↓, β-catenin↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Fisetin effect on Cancer Cells
Rank Pathway / Axis Cancer Cells Normal Cells Label Primary Interpretation Notes
1 PI3K → AKT → mTOR axis ↓ AKT / ↓ mTOR signaling ↔ adaptive suppression Driver Loss of survival and growth signaling Fisetin consistently suppresses pro-survival PI3K/AKT signaling, supporting growth inhibition and sensitization to stress
2 NF-κB signaling ↓ NF-κB activation ↓ inflammatory NF-κB tone Driver Suppression of inflammatory survival transcription NF-κB inhibition contributes to anti-inflammatory effects and reduced tumor-supportive signaling
3 Reactive oxygen species (ROS) ↑ ROS (context- & dose-dependent) ↓ ROS Conditional Driver Biphasic redox modulation Fisetin can act as a pro-oxidant in cancer cells at higher stress/dose while remaining antioxidant in normal cells
4 Mitochondrial integrity / intrinsic apoptosis ↓ ΔΨm; ↑ caspase activation ↔ preserved Secondary Execution of intrinsic apoptosis Mitochondrial apoptosis occurs downstream of signaling and redox disruption
5 Cell cycle regulation ↑ G1 or G2/M arrest ↔ spared Phenotypic Cytostatic growth control Cell-cycle arrest reflects upstream pathway inhibition rather than direct CDK blockade
6 Senescence / senolytic action ↑ senescence clearance (senescent-like tumor/stroma subsets) ↓ senescent cell burden (selective) Secondary Selective vulnerability of senescent-like cells Fisetin is commonly described as senolytic; in cancer context this may impact tumor microenvironment and therapy-induced senescence
7 MAPK stress signaling (JNK / p38) ↑ JNK / ↑ p38 (context-dependent) ↔ minimal Secondary Stress-mediated apoptosis signaling MAPK activation often follows ROS increase and supports apoptotic signaling
8 NRF2 antioxidant response ↑ NRF2 (adaptive, context-dependent) ↑ NRF2 (protective) Adaptive Stress compensation NRF2 activation reflects redox buffering responses rather than primary cytotoxicity
9 Migration / invasion (EMT, MMP axis) ↓ migration & invasion ↔ Phenotypic Anti-metastatic phenotype Reduced EMT and protease activity limit invasive behavior downstream of signaling changes


RenoP, K,Renoprotection: Click to Expand ⟱
Source:
Type:
Protects kidneys
-Same as nephroprotective
Opposite is : Nephrotoxicity is toxicity in the kidneys
Scientific Papers found: Click to Expand⟱
2827- FIS,    The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
- Review, Var, NA
*antiOx↑, effective antioxidant, anti-inflammatory
*Inflam↓,
neuroP↑, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential.
hepatoP↑,
RenoP↑,
cycD1/CCND1↓, Figure 3
TumCCA↑,
MMPs↓,
VEGF↓,
MAPK↓,
NF-kB↓,
angioG↓,
Beclin-1↑,
LC3s↑,
ATG5↑,
Bcl-2↓,
BAX↑,
Casp↑,
TNF-α↓,
Half-Life↓, Fisetin was given at an effective dosage of 223 mg/kilogram intraperitoneally in mice. The plasma concentration declined biophysically, with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h,
MMP↓, Fisetin powerfully improved apoptotic cells and caused the depolarization of the mitochondrial membrane.
mt-ROS↑, Fisetin played a role in the induction of apoptosis, independently of p53, and increased mitochondrial ROS generation.
cl‑PARP↑, fisetin-induced sub-G1 population as well as PARP cleavage.
CDK2↓, Moreover, the activities of cyclin-dependent kinases (CDK) 2 as well as CDK4 were decreased by fisetin and also inhibited CDK4 activity in a cell-free system, demonstrating that it might directly inhibit the activity of CDK4
CDK4↓,
Cyt‑c↑, Moreover, release of cytochrome c and Smac/Diablo was induced by fisetin
Diablo↑,
DR5↑, Fisetin caused an increase in the protein levels of cleaved caspase-8, DR5, Fas ligand, and TNF-related apoptosis-inducing ligand
Fas↑,
PCNA↓, Fisetin decreased proliferation-related proteins such as PCNA, Ki67 and phosphorylated histone H3 (p-H3) and decreased the expression of cell growth
Ki-67↓,
p‑H3↓,
chemoP↑, Paclitaxel treatment only showed more toxicity to normal cells than the combination of flavonoids with paclitaxel, suggesting that fisetin might bring some safety against paclitaxel-facilitated cytotoxicity.
Ca+2↑, Fisetin encouraged apoptotic cell death via increased ROS and Ca2+, while it increased caspase-8, -9 and -3 activities and reduced the mitochondrial membrane potential in HSC3 cells.
Dose↝, After fisetin treatment at 40 µM, invasion was reduced by 87.2% and 92.4%, whereas after fisetin treatment at 20 µM, invasion was decreased by 52.4% and 59.4% in SiHa and CaSki cells, respectively
CDC25↓, This study proposes that fisetin caused the arrest of the G2/M cell cycle via deactivating Cdc25c as well Cdc2 via the activation of Chk1, 2 and ATM
CDC2↓,
CHK1↑,
Chk2↑,
ATM↑,
PCK1↓, fisetin decreases the levels of SOS-1, pEGFR, GRB2, PKC, Ras, p-p-38, p-ERK1/2, p-JNK, VEGF, FAK, PI3K, RhoA, p-AKT, uPA, NF-ĸB, MMP-7,-9 and -13, whereas it increases GSK3β as well as E-cadherin in U-2 OS
RAS↓,
p‑p38↓,
Rho↓,
uPA↓,
MMP7↓,
MMP13↓,
GSK‐3β↑,
E-cadherin↑,
survivin↓, whereas those of survivin and BCL-2 were reduced in T98G cells
VEGFR2↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2↓, The downregulation of cIAP-2 by fisetin
STAT3↓, fisetin induced apoptosis in TPC-1 cells via the initiation of oxidative damage and enhanced caspases expression by downregulating STAT3 and JAK 1 signaling
JAK1↓,
mTORC1↓, Fisetin acts as a dual inhibitor of mTORC1/2 signaling,
mTORC2↓,
NRF2↑, Moreover, In JC cells, the Nrf2 expression was gradually increased by fisetin from 8 h to 24 h

2828- FIS,    Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review
- Review, Var, NA
*neuroP↑, As a hydrophobic agent, FIS readily penetrates cell membranes and accumulates in cells to exert neuroprotective, neurotrophic and antioxidant effects
*antiOx↑,
*Inflam↓, FIS treatment may include alleviating inflammation, cell apoptosis and oxidative stress
RenoP↑, alleviates cell apoptosis and inflammation in acute kidney injury
COX2↓, FIS induces apoptosis in various tumor cells by, for example, inhibiting cyclooxygenase-2, inhibiting the Wnt/EGFR/NF-κB pathway, activating the caspase-3 cascade
Wnt↓,
EGFR↓,
NF-kB↓,
Casp3↑,
Ca+2↑, activating the caspase-3 and Ca2+ dependent endonuclease, and activating the caspase-8/caspase-3 dependent pathway via ERK1/2.
Casp8↑,
TumCCA↑, FIS controls the cell cycle and inhibits cyclin-dependent kinases (CDKs) in human cancer cell lines,
CDK1↓,
PI3K↓, by inhibition of PI3K/Akt/mTOR signaling [20], mitogen-activated protein kinases (MAPK) [21], and nuclear transcription factor (NF-κB)
Akt↓,
mTOR↓,
MAPK↓,
*P53↓, FIS inhibits aging by reducing p53, p21 and p16 expression in mouse and human tissues
*P21↓,
*p16↓,
mTORC1↓, FIS induces autophagic cell death by inhibiting both the mTORC1 and mTORC2 pathways
mTORC2↓,
P53↑, FIS significantly increases the expression of p53 and p21 proteins and lowers the levels of cyclin D1 [27,28], cyclin A, CDK4 and CDK2, thus contributing to cell-cycle arrest.
P21↑,
cycD1/CCND1↓,
cycA1/CCNA1↓,
CDK2↓,
CDK4↓,
BAX↑, FIS also increases Bax [27,28] and Bak [27] protein expression, but reduces the levels of Bcl-2 [27,28], Bcl-xL [27] and PCNA [28], and then starts the mitochondrial apoptotic pathway.
Bcl-2↓,
PCNA↓,
HER2/EBBR2↓, FIS reduces HER2 tyrosine phosphorylation in a dose-dependent manner and aids in proteasomal degradation of HER2 rather than lysosomal degradation
Cyt‑c↑, FIS cells causes destabilization of the mitochondrial membrane and an increase in cytochrome c levels, which is consistent with the loss of mitochondrial membrane integrity.
MMP↓,
cl‑Casp9↑,
MMP2↓, FIS reduces the enzymatic activity of both MMP-2 and MMP-9.
MMP9↓,
cl‑PARP↑, cell membrane, mitochondrial depolarization, activation of caspase-7, -8 and -9, and cleavage of PARP
uPA↓, interestingly, the promoter activity of the uPA gene is suppressed by FIS
DR4↑, induces upregulation of DR4 and DR5 death receptor expression in a dose-dependent manner
DR5↑,
ROS↓, FIS induces an increase in intracellular Ca2+ but reduces the production of ROS in WEHI-3 cells (myelomonocytic leukemia)
AIF↑, It also increases the levels of caspase-3 and AIF mRNA, but also increases necrosis markers including RIP3 and PARP1
CDC25↓, FIS reduces the expression of cdc25a, but increases the expression of p-p53, Chk1, p21 and p27, which may lead to a G0/G1 arrest.
Dose↑, FIS in concentrations from 0 to 10 μM does not affect cell viability; however, its use at concentrations of 20–40 μM significantly reduces the viability of lung cancer cells
CHOP↑, CaKi : FIS induces upregulation of CHOP expression and ROS production
ROS↑, NCI-H460 :FIS increases the ER stress signaling FIS increases the level of mitochondrial ROS FIS induces mitochondrial Ca2+ overloading and ER stress FIS induced ER stress-mediated cell death via activation of the MAPK pathway
cMyc↓, FIS influences proliferation related genes such as cyclin D1, c-myc and cyclooxygenase (COX)-2 by downregulating them.
cardioP↑, cardioprotective activity


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

NRF2↑, 1,   ROS↓, 1,   ROS↑, 1,   mt-ROS↑, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   CDC2↓, 1,   CDC25↓, 2,   MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 1,   PCK1↓, 1,  

Cell Death ⓘ

Akt↓, 1,   BAX↑, 2,   Bcl-2↓, 2,   Casp↑, 1,   Casp3↑, 1,   Casp8↑, 1,   cl‑Casp9↑, 1,   Chk2↑, 1,   Cyt‑c↑, 2,   Diablo↑, 1,   DR4↑, 1,   DR5↑, 2,   Fas↑, 1,   IAP2↓, 1,   MAPK↓, 2,   p‑p38↓, 1,   survivin↓, 1,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 1,  

Transcription & Epigenetics ⓘ

p‑H3↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 1,  

Autophagy & Lysosomes ⓘ

ATG5↑, 1,   Beclin-1↑, 1,   LC3s↑, 1,  

DNA Damage & Repair ⓘ

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

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 2,   CDK4↓, 2,   cycA1/CCNA1↓, 1,   cycD1/CCND1↓, 2,   P21↑, 1,   TumCCA↑, 2,  

Proliferation, Differentiation & Cell State ⓘ

GSK‐3β↑, 1,   mTOR↓, 1,   mTORC1↓, 2,   mTORC2↓, 2,   PI3K↓, 1,   RAS↓, 1,   STAT3↓, 1,   Wnt↓, 1,  

Migration ⓘ

Ca+2↑, 2,   E-cadherin↑, 1,   Ki-67↓, 1,   MMP13↓, 1,   MMP2↓, 1,   MMP7↓, 1,   MMP9↓, 1,   MMPs↓, 1,   Rho↓, 1,   uPA↓, 2,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   EGFR↓, 1,   VEGF↓, 1,   VEGFR2↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   JAK1↓, 1,   NF-kB↓, 2,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

Dose↑, 1,   Dose↝, 1,   Half-Life↓, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   HER2/EBBR2↓, 1,   Ki-67↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   chemoP↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   RenoP↑, 2,  
Total Targets: 82

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 2,  

DNA Damage & Repair ⓘ

p16↓, 1,   P53↓, 1,  

Cell Cycle & Senescence ⓘ

P21↓, 1,  

Immune & Inflammatory Signaling ⓘ

Inflam↓, 2,  

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 6

Scientific Paper Hit Count for: RenoP, K,Renoprotection
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

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