condition found tbRes List
RES, Resveratrol: Click to Expand ⟱
Features: polyphenol
Found in red grapes and products made with grapes.
Resveratrol is a polyphenol compound found in various plant species, including grapes, berries, and peanuts.
• Anti-inflammatory effects, Antioxidant effects:
- Antiplatelet aggregation for stroke prevention
- BioAvialability use piperine
- some sources may use Japanese knotweed roots (Reynoutria Japonica - root) as source which might contain Emodin (laxative)
-known as Nrf2 activator, both in cancer and normal cells. Which raises controversity of use in ROS↑ therapies. Interestingly there are reports of NRF2↑ and ROS↑ in cancer cells. This raises the question of if it is a chemosensitizer. However other reports indicate NRF2 droping with Res, indicating it maybe a chemosenstizer.
- RES is also considered to be them most effective natural SIRT1↑ -activating compound (STACs).

However, in the presence of certain metals, such as copper or iron, resveratrol can undergo a process called Fenton reaction, which can lead to the generation of reactive oxygen species (ROS). The pro-oxidant effects of resveratrol are often observed at high concentrations, typically above 50-100 μM, and in the presence of certain metals or other pro-oxidant agents. In contrast, the antioxidant effects of resveratrol are typically observed at lower concentrations, typically below 10-20 μM.

Clinical trials have used doses ranging from 150 mg to 5 grams per day. Lower doses (< 1 g/day) are often well-tolerated, but higher doses might be necessary for therapeutic effects and can be associated with side effects.

-Note half-life 1-3 hrs?.
BioAv poor: min 5uM/L required for chemopreventive effects, but 25mg Oral only yeilds 20nM. co-administration of piperine
Pathways:
- usually induce ROS production in cancer cells, while reducing ROS in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Lowers AntiOxidant defense in Cancer Cells: NRF2(typically increased), TrxR↓**, SOD↓, GSH↓ Catalase↓ HO1↓(wrong direction), GPx↓
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, FAK↓, RhoA↓, NF-κB↓, CXCR4↓, SDF1↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, EZH2↓, P53↑, HSP↓, Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓, TOP1↓, TET1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, FGF↓, PDGF↓, EGFR↓, Integrins↓,
- inhibits Cancer Stem Cells : CSC↓, CK2↓, Hh↓, CD133↓, CD24↓, β-catenin↓, sox2↓, notch2↓, nestin↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells


Cyt‑c, cyt-c Release into Cytosol: Click to Expand ⟱
Source:
Type:
Cytochrome c
** The term "release of cytochrome c" ** an increase in level for the cytosol.
Small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis.

The term "release of cytochrome c" refers to a critical step in the process of programmed cell death, also known as apoptosis.
In its new location—the cytosol—cytochrome c participates in the apoptotic signaling pathway by helping to form the apoptosome, which activates caspases that execute cell death.
Cytochrome c is a small protein normally located in the mitochondrial intermembrane space. Its primary role in healthy cells is to participate in the electron transport chain, a process that helps produce energy (ATP) through oxidative phosphorylation.
Mitochondrial outer membrane permeability leads to the release of cytochrome c from the mitochondria into the cytosol.
The release of cytochrome c is a pivotal event in apoptosis where cytochrome c moves from the mitochondria to the cytosol, initiating a chain reaction that leads to programmed cell death.

On the one hand, cytochrome c can promote cancer cell survival and proliferation by regulating the activity of various signaling pathways, such as the PI3K/AKT pathway. This can lead to increased cell growth and resistance to apoptosis, which are hallmarks of cancer.
On the other hand, cytochrome c can also induce apoptosis in cancer cells by interacting with other proteins, such as Apaf-1 and caspase-9. This can lead to the activation of the intrinsic apoptotic pathway, which can result in the death of cancer cells.
Overexpressed in Breast, Lung, Colon, and Prostrate.
Underexpressed in Ovarian, and Pancreatic.
Scientific Papers found: Click to Expand⟱
3067- RES,    Proteomic Profiling Reveals That Resveratrol Inhibits HSP27 Expression and Sensitizes Breast Cancer Cells to Doxorubicin Therapy
- in-vitro, BC, MCF-7
Apoptosis↑, Consistently, we demonstrated that resveratrol induces apoptosis in MCF-7 cells
MMP↓, Apoptosis was associated with a significant increase in mitochondrial permeability transition, cytochrome c release in cytoplasm, and caspases -3 and -9 independent cell death.
Cyt‑c↑,
Casp3↑,
Casp9↑,
HSP27↓, We propose that potential modulation of HSP27 levels using natural alternative agents, as resveratrol, may be an effective adjuvant in breast cancer therapy

3061- RES,    The Anticancer Effects of Resveratrol: Modulation of Transcription Factors
- Review, Var, NA
AhR↓, Several reports demonstrate the inhibitory effects of resveratrol on AhR-mediated activation of phase I enzymes.
NRF2↑, Bishayee et al. (18) demonstrated that attenuation of DENA (diethyl nitrosamine)-induced liver carcinogenesis by resveratrol was mediated by increased Nrf2 expression.
*NQO1↑, Induction of Nrf2 signaling by resveratrol resulted in increased expression of NQO1, heme-oxygenase 1 (HO-1), and glutamate cysteine ligase catalytic subunit in cigarette smoke extract-treated bronchial epithelial cells
*HO-1↑,
*GSH↑, observed restored glutathione levels in cigarette smoke extract-treated A549 lung alveolar epithelial cancer cells by resveratrol;
P53↑, we highlight reported resveratrol-induced, p53-mediated anticancer mechanisms.
Cyt‑c↑, release of mitochondria proteins (e.g. cytochrome c, Smac/DIABLO, etc.) to the cytosol, thus triggering suppression of inhibitors of apoptosis proteins (e.g. Bcl2, Bcl-XL, survivin, XIAP, etc.) and caspase activation in several cancers
Diablo↑,
Bcl-2↓,
Bcl-xL↓,
survivin↓,
XIAP↓,
FOXO↑, activation of FoxO transcription factors is implicated in the observed anticancer activities of resveratrol.
p‑PI3K↓, resveratrol's ability to inhibit the phosphorylation of PI3K/Akt (
p‑Akt↓,
BIM↑, Bim/TRAIL/DR4/DR5/p27KIP1 induction and cyclin D1 inhibition) of resveratrol on prostate cancer cells
DR4↑,
DR5↑,
p27↑,
cycD1↓,
SIRT1↑, resveratrol is considered a SIRT1 agonist
NF-kB↓, resveratrol not only curbs expression of NF-κB, but also impedes the phosphorylation of IκBα thereby keeping the constitutive NF-κB subunit in an inactive state, resulting in suppression of the inflammatory
ATF3↑, Furthermore, increased ATF3 expression by resveratrol facilitated induction of apoptosis

3078- RES,    The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment
- Review, Pca, NA
*ROS↓, RSV appears to be both pro- and anti-oxidant, depending on the circumstances [76]. In non-cancer tissues, RSV serves as an antioxidant [77], and therefore RSV can exert a beneficial effect on a wide variety of issues, including neuronal [78], anti-in
ROS↑, However, to cancer cells with low pH environments due to the Warburg Effect, RSV shows more pro-oxidant characteristics.
DNAdam↑, RSV can induce cancer cell death by inducing ROS accumulation, which subsequently leads to oxidative DNA damage and apoptosis
Apoptosis↑,
Hif1a↑, Wang et al. demonstrated that RSV-enhanced cancer cell death is due to the upregulation of HIF1α, which enhances ROS concentration in the TME beyond the limit for survival
Casp3↑, superoxide can activate caspases 9 and 3, and subsequently promote the release of cytochrome C
Casp9↑,
Cyt‑c↑,
Dose↝, It is important to note that low concentration of RSV can serve as a pro-oxidant that favors cell survival, and pro-apoptotic effects occur only at relatively higher RSV concentrations to stimulate superoxide production.
MMPs↓, inhibitory effect of RSV on MMPs has been shown in many cancer types, and RSV is capable of inhibiting both MMP-2 and MMP-9
MMP2↓,
MMP9↓,
EMT↓, RSV can restore the epithelial phenotype of the mesenchymal cells and inhibit the expression of EMT-related markers
E-cadherin↑, RSV can inhibit EMT by up- and downregulating E-cadherin and N-cadherin, respectively, in prostate cancer cells.
N-cadherin↓,
AR↓, RSV can repress AR function by inhibiting AR transcriptional activity

2566- RES,    A comprehensive review on the neuroprotective potential of resveratrol in ischemic stroke
- Review, Stroke, NA
*neuroP↑, comprehensive overview of resveratrol's neuroprotective role in IS
*NRF2↑, Findings from previous studies suggest that Nrf2 activation can significantly reduce brain injury following IS and lead to better outcomes
*SIRT1↑, neuroprotective effects by activating nuclear factor erythroid 2-related factor 2 (NRF2) and sirtuin 1 (SIRT1) pathways.
*PGC-1α↑, IRT1 activation by resveratrol triggers the deacetylation and activation of downstream targets like peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and forkhead box protein O (FOXO)
*FOXO↑,
*HO-1↑, ctivation of NRF2 through resveratrol enhances the expression of antioxidant enzymes, like heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), which neutralize reactive oxygen species and mitigate oxidative stress in the ischemic bra
*NQO1↑,
*ROS↓,
*BP↓, Multiple studies have demonstrated that resveratrol presented protective effects in IS, it can mediate blood pressure and lipid profiles which are the main key factors in managing and preventing stroke
*BioAv↓, The residual quantity of resveratrol undergoes metabolism, with the maximum reported concentration of free resveratrol being 1.7–1.9 %
*Half-Life↝, The levels of resveratrol peak 60 min following ingestion. Another study found that within 6 h, there was a further rise in resveratrol levels. This increase can be attributed to intestinal recirculation of metabolites
*AMPK↑, Resveratrol also increases AMPK and inhibits GSK-3β (glycogen synthase kinase 3 beta) activity in astrocytes, which release energy, makes ATP available to neurons and reduces ROS
*GSK‐3β↓,
*eff↑, Furthermore, oligodendrocyte survival is boosted by resveratrol, which may help to preserve brain homeostasis following a stroke
*AntiAg↑, resveratrol may suppress platelet activation and aggregation caused by collagen, adenosine diphosphate, and thrombin
*BBB↓, Although resveratrol is a highly hydrophobic molecule, it is exceedingly difficult to penetrate a membrane like the BBB. However, an alternate administration is through the nasal cavity in the olfactory area, which results in a more pleasant route
*Inflam↓, Resveratrol's anti-inflammatory effects have been demonstrated in many studies
*MPO↓, Resveratrol dramatically lowered the amounts of cerebral infarcts, neuronal damage, MPO activity, and evans blue (EB) content in addition to neurological impairment scores.
*TLR4↓, TLR4, NF-κB p65, COX-2, MMP-9, TNF-α, and IL-1β all had greater levels of expression after cerebral ischemia, whereas resveratrol decreased these amounts
*NF-kB↓,
*p65↓,
*MMP9↓,
*TNF-α↓,
*IL1β↓,
*PPARγ↑, Previous studies have shown that resveratrol activates the PPAR -γ coactivator 1α (PGC-1 α), which has free radical scavenging properties
*MMP↑, Resveratrol can prevent mitochondrial membrane depolarization, preserve adenosine triphosphate (ATP) production, and inhibit the release of cytochrome c
*ATP↑,
*Cyt‑c∅,
*mt-lipid-P↓, mitochondrial lipid peroxidation (LPO), protein carbonyl, and intracellular hydrogen peroxide (H2O2) content were significantly reduced in the resveratrol treatment group, while the expression of HSP70 and metallothionein were restored
*H2O2↓,
*HSP70/HSPA5↝,
*Mets↝,
*eff↑, Shin et al. showed that 5 mg/kg intravenous (IV) resveratrol reduced infarction volume by 36 % in an MCAO mouse model.
*eff↑, This study indicates that resveratrol holds the potential to improve stroke outcomes before ischemia as a pre-treatment strategy
*motorD↑, resveratrol treatment significantly reduced infarct volume and prevented motor impairment, increased glutathione, and decreased MDA levels compared to the control group,
*MDA↓,
*NADH:NAD↑, Resveratrol treatment significantly enhanced the intracellular NAD+/NADH ratio
eff↑, Pretreatment with resveratrol (20 or 40 mg/kg) significantly lowered the cerebral edema, infarct volume, lipid peroxidation products, and inflammatory markers
eff↑, Intraperitoneal administration of resveratrol at a dose of 50 mg/kg reduced cerebral ischemia reperfusion damage, brain edema, and BBB malfunction

2329- RES,    Resveratrol induces apoptosis in human melanoma cell through negatively regulating Erk/PKM2/Bcl-2 axis
- in-vitro, Melanoma, A375
P53↑, In the present study, we found that resveratrol dramatically inhibited melanoma cell proliferation and induced cell apoptosis through upregulation of p53 in a concentration-dependent manner.
Bcl-2↓, resveratrol downregulated antiapoptotic protein Bcl-2 and activated Bax in the protein levels by promoting Bcl-2 degradation and cytochrome c release.
BAX↑,
Cyt‑c↑,
ERK↓, apoptosis induction of resveratrol in melanoma cells and suggested that downregulating Erk/PKM2/Bcl-2 axis appears to be a new approach for the prevention or treatment of melanoma.
PKM2↓,
Apoptosis↑,
γH2AX↑, levels of γH2AX increased significantly in melanoma cells after the addition of resveratrol
Casp3↑, Active Caspase3 and cleaved PARP1 were increased in resveratrol-treated cells
cl‑PARP1↑,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Results for Effect on Cancer/Diseased Cells:
AhR↓,1,   p‑Akt↓,1,   Apoptosis↑,3,   AR↓,1,   ATF3↑,1,   BAX↑,1,   Bcl-2↓,2,   Bcl-xL↓,1,   BIM↑,1,   Casp3↑,3,   Casp9↑,2,   cycD1↓,1,   Cyt‑c↑,4,   Diablo↑,1,   DNAdam↑,1,   Dose↝,1,   DR4↑,1,   DR5↑,1,   E-cadherin↑,1,   eff↑,2,   EMT↓,1,   ERK↓,1,   FOXO↑,1,   Hif1a↑,1,   HSP27↓,1,   MMP↓,1,   MMP2↓,1,   MMP9↓,1,   MMPs↓,1,   N-cadherin↓,1,   NF-kB↓,1,   NRF2↑,1,   p27↑,1,   P53↑,2,   cl‑PARP1↑,1,   p‑PI3K↓,1,   PKM2↓,1,   ROS↑,1,   SIRT1↑,1,   survivin↓,1,   XIAP↓,1,   γH2AX↑,1,  
Total Targets: 42

Results for Effect on Normal Cells:
AMPK↑,1,   AntiAg↑,1,   ATP↑,1,   BBB↓,1,   BioAv↓,1,   BP↓,1,   Cyt‑c∅,1,   eff↑,3,   FOXO↑,1,   GSH↑,1,   GSK‐3β↓,1,   H2O2↓,1,   Half-Life↝,1,   HO-1↑,2,   HSP70/HSPA5↝,1,   IL1β↓,1,   Inflam↓,1,   mt-lipid-P↓,1,   MDA↓,1,   Mets↝,1,   MMP↑,1,   MMP9↓,1,   motorD↑,1,   MPO↓,1,   NADH:NAD↑,1,   neuroP↑,1,   NF-kB↓,1,   NQO1↑,2,   NRF2↑,1,   p65↓,1,   PGC-1α↑,1,   PPARγ↑,1,   ROS↓,2,   SIRT1↑,1,   TLR4↓,1,   TNF-α↓,1,  
Total Targets: 36

Scientific Paper Hit Count for: Cyt‑c, cyt-c Release into Cytosol
5 Resveratrol
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:141  Target#:77  State#:%  Dir#:%
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