PI3K Cancer Research Results

PI3K, Phosphatidylinositide-3-Kinases: Click to Expand ⟱
Source: HalifaxProj(inhibit) CGL-CS
Type:
Phosphatidylinositol 3-kinase (PtdIns3K or PI3K) is a family of enzymes that play a crucial role in cell signaling pathways, particularly in the regulation of cell growth, survival, and metabolism. The PI3K pathway is one of the most frequently altered pathways in human cancer. Inhibition of the PI3K pathway has been explored as a therapeutic strategy for cancer treatment. Several PI3K inhibitors have been developed and are currently being tested in clinical trials. These inhibitors can target specific components of the pathway, such as PI3K, AKT, or mTOR.

Class I phosphoinositide 3-kinase (PI3K)
Class III PtdIns3K
In contrast to the class III PtdIns3K as a positive regulator of autophagy, class I PI3K-AKT signaling has an opposing effect on the initiation of autophagy.

PI3K inhibitors include:
-Idelalisib , Copanlisib, Alpelisib
-LY294002?
-Wortmannin: potent PI3K inhibitor, has some associated toxicity.
-Quercetin:
-Curcumin
-Resveratrol
-Epigallocatechin Gallate (EGCG)
Scientific Papers found: Click to Expand⟱
3272- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*antiOx↑, LA has long been touted as an antioxidant,
*glucose↑, improve glucose and ascorbate handling,
*eNOS↑, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*NRF2↑,
*MMP9↓,
*VCAM-1↓,
*NF-kB↓,
*cardioP↑, used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits,
*cognitive↑,
*eff↓, The efficiency of LA uptake was also lowered by its administration in food,
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies;
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑, LA markedly increases intracellular glutathione (GSH),
*PKCδ↑, PKCδ, LA activates Erk1/2 [92,93], p38 MAPK [94], PI3 kinase [94], and Akt
*ERK↑,
*p38↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN [95],
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, stimulate GLUT4 translocation
*GLUT1↑, LA-stimulated translocation of GLUT1 and GLUT4.
*Inflam↓, LA as an anti-inflammatory agent

3437- ALA,    Revisiting the molecular mechanisms of Alpha Lipoic Acid (ALA) actions on metabolism
- Review, Var, NA
*IronCh↑, ALA functions as a metabolic regulator, metal chelator, and a powerful antioxidant.
*antiOx↑,
*ROS↓, It quenches reactive oxygen species (ROS), restores exogenous and endogenous antioxidants such as vitamins and Glutathione (GSH), and repairs oxidized proteins
*GSH↑,
*NF-kB↓, inhibition of the activation of nuclear factor kappa B (NF-κB)
*AMPK⇅, activation of peripheral AMPK and inhibition of hypothalamic AMPK
*FAO↑, ALA has been found to activate peripheral AMPK, thereby enhancing fatty acid oxidation and glucose uptake in muscle cells
*GlucoseCon↑,
*PI3K↑, It stimulates glucose uptake by increasing the activity of PI3K and Akt which are crucial for the translocation of glucose transporters like GLUT4 to the cell membrane, mimicking the action of insulin
*Akt?,

3539- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*ROS↓, scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age.
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑,
*antiOx↑, LA has long been touted as an antioxidant
*NRF2↑, activate Phase II detoxification via the transcription factor Nrf2
*MMP9↓, lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*VCAM-1↓,
*NF-kB↓,
*cognitive↑, it has been used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits, and has been implicated as a modulator of various inflammatory signaling pathways
*Inflam↓,
*BioAv↝, LA bioavailability may be dependent on multiple carrier proteins.
*BioAv↝, observed that approximately 20-40% was absorbed [
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies
*H2O2∅, Neither species is active against hydrogen peroxide
*neuroP↑, chelation of iron and copper in the brain had a positive effect in the pathobiology of Alzheimer’s Disease by lowering free radical damage
*PKCδ↑, In addition to PKCδ, LA activates Erk1/2 [92, 93], p38 MAPK [94], PI3 kinase [94], and Akt [94-97].
*ERK↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, In skeletal muscle, LA is proposed to recruit GLUT4 from its storage site in the Golgi to the sarcolemma, so that glucose uptake is stimulated by the local increase in transporter abundance.
*GlucoseCon↑,
*BP↝, Feeding LA to hypertensive rats normalized systolic blood pressure and cytosolic free Ca2+
*eff↑, Clinically, LA administration (in combination with acetyl-L-carnitine) showed some promise as an antihypertensive therapy by decreasing systolic pressure in high blood pressure patients and subjects with the metabolic syndrome
*ICAM-1↓, decreased demyelination and spinal cord expression of adhesion molecules (ICAM-1 and VCAM-1)
*VCAM-1↓,
*Dose↝, Considering the transient cellular accumulation of LA following an oral dose, which does not exceed low micromolar levels, it is entirely possible that some of the cellular effects of LA when given at supraphysiological concentrations may be not be c

4283- ALC,    Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice
- in-vivo, NA, NA
*BDNF↑, In addition, ALC (100 mg/kg, i.p.) also reversed depressive-like behavior and the down-regulation of phosphorylated AKT (pAKT), brain-derived neurotrophic factor (BDNF) and neuropeptide VGF in the hippocampus and prefrontal cortex of mice induced by
*p‑Akt↑,
*PI3K↑,

4280- Api,    Protective effects of apigenin in neurodegeneration: An update on the potential mechanisms
- Review, AD, NA - Review, Park, NA
*neuroP↑, Apigenin, a flavonoid found in various herbs and plants, has garnered significant attention for its neuroprotective properties
*antiOx↑, shown to possess potent antioxidant activity, which is thought to play a crucial role in its neuroprotective effects
*ROS↓, Apigenin has been demonstrated to scavenge ROS, thereby reducing oxidative stress and mitigating the damage to neurons
*Inflam↓, apigenin has been found to possess anti-inflammatory properties.
*TNF-α↓, inhibit the production of pro-inflammatory cytokines, such as TNF-α and IL-1β, which are elevated in neurodegenerative diseases
*IL1β↓,
*PI3K↑, apigenin has been shown to activate the PI3K/Akt signaling pathway, which is involved in promoting neuronal survival and preventing apoptosis.
*Akt↑,
*BBB↑, Apigenin has additional neuroprotective properties due to its ability to cross the BBB and enter the brain
*NRF2↑, figure 1
*SOD↑, pigenin has also been shown to activate various antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx)
*GPx↑,
*MAPK↓, Apigenin inhibits the MAPK signalling system, which significantly reduces oxidative stress-induced damage in the brain
*Catalase↑, , including SOD, catalase, GPx and heme oxygenase-1 (HO-1) [37].
*HO-1↑,
*COX2↓, apigenin has the ability to inhibit the expression and function of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE-2), enzymes that produce inflammatory mediators
*PGE2↓,
*PPARγ↑, apigenin has the ability to inhibit the expression and function of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE-2), enzymes that produce inflammatory mediators
*TLR4↓,
*GSK‐3β↓, Apigenin can inhibit the activity of GSK-3β,
*Aβ↓, Inhibiting GSK-3 can reduce Aβ production and prevent neurofibrillary disorders.
*NLRP3↓, Apigenin suppresses nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation by upregulating PPAR-γ
*BDNF↑, Apigenin causes upregulation of BDNF and TrkB expression in several animal models
*TrkB↑,
*GABA↑, Apigenin enhances GABAergic signaling by increasing the frequency of chloride channel opening, leading to increased inhibitory neurotransmission
*AChE↓, It blocks acetylcholinesterase and increases acetylcholine availability.
*Ach↑,
*5HT↑, Apigenin has been shown to increase 5-HT levels, decrease 5-HT turnover, and prevent dopamine changes.
*cognitive↑, Apigenin increases the availability of acetylcholine in the synapse after inhibiting AChE, thereby enhancing cholinergic neurotransmission and improving cognitive function and memory
*MAOA↓, apigenin acts as a monoamine oxidase (MAO) inhibitor and MAO inhibitors increase the levels of monoamines in the brain

4804- ASTX,    Astaxanthin in cancer therapy and prevention (Review)
- Review, Var, NA - Review, AD, NA
*antiOx↑, gained significant attention for its potent antioxidant, anti-inflammatory and anti-proliferative properties.
*Inflam↓,
ChemoSen⇅, In some instances, it reduces the cytotoxicity of cisplatin, particularly with cisplatin on the SKBR3 breast cancer cell line, indicating a potential protective effect. In certain cases, AXT enhances the cytotoxic effect of the chemotherapy drugs
chemoP↑, The present review detailed both in vitro and in vivo studies highlighting the effectiveness of AXT in sensitizing cancer cells to chemotherapy, thereby enhancing therapeutic outcomes and potentially reducing treatment-related side effects.
BioAv↑, incorporation of AXT in nanoparticle-based delivery systems has further improved its bioavailability
TumCP↑, AXT exhibits hormetic effects on U251-MG, T98G and CRT-MG cell lines, where low doses stimulate cell proliferation
ROS⇅, while higher doses induce apoptosis by triggering a dose-dependent oxidative stress response, significantly increasing reactive oxygen species (ROS) levels and promoting apoptosis
Apoptosis↑,
PI3K↑, AXT activates the PI3K/Akt/GSK3β pathway, leading to the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, in SH-SY5Y cells under oxygen and glucose deprivation conditions
Akt↑,
GSK‐3β↑,
NRF2↑,
AntiCan↑, antioxidant, AXT has the potential to act as both an anticancer drug and a neuroprotectant.
*neuroP↑, AXT protects against oxidative stress, which causes mitochondrial dysfunction and apoptosis, thereby reducing the detrimental effects associated with neurodegenerative diseases such as Alzheimer's, Parkinson's
eff↑, The synergistic cytotoxic effect of AXT with melatonin showed enhanced efficacy in the T47D cell line compared with the MDA-MB-231 line
AntiTum↑, AXT effectively reduced tumor size and the number of cancer cells in mice, supporting its potential anti-tumor activity.

4276- BA,    Baicalin Attenuates Oxygen–Glucose Deprivation/Reoxygenation–Induced Injury by Modulating the BDNF-TrkB/PI3K/Akt and MAPK/Erk1/2 Signaling Axes in Neuron–Astrocyte Cocultures
- in-vivo, Stroke, NA
*BDNF↑, has been indicated to protect neurons by promoting brain-derived neurotrophic factor (BDNF).
*neuroP↑, neuroprotective mechanisms of baicalin against oxygen–glucose deprivation/reoxygenation
*TrkB↑, baicalin significantly increased the expressions of TrkB, PI3K/AKT, and MAPK/ERK.
*PI3K↑,
*Akt↑,
*MAPK↑,
*ERK↑,
*NO↓, elevation of NO and MDA was significantly attenuated by BCL treatment.
*MDA↓,
*SOD↑, BCL treatment increased the expression level of SOD
*TNF-α↓, OGD/R treatment significantly increased the expression levels of TNF-α, IL-1β, and IL-6 (p < 0.01). Compared with that in the OGD/R group, BCL robustly reduced the release of inflammatory cytokines
*IL1β↓,
*IL6?,

3681- BBR,    The efficacy and mechanism of berberine in improving aging-related cognitive dysfunction: A study based on network pharmacology
- in-vivo, AD, NA
*memory↑, treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal
*cognitive↑,
MAPK↑, core targets of berberine for improving cognitive function, include Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1.
*Akt↑,
*PI3K↑, PI3K-Akt signaling pathway and MAPK signaling pathway were significantly enriched.
*TP53↑, Tp53 and Jun expression showed a decreasing trend and were significantly lower in the BBR-H group
*Jun↓,
*HSP90↑, src, Ctnnb1, Akt1, Pik3ca, and Hsp90aa1 exhibited an increasing tendency in both the BBR-L and BBR-H groups
*neuroP↑, Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine.
*Inflam↓, pharmacological effects of BBR, including anti-inflammatory
*antiOx↑, BBR has antioxidant properties as well as protective effects against neurodegenerative diseases
*p16↓, BBR reduces the expression of P16 in brain tissue of cognitive dysfunctions mice
*ER Stress↓, inhibition of endoplasmic reticulum stress

5483- BM,    The Role of Bacopa monnieri in Alzheimer’s Disease: Mechanisms and Potential Clinical Use—A Review
- Review, AD, NA
*cognitive↑, Bacopa monnieri, also known as brahmi, which has gained particular popularity for its cognitive-function-enhancing properties and neuroprotective effects.
*neuroP↑,
*PI3K↑, figure 3
*Akt↑,
*GSK‐3β↓,
*tau↓,
*ROS↓,
*MMP3↓,
*Casp1↓,
*Casp3↓,
*NF-kB↓,
*TNF-α↓,
*IL6↓,

5482- BM,    Bacopa monnieri protects SH-SY5Y cells against tert-Butyl hydroperoxide-induced cell death via the ERK and PI3K pathways
- in-vitro, Nor, NA
*neuroP↑, The neuroprotective effect of BM was evaluated
*ERK↑, BM by activation of ERK/MAPK and PI3K/Akt signaling pathways protects SH-SY5Y cells from TBHP-induced cell death.
*Akt↑,
*MAPK↑,
*PI3K↑,
*Inflam↓, Mechanistically, BM has been reported to have anti-inflammatory, anti-depressant and antioxidant effects9–12
antiOx↑, enhancement of antioxidant enzymes

5474- BM,    Pharmacological attributes of Bacopa monnieri extract: Current updates and clinical manifestation
*memory↑, Bacopa monnieri has been used for centuries in Ayurvedic medicine, alone or in combination with other herbs, as a memory and learning enhancer, sedative, and anti-epileptic.
*neuroP↑, Brahmi as a lead formulation for treating neurological disorders and exerting cognitive-enhancing effects.
*cognitive↑,
*hepatoP↑, figure 1
*antiOx↑,
*AntiDiabetic↑,
*fatigue↓,
*GSK‐3β↓, figure 3
*PI3K↑,
*Akt↑,
*tau↓,
*ROS↓, The neuroprotective properties of these bioactive components include reduction of ROS, neuroinflammation, aggregation inhibition of amyloid-β and improvement of cognitive and learning behavior.
*Inflam↓,

4263- CA,    Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action
- Review, AD, NA
*neuroP↑, neuroprotective effect of CA on neuronal cells subjected to ischemia/hypoxia injury via the scavenging or reduction of ROS (reactive oxygen species) and NO (nitric oxide) and inhibition of COX-2 and MAPK pathways
*ROS↓,
*NO↓,
*COX2↓,
*MAPK↓,
*NRF2↑, CA is known to activate the Keap1/Nrf2 pathway, thereby resulting in the production of cytoprotective proteins.
*GSH↑, activation of GSH metabolism
*HO-1↑, activation of Nrf2 target genes, including heme oxygenase 1 (HO-1) and thioredoxin reductase 1 (TXNRD1)
*5HT↑, Observations of increased serotonin and BDNF suggest that CA may represent a novel therapeutic avenue for depressive behaviors that should be further explored.
*BDNF↑, 10 μM CA results in a 1.5-fold increase in levels of BDNF
*PI3K↑, CA has been shown to mediate the activation of the PI3K/Akt/NF-κB pathway
*Akt↑,
*NF-kB↑,
*BBB↑, CA was shown to ameliorate brain edema and blood-brain barrier (BBB) disruption
*SIRT1↑, CA was also shown to increase SIRT1
*memory↑, CA was shown to significantly improve short-term and spatial memory attributes in rat models of AD
*Aβ↓, CA also delayed the deposition of Aβ and protected cells against Aβ-induced cholinergic and mitochondrial dysfunction in a Caenorhabditis elegans model of AD
*NLRP3↓, CA also inhibits the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which plays a critical role in the pathogenesis of neurodegenerative disorders, including AD and PD and COVID-19

5849- CAP,    The Impact of TRPV1 on Cancer Pathogenesis and Therapy: A Systematic Review
- Review, Var, NA
TRPV1↑, TRPV1 belongs to the transient receptor potential channel vanilloid subfamily and is also known as the capsaicin receptor and vanilloid receptor 1 (VR1).
Ca+2↑, The activation of TRPV1 induces the cellular influx of Ca2+ and Na+ ions 17-19, and the excess intracellular Ca2+ and Na+ leads to cell death 20.
TumCD↑,
TumCCA↑, Induced cell cycle arrest in G0/G1 phase and apoptosis by activating p53 to upregulate Fas/CD95 in TRPV1-overexpressing cells
Apoptosis↑,
P53↑,
Fas↑,
PI3K↑, Activated PI3K and p44/42 MAPK pathways to suppress ceramide production and increased androgen receptor expression
AR↑,
STAT3↓, attenuating STAT3 phosphorylation
ROS↑, Induced apoptosis by producing ROS originating from the mitochondria
MMP↓, Disrupted mitochondrial membrane potential and suppressed ATP synthesis to induce apoptosis
ATP↓,
CHOP↑, Stimulated ROS generation, increased CHOP expression level, and promoted apoptosis
TumCMig↓, As TRPV1 serves as the main Ca2+-influx channel, it is reasonable to suggest that TRPV1 could act as an enhancer or inhibitor of migration and invasion in a tissue- or cell-specific manner.
Twist↓, Capsaicin downregulated Tiwst1, Snail1, MMP2, and MMP9 and upregulated E-cadherin
Snail↓,
MMP2↓,
MMP9↓,
E-cadherin↑,

5768- CAPE,    Neuroprotective Potential of Caffeic Acid Phenethyl Ester (CAPE) in CNS Disorders: Mechanistic and Therapeutic Insights
- Review, AD, NA - Review, Park, NA - Review, Stroke, NA
*antiOx↑, it possesses antioxidant, anti-inflammatory, antimitogenic, and anti-cancer activities, as shown by preclinical studies.
*Inflam↑,
*AntiCan↑,
*NRF2↑, figure 1
*GSK‐3β↑,
*Akt↑,
*PI3K↑, directly activates the PI3/Akt signaling pathway as well as leads to increased phosphorylation of GSK-3β to yield it inactive
*ROS↓, decrease in the reactive oxygen species levels (ROS)
*SOD↑,
*GSH↑,
*MDA↓,
*tau↓, reduced hyperphosphorylation of Tau protein
*neuroP↑, Accorded neuroprotection through increased PI3K activity and eNOS mediated nitric oxide synthesis
*memory↑, CAPE treatment in the doses of 6 mg/kg for 28 days led to an improvement in spatial memory and reduction in the malondialdehyde (MDA),
*AChE↓, Other mechanisms which may contribute to its beneficial effect include the inhibition of acetylcholinesterase activity, which has also been reported by several authors
*other↝, Different studies have demonstrated the effectiveness of CAPE in stroke models through its anti-inflammatory and antioxidant properties.
*lipid-P↓, decreasing membrane fluidity, lipid peroxidation, release of cardiolipin, and Cyt c

2780- CHr,    Anti-cancer Activity of Chrysin in Cancer Therapy: a Systematic Review
- Review, Var, NA
*antiOx↑, antioxidant (13), anti-inflammatory (14), antibacterial (15), anti-hypertensive (16), anti-allergic (17), vasodilator (18),
Inflam↓,
*hepatoP↑, anti-diabetic (19), anti-anxiety (10), anti-viral (20), anti-estrogen (21), liver protective (22), anti-aging (23), anti-seizure (24), and anti-cancer effects (25)
AntiCan↑,
Cyt‑c↑, (1) facilitating the release of cytochrome C from the mitochondria,
Casp3↑, (2) activating caspase-3 and inhibiting the activity of the XIAP molecule,
XIAP↓,
p‑Akt↓, (3) reducing AKT phosphorylation and triggering the PI3K pathway and induction of apoptosis
PI3K↑,
Apoptosis↑,
COX2↓, chrysin interacts weakly with COX-1 binding site whereas displayed a remarkable interaction with COX-2.
FAK↓, ESCC cells: resultant blockage of the FAK/AKT signaling pathways
AMPK↑, A549: activation of AMPK by chrysin contributes to Akt suppression
STAT3↑, 4T1cell: inhibited STAT3 activation
MMP↓, Chrysin induces apoptosis through the intrinsic mitochondrial pathway that disrupts mitochondrial membrane potential (MMP) and increases DNA fragmentation.
DNAdam↑,
BAX↑, produces pro-apoptotic proteins, including Bax and Bak, and activates caspase-9 and caspase-3 in various cancer cells
Bak↑,
Casp9↑,
p38↑, chrysin can inhibit tumor growth by activating P38 MAPK and stopping the cell cycle
MAPK↑,
TumCCA↑,
ChemoSen↑, beneficial in inhibiting chemotherapy resistance of cancer cells
HDAC8↓, chrysin suppresses tumorigenesis by inhibiting histone deacetylase 8 (HDAC8)
Wnt↓, chrysin can attenuate Wnt and NF-κB signaling pathways
NF-kB↓,
angioG↓, chrysin can inhibit angiogenesis and inducing apoptosis in HTh7 cells, 4T1 mice, and MDA-MB-231 cells
BioAv↓, low bioavailability of flavonoids such as chrysin

2791- CHr,    Chrysin attenuates progression of ovarian cancer cells by regulating signaling cascades and mitochondrial dysfunction
- in-vitro, Ovarian, OV90
TumCP↓, chrysin inhibited ovarian cancer cell proliferation and induced cell death by increasing reactive oxygen species (ROS) production and cytoplasmic Ca2+ levels as well as inducing loss of mitochondrial membrane potential (MMP).
TumCD↑,
ROS↑,
Ca+2↑,
MMP↓,
MAPK↑, chrysin activated mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in ES2 and OV90 cells in concentration-response experiments
PI3K↑, results indicate that the chrysin-induced activation of PI3K and MAPK signaling molecules, which induced apoptosis,
p‑Akt↑, Chrysin stimulated the phosphorylation of AKT and P70S6K proteins in both ES2 and OV90 cells compared to the untreated control cell
PCNA↓, treatment with chrysin attenuated the abundant expression of PCNA protein in both ES2 and OV90 cells
p‑p70S6↑,
p‑ERK↑, chrysin activated the phospho-ERK1/2, p38, and JNK proteins as members of the MAPK pathway in the ovarian cancer cells
p38↑,
JNK↑,
DNAdam↑, stimulates apoptotic events in prostate cancer cells by the accumulation of DNA fragmentation, an increase in the population of cells in the sub-G1 phase of the cell cycle
TumCCA↑,
chemoP↑, combination therapy with chrysin enhances the therapeutic effect of the chemotherapeutic agent, docetaxel, in lung cancer by reducing its adverse effects

4773- CoQ10,    Coenzyme Q10 inhibits the activation of pancreatic stellate cells through PI3K/AKT/mTOR signaling pathway
- in-vitro, Nor, NA
*other↓, Our finding suggests that CoQ10 inhibits the activation of PSCs by suppressing autophagy through activating the PI3K/AKT/mTOR signaling pathway.
*PI3K↑, PI3K/AKT/mTOR signaling pathway were dose-dependently upregulated with increased CoQ10 concentrations
*Akt↑,
*mTOR↑,
*ROS↓, In this study, CoQ10 significantly reduced the intracellular level of ROS in PSCs.

3576- CUR,    Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease
- Review, AD, NA
*Inflam↓, known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions.
*antiOx↑,
*memory↑,
*Aβ↓, curcumin prevents Aβ aggregation and crosses the blood-brain barrier,
*BBB↑,
*cognitive↑, curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD
*tau↓, curcumin's effect on inhibition of A and tau,copper binding ability, cholesterol lowering ability, anti-inflammatory and modulation of microglia, acetylcholinesterase (AChE) inhibition, antioxidant properties,
*LDL↓,
*AChE↓,
*IL1β↓, Curcumin reduced the levels of oxidized proteins and IL1B in the brains of APP mice
*IronCh↑, Curcumin binds to redox-active metals, iron and copper
*neuroP↑, Curcumin, a neuroprotective agent, has poor brain bioavailability.
*BioAv↝,
*PI3K↑, They found that curcumin significantly upregulates phosphatidylinositol 3-kinase (PI3K), Akt, nuclear factor E2-related factor-2 (Nrf2), heme oxygenase 1, and ferritin expression
*Akt↑,
*NRF2↑,
*HO-1↑,
*Ferritin↑,
*HO-2↓, and that it significantly downregulates heme oxygenase 2, ROS, and A40/42 expression.
*ROS↓,
*Ach↑, significant increase in brain ACh, glutathione, paraoxenase, and BCL2 levels with respect to untreated group associated with significant decrease in brain AChE activity,
*GSH↑,
*Bcl-2↑,
*ChAT↑, nvestigation revealed that the selected treatments caused marked increase in ChAT positive cells.

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

1860- dietFMD,  Chemo,    Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape
- in-vitro, BC, SUM159 - in-vitro, BC, 4T1
PI3K↑, FMD activates PI3K-AKT, mTOR, and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression.
Akt↑,
mTOR↑,
CDK4↑,
CDK6↑,
hyperG↓, FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs.
TumCG↓, cycles of FMD significantly slowed down tumor growth, reduced tumor size, and caused an increased expression of intratumor Caspase3
TumVol↓,
Casp3↑,
BG↓, confirming our hypothesis that lowering intracellular glucose levels (through reduced extracellular levels or reduced uptake) reduces CSC survival
eff↑, 2DG potentiated the effect of FMD both in terms of delaying tumor progression and in decreasing the number of mammospheres derived by tumor masses,
eff∅, metformin did not show any additive or synergistic antitumor effect when combined with the FMD, thus suggesting that FMD and metformin have redundant effects on blood glucose levels
PKA↓, We have previously shown that prolonged fasting reduces the activity of protein kinase A (PKA) in different types of normal cells
KLF5↓, PKA inhibition resulted in the downregulation of KLF5, a potential therapeutic target for TNBC
p‑GSK‐3β↑, (GSK3β) phosphorylation
Nanog↓, stemness-associated genes NANOG and OCT4, and KLF2 and TBX3,
OCT4↓,
KLF2↓,
eff↑, Combining FMD cycles with PI3K/AKT/mTOR inhibitors results in long-term animal survival and reduces treatment-induced side effects
ROS↑, FMD resulted in an increased expression of pro-apoptotic molecules, such as BIM, and ASK1, a critical cellular stress sensor frequently activated by ROS, whose production was previously shown to be increased by the FMD
BIM↑,
ASK1↑,
PI3K↑, FMD cycles upregulate PI3K-AKT and mTOR pathways and downregulate CCNB-CDK1 while upregulating CCND-CDK4/6 signaling axes
Akt↑,
mTOR↑,
CDK1↓,
CDK4↑,
CDK6↑,
eff↑, combining STS with pictilisib, ipatasertib, and rapamycin, selective inhibitors for PI3K, AKT, and mTOR, respectively, resulted in enhanced cancer cell death and reduction of mammosphere numbers in SUM159 cells

2826- FIS,    Fisetin induces apoptosis in breast cancer MDA-MB-453 cells through degradation of HER2/neu and via the PI3K/Akt pathway
- in-vitro, BC, MDA-MB-453
Apoptosis↑, fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half-life, decreasing enolase phosphorylation, and alteration of PI3K/AKT
p‑ENO1↓,
DNAdam↑, displaying DNA fragmentation pattern
PI3K↑, Fisetin increased PI3K activity at 10 uM, which gradually declines on treatment with higher concentrations (25 or 50 uM)
p‑Akt↑, Fisetin (10 uM) increased phosphorylation of Akt in MDA-MB-453 cells greater than control. Higher concentrations of fisetin (25 or 50 uM) gradually decreased the phosphorylation of Akt.
HER2/EBBR2↓, fisetin induced HER2 depletion

4247- GI,    6-Shogaol from Dried Ginger Protects against Intestinal Ischemia/Reperfusion by Inhibiting Cell Apoptosis via the BDNF/TrkB/PI3K/AKT Pathway
- vitro+vivo, NA, NA
*BDNF↑, activating BDNF/TrkB/PI3K/AKT signaling pathway and inhibiting II/R-induced cell apoptosis. The outcome is further validated both in vivo and in vitro.
*TrkB↑,
*PI3K↑,
*Akt↑,
*Apoptosis↓,
*Inflam↓, dried ginger, behaviors multiple biological activities, including anti-inflammation, antioxidation, and anti-apoptosis.
*antiOx↑,

4302- Gins,    Panax ginseng: A modulator of amyloid, tau pathology, and cognitive function in Alzheimer's disease
- Review, AD, NA
*neuroP↑, highlighting neuroprotective mechanisms, such as the inhibition of Aβ production, enhanced Aβ clearance, and suppression of tau hyperphosphorylation.
*Aβ↓,
*p‑tau↓,
*cognitive↑, Research on P. ginseng and its bioactive ginsenosides has shown potential for improving cognitive function in AD models
*eff↑, particularly pronounced effects in individuals lacking apolipoprotein ε4 allele.
*PKA↑, Upregulates the PKA/CREB signaling pathway
*CREB↑,
*BACE↓, Inhibits BACE1 activity
*ADAM10↑, Enhances the expression of ADAM10 and reduces BACE1 expression through the activation of MAPK/ERK and PI3K/AKT
*MAPK↑,
*ERK↑,
*PI3K↑,
*Akt↑,
*NRF2↑, Activates the Nrf2/Keap1 signaling pathway
*PPARγ↓, Inhibits PPARγ phosphorylation and upregulates the expression of IDE
*IDE↑,
*APP↓, downregulates the expression of BACE1 and APP
*PP2A↑, Ginsenoside Rb1 enhances PP2A levels, thereby facilitating tau dephosphorylation and reducing p-tau levels observed in animal studies
*memory↑, The 400 mg dose of ginseng extract significantly improved “Quality of Memory” and “Secondary Memory” at all post-dose time points,

3829- Gins,    Traditional Chinese Medicine: Role in Reducing β-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer’s Disease
- Review, AD, NA
*cognitive↑, strong therapeutic effects on cognitive impairments and neurodegeneration
*neuroP↑,
*Aβ↓, It inhibits Aβ1-42 and tau pathology, increases the mRNA and protein expression of PI3K, p-Akt/Akt,
*tau↓,
*PI3K↑,
*Akt↑,
*memory↑, GP improves the memory capacity and cognitive function by activating PI3K/Akt signaling pathway

3532- Lyco,    Lycopene alleviates oxidative stress via the PI3K/Akt/Nrf2pathway in a cell model of Alzheimer’s disease
- in-vitro, AD, NA
*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↑,
*Aβ↓, Lycopene possibly prevents Aβ-induced damage by activating the PI3K/Akt/Nrf2 signaling pathway and reducing the expression of BACE in M146L cells.
*Apoptosis↓, Lycopene alleviates apoptosis in M146L cells
*neuroP↑, lycopene shows the neuroprotective effects of antioxidative damage and antiapoptotic by reducing the phosphorylation of PI3K/Akt

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↓,

486- MF,    mTOR Activation by PI3K/Akt and ERK Signaling in Short ELF-EMF Exposed Human Keratinocytes
- in-vitro, Nor, HaCaT
*mTOR↑,
*PI3K↑, HaCaT cells exposed for 1h to 50Hz/1mT showed an increased percentage of cells in the S phase, through a significantly activation of the PI3K, JNK and ERK pathways
*Akt↑,
*p‑ERK↑,
*other↑, increases in the percentage of cells in the S phase and decrease in the percentage of cells in G0/G1 phase
*p‑JNK↑,
*p‑P70S6K↑,

1141- Myr,    Myricetin: targeting signaling networks in cancer and its implication in chemotherapy
- Review, NA, NA
*PI3K↑, apoptotic potential of myricetin is specific for affected cells. In healthy cells, it activates PI3K/Akt signaling and inhibits ERK/JNK pathway to induce cytoprotective influence
*Akt↑,
p‑Akt↓,
SIRT3↑,
p‑ERK↓,
p38↓,
VEGF↓,
MEK↓, MEK1
MKK4↓,
MMP9↓,
Raf↓,
F-actin↓,
MMP2↓,
COX2↓,
BMP2↓,
cycD1/CCND1↓,
Bax:Bcl2↑,
EMT↓,
EGFR↓,
TumAuto↑,

1987- PTL,  Rad,    A NADPH oxidase dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells
- in-vitro, Pca, PC3 - in-vitro, Nor, PrEC
selectivity↑, parthenolide (PN), a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells.
RadioS↑,
ROS↑, oxidative stress in PC3 cells but not in PrEC cells
*ROS∅, oxidative stress in PC3 cells but not in PrEC cells
NADPH↑, In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, MnSOD, CAT
Trx↓,
PI3K↑,
Akt↑,
p‑FOXO3↓, downregulation of FOXO3a targets, antioxidant enzyme manganese superoxide dismutase (MnSOD) and catalase
SOD2↓, MnSOD
Catalase↓,
radioP↑, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells
*NADPH∅, Parthenolide activates NADPH oxidase in PC3 cells but not in PrEC cells
*GSH↑, increases glutathione (GSH) in PrEC cells(normal cells)
*GSH/GSSG↑, GSH/GSSG ratio is not significantly changed by parthenolide in PC3 cells but is increased 2.4 fold in PrEC cells (normal cells)
*NRF2↑, The induction of GSH may be due to the activation of the Nrf2/ARE (antioxidant/electrophile response element) pathway

98- QC,    Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway
- in-vivo, Stroke, NA
*Bcl-2↑,
*BAX↓,
*Bax:Bcl2↓, Que postconditioning significantly decreased Bax expression and increased Bcl-2 expression
*cardioP↑, cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.
*Akt↑,
*PI3K↑,
*LDH↓, Que postconditioning reduced the levels of CK (1642.9±194.3 vs 2679.5±194.3 U/L, P<0.05) and LDH (1273.6±176.5 vs 2618±197.7 U/L, P<0.05) compared to the I/R group

3608- QC,    Chronic diseases, inflammation, and spices: how are they linked?
- Review, Var, NA
AntiCan↑, anti-cancer, anti-inflammatory, and anti-oxidant properties of this phytochemical are demonstrated by numerous studies
*Inflam↓,
*antiOx↑,
*NF-kB↓, ability to downregulate NF-κB and MAPK pathways and enhance PI3K/Akt and Nrf2 pathways
*MAPK↓,
*PI3K↑,
*Akt↑,
*NRF2↑,

3341- QC,    Antioxidant Activities of Quercetin and Its Complexes for Medicinal Application
- Review, Var, NA - Review, Stroke, NA
*antiOx↑, we highlight the recent advances in the antioxidant activities, chemical research, and medicinal application of quercetin.
*BioAv↑, Moreover, owing to its high solubility and bioavailability,
*GSH↑, Animal and cell studies found that quercetin induces GSH synthesis
*AChE↓, In this way, it has a stronger inhibitory effect against key enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are associated with oxidative properties
*BChE↓,
*H2O2↓, Quercetin has been shown to alleviate the decline of manganese-induced antioxidant enzyme activity, the increase of AChE activity, hydrogen peroxide generation, and lipid peroxidation levels in rats, thereby preventing manganese poisoning
*lipid-P↓,
*SOD↑, quercetin significantly enhanced the expression levels of endogenous antioxidant enzymes such as Cu/Zn SOD, Mn SOD, catalase (CAT), and GSH peroxidase in the hippocampal CA1 pyramidal neurons of animals suffering from ischemic injury.
*SOD2↑,
*Catalase↑,
*GPx↑,
*neuroP↑, Thus, quercetin may be a potential neuroprotective agent for transient ischemia
*HO-1↑, quercetin can promote fracture healing in smokers by removing free radicals and upregulating the expression of heme-oxygenase- (HO-) 1 and superoxide-dismutase- (SOD-) 1, which protects primary human osteoblasts exposed to cigarette smoke
*cardioP↑, Quercetin has also been shown to prevent heart damage by clearing oxygen-free radicals caused by lipopolysaccharide (LPS)-induced endotoxemia.
*MDA↓, quercetin treatment increased the levels of SOD and CAT and reduced the level of MDA after LPS induction, suggesting that quercetin enhanced the antioxidant defense system
*NF-kB↓, quercetin promotes disease recovery by downregulating the expression of NIK and NF-κB including IKK and RelB, and upregulating the expression of TRAF3.
*IKKα↓,
*ROS↓, quercetin controls the development of atherosclerosis induced by a high-fructose diet by inhibiting ROS and enhancing PI3K/AKT.
*PI3K↑,
*Akt↑,
*hepatoP↑, Quercetin exerts antioxidant and hepatoprotective effects against acute liver injury in mice induced by tertiary butyl hydrogen peroxide. T
P53↑, Quercetin prevents cancer development by upregulating p53, which is the most common inactivated tumor suppressor. It also increases the expression of BAX, a downstream target of p53 and a key pro-apoptotic gene in HepG2 cells
BAX↑,
IGF-1R↓, Studies have found that insulin-like growth factor receptor 1 (IGFIR), AKT, androgen receptor (AR), and cell proliferation and anti-apoptotic proteins are increased in cancer, but quercetin supplementation normalizes their expression
Akt↓,
AR↓,
TumCP↓,
GSH↑, Moreover, quercetin significantly increases antioxidant enzyme levels, including GSH, SOD, and CAT, and inhibits lipid peroxides, thereby preventing skin cancer induced by 7,12-dimethyl Benz
SOD↑,
Catalase↑,
lipid-P↓,
*TNF-α↓, Heart: increases TNF-α, and prevents Ca2+ overload-induced myocardial cell injury
*Ca+2↓,

3338- QC,    Quercetin: Its Antioxidant Mechanism, Antibacterial Properties and Potential Application in Prevention and Control of Toxipathy
- Review, Var, NA - Review, Stroke, NA
*antiOx↑, The antioxidant mechanism of quercetin in vivo is mainly reflected in its effects on glutathione (GSH), signal transduction pathways, reactive oxygen species (ROS), and enzyme activities.
*GSH↑,
*ROS↓,
*Dose↑, antioxidant properties of quercetin show a concentration dependence in the low dose range but too much of the antioxidant brings about the opposite result
*NADPH↓, quercetin counteracts atherosclerosis by reversing the increased expression of NADPH oxidase i
*AMP↓, decreases in activation of AMP-activated protein kinase, thereby inhibiting NF-κB signaling
*NF-kB↓,
*p38↑, quercetin improves the antioxidant capacity of cells by activating the intracellular p38 MAPK pathway, increasing intracellular GSH levels and providing a source of hydrogen donors in the scavenging of free radical reactions.
*MAPK↑,
*SOD↑, quercetin achieves protection against acute spinal cord injury by up-regulating the activity of SOD, down-regulating the level of malondialdehyde (MDA), and inhibiting the p38MAPK/iNOS signaling pathway
*MDA↓,
*iNOS↓,
*Catalase↑, quercetin reduces imiquimod (IMQ)-induced MDA levels in skin tissues and enhances catalase, SOD, and GSH activities, which together improve the antioxidant properties of the body
*PI3K↑, It also controls the development of atherosclerosis induced by high fructose diet by enhancing PI3K/AKT and inhibiting ROS
*Akt↑,
*lipid-P↓, Quercetin enhances antioxidant activity and inhibits lipid cultivation, and it is effective in the treatment of oxidative liver damag
*memory↑, reversed hypoxia-induced memory impairment
*radioP↑, Quercetin protects cells from radiation and genotoxicity-induced damage by increasing endogenous antioxidant and scavenging free radical levels
*neuroP↑, This suggests that quercetin may be a potential neuroprotective agent against ischemia, which protects CA1 vertebral neurons from I/R injury in the hippocampal region of animals
*MDA↓, quercetin significantly reduced MDA levels and increased SOD and catalase levels.

2443- RES,    Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review
- Review, Var, NA
*antiOx↑, Resveratrol has shown strong antioxidant properties in many studies
*ROS↓,
*PTEN↑, resveratrol upregulated the phosphatase and tensin homolog (PTEN), which decreased Akt phosphorylation, leading to an upregulation of antioxidant enzyme mRNA levels such as catalase (CAT) and superoxide dismutase (SOD)
*Akt↓,
*Catalase↑,
*SOD↑,
*ERK↓, modulating antioxidant enzymes through downregulation of extracellular signal-regulated kinase (ERK)
*GSH↑, thus the levels of antioxidants like glutathione (GSH) increased, and free radicals were directly scavenged
*AMPK↑, resveratrol activated adenosine monophosphate (AMP)-activated protein kinase (AMPK) to maintain the structural stability of forkhead box O1 (FoxO1)
*FOXO1↝,
*RNS↓, Generally, resveratrol protects against oxidative stress mainly by (i) reducing ROS/reactive nitrogen species (RNS) generation; (ii) directly scavenging free radicals; (iii) improving endogenous antioxidant enzymes (e.g., SOD, CAT, and GSH);
*Catalase↑,
*cardioP↑, In summary, the cardiovascular protective effects of resveratrol mainly depend on the capabilities of reducing oxidative stress and alleviating inflammation through Nrf2 and/or SIRT1 activation, PI3K/eNOS upregulation, and NF-κB downregulation.
*PI3K↑,
*eNOS↑,
hepatoP↑, Resveratrol has shown its protective impacts on several liver diseases in some studies

4288- RES,    Trans-resveratrol Inhibits Tau Phosphorylation in the Brains of Control and Cadmium Chloride-Treated Rats by Activating PP2A and PI3K/Akt Induced-Inhibition of GSK3β
- in-vivo, AD, NA
*memory↑, RES improved both short and long-term memory as analyzed by novel object recognition task and significantly increased brain levels of glutathione in both control and CdCl2-treated rats.
*GSH↑,
*ROS↓, It also inhibited ROS levels of malondialdehyde in the brains of CdCl2-treated rats.
*MDA↓,
*p‑tau↓, RES decreased the phosphorylation rate of Tau at Ser199 and Ser296.
*PI3K↑, RES activated PI3K/Akt signaling pathway in both control and CdCl2 treated rats by increasing levels of p-PI3K (Tyr607) and p-Akt (Ser473)
*Akt↑,
*AMPK↑, significant increase in the levels of AMPK and p-AMPK, known upstream regulators of PI3K/Akt signaling pathway.
*PP2A↑, RES inhibits Tau phosphorylation in rat’s brain by activating PP2A protein and AMPK/PI3K/Akt-induced inhibition of GSK3β.
*GSK‐3β↓,

1748- RosA,    The Role of Rosmarinic Acid in Cancer Prevention and Therapy: Mechanisms of Antioxidant and Anticancer Activity
- Review, Var, NA
AntiCan↑, RA exhibits significant potential as a natural agent for cancer prevention and treatment
*BioAv↝, Various factors, including its lipophilic nature, stability in the gastrointestinal tract, and interactions with food, can significantly influence its absorption
*CardioT↓, RA attenuated these effects by reducing ROS levels, indicating its potential role as a cardioprotective agent during chemotherapy.
*Iron↓, Another significant mechanism antioxidant activity of RA is its capacity to chelate transition metal ions, particularly iron (Fe2+) and copper (Cu2+), which can catalyze the formation of highly reactive hydroxyl radicals through the Fenton reaction.
*ROS↓, forming stable complexes with Fe2+ and Cu2+, thus inhibiting their pro-oxidant activity.
*SOD↑, SOD, CAT, and GPx, play crucial roles in neutralizing ROS and maintaining cellular redox homeostasis. RA upregulates the expression and activity of these enzymes
*Catalase↑,
*GPx↑,
*NRF2↑, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a primary regulator of the antioxidant response
MARK4↓, Anwar’s study demonstrated that RA inhibited MARK4 activity in MDA-MB-231 breast cancer cells, resulting in dose-dependent apoptosis
MMP9↓, RA effectively inhibited cancer cell invasion and migration by reducing matrix metalloproteinase-9 (MMP-9) activity
TumCCA↑, caused cell cycle arrest
Bcl-2↓, RA downregulates Bcl-2 expression and upregulates Bax, thereby promoting apoptosis
BAX↑,
Apoptosis↑,
E-cadherin↑, promoting E-cadherin expression, while downregulating N-cadherin and vimentin
N-cadherin↓,
Vim↓,
Gli1↓, induced apoptosis by downregulating Gli1, a key component of the Hedgehog signaling pathway,
HDAC2↓, RA induced apoptosis by modulating histone deacetylase 2 (HDAC2) expression
Warburg↓, anti-Warburg effect of RA in colorectal carcinoma
Hif1a↓, RA inhibits hypoxia-inducible factor-1 alpha (HIF-1α) and downregulates miR-155
miR-155↓,
p‑PI3K↑, RA has been shown to upregulate p-PI3K, protecting cells through the PI3K/Akt pathway,
ROS↑, RA, induces significant ROS generation in A549 cells, which triggers both apoptosis and autophagy.
*IronCh↑, RA’s dual nature as both a phenolic acid and a flavonoid-related compound enables it to chelate metal ions and prevent the formation of free radicals,

2220- SK,    Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades
- in-vivo, Nor, NA
*RenoP↑, Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture.
*ROS↓, Shikonin Defended against Renal Oxidative Stress and Activated the SIRT1/Nrf2/HO-1 Cascades in Rats with Gentamicin-Induced Renal Damage
*SIRT1↓,
*NRF2↑,
*HO-1↑,
*GSH↑, significant rise in GSH, TAC levels, and SOD activity, as well as SIRT1, Nrf2, and HO-1 protein levels
*TAC↑,
*SOD↑,
*MDA↓, significant decrease in the renal MDA, NO, and iNOS
*NO↓,
*iNOS↓,
*NHE3↑, shikonin treatment significantly and dose-dependently enhanced the reduced NHE3 level and mRNA expression induced by repeated gentamicin injections,
*PI3K↑, in the current study, shikonin treatment of the gentamicin-injected groups increased PI3K

4216- SSE,    Selenium ameliorates mercuric chloride-induced brain damage through activating BDNF/TrKB/PI3K/AKT and inhibiting NF-κB signaling pathways
- in-vitro, NA, NA
*BDNF↑, In summary, Na2SeO3 ameliorated HgCl2-induced brain injury via inhibiting apoptosis and inflammation through activating BDNF/TrKB/PI3K/AKT and suppressing NF-κB pathways.
*TrkB↓,
*PI3K↑,
*Akt↑,
*neuroP↑, Se has neuroprotective effects and antagonize the toxicity of heavy metals

2138- TQ,    Thymoquinone has a synergistic effect with PHD inhibitors to ameliorate ischemic brain damage in mice
- in-vivo, Nor, NA
*Hif1a↑, TQ can activate the HIF-1α pathway and its downstream genes such as VEGF, TrkB, and PI3K, which in turn enhance angiogenesis and neurogenesis.
*VEGF↑,
*TrkB↑,
*PI3K↑,
*angioG↑, which in turn enhance angiogenesis and neurogenesis.
*neuroG↑,
*motorD↑, TQ has the same effect as DMOG to activate HIF-1 α and can improve motor dysfunction after ischemic stroke

2106- TQ,    Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy
- Review, Var, NA
Apoptosis↑, The anticancer power of TQ is accomplished by several aspects; including promotion of apoptosis, arrest of cell cycle and ROS generation.
TumCCA↑,
ROS↑,
*Catalase↑, activation of antioxidant cytoprotective enzymes including, CAT, SOD, glutathione reductase (GR) [80], glutathione-S-transferase (GST) [81] and glutathione peroxidase (GPx) - scavenging H2O2 and superoxide radicals and preventing lipid peroxidation
*SOD↑,
*GR↑,
*GSTA1↓,
*GPx↑,
*H2O2↓,
*ROS↓,
*lipid-P↓,
*HO-1↑, application of TQ to HaCaT (normal) cells promoted the expression of HO-1 in a concentration and time-dependent pattern
p‑Akt↓, TQ could induce ROS which provoked phosphorylation and activation of Akt and AMPK-α
AMPKα↑,
NK cell↑, TQ was outlined to enhance natural killer (NK) cells activity
selectivity↑, Many researchers have noticed that the growth inhibitory potential of TQ is particular to cancer cells
Dose↝, Moreover, TQ has a dual effect in which it can acts as both pro-oxidant and antioxidant in a dose-dependent manner; it acts as an antioxidant at low concentration whereas, at higher concentrations it possess pro-oxidant property
eff↑, Pro-oxidant property of TQ occurs in the presence of metal ions including copper and iron which induce conversion of TQ into semiquinone. This leads to generation of reactive oxygen species (ROS) causing DNA damage and induction of cellular apoptosis
GSH↓, TQ for one hour resulted in three-fold increase of ROS while reduced GSH level by 60%
eff↓, pre-treatment of cells with N-acetylcysteine, counteracted TQ-induced ROS production and alleviated growth inhibition
P53↑, TQ provokes apoptosis in MCF-7 cancer cells by up regulating the expression of P53 by time-dependent manner.
p‑STAT3↓, TQ inhibited the phosphorylation of STAT3
PI3K↑, via up regulation of PI3K and MPAK signalling pathway
MAPK↑,
GSK‐3β↑, TQ produced apoptosis in cancer cells and modulated Wnt signaling by activating GSK-3β, translocating β-catenin
ChemoSen↑, Co-administration of TQ and chemotherapeutic agents possess greater cytotoxic influence on cancer cells.
RadioS↑, Treatment of cells with both TQ and IR enhanced the antiproliferative power of TQ as observed by shifting the IC50 values for MCF7 and T47D cells from ∼104 and 37 μM to 72 and 18 μM, respectively.
BioAv↓, TQ cannot be used as the primary therapeutic agent because of its poor bioavailability [177,178] and lower efficacy
NRF2↑, TQ to HaCaT cells promoted the expression of HO-1 in a concentration and time-dependent pattern. This was achieved via increasing stabilization of Nrf2

2283- VitK2,    Vitamin K Contribution to DNA Damage—Advantage or Disadvantage? A Human Health Response
- Review, Var, NA
*ER Stress↓, protective effect of vitamin K on blood vessels, by reducing inflammation and stress ER
*toxicity↓, Natural forms of vitamin K–K1 and K2—have only a low potential for toxicity
*toxicity↑, However, K3 may demonstrate harmful potential: synthetic vitamin K3 can lead to liver damage
ROS↑, Like another quinone, doxorubicin, menadione exerts its cytotoxic effects by stimulating the generation of oxidative stress, leading to DNA damage
PI3K↑, In bladder cancer cells (T24), vitamin K2 significantly induces PI3K/Akt phosphorylation and increases expression of HIF-1α, intensifying glucose consumption and lactate formation.
Akt↑,
Hif1a↑,
GlucoseCon↑,
lactateProd↑,
ChemoSen↑, Numerous studies indicate that the K vitamins have an additive or synergistic effect on various chemotherapeutic agents.
eff↑, A strong synergism between K1 and sorafenib has been demonstrated in numerous studies
eff↑, ascorbic acid (AA), has a synergistic effect on K3 [73,122,123]. The AA/K3 association leads to an excessive increase in oxidative stress and a decrease in the potential of the mitochondrial membrane, which is a crucial trigger of tumor cell death

1214- VitK2,    Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells
- in-vitro, Bladder, T24/HTB-9 - in-vitro, Bladder, J82
Glycolysis↑, Vitamin K2 renders bladder cancer cells more dependence on glycolysis than TCA cycle
GlucoseCon↑, results suggest that Vitamin K2 is able to induce metabolic stress, including glucose starvation and energy shortage, in bladder cancer cells, upon glucose limitation.
lactateProd↑,
TCA↓, Vitamin K2 promotes glycolysis and inhibits TCA cycle in bladder cancer cells
PI3K↑,
Akt↑,
AMPK↑, Vitamin K2 remarkably activated AMPK pathway
mTORC1↓,
TumAuto↑,
GLUT1↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
HK2↑,
LDHA↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
ACC↓, Vitamin K2 remarkably decreased the amounts of Acetyl coenzyme A (Acetyl-CoA) in T24 cells
PDH↓, suggesting that Vitamin K2 inactivates PDH
eff↓, Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death.
cMyc↓, c-MYC protein level was also significantly reduced in T24 cells following treatment with Vitamin K2 for 18 hours
Hif1a↑, Besides, the increased expression of GLUT-1, HIF-1α, p-AKT and p-AMPK were also detected in Vitamin K2-treated tumor group
p‑Akt↑,
eff↓, 2-DG, 3BP and DCA-induced glycolysis attenuation significantly prevented metabolic stress and rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
eff↓, inhibition of PI3K/AKT and HIF-1α notably attenuated Vitamin K2-upregulated glycolysis, indicating that Vitamin K2 promotes glycolysis in bladder cancer cells via PI3K/AKT and HIF-1α signal pathways.
eff↓, (NAC, a ROS scavenger) not only alleviated Vitamin K2-induced AKT activation and glycolysis promotion, but also significantly suppressed the subsequent AMPK-dependent autophagic cell death.
eff↓, glucose supplementation not only restored c-MYC expression, but also rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
ROS↑, under glucose limited condition, the increased glycolysis inevitably resulted in metabolic stress, which augments ROS accumulation due to lack of glucose for sustained glycolysis.


Showing Research Papers: 1 to 42 of 42

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 42

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   Catalase↓, 1,   Catalase↑, 1,   GSH↓, 1,   GSH↑, 1,   hyperG↓, 1,   lipid-P↓, 1,   NRF2↓, 1,   NRF2↑, 2,   ROS↑, 10,   ROS⇅, 1,   SIRT3↑, 1,   SOD↑, 2,   SOD2↓, 1,   Trx↓, 1,  

Metal & Cofactor Biology ⓘ

KLF5↓, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 1,   MEK↓, 1,   MKK4↓, 1,   MMP↓, 3,   Raf↓, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACC↓, 1,   AMPK↑, 3,   cMyc↓, 1,   p‑ENO1↓, 1,   GlucoseCon↑, 2,   Glycolysis↑, 1,   HK2↑, 1,   lactateProd↑, 2,   LDHA↑, 1,   NADPH↑, 1,   PDH↓, 1,   SIRT1↑, 1,   TCA↓, 1,   Warburg↓, 1,  

Cell Death ⓘ

Akt↓, 2,   Akt↑, 6,   p‑Akt↓, 4,   p‑Akt↑, 3,   Apoptosis↑, 6,   ASK1↑, 1,   Bak↑, 1,   BAX↑, 3,   Bax:Bcl2↑, 1,   Bcl-2↓, 1,   BIM↑, 1,   BMP2↓, 1,   Casp3↑, 2,   Casp9↑, 1,   Cyt‑c↑, 1,   Fas↑, 1,   JNK↑, 1,   MAPK↑, 4,   p38↓, 1,   p38↑, 2,   TRPV1↑, 1,   TumCD↑, 2,  

Kinase & Signal Transduction ⓘ

AMPKα↑, 1,   HER2/EBBR2↓, 1,   p‑p70S6↑, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 1,  

Autophagy & Lysosomes ⓘ

TumAuto↑, 2,  

DNA Damage & Repair ⓘ

DNAdam↑, 4,   P53↑, 3,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK4↑, 2,   cycD1/CCND1↓, 1,   TumCCA↑, 6,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,   p‑ERK↓, 1,   p‑ERK↑, 1,   p‑FOXO3↓, 1,   Gli1↓, 1,   GSK‐3β↑, 2,   p‑GSK‐3β↑, 1,   HDAC2↓, 1,   HDAC8↓, 1,   IGF-1↓, 1,   IGF-1R↓, 1,   mTOR↓, 1,   mTOR↑, 2,   mTORC1↓, 1,   Nanog↓, 1,   OCT4↓, 1,   PI3K↑, 12,   p‑PI3K↑, 1,   STAT3↓, 1,   STAT3↑, 1,   p‑STAT3↓, 1,   TumCG↓, 1,   Wnt↓, 1,  

Migration ⓘ

Ca+2↑, 2,   E-cadherin↑, 2,   F-actin↓, 1,   FAK↓, 1,   KLF2↓, 1,   MARK4↓, 1,   miR-155↓, 1,   MMP2↓, 2,   MMP9↓, 3,   N-cadherin↓, 1,   PKA↓, 1,   Snail↓, 1,   TumCMig↓, 1,   TumCP↓, 2,   TumCP↑, 1,   Twist↓, 1,   Vim↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   EGFR↓, 1,   Hif1a↓, 2,   Hif1a↑, 2,   VEGF↓, 1,  

Barriers & Transport ⓘ

GLUT1↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   Inflam↓, 1,   NF-kB↓, 1,   NK cell↑, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,   AR↑, 1,   CDK6↑, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 2,   BioAv↑, 1,   ChemoSen↑, 3,   ChemoSen⇅, 1,   Dose↝, 1,   eff↓, 6,   eff↑, 7,   eff↝, 1,   eff∅, 1,   RadioS↑, 2,   selectivity↑, 2,  

Clinical Biomarkers ⓘ

AR↓, 1,   AR↑, 1,   BG↓, 1,   EGFR↓, 1,   GutMicro↑, 1,   HER2/EBBR2↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 4,   AntiTum↑, 1,   chemoP↑, 2,   hepatoP↑, 1,   OS↑, 1,   radioP↑, 1,   Risk↓, 1,   TumVol↓, 1,  
Total Targets: 148

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 17,   Catalase↑, 7,   GPx↑, 4,   GSH↑, 12,   GSH/GSSG↑, 1,   GSTA1↓, 1,   H2O2↓, 2,   H2O2∅, 1,   HO-1↑, 6,   HO-2↓, 1,   Iron↓, 1,   lipid-P↓, 4,   MDA↓, 8,   NRF2↓, 1,   NRF2↑, 12,   RNS↓, 1,   ROS↓, 18,   ROS∅, 1,   SOD↑, 9,   SOD2↑, 1,   TAC↑, 1,  

Metal & Cofactor Biology ⓘ

Ferritin↑, 1,   IronCh↑, 5,  

Core Metabolism/Glycolysis ⓘ

AMP↓, 1,   AMPK↑, 4,   AMPK⇅, 1,   CREB↑, 1,   FAO↑, 1,   glucose↑, 1,   GlucoseCon↑, 2,   LDH↓, 1,   LDL↓, 1,   NADPH↓, 1,   NADPH∅, 1,   PPARγ↓, 1,   PPARγ↑, 1,   SIRT1↓, 1,   SIRT1↑, 1,  

Cell Death ⓘ

Akt?, 1,   Akt↓, 1,   Akt↑, 25,   p‑Akt↑, 1,   Apoptosis↓, 2,   BAX↓, 1,   Bax:Bcl2↓, 1,   Bcl-2↑, 2,   Casp1↓, 1,   Casp3↓, 1,   iNOS↓, 2,   p‑JNK↑, 1,   MAPK↓, 3,   MAPK↑, 6,   p38↑, 2,  

Transcription & Epigenetics ⓘ

Ach↑, 2,   other↓, 1,   other↑, 1,   other↝, 1,  

Protein Folding & ER Stress ⓘ

ER Stress↓, 2,   HSP90↑, 1,  

DNA Damage & Repair ⓘ

DNArepair↑, 1,   p16↓, 1,   TP53↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1,   ERK↑, 5,   p‑ERK↑, 1,   FOXO1↝, 1,   GSK‐3β↓, 4,   GSK‐3β↑, 1,   Jun↓, 1,   mTOR↑, 2,   neuroG↑, 1,   p‑P70S6K↑, 1,   PI3K↑, 30,   PTEN↓, 2,   PTEN↑, 1,  

Migration ⓘ

APP↓, 1,   Ca+2↓, 1,   MMP3↓, 1,   MMP9↓, 2,   PKA↑, 1,   PKCδ↑, 2,   VCAM-1↓, 3,  

Angiogenesis & Vasculature ⓘ

angioG↑, 1,   eNOS↑, 2,   Hif1a↑, 1,   NO↓, 3,   VEGF↑, 1,  

Barriers & Transport ⓘ

BBB↑, 5,   GLUT1↑, 1,   GLUT4↑, 2,   NHE3↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   ICAM-1↓, 1,   IKKα↓, 1,   IL1β↓, 3,   IL6?, 1,   IL6↓, 1,   Inflam↓, 10,   Inflam↑, 1,   NF-kB↓, 7,   NF-kB↑, 1,   PGE2↓, 1,   TLR4↓, 1,   TNF-α↓, 4,  

Synaptic & Neurotransmission ⓘ

5HT↑, 2,   AChE↓, 4,   ADAM10↑, 1,   BChE↓, 1,   BDNF↑, 6,   ChAT↑, 1,   GABA↑, 1,   MAOA↓, 1,   tau↓, 5,   p‑tau↓, 2,   TrkB↓, 1,   TrkB↑, 4,  

Protein Aggregation ⓘ

Aβ↓, 6,   BACE↓, 2,   IDE↑, 1,   NLRP3↓, 2,   PP2A↑, 2,  

Hormonal & Nuclear Receptors ⓘ

GR↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   BioAv↝, 4,   Dose↑, 1,   Dose↝, 1,   eff↓, 1,   eff↑, 2,  

Clinical Biomarkers ⓘ

BP↝, 1,   Ferritin↑, 1,   IL6?, 1,   IL6↓, 1,   LDH↓, 1,   TP53↑, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   AntiDiabetic↑, 1,   cardioP↑, 4,   CardioT↓, 1,   cognitive↑, 9,   fatigue↓, 1,   hepatoP↑, 3,   memory↑, 9,   motorD↑, 1,   neuroP↑, 17,   radioP↑, 1,   RenoP↑, 1,   toxicity↓, 1,   toxicity↑, 1,  
Total Targets: 148

Scientific Paper Hit Count for: PI3K, Phosphatidylinositide-3-Kinases
4 Quercetin
3 Alpha-Lipoic-Acid
3 Bacopa monnieri
2 Chrysin
2 diet FMD Fasting Mimicking Diet
2 Ginseng
2 Lycopene
2 Resveratrol
2 Thymoquinone
2 Vitamin K2
1 Acetyl-l-carnitine
1 Apigenin (mainly Parsley)
1 Astaxanthin
1 Baicalin
1 Berberine
1 Carnosic acid
1 Capsaicin
1 Caffeic Acid Phenethyl Ester (CAPE)
1 Coenzyme Q10
1 Curcumin
1 Chemotherapy
1 Fisetin
1 Ginger/6-Shogaol/Gingerol
1 Magnetic Fields
1 Myricetin
1 Parthenolide
1 Radiotherapy/Radiation
1 Rosmarinic acid
1 Shikonin
1 Selenite (Sodium)
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#:252  State#:%  Dir#:2
  wNotes=on  sortOrder:rid,rpid

 

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