Table 5.

Antioxidants influence PI3K/Akt and/or activities

Antioxidants	Model system	Observed effects	Ref.
Anthocyanidins	Hypercholesterolaemic patients, human stomach cancer cells, human breast cancer cells, human hepato-carcinoma cells.	Suppress PI3K/Akt signaling pathway via epidermal growth factor receptor pathway, or levels of pSGSK3β and β-catenin in a tumor xenograft model.	[163–166]
Mulberry anthocyanidin	Human liver cancer cells.	Activate PI3K/Akt.	[167]
Berberine	Human melanoma cells, SD rats.	Inhibit PI3K/Akt and/or GSK3β activities.	[52, 168]
	Murine neural crest cells, murine primary neurons, mice with cerebral and reperfusion, human chondrosarcoma cells.	Increase PI3K/Akt activities and cell growth/survival in other studies.	[169, 170]
Curcumin	Human Burkitts’ lymphoma, human esophageal cancer cells, human renal cancer cells.	Enhance radiation- or PI3K/Akt inhibitors-induced or directly induce apoptosis by suppression of PI3K/Akt signaling pathway.	[171–173]
	Rat cardiomyocytes, human prostate cancer cells, Balb/c mice.	Protect cells from apoptosis induced by a high glucose level via upregulation of Akt/GSK3β serine/threonine phosphorylation levels via protein phosphatase-dependent mechanism or inhibits GSK3β activity in vitro or in vivo.	[174–176]
Ergosterol	Streptozotocin-induced diabetes in mice, human cancer cells.	Restore PI3K/Akt signaling damaged in diabetic mice; ergosterol-related compounds induce cell apoptosis depending on a protein-promoted Akt activation.	[177, 178]
Garlicin	Human cellosaurus cells	Suppress PI3K/Akt pathway.	[179]
Garlic	Fructose-fed diabetic SD rats	Activate PI3K/Akt in Diabetes rats.	[96]
Luteolin	Human epidermoid carcinoma cells and their murine cells xenograft model, human umbilical vein endothelial cells, human prostate cancer cells, human colon cancer cells, human glioblastoma cells.	Inhibit VEGF-increased PI3K/Akt activities or IGF-1-increased the phosphorylation levels of PI3K/Akt/GSK3 or down-regulate PI3K/Akt pathway.	[180–183]
	Cardiomyocyte in rats with ischemia/reperfusion, murine neural crest cells.	Decrease apoptosis via PI3K/Akt pathway in a rat model or persistently activate Akt in cells.	[184, 185]
Lycopene	Prostate epithelial cells.	Inhibit IGF-1-induced Akt/GSK3 serine/threonine phosphorylation levels.	[83]
	Patients, human prostate cells.	Its effects on PI3K/Akt pathway are inhibitory in prostate cancer.	[186]
Phytoestrogens	Human embryonic kidney cells, mouse preosteoblastic cells.	Increase phosphorylation levels of Akt and GSK3β as well as the Wnt/β-catenin signaling.	[187]
Isoflavones	Human cancer cells	Inhibit PI3K/Akt signaling in cancer cells.	[188]
Soy isoflavone	SD rats with myocardial ischemia/reperfusion.	Gain PI3K/Akt pathway activities in ovariectomized rats.	[189]
Daidzein or genistein	Nude mice with various tumors	Up-regulate or down-regulate GSK3 gene/protein expression, and both belong to isoflavones.	[190]
Psoralidin	Human lung fibroblasts, mice.	A coumestan derivative suppresses pro-inflammatory cytokines and regulates PI3K/Akt pathway.	[191]
Resveratrol	Mouse cardiac fibroblasts, human glioma cells.	Inhibit high glucose-induced PI3K/Akt pathway and inflammation or reduces PI3K/Akt activities.	[63, 192]
	Neural crest cells, APP/PS1 mice.	Protect cells from apoptosis induced by high glucose via activation of PI3K/Akt pathways and increase in vivo pSGSK3β levels.	[193, 194]
Lignan including  honokiol and  sauchinone	Human prostate cancer cells, human myeloid leukaemic cells, mouse microphage, mouse lymphoblast, splenic lymphocytes, human glioma, breast and prostate cancer cells, human hepatocytes, WT and a Nrf2 KO C57/BL6 mice.	Inhibits Akt signaling and generate anti-inflammatory effect via inhibition of PI3K/Akt pathway or mediate suppression of PI3K; however sauchinone, augments in vivo pSGSK3β levels.	[195–198]

^a Nrf2 nuclear factor (erythroid derived 2)-like 2