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| Substances | Effect and mechanism | Target population | Reference |
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Cardiovascular | Renin-angiotensin-aldosterone-system (RAAS) inhibitors | Inhibits NADPH-PKC-β–p66Shc axis, so decrease ROS level and cellular apoptosis | — | [20] |
Carvedilol | Reduces ROS level and inflammatory markers | Streptozotocin-induced diabetic rat | [88] |
Adiponectin | Prevents myocardial injury by inhibition of p66Shc | High glucose-treated human cardiac myocytes | [89] |
Pioglitazone | Partially preserves HSPC mobilization by PPAR-γ activation and downregulation of OSM and p66Shc | In diabetic rats and diabetic patients | [92] |
PKC inhibitors like ruboxistaurin and GF109203X | Decrease diabetes-related cardiovascular complication and rescue endothelial vasodilation through reducing NADPH-related ROS production and modulating p66Shc | Diabetic patients | [12, 24] |
C peptide | Inhibits persistent overactivation of p66Shc and p53 after glucose normalization, reduces ONOO(-) and ROS production, decreases endothelial cell apoptosis, and improves vascular injury | In vitro and in vivo in human umbilical vein endothelial cells and diabetic mice | [34, 94] |
Vitamin D receptor agonist | Inhibits PIN1-p66Shc axis and improves vascular dysfunction | Streptozotocin-induced diabetic mice | [95] |
Diabetic nephropathy | RAAS inhibitors | Since angiotensin II upregulates p66Shc in proximal tubule cells, RAAS inhibitors can have protective effect | — | [10] |
Probucol | Epigenetically downregulates p66Shc expression and can prevent diabetes-induced renal tubular injury | Streptozotocin-induced diabetic mice and high glucose-treated HK-2 cells | [28, 94] |
Piperazine ferulate (PF) | Can inhibit p66Shc and has protective effect against high glucose-induced mesangial injury | In vitro mesangial cells and in vivo on diabetic mice | [102] |
Enzastaurin | Inhibits PKCβ-p66shc-NADPH oxidase pathway and has protective effect against diabetic nephropathy | Streptozotocin-induced diabetic rats and in vitro on high glucose-treated human renal proximal tubule epithelial cells (HK-2 cells) | [45] |
Rottlerin | A PKCδ inhibitor, thus has inhibitory effect on PKCδ/p66Shc axis | High glucose-treated HK-2 cells | [99] |
Corcumin | Inhibits PKCβII/p66Shc axis and prevents diabetic nephropathy | Streptozotocin-induced diabetic rats | [105] |
Dioscorea zingiberensis | Possibly inhibits p66Shc activity. It shows protective effects against diabetic-induced nephropathy. | High-fat diet/streptozotocin-induced diabetic mice | [106] |
Activated protein C (aPC) | Causes epigenetic changes in p66Shc promoter and suppresses its expression | Rats with diabetic nephropathy | [10, 107]. |
Resveratrol | Activates SIRT1, thus suppresses p66Shc and improves mitochondrial function | Glucose-treated mesangial cells and | [10] |
Retinopathy | Exendin-4 | By inhibition of JNK, protein kinase-β, and p66Shc, it has protective effect against diabetic retinopathy | Adult human retinal pigment epithelial-19 cells | [110] |
Wound healing | Ganoderma lucidum polysaccharide (Gl-PS) | Improves diabetic wound healing and increases angiogenesis. p66Shc suppression is one of its mechanisms | STZ-induced diabetic mice | [112] |
Erectile dysfunction | Argirein | Inhibiton of p66Shc overactivity | Diabetic rats | [116] |
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