Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes.

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.

Ganoderic acid A alleviates hypoxia-induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways.

Effects of ganoderic acid A (GAA), a lanostane triterpene, on hypoxia-ischemia encephalopathy (HIE) remain unclear. We aimed to figure out the specific role of GAA in hypoxia-treated neural stem cells (NSCs) as well as the regulatory mechanisms. Primary rat NSCs were incubated under hypoxia to simulate HIE. Viability and apoptosis of hypoxia-injured NSCs were measured by cell counting kit-8 and flow cytometry assays, respectively. Proteins related to apoptosis, autophagy, and the PI3K/AKT/mTOR pathways were evaluated by Western blot analysis. LY294002 and rapamycin were added to inhibit the PI3K/AKT pathway and mTOR pathway, respectively. Enzyme-linked immunosorbent assay was carried out to test the release of proinflammatory cytokines. We found that hypoxia-induced decrease of cell viability, increases of apoptotic cells and autophagy, and the release of IL-6, IL-1ß, and TNF-α were all attenuated by GAA stimulation. Activation of caspases induced by hypoxia was alleviated by GAA. Furthermore, we found that inhibition of the PI3K/AKT pathway eliminated the effects of GAA on apoptosis and proinflammatory cytokines release in hypoxia-injured NSCs. Meanwhile, inhibition of the mTOR pathway abrogated the effects of GAA on cell autophagy in hypoxia-injured NSCs. In conclusion, GAA alleviated hypoxia-induced injury in NSCs might be through activating the PI3K/AKT and mTOR pathways.