Cancer cells are continuously challenged by adverse environmental factors including hypoxia, metabolite restriction, and immune reactions, and must adopt diverse strategies to survive. Heat shock protein (Hsp) 70 plays a central role in protection against stress-induced cell death by maintaining protein homeostasis and interfering with the process of programmed cell death. Recent findings have suggested that Hsp70 acetylation is a key regulatory modification required for its chaperone activity, but its relevance in the process of programmed cell death and the underlying mechanisms involved are not well understood. In this study, we sought to investigate mechanisms mediated by Hsp70 acetylation in relation to apoptotic and autophagic programmed cell death. Upon stress-induced apoptosis, Hsp70 acetylation inhibits apoptotic cell death, mediated by Hsp70 association with apoptotic protease-activating factor (Apaf)-1 and apoptosis-inducing factor (AIF), key modulators of caspase-dependent and -independent apoptotic pathways, respectively. Hsp70 acetylation also attenuated autophagic cell death associated with upregulation of autophagy-related genes and autophagosome induction. Collectively, these results suggest that the acetylation of Hsp70 plays key regulatory roles in cell death pathways as well as in its function as a chaperone, together enabling cellular protection in response to stress.

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G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

G-protein-coupled receptor 119 (GPR119) represents a promising target for the treatment of type 2 diabetes as it can increase both GLP-1 secretion from intestinal L cells and glucose-stimulated insulin secretion (GSIS) from pancreatic β cells. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received much interest for the treatment of type 2 diabetes. Here, we identified a novel small-molecule GPR119 agonist, YH18421 and evaluated its therapeutic potential. YH18421 specifically activated human GPR119 with high potency and potentiated GLP-1 secretion and GSIS in vitro cell based systems. In normal mice, single oral administration of YH18421 improved glucose tolerance. Combined treatment of YH18421 and the DPP-4 inhibitor augmented both plasma active GLP-1 levels and glycemic control. In diet induced obese (DIO) mice model, glucose lowering effect of YH18421 was maintained after 4 weeks of repeat dosing and YH18421 acted additively with DPP-IV inhibitor. We also observed that YH18421 inhibited weight gain during 4 weeks of administration in DIO mice. These data demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and combination with the DPP-IV inhibitor maybe an effective strategy for the treatment of type 2 diabetes.