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Aims/Introduction: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α‐cells. Materials and Methods: Experiments were carried out in high‐fat, high‐sucrose diet‐fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme‐linked immunosorbent assay; the latter eliminates cross‐reactivities with other proglucagon‐derived peptides. Results: Plasma glucagon, insulin and glucagon‐like peptide‐1 levels were increased by imeglimin administration in high‐fat, high‐sucrose diet‐fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long‐term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long‐term administration of imeglimin did not alter α‐cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein‐1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. Conclusions: Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single‐strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin‐dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho‐histone H3 (p‐hH3)‐positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p‐hH3‐positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine‐mediated DNA damage, namely DNA double‐strand breaks, as shown by increased γ‐H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC‐derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC. [ABSTRACT FROM AUTHOR]

Objective: The hypothalamus is the brain center that controls the energy balance. Anorexigenic proopiomelanocortin (POMC) neurons and orexigenic AgRP neurons in the arcuate nucleus of the hypothalamus plays critical roles in energy balance regulation. FoxO1 is a transcription factor regulated by insulin signaling that is deacetylated by Sirt1, a nicotinamide adenine dinucleotide- (NAD(+) -) dependent deacetylase. Overexpression of insulin-resistant constitutively-nuclear FoxO1 (CN-FoxO1) in POMC neurons leads to obesity, whereas Sirt1 overexpression in POMC neurons leads to leanness. Whether overexpression of Sirt1 in POMC neurons could rescue the obesity caused by insulin-resistant CN-FoxO1 was tested here.Methods: POMC neuron-specific CN-FoxO1/Sirt1 double-KI (DKI) mice were analyzed.Results: The obese phenotype of CN-FoxO1 KI mice was rescued in male DKI mice. Reduced O2 consumption, increased adiposity, and fewer POMC neurons observed in CN-FoxO1 mice were rescued in male DKI mice without affecting food intake and locomotor activity. Sirt1 overexpression decreased FoxO1 acetylation and protein levels without affecting its nuclear localization in mouse embryonic fibroblasts and hypothalamic N41 cells.Conclusions: Sirt1 rescues the obesity induced by insulin-resistant CN-FoxO1 in POMC neurons of male mice by decreasing FoxO1 protein through deacetylation. Sirt1 ameliorates obesity caused by a genetic model of central insulin resistance. [ABSTRACT FROM AUTHOR]