Previously, compound 19e, a novel heteroaryl-containing benzamide derivative, was identified as a potent glucokinase activator (GKA) and showed a glucose-lowering effect in diabetic mice. In this study, the anti-apoptotic actions of 19e were evaluated in INS-1 pancreatic beta-cells co-treated with TNF-α and IL-1β to induce cell death. Compound 19e protected INS-1 cells from cytokine-induced cell death, and the effect was similar to treatment with another GKA or exendin-4. Compound 19e reduced annexin-V stained cells and the expression of cleaved caspase-3 and poly (ADP-ribose) polymerase protein, as well as upregulated the expression of B-cell lymphoma-2 protein. Compound 19e inhibited apoptotic signaling via induction of the ATP content, and the effect was correlated with the downregulation of nuclear factor-κB p65 and inducible nitric oxide synthase. Further, 19e increased NAD-dependent protein deacetylase sirtuin-1 (SIRT1) deacetylase activity, and the anti-apoptotic effect of 19e was attenuated by SIRT1 inhibitor or SIRT1 siRNA treatment. Our results demonstrate that the novel GKA, 19e, prevents cytokine-induced beta-cell apoptosis via SIRT1 activation and has potential as a therapeutic drug for the preservation of pancreatic beta-cells.

中文翻译：

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化合物19e是新型的葡萄糖激酶激活剂，可防止INS-1细胞中细胞因子诱导的β细胞凋亡。

以前，化合物19e是一种新型的含杂芳基的苯甲酰胺衍生物，被确定为有效的葡萄糖激酶激活剂（GKA），并在糖尿病小鼠中表现出降糖作用。在这项研究中，在与TNF-α和IL-1β共同诱导细胞死亡的INS-1胰岛β细胞中评估了19e的抗凋亡作用。化合物19e保护INS-1细胞免受细胞因子诱导的细胞死亡，其作用类似于另一种GKA或exendin-4的治疗。化合物19e减少了膜联蛋白-V染色的细胞和裂解的caspase-3和聚（ADP-核糖）聚合酶蛋白的表达，并上调了B细胞淋巴瘤2蛋白的表达。化合物19e通过诱导ATP含量抑制凋亡信号转导，其作用与核因子-κBp65和诱导型一氧化氮合酶的下调有关。此外，19e增加了NAD依赖性蛋白脱乙酰基酶Sirtuin-1（SIRT1）脱乙酰基酶的活性，并且通过SIRT1抑制剂或SIRT1 siRNA处理减弱了19e的抗凋亡作用。我们的结果表明，新型GKA 19e可通过SIRT1激活阻止细胞因子诱导的β细胞凋亡，并具有作为治疗胰腺β细胞的治疗药物的潜力。