Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet β-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to β-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve β-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for the PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in β-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of β-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet β-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring β-cell mass and islet size, respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD-impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet β-cells both in vitro and in vivo.

中文翻译：

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Tectorigenin 通过激活 ERK 和减少 ER 应激来增强 PDX1 表达并保护胰腺 β 细胞。

胰腺/十二指肠同源框蛋白 1 (PDX1) 是调节胰岛 β 细胞增殖、分化和功能的重要转录因子。PDX1 的表达降低被认为是导致糖尿病中 β 细胞丢失和功能障碍的原因。因此，促进 PDX1 表达可能是保护 β 细胞质量和功能的有效策略。此前，我们建立了一个 PDX1 启动子依赖性荧光素酶系统来筛选可以促进 PDX1 表达的试剂。天然化合物鸢尾黄素 (TG) 被鉴定为一种有前途的候选物，可以增强 PDX1 基因启动子的活性。在这项研究中，我们首先证明了 TG 可以通过激活细胞外信号相关激酶 (ERK) 来促进 PDX1 在 β 细胞中的表达，如 ERK 磷酸化增加所示；在正常或葡萄糖毒性/脂毒性条件下观察到这种效应。然后我们发现 TG 可以通过激活 ERK 和减少活性氧和内质网 (ER) 应激来抑制诱导的细胞凋亡并提高 β 细胞在糖毒性和脂毒性下的活力。这些作用在体内也同样适用：预防性或治疗性使用 TG 可以明显抑制 ER 应激并减少给予高脂肪/高蔗糖饮食 (HFHSD) 的小鼠胰腺中的胰岛 β 细胞凋亡，从而显着维持或分别恢复 β 细胞质量和胰岛大小。因此，TG 的预防性和治疗性使用都改善了小鼠 HFHSD 受损的葡萄糖代谢，这可以通过改善高血糖和葡萄糖耐受不良来证明。综合起来，TG，