Luo Yunfei, Sun Shaohua, Zhang Yuying, Liu Shuang, Zeng Haixia, Li Jin-E, Huang Jiadian, Fang Lixuan, Yang Shiqi, Yu Peng, Liu Jianping
Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People's Republic of China.
Department of Metabolism and Endocrinology, XinSteel Center Hospital, Xinyu, Jiangxi, 338000, People's Republic of China.
Drug Des Devel Ther. 2024 Dec 5;18:5685-5700. doi: 10.2147/DDDT.S485729. eCollection 2024.
Oltipraz has various applications, including for treating cancer, liver fibrosis, and cirrhosis. However, its role in regulating metabolic processes, inflammation, oxidative stress, and insulin resistance in STZ-induced T2DM remains unclear. Hence, a comprehensive understanding of how oltipraz ameliorates diabetes, particularly inflammation and oxidative stress, is imperative.
The negative control (NC), T2DM model (T2DM), and T2DM models treated with oltipraz (OLTI) and metformin (MET) were constructed. The RNA sequencing (RNA-Seq) was performed on the pancreatic tissues. H&E staining was conducted on the liver and pancreatic tissues. The intraperitoneal glucose tolerance test (IPGTT), blood glucose and lipids, inflammatory factors, and oxidative stress indexes were measured. qPCR and Western blotting examined the nuclear factor erythroid-derived 2-like 2 (Nrf2) hemoglobin-1 (HO-1) signaling pathway, cell apoptosis-related genes, and Reg3g levels. Immunofluorescence (IF) analysis of the pancreas was performed to measure insulin secretion.
A total of 256 DEGs were identified in OLTI_vs_T2DM, and they were mainly enriched in circadian rhythm, cAMP, AMPK, insulin, and MAPK signaling pathways. Moreover, Reg3g exhibits reduced expression in T2DM_vs_NC, and elevated expression in OLTI_vs_T2DM, yet remains unchanged in MET_vs_T2DM. OLTI reduced fasting blood glucose and alleviated T2DM-induced weight loss. It improved blood glucose and insulin resistance, decreased blood lipid metabolism, reduced inflammation and oxidative stress through the Nrf2/HO-1 signaling pathway, mitigated pancreatic and liver tissue injury, and enhanced pancreatic β-cell insulin secretion. OLTI exhibited anti-apoptosis effects in T2DM. Moreover, OLTI exhibits superior antioxidant activity than metformin.
In summary, OLTI improves blood glucose and insulin resistance, decreases blood lipid metabolism, reduces inflammation and apoptosis, suppresses oxidative stress through the Nrf2/HO-1 signaling pathway, mitigates pancreatic and liver tissue injury, and enhances pancreatic β-cell insulin secretion, thereby mitigating T2DM symptoms. Moreover, Reg3g could be an important target for OLTI treatment of T2DM.
奥替普拉有多种应用，包括治疗癌症、肝纤维化和肝硬化。然而，其在调节链脲佐菌素诱导的2型糖尿病（T2DM）的代谢过程、炎症、氧化应激和胰岛素抵抗中的作用仍不清楚。因此，全面了解奥替普拉如何改善糖尿病，特别是炎症和氧化应激，势在必行。
构建阴性对照（NC）、T2DM模型（T2DM）以及用奥替普拉（OLTI）和二甲双胍（MET）治疗的T2DM模型。对胰腺组织进行RNA测序（RNA-Seq）。对肝脏和胰腺组织进行苏木精-伊红（H&E）染色。测量腹腔内葡萄糖耐量试验（IPGTT）、血糖和血脂、炎症因子及氧化应激指标。采用qPCR和蛋白质印迹法检测核因子红细胞衍生2样2（Nrf2）血红素加氧酶-1（HO-1）信号通路、细胞凋亡相关基因及Reg3g水平。对胰腺进行免疫荧光（IF）分析以测量胰岛素分泌。
在OLTI_vs_T2DM中总共鉴定出256个差异表达基因（DEG），它们主要富集于昼夜节律、环磷酸腺苷（cAMP）、腺苷酸活化蛋白激酶（AMPK）、胰岛素和丝裂原活化蛋白激酶（MAPK）信号通路。此外，Reg3g在T2DM_vs_NC中表达降低，在OLTI_vs_T2DM中表达升高，但在MET_vs_T2DM中保持不变。OLTI降低空腹血糖并减轻T2DM诱导的体重减轻。它改善血糖和胰岛素抵抗，降低血脂代谢，通过Nrf2/HO-1信号通路减轻炎症和氧化应激，减轻胰腺和肝脏组织损伤，并增强胰腺β细胞胰岛素分泌。OLTI在T2DM中表现出抗凋亡作用。此外，OLTI表现出比二甲双胍更强的抗氧化活性。
总之，OLTI改善血糖和胰岛素抵抗，降低血脂代谢，减轻炎症和凋亡，通过Nrf2/HO-1信号通路抑制氧化应激，减轻胰腺和肝脏组织损伤，并增强胰腺β细胞胰岛素分泌，从而减轻T2DM症状。此外，Reg3g可能是OLTI治疗T2DM的重要靶点。
