淫羊藿苷通过 GPER/Sirt1/HMGB1 信号通路抑制炎症,从而减轻 1 型糖尿病大鼠的血管内皮功能障碍

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Chinese Journal of Natural Medicines Pub Date : 2024-04-01 DOI:10.1016/S1875-5364(24)60618-7
Wenhui YAO , Rongpin TAO , Kai WANG, Xuansheng DING
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引用次数: 0

摘要

淫羊藿苷是从淫羊藿中提取的一种黄酮苷。本研究旨在研究淫羊藿苷通过抑制高迁移率组盒 1(HMGB1)相关炎症对 1 型糖尿病大鼠血管的保护作用,并探索其潜在机制。在链脲佐菌素(STZ)诱导的糖尿病大鼠体内,通过血管反应性研究评估了冰片花素对血管功能障碍的影响。研究人员采用了 Western 印迹和免疫荧光方法来检测目标蛋白的表达。酶联免疫吸附试验(ELISA)测定了 HMGB1 和促炎细胞因子的释放。结果显示,服用冰片苷能增强乙酰胆碱诱导的糖尿病大鼠主动脉血管扩张。它还显著减少了糖尿病大鼠和高葡萄糖(HG)诱导的人脐静脉内皮细胞(HUVECs)中白细胞介素-8(IL-8)、IL-6、IL-1β和肿瘤坏死因子-α(TNF-α)等促炎细胞因子的释放。研究结果还揭示了 rHMGB1 可增加 HUVECs 培养液中的促炎细胞因子。在糖尿病大鼠和 HG 诱导的 HUVEC 中,HMGB1 的释放增加以及 HMGB1 相关炎症因子(包括高级糖化终产物 (RAGE)、Toll 样受体 4 (TLR4) 和磷酸化 p65 (p-p65))的表达上调均被冰片花素显著抑制。值得注意的是,冰片素抑制了 HG 诱导的 HUVEC 中 HMGB1 从细胞核向细胞质的转位。同时,冰片素还能激活G蛋白偶联雌激素受体(GPER)和sirt1。为了探讨GPER和Sirt1在冰片素抑制HMGB1释放和HMGB诱导炎症中的作用,本研究使用了GPER抑制剂和Sirt1抑制剂。这些抑制剂削弱了冰醋酸对 HMGB1 释放和 HMGB1 诱导炎症的影响。特别是,GPER 抑制剂还抑制了冰片素对 Sirt1 的激活。这些研究结果表明,冰片素能激活 GPER 并增加 Sirt1 的表达,进而减少 HMGB1 的转运和释放,从而通过抑制炎症改善 1 型糖尿病大鼠的血管内皮功能。
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Icariin attenuates vascular endothelial dysfunction by inhibiting inflammation through GPER/Sirt1/HMGB1 signaling pathway in type 1 diabetic rats

Icariin, a flavonoid glycoside, is extracted from Epimedium. This study aimed to investigate the vascular protective effects of icariin in type 1 diabetic rats by inhibiting high-mobility group box 1 (HMGB1)-related inflammation and exploring its potential mechanisms. The impact of icariin on vascular dysfunction was assessed in streptozotocin (STZ)-induced diabetic rats through vascular reactivity studies. Western blotting and immunofluorescence assays were performed to measure the expressions of target proteins. The release of HMGB1 and pro-inflammation cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The results revealed that icariin administration enhanced acetylcholine-induced vasodilation in the aortas of diabetic rats. It also notably reduced the release of pro-inflammatory cytokines, including interleukin-8 (IL-8), IL-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). The results also unveiled that the pro-inflammatory cytokines in the culture medium of HUVECs could be increased by rHMGB1. The increased release of HMGB1 and upregulated expressions of HMGB1-related inflammatory factors, including advanced glycation end products (RAGE), Toll-like receptor 4 (TLR4), and phosphorylated p65 (p-p65) in diabetic rats and HG-induced HUVECs, were remarkably suppressed by icariin. Notably, HMGB1 translocation from the nucleus to the cytoplasm in HUVECs under HG was inhibited by icariin. Meanwhile, icariin could activate G protein-coupled estrogen receptor (GPER) and sirt1. To explore the role of GPER and Sirt1 in the inhibitory effect of icariin on HMGB1 release and HMGB-induced inflammation, GPER inhibitor and Sirt1 inhibitor were used in this study. These inhibitors diminished the effects of icariin on HMGB1 release and HMGB1-induced inflammation. Specifically, the GPER inhibitor also negated the activation of Sirt1 by icariin. These findings suggest that icariin activates GPER and increases the expression of Sirt1, which in turn reduces HMGB1 translocation and release, thereby improving vascular endothelial function in type 1 diabetic rats by inhibiting inflammation.

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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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