糖尿病中的高血糖通过非酶反应增加晚期糖基化终产物（AGE）的产生。 AGE 与其受体 (RAGE) 之间的相互作用会导致氧化和炎症应激，这在糖尿病肾病的发展中起着关键作用。 Syzygium cumini (SC) L. (DC.) 顺势疗法制剂即。 （200C、30C和母酊[MT]）用于治疗糖尿病。本研究旨在阐明SC制剂（200C、30C和MT）对核因子红细胞2相关因子2（Nrf2）的调节作用- 核因子-κB (NF-κB) 通路和线粒体功能障碍在减轻糖尿病肾病中的作用。用 SC 制剂治疗链脲佐菌素诱导的糖尿病大鼠（200C、30C、MT；蒸馏水 1:20 稀释；600 μL/kg 体重） ）和二甲双胍（45 毫克/公斤体重）每天两次，持续 40 天。通过生化参数和组织学检查评估DN。分析肾组织裂解物的糖化标记物。通过蛋白质印迹和 RT-qPCR 测定 Nrf2、NF-κB 和线粒体功能障碍信号的蛋白质和基因水平。对肾脏进行免疫组织化学分析。在体外，在 SC 制剂（200℃、30℃、MT）存在下，用甲基乙二醛（MGO - 55 mM）将人血清白蛋白（HSA - 10 mg/ml）糖化八天。将糖化样品 (400 μg/mL) 与肾细胞 (HEK-293) 一起孵育 24 小时。通过蛋白质印迹、RT-qPCR 和流式细胞术进一步分析活性氧的产生、Nrf2 核转位以及 Nrf2 和凋亡标记物的蛋白质或基因表达。进行没食子酸和鞣花酸与 HSA-MGO 复合物的分子对接。使用 SC 制剂治疗链脲佐菌素诱导的糖尿病大鼠的体内实验显示，生化参数得到改善，肾功能得以保留，并以剂量​​依赖性方式减少了糖基化加合物的形成。此外，SC制剂下调了RAGE、NF-κB、血管内皮生长因子（VEGF）和肿瘤坏死因子α（TNF-α）等炎症介质，同时上调了Nrf2依赖性抗氧化和解毒途径。他们下调了 B 细胞淋巴瘤 2 (Bcl-2) 相关 X 蛋白 (BAX)、C/EBP 同源蛋白 (CHOP)、Dynamin 相关蛋白 1 (DRP1)，并上调了 BCL 2 基因表达。值得注意的是，SC 制剂促进了 Nrf2 的核转位，导致抗氧化酶上调和氧化应激标记物下调。分子对接研究揭示了没食子酸 (-5.26 kcal/mol) 和鞣花酸 (-4.71 kcal/mol) 与 HSA-MGO 复合物之间的良好相互作用。SC 制剂通过 Nrf2 依赖性机制减轻肾细胞凋亡和线粒体功能障碍。版权所有 © 2024爱思唯尔 B.V. 出版

Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. (200C, 30C, and mother tincture [MT]) are used to treat diabetes.This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating Diabetic nephropathy.Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 μL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 μg/mL) were incubated with renal cells (HEK-293) for 24 hours. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed.In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex.SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.Copyright © 2024. Published by Elsevier B.V.