Empagliflozin attenuates pyroptosis by regulating thioredoxin-NLRP3 inflammasome axis in a high fat cholesterol diet/streptozotocin model of atherosclerosis.

IF 3.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of Pharmacy and Pharmacology Pub Date : 2025-10-01 DOI:10.1093/jpp/rgaf051

Nevien Hendawy, Sayed M El-Sayed, Doaa M AbdelWahed, Sedra Hesham Salaheldin, Sally A Abuelezz

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引用次数: 0

Abstract

Objectives: Oxidative stress (OS), inflammation, and pyroptosis are hallmarks of atherosclerosis pathogenesis. Thioredoxin-interacting protein (TXNIP) crosslinks them through activating nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The current work addresses the potentials of empagliflozin (EMPA) on OS markers, thioredoxin (TRX), and TXNIP, downstream mediators of NLRP3 inflammasome and the executioner of pyroptosis; gasdermin D (GSDMD) in a model of atherosclerosis.

Methods: Atherosclerosis was induced by high fat cholesterol diet (HFCD) and streptozotocin (STZ) in male Wistar rats. Five groups were allocated: Control group, HFCD-STZ group, and three orally EMPA treated groups with HFCD-STZ in doses (2.5, 5, and 10 mg/kg/d for 4 weeks). To access the underlying mechanism of EMPA on atherosclerosis, serum glycated haemoglobin, lipid profile, inflammatory cytokines, and aortic OS markers were evaluated. Polymerase chain reaction analysis of NLRP3 inflammasome components, TRX, TXNIP, GSDMD, and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions were performed. Histopathological studies further confirmed EMPA's effects on atherosclerosis.

Key findings: EMPA ameliorates metabolic and histopathological alterations, inflammation, OS, TRRX/TXNIP reversal, VCAM-1, activation of NLRP3 inflammasome, and pyroptosis axis.

Conclusions: EMPA displayed antioxidant and anti-inflammatory effects through attenuating the OS/TXNIP/NLRP3/GSDMD axis in an experimental model of atherosclerosis.

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在高脂胆固醇饮食/链脲佐菌素动脉粥样硬化模型中，恩格列净通过调节硫氧还毒素- nlrp3炎症小体轴来减轻焦亡。

目的：氧化应激（OS）、炎症和焦亡是动脉粥样硬化发病的标志。硫氧还蛋白相互作用蛋白（TXNIP）通过激活核苷酸结合域、富含亮氨酸的家族、含pyrin结构域-3 （NLRP3）炎症小体途径将它们交联。目前的工作是研究恩格列净（EMPA）对OS标记物、硫氧还蛋白（TRX）和TXNIP （NLRP3炎性体的下游介质和焦亡的执行者）的潜力；GSDMD在动脉粥样硬化模型中的作用。方法：采用高脂胆固醇饮食（HFCD）和链脲佐菌素（STZ）诱导雄性Wistar大鼠动脉粥样硬化。分为5组：对照组、HFCD-STZ组和3个口服EMPA处理组，剂量分别为2.5、5、10 mg/kg/d，连续4周。为了了解EMPA对动脉粥样硬化的潜在机制，我们评估了血清糖化血红蛋白、脂质谱、炎症细胞因子和主动脉OS标志物。采用聚合酶链反应分析NLRP3炎性小体组分、TRX、TXNIP、GSDMD和血管细胞粘附分子-1 (VCAM-1) mRNA表达。组织病理学研究进一步证实了EMPA对动脉粥样硬化的作用。主要发现：EMPA改善代谢和组织病理学改变、炎症、OS、TRRX/TXNIP逆转、VCAM-1、NLRP3炎性体激活和焦亡轴。结论：EMPA通过降低动脉粥样硬化实验模型的OS/TXNIP/NLRP3/GSDMD轴具有抗氧化和抗炎作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Pharmacy and Pharmacology 医学-药学

CiteScore

6.60

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： JPP keeps pace with new research on how drug action may be optimized by new technologies, and attention is given to understanding and improving drug interactions in the body. At the same time, the journal maintains its established and well-respected core strengths in areas such as pharmaceutics and drug delivery, experimental and clinical pharmacology, biopharmaceutics and drug disposition, and drugs from natural sources. JPP publishes at least one special issue on a topical theme each year.