Gastroprotective Effect of Linagliptin on Indomethacin-Induced Gastric Ulceration in Mice: Crosstalk Between Oxidative Stress and Inflammasome Pathways

IF 4.9 Q1 CHEMISTRY, MEDICINAL

ACS Pharmacology and Translational Science Pub Date : 2025-03-04 DOI:10.1021/acsptsci.4c0069510.1021/acsptsci.4c00695

Maha E. Wally*, and , Mohamed H. Aly*,

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引用次数: 0

Abstract

The clinical efficacy of indomethacin, a nonsteroidal anti-inflammatory drug, is hindered by its high ulcerogenic potential. Linagliptin, a dipeptidyl peptidase-4 inhibitor, has demonstrated anti-inflammatory properties through NLRP3 inflammasome modulation; however, its possible antiulcerogenic effect remains unclear. This study aimed to examine the potential prophylactic effect of linagliptin against indomethacin-induced gastric ulcers with a focus on NLRP3 inflammasome signaling. Gastric ulcers were induced using indomethacin and compared to pretreatment with linagliptin or the standard prophylactic omeprazole. Gastric injury was confirmed by gross morphology, ulcer scoring, and histopathological assessments. Additionally, redox status markers glutathione reductase (GSH), malondialdehyde (MDA), and Nrf2/Keap-1/HO-1 were evaluated in the gastric tissue. Immunohistochemical analysis of pNF-κB, NLRP3, and Caspase-1 inflammasome parameters was also conducted. Finally, measurement of gastric levels of Gasdermin-D was performed, as well as immunohistochemical and gene expression of IL-1β. Pretreatment with linagliptin suppressed all features of mucosal damage as well as inflammatory cell infiltration. The antioxidant effect of linagliptin was evident in low MDA, high GSH gastric levels, and high immunohistochemical reactivity of gastric tissues against Nrf2 and HO-1 antibodies, as well as low gastric levels of keap1. The overly active inflammasome pathway observed in indomethacin-induced ulcerated samples was reinstated by linagliptin, as seen in the suppression of pNF-κB, NLRP3, Caspase-1, and IL-1β immunohistochemical reactivity as well as Gasdermin-D levels. Our study showed that NLRP3 inflammasome contributes to the pathogenesis of indomethacin-mediated gastric injury and that linagliptin exhibits a protective effect against indomethacin-induced gastric ulcers, possibly through activation of the Nrf2/HO-1 antioxidant pathway and inhibition of the NLRP3 inflammasome axis.

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利格列汀对消炎痛致小鼠胃溃疡的保护作用：氧化应激与炎性体通路的串扰

吲哚美辛是一种非甾体抗炎药，其临床疗效因其高致溃疡性而受到阻碍。利格列汀是一种二肽基肽酶-4抑制剂，通过NLRP3炎性小体调节显示出抗炎特性；然而，其可能的抗溃疡作用尚不清楚。本研究旨在研究利格列汀对吲哚美辛诱导的胃溃疡的潜在预防作用，重点关注NLRP3炎症小体信号传导。用吲哚美辛诱导胃溃疡，并与预处理用利格列汀或标准预防用奥美拉唑进行比较。通过大体形态、溃疡评分和组织病理学评估证实胃损伤。此外，测定胃组织中氧化还原状态标记物谷胱甘肽还原酶（GSH）、丙二醛（MDA）和Nrf2/Keap-1/HO-1。免疫组化分析pNF-κB、NLRP3和Caspase-1炎性体参数。最后，测定胃内Gasdermin-D水平，以及免疫组化和IL-1β基因表达。利格列汀预处理可抑制粘膜损伤的所有特征以及炎症细胞浸润。利格列汀抗氧化作用明显，胃组织对Nrf2和HO-1抗体免疫组化反应性高，胃组织中keap1水平低。在吲哚美辛诱导的溃疡样品中观察到的过度活跃的炎性体途径在利格列汀的作用下得以恢复，这可以通过抑制pNF-κB、NLRP3、Caspase-1和IL-1β的免疫组织化学反应性以及Gasdermin-D水平来观察。我们的研究表明，NLRP3炎性小体参与了吲哚美辛介导的胃损伤的发病机制，利格列汀可能通过激活Nrf2/HO-1抗氧化途径和抑制NLRP3炎性小体轴，对吲哚美辛诱导的胃溃疡表现出保护作用。

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

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