Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt.
Life Sci. 2021 May 15;273:119295. doi: 10.1016/j.lfs.2021.119295. Epub 2021 Mar 2.
Dipeptidyl peptidase-4 (DPP-4) has been involved in the pathogenesis of inflammatory bowel diseases (IBD), yet the underlying mechanisms remain inconclusive. The present study aimed to investigate the potential of linagliptin, a potent/selective DPP-4 inhibitor with marked anti-inflammatory actions, to attenuate trinitrobenzene sulfonic acid (TNBS)-evoked colitis in rats; an experimental model of IBD, and the implicated molecular mechanisms. This may add to the clinical utility of linagliptin for the management of patients with coexisting IBD and diabetes mellitus. Notably, no former studies have linked JAK2/STAT3, HMGB1/NF-κB, and Nrf2/HO-1 signaling in TNBS-evoked colitis.
Western blotting and ELISA were used to determine the levels of target signals.
Administration of linagliptin (1.5 mg/kg; p.o.) mitigated the colitis severity via diminishing the disease activity index, colon weight/length ratio, and macroscopic scores. Linagliptin also lowered the colonic histologic scores and leukocyte invasion. Notably, linagliptin inhibited the colonic DPP-4 activity and upregulated the expression of intestinotrophic GLP-2 without incurring hypoglycemia in animals. Linagliptin curbed inflammation through the suppression of colonic IL-6, TNF-α, and myeloperoxidase and upregulation of IL-10. It also inhibited the IL-6/JAK2/STAT3 pathway via downregulating p-JAK2/JAK2 and p-STAT3/STAT3 protein expression and HMGB1/RAGE/NF-κB cascade through lowering HMGB1, RAGE, and p-NF-κB p65/NF-κB p65 protein expression. In the context of mucosal oxidative stress, linagliptin diminished lipid peroxides and augmented GSH, GPx, and total antioxidant capacity. It also activated Nrf2/HO-1 pathway via upregulating Nrf2 and HO-1 protein expression.
Linagliptin shows a promise for the management of IBD via targeting IL-6/JAK2/STAT3, HMGB1/RAGE/NF-κB, and Nrf2/HO-1 pathways.
二肽基肽酶-4（DPP-4）已参与炎症性肠病（IBD）的发病机制，但潜在机制仍不确定。本研究旨在探讨强效/选择性 DPP-4 抑制剂利那列汀（具有显著抗炎作用）减弱三硝基苯磺酸（TNBS）诱导的大鼠结肠炎的潜力；这是一种 IBD 的实验模型，以及所涉及的分子机制。这可能增加利那列汀在管理同时患有 IBD 和糖尿病患者中的临床应用。值得注意的是，以前没有研究将 JAK2/STAT3、HMGB1/NF-κB 和 Nrf2/HO-1 信号通路与 TNBS 诱导的结肠炎联系起来。
使用 Western blot 和 ELISA 来确定目标信号的水平。
给予利那列汀（1.5mg/kg；po）通过降低疾病活动指数、结肠重量/长度比和宏观评分来减轻结肠炎的严重程度。利那列汀还降低了结肠组织学评分和白细胞浸润。值得注意的是，利那列汀抑制了结肠 DPP-4 活性并上调了肠营养因子 GLP-2 的表达，而不会在动物中引起低血糖。利那列汀通过抑制结肠 IL-6、TNF-α 和髓过氧化物酶以及上调 IL-10 来抑制炎症。它还通过下调 p-JAK2/JAK2 和 p-STAT3/STAT3 蛋白表达以及通过降低 HMGB1、RAGE 和 p-NF-κB p65/NF-κB p65 蛋白表达来抑制 IL-6/JAK2/STAT3 通路。在黏膜氧化应激的情况下，利那列汀减少了脂质过氧化物并增加了 GSH、GPx 和总抗氧化能力。它还通过上调 Nrf2 和 HO-1 蛋白表达来激活 Nrf2/HO-1 通路。
利那列汀通过靶向 IL-6/JAK2/STAT3、HMGB1/RAGE/NF-κB 和 Nrf2/HO-1 通路显示出治疗 IBD 的潜力。
