Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu, 221004, China.
Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
Eur J Pharmacol. 2023 Jan 15;939:175469. doi: 10.1016/j.ejphar.2022.175469. Epub 2022 Dec 15.
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract (GI). Currently, the treatment options for IBD are limited. It has been reported that a novel bioactive mitochondrial-derived peptide (MOTS-c) encoded in the mitochondrial 12S rRNA, suppresses inflammatory response by enhancing the phagocytosis of macrophages. The aim of this study was to investigate the protective effects of MOTS-c against dextran sulfate sodium (DSS)-induced colitis. The results showed that intraperitoneal (i.p.) administration of MOTS-c significantly ameliorated the symptoms of DSS-induced experimental colitis, such as body weight loss, colon length shortening, diarrhea, and histological damage. MOTS-c down-regulated the expression of pro-inflammatory cytokines, decreased the plasma levels of myeloperoxidase, and inhibited the activation of macrophages and recruitment of neutrophils. Moreover, treatment with MOTS-c exhibited anti-apoptotic effects and significantly suppressed the phosphorylation of AMPKα1/2, ERK, and JNK. Notably, oral administration of MOTS-c did not result in any significant improvements. Screening of cell penetrating peptides was performed, (PRR)5 was linked to the C-terminus of MOTS-c through a linker to synthesize a new molecule (termed MP) with better penetration into the colon epithelium. In vitro experiments revealed the longer half-life of MP than MOTS-c, and in vivo experiments showed that oral administration of MP significantly ameliorated DSS-induced colitis. CONCLUSION: The present results demonstrate a protective role of MOTS-c in experimental IBD.
炎症性肠病（IBD）是一种慢性复发性胃肠道（GI）炎症性疾病。目前，IBD 的治疗选择有限。据报道，一种新型生物活性线粒体衍生肽（MOTS-c），编码在线粒体 12S rRNA 中，通过增强巨噬细胞的吞噬作用来抑制炎症反应。本研究旨在研究 MOTS-c 对葡聚糖硫酸钠（DSS）诱导的结肠炎的保护作用。结果表明，MOTS-c 腹腔注射可显著改善 DSS 诱导的实验性结肠炎的症状，如体重减轻、结肠缩短、腹泻和组织学损伤。MOTS-c 下调促炎细胞因子的表达，降低血浆髓过氧化物酶水平，并抑制巨噬细胞的激活和中性粒细胞的募集。此外，MOTS-c 治疗表现出抗凋亡作用，并显著抑制 AMPKα1/2、ERK 和 JNK 的磷酸化。值得注意的是，口服 MOTS-c 没有带来任何显著的改善。对细胞穿透肽进行了筛选，（PRR）5 通过连接子与 MOTS-c 的 C 末端相连，合成一种具有更好穿透结肠上皮能力的新分子（称为 MP）。体外实验表明 MP 的半衰期比 MOTS-c 长，体内实验表明口服 MP 可显著改善 DSS 诱导的结肠炎。结论：本研究结果表明 MOTS-c 在实验性 IBD 中具有保护作用。
