Calpain Inhibitor Calpeptin Improves Pancreatic Fibrosis in Mice with Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells

IF 2.4 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jie Shen, Wenqin Xiao, Guanzhao Zong, Pengli Song, Chuanyang Wang, Jingpiao Bao, Qi Peng, Zhu Mei, Jingjing Wang, Ruiyan Wang, Jing Jiang, Rong Wan, Jianbo Ni, Xingpeng Wang, Guoyong Hu
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Abstract

Background:: Pancreatic fibrosis is a hallmark feature of chronic pancreatitis (CP), resulting in persistent damage to the pancreas. The sustained activation of pancreatic stellate cells (PSCs) plays a pivotal role in the progression of pancreatic fibrosis and is a major source of extracellular matrix (ECM) deposition during pancreatic injury. Methods:: Calpain is a calcium-independent lysosomal neutral cysteine endopeptidase and was found to be correlated to various fibrotic diseases. Studies have revealed that calpeptin, a calpain inhibitor, can improve the fibrosis process of multiple organs. This study investigated the effect of the calpain inhibitor, calpeptin, on fibrosis in experimental CP and activation of cultured PSCs in mice. CP was induced in mice by repeated injections of cerulein for four weeks in vivo, and the activation process of mouse PSCs was isolated and cultured in vitro. Then, the inhibitory effect of calpeptin on pancreatic fibrosis was confirmed based on the histological damage of CP, the expression of α-smooth muscle actin (α-SMA) and collagen-Iα1(Col1α1), and the decrease in mRNA levels of calpain-1 and calpain-2. Results:: In addition, it was revealed that calpeptin can inhibit the activation process of PSCs and induce significant PSCs apoptosis by downregulating the expression of calpain-1, calpain-2 and TGF-β1, and the expression and phosphorylation of smad3 in vitro. Conclusion:: These results suggest that the calpain inhibitor, calpeptin, plays a key role in the regulation of PSC activation by inhibiting the TGF-β1/smad3 signaling pathway, which supports the potential of calpeptin as an inhibitor of pancreatic fibrosis in mice by interfering with calpain.
钙蛋白酶抑制剂钙蛋白通过抑制胰腺星状细胞的活化改善慢性胰腺炎小鼠的胰腺纤维化
背景::胰腺纤维化是慢性胰腺炎(CP)的一个标志性特征,会导致胰腺持续受损。胰腺星状细胞(PSCs)的持续活化在胰腺纤维化的进展中起着关键作用,是胰腺损伤期间细胞外基质(ECM)沉积的主要来源。研究方法钙蛋白酶是一种钙依赖性溶酶体中性半胱氨酸内肽酶,被发现与多种纤维化疾病有关。研究发现,钙蛋白酶抑制剂钙蛋白肽能改善多个器官的纤维化进程。本研究探讨了钙蛋白酶抑制剂钙蛋白酶对实验性小鼠CP纤维化和培养的造血干细胞活化的影响。通过连续四周在小鼠体内反复注射钙蛋白诱导小鼠CP,并分离和体外培养小鼠PSCs的活化过程。然后,根据 CP 的组织学损伤、α-平滑肌肌动蛋白(α-SMA)和胶原-α1(Col1α1)的表达以及钙蛋白酶-1 和钙蛋白酶-2 mRNA 水平的下降,证实钙蛋白酶对胰腺纤维化的抑制作用。结果显示此外,研究还发现钙泊平素可通过下调体外钙蛋白酶-1、钙蛋白酶-2和TGF-β1的表达以及smad3的表达和磷酸化,抑制PSCs的活化过程并诱导PSCs显著凋亡。结论这些结果表明,钙蛋白酶抑制剂钙蛋白酶通过抑制 TGF-β1/smad3 信号通路,在调控 PSC 活化过程中发挥了关键作用,这支持了钙蛋白酶通过干扰钙蛋白酶作为小鼠胰腺纤维化抑制剂的潜力。
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来源期刊
Current molecular pharmacology
Current molecular pharmacology Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
4.90
自引率
3.70%
发文量
112
期刊介绍: Current Molecular Pharmacology aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs under development, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics, and metabonomics applications to drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level. The journal publishes full-length/mini reviews, original research articles and thematic issues on molecular pharmacology. Current Molecular Pharmacology is an essential journal for every scientist who is involved in drug design and discovery, target identification, target validation, preclinical and clinical development of drugs therapeutically useful in human disease.
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