Fenbufen Alleviates Severe Acute Pancreatitis by Suppressing Caspase-1/Caspase-11-mediated Pyroptosis in Mice.

IF 7.2 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current molecular pharmacology Pub Date : 2024-01-01 DOI:10.2174/1874467217666230511095540

Shien Shen, Wenqin Xiao, Weiliang Jiang, Kai Li, Xingya Guo, Guanzhao Zong, Chuanyang Wang, Jingpiao Bao, Jiahui Chen, Zhiyuan Cheng, Jie Shen, Rong Wan

{"title":"Fenbufen Alleviates Severe Acute Pancreatitis by Suppressing Caspase-1/Caspase-11-mediated Pyroptosis in Mice.","authors":"Shien Shen, Wenqin Xiao, Weiliang Jiang, Kai Li, Xingya Guo, Guanzhao Zong, Chuanyang Wang, Jingpiao Bao, Jiahui Chen, Zhiyuan Cheng, Jie Shen, Rong Wan","doi":"10.2174/1874467217666230511095540","DOIUrl":null,"url":null,"abstract":"Aim: In the present study, we aimed to investigate the effects of Fenbufen treatment on the SAP model induced by caerulein and lipopolysaccharide.Background: Severe acute pancreatitis (SAP) is an extremely dangerous disease with high mortality, which is associated with inflammatory response and acinar cell death. The caspase family plays an important role in cell death, such as caspase-1 and caspase-11 in pyroptosis. In recent years, caspases have been shown to be a novel pharmacological target of Fenbufen.Objective: Effects of Fenbufen on pancreatic tissue damage and serum levels of lipase and amylase in SAP in mice; Effect of Fenbufen on caspase-1 pathway in SAP in mice; Effect of Fenbufen on caspase-1/caspase-11-mediated pyroptosis of PACs in SAP in mice; Effect of Fenbufen on isolated PACs and caspase-1/caspase-11-mediated pyroptosis in vitro.Methods: In vivo, eighteen female C57BL/6 mice were randomly divided into 3 groups: the NC group, the SAP group, and the Fenbufen +SAP group with 6 mice in each group. The SAP model was induced by intraperitoneal injection of caerulein and lipopolysaccharide. The pathological changes in pancreatic and the serum levels of lipase and amylase and the relative gene and protein expressions in each group were compared. In vitro, pancreatic acinar cells were assigned to 5 groups: medium group, SAP group, Fenbufen 100μM group, Fenbufen 200μM group, and Fenbufen 400μM group. The cell damage and the relative gene and protein expressions in each group were evaluated.Results: Our results showed that Fenbufen ameliorated the severity of SAP and decreased the serum levels of lipase and amylase. Meanwhile, the in vivo and in vitro data demonstrated that Fenbufen inhibited the activation of caspase-1 and caspase-11, decreasing the levels of IL-1β, IL-18, and GSDMD. In in vitro experiments, we found that by inhibiting the activation of caspase-1 and caspase-11, Fenbufen significantly reduced lactate dehydrogenase (LDH) excretion by acinar cells.Conclusion: In general, our data showed that Fenbufen could protect the pancreatic acinar cell from injury by inhibiting pyroptosis.","PeriodicalId":10865,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e110523216783"},"PeriodicalIF":7.2000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current molecular pharmacology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.2174/1874467217666230511095540","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Aim: In the present study, we aimed to investigate the effects of Fenbufen treatment on the SAP model induced by caerulein and lipopolysaccharide.

Background: Severe acute pancreatitis (SAP) is an extremely dangerous disease with high mortality, which is associated with inflammatory response and acinar cell death. The caspase family plays an important role in cell death, such as caspase-1 and caspase-11 in pyroptosis. In recent years, caspases have been shown to be a novel pharmacological target of Fenbufen.

Objective: Effects of Fenbufen on pancreatic tissue damage and serum levels of lipase and amylase in SAP in mice; Effect of Fenbufen on caspase-1 pathway in SAP in mice; Effect of Fenbufen on caspase-1/caspase-11-mediated pyroptosis of PACs in SAP in mice; Effect of Fenbufen on isolated PACs and caspase-1/caspase-11-mediated pyroptosis in vitro.

Methods: In vivo, eighteen female C57BL/6 mice were randomly divided into 3 groups: the NC group, the SAP group, and the Fenbufen +SAP group with 6 mice in each group. The SAP model was induced by intraperitoneal injection of caerulein and lipopolysaccharide. The pathological changes in pancreatic and the serum levels of lipase and amylase and the relative gene and protein expressions in each group were compared. In vitro, pancreatic acinar cells were assigned to 5 groups: medium group, SAP group, Fenbufen 100μM group, Fenbufen 200μM group, and Fenbufen 400μM group. The cell damage and the relative gene and protein expressions in each group were evaluated.

Results: Our results showed that Fenbufen ameliorated the severity of SAP and decreased the serum levels of lipase and amylase. Meanwhile, the in vivo and in vitro data demonstrated that Fenbufen inhibited the activation of caspase-1 and caspase-11, decreasing the levels of IL-1β, IL-18, and GSDMD. In in vitro experiments, we found that by inhibiting the activation of caspase-1 and caspase-11, Fenbufen significantly reduced lactate dehydrogenase (LDH) excretion by acinar cells.

Conclusion: In general, our data showed that Fenbufen could protect the pancreatic acinar cell from injury by inhibiting pyroptosis.

查看原文本刊更多论文

芬布芬通过抑制小鼠Caspase-1/ caspase -11介导的焦亡来缓解严重急性胰腺炎。

目的:探讨芬布芬治疗对蛋白和脂多糖诱导的SAP模型的影响。背景:严重急性胰腺炎(SAP)是一种死亡率极高的危险疾病，与炎症反应和腺泡细胞死亡有关。caspase家族在细胞死亡中起重要作用，如caspase-1和caspase-11在细胞焦亡中起重要作用。近年来，半胱天冬酶已被证明是芬布芬的一个新的药理靶点。目的:探讨芬布芬对SAP小鼠胰腺组织损伤及血清脂肪酶、淀粉酶水平的影响;芬布芬对小鼠SAP caspase-1通路的影响芬布芬对小鼠SAP中caspase-1/caspase-11介导的PACs焦亡的影响芬布芬对离体PACs及caspase-1/caspase-11介导的离体焦亡的影响。方法:将18只雌性C57BL/6小鼠在体内随机分为3组:NC组、SAP组和芬布芬+SAP组，每组6只。通过腹腔注射蛋白和脂多糖建立大鼠SAP模型。比较各组胰腺病理变化及血清脂肪酶、淀粉酶水平及相关基因、蛋白表达情况。体外将胰腺腺泡细胞分为5组:培养基组、SAP组、芬布芬100μM组、芬布芬200μM组、芬布芬400μM组。观察各组细胞损伤及相关基因、蛋白表达情况。结果:芬布芬改善了SAP的严重程度，降低了血清脂肪酶和淀粉酶的水平。同时，体内和体外数据显示，芬布芬抑制caspase-1和caspase-11的激活，降低IL-1β、IL-18和GSDMD的水平。在体外实验中，我们发现芬布芬通过抑制caspase-1和caspase-11的激活，显著降低了腺泡细胞乳酸脱氢酶(LDH)的分泌。结论:总的来说，我们的数据表明芬布芬可以通过抑制胰腺腺泡细胞焦亡来保护胰腺腺泡细胞免受损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

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.