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1.
Pancreas ; 49(10): 1335-1341, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33122522

RESUMO

OBJECTIVES: Pancreatic acinar necrosis is a typical feature in the early phase of severe acute pancreatitis (SAP). Muscarinic acetylcholine receptor M3 (CHRM3) has been reported to play important roles in promoting insulin secretion and tumor cell proliferation, but its effect on necrosis remains unknown. This study revealed the important role of CHRM3 in regulating L-arginine-induced SAP and the molecular mechanisms. METHODS: To verify the function of CHRM3, pancreatic tissues and primary acinar cells of CRISPR/Cas9-mediated Chrm3 knockout mice were used in CHRM3 knockdown experiments, and to ascertain the CHRM3 overexpression, PLV-EGFP-Chrm3 plasmids were transfected in acinar cells in vitro. RESULTS: In L-arginine-induced SAP, CHRM3 is activated and regulates SAP through the mitogen-activated protein kinase/p38 pathway. Moreover, the expression of miR-31-5p decreased in the SAP model both in vitro and in vivo. Mir-31-5p effects the necrosis of acinar cells in SAP by upregulating the target gene RIP3, and miR-31-5p is a downstream miRNA of CHRM3. CONCLUSIONS: Necrosis in L-arginine-induced SAP is promoted by CHRM3 through the mitogen-activated protein kinase-p38/miR-31-5p/RIP3 axis.


Assuntos
Células Acinares/enzimologia , MicroRNAs/metabolismo , Pâncreas/enzimologia , Pancreatite/prevenção & controle , Receptor Muscarínico M3/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células Acinares/patologia , Animais , Arginina , Células Cultivadas , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Necrose , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/enzimologia , Pancreatite/patologia , Fosforilação , Receptor Muscarínico M3/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais
2.
J Cell Biochem ; 121(3): 2618-2631, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31692054

RESUMO

Acinar cells in acute pancreatitis (AP) die through apoptosis and necrosis, the impacts of which are quite different. Early clinical interference strategies on preventing the progress of AP to severe acute pancreatitis (SAP) are the elimination of inflammation response and inhibition of necrosis. Muscarinic acetylcholine receptor M3 was encoded by Chrm3 gene. It is one of the best-characterized receptors of pancreatic ß cells and regulates insulin secretion, but its function in AP remains unclear. In this study, we explored the function of Chrm3 gene in the regulation of cell death in l-arginine-induced SAP animal models. We found that Chrm3 was upregulated in pancreatitis, and we further confirmed the localization of Chrm3 resided in both pancreatic islets and acinar cell membranes. The reduction of Chrm3 decreased the pathological lesion of SAP and reduced amylase activities in serum. Consistently, Chrm3 can suppress acinar cells necrosis markedly, but has no effect on regulating apoptosis after l-arginine treatment. It was shown that Chrm3 attenuated acinar cells necrosis at least in part by stabilizing caspase-8. Thus, this study indicates that Chrm3 is critical participants in SAP, and regulation of Chrm3 expression might be a useful therapeutic strategy for preventing pathologic necrosis.


Assuntos
Células Acinares/patologia , Caspase 8/metabolismo , Necrose , Pancreatite/prevenção & controle , Substâncias Protetoras/farmacologia , Receptor Muscarínico M3/fisiologia , Transcriptoma , Células Acinares/metabolismo , Animais , Arginina/toxicidade , Caspase 8/química , Caspase 8/genética , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pancreatite/induzido quimicamente , Pancreatite/patologia
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