前瞻性探讨苯丙素糖苷作为 cGAS-STING 信号通路调节剂在非酒精性脂肪性胰腺动物模型治疗中的作用。

Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model.

机构信息

Department of Gastroenterology, Hepatology & Infectious Disease, Faculty of Medicine, Benha University, Benha, 13518, Egypt.

Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

出版信息

Biol Res. 2023 Mar 13;56(1):11. doi: 10.1186/s40659-023-00423-8.

DOI:10.1186/s40659-023-00423-8

PMID:36915161

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10010022/

Abstract

BACKGROUND

Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis.

METHODS

The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding.

RESULTS

The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals.

CONCLUSION

benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.

摘要

背景

非酒精性脂肪性胰腺炎（NAFP）是代谢综合征的表现之一，需要进一步研究以确定其分子决定因素并找到有效的药物。我们旨在通过靶向胰腺 cGAS-STING 通路相关基因（DDX58、NFκB1 和 CHUK）及其上游调节剂 miRNA（miR-1976）来研究苯丙烯基糖苷对 NAFP 管理的潜在影响，这些基因和 miRNA 是从生物信息学分析中检索到的。

方法

大鼠分别喂食正常饲料或高脂肪高蔗糖饮食（HFHS），作为 NAFP 的营养模型。8 周后，HFHS 喂养的大鼠随机分为 4 组；未治疗的 HFHS 组（NAFP 模型组）和 3 个治疗组，每天分别给予 3 个剂量的苯丙烯基糖苷（10、20 和 30mg/kg），平行于 HFHS 喂养 4 周。

结果

分子分析表明，苯丙烯基糖苷可通过下调 DDX58、NFκB1 和 CHUK mRNA 的表达和上调 miR-1976 的表达来调节胰腺 cGAS-STING 通路相关基因的表达。此外，应用治疗可逆转未治疗的 NAFP 组观察到的胰岛素抵抗、炎症和纤维化，表现为改善血脂谱、降低体重和血清脂肪酶和淀粉酶水平、降低 NFκB1 和 caspase-3 蛋白水平，以及治疗动物胰腺切片中胶原纤维面积百分比显著减少。