Paritaprevir ameliorates experimental acute lung injury in vitro and in vivo

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2023-06-12 DOI:10.1007/s12272-023-01451-4
Rui Ren, Xin Wang, Zehui Xu, Wanglin Jiang
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Abstract

Paritaprevir is a potent inhibitor of the NS3/4A protease used to treat chronic hepatitis C virus infection. However, its therapeutic effect on acute lung injury (ALI) remains to be elucidated. In this study, we investigated the effect of paritaprevir on a lipopolysaccharide (LPS)-induced two-hit rat ALI model. The anti-ALI mechanism of paritaprevir was also studied in human pulmonary microvascular endothelial (HM) cells following LPS-induced injury in vitro. Administration of 30 mg/kg paritaprevir for 3 days protected rats from LPS-induced ALI, as reflected by the changes in the lung coefficient (from 0.75 to 0.64) and lung pathology scores (from 5.17 to 5.20). Furthermore, the levels of the protective adhesion protein VE-cadherin and tight junction protein claudin-5 increased, and the cytoplasmic p-FOX-O1 and nuclear β-catenin and FOX-O1 levels decreased. Similar effects were observed in vitro with LPS-treated HM cells, including decreased nuclear β-catenin and FOX-O1 levels and higher VE-cadherin and claudin-5 levels. Moreover, β-catenin inhibition resulted in higher p-FOX-O1 levels in the cytoplasm. These results suggested that paritaprevir could alleviate experimental ALI via the β-catenin/p-Akt/ FOX-O1 signaling pathway.

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Paritaprevir在体外和体内改善实验性急性肺损伤
Paritarevir是NS3/4A蛋白酶的有效抑制剂,用于治疗慢性丙型肝炎病毒感染。然而,其对急性肺损伤(ALI)的治疗作用仍有待阐明。在本研究中,我们研究了帕利他韦对脂多糖(LPS)诱导的两次撞击大鼠ALI模型的影响。本文还研究了帕利他韦在体外LPS诱导的人肺微血管内皮细胞损伤后的抗ALI机制。30 mg/kg帕利他韦连续3天可保护大鼠免受LPS诱导的ALI,肺系数(从0.75到0.64)和肺病理评分(从5.17到5.20)的变化反映了这一点。此外,保护性粘附蛋白VE钙粘蛋白和紧密连接蛋白claudin-5的水平增加,β-连环蛋白和FOX-O1水平下降。LPS处理的HM细胞在体外也观察到类似的作用,包括降低核β-连环蛋白和FOX-O1水平,以及升高VE钙粘蛋白和claudin-5水平。此外,β-连环蛋白抑制导致细胞质中p-FOX-O1水平升高。这些结果表明,帕利他韦可以通过β-catenin/p-Akt/FOX-O1信号通路减轻实验性ALI。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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