Carnosol alleviates sepsis-induced pulmonary endothelial barrier dysfunction by targeting nuclear factor erythroid2-related factor 2/sirtuin-3 signaling pathway to attenuate oxidative damage

作者全名："Li, Xingbing; Wang, Shuo; Luo, Minghao; Wang, Ming; Wu, Shaoping; Liu, Chang; Wang, Fengxian; Li, Yong"

作者地址："[Li, Xingbing; Wang, Ming; Wu, Shaoping; Liu, Chang; Li, Yong] Chongqing Hosp Tradit Chinese Med, Dept Cardiol, Chongqing, Peoples R China; [Wang, Shuo; Wang, Fengxian] Third Mil Med Univ, Daping Hosp, Dept Cardiol, Chongqing, Peoples R China; [Luo, Minghao] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiol, Chongqing, Peoples R China; [Li, Yong] Chongqing Hosp Tradit Chinese Med, Dept Cardiol, Chongqing 400021, Peoples R China"

通信作者："Li, Y (通讯作者)，Chongqing Hosp Tradit Chinese Med, Dept Cardiol, Chongqing 400021, Peoples R China."

来源：PHYTOTHERAPY RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001174117800001

JCR分区：Q1

影响因子：7.2

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：ALI; carnosol; endothelium barrier; Nrf2; SIRT3

摘要："Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti-inflammatory properties, but its role in treating sepsis-induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis-induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)-induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC-1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor-erythroid 2-related factor (Nrf2)/sirtuin-3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS-induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS-induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO-1, and vascular endothelial-Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway. The lung sirtuin-3(SIRT3) expression decreased during acute lung injury. Carnosol increased nuclear factor-erythroid 2-related factor 2 (Nrf2) translocation to promote SIRT3 expression. SIRT3, a mitochondrial protein, plays a vital role in the regulation of redox balance and mitochondrial functions. Carnosol significantly reduced mitochondrial reactive oxygen species (ROS) and protected mitochondrial function in endothelial cells by activating SIRT3, on the one hand, carnosol reduced mitochondrial pathway apoptosis by reducing mitochondria ROS; in addition, carnosol restored the expression of E-cadherin, Occludin, and ZO-1 by reducing oxidative stress. Carnosol protected endothelial barrier by strengthening endothelial cell junctions and inhibiting cell apoptosis. Furthermore, an intact endothelial barrier plays an important role in preventing pulmonary edema and inflammatory cell infiltration. In a word, carnosol alleviates sepsis-induced pulmonary endothelial barrier dysfunction by targeting the Nrf2/SIRT3 signaling pathway to attenuate oxidative damage. image"

基金机构：Chongqing Scientific Research Institutions Performance Incentive and Guidance Project

基金资助正文：No Statement Available