title: Sinomenine hydrochloride protects against polymicrobial sepsis via autophagy.
abstract: Sepsis, a systemic inflammatory response to infection, is the major cause of death in intensive care units (ICUs). The mortality rate of sepsis remains high even though the treatment and understanding of sepsis both continue to improve. Sinomenine (SIN) is a natural alkaloid extracted from Chinese medicinal plant Sinomenium acutum, and its hydrochloride salt (Sinomenine hydrochloride, SIN-HCl) is widely used to treat rheumatoid arthritis (RA). However, its role in sepsis remains unclear. In the present study, we investigated the role of SIN-HCl in sepsis induced by cecal ligation and puncture (CLP) in BALB/c mice and the corresponding mechanism. SIN-HCl treatment improved the survival of BALB/c mice that were subjected to CLP and reduced multiple organ dysfunction and the release of systemic inflammatory mediators. Autophagy activities were examined using Western blotting. The results showed that CLP-induced autophagy was elevated, and SIN-HCl treatment further strengthened the autophagy activity. Autophagy blocker 3-methyladenine (3-MA) was used to investigate the mechanism of SIN-HCl in vitro. Autophagy activities were determined by examining the autophagosome formation, which was shown as microtubule-associated protein light chain 3 (LC3) puncta with green immunofluorescence. SIN-HCl reduced lipopolysaccharide (LPS)-induced inflammatory cytokine release and increased autophagy in peritoneal macrophages (PM). 3-MA significantly decreased autophagosome formation induced by LPS and SIN-HCl. The decrease of inflammatory cytokines caused by SIN-HCl was partially aggravated by 3-MA treatment. Taken together, our results indicated that SIN-HCl could improve survival, reduce organ damage, and attenuate the release of inflammatory cytokines induced by CLP, at least in part through regulating autophagy activities.
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. jiangyu146@hotmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha 410013, China. gaomin1984@aliyun.com.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. wwmyouc@163.com.
authors.forename: Wenmei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. langyj386@sina.com.
authors.forename: Yuejiao
authors.initials: Y
authors.lastname: Lang
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. tongzhongyi2008@163.com.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Tong
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. wangkangkai@csu.edu.cn.
authors.forename: Kangkai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. Zhanghuali@csu.edu.cn.
authors.forename: Huali
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. Chen02gw@yahoo.com.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Chen
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. LiuMD2005@126.com.
authors.forename: Meidong
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100037, China. c_ff@sina.com.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China. xiaoxianzhong@csu.edu.cn.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002432:Cecum / Q000601:surgery; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007668:Kidney / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D015996:Survival Rate
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D009019:Morphinans; C025946:3-methyladenine; C009271:sinomenine; D000225:Adenine