title: The Matrine Derivate MASM Prolongs Survival, Attenuates Inflammation, and Reduces Organ Injury in Murine Established Lethal Sepsis.
abstract: BACKGROUND
  MASM, a novel derivative of matrine, has inhibitory effects on activation of macrophages, dendritic cells, and hepatic stellate cells and binds to ribosomal protein S5 (RPS5). This study was designed to evaluate the effect of MASM on murine-established lethal sepsis and its mechanisms.
  
  
  METHODS
  Mouse peritoneal macrophages and RAW264.7 cells that were infected with recombinant lentiviruses encoding shRPS5 were incubated with lipopolysaccharide (LPS) in the absence or presence of MASM in vitro. Endotoxemia induced by LPS injection and sepsis induced by cecal ligation and puncture was followed by MASM treatment.
  
  
  RESULTS
  MASM markedly attenuated LPS-induced release and messenger RNA expression of tumor necrosis factor α, interleukin 6, and NO/inducible NO synthase in murine peritoneal macrophages and RAW264.7 cells. Meanwhile, MASM inhibited LPS-induced activation of nuclear factor κB and MAPK pathways. Consistently, RPS5 suppressed LPS-induced inflammatory responses and at least in part mediated the antiinflammatory effect of MASM in vitro. Remarkably, delayed administration of MASM could significantly reduce mortality in mouse sepsis models, which was associated with the reduction in the inflammatory response, the attenuation in multiple organ injury, and the enhanced bacterial clearance.
  
  
  CONCLUSIONS
  MASM could be further explored for the treatments of sepsis, especially for administration later after the onset of sepsis.
authors.affiliation: School of Pharmacy, Second Military Medical University.|Department of Pharmacy, Shanghai East Hospital, Tongji University, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Ke-Qi
authors.initials: KQ
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Wei-Heng
authors.initials: WH
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Yang
authors.initials: Y
authors.lastname: Qi
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Shanghai East Hospital, Tongji University, China.
authors.forename: Zhi-Gao
authors.initials: ZG
authors.lastname: He
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Hu
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Zhang
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage*; D000818:Animals; D004195:Disease Models, Animal; D007155:Immunologic Factors / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011807:Quinolizines / Q000008:administration & dosage*; D000067996:RAW 264.7 Cells / Q000187:drug effects / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology*; D016019:Survival Analysis; D000093842:Matrines
chemical_list: D000470:Alkaloids; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D011807:Quinolizines; D000093842:Matrines
keywords: MAPK; NF-κB; inflammation; macrophages; matrine derivative; ribosomal protein S5; sepsis