Protective Effects of Chelerythrine Against Lipopolysaccharide-Induced Endotoxic Shock in Mice
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Protective Effects of Chelerythrine Against Lipopolysaccharide-Induced Endotoxic Shock in Mice Xiaofeng Niu,1 Qingli Mu,1 Weifeng Li,1,2 Huimin Huang,1 Huan Yao,1 and Huani Li1
Abstract—Chelerythrine (CHE), a quaternary benzo[c]phenanthridine alkaloid, exhibits a wide spectrum of pharmacological effects. Although CHE has been used to treat various diseases, the protective effects of CHE on lipopolysaccharide (LPS)-induced endotoxic shock have not been explored. The aims of the study were to investigate the protective effects of CHE on LPS-induced endotoxic shock in mice and clarify the mechanism of the effects. We found that pretreatment with CHE (1, 5, and 10 mg/kg, po) at 1 and 12 h before injected intraperitoneally with 1 mg/kg LPS markedly decreased the production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and myeloperoxidase (MPO) and attenuated the lung histopathological changes. Meanwhile, the effects were dependent on the inhibition of the expression of p65 nuclear factor κB (NF-κB). The protective effects of CHE on LPS-induced endotoxic shock can be attributed to attenuating inflammatory cytokines and inhibition of the expression of NF-κB. KEY WORDS: chelerythrine; lipopolysaccharide; endotoxic shock; inflammatory cytokines; p65 NF-κB.
INTRODUCTION Inflammation, a response to mechanical stress, infection, and shock, is mediated by series inflammation mediators produced by macrophages and leukocytes [1]. Lipopolysaccharide, a glycolipid constituent of the outer membrane of Gram-negative bacteria, is an endotoxin-induced acute inflammation reaction septic shock and sepsis [2]. Sepsis, associated with high morbidity and mortality, is characterized by hypotension, organ perfusion, and multiorgan dysfunction [3]. Endotoxic shock, involved in the secretion of cytokines and chemokines, will trigger series of symptoms such as increased blood flow, leukocyte infiltration, and release of proteases [4]. Most inflammation reaction induced by (LPS) is triggered by endogenous mediators such as interleukin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNF-α); among these cytokines, TNF-α plays a
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School of Pharmacy, Xi’an Jiaotong University, No. 76 Western Yanta Road, Xi’an, 710061( Shaanxi Province, People’s Republic of China 2 To whom correspondence should be addressed at School of Pharmacy, Xi’an Jiaotong University, No. 76 Western Yanta Road, Xi’an, 710061( Shaanxi Province, People’s Republic of China. E-mail: [email protected]
significant role in endotoxic shock [5, 6]. TNF-α, regarded as the first-line cytokine, can induce most characteristics of endotoxic shock and decreases the production of inflammatory cytokines including IL-6 and IL-12 [7–9]. The balance of the circulating levels of pro-inflammatory effect and anti-inflammatory effect of IL-6, which is involved in the pathophysiology of septic shock, determines the severity of disease [10, 11]. Nuclear factor κB (NF-κB), which plays a critical role in the response to cytokines and stress, is responsible for the transcription o
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