Asiatic acid attenuates lipopolysaccharide-induced injury by suppressing activation of the Notch signaling pathway
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Xiong Yuyun1,*, Cheng Xi2,*, Yin Qing1, Xia Lin1, Rui Ke1 and Sun Bingwei3
1Department of Clinical Laboratory, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
2Atom Bioscience and Pharmaceutical Co., Ltd., Zhenjiang, Jiangsu 212001, P.R. China
3Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
*These authors contributed equally to this work
Xiong Yuyun, email: [email protected]
Keywords: asiatic acid; lipopolysaccharide; Notch; sepsis
Received: September 01, 2017 Accepted: November 14, 2017 Epub: January 23, 2018 Published: March 13, 2018
Sepsis is a severe multisystem disease with high mortality rates and limited treatment options. However, advances during the last decade have opened opportunities to develop novel therapeutic strategies. The Notch signaling pathway plays a critical role in inflammation, and its inhibition offers an avenue to treat inflammatory diseases, such as sepsis. Asiatic acid (AA), a triterpenoid isolated from Centella asiatica, reportedly exerts anti-oxidant, anti-tumor, and anti-inflammatory effects, but its mechanisms remain unclear. In our study, we found that AA decreased levels of interleukin-1β (IL-1β), IL-6, alanine aminotransferase and blood urea nitrogen in serum; attenuated liver, lung and kidney damage; and improved the survival among mice with experimental sepsis. AA also reduced lipopolysaccharide-stimulated expression of proinflammatory mediators, including nitric oxide, IL-1β and IL-6 in RAW 264.7 macrophages. Notably, we demonstrated for the first time that AA is a novel small molecule inhibitor of the Notch signaling pathway. Its effects include upregulation of Notch receptor (Notch3) and delta-like ligand (DLL4), inhibition of Notch3 binding to the IL-6 promoter and regulation of mitochondrial function. These novel effects of AA may provide new approaches and strategies for the treatment of inflammatory disorders.
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