PMID- 28280123 OWN - NLM STAT- MEDLINE DCOM- 20170508 LR - 20181119 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 361 IP - 2 DP - 2017 May TI - Mogroside IIIE, a Novel Anti-Fibrotic Compound, Reduces Pulmonary Fibrosis through Toll-Like Receptor 4 Pathways. PG - 268-279 LID - 10.1124/jpet.116.239137 [doi] AB - Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, and eventually most patients develop respiratory failure with a median survival rate of 2 to 3 years after diagnosis due to the lack of clinically effective therapies. Mogroside IIIE (MGIIIE), a cucurbitane-type compound, was isolated from Siraitia grosvenorii MGIIIE has shown the strongest inhibition of nitric oxide release, a crucial inflammatory factor, from lipopolysaccharide (LPS)-treated RAW264.7 cells compared with other mogrosides. In the pulmonary fibrosis mouse model induced by bleomycin, MGIIIE treatment attenuated pulmonary fibrosis, indicated as a reduction in myeloperoxidase activity, collagen deposition, and pathologic score. MGIIIE also significantly suppressed expression of several important fibrotic markers, e.g., alpha-smooth muscle actin, collagen I, transforming growth factor-beta (TGF-beta) signal, and metalloproteinases-9/tissue inhibitor of metalloproteinase-1. Furthermore, MGIIIE blocked tansdifferentiation of lung resident fibroblasts into myofibroblast-like cells induced by TGF-beta or LPS and subsequently inhibited collagen production in lung fibroblasts. These data indicate that MGIIIE is a potent inhibitor for pulmonary fibrosis. In vitro and in vivo mechanistic studies have shown that MGIIIE significantly decreased expression of toll-like receptor 4 (TLR4) and its downstream signals of myeloid differentiation factor 88 (MyD88)/mitogen-activated protein kinase (MAPK), an inflammatory signal essential for extracellular matrix (ECM) deposition in pulmonary fibroblasts. Taken together, these results demonstrate that MGIIIE significantly prevents pulmonary fibrosis by inhibiting pulmonary inflammation and ECM deposition through regulating TLR4/MyD88-MAPK signaling. Our study suggests that MGIIIE may have therapeutic potential for treating pulmonary fibrosis in clinical settings. CI - Copyright (c) 2017 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Tao, Lijun AU - Tao L AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China. FAU - Yang, Jinyu AU - Yang J AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China. FAU - Cao, Fengyan AU - Cao F AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China. FAU - Xie, Haifeng AU - Xie H AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China. FAU - Zhang, Mian AU - Zhang M AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China. FAU - Gong, Yanqing AU - Gong Y AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China gongy@mail.med.upenn.edu zhangchaofeng@cpu.edu.cn. FAU - Zhang, Chaofeng AU - Zhang C AD - (L.T., J.Y., F.C., M.Z., C.Z.,) Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, People's Republic of China; (Y.G.) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and (H.X.) Chengdu Biopurity Phytochemicals Ltd. Chengdu, People's Republic of China gongy@mail.med.upenn.edu zhangchaofeng@cpu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170309 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (11-oxomogroside III) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Glycosides) RN - 0 (TLR4 protein, human) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology MH - Disease Models, Animal MH - Drug Monitoring/methods MH - Fibroblasts/drug effects/metabolism MH - Glycosides/*pharmacology MH - *Idiopathic Pulmonary Fibrosis/drug therapy/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Signal Transduction/drug effects MH - Tissue Inhibitor of Metalloproteinase-1/metabolism MH - Toll-Like Receptor 4/*metabolism EDAT- 2017/03/11 06:00 MHDA- 2017/05/10 06:00 CRDT- 2017/03/11 06:00 PHST- 2016/11/30 00:00 [received] PHST- 2017/03/07 00:00 [accepted] PHST- 2017/03/11 06:00 [pubmed] PHST- 2017/05/10 06:00 [medline] PHST- 2017/03/11 06:00 [entrez] AID - jpet.116.239137 [pii] AID - 10.1124/jpet.116.239137 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2017 May;361(2):268-279. doi: 10.1124/jpet.116.239137. Epub 2017 Mar 9.