title: Mogroside IIIE, a Novel Anti-Fibrotic Compound, Reduces Pulmonary Fibrosis through Toll-Like Receptor 4 Pathways.
abstract: 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 fromSiraitia grosvenoriiMGIIIE 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.,α-smooth muscle actin, collagen I, transforming growth factor-β(TGF-β) signal, and metalloproteinases-9/tissue inhibitor of metalloproteinase-1. Furthermore, MGIIIE blocked tansdifferentiation of lung resident fibroblasts into myofibroblast-like cells induced by TGF-βor 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.
authors.affiliation: (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.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tao
authors.affiliation: (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.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: (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.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Cao
authors.affiliation: (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.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: (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.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: (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.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.affiliation: (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.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology*; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C522658:11-oxomogroside III; D000893:Anti-Inflammatory Agents; D006027:Glycosides; C495345:TLR4 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D051197:Toll-Like Receptor 4