title: Hesperetin derivative-7 inhibits PDGF-BB-induced hepatic stellate cell activation and proliferation by targeting Wnt/β-catenin pathway.
abstract: Liver fibrosis results from a continuous wound-healing response of the liver to repeated injury. Hesperidin (HDN) is a naturally occurring flavanone glycoside, which is extracted from fruit peels of the genus citrus. Previous studies focused on the anti-inflammation, anti-tumor and anti-oxidant roles of HDN. However, the role of HDN in hepatic fibrosis is still unknown. Here, we evaluated the role of HDND-7, a derivative of HDN which has better water solubility and bioavailability, in the activation and proliferation of PDGF-BB-induced hepatic stellate cells (HSCs), then we investigated the anti-fibrotic effect of HDND-7 in CCl4-induced mouse model of liver fibrosis. The study aimed to determine whether HDND-7 could affect the survival of HSC-T6 in vitro, while evaluating its anti-fibrotic efficacy on CCl4-induced liver fibrosis in Kunming mice. Our results revealed that HDND-7 inhibited the proliferation and activation of PDGF-BB-treated HSC-T6 cells in a time- and dose-dependent manner. In addition, administration of HDND-7 significantly attenuated liver fibrosis, as evident by the dramatic down-regulation of α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) in both mRNA and protein levels in vivo and in vitro. Furthermore, we also found that HDND-7 decreased the expression of β-catenin and the downstream proteins, cyclind1 and C-myc, indicating that HDND-7 may inhibit the activation and proliferation of PDGF-BB-induced HSC-T6 and attenuate liver fibrosis, at least in part, through targeting the Wnt/β-catenin signaling pathway. Hence HDND-7 might be employed as a promising natural supplement for liver fibrosis drug therapy.
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Lin
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Ling-Na
authors.initials: LN
authors.lastname: Kong
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Tao-Tao
authors.initials: TT
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Institute for Innovative Drug Industrial Generic Technology Research of Anhui, Hefei 230032, China. Electronic address: lj@ahmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D006569:Hesperidin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020574:Proto-Oncogene Proteins c-sis; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000199:Actins; D000077214:Becaplermin; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D006569:Hesperidin; D020574:Proto-Oncogene Proteins c-sis; C544013:alpha-smooth muscle actin, mouse; C498862:Acta2 protein, rat
keywords: Activation; HDND-7; Proliferation; Wnt/β-catenin signaling