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Hexa Histidine-Tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species.
Dat, Ninh Quoc; Thuy, Le Thi Thanh; Hieu, Vu Ngoc; Hai, Hoang; Hoang, Dinh Viet; Thi Thanh Hai, Nguyen; Thuy, Tuong Thi Van; Komiya, Tohru; Rombouts, Krista; Dong, Minh Phuong; Hanh, Ngo Vinh; Hoang, Truong Huu; Sato-Matsubara, Misako; Daikoku, Atsuko; Kadono, Chiho; Oikawa, Daisuke; Yoshizato, Katsutoshi; Tokunaga, Fuminori; Pinzani, Massimo; Kawada, Norifumi.
Afiliación
  • Dat NQ; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Thuy LTT; Department of Pediatrics, Hanoi Medical University, Hanoi, Vietnam.
  • Hieu VN; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Hai H; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Hoang DV; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Thi Thanh Hai N; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Thuy TTV; Department of Biochemistry, Hanoi Medical University, Hanoi, Vietnam.
  • Komiya T; Biological Resources Vinmec Tissue Bank, Vinmec Healthcare System, Hanoi, Vietnam.
  • Rombouts K; Department of Biology, Faculty of Science, Osaka City University, Osaka, Japan.
  • Dong MP; Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom.
  • Hanh NV; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Hoang TH; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Sato-Matsubara M; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Daikoku A; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Kadono C; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Oikawa D; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Yoshizato K; Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Tokunaga F; Academic Advisor's Office, PhoenixBio Co., Ltd., Hiroshima, Japan.
  • Pinzani M; Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • Kawada N; Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Hepatology ; 73(6): 2527-2545, 2021 06.
Article en En | MEDLINE | ID: mdl-33576020
BACKGROUND AND AIMS: Antifibrotic therapy remains an unmet medical need in human chronic liver disease. We report the antifibrotic properties of cytoglobin (CYGB), a respiratory protein expressed in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis. APPROACH AND RESULTS: Cygb-deficient mice that had bile duct ligation-induced liver cholestasis or choline-deficient amino acid-defined diet-induced steatohepatitis significantly exacerbated liver damage, fibrosis, and reactive oxygen species (ROS) formation. All of these manifestations were attenuated in Cygb-overexpressing mice. We produced hexa histidine-tagged recombinant human CYGB (His-CYGB), traced its biodistribution, and assessed its function in HSCs or in mice with advanced liver cirrhosis using thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). In cultured HSCs, extracellular His-CYGB was endocytosed and accumulated in endosomes through a clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type 1 alpha 1 production and α-smooth muscle actin expression. Replacement the iron center of the heme group with cobalt nullified the effect of His-CYGB. In addition, His-CYGB induced interferon-ß secretion by HSCs that partly contributed to its antifibrotic function. Momelotinib incompletely reversed the effect of His-CYGB. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis, and oxidative cell damage in mice administered TAA or DDC mice without adverse effects. RNA-sequencing analysis revealed the down-regulation of inflammation- and fibrosis-related genes and the up-regulation of antioxidant genes in both cell culture and liver tissues. The injected His-CYGB predominantly localized to HSCs but not to macrophages, suggesting specific targeting effects. His-CYGB exhibited no toxicity in chimeric mice with humanized livers. CONCLUSIONS: His-CYGB could have antifibrotic clinical applications for human chronic liver diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Estrelladas Hepáticas / Hígado Graso / Citoglobina / Cirrosis Hepática Límite: Animals Idioma: En Revista: Hepatology Año: 2021 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Estrelladas Hepáticas / Hígado Graso / Citoglobina / Cirrosis Hepática Límite: Animals Idioma: En Revista: Hepatology Año: 2021 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos