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For: de Mochel NSR, Seronello S, Wang SH, Ito C, Zheng JX, Liang TJ, Lambeth JD, Choi J. Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology 2010;52:47-59. [PMID: 20578128 PMCID: PMC3141587 DOI: 10.1002/hep.23671] [Citation(s) in RCA: 144] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

For:	de Mochel NSR, Seronello S, Wang SH, Ito C, Zheng JX, Liang TJ, Lambeth JD, Choi J. Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology 2010;52:47-59. [PMID: 20578128 PMCID: PMC3141587 DOI: 10.1002/hep.23671] [Citation(s) in RCA: 144] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

Number

Cited by Other Article(s)

Gangadhara NY, B M, Kumar PK, Krishna H, Shivakumar A, Sadashivanna RH, Krishnegowda A. Evaluation of peroxidase mimicking behaviour of V₂O₅ nanozymes with various morphologies and its application as glucose sensor via cascade mechanism in human serum samples. Biochem Biophys Res Commun 2025;762:151758. [PMID: 40199131 DOI: 10.1016/j.bbrc.2025.151758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/21/2025] [Accepted: 04/03/2025] [Indexed: 04/10/2025]

Johar D, Bedair El-Assal AH, Abou-El-Makarem MM, Hammouda EFA, Hegazy MS, Zaky S. Do oxidized low-density lipoproteins link to extra hepatic manifestations in chronic, non-cirrhotic HCV patients? Metabol Open 2025;25:100339. [PMID: 39790936 PMCID: PMC11714377 DOI: 10.1016/j.metop.2024.100339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/07/2024] [Accepted: 12/09/2024] [Indexed: 01/12/2025] Open

Abstract

Background

Tissue damage by viral hepatitis is a major cause of morbidity and mortality worldwide. Oxidation reactions and reactive oxygen species (ROS) transform proteins and lipids in plasma low-density lipoproteins (LDL) into the abnormal oxidized LDL (ox-LDL). Hepatitis C virus (HCV) infection induces oxidative/nitrosative stress from multiple sources, including the inducible nitric oxide synthase (iNOS), the mitochondrial electron transport chain, hepatocyte NAD(P)H oxidases (NOX enzymes), and inflammation. Further, HCV decreases reduced glutathione (GSH) synthesis and regeneration.

Design

Cross-section.

Objective

to quantify ox-LDL in serum of chronic non-cirrhotic HCV patients, and to assess ox-LDL association with HCV-induced extra hepatic manifestations.

Patients and methods

Twenty chronic, non-cirrhotic HCV female patients with extra hepatic manifestations, twenty chronic, non-cirrhotic female HCV patients without extra hepatic manifestations and twenty healthy age, sex matched controls.

Methods

Serum was used for determination of liver function tests, ox-LDL and the extracellular antioxidant enzyme Superoxide Dismutase EC CuZn-SOD.

Results

Patients with extra hepatic manifestations had statistically higher ox-LDL (76.63 ± 6.86 μg/L) than patients without extra hepatic manifestations (63.05 ± 6.6 μg/L) p < 0.001, and both patient groups had higher ox-LDL levels than the control group (44.1 ± 4.1 μg/L) p < 0.001. EC CuZn-SOD correlated negatively with ox-LDL in HCV patients with extra hepatic manifestation only.

Conclusion

Extra hepatic manifestations were not risk for anthropometric changes seen with HCV infection. Extra hepatic manifestations were associated with high serum ox-LDL. High serum levels of ox-LDL associated with- or were due to deregulated expression of serum EC CuZn-SOD in chronic HCV patients.

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Yu S, Wang Y, Shi Y, Yu S, Zhao B, Liao N, Liu X. Reduced glutathione enhances adipose tissue-derived mesenchymal stem cell engraftment efficiency for liver fibrosis by targeting TGFβ1/SMAD3/NOX4 pathway. Bioeng Transl Med 2025;10:e10735. [PMID: 40060764 PMCID: PMC11883125 DOI: 10.1002/btm2.10735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/14/2024] [Accepted: 11/14/2024] [Indexed: 01/23/2025] Open

Affiliation(s)

Shaoxiong Yu The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina
Yingchao Wang The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina
Yingjun Shi The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina
Saihua Yu The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina
Bixing Zhao The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina
Naishun Liao The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina
Xiaolong Liu The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina Mengchao Med‐X CenterFuzhou UniversityFuzhouChina The Liver Center of Fujian ProvinceFujian Medical UniversityFuzhouChina

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Cusato J, Mulasso A, Ferrara M, Manca A, Accardo G, Palermiti A, Antonucci M, Bianco G, Chiara F, Mula J, Tettoni MC, Cuomo S, Trevisan G, Bonora S, Di Perri G, Lupo C, Rainoldi A, D’Avolio A. How Antiretroviral Drug Concentrations Could Be Affected by Oxidative Stress, Physical Capacities and Genetics: A Focus on Dolutegravir Treated Male PLWH. Antioxidants (Basel) 2025;14:82. [PMID: 39857416 PMCID: PMC11759814 DOI: 10.3390/antiox14010082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open

Affiliation(s)

Jessica Cusato Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (J.M.); (A.D.)
Anna Mulasso NeuroMuscular Function\|Research Group, School of Exercise and Sport Sciences, SUISM, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Micol Ferrara ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy; (M.F.); (M.A.); (M.C.T.)
Alessandra Manca Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (J.M.); (A.D.)
Guido Accardo Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Alice Palermiti Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (J.M.); (A.D.)
Miriam Antonucci ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy; (M.F.); (M.A.); (M.C.T.)
Gianluca Bianco Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (J.M.); (A.D.)
Francesco Chiara Laboratory of Clinical Pharmacology S. Luigi A.O.U., Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole, Orbassano, 10043 Turin, Italy;
Jacopo Mula Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (J.M.); (A.D.)
Maria Cristina Tettoni ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy; (M.F.); (M.A.); (M.C.T.)
Simone Cuomo NeuroMuscular Function\|Research Group, School of Exercise and Sport Sciences, SUISM, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Giulia Trevisan Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Stefano Bonora Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Giovanni Di Perri Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Corrado Lupo NeuroMuscular Function\|Research Group, School of Exercise and Sport Sciences, SUISM, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Alberto Rainoldi NeuroMuscular Function\|Research Group, School of Exercise and Sport Sciences, SUISM, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Antonio D’Avolio Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (J.M.); (A.D.)

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Kim JY, Kang W, Yang S, Park SH, Ha SY, Paik YH. NADPH oxidase 4 deficiency promotes hepatocellular carcinoma arising from hepatic fibrosis by inducing M2-macrophages in the tumor microenvironment. Sci Rep 2024;14:22358. [PMID: 39333166 PMCID: PMC11437090 DOI: 10.1038/s41598-024-72721-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 09/10/2024] [Indexed: 09/29/2024] Open

Cusato J, Mulasso A, Ferrara M, Manca A, Antonucci M, Accardo G, Palermiti A, Bianco G, Chiara F, Mula J, Maddalone MG, Tettoni MC, Cuomo S, Trevisan G, Bonora S, Di Perri G, Lupo C, Rainoldi A, D’Avolio A. Studying the Changes in Physical Functioning and Oxidative Stress-Related Molecules in People Living with HIV after Switching from Triple to Dual Therapy. Antioxidants (Basel) 2024;13:518. [PMID: 38790623 PMCID: PMC11117521 DOI: 10.3390/antiox13050518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open

Affiliation(s)

Jessica Cusato Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)
Anna Mulasso NeuroMuscolarFunction\|Research Group, Department of Medical Sciences, University of Turin, 10128 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Micol Ferrara ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy; (M.F.); (M.A.); (M.C.T.)
Alessandra Manca Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)
Miriam Antonucci ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy; (M.F.); (M.A.); (M.C.T.)
Guido Accardo Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Alice Palermiti Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)
Gianluca Bianco Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)
Francesco Chiara Laboratory of Clinical Pharmacology S. Luigi A.O.U., Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole, Orbassano, 10043 Turin, Italy;
Jacopo Mula Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)
Maria Grazia Maddalone Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)
Maria Cristina Tettoni ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy; (M.F.); (M.A.); (M.C.T.)
Simone Cuomo NeuroMuscolarFunction\|Research Group, Department of Medical Sciences, University of Turin, 10128 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Giulia Trevisan Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Stefano Bonora Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Giovanni Di Perri Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (G.A.); (G.T.); (S.B.); (G.D.P.)
Corrado Lupo NeuroMuscolarFunction\|Research Group, Department of Medical Sciences, University of Turin, 10128 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Alberto Rainoldi NeuroMuscolarFunction\|Research Group, Department of Medical Sciences, University of Turin, 10128 Turin, Italy; (A.M.); (S.C.); (C.L.); (A.R.)
Antonio D’Avolio Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy; (J.C.); (A.P.); (G.B.); (J.M.); (M.G.M.)

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Chida T, Watanabe S, Ohta K, Noritake H, Ito M, Suzuki T, Suda T, Kawata K. Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress. Free Radic Biol Med 2024;212:199-206. [PMID: 38103659 DOI: 10.1016/j.freeradbiomed.2023.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]

Sinha S, Hassan N, Schwartz RE. Organelle stress and alterations in interorganelle crosstalk during liver fibrosis. Hepatology 2024;79:482-501. [PMID: 36626634 DOI: 10.1097/hep.0000000000000012] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/03/2022] [Indexed: 01/12/2023]

Abstract

The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.

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LAGAL DJ, BÁRCENA JA, REQUEJO-AGUILAR R, PADILLA CA, LETO TL. NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity. ADVANCES IN REDOX RESEARCH 2023;9:100080. [PMID: 37900981 PMCID: PMC10611439 DOI: 10.1016/j.arres.2023.100080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]

Hu TH, Wu JC, Huang ST, Chu TH, Han AJ, Shih TW, Chang YC, Yang SM, Ko CY, Lin YW, Kung ML, Tai MH. HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria. J Biol Chem 2023;299:105335. [PMID: 37827291 PMCID: PMC10654039 DOI: 10.1016/j.jbc.2023.105335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 10/14/2023] Open

Abstract

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

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Affiliation(s)

Tsung-Hui Hu Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
Jian-Ching Wu Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
Shih-Tsung Huang Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan
Tian-Huei Chu Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
Ai-Jie Han Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
Ting-Wei Shih Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
Yi-Chen Chang Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan
Shih-Ming Yang Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
Chou-Yuan Ko Department of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
Yu-Wei Lin Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
Mei-Lang Kung Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Ming-Hong Tai Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan.

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Hung SH, Yang TH, Cheng YF, Chen CS, Lin HC. Associations of Head and Neck Cancer with Hepatitis B Virus and Hepatitis C Virus Infection. Cancers (Basel) 2023;15:4510. [PMID: 37760479 PMCID: PMC10526944 DOI: 10.3390/cancers15184510] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open

Thiyagarajah K, Basic M, Hildt E. Cellular Factors Involved in the Hepatitis D Virus Life Cycle. Viruses 2023;15:1687. [PMID: 37632029 PMCID: PMC10459925 DOI: 10.3390/v15081687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/30/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open

Wróblewska J, Wróblewski M, Hołyńska-Iwan I, Modrzejewska M, Nuszkiewicz J, Wróblewska W, Woźniak A. The Role of Glutathione in Selected Viral Diseases. Antioxidants (Basel) 2023;12:1325. [PMID: 37507865 PMCID: PMC10376684 DOI: 10.3390/antiox12071325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open

Smirnova OA, Ivanova ON, Mukhtarov F, Valuev-Elliston VT, Fedulov AP, Rubtsov PM, Zakirova NF, Kochetkov SN, Bartosch B, Ivanov AV. Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response. Antioxidants (Basel) 2023;12:974. [PMID: 37107349 PMCID: PMC10136299 DOI: 10.3390/antiox12040974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/20/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open

Affiliation(s)

Olga A. Smirnova Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Olga N. Ivanova Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Furkat Mukhtarov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Vladimir T. Valuev-Elliston Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Artemy P. Fedulov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Petr M. Rubtsov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Natalia F. Zakirova Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Sergey N. Kochetkov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)
Birke Bartosch Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69434 Lyon, France;
Alexander V. Ivanov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.A.S.); (O.N.I.); (F.M.); (V.T.V.-E.); (A.P.F.); (P.M.R.); (N.F.Z.); (S.N.K.)

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Ivanova ON, Krasnov GS, Snezhkina AV, Kudryavtseva AV, Fedorov VS, Zakirova NF, Golikov MV, Kochetkov SN, Bartosch B, Valuev-Elliston VT, Ivanov AV. Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells. Biomolecules 2023;13:714. [PMID: 37189460 PMCID: PMC10136275 DOI: 10.3390/biom13040714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/10/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open

Golikov MV, Bartosch B, Smirnova OA, Ivanova ON, Ivanov AV. Plasma-Like Culture Medium for the Study of Viruses. mBio 2023;14:e0203522. [PMID: 36515528 PMCID: PMC9973327 DOI: 10.1128/mbio.02035-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open

Gabbia D, Carpi S, Sarcognato S, Zanotto I, Sayaf K, Colognesi M, Polini B, Digiacomo M, Macchia M, Nieri P, Carrara M, Cazzagon N, Russo FP, Guido M, De Martin S. The phenolic compounds tyrosol and hydroxytyrosol counteract liver fibrogenesis via the transcriptional modulation of NADPH oxidases and oxidative stress-related miRNAs. Biomed Pharmacother 2023;157:114014. [PMID: 36379119 DOI: 10.1016/j.biopha.2022.114014] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 11/13/2022] Open

Damle VG, Wu K, Arouri DJ, Schirhagl R. Detecting free radicals post viral infections. Free Radic Biol Med 2022;191:8-23. [PMID: 36002131 DOI: 10.1016/j.freeradbiomed.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022]

Biswas L, Niveria K, Verma AK. Paradoxical role of reactive oxygen species in bone remodelling: implications in osteoporosis and possible nanotherapeutic interventions. EXPLORATION OF MEDICINE 2022. [DOI: 10.37349/emed.2022.00102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open

Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022;77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]

Ma Y, Lee G, Heo SY, Roh YS. Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease. Antioxidants (Basel) 2021;11:antiox11010091. [PMID: 35052595 PMCID: PMC8772974 DOI: 10.3390/antiox11010091] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open

Li X, Lin H, Zhang X, Jaspers RT, Yu Q, Ji Y, Forouzanfar T, Wang D, Huang S, Wu G. Notoginsenoside R1 attenuates oxidative stress-induced osteoblast dysfunction through JNK signalling pathway. J Cell Mol Med 2021;25:11278-11289. [PMID: 34786818 PMCID: PMC8650043 DOI: 10.1111/jcmm.17054] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/25/2021] [Accepted: 10/19/2021] [Indexed: 12/16/2022] Open

Affiliation(s)

Xumin Li Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam (VUA), Amsterdam Movement Science, Amsterdam, The Netherlands.,Laboratory for Myology, Amsterdam Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam (VUA), Amsterdam, The Netherlands
Haiyan Lin Savaid Stomatology School, Hangzhou Medical College, Hangzhou, PR China
Xiaorong Zhang Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Laboratory for Myology, Amsterdam Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam (VUA), Amsterdam, The Netherlands.,Department of Endodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China
Richard T Jaspers Laboratory for Myology, Amsterdam Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam (VUA), Amsterdam, The Netherlands
Qihao Yu Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Department of Endodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China
Yinghui Ji Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Laboratory for Myology, Amsterdam Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam (VUA), Amsterdam, The Netherlands
Tim Forouzanfar Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam (VUA), Amsterdam Movement Science, Amsterdam, The Netherlands
Dongyun Wang Stomatological Center, Peking University Shenzhen Hospital, Shenzhen, PR China
Shengbin Huang Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China.,Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), Amsterdam, The Netherlands
Gang Wu Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam (VUA), Amsterdam Movement Science, Amsterdam, The Netherlands.,Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), Amsterdam, The Netherlands

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Herranz-Itúrbide M, Peñuelas-Haro I, Espinosa-Sotelo R, Bertran E, Fabregat I. The TGF-β/NADPH Oxidases Axis in the Regulation of Liver Cell Biology in Health and Disease. Cells 2021;10:cells10092312. [PMID: 34571961 PMCID: PMC8470857 DOI: 10.3390/cells10092312] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 12/28/2022] Open

Affiliation(s)

Macarena Herranz-Itúrbide TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.) Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
Irene Peñuelas-Haro TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.) Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
Rut Espinosa-Sotelo TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.) Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
Esther Bertran TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.) Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
Isabel Fabregat TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.) Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08907 Barcelona, Spain Correspondence: ; Tel.: +34-932-607-828

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Yu L, Shen S, Zu Y, Huang J, Li H, Wang S. Hepatitis C virus and carpal tunnel syndrome in hemodialysis patients: a single center cross-sectional study. Ren Fail 2021;42:1076-1082. [PMID: 33070671 PMCID: PMC7594751 DOI: 10.1080/0886022x.2020.1832522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open

Hatta MNA, Mohamad Hanif EA, Chin SF, Neoh HM. Pathogens and Carcinogenesis: A Review. BIOLOGY 2021;10:533. [PMID: 34203649 PMCID: PMC8232153 DOI: 10.3390/biology10060533] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 12/24/2022]

Jeong JH, Yi J, Hwang MK, Hong SJ, Sohn WM, Kim TS, Pak JH. The Overactivation of NADPH Oxidase during Clonorchis sinensis Infection and the Exposure to N-Nitroso Compounds Promote Periductal Fibrosis. Antioxidants (Basel) 2021;10:869. [PMID: 34071467 PMCID: PMC8227395 DOI: 10.3390/antiox10060869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/17/2021] [Accepted: 05/26/2021] [Indexed: 11/16/2022] Open

Effect of Reactive Oxygen Species on the Endoplasmic Reticulum and Mitochondria during Intracellular Pathogen Infection of Mammalian Cells. Antioxidants (Basel) 2021;10:antiox10060872. [PMID: 34071633 PMCID: PMC8229183 DOI: 10.3390/antiox10060872] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/24/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023] Open

Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C. Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants (Basel) 2021;10:364. [PMID: 33670839 PMCID: PMC7997318 DOI: 10.3390/antiox10030364] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open

Konno T, Melo EP, Chambers JE, Avezov E. Intracellular Sources of ROS/H₂O₂ in Health and Neurodegeneration: Spotlight on Endoplasmic Reticulum. Cells 2021;10:233. [PMID: 33504070 PMCID: PMC7912550 DOI: 10.3390/cells10020233] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 02/08/2023] Open

Vandierendonck A, Degroote H, Vanderborght B, Verhelst X, Geerts A, Devisscher L, Van Vlierberghe H. NOX1 inhibition attenuates the development of a pro-tumorigenic environment in experimental hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021;40:40. [PMID: 33485364 PMCID: PMC7824948 DOI: 10.1186/s13046-021-01837-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 01/11/2021] [Indexed: 01/03/2023]

Abstract

Background

The poor prognosis of advanced HCC and limited efficacy of current systemic treatments emphasize the need for new or combined targeted therapies. The development of HCC is a multistage process in which liver injury appears in a complex microenvironment associated with oxidative stress. NOX enzymes are the main source of ROS during hepatocarcinogenesis and NOX1 in particular has shown correlation with poor prognosis of HCC patients. This study evaluates the effect of pharmacological NOX1 inhibition on the development and progression of HCC and its effect on the tumor microenvironment.

Methods

The in vitro cytotoxic effects of the NOX1 inhibitor GKT771 (Genkyotex) on human Huh7 and Hep3B and murine Hepa1-6 HCC cell lines, the human THP1 monocyte cell line and mouse macrophages were evaluated via MTT, LDH activity and CaspGlo® assays. In order to induce in vivo HCC, male SV129 wild-type mice received weekly IP injections of diethylnitrosamine (DEN) (35 mg/kg) for 20–25 weeks. Mice were treated with vehicle or GKT771 (30 mg/kg) via oral gavage, daily or twice daily, in preventive and therapeutic studies. The liver damage was evaluated for inflammation, angiogenesis, fibrosis and HCC development via histology, RT-qPCR, multiplex analyses and ROS levels.

Results

A concentration-dependent reduction in cellular activity of the human HCC cell lines without cytotoxicity was observed. GKT771 treatment reduced LPS-induced pro-inflammatory bone-marrow derived macrophage polarization. DEN injections resulted in 100 % tumor formation and the induction of HCC markers which could be reduced by twice daily dosing of GKT771 at early onset of advanced HCC. DEN-induced HCC resulted in an upregulation of pro-inflammatory, angiogenic and fibrotic markers which was less pronounced in GKT771 treated mice in all treatment regimens. In line, liver fibrosis was induced in HCC mice and this to a lesser extend upon GKT771 treatment.

Conclusions

NOX1 inhibition showed to be safe and well tolerated and was able to attenuate the induction of a pro-inflammatory, angiogenic and pro-fibrotic microenvironment suggesting that this might be a promising adjuvant therapeutic strategy in the treatment of advanced HCC.

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Affiliation(s)

Astrid Vandierendonck Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Blok B, 2nd floor, 9000, Ghent, Belgium
Helena Degroote Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Blok B, 2nd floor, 9000, Ghent, Belgium. .,Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 3, 9000, Ghent, Belgium.
Bart Vanderborght Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Blok B, 2nd floor, 9000, Ghent, Belgium.,Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 3, 9000, Ghent, Belgium
Xavier Verhelst Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Blok B, 2nd floor, 9000, Ghent, Belgium
Anja Geerts Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Blok B, 2nd floor, 9000, Ghent, Belgium
Lindsey Devisscher Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 3, 9000, Ghent, Belgium.
Hans Van Vlierberghe Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Blok B, 2nd floor, 9000, Ghent, Belgium

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Gravier-Hernández R, Gil-Del Valle L, Valdes-Alonso L, Hernández-Ayala N, Bermúdez-Alfonso Y, Hernández-Requejo D, Rosell-Guerra T, Hernández-González-Abreu MC. Oxidative stress in hepatitis C virus-human immunodeficiency virus co-infected patients. Ann Hepatol 2021;19:92-98. [PMID: 31607646 DOI: 10.1016/j.aohep.2019.05.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 05/22/2019] [Accepted: 05/22/2019] [Indexed: 02/04/2023]

Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021;81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

A Potential Role for Mitochondrial DNA in the Activation of Oxidative Stress and Inflammation in Liver Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020. [PMID: 32393967 PMCID: PMC7683147 DOI: 10.1155/2020/5835910] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]

D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020;26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open

Fu N, Li D, Li W, Zhao W, Zhang S, Liu L, Zhao S, Du J, Kong L, Wang R, Zhang Y, Nan Y. Glutamate-Cysteine Ligase Catalytic Subunit Attenuated Hepatitis C Virus-Related Liver Fibrosis and Suppressed Endoplasmic Reticulum Stress. Front Mol Biosci 2020;7:199. [PMID: 33015132 PMCID: PMC7461853 DOI: 10.3389/fmolb.2020.00199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022] Open

Affiliation(s)

Na Fu Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Dongdong Li Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Wencong Li Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Wen Zhao Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Siyu Zhang Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Lingdi Liu Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Suxian Zhao Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Jinghua Du Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Lingbo Kong Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Rongqi Wang Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Yuguo Zhang Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China
Yuemin Nan Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, China

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Xuan W, Song D, Yan Y, Yang M, Sun Y. Police Violence among Adults Diagnosed with Mental Disorders. HEALTH & SOCIAL WORK 2020;45:81-89. [PMID: 32393967 PMCID: PMC7683147 DOI: 10.1093/hsw/hlaa003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/25/2019] [Accepted: 05/15/2019] [Indexed: 06/11/2023]

Wang J, Tan Q, Wang W, Yu J. Mechanism of the Regulatory Effect of Overexpression of circMTO1 on Proliferation and Apoptosis of Hepatoma Cells via miR-9-5p/NOX4 Axis. Cancer Manag Res 2020;12:3915-3925. [PMID: 32547227 PMCID: PMC7263879 DOI: 10.2147/cmar.s240719] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 04/27/2020] [Indexed: 12/25/2022] Open

Firpo MR, Mounce BC. Diverse Functions of Polyamines in Virus Infection. Biomolecules 2020;10:E628. [PMID: 32325677 PMCID: PMC7226272 DOI: 10.3390/biom10040628] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/10/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022] Open

Chen J, Xu Q, Zhang Y, Zhang H. RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Chronic Hepatitis and Acute-on-chronic Liver Failure Caused By HBV. Sci Rep 2020;10:1528. [PMID: 32001731 PMCID: PMC6992791 DOI: 10.1038/s41598-020-58233-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 01/13/2020] [Indexed: 11/25/2022] Open

Ma N, Liu W, Zhang X, Gao X, Yu F, Guo W, Meng Y, Gao P, Zhou J, Yuan M, Mi Y, Zhang L, Qi S, Li L, Wang L, Su Q, Yang L, Liu D. Oxidative Stress-Related Gene Polymorphisms Are Associated With Hepatitis B Virus-Induced Liver Disease in the Northern Chinese Han Population. Front Genet 2020;10:1290. [PMID: 31969899 PMCID: PMC6960262 DOI: 10.3389/fgene.2019.01290] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/22/2019] [Indexed: 12/11/2022] Open

Abstract

Oxidative stress is closely related to the occurrence and development of various diseases such as cancer, diabetes, and cardiovascular and infectious diseases. We identified six critical genetic variants related to oxidative stress, and evaluated their main effects and their interaction effects on hepatitis B virus (HBV)-induced liver diseases. We enrolled 3,128 Han Chinese subjects into five groups: healthy controls, chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and natural clearance. We then determined the genotypes in each group for CYBA-rs4673, NCF4-rs1883112, NOX4-rs1836882, rs3017887, SOD2-rs4880, and GCLM-rs41303970, and evaluated the association between these variants and HBV-induced liver diseases. Gene-gene interactions were evaluated using generalized multifactor dimensionality reduction, logistic regression, and four-by-two tables. Significant associations were observed between healthy controls and the CIB group (CHB+LC+HCC). The CYBA-rs4673AG genotype was associated with a 1.356 rate of susceptibility of HBV-induced liver disease compared to the wild type GG genotype. The NCF4-rs1883112G allele occurred more frequently in healthy controls than in the CIB group in all three models (dominant, codominant, and recessive). Nox4-rs1836882 TC showed a protective association, being more frequent in healthy controls compared to the wild type TT genotype. GCLM-rs41303970A was associated with HBV-induced liver disease. The overall best model by multifactor dimensionality reduction was a five factor interaction model that had the highest cross validation consistency (10/10) and test accuracy (0.5669), P= 0.001. Oxidative stress-related gene polymorphisms are likely to be associated with HBV-induced liver disease, suggesting that information on these variations is useful for risk assessment of HBV-induced liver disease.

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Affiliation(s)

Ning Ma Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Wenxuan Liu Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Xiaolin Zhang Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Xia Gao Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Fengxue Yu The Hebei Key Laboratory of Gastroenterology, Division of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
Weiheng Guo Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Yanxin Meng Antenatal Diagnosis Center, The Fourth Hospital of Shijiazhuang, Shijiazhuang, China
Ping Gao Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Jin Zhou Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Meina Yuan Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Yingjun Mi Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Lei Zhang Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Sufen Qi Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Lu Li Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
Luyao Wang Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Qiao Su School of Basic Medicine, Hebei Medical University, Shijiazhuang, China
Lei Yang Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
Dianwu Liu Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China

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Sevastianos VA, Voulgaris TA, Dourakis SP. Hepatitis C, systemic inflammation and oxidative stress: correlations with metabolic diseases. Expert Rev Gastroenterol Hepatol 2020;14:27-37. [PMID: 31868062 DOI: 10.1080/17474124.2020.1708191] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Li S, Li H, Xu X, Saw PE, Zhang L. Nanocarrier-mediated antioxidant delivery for liver diseases. Theranostics 2020;10:1262-1280. [PMID: 31938064 PMCID: PMC6956819 DOI: 10.7150/thno.38834] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open

Bender D, Hildt E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int J Mol Sci 2019;20:ijms20184659. [PMID: 31546975 PMCID: PMC6769940 DOI: 10.3390/ijms20184659] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open

Kukhanova MK, Tunitskaya VL, Smirnova OA, Khomich OA, Zakirova NF, Ivanova ON, Ziganshin R, Bartosch B, Kochetkov SN, Ivanov AV. Hepatitis C Virus RNA-Dependent RNA Polymerase Is Regulated by Cysteine S-Glutathionylation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019;2019:3196140. [PMID: 31687077 PMCID: PMC6800943 DOI: 10.1155/2019/3196140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022]

Eun HS, Chun K, Song IS, Oh CH, Seong IO, Yeo MK, Kim KH. High nuclear NADPH oxidase 4 expression levels are correlated with cancer development and poor prognosis in hepatocellular carcinoma. Pathology 2019;51:579-585. [PMID: 31443922 DOI: 10.1016/j.pathol.2019.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 04/29/2019] [Accepted: 05/07/2019] [Indexed: 11/30/2022]

Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019;2019:1409582. [PMID: 31531178 PMCID: PMC6720866 DOI: 10.1155/2019/1409582] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/09/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023]

Ramos-Tovar E, Muriel P. Free radicals, antioxidants, nuclear factor-E2-related factor-2 and liver damage. J Appl Toxicol 2019;40:151-168. [PMID: 31389060 DOI: 10.1002/jat.3880] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/03/2019] [Accepted: 07/04/2019] [Indexed: 12/11/2022]

ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019;2019:6175804. [PMID: 31467634 PMCID: PMC6701375 DOI: 10.1155/2019/6175804] [Citation(s) in RCA: 498] [Impact Index Per Article: 83.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/24/2019] [Indexed: 02/08/2023]

Thaker SK, Ch'ng J, Christofk HR. Viral hijacking of cellular metabolism. BMC Biol 2019;17:59. [PMID: 31319842 PMCID: PMC6637495 DOI: 10.1186/s12915-019-0678-9] [Citation(s) in RCA: 334] [Impact Index Per Article: 55.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open

Liang S, Ma HY, Zhong Z, Dhar D, Liu X, Xu J, Koyama Y, Nishio T, Karin D, Karin G, Mccubbin R, Zhang C, Hu R, Yang G, Chen L, Ganguly S, Lan T, Karin M, Kisseleva T, Brenner DA. NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice. Gastroenterology 2019;156:1156-1172.e6. [PMID: 30445007 PMCID: PMC6409207 DOI: 10.1053/j.gastro.2018.11.019] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 11/06/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023]

Abstract

BACKGROUND & AIMS

Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen.

METHODS

Fourteen-day-old Nox1^-/- mice, Nox4^-/- mice, Nox1^-/-Nox4^-/- (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1^ΔHep), hepatic stellate cells (Nox1^ΔHep), or macrophages (Nox1^ΔMac). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8-12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots.

RESULTS

Nox4^-/- mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1^-/- mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1^ΔHep and Nox1^ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1^ΔMac developed fewer and smaller tumors, similar to Nox1^-/- mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1^-/- or Nox1^ΔMac, mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1^ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle.

CONCLUSIONS

In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.

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Affiliation(s)

Shuang Liang Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Hsiao-Yen Ma Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Zhenyu Zhong Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
Debanjan Dhar Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
Xiao Liu Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Jun Xu Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Yukinori Koyama Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,4Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Takahiro Nishio Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,4Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Daniel Karin Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Gabriel Karin Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Ryan Mccubbin Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Cuili Zhang Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,5School of Public Health, Shandong University, Jinan, 250012, China
Ronglin Hu Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,6Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Guizhi Yang Guangdong Pharmaceutical University, Guangzhou 510006, China
Li Chen Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Souradipta Ganguly Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Tian Lan Guangdong Pharmaceutical University, Guangzhou 510006, China
Michael Karin Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
Tatiana Kisseleva Department of Surgery, School of Medicine, University of California San Diego, La Jolla, California.
David A. Brenner Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,*Correspondence: To whom correspondence should be addressed. ;

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