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Hatami-Sadr A, Ghorbaninezhad F, Naseri B, Youshanlui MA, Eslami S, Masoumi J, Shirmohammadi A, Seyedgholamisharabiani SE, Baradaran B. Unveiling rifampin's impact on OSCC lysate-pulsed DCs: From inflammatory to anti-inflammatory landscape. Tissue Cell 2025; 95:102920. [PMID: 40253800 DOI: 10.1016/j.tice.2025.102920] [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: 10/01/2024] [Revised: 04/09/2025] [Accepted: 04/11/2025] [Indexed: 04/22/2025]
Abstract
Dendritic cells (DCs) play a critical role in immune responses, being essential antigen-presenting cells (APCs) for T cell activation. In the context of cancer immunotherapy, DCs are pivotal for eliciting robust CD4+ and CD8+ T cell responses against tumor antigens. However, in oral squamous cell carcinoma (OSCC), DCs encounter challenges due to the immunosuppressive tumor microenvironment (TME). Factors like vascular endothelial growth factor (VEGF) and interleukin (IL)-6 in OSCC hinder DC function and maturation. To address this, current research has focused on enhancing DC immunogenicity to boost anti-tumor immunity. Rifampin, known for its antibacterial properties, presents immunomodulatory effects that could be beneficial in augmenting DC function in cancer therapy. This study investigates the impact of rifampin treatment on OSCC lysate-loaded-DCs. Results show that rifampin enhances the expression of key inflammatory factors while reducing anti-inflammatory mediators in DCs. Moreover, rifampin treatment enhances the immune-stimulatory capabilities of OSCC lysate-loaded-DCs, potentially improving their effectiveness in cancer immunotherapy.
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Affiliation(s)
| | - Farid Ghorbaninezhad
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sahand Eslami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Adileh Shirmohammadi
- Department of Periodontology, Dentistry Faculty Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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2
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Link F, Li Y, Zhao J, Munker S, Fan W, Nwosu ZC, Yao Y, Wang S, Huang C, Liebe R, Hammad S, Liu H, Shao C, Gao C, Sun B, Török NJ, Ding H, Ebert MP, Weng H, Ten Dijke P, Drasdo D, Dooley S, Wang S. ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation. Gut 2025; 74:424-439. [PMID: 39448254 DOI: 10.1136/gutjnl-2024-333213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 07/24/2024] [Indexed: 10/26/2024]
Abstract
OBJECTIVE Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. DESIGN RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue and computer simulations. RESULTS Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation while KTFR treatment reversed Ecm1-KO-mediated and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-β1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. CONCLUSION Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-β1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD.
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Affiliation(s)
- Frederik Link
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yujia Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jieling Zhao
- INRIA de Saclay, Palaiseau, France
- IfADo, Dortmund, Germany
| | - Stefan Munker
- Department of Medicine II, University Hospital, LMU, Munich, Germany
- Liver Center Munich, University Hospital, LMU, Munich, Germany
| | - Weiguo Fan
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Zeribe C Nwosu
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Ye Yao
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Shanshan Wang
- Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Chenjun Huang
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Roman Liebe
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University, Magdeburg, Germany
| | - Seddik Hammad
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hui Liu
- Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, People's Republic of China
| | - Chen Shao
- Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, People's Republic of China
| | - Chunfang Gao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Bing Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Natalie J Török
- Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, People's Republic of China
| | - Matthias Pa Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center, Mannheim, Germany
| | - Honglei Weng
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Dirk Drasdo
- INRIA de Saclay, Palaiseau, France
- IfADo, Dortmund, Germany
| | - Steven Dooley
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sai Wang
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Yousefi Z, Nourbakhsh M, Sahebghadam Lotfi A. Pirfenidone Downregulates eIF6, P311, and TGF-β Expression and Improves Liver Fibrosis Induced by Bile Duct Ligation in Wistar Rats: Evidence for Liver Regeneration. DNA Cell Biol 2025; 44:109-124. [PMID: 39681345 DOI: 10.1089/dna.2024.0194] [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] [Indexed: 12/18/2024] Open
Abstract
Liver fibrosis (LF) is a clinical disorder characterized by inflammation and excessive accumulation of extracellular matrix (ECM). This study investigates the effects of the antifibrotic compound pirfenidone (PFD) on improving LF through histological changes and modulation of eukaryotic translation initiation factor 6 (eIF6), P311, and transforming growth factor beta (TGF-β) in rats with bile duct ligation (BDL)-induced LF. Rats received daily doses of PFD (200 and 500 mg/kg) for 4 weeks. The study encompassed biochemical, pathological, and immunohistochemical (IHC) analyses. mRNA levels of eIF6, P311, TGF-β, ECM deposition, hepatic stellate cell (HSC) activation, and inflammatory mediator genes were measured by RT-qPCR. Protein levels of eIF6, P311, and TGF-β were detected by western blotting. Compared with the BDL group, PFD dose-dependently reduced hydroxyproline content, liver index, biochemical parameters, fibrosis score, and fibrosis area. PFD also modulated BDL-induced hepatic inflammation, ECM accumulation, and HSC activation. IHC staining of Ki-67 and hepatocyte paraffin-1 revealed that PFD enhanced liver regeneration. The research confirmed that PFD gradually downregulated elevated eIF6, P311, and TGF-β levels in BDL-induced LF. These findings suggest that PFD could be a potential treatment for LF, as it may help attenuate fibrosis and enhance liver regeneration, possibly through the modulation of these specific markers.
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Affiliation(s)
- Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mitra Nourbakhsh
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Baek JS, Lee JH, Kim JH, Cho SS, Kim YS, Yang JH, Shin EJ, Kang HG, Kim SJ, Ahn SG, Park EY, Baek DJ, Yim SK, Kang KW, Ki SH, Kim KM. An inducible sphingosine kinase 1 in hepatic stellate cells potentiates liver fibrosis. Biochem Pharmacol 2024; 229:116520. [PMID: 39236934 DOI: 10.1016/j.bcp.2024.116520] [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: 12/06/2023] [Revised: 08/19/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
Hepatic stellate cells (HSCs) play a role in hepatic fibrosis and sphingosine kinase (SphK) is involved in biological processes. As studies on the regulatory mechanisms and functions of SphK in HSCs during liver fibrosis are currently limited, this study aimed to elucidate the regulatory mechanism and connected pathways of SphK upon HSC activation. The expression of SphK1 was higher in HSCs than in hepatocytes, and upregulated in activated primary HSCs. SphK1 was also increased in liver homogenates of carbon tetrachloride-treated or bile duct ligated mice and in transforming growth factor-β (TGF-β)-treated LX-2 cells. TGF-β-mediated SphK1 induction was due to Smad3 signaling in LX-2 cells. SphK1 modulation altered the expression of liver fibrogenesis-related genes. This SphK1-mediated profibrogenic effect was dependent on SphK1/sphingosine-1-phosphate/sphingosine-1-phosphate receptor signaling through ERK. Epigallocatechin gallate blocked TGF-β-induced SphK1 expression and hepatic fibrogenesis by attenuating Smad and MAPK activation. SphK1 induced by TGF-β facilitates HSC activation and liver fibrogenesis, which is reversed by epigallocatechin gallate. Accordingly, SphK1 and related signal transduction may be utilized to treat liver fibrosis.
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Affiliation(s)
- Jin Sol Baek
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Ji Hyun Lee
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Ji Hye Kim
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Sam Seok Cho
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
| | - Yun Seok Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Pharmacy, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do 58245, Republic of Korea
| | - Eun Jin Shin
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
| | - Hyeon-Gu Kang
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea
| | - Seok-Jun Kim
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea
| | - Dong Jae Baek
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea
| | - Sung-Kun Yim
- Marine Biotechnology Research Center, Jeonnam Bioindustry Foundation, 21-7, Nonggongdanji 4Gil, Wando-eup, Wando-gun, Jeollanam-do 59108, Republic of Korea
| | - Keon Wook Kang
- Department of Pharmacy, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Sung Hwan Ki
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Kyu Min Kim
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea.
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5
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Min K, Yenilmez B, Kelly M, Echeverria D, Elleby M, Lifshitz LM, Raymond N, Tsagkaraki E, Harney SM, DiMarzio C, Wang H, McHugh N, Bramato B, Morrison B, Rothstein JD, Khvorova A, Czech MP. Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis. eLife 2024; 12:RP89136. [PMID: 38564479 PMCID: PMC10987092 DOI: 10.7554/elife.89136] [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] [Indexed: 04/04/2024] Open
Abstract
Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.
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Affiliation(s)
- Kyounghee Min
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Mark Kelly
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Dimas Echeverria
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Michael Elleby
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Lawrence M Lifshitz
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Naideline Raymond
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Emmanouela Tsagkaraki
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Shauna M Harney
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Chloe DiMarzio
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Hui Wang
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Nicholas McHugh
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Brianna Bramato
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Brett Morrison
- Department of Neurology, Johns Hopkins School of MedicineBaltimoreUnited States
| | - Jeffery D Rothstein
- Department of Neurology, Johns Hopkins School of MedicineBaltimoreUnited States
| | - Anastasia Khvorova
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
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Shree Harini K, Ezhilarasan D. Flavonoids-based nanomedicines for the treatment of liver fibrosis: A recent progress. J Drug Deliv Sci Technol 2024; 93:105467. [DOI: 10.1016/j.jddst.2024.105467] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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7
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Lee JH, Kim KM, Jung EH, Lee HR, Yang JH, Cho SS, Ki SH. Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation. Int J Mol Sci 2023; 24:14826. [PMID: 37834275 PMCID: PMC10573240 DOI: 10.3390/ijms241914826] [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: 07/12/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-β (TGF-β) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-β-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-β. TGF-β-induced parkin was due to Smad3. TGF-β facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-β did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-β. Collectively, parkin-involved mitophagy by TGF-β facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis.
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Affiliation(s)
- Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Hee Jung
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Hye Rim Lee
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea;
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea (E.H.J.); (H.R.L.); (S.S.C.)
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8
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Nam Y, Kim M, Erdenebileg S, Cha KH, Ryu DH, Kim HY, Lee SH, Jung JH, Nho CW. Sanguisorba officinalis L. Ameliorates Hepatic Steatosis and Fibrosis by Modulating Oxidative Stress, Fatty Acid Oxidation, and Gut Microbiota in CDAHFD-Induced Mice. Nutrients 2023; 15:3779. [PMID: 37686810 PMCID: PMC10490207 DOI: 10.3390/nu15173779] [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: 07/31/2023] [Revised: 08/19/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases and encompasses non-alcoholic steatosis, steatohepatitis, and fibrosis. Sanguisorba officinalis L. (SO) roots have traditionally been used for their antioxidant properties and have beneficial effects on metabolic disorders, including diabetes and obesity. However, its effects on hepatic steatosis and fibrosis remain unclear. In this study, we explored the effects of a 95% ethanolic SO extract (SOEE) on NAFLD and fibrosis in vivo and in vitro. The SOEE was orally administered to C57BL/6J mice fed a choline-deficient, L-amino-acid-defined, high-fat diet for 10 weeks. The SOEE inhibited hepatic steatosis by modulating hepatic malondialdehyde levels and the expression of oxidative stress-associated genes, regulating fatty-acid-oxidation-related genes, and inhibiting the expression of genes that are responsible for fibrosis. The SOEE suppressed the deposition of extracellular matrix hydroxyproline and mRNA expression of fibrosis-associated genes. The SOEE decreased the expression of fibrosis-related genes in vitro by inhibiting SMAD2/3 phosphorylation. Furthermore, the SOEE restored the gut microbial diversity and modulated specific bacterial genera associated with NAFLD and fibrosis. This study suggests that SOEE might be the potential candidate for inhibiting hepatic steatosis and fibrosis by modulating oxidative stress, fatty acid oxidation, and gut microbiota composition.
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Affiliation(s)
- Yunseong Nam
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Myungsuk Kim
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26493, Republic of Korea
| | - Saruul Erdenebileg
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Kwang Hyun Cha
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26493, Republic of Korea
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
| | - Da Hye Ryu
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Ho Youn Kim
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Su Hyeon Lee
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Je Hyeong Jung
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Chu Won Nho
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
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9
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Liu Y, Lyu Y, Zhu L, Wang H. Role of TRP Channels in Liver-Related Diseases. Int J Mol Sci 2023; 24:12509. [PMID: 37569884 PMCID: PMC10420300 DOI: 10.3390/ijms241512509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). The disruption of the liver's normal structure and function by diverse pathogenic factors imposes a significant healthcare burden. At present, most of the treatments for liver disease are palliative in nature, rather than curative or restorative. Transient receptor potential (TRP) channels, which are extensively expressed in the liver, play a crucial role in regulating intracellular cation concentration and serve as the origin or intermediary stage of certain signaling pathways that contribute to liver diseases. This review provides an overview of recent developments in liver disease research, as well as an examination of the expression and function of TRP channels in various liver cell types. Furthermore, we elucidate the molecular mechanism by which TRP channels mediate liver injury, liver fibrosis, and hepatocellular carcinoma (HCC). Ultimately, the present discourse delves into the current state of research and extant issues pertaining to the targeting of TRP channels in the treatment of liver diseases and other ailments. Despite the numerous obstacles encountered, TRP channels persist as an extremely important target for forthcoming clinical interventions aimed at treating liver diseases.
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Affiliation(s)
- Yusheng Liu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; (Y.L.); (Y.L.)
| | - Yihan Lyu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; (Y.L.); (Y.L.)
| | - Lijuan Zhu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing 210009, China;
| | - Hongmei Wang
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; (Y.L.); (Y.L.)
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10
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Shree Harini K, Ezhilarasan D. Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases. Hepatobiliary Pancreat Dis Int 2023; 22:333-345. [PMID: 36448560 DOI: 10.1016/j.hbpd.2022.10.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 10/13/2022] [Indexed: 11/04/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as "two-hit hypothesis", advancing with a "third hit" of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/β-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/β-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.
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Affiliation(s)
- Karthik Shree Harini
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600 077, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600 077, India.
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11
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van Son KC, Verschuren L, Hanemaaijer R, Reeves H, Takkenberg RB, Drenth JPH, Tushuizen ME, Holleboom AG. Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease. Cancers (Basel) 2023; 15:1308. [PMID: 36831649 PMCID: PMC9954729 DOI: 10.3390/cancers15041308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.
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Affiliation(s)
- Koen C. van Son
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Lars Verschuren
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Roeland Hanemaaijer
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Helen Reeves
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne NE2 4HH, UK
| | - R. Bart Takkenberg
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Joost P. H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Adriaan G. Holleboom
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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12
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Dietary oxidized frying oil activates hepatic stellate cells and accelerates the severity of carbon tetrachloride- and thioacetamide-induced liver fibrosis in mice. J Nutr Biochem 2023; 115:109267. [PMID: 36641072 DOI: 10.1016/j.jnutbio.2023.109267] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 11/18/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
Deep-frying is a common cooking practice worldwide, and after repeated heating's, the oil undergoes various chemical reactions, including hydrolysis, polymerization, lipid oxidation, and the Maillard reaction. Studies have pointed out that oxidized dietary frying oil may cause teratogenesis in mice and increase cancer and cardiovascular risks. The liver is the main organ involved in dietary nutrient catabolism, detoxification, bile production, and lipid metabolism. Nevertheless, the effects of oxidized frying oil exposure on the activation of hepatic stellate cells (HSCs) and liver fibrosis are still unclear. In this study, we showed that exposure to oxidized frying oil enhanced the sensitivity of HSCs to transforming growth factor (TGF)-β1-induced α-smooth muscle actin (α-SMA), collagen 1a2, collagen 1a1, metalloproteinase-2, and phosphorylated smad2/3 activation. In both carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis mouse models, we showed that long-term administration of a 10% fried oil-containing diet significantly upregulated fibrogenesis genes expression and deposition of hepatic collagen. Furthermore, long-term fried oil exposure not only promoted macrophage infiltration and increased inflammatory-related gene expression, but also accumulated excess cholesterol and lipid peroxidation in the liver tissues. In conclusion, our study demonstrated that feeding a fried oil-containing diet may trigger TGF-β1-induced HSCs activation and thereby promote liver damage and fibrosis progression through enhancing the inflammatory response and lipid peroxidation.
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13
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Peng H, Zhong L, Cheng L, Chen L, Tong R, Shi J, Bai L. Ganoderma lucidum: Current advancements of characteristic components and experimental progress in anti-liver fibrosis. Front Pharmacol 2023; 13:1094405. [PMID: 36703748 PMCID: PMC9872944 DOI: 10.3389/fphar.2022.1094405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023] Open
Abstract
Ganoderma lucidum (G. lucidum, Lingzhi) is a well-known herbal medicine with a variety of pharmacological effects. Studies have found that G. lucidum has pharmacological effects such as antioxidant, antitumor, anti-aging, anti-liver fibrosis, and immunomodulation. The main active components of G. lucidum include triterpenoids, polysaccharides, sterols, peptides and other bioactive components. Among them, the triterpenoids and polysaccharide components of G. lucidum have a wide range of anti-liver fibrotic effects. Currently, there have been more reviews and studies on the antioxidant, antitumor, and anti-aging properties of G. lucidum. Based on the current trend of increasing number of liver fibrosis patients in the world, we summarized the role of G.lucidum extract in anti-liver fibrosis and the effect of G. lucidum extract on liver fibrosis induced by different pathogenesis, which were discussed and analyzed. Research and development ideas and references are provided for the subsequent application of G. lucidum extracts in anti-liver fibrosis treatment.
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Affiliation(s)
- Haoyuan Peng
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Zhong
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lin Cheng
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Lu Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rongsheng Tong
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China,Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jianyou Shi
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China,Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,*Correspondence: Jianyou Shi, ; Lan Bai,
| | - Lan Bai
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China,Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,*Correspondence: Jianyou Shi, ; Lan Bai,
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14
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Liu SQ, Deng X, Zhu CP, Cui YL, Xie WF, Zhang X. Depletion of Tgfbr2 in hepatocytes alleviates liver fibrosis and restores hepatic function in fibrotic mice. J Dig Dis 2023; 24:39-50. [PMID: 36967587 DOI: 10.1111/1751-2980.13161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 05/03/2023]
Abstract
OBJECTIVES Previous studies have demonstrated the pivotal role of transforming growth factor (TGF)-β signaling in activating hepatic stellate cells during liver fibrosis. In this study we aimed to demonstrate the effects and underlying mechanism of TGF-β signaling in hepatocytes on hepatic fibrogenesis. METHODS Hepatocyte-specific Tgfbr2-knockout (Tgfbr2HKO ) mice were generated by AAV8-TBG-Cre injection via the tail vein of Tgfbr2f/f mice. CCl4 was injected intraperitoneally twice a week for 4 weeks to establish the fibrotic mouse model. The expression of the fibrogenesis markers was evaluated by immunohistochemistry, western blot, and real-time polymerase chain reaction (PCR). RNA-seq analysis was used to detect the transcriptional profiles of primary hepatocytes isolated from Tgfbr2HKO mice and control mice. RESULTS The expression of TβR2 (Tgfbr2) was markedly upregulated in hepatocytes of the fibrotic liver. Tgfbr2 depletion in hepatocytes decreased the expressions of profibrogenic markers (Col1a1 and Acta2) in the CCl4 -treated fibrotic liver. RNA-seq analysis revealed that Tgfbr2 deletion in hepatocytes significantly reduced the inflammatory response and suppressed epithelial-mesenchymal transition of hepatocytes accompanied by upregulation of the metabolic pathways during liver fibrosis. Moreover, the expressions of hepatocyte nuclear factors (HNFs), including Hnf4α, Foxa1, Foxa2, and Foxa3, which are important for maintaining liver metabolism and homeostasis, were decreased in fibrotic livers and significantly increased after Tgfbr2 blockade. CONCLUSION Blocking the TGF-β signaling pathway in hepatocytes reduces hepatic fibrosis and improves hepatic function in fibrotic livers.
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Affiliation(s)
- Shu Qing Liu
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xing Deng
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Chang Peng Zhu
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ya Lu Cui
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wei Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xin Zhang
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
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15
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Cho SS, Yang JH, Lee JH, Baek JS, Ku SK, Cho IJ, Kim KM, Ki SH. Ferroptosis contribute to hepatic stellate cell activation and liver fibrogenesis. Free Radic Biol Med 2022; 193:620-637. [PMID: 36370962 DOI: 10.1016/j.freeradbiomed.2022.11.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Ferroptosis is a widely known regulator of cell death in connection with the redox state as a consequence of the depletion of glutathione or accumulation of lipid peroxidation. Hepatic stellate cells (HSCs) play a pivotal role in the progression of hepatic fibrosis by increasing the production and secretion of the extracellular matrix. However, the role of ferroptosis in HSC activation and liver fibrogenesis has not been clearly elucidated. The ferroptosis inducer RAS-selective lethal 3 (RSL3) or erastin treatment in HSCs caused cell death. This effect was suppressed only after exposure to ferroptosis inhibitors. We observed induction of ferroptosis by RSL3 treatment in HSCs supported by decreased glutathione peroxidase 4, glutathione deficiency, reactive oxygen species generation, or lipid peroxidation. Interestingly, RSL3 treatment upregulated the expression of plasminogen activator inhibitor-1, a representative fibrogenic marker of HSCs. In addition, treatment with ferroptosis-inducing compounds increased c-JUN phosphorylation and activator protein 1 luciferase activity but did not alter Smad phosphorylation and Smad-binding element luciferase activity. Chronic administration of iron dextran to mice causes ferroptosis of liver in vivo. The expression of fibrosis markers, such as alpha-smooth muscle actin and plasminogen activator inhibitor-1, was increased in the livers of mice with iron accumulation. Hepatic injury accompanying liver fibrosis was observed based on the levels of alanine aminotransferase, aspartate aminotransferase, and hematoxylin and eosin staining. Furthermore, we found that both isolated primary hepatocyte and HSCs undergo ferroptosis. Consistently, cirrhotic liver tissue of patients indicated glutathione peroxidase 4 downregulation in fibrotic region. In conclusion, our results suggest that ferroptosis contribute to HSC activation and the progression of hepatic fibrosis.
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Affiliation(s)
- Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jin Sol Baek
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Sae Kwang Ku
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Il Je Cho
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452, Republic of Korea.
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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16
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Wallace SJ, Tacke F, Schwabe RF, Henderson NC. Understanding the cellular interactome of non-alcoholic fatty liver disease. JHEP Rep 2022; 4:100524. [PMID: 35845296 PMCID: PMC9284456 DOI: 10.1016/j.jhepr.2022.100524] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. Non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, has become the leading indication for liver transplantation in both Europe and the USA. Liver fibrosis is the consequence of sustained, iterative liver injury, and the main determinant of outcomes in NASH. The liver possesses remarkable inherent plasticity, and liver fibrosis can regress when the injurious agent is removed, thus providing opportunities to alter long-term outcomes through therapeutic interventions. Although hepatocyte injury is a key driver of NASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cellular components of the fibrotic niche include endothelial cells, macrophages, passaging immune cell populations and myofibroblasts. In this review, we will describe how rapidly evolving technologies such as single-cell genomics, spatial transcriptomics and single-cell ligand-receptor analyses are transforming our understanding of the cellular interactome in NAFLD/NASH, and how this new, high-resolution information is being leveraged to develop rational new therapies for patients with NASH.
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Key Words
- BAs, bile acids
- CCL, C-C motif chemokine ligand
- CCR, C-C motif chemokine receptor
- CLD, chronic liver disease
- CTGF, connective tissue growth factor
- CXCL, C-X-C motif chemokine ligand
- CXCR, C-X-C motif chemokine receptor
- DAMP, damage-associated molecular pattern
- ECM, extracellular matrix
- ER, endoplasmic reticulum
- FGF, fibroblast growth factor
- FXR, farnesoid X receptor
- HSCs, hepatic stellate cells
- IL, interleukin
- ILC, innate lymphoid cell
- KCs, Kupffer cells
- LSECs, liver sinusoidal endothelial cells
- MAIT, mucosal-associated invariant T
- MAMPS, microbiota-associated molecular patterns
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NK(T), natural killer (T)
- NLR, Nod like receptors
- Non-alcoholic fatty liver disease (NAFLD)
- PDGF, platelet-derived growth factor
- PFs, portal fibroblasts
- SASP, senescence-associated secretory phenotype
- TGF, transforming growth factor
- TLR, Toll-like receptor
- TNF, tumour necrosis factor
- VEGF, vascular endothelial growth factor
- antifibrotic therapies
- cellular interactome
- cirrhosis
- fibrosis
- single-cell genomics
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Affiliation(s)
- Sebastian J. Wallace
- Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Robert F. Schwabe
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Medicine, Columbia University, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Neil C. Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, UK
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Protective Mechanism of Nostoc sphaeroides Kütz. Polysaccharide on Liver Fibrosis by HFD-Induced Liver Fat Synthesis and Oxidative Stress. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1745244. [PMID: 35836833 PMCID: PMC9276475 DOI: 10.1155/2022/1745244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/21/2022] [Accepted: 06/14/2022] [Indexed: 11/23/2022]
Abstract
Nostoc sphaeroides Kütz. polysaccharide (NSKP) is one of the main components of Nostoc sphaeroides Kütz. and is often used as health food. We investigated whether NSKP interferes with the progression of liver fibrosis. Male mice were randomly divided into 4 groups: control (C), high-fat diet (M), high-fat diet + 0.4 g/kg NSKP (L), and high-fat diet + 0.8 g/kg NSKP (H). C was fed standard diet, M was fed high-fat diet, and L and H were fed high-fat diet in addition to gavage of 0.4 g/kg or 0.8 g/kg NSKP, respectively, for 22 weeks. At the end of the experiment, the serum and liver oxidative stress, fat accumulation, and fibrosis indexes were detected. The histopathology of liver was also observed. The results showed that the rice of NSKP, compared with M, improved blood lipid level, liver total cholesterol (TC), triglyceride (TG), and liver antioxidant capacity and effectively interfered with liver fibrosis related indicators. So it is interesting to note that NSKP appeared to be effective in liver injury; further experiments are necessary to clarify the exact mechanisms involved.
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18
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Guo H, Ruan C, Zhan X, Pan H, Luo Y, Gao K. Crocetin Protected Human Hepatocyte LO2 Cell From TGF-β-Induced Oxygen Stress and Apoptosis but Promoted Proliferation and Autophagy via AMPK/m-TOR Pathway. Front Public Health 2022; 10:909125. [PMID: 35836988 PMCID: PMC9273739 DOI: 10.3389/fpubh.2022.909125] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To investigate the protective effects of crocetin against transforming growth factor-β (TGF-β)—induced injury in LO2 cells. Methods Human hepatocyte LO2 cells were pre-treated with crocetin (10 μM) for 6, 12, and 24 h, and then induced by TGF-β. Proliferation, oxidative stress, apoptosis, autophagy, and related proteins were assessed. Results Crocetin pre-treating promoted proliferation but suppressed apoptosis in TGF-β-induced LO2 cells. Crocetin protected LO2 cells from TGF-β-induced inflammation and oxygen stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) but enhancing superoxide dismutase (SOD) and glutathione (GSH). Autophagy was suppressed in TGF-β but crocetin promoted autophagy in LO2 cells by mediating Adenosine 5'-monophosphate—activated protein kinase (AMPK)/mammalian target of rapamycin (m-TOR) signaling pathway via upregulating p-AMPK and p-Beclin-1 but downregulating p-mTOR. Conclusions Crocetin protected LO2 cells from TGF-β-induced damage by promoting proliferation and autophagy, and suppressing apoptosis and anti-inflammation via regulation of AMPK/m-TOR signaling pathway.
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Affiliation(s)
- Hongxing Guo
- Department of Gastroenterology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Chenyu Ruan
- Department of Gastroenterology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Xiuhong Zhan
- Department of Gastroenterology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Hao Pan
- Department of Gastroenterology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Yumei Luo
- Department of Gastroenterology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Ke Gao
- Department of Pathology, Foshan Fosun Chancheng Hospital, Foshan, China
- *Correspondence: Ke Gao
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19
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Liver Steatosis: A Marker of Metabolic Risk in Children. Int J Mol Sci 2022; 23:ijms23094822. [PMID: 35563210 PMCID: PMC9100068 DOI: 10.3390/ijms23094822] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.
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Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer 2022; 21:104. [PMID: 35461253 PMCID: PMC9033932 DOI: 10.1186/s12943-022-01569-x] [Citation(s) in RCA: 521] [Impact Index Per Article: 173.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/18/2022] [Indexed: 02/08/2023] Open
Abstract
Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
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21
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Czaja AJ. Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis. Dig Dis Sci 2022; 67:1163-1186. [PMID: 33835375 DOI: 10.1007/s10620-021-06968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8+ T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4+ and CD8+ T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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22
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Xu P, Luo A, Xiong C, Ren H, Yan L, Luo Q. SCUBE3 downregulation modulates hepatocellular carcinoma by inhibiting CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway. Cancer Cell Int 2022; 22:1. [PMID: 34980127 PMCID: PMC8725472 DOI: 10.1186/s12935-021-02402-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES We aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression. METHODS The role of SCUBE3 in HCC cell proliferation, apoptosis, and cell cycle in vitro were detected using MTT assay, colony formation assay, 5-ethynyl-2´-deoxyuridine assay (EDU), Celigo cell counting assay, Caspase3/7 activity assay, and flow cytometry. The effect of SCUBE3 on HCC cell proliferation in vivo was inspected by a xenograft tumour model in nude mice. The related mechanisms were further studied. RESULTS The level of SCUBE3 was upregulated in HCC tissues and cell lines. Knockdown of SCUBE3 inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in HCC cell lines in vitro and in vivo. Screening of cell cycle-related proteins revealed that CCNL2, CDK6, CCNE1, and CCND1 exhibited a significantly different expression profile. We found that SCUBE3 may promote the proliferation of HCC cells by regulating CCNE1 expression. The pathway enrichment analysis showed that the TGFβ signalling pathway and the PI3K/AKT signalling pathway were significantly altered. Co-immunoprecipitation results showed that SCUBE3 binds to the TGFβRII receptor. SCUBE3 knockdown inhibited the PI3K/AKT signalling pathway and the phosphorylation of GSK3β to inhibit its kinase activity. CONCLUSIONS SCUBE3 promotes HCC development by regulating CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway. In addition, SCUBE3 may be a new molecular target for the clinical diagnosis and treatment of HCC.
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Affiliation(s)
- Pan Xu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Aoran Luo
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Chuan Xiong
- Biotechnology and Nuclear Technology Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu, 610061, People's Republic of China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Liang Yan
- Clinical Laboratory Department, Chongqing Hygeia Cancer Hospital, 200 SiXian Road, Chongqing, 401332, People's Republic of China.
| | - Qiang Luo
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
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23
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Torre P, Motta BM, Sciorio R, Masarone M, Persico M. Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System. Front Med (Lausanne) 2021; 8:781567. [PMID: 34957156 PMCID: PMC8695879 DOI: 10.3389/fmed.2021.781567] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a "chronic wound healing reaction," is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.
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Affiliation(s)
- Pietro Torre
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Benedetta Maria Motta
- Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Baronissi, Italy
| | - Roberta Sciorio
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
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24
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Jia W, Liang S, Cheng B, Ling C. The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment. Front Oncol 2021; 11:763519. [PMID: 34868982 PMCID: PMC8636329 DOI: 10.3389/fonc.2021.763519] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/28/2021] [Indexed: 01/10/2023] Open
Abstract
Invasion and metastasis are the main reasons for the high mortality of liver cancer, which involve the interaction of tumor stromal cells and malignant cells. Cancer-associated fibroblasts (CAFs) are one of the major constituents of tumor stromal cells affecting tumor growth, invasion, and metastasis. The heterogeneous properties and sources of CAFs make both tumor-supporting and tumor-suppression effects possible. The mechanisms for CAFs in supporting hepatocellular carcinoma (HCC) progression can be categorized into upregulated aggressiveness and stemness, transformed metabolism toward glycolysis and glutamine reductive carboxylation, polarized tumor immunity toward immune escape of HCC cells, and increased angiogenesis. The tumor-suppressive effect of fibroblasts highlights the functional heterogenicity of CAF populations and provides new insights into tumor–stromal interplay mechanisms. In this review, we introduced several key inflammatory signaling pathways in the transformation of CAFs from normal stromal cells and the heterogeneous biofunctions of activated CAFs. In view of the pleiotropic regulation properties of traditional Chinese medicine (TCM) and heterogeneous effects of CAFs, we also introduced the application and values of TCM in the treatment of HCC through targeting CAFs.
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Affiliation(s)
- Wentao Jia
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
| | - Shufang Liang
- Department of Traditional Chinese Medicine, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Binbin Cheng
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
| | - Changquan Ling
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
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Panwar A, Das P, Tan LP. 3D Hepatic Organoid-Based Advancements in LIVER Tissue Engineering. Bioengineering (Basel) 2021; 8:185. [PMID: 34821751 PMCID: PMC8615121 DOI: 10.3390/bioengineering8110185] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/04/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
Liver-associated diseases and tissue engineering approaches based on in vitro culture of functional Primary human hepatocytes (PHH) had been restricted by the rapid de-differentiation in 2D culture conditions which restricted their usability. It was proven that cells growing in 3D format can better mimic the in vivo microenvironment, and thus help in maintaining metabolic activity, phenotypic properties, and longevity of the in vitro cultures. Again, the culture method and type of cell population are also recognized as important parameters for functional maintenance of primary hepatocytes. Hepatic organoids formed by self-assembly of hepatic cells are microtissues, and were able to show long-term in vitro maintenance of hepato-specific characteristics. Thus, hepatic organoids were recognized as an effective tool for screening potential cures and modeling liver diseases effectively. The current review summarizes the importance of 3D hepatic organoid culture over other conventional 2D and 3D culture models and its applicability in Liver tissue engineering.
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Affiliation(s)
- Amit Panwar
- School of Materials Science & Engineering, Nanyang Technological University, Singapore 639798, Singapore;
- Faculty of Biotechnology, Institute of Bio-Sciences and Technology, Shri Ramswaroop Memorial University, Lucknow-Deva Road Barabanki, Uttar Pradesh 225003, India
| | - Prativa Das
- The Henry Samueli School of Engineering, University of California, Irvine, CA 92617, USA;
| | - Lay Poh Tan
- School of Materials Science & Engineering, Nanyang Technological University, Singapore 639798, Singapore;
- Singapore Centre for 3D Printing (SC3DP), Singapore 639798, Singapore
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26
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Sánchez PS, Rigual MDM, Djouder N. Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development. Cancers (Basel) 2021; 13:cancers13205045. [PMID: 34680192 PMCID: PMC8534267 DOI: 10.3390/cancers13205045] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary The liver is continuously exposed to several harmful factors, subsequently activating sophisticated mechanisms set-up in order to repair and regenerate the damaged liver and hence to prevent its failure. When the injury becomes chronic, the regenerative response becomes perpetual and goes awry, leading to cirrhosis with a fatal liver dysfunction. Cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC), the most common, usually lethal, human primary liver neoplasm with very limited therapeutic options. Considering the pivotal role of immune factors in the development of cirrhosis, here we review and discuss the inflammatory pathways and components implicated in the development of cirrhosis. A better understanding of these circuits would help the design of novel strategies to prevent and treat cirrhosis and HCC, two lethal diseases. Abstract Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis.
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Affiliation(s)
| | | | - Nabil Djouder
- Correspondence: ; Tel.: +34-3-491-732-8000 (ext. 3830); Fax: +34-3-491-224-6914
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27
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Tadokoro T, Morishita A, Masaki T. Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA. Int J Mol Sci 2021; 22:8139. [PMID: 34360904 PMCID: PMC8347497 DOI: 10.3390/ijms22158139] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023] Open
Abstract
Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are still under development and remain an unmet medical need. To solve this problem, it is essential to elucidate the pathogenesis of liver fibrosis in detail from a molecular and cellular perspective and to develop targeted therapeutic agents based on this information. Recently, microRNAs (miRNAs), functional RNAs of 22 nucleotides, have been shown to be involved in the pathogenesis of liver fibrosis. In addition, extracellular vesicles called "exosomes" have been attracting attention, and research is being conducted to establish noninvasive and extremely sensitive biomarkers using miRNAs in exosomes. In this review, we summarize miRNAs directly involved in liver fibrosis, miRNAs associated with diseases leading to liver fibrosis, and miRNAs related to complications of cirrhosis. We will also discuss the efficacy of each miRNA as a biomarker of liver fibrosis and pathology, and its potential application as a therapeutic agent.
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Affiliation(s)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (T.T.); (T.M.)
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He Y, Guo X, Lan T, Xia J, Wang J, Li B, Peng C, Chen Y, Hu X, Meng Z. Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling. Stem Cell Res Ther 2021; 12:396. [PMID: 34256837 PMCID: PMC8278604 DOI: 10.1186/s13287-021-02468-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models. METHODS Wistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2×106 hUC-MSCs, 4×106 hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation. RESULTS The application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs. CONCLUSIONS hUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway.
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Affiliation(s)
- Yulin He
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Xingrong Guo
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Tingyu Lan
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
- Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Jianbo Xia
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Wuhan, 430070, Hubei, China
| | - Jinsong Wang
- Shenzhen Beike Biotechnology Research Institute, Nanshan District, Shenzhen, 518057, China
| | - Bei Li
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Chunyan Peng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Yue Chen
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Xiang Hu
- Shenzhen Beike Biotechnology Research Institute, Nanshan District, Shenzhen, 518057, China.
| | - Zhongji Meng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China.
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
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Xie X, Dou CY, Zhou Y, Zhou Q, Tang HB. MicroRNA-503 Targets Mothers Against Decapentaplegic Homolog 7 Enhancing Hepatic Stellate Cell Activation and Hepatic Fibrosis. Dig Dis Sci 2021; 66:1928-1939. [PMID: 32648079 DOI: 10.1007/s10620-020-06460-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/28/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The hyper-accumulation of extracellular matrix (ECM) is the leading cause of hepatic fibrosis, and TGF-β-induced activation of hepatic stellate cells (HSCs) is the central event of hepatic fibrosis pathogenesis. The deregulation and dysfunction of miRNAs in hepatic fibrosis have been reported previously. AIMS To identify miRNA(s) playing a role in HSC activation and the underlying mechanism. METHODS We analyzed online microarray expression datasets from Gene Expression Omnibus (GEO) for differentially expressed miRNAs in hepatic fibrosis-related disease liver tissues, examined the specific effects of the candidate miRNA on TGF-β-induced HSC activation, and screened for the targets of the candidate miRNA in the TGF-β/SMAD signaling. Then, the predicted miRNA-mRNA binding, the specific effects of the target mRNA, and the dynamic effects of miRNA and mRNA on TGF-β-induced HSC activation were investigated. RESULTS The miR-503 expression was upregulated in TGF-β-activated HSCs. miR-503 overexpression enhanced, while miR-503 inhibition attenuated TGF-β-induced HSC proliferation and ECM accumulation in HSCs. miR-503 targeted SMAD7 to inhibit SMAD7 expression. SMAD7 knockdown also aggravated TGF-β-induced HSC proliferation and ECM accumulation in HSCs. The effects of miR-503 overexpression on TGF-β-induced HSC activation were partially reversed by SMAD7 overexpression. In CCl4-induced hepatic fibrosis model in rats, miR-503 overexpression aggravated, whereas SMAD7 overexpression improved CCl4-induced fibrotic changes in rats' liver tissues. The effects of miR-503 overexpression on CCl4-induced fibrotic changes were partially reversed by SMAD7 overexpression. CONCLUSION miR-503 acts on HSC activation and hepatic fibrosis through SMAD7. The miR-503/SMAD7 axis enhances HSC activation and hepatic fibrosis through the TGF-β/SMAD pathway.
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Affiliation(s)
- Xia Xie
- Department of Infectious Diseases, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China
| | - Cheng-Yun Dou
- Department of Infectious Diseases, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China
| | - Yu Zhou
- Department of Pathology, The Second Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Quan Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China
| | - Hai-Bo Tang
- Department of Infectious Diseases, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China.
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Yang M, Ma F, Guan M. Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Metabolites 2021; 11:metabo11050320. [PMID: 34067649 PMCID: PMC8156407 DOI: 10.3390/metabo11050320] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 01/10/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and may progress to cirrhosis or even hepatocellular carcinoma. A number of steroid hormones are important regulators of lipid homeostasis through fine tuning the expression of genes related to lipid synthesis, export, and metabolism. Dysregulation of such pathways has been implicated in the pathogenesis of NAFLD. The aim of this review is to clarify the potential impact of steroid hormones on NAFLD. We also highlight potential interventions through modulating steroid hormone levels or the activities of their cognate receptors as therapeutic strategies for preventing NAFLD.
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Affiliation(s)
- Meng Yang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Institute of Aging Research, Guangdong Medical University, Dongguan 523808, China;
- Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Feng Ma
- Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Min Guan
- Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Correspondence: ; Tel.: +86-755-86585232
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Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 and TAA-Induced Liver Fibrosis in Mice. Int J Mol Sci 2021; 22:ijms22062934. [PMID: 33805788 PMCID: PMC7998170 DOI: 10.3390/ijms22062934] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/25/2022] Open
Abstract
Persistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohydrate content. It is mainly used in epilepsy and Alzheimer’s disease. However, the effects of the ketogenic diet on liver fibrosis remains unknown. Through ketogenic diet consumption, β-hydroxybutyrate (bHB) and acetoacetate (AcAc) are two ketone bodies that are mainly produced in the liver. It is reported that bHB and AcAc treatment decreases cancer cell proliferation and promotes apoptosis. However, the influence of bHB and AcAc in hepatic stellate cell (HSC) activation and liver fibrosis are still unclear. Therefore, this study aimed to investigate the effect of the ketogenic diet and ketone bodies in affecting liver fibrosis progression. Our study revealed that feeding a high-fat ketogenic diet increased cholesterol accumulation in the liver, which further enhanced the carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis. In addition, more severe liver inflammation and the loss of hepatic antioxidant and detoxification ability were also found in ketogenic diet-fed fibrotic mouse groups. However, the treatment with ketone bodies (bHB and AcAc) did not suppress transforming growth factor-β (TGF-β)-induced HSC activation, platelet-derived growth factor (PDGF)-BB-triggered proliferation, and the severity of CCl4-induced liver fibrosis in mice. In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression. Since a different ketogenic diet composition may exert different metabolic effects, more evidence is necessary to clarify the effects of a ketogenic diet on disease treatment.
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He C, Shu B, Zhou Y, Zhang R, Yang X. The miR-139-5p/peripheral myelin protein 22 axis modulates TGF-β-induced hepatic stellate cell activation and CCl 4-induced hepatic fibrosis in mice. Life Sci 2021; 276:119294. [PMID: 33675896 DOI: 10.1016/j.lfs.2021.119294] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 12/12/2022]
Abstract
Hepatic stellate cells (HSCs) are the major source of extracellular matrix (ECM)-producing myofibroblasts. When activated by multiple injuries, HSCs become proliferative, contractile, inflammatory and chemotactic and are characterized by enhanced ECM production, which plays a central role in hepatic fibrosis initiation and progression. In the present study, through bioinformatics analysis, we identified the abnormal upregulation of Peripheral Myelin Protein 22 (PMP22) in fibrotic murine liver. In CCl4-induced hepatic fibrosis model in mice and TGF-β-activated hHSCs, PMP22 was observed remarkably upregulated. In TGF-β-stimulated hHSCs, PMP22 silencing hindered, whereas PMP22 overexpression aggravated TGF-β-induced hHSC activation. In CCl4-induced hepatic fibrosis model in mice, PMP22 silencing improved CCl4-caused liver damage and fibrotic changes. Through online tools prediction and experimental validation, miR-139-5p was found to bind to the 3'UTR of PMP22 and negatively regulate the expression of PMP22. In contrast to PMP22 silencing, miR-139-5p inhibition enhanced TGF-β-induced hHSC activation; the effects of miR-139-5p inhibition on TGF-β-induced hHSC activation were partially reversed by PMP22 silencing. In conclusion, we identify the abnormal upregulation of PMP22 in TGF-β-activated HSCs and CCl4-induced hepatic fibrosis model in mice, as well as the pro-fibrotic role of PMP22 through aggravating TGF-β-induced HSCs activation. miR-139-5p targets the 3'UTR of PMP22 and inhibits PMP22 expression; miR-139-5p hinders TGF-β-induced HSCs activation through targeting PMP22.
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Affiliation(s)
- Chao He
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Bo Shu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yingxia Zhou
- Department of Surgical Operation, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Ruizhi Zhang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xin Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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Ba HZ, Liang ZH, Kim HS, Cao W. TGF- β1 can be regulated by NDRG2 via the NF-κB pathway in hypoxia-induced liver fibrosis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:505. [PMID: 33850902 PMCID: PMC8039646 DOI: 10.21037/atm-21-1298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Background The identification of the important elements that control hepatic stellate cell (HSC) activation will expand our understanding of the mechanism of liver fibrosis induced by hypoxia and affect the outcome of clinical treatment. A previous research demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of fibrosis and a downstream target gene of hypoxia-inducible factor 1 (HIF-1). In this research, we studied the expression and function of NDRG2 in liver fibrosis induced by hypoxia. Methods LX-2 cells/NF-κB-silenced LX-2 cells were exposed to hypoxic conditions (1% O2) to activate HSCs in vitro. The protein and mRNA expression levels of NDRG2, α-SMA and transforming growth factor beta 1 (TGF-β1) were evaluated by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. Functional studies were performed using adenovirus-mediated gene upregulation. Results The NDRG2 mRNA and protein levels were reduced under hypoxic conditions in LX-2 cells and overexpression of NDRG2 resulted in a decrease in the expression of TGF-β1 and α-SMA. Interestingly, no relationship was observed between NDRG2 and TGF-β1 when the NF-κB pathway was blocked, which indicates that NDRG2 can regulate the expression of TGF-β1 in LX-2 cells via the NF-κB pathway under hypoxic conditions. Conclusions NDRG2 may regulate the expression of TGF-β1 via the NF-κB pathway and may be a novel therapeutic target for liver fibrosis induced by hypoxia.
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Affiliation(s)
- Hong-Zhen Ba
- Department of Medical Imaging, Yan'an University Medical College, Yan'an, China
| | - Zhi-Hui Liang
- Department of Radiology, The 980 Hospital of PLA Logistic Force, Shijiazhuang, China
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, Korea
| | - Wei Cao
- Department of Interventional Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
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Martinez-Castillo M, Hernandez-Barragan A, Flores-Vasconcelos I, Galicia-Moreno M, Rosique-Oramas D, Perez-Hernandez JL, Higuera-De la Tijera F, Montalvo-Jave EE, Torre-Delgadillo A, Cordero-Perez P, Muñoz-Espinosa L, Kershenobich D, Gutierrez-Reyes G. Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients. World J Hepatol 2021; 13:218-232. [PMID: 33708351 PMCID: PMC7934014 DOI: 10.4254/wjh.v13.i2.218] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/14/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans. AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC). METHODS A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest ® and/or FibroScan ® . Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays. RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 (P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 (P < 0.001). CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.
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Affiliation(s)
- Moises Martinez-Castillo
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Abigail Hernandez-Barragan
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Ivonne Flores-Vasconcelos
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Marina Galicia-Moreno
- Department of Molecular Biology and Genomics, Institute of Molecular Biology in Medicine and Gene Therapy, Health Science University Center, University of Guadalajara, Guadalajara 06726, Mexico
| | - Dorothy Rosique-Oramas
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Jose Luis Perez-Hernandez
- Department of Gastroenterology, General Hospital of Mexico "Dr. Eduardo Liceaga," Mexico City 06726, Mexico
| | | | - Eduardo E Montalvo-Jave
- Department of General Surgery, General Hospital of Mexico "Dr. Eduardo Liceaga," School of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Aldo Torre-Delgadillo
- Hepatology and Liver Transplant, National Institute of Medical Sciences and Nutrition "Salvador Zubirán," Mexico City 06726, Mexico
| | - Paula Cordero-Perez
- University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo Leon, Monterrey 06726, Mexico
| | - Linda Muñoz-Espinosa
- University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo Leon, Monterrey 06726, Mexico
| | - David Kershenobich
- Hepatology and Liver Transplant, National Institute of Medical Sciences and Nutrition "Salvador Zubirán," Mexico City 06726, Mexico
| | - Gabriela Gutierrez-Reyes
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico.
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Wu Z, Huang S, Zheng X, Gu S, Xu Q, Gong Y, Zhang J, Fu B, Tang L. Regulatory long non-coding RNAs of hepatic stellate cells in liver fibrosis (Review). Exp Ther Med 2021; 21:351. [PMID: 33732324 PMCID: PMC7903415 DOI: 10.3892/etm.2021.9782] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 04/29/2020] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis (LF) is a continuous wound healing process caused by numerous chronic hepatic diseases and poses a major threat to human health. Activation of hepatic stellate cells (HSCs) is a critical event in the development of hepatic fibrosis. Long non-coding RNAs (lncRNAs) that are involved in HSC activation, participate in the development of LF and are likely to be therapeutic targets for LF. In the present review, the cellular signaling pathways of LF with respect to HSCs were discussed. In particular, this present review highlighted the current knowledge on the role of lncRNAs in activating or inhibiting LF, revealing lncRNAs that are likely to be biomarkers or therapeutic targets for LF. Additional studies should be performed to elucidate the potential of lncRNAs in the diagnosis and prognosis of LF and to provide novel therapeutic approaches for the reversion of LF.
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Affiliation(s)
- Zhengjie Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Shunmei Huang
- Department of Geriatrics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Xiaoqin Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Silan Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Qiaomai Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Yiwen Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jiaying Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Bin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Lingling Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Xu F, Tautenhahn HM, Dirsch O, Dahmen U. Modulation of Autophagy: A Novel "Rejuvenation" Strategy for the Aging Liver. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6611126. [PMID: 33628363 PMCID: PMC7889356 DOI: 10.1155/2021/6611126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/08/2020] [Accepted: 01/23/2021] [Indexed: 12/11/2022]
Abstract
Aging is a natural life process which leads to a gradual decline of essential physiological processes. For the liver, it leads to alterations in histomorphology (steatosis and fibrosis) and function (protein synthesis and energy generation) and affects central hepatocellular processes (autophagy, mitochondrial respiration, and hepatocyte proliferation). These alterations do not only impair the metabolic capacity of the liver but also represent important factors in the pathogenesis of malignant liver disease. Autophagy is a recycling process for eukaryotic cells to degrade dysfunctional intracellular components and to reuse the basic substances. It plays a crucial role in maintaining cell homeostasis and in resisting environmental stress. Emerging evidence shows that modulating autophagy seems to be effective in improving the age-related alterations of the liver. However, autophagy is a double-edged sword for the aged liver. Upregulating autophagy alleviates hepatic steatosis and ROS-induced cellular stress and promotes hepatocyte proliferation but may aggravate hepatic fibrosis. Therefore, a well-balanced autophagy modulation strategy might be suitable to alleviate age-related liver dysfunction. Conclusion. Modulation of autophagy is a promising strategy for "rejuvenation" of the aged liver. Detailed knowledge regarding the most devastating processes in the individual patient is needed to effectively counteract aging of the liver without causing obvious harm.
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Affiliation(s)
- Fengming Xu
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, Chemnitz 09111, Germany
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
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Sanz-García C, Fernández-Iglesias A, Gracia-Sancho J, Arráez-Aybar LA, Nevzorova YA, Cubero FJ. The Space of Disse: The Liver Hub in Health and Disease. LIVERS 2021; 1:3-26. [DOI: 10.3390/livers1010002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
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Affiliation(s)
- Carlos Sanz-García
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luis Alfonso Arráez-Aybar
- Department of Anatomy and Embriology, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
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Abstract
Hepatic stellate cells (HSCs) are resident non-parenchymal liver pericytes whose plasticity enables them to regulate a remarkable range of physiologic and pathologic responses. To support their functions in health and disease, HSCs engage pathways regulating carbohydrate, mitochondrial, lipid, and retinoid homeostasis. In chronic liver injury, HSCs drive hepatic fibrosis and are implicated in inflammation and cancer. To do so, the cells activate, or transdifferentiate, from a quiescent state into proliferative, motile myofibroblasts that secrete extracellular matrix, which demands rapid adaptation to meet a heightened energy need. Adaptations include reprogramming of central carbon metabolism, enhanced mitochondrial number and activity, endoplasmic reticulum stress, and liberation of free fatty acids through autophagy-dependent hydrolysis of retinyl esters that are stored in cytoplasmic droplets. As an archetype for pericytes in other tissues, recognition of the HSC's metabolic drivers and vulnerabilities offer the potential to target these pathways therapeutically to enhance parenchymal growth and modulate repair.
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Affiliation(s)
- Parth Trivedi
- Division of Liver Diseases, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Shuang Wang
- Division of Liver Diseases, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Scott L Friedman
- Division of Liver Diseases, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Urushima H, Yuasa H, Matsubara T, Kuroda N, Hara Y, Inoue K, Wake K, Sato T, Friedman SL, Ikeda K. Activation of Hepatic Stellate Cells Requires Dissociation of E-Cadherin-Containing Adherens Junctions with Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 191:438-453. [PMID: 33345995 DOI: 10.1016/j.ajpath.2020.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022]
Abstract
Hepatic stellate cells (HSCs) are resident mesenchymal cells in the space of Disse interposed between liver sinusoidal endothelial cells and hepatocytes. Thorn-like microprojections, or spines, project out from the cell surface of HSCs, crossing the space of Disse, to establish adherens junctions with neighboring hepatocytes. Although HSC activation is initiated largely from stimulation by adjacent cells, isolated HSCs also activate spontaneously in primary culture on plastic. Therefore, other unknown HSC-initiating factors apart from paracrine stimuli may promote activation. The dissociation of adherens junctions between HSCs and hepatocytes as an activating signal for HSCs was explored, establishing epithelial cadherin (E-cadherin) as an adhesion molecule linking hepatocytes and HSCs. In vivo, following carbon tetrachloride-induced liver injury, HSCs lost their spines and dissociated from adherens junctions in the early stages of injury, and were subsequently activated along with an increase in YAP/TAZ expression. After abrogation of liver injury, HSCs reconstructed their spines and adherens junctions. In vitro, reconstitution of E-cadherin-containing adherens junctions by forced E-cadherin expression quiesced HSCs and suppressed TAZ expression. Additionally, increase of TAZ expression leading to the activation of HSCs by autocrine stimulation of transforming growth factor-β, was revealed as a mechanism of spontaneous activation. Thus, we have uncovered a critical event required for HSC activation through enhanced TAZ-mediated mechanotransduction after the loss of adherens junctions between HSCs and hepatocytes.
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Affiliation(s)
- Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
| | - Hideto Yuasa
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Noriyuki Kuroda
- Department of Anatomy, Tissue and Cell Biology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Yaiko Hara
- Department of Anatomy, Tissue and Cell Biology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Kouji Inoue
- Research Center of Electron Microscopy, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Kenjiro Wake
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan; Research Center of Electron Microscopy, School of Dental Medicine, Tsurumi University, Yokohama, Japan; Liver Research Unit, Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Tetsuji Sato
- Department of Anatomy, Tissue and Cell Biology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
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Song LJ, Yin XR, Mu SS, Li JH, Gao H, Zhang Y, Dong PP, Mei CJ, Hua ZC. The Differential and Dynamic Progression of Hepatic Inflammation and Immune Responses During Liver Fibrosis Induced by Schistosoma japonicum or Carbon Tetrachloride in Mice. Front Immunol 2020; 11:570524. [PMID: 33117360 PMCID: PMC7575768 DOI: 10.3389/fimmu.2020.570524] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis can result from various causes and could progress to cirrhosis and cancer; however, there are no effective treatments due to that its molecular mechanism is unclear. liver fibrosis model made by Schistosoma japonicum (S. japonicum) infection or Carbon tetrachloride (CCl4) intraperitoneal injection is a conventional model used in liver fibrosis-related studies for mechanism or pharmaceutical research purposes. But the differences in the pathological progression, immune responses and the underlying mechanism between the two liver fibrosis model have not been carefully compared and characterized, which hinders us from correctly understanding and making better use of the two models. In the present study, the pathological changes to the liver, and the cytokines, inflammatory factors, macrophages, and lymphocytes subsets involved were analyzed in the liver fibrosis model of S. japonicum infection or CCl4 intraperitoneal injection. Additionally, the pathological progression, immune responses and the underlying injury mechanism in these two models were compared and characterized. The results showed that the changing trend of interleukin-13 (IL-13), transforming growth factor beta (TGF-β), inflammatory factors, and M1, M2 macrophages, were consistent with the development trend of fibrosis regardless of whether liver fibrosis was caused by S. japonicum or CCl4. For lymphocyte subsets, the proportions of CD3+ T cells and CD4+ T cells decreased gradually, while proportion of CD8+ T cells peaked at 6 weeks in mice infected with S. japonicum and at 12 weeks in mice injected with CCl4. With prolonged S. japonicum infection time, Th1 (CD4+IFN-γ+) immunity converted to Th2 (CD4+IL-4+)/Th17 (CD4+IL-17+) with weaker regulatory T cell (Treg) (CD4+CD25+FOXP3+) immunity. However, in liver fibrosis caused by CCl4, Th1 cells occupied the dominant position, while proportions of Th2, Th17, and Treg cells decreased gradually. In conclusion, liver fibrosis was a complex pathological process that was regulated by a series of cytokines and immune cells. The pathological progressions and immune responses to S. japonicum or CCl4 induced liver fibrosis were different, possibly because of their different injury mechanisms. The appropriate animal model should be selected according to the needs of different experiments and the pathogenic factors of liver fibrosis in the study.
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Affiliation(s)
- Li-Jun Song
- School of Life Sciences and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.,National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China.,Public Health Research Center, Jiangnan University, Wuxi, China
| | - Xu-Ren Yin
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Sha-Sha Mu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Jia-Huang Li
- School of Life Sciences and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.,School of Biopharmacy, China Pharmaceutical University, Nanjing, China.,Jiangsu TargetPharma Laboratories Inc., Changzhou High-Tech Research Institute of Nanjing University, Changzhou, China
| | - Hong Gao
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ying Zhang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Pan-Pan Dong
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Cong-Jin Mei
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Zi-Chun Hua
- School of Life Sciences and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.,School of Biopharmacy, China Pharmaceutical University, Nanjing, China.,Jiangsu TargetPharma Laboratories Inc., Changzhou High-Tech Research Institute of Nanjing University, Changzhou, China
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41
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Barry AE, Baldeosingh R, Lamm R, Patel K, Zhang K, Dominguez DA, Kirton KJ, Shah AP, Dang H. Hepatic Stellate Cells and Hepatocarcinogenesis. Front Cell Dev Biol 2020; 8:709. [PMID: 32850829 PMCID: PMC7419619 DOI: 10.3389/fcell.2020.00709] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.
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Affiliation(s)
- Anna E Barry
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
| | - Rajkumar Baldeosingh
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
| | - Ryan Lamm
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Keyur Patel
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Kai Zhang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
| | - Dana A Dominguez
- Department of General Surgery, UCSF East Bay, Oakland, CA, United States
| | - Kayla J Kirton
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Ashesh P Shah
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
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42
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Yang YR, Bu FT, Yang Y, Li H, Huang C, Meng XM, Zhang L, Lv XW, Li J. LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway. Mol Immunol 2020; 126:31-39. [PMID: 32745796 DOI: 10.1016/j.molimm.2020.07.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/23/2020] [Accepted: 07/08/2020] [Indexed: 12/17/2022]
Abstract
Activated hepatic stellate cells (HSCs) are the major cell type involved in the deposition of extracellular matrix (ECM) during the development of hepatic fibrosis. In this study, we revealed that left-right determination factor 2 (LEFTY2), one of the proteins belonging to the transforming growth factor-β (TGF-β) protein superfamily, was remarkedly decreased in human hepatic fibrosis tissues and in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. In addition, TGF-β1 treatment markedly reduced the level of LEFTY2 in HSCs. Importantly, overexpression of LEFTY2 suppressed the activation and proliferation of HSCs. LEFTY2 inhibited the expression of TGF-β1-induced fibrosis-associated genes (α-SMA and COL1a1) in human (LX-2) and rat (HSC-T6) HSC cell lines in vitro. Mechanistically, we demonstrated, for the first time, the role of LEFTY2 in inhibiting TGF-β1/Smad3 signaling, suggesting that there is a mutual antagonism between LEFTY2 and TGF-β1/Smad3 signaling during liver fibrosis. Similarly, we observed that LEFTY2 has a negative effect on its downstream genes, including c-MYC, CDK4, and cyclin D1, in liver fibrosis. Collectively, our data strongly indicated that LEFTY2 plays an important role in controlling the proliferation and activation of HSCs in the progression of liver fibrosis and this could be a potential therapeutic target for its treatment.
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Affiliation(s)
- Ya-Ru Yang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; Department of Clinical Pharmacology, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China
| | - Fang-Tian Bu
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Yang Yang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Hao Li
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Xiao-Ming Meng
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Xiong-Wen Lv
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
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43
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Jiang M, Cui BW, Wu YL, Zhang Y, Shang Y, Liu J, Yang HX, Qiao CY, Zhan ZY, Ye H, Jin Q, Nan JX, Lian LH. P2X7R orchestrates the progression of murine hepatic fibrosis by making a feedback loop from macrophage to hepatic stellate cells. Toxicol Lett 2020; 333:22-32. [PMID: 32721574 DOI: 10.1016/j.toxlet.2020.07.023] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/15/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023]
Abstract
HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-β-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1β secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis.
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Affiliation(s)
- Min Jiang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Ben-Wen Cui
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Yu Zhang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Yue Shang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Jian Liu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Hong-Xu Yang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Chun-Ying Qiao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Zi-Ying Zhan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Huan Ye
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Quan Jin
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China; Clinical Research Center, Yanbian University Hospital, Yanji, Jilin Province, 133002, China.
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China.
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44
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Balaphas A, Meyer J, Perozzo R, Zeisser-Labouebe M, Berndt S, Turzi A, Fontana P, Scapozza L, Gonelle-Gispert C, Bühler LH. Platelet Transforming Growth Factor-β1 Induces Liver Sinusoidal Endothelial Cells to Secrete Interleukin-6. Cells 2020; 9:1311. [PMID: 32466100 PMCID: PMC7290849 DOI: 10.3390/cells9051311] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/17/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023] Open
Abstract
The roles and interactions of platelets and liver sinusoidal endothelial cells in liver regeneration are unclear, and the trigger that initiates hepatocyte proliferation is unknown. We aimed to identify the key factors released by activated platelets that induce liver sinusoidal endothelial cells to produce interleukin-6 (IL-6), a cytokine implicated in the early phase of liver regeneration. We characterized the releasate of activated platelets inducing the in vitro production of IL-6 by mouse liver sinusoidal endothelial cells and observed that the stimulating factor was a thermolabile protein. Following gel filtration, a single fraction of activated platelet releasate induced a maximal IL-6 secretion by liver sinusoidal endothelial cells (90.2 ± 13.9 versus control with buffer, 9.0 ± 0.8 pg/mL, p < 0.05). Mass spectroscopy analysis of this fraction, followed by in silico processing, resulted in a reduced list of 18 candidates. Several proteins from the list were tested, and only recombinant transforming growth factor β1 (TGF-β1) resulted in an increased IL-6 production up to 242.7 ± 30.5 pg/mL, which was comparable to non-fractionated platelet releasate effect. Using neutralizing anti-TGF-β1 antibody or a TGF-β1 receptor inhibitor, IL-6 production by liver sinusoidal endothelial cells was dramatically reduced. These results support a role of platelet TGF-β1 β1 in the priming phase of liver regeneration.
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Affiliation(s)
- Alexandre Balaphas
- Division of Digestive Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland;
- Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Jeremy Meyer
- Division of Digestive Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland;
- Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Remo Perozzo
- Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland; (M.Z.-L.); (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland
| | - Magali Zeisser-Labouebe
- Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland; (M.Z.-L.); (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland
| | - Sarah Berndt
- Regen Lab SA, En Budron b2, 1052 Le Mont-sur-Lausanne, Switzerland; (S.B.); (A.T.)
| | - Antoine Turzi
- Regen Lab SA, En Budron b2, 1052 Le Mont-sur-Lausanne, Switzerland; (S.B.); (A.T.)
| | - Pierre Fontana
- Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland;
- Geneva Platelet Group, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Leonardo Scapozza
- Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland; (M.Z.-L.); (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland
| | - Carmen Gonelle-Gispert
- Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland; (C.G.-G.); (L.H.B.)
| | - Leo H. Bühler
- Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland; (C.G.-G.); (L.H.B.)
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45
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Xu F, Hua C, Tautenhahn HM, Dirsch O, Dahmen U. The Role of Autophagy for the Regeneration of the Aging Liver. Int J Mol Sci 2020; 21:ijms21103606. [PMID: 32443776 PMCID: PMC7279469 DOI: 10.3390/ijms21103606] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023] Open
Abstract
Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.
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Affiliation(s)
- Fengming Xu
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Chuanfeng Hua
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, 09111 Chemnitz, Germany;
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
- Correspondence: ; Tel.: +49-03641-9325350
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46
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Chan YT, Wang N, Tan HY, Li S, Feng Y. Targeting Hepatic Stellate Cells for the Treatment of Liver Fibrosis by Natural Products: Is It the Dawning of a New Era? Front Pharmacol 2020; 11:548. [PMID: 32425789 PMCID: PMC7212390 DOI: 10.3389/fphar.2020.00548] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a progressive liver damage condition that is worth studying widely. It is important to target and alleviate the disease at an early stage before turning into later cirrhosis or liver cancer. There are currently no direct medicines targeting the attenuation or reversal of liver fibrosis, and so there is an urgent need to look into this area. Traditional Chinese Medicine has a long history in using herbal medicines to treat liver diseases including fibrosis. It is time to integrate the ancient wisdom with modern science and technology to look for the best solution to the disease. In this review, the principal concept of the pathology of liver fibrosis will be described, and then some of the single compounds isolated from herbal medicines, including salvianolic acids, oxymatrine, curcumin, tetrandrine, etc. will be discussed from their effects to the molecular mechanism behind. Molecular targets of the compounds are analyzed by network pharmacology approach, and TGFβ/SMAD was identified as the most common pathway. This review serves to summarize the current findings of herbal medicines combining with modern medicines in the area of fibrosis. It hopefully provides insights in further pharmaceutical research directions.
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Affiliation(s)
| | | | | | | | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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47
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Dhar D, Baglieri J, Kisseleva T, Brenner DA. Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood) 2020; 245:96-108. [PMID: 31924111 PMCID: PMC7016420 DOI: 10.1177/1535370219898141] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma.
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Affiliation(s)
- Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jacopo Baglieri
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA
| | - David A Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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48
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Chen H, Tan P, Qian B, Du Y, Wang A, Shi H, Huang Z, Huang S, Liang T, Fu W. Hic-5 deficiency protects cerulein-induced chronic pancreatitis via down-regulation of the NF-κB (p65)/IL-6 signalling pathway. J Cell Mol Med 2019; 24:1488-1503. [PMID: 31797546 PMCID: PMC6991662 DOI: 10.1111/jcmm.14833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/16/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-κB (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α-SMA and Col1a1. Therefore, we determined whether suppressing NF-κB/p65 alleviated CP by treating mice with the NF-κB/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-κB/p65 inhibition. These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis.
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Affiliation(s)
- Hao Chen
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Peng Tan
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Baolin Qian
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yichao Du
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ankang Wang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hao Shi
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhiwei Huang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shiyao Huang
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tiancheng Liang
- Luzhou Municipal Hospital of Traditional Chinese Medicine, Luzhou, China
| | - Wenguang Fu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
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49
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Moon MY, Kim HJ, Kim MJ, Uhm S, Park JW, Suk KT, Park JB, Kim DJ, Kim SE. Rap1 regulates hepatic stellate cell migration through the modulation of RhoA activity in response to TGF‑β1. Int J Mol Med 2019; 44:491-502. [PMID: 31173168 PMCID: PMC6605627 DOI: 10.3892/ijmm.2019.4215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 05/28/2019] [Indexed: 01/02/2023] Open
Abstract
Although the migration of hepatic stellate cells (HSCs) is important for hepatic fibrosis, the regulation of this migration is poorly understood. Notably, transforming growth factor (TGF)‑β1 induces monocyte migration to sites of injury or inflammation during the early phase, but inhibits cell migration during the late phase. In the present study, the role of transforming protein RhoA signaling in TGF‑β1‑induced HSC migration was investigated. TGF‑β1 was found to increase the protein and mRNA levels of smooth muscle actin and collagen type I in HSC‑T6 cells. The level of RhoA‑GTP in TGF‑β1‑stimulated cells was significantly higher than that in control cells. Furthermore, the phosphorylation of cofilin and formation of filamentous actin (F‑actin) were more marked in TGF‑β1‑stimulated cells than in control cells. Additionally, TGF‑β1 induced the activation of nuclear factor‑κB, and the expression of extracellular matrix proteins and several cytokines in HSC‑T6 cells. The active form of Rap1 (Rap1 V12) suppressed RhoA‑GTP levels, whereas the dominant‑negative form of Rap1 (Rap1 N17) augmented RhoA‑GTP levels. Therefore, the data confirmed that Rap1 regulated the activation of RhoA in TGF‑β1‑stimulated HSC‑T6 cells. These findings suggest that TGF‑β1 regulates Rap1, resulting in the suppression of RhoA, activation of and formation of F‑actin during the migration of HSCs.
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Affiliation(s)
- Mi-Young Moon
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, Gyeonggi 14068
| | - Hee-Jun Kim
- Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi 14066
| | - Mo-Jong Kim
- Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi 14066
| | - Sunho Uhm
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, Gyeonggi 14068
| | - Ji-Won Park
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, Gyeonggi 14068
| | - Ki-Tae Suk
- Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon, Gangwon 24253
| | - Jae-Bong Park
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Dong-Jun Kim
- Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon, Gangwon 24253
| | - Sung-Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, Gyeonggi 14068
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Xu T, Huang S, Huang Q, Ming Z, Wang M, Li R, Zhao Y. Kaempferol attenuates liver fibrosis by inhibiting activin receptor-like kinase 5. J Cell Mol Med 2019; 23:6403-6410. [PMID: 31273920 PMCID: PMC6714241 DOI: 10.1111/jcmm.14528] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 06/03/2019] [Accepted: 06/14/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a common public health problem. Patients with liver fibrosis are more likely to develop cirrhosis, or hepatocellular carcinoma (HCC) as a more serious consequence. Numerous therapeutic approaches have emerged, but the final clinical outcome remains unsatisfactory. Here, we discovered a flavonoid natural product kaempferol that could dramatically ameliorate liver fibrosis formation. Our data showed that intraperitoneal injection of kaempferol could significantly decrease the necroinflammatory scores and collagen deposition in the liver tissue. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), laminin (LN) and hyaluronic acid (HA) levels were significantly down-regulated in kaempferol treatment group compared with those in the control group. Our study also demonstrated that kaempferol markedly inhibited the synthesis of collagen and activation of hepatic stellate cells (HSCs) both in vivo and in vitro. Furthermore, the results of Western blotting revealed that kaempferol could down-regulate Smad2/3 phosphorylation dose-dependently. These bioactivities of kaempferol may result from its targeted binding to the ATP-binding pocket of activin receptor-like kinase 5 (ALK5), as suggested by the molecular docking study and LanthaScreen Eu kinase binding assay. Above all, our data indicate that kaempferol may prove to be a novel agent for the treatment of liver fibrosis or other fibroproliferative diseases.
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Affiliation(s)
- Taifu Xu
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China.,Department of General Surgery, The Fourth Affiliated Hospital, Guangxi Medical University, Guangxi, China
| | - Shan Huang
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Qianrong Huang
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Zhiyong Ming
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Min Wang
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Rongrui Li
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Yinnong Zhao
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
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