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Bakrania A, Mo Y, Zheng G, Bhat M. RNA nanomedicine in liver diseases. Hepatology 2025; 81:1847-1877. [PMID: 37725757 PMCID: PMC12077345 DOI: 10.1097/hep.0000000000000606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023]
Abstract
The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.
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Affiliation(s)
- Anita Bakrania
- Department of Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Department of Medicine, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Yulin Mo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Department of Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Department of Medicine, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Ontario, Canada
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Shao W, Xu H, Zeng K, Ye M, Pei R, Wang K. Advances in liver organoids: replicating hepatic complexity for toxicity assessment and disease modeling. Stem Cell Res Ther 2025; 16:27. [PMID: 39865320 PMCID: PMC11771052 DOI: 10.1186/s13287-025-04139-2] [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: 07/04/2024] [Accepted: 01/13/2025] [Indexed: 01/28/2025] Open
Abstract
The lack of in vivo accurate human liver models hinders the investigation of liver-related diseases, injuries, and drug-related toxicity, posing challenges for both basic research and clinical applications. Traditional cellular and animal models, while widely used, have significant limitations in replicating the liver's complex responses to various stressors. Liver organoids derived from human pluripotent stem cells, adult stem cells primary cells, or tissues can mimic diverse liver cell types, major physiological functions, and architectural features. Recent advancements in the field have shown that some liver organoids have sufficient accuracy to replicate specific aspects of the human liver's complexity. This review highlights recent progress in liver organoid research, with a particular emphasis on their potential for toxicity assessment and disease modeling. The intrinsic advantages of liver organoids include higher sensitivity and suitability for long-term studies, which enhance the predictive value in drug and nanomaterial toxicity testing. The integration of liver organoids with microfluidic devices enables the simulation of the liver microenvironment and facilitates high-throughput drug screening. The liver organoids also serve as ideal platforms for studying liver diseases such as hepatitis, liver fibrosis, viral liver diseases, and monogenic diseases. Additionally, this review discusses the advantages and limitations of liver organoids along with potential avenues for future research.
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Affiliation(s)
- Weidong Shao
- Organoid Innovation Center, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Rd, Suzhou, Jiangsu, 215123, China
- China Pharmaceutical University, 639 Longmian Rd, Nanjing, Jiangsu, 210009, China
| | - Hui Xu
- Organoid Innovation Center, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Rd, Suzhou, Jiangsu, 215123, China
| | - Kanghua Zeng
- Organoid Innovation Center, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Rd, Suzhou, Jiangsu, 215123, China
| | - Mingzhou Ye
- Organoid Innovation Center, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Rd, Suzhou, Jiangsu, 215123, China
| | - Renjun Pei
- Organoid Innovation Center, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Rd, Suzhou, Jiangsu, 215123, China.
| | - Kai Wang
- Organoid Innovation Center, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Rd, Suzhou, Jiangsu, 215123, China.
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Dong S, An S, Liu Q, Wang X, Hu Y, Jiang A. Study on the Synergistic Mechanism of Photodynamic Therapy Combined With Ferroptosis Inducer to Induce Ferroptosis in Cholangiocarcinoma. Lasers Surg Med 2024; 56:845-853. [PMID: 39468974 DOI: 10.1002/lsm.23857] [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: 08/10/2024] [Revised: 09/19/2024] [Accepted: 10/14/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Photodynamic therapy (PDT) induced lipid peroxidation reaction can lead to necrosis and apoptosis of extrahepatic cholangiocarcinoma (ECC) cells, reducing the tumor load. However, the depth of action of PDT is shallow, and its therapy efficacy is weak, making it difficult to achieve eradication even with multiple treatments. OBJECTIVES This study aims to investigate the mechanism and main pathways of ferroptosis in cholangiocarcinoma under Hematoporphyrin-mediated photodynamic therapy, and to compare the effects of different ferroptosis inducers on photodynamic therapy-induced ferroptosis in cholangiocarcinoma. To provide an experimental basis for selecting appropriate ferroptosis-inducing agents and synergizing with photodynamic therapy during the clinical perioperative period. METHODS The Cell Counting Kit-8 (CCK-8) was used to examine the cytotoxicity of cholangiocarcinoma cells following PDT. Flow cytometry was used to detect apoptotic cell percentage and cell cycle changes to assess the enhanced photodynamic production of reactive oxygen species (ROS) by different ferroptosis inducers, confocal imaging was used to de-assay ROS content. Western blot analysis was employed to detect the expression of GPX4 、FSP1、ASCL4 and SLC7A11. Furthermore, a fluorescence spectrophotometric assay was used to quantify the alterations in lipid peroxides (MDA, LPO, GSH, and Fe2+). RESULTS The combination of PDT with Lenvatinib or Erastin resulted in increased ROS levels, and decreased GSH content, tumor cells were inhibited in the G2 phase, and the proportion of apoptotic cells increased. Additionally, GPX4, FSP1, and SLC7A11 protein expression decreased, whereas ASCL4 increased This was accompanied by heightened levels of Fe2+, LPO, and MDA. Induction of the ferroptosis pathway was observed to enhance the therapeutic efficacy of PDT. CONCLUSION Our findings suggest that Erastin or Lenvatinib can enhance the induction of ferroptosis in cholangiocarcinoma cells by photodynamic therapy by increasing intracellular ROS and inhibiting intracellular antioxidant pathways.
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Affiliation(s)
- Sifan Dong
- Department of Hepatobiliary Pancreas and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, China
| | - Shiqi An
- Department of Hepatobiliary Pancreas and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, China
| | - Qifan Liu
- Department of Hepatobiliary Pancreas and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, China
| | - Xujia Wang
- Department of Hepatobiliary Pancreas and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, China
| | - Yongmei Hu
- Department of Hepatobiliary Pancreas and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, China
| | - An Jiang
- Department of Hepatobiliary Pancreas and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, China
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Guan Y, Peltz G. Hepatic organoids move from adolescence to maturity. Liver Int 2024; 44:1290-1297. [PMID: 38451053 DOI: 10.1111/liv.15893] [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: 08/17/2023] [Revised: 02/08/2024] [Accepted: 02/28/2024] [Indexed: 03/08/2024]
Abstract
Since organoids were developed 15 years ago, they are now in their adolescence as a research tool. The ability to generate 'tissue in a dish' has created enormous opportunities for biomedical research. We examine the contributions that hepatic organoids have made to three areas of liver research: as a source of cells and tissue for basic research, for drug discovery and drug safety testing, and for understanding disease pathobiology. We discuss the features that enable hepatic organoids to provide useful models for human liver diseases and identify four types of advances that will enable them to become a mature (i.e., adult) research tool over the next 5 years. During this period, advances in single-cell RNA sequencing and CRISPR technologies coupled with improved hepatic organoid methodology, which enables them to have a wider range of cell types that are present in liver and to be grown in microwells, will generate discoveries that will dramatically advance our understanding of liver development and the pathogenesis of liver diseases. It will generate also new approaches for treating liver fibrosis, which remains a major public health problem with few treatment options.
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Affiliation(s)
- Yuan Guan
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Gary Peltz
- Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, USA
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Trinh-Minh T, Chen CW, Tran Manh C, Li YN, Zhu H, Zhou X, Chakraborty D, Zhang Y, Rauber S, Dees C, Lin NY, Kah D, Gerum R, Bergmann C, Kreuter A, Reuter C, Groeber-Becker F, Eckes B, Distler O, Fabry B, Ramming A, Schambony A, Schett G, Distler JH. Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis. J Clin Invest 2024; 134:e159884. [PMID: 38747285 PMCID: PMC11093613 DOI: 10.1172/jci159884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 03/20/2024] [Indexed: 05/19/2024] Open
Abstract
Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-β in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-β. The activation of latent TGF-β requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-β, rebalanced TGF-β signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-β in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.
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Affiliation(s)
- Thuong Trinh-Minh
- Department of Rheumatology and
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, North-Rhine-Westphalia, Germany
| | - Chih-Wei Chen
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Cuong Tran Manh
- Department of Rheumatology and
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, North-Rhine-Westphalia, Germany
| | - Yi-Nan Li
- Department of Rheumatology and
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, North-Rhine-Westphalia, Germany
| | - Honglin Zhu
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Xiang Zhou
- Department of Rheumatology and
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, North-Rhine-Westphalia, Germany
| | - Debomita Chakraborty
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Yun Zhang
- Department of Rheumatology and
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, North-Rhine-Westphalia, Germany
| | - Simon Rauber
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Clara Dees
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Neng-Yu Lin
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Delf Kah
- Department of Physics, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Bavaria, Germany
| | - Richard Gerum
- Department of Physics, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Bavaria, Germany
| | - Christina Bergmann
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Alexander Kreuter
- Clinic for Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Clinic Oberhausen, North-Rhine-Westphalia, Germany
| | - Christiane Reuter
- Translational Center for Regenerative Therapies, Fraunhofer Institute for Silicate Research (ISC) Würzburg, Bavaria, Germany
| | - Florian Groeber-Becker
- Translational Center for Regenerative Therapies, Fraunhofer Institute for Silicate Research (ISC) Würzburg, Bavaria, Germany
| | - Beate Eckes
- Translational Matrix Biology, University of Cologne, Cologne, North-Rhine-Westphalia, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, North-Rhine-Westphalia, Germany
| | - Oliver Distler
- Rheumaklinik, University Hospital Zurich, Zurich, Switzerland
| | - Ben Fabry
- Department of Physics, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Bavaria, Germany
| | - Andreas Ramming
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Alexandra Schambony
- Division of Developmental Biology, Biology Department, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Bavaria, Germany
| | - Georg Schett
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bavaria, Germany
- German Center for Immunotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University of Erlangen, Erlangen, Bavaria, Germany
| | - Jörg H.W. Distler
- Department of Rheumatology and
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, North-Rhine-Westphalia, Germany
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lee MJ. A review of liver fibrosis and cirrhosis regression. J Pathol Transl Med 2023; 57:189-195. [PMID: 37461143 PMCID: PMC10369136 DOI: 10.4132/jptm.2023.05.24] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/20/2023] [Accepted: 05/24/2023] [Indexed: 07/30/2023] Open
Abstract
Cirrhosis has traditionally been considered an irreversible process of end-stage liver disease. With new treatments for chronic liver disease, there is regression of fibrosis and cirrhosis, improvement in clinical parameters (i.e. liver function and hemodynamic markers, hepatic venous pressure gradient), and survival rates, demonstrating that fibrosis and fibrolysis are a dynamic process moving in two directions. Microscopically, hepatocytes push into thinning fibrous septa with eventual perforation leaving behind delicate periportal spikes in the portal tracts and loss of portal veins. Obliterated portal veins during progressive fibrosis and cirrhosis due to parenchymal extinction, vascular remodeling and thrombosis often leave behind a bile duct and hepatic artery within the portal tract. Traditional staging classification systems focused on a linear, progressive process; however, the Beijing classification system incorporates both the bidirectional nature for the progression and regression of fibrosis. However, even with regression, vascular lesions/remodeling, parenchymal extinction and a cumulative mutational burden place patients at an increased risk for developing hepatocellular carcinoma and should continue to undergo active clinical surveillance. It is more appropriate to consider cirrhosis as another stage in the evolution of chronic liver disease as a bidirectional process rather than an end-stage, irreversible state.
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Affiliation(s)
- Michael J. Lee
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
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8
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Li R, Zhang D, Han Y, Chen K, Guo W, Chen Y, Wang S. Neddylation of EphB1 Regulates Its Activity and Associates with Liver Fibrosis. Int J Mol Sci 2023; 24:3415. [PMID: 36834826 PMCID: PMC9964663 DOI: 10.3390/ijms24043415] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Liver fibrosis is a pathological process characterized by the excessive synthesis and accumulation of extracellular matrix proteins (ECMs) contributed mainly by the activated hepatic stellate cells (HSCs). Currently, no direct and effective anti-fibrotic agents have been approved for clinical use worldwide. Although the dysregulation of Eph receptor tyrosine kinase EphB2 has been reported to associate with the development of liver fibrosis, the involvement of other Eph family members in liver fibrosis remains underexplored. In this study, we found that the expression of EphB1 is significantly increased accompanying remarkable neddylation in activated HSCs. Mechanistically, this neddylation enhanced the kinase activity of EphB1 by the prevention of its degradation, thereby promoting the proliferation, migration, and activation of HSCs. Our findings revealed the involvement of EphB1 in the development of liver fibrosis through its neddylation, which provides new insights into the Eph receptor signaling and a potential target for the treatment of liver fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - Shuzhen Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
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Luo F, Yu Y, Li M, Chen Y, Zhang P, Xiao C, Lv G. Polymeric nanomedicines for the treatment of hepatic diseases. J Nanobiotechnology 2022; 20:488. [PMCID: PMC9675156 DOI: 10.1186/s12951-022-01708-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 11/14/2022] [Indexed: 11/21/2022] Open
Abstract
The liver is an important organ in the human body and performs many functions, such as digestion, detoxification, metabolism, immune responses, and vitamin and mineral storage. Therefore, disorders of liver functions triggered by various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and transplant rejection, significantly threaten human health worldwide. Polymer-based nanomedicines, which can be easily engineered with ideal physicochemical characteristics and functions, have considerable merits, including contributions to improved therapeutic outcomes and reduced adverse effects of drugs, in the treatment of hepatic diseases compared to traditional therapeutic agents. This review describes liver anatomy and function, and liver targeting strategies, hepatic disease treatment applications and intrahepatic fates of polymeric nanomedicines. The challenges and outlooks of hepatic disease treatment with polymeric nanomedicines are also discussed.
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Affiliation(s)
- Feixiang Luo
- grid.430605.40000 0004 1758 4110Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 People’s Republic of China
| | - Ying Yu
- grid.430605.40000 0004 1758 4110Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 People’s Republic of China
| | - Mingqian Li
- grid.430605.40000 0004 1758 4110Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 People’s Republic of China
| | - Yuguo Chen
- grid.430605.40000 0004 1758 4110Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 People’s Republic of China
| | - Peng Zhang
- grid.9227.e0000000119573309Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 People’s Republic of China
| | - Chunsheng Xiao
- grid.9227.e0000000119573309Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 People’s Republic of China
| | - Guoyue Lv
- grid.430605.40000 0004 1758 4110Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 People’s Republic of China
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10
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Tang X, Li X, Li M, Zhong X, Fu W, Ao M, Xuan J. Enhanced US/CT/MR imaging of integrin αvβ3 for liver fibrosis staging in rat. Front Chem 2022; 10:996116. [PMID: 36262337 PMCID: PMC9574014 DOI: 10.3389/fchem.2022.996116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis is a global health challenge with high morbidity and mortality rates, and diagnostic sensitivity of liver fibrosis tests can be increased using multimodal molecular agents. We designed cyclic arginine-glycine-aspartic acid (cRGD)-modified nanoparticles (NPs) using ultrasound (US)/computed tomography (CT)/magnetic resonance (MR) triple-modality imaging to evaluate liver fibrosis stages. In vitro and in vivo studies were conducted using primary hepatic stellate cells (HSCs) and a rat model of liver fibrosis induced by carbon tetrachloride (CCl4). Our results showed cRGD-poly(lactic-co-glycolic acid)-Fe3O4-perfluorocarbon bromide (cRGD-PLGA-Fe3O4-PFOB) NPs were preferentially internalised by activated HSCs (aHSCs). The main cell types expressing integrin αvβ3 during liver fibrogenesis were the aHSCs. The protein levels of αv and β3 expressed on aHSCs increased with the progression of liver fibrosis. After intravenous injection of cRGD-PLGA-Fe3O4-PFOB NPs, the echo intensity (EI) values, CT values, and T2 values of liver parenchyma correlated well with liver fibrosis severity. cRGD-PLGA-Fe3O4-PFOB NPs as multifunction contrast agents showed great potential to reflect the degree of HSC activation and distinguish among different liver fibrotic stages. The ligand-directed and integrin αvβ3-mediated accumulation provides active and passive targeting capabilities, permitting the targeted multimodal imaging of cRGD-PLGA-Fe3O4-PFOB NPs, which delivers accurate non-invasive diagnosis and real-time monitoring of liver fibrosis development.
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Affiliation(s)
- Xueyao Tang
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Ultrasound, The Third People’s Hospital of Chengdu, Clinical College of Southwest Jiao Tong University, The Second Affiliated Chengdu Hospital of Chongqing Medical University, Chengdu, China
| | - Xuan Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Ultrasound, Sichuan Provincial People’s Hospital, Chengdu, China
| | - Mingxing Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoling Zhong
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenguang Fu
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Meng Ao
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, China
- *Correspondence: Jiqing Xuan, ; Meng Ao,
| | - Jiqing Xuan
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: Jiqing Xuan, ; Meng Ao,
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11
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Dai YK, Zhao ZM, Liu C. Treatment of Liver Fibrosis: A 20-Year Bibliometric and Knowledge-Map Analysis. Front Pharmacol 2022; 13:942841. [PMID: 35903335 PMCID: PMC9315937 DOI: 10.3389/fphar.2022.942841] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/13/2022] [Indexed: 11/22/2022] Open
Abstract
Objectives: To analyze the research hotspots, evolution, and trends of the treatment of liver fibrosis in the recent 20 years, bibliometric and knowledge-map analysis were used. Methods: Publications associated with the treatment of liver fibrosis were retrieved from the Web of Science Core Collection on 16 April 2022. CiteSpace 5.8.R3 and VOSviewer 1.6.18 were calculated to perform bibliometric and knowledge-map analysis. Results: A total of 72,686 authors from 200 institutions in 134 countries/regions published 15,237 studies in different academic journals. United States was the most productive country, and Shanghai Jiao Tong University was the most published institution. Trauner Michael had the most published articles, whereas Scott L. Friedman was the most frequently co-cited author. Moreover, there was frequent inter-institution cooperation between countries in the years 2015 and after, but the before years showed rare inter-institution cooperation. The journal HEPATOLOGY was both the most published publication and the most frequently co-cited one in this field. Screened keywords, such as virus infection, inflammation, oxidative stress, activation of hepatic stellate cell (HSC), and hepatocellular apoptosis, could be both therapeutic targets and pathological mechanisms in terms of liver fibrosis. Furthermore, long-term suppression of hepatitis B virus replication and the activation of HSC were the latest hotspots and topics related to the treatment of liver fibrosis. Besides, the treatments of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis were also involved in the treatment of liver fibrosis, which were both emerging topics and rapidly developing hot fields. Conclusion: This bibliometric analysis conducted a full overview of the treatment of liver fibrosis, which provided important clues and ideas for scholars focusing on this field. Not only that, the field is still in a stage of rapid development and will continue to be a research hotspot in the future.
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Affiliation(s)
- Yun-Kai Dai
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi-Min Zhao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- *Correspondence: Chenghai Liu, ; Zhi-Min Zhao,
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, China
- *Correspondence: Chenghai Liu, ; Zhi-Min Zhao,
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12
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Zhou L, Li Y, Liang Q, Liu J, Liu Y. Combination therapy based on targeted nano drug co-delivery systems for liver fibrosis treatment: A review. J Drug Target 2022; 30:577-588. [PMID: 35179094 DOI: 10.1080/1061186x.2022.2044485] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Liver fibrosis is the hallmark of liver disease and occurs prior to the stages of cirrhosis and hepatocellular carcinoma. Any type of liver damage or inflammation can result in fibrosis. Fibrosis does not develop overnight, but rather as a result of the long-term action of injury factors. At present, however, there are no good treatment methods or specific drugs other than removing the pathogenic factors. Drug application is still limited, which means that drugs with good performance in vitro cannot achieve good therapeutic effects in vivo, owing to various factors such as poor drug targeting, large side effects, and strong hydrophobicity. Hepatic stellate cells (HSC) are the primary effector cells in liver fibrosis. The nano-drug delivery system is a new and safe drug delivery system that has many advantages which are widely used in the field of liver fibrosis. Drug resistance and side effects can be reduced when two or more drugs are used in combination drug delivery. Combination therapy of drugs with different targets has emerged as a novel approach to treating liver fibrosis, and the nano co-delivery system enhances the benefits of combination therapy. While nano co-delivery systems can maximize benefits while avoiding drug side effects, this is precisely the advantage of the nano co-delivery system. This review briefly described the pathogenesis and current treatment strategies, the different co-delivery systems of combination drugs in the nano delivery system, and targeting strategies for nano delivery systems on liver fibrosis therapy. Because of their superior performance, nano delivery systems and targeting drug delivery systems have received a lot of attention in the new drug delivery system. The new delivery systems offer a new pathway in the treatment of liver fibrosis, and it is believed that it can be a new treatment for fibrosis in the future. Nano co-delivery system of combination drugs and targeting strategies has proven the effectiveness of anti-fibrosis at the experimental level.
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Affiliation(s)
- Liyue Zhou
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yifan Li
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Qiangwei Liang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Jinxia Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China.,Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
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13
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Chen Z, Lin Z, Yu J, Zhong H, Zhuo X, Jia C, Wan Y. Mitofusin-2 Restrains Hepatic Stellate Cells' Proliferation via PI3K/Akt Signaling Pathway and Inhibits Liver Fibrosis in Rats. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:6731335. [PMID: 35083025 PMCID: PMC8786480 DOI: 10.1155/2022/6731335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/20/2021] [Accepted: 12/24/2021] [Indexed: 12/20/2022]
Abstract
The mitochondrial GTPase mitofusin-2 (MFN2) gene can suppress the cell cycle and regulate cell proliferation in a number of cell types. However, its function in hepatic fibrosis remains largely unexplored. We attempted to understand the mechanism of MFN2 in hepatic stellate cell (HSC) proliferation and the development of hepatic fibrosis. Rat HSC-T6 HSC were cultured and transfected by adenovirus- (Ad-) Mfn2 or its negative control (NC) vector (Ad-green fluorescent protein (GFP)); a rat liver cirrhosis model was established via subcutaneous injection with carbon tetrachloride (CCl4). Seventy-two rats were randomly divided into four groups: CCl4, Mfn2, GFP, and NC. Ad-Mfn2 or Ad-GFP was transfected into the circulation via intravenous injection at day 1, 14, 28, 42, or 56 after the first injection of CCl4 in the Mfn2/GFP groups. Biomarkers related to HSC proliferation and the development of hepatic fibrosis were detected using western blotting, hematoxylin-eosin and Masson staining, and immunohistochemistry. In vitro, Mfn2 interfered specifically with platelet-derived growth factor- (PDGF-) induced signaling pathway (phosphatidylinositol 3-kinase- (PI3K-) AKT), inhibiting HSC-T6 cell activation and proliferation. During the process of hepatic fibrosis in vivo, extracellular collagen deposition and the expression of fibrosis-related proteins increased progressively, while Mfn2 expression decreased gradually. Upregulating Mfn2 expression at the early stage of fibrosis impeded the process, triggered the downregulation of type I collagen, and antagonized the formation of factors associated with liver fibrosis. Mfn2 suppresses HSC proliferation and activation and exhibits antifibrotic potential in early-stage hepatic fibrosis. Therefore, it may represent a significant therapeutic target for eradicating hepatic fibrosis.
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Affiliation(s)
- Zhiping Chen
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Zeyu Lin
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Jiandong Yu
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Haifeng Zhong
- Department of Hepatobiliary Surgery, Meizhou People's Hospital, Meizhou Hospital Affiliate to Sun Yat-Sen University, Meizhou 514021, Guangdong Province, China
| | - Xianhua Zhuo
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
| | - Changku Jia
- Department of Hepatobiliary Surgery, The Affiliated Hangzhou First People's Hospital,School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Yunle Wan
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510650, Guangdong Province, China
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14
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Ren L, Li J, Liu L, Wu W, Zhao D, Zhang K, Xin X, Yang L, Yin L. Resolving hepatic fibrosis via suppressing oxidative stress and an inflammatory response using a novel hyaluronic acid modified nanocomplex. Biomater Sci 2021; 9:8259-8269. [PMID: 34761752 DOI: 10.1039/d1bm01499d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic fibrosis remains a serious threat to human health globally and there are no effective antifibrotic pharmacotherapeutic strategies, to date. Upon the activation of hepatic stellate cells, excess deposition of the extracellular matrix occurs, acting as a trigger that generates reactive oxygen species and an inflammatory response, thereby exacerbating the development of hepatic fibrosis and inflammation. In this study, we incorporated an idea that targets key pathways for developing novel anti-fibrosis nanomedicine. Previous studies have reported the potential of LY294002 (LY) as a PI3K/Akt inhibitor that suppresses the HSC activation and fibrosis development; however, its poor water solubility impedes further investigation. Moreover, the proliferation of HSC, severe oxidative stress and inflammatory conditions could be undermined by oridonin (ORD) treatment. Herein, we developed an HA-ORD/LY-Lips nanocomplex, where LY294002 was encapsulated into liposomes to prepare LY-Lips while ORD was conjugated with a hyaluronic acid (HA) polymer acting as a prodrug HA-ORD. The complex exerts great potential in improving the liver-targeted drug release. We adopted a series of in vitro and in vivo evaluations which demonstrate that HA-ORD/LY-Lips can significantly avert activation of hepatic stellate cells via scavenging reactive oxygen species and suppressing an inflammatory response. Our work implements a proof of concept strategy for fibrosis treatment based on the dual antioxidative and anti-inflammatory mechanisms, which may be applicable to treat liver fibrosis associated with a dysregulated inflammatory microenvironment.
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Affiliation(s)
- Lianjie Ren
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. .,Center for Drug Evaluation, NMPA, Beijing 100022, China
| | - Jingjing Li
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Lisha Liu
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Wantao Wu
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Di Zhao
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Kai Zhang
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Xiaofei Xin
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Lei Yang
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Lifang Yin
- Jiangsu Province Engineering Research Center for R&D and Evaluation of Intelligent Drugs and Key Functional Excipients, China Pharmaceutical University, Nanjing 210009, China. .,Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. .,State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
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15
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Niu L, Hou Y, Jiang M, Bai G. The rich pharmacological activities of Magnolia officinalis and secondary effects based on significant intestinal contributions. JOURNAL OF ETHNOPHARMACOLOGY 2021; 281:114524. [PMID: 34400262 DOI: 10.1016/j.jep.2021.114524] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 08/01/2021] [Accepted: 08/13/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Magnolia officinalis Cortex (M. officinalis) is a traditional herbal drug widely used in Asian countries. Depending on its multiple biological activities, M. officinalis is used to regulate gastrointestinal (GI) motility, relieve cough and asthma, prevent cardiovascular and cerebrovascular diseases, and treat depression and anxiety. AIM OF THE REVIEW We aimed to review the abundant form of pharmacodynamics activity and potential mechanisms of action of M. officinalis and the characteristics of the internal processes of the main components. The potential mechanisms of local and distance actions of M. officinalis based on GI tract was provided, and it was used to reveal the interconnections between traditional use, phytochemistry, and pharmacology. MATERIALS AND METHODS Published literatures about M. officinalis and its main components were collected from several scientific databases, including PubMed, Elsevier, ScienceDirect, Google Scholar and Web of Science etc. RESULTS: M. officinalis was shown multiple effects including effects on digestive system, respiratory system, central system, which is consistent with traditional applications, as well as some other activities such as cardiovascular system, anticancer, anti-inflammatory and antioxidant effects and so on. The mechanisms of these activities are abundant. Its chief ingredients such as magnolol and honokiol can be metabolized into active metabolites in vivo, which can increase water solubility and bioavailability and exert pharmacological activity in the whole body. In the GI tract, M. officinalis and its main ingredient can regulate GI hormones and substance metabolism, protect the intestinal barrier and affect the gut microbiota (GM). These actions are effective to improve local discomfort and some distal symptoms such as depression, asthma, or metabolic disorders. CONCLUSIONS Although M. officinalis has rich pharmacological effects, the GI tract makes great contributions to it. The GI tract is not only an important place for absorption and metabolism but also a key site to help M. officinalis exert local and distal efficacy. Pharmacodynamical studies on the efficacies of distal tissues based on the contributions of the GI tract hold great potential for understanding the benefits of M. officinalis and providing new ideas for the treatment of important diseases.
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Affiliation(s)
- Lin Niu
- Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People's Republic of China
| | - Yuanyuan Hou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
| | - Min Jiang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
| | - Gang Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China.
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16
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Zhou Y, Wu R, Cai FF, Zhou WJ, Lu YY, Zhang H, Chen QL, Sun MY, Su SB. Development of a novel anti-liver fibrosis formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis. PHARMACEUTICAL BIOLOGY 2021; 59:1594-1606. [PMID: 34808067 PMCID: PMC8635660 DOI: 10.1080/13880209.2021.1999275] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 10/22/2021] [Indexed: 05/13/2023]
Abstract
CONTEXT Xiaoyaosan decoction (XYS), a classical Traditional Chinese Medicine (TCM) formula is used to treat liver fibrosis in clinics. OBJECTIVE This study explores defined compound combinations from XYS decoction to treat liver fibrosis. MATERIALS AND METHODS Network pharmacology combined with transcriptomics analysis was used to analyze the XYS decoction and liver depression and spleen deficiency syndrome liver fibrosis. From the constructed XYS-Syndrome-liver fibrosis network, the top 10 active formulas were developed by topological analysis according to network stability. The most active formula was determined by in vitro study. The anti-fibrosis effect was evaluated by in vitro and in vivo studies. RESULTS According to the network XYS-Syndrome-liver fibrosis network, 8 key compounds and 255 combinations were predicted from in XYS. Luteolin, licochalcone A, aloe-emodin and acacetin formula (LLAAF) had a synergistic effect on the proliferation inhibition of hepatic stellate cells compared to individual compounds alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rats. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signalling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signalling in vitro and in vivo. CONCLUSIONS This study developed a novel anti-liver formula LLAAF from XYS, and demonstrated its anti-liver fibrotic activity which may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signalling.
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Affiliation(s)
- Yuan Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fei-fei Cai
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Jun Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi-Yu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi-Long Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ming-Yu Sun
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shi-Bing Su
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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17
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A human multi-lineage hepatic organoid model for liver fibrosis. Nat Commun 2021; 12:6138. [PMID: 34686668 PMCID: PMC8536785 DOI: 10.1038/s41467-021-26410-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.
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18
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Fu Y, Xiao Z, Tian X, Liu W, Xu Z, Yang T, Hu Y, Zhou X, Fang J, Gao S, Zhang D, Mu Y, Zhang H, Hu Y, Huang C, Chen J, Liu P. The Novel Chinese Medicine JY5 Formula Alleviates Hepatic Fibrosis by Inhibiting the Notch Signaling Pathway. Front Pharmacol 2021; 12:671152. [PMID: 34630075 PMCID: PMC8493219 DOI: 10.3389/fphar.2021.671152] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 09/06/2021] [Indexed: 12/23/2022] Open
Abstract
Advanced liver fibrosis can lead to cirrhosis, resulting in an accelerated risk of hepatocellular carcinoma and liver failure. Fuzheng Huayu formula (FZHY) is a traditional Chinese medicine formula treated liver fibrosis in China approved by a Chinese State Food and Drug Administration (NO: Z20050546), composed of Salvia Miltiorrhiza bge., Prunus davidiana (Carr.) Franch., cultured Cordyceps sinensis (BerK.) Sacc. Mycelia, Schisandra chinensis (Turcz.) Baill., Pinus massoniana Lamb., and Gynostemma pentaphyllum (Thunb.) Makino. However, the main active substances and mechanism of FZHY are unclear. The aim of this study is to identify a novel anti-fibrotic compound, which consists of the main active ingredients of FZHY, and investigate its mechanism of pharmacological action. The main active ingredients of FZHY were investigated by quantitative analysis of FZHY extracts and FZHY-treated plasma and liver in rats. The anti-fibrotic composition of the main active ingredients was studied through uniform design in vivo, and its mechanism was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced liver fibrosis models in rats and mice, and transforming growth factor beta 1-induced LX-2 cell activation model in vitro. A novel Chinese medicine, namely JY5 formula, consisting of salvianolic acid B, schisantherin A, and amygdalin, the main active ingredients of FZHY, significantly alleviated hepatic hydroxyproline content and collagen deposition in CCl4-and BDL-induced fibrotic liver in rats and mice. In addition, JY5 inhibited the activation of hepatic stellate cells (HSCs) by inactivating Notch signaling in vitro and in vivo. In this study, we found a novel JY5 formula, which exerted anti-hepatic fibrotic effects by inhibiting the Notch signaling pathway, consequently suppressing HSCs activation. These results provide an adequate scientific basis for clinical research and application of the JY5 formula, which may be a potential novel therapeutic candidate for liver fibrosis.
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Affiliation(s)
- Yadong Fu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Zhun Xiao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Xiaoting Tian
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Zhou Xu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Tao Yang
- Department of Cardiology, Cardiovascular Research Institute, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yonghong Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Xiaoxi Zhou
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Jing Fang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Siqi Gao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Dingqi Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yiyang Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Chenggang Huang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
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19
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Weber F, Casalini T, Valentino G, Brülisauer L, Andreas N, Koeberle A, Kamradt T, Contini A, Luciani P. Targeting transdifferentiated hepatic stellate cells and monitoring the hepatic fibrogenic process by means of IGF2R-specific peptides designed in silico. J Mater Chem B 2021; 9:2092-2106. [PMID: 33595041 DOI: 10.1039/d0tb02372h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The lack of accurate and easily applicable methods for the diagnosis of liver fibrosis, a disease characterized by an accumulation of the extracellular matrix released by activated hepatic stellate cells (HSCs), has been a major limitation for the clinical management of liver diseases. The identification of biomarkers specific to liver microstructure alterations, combined with a non-invasive optical imaging modality, could guide clinicians towards a therapeutic strategy. In this study, structural information of the insulin-like growth factor 2 receptor (IGF2R), an overexpressed protein on activated HSCs, was used for in silico screening of novel IGF2R-specific peptide ligands. Molecular dynamics simulations, followed by computational alanine scanning of the IGF2R/IGF2 complex, led to the identification of a putative peptide sequence containing the most relevant amino acids for the receptor-ligand interaction (IGF2 E12-C21). The Residue Scan tool, implemented in the MOE software, was then used to optimize the binding affinity of this sequence by amino acid mutations. The designed peptides and their associated scrambled sequences were fluorescently labelled and their binding affinity to LX-2 cells (model for activated human HSCs) was tested using flow cytometry and confocal microscopy. In vitro binding was verified for all sequences (KD ≤ 13.2 μM). With respect to the putative binding sequence, most mutations led to an increased affinity. All sequences have shown superior binding compared to their associated scrambled sequences. Using HPLC, all peptides were tested in vitro for their proteolytic resistance and showed a stability of ≥60% intact after 24 h at 37 °C in 50% v/v FBS. In view of their prospective diagnostic application, a comparison of binding affinity was performed in perpetuated and quiescent-like LX-2 cells. Furthermore, the IGF2R expression for different cell phenotypes was analysed by a quantitative mass spectrometric approach. Our peptides showed increased binding to the perpetuated cell state, indicating their good selectivity for the diagnostically relevant phenotype. In summary, the increased binding affinity of our peptides towards perpetuated LX-2 cells, as well as the satisfactory proteolytic stability, proves that the in silico designed sequences offer a new potential strategy for the targeting of hepatic fibrosis.
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Affiliation(s)
- Florian Weber
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland. and Department of Pharmaceutical Technology, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Tommaso Casalini
- Institute of Mechanical Engineering and Material Technology, Department of Innovative Technology, SUPSI, Manno, Switzerland and Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Gina Valentino
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland. and Department of Pharmaceutical Technology, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Lorine Brülisauer
- Department of Pharmaceutical Technology, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Nico Andreas
- Institute of Immunology, Jena University Hospital, Jena, Germany
| | - Andreas Koeberle
- Michael Popp Institute and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innsbruck, Austria and Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Thomas Kamradt
- Institute of Immunology, Jena University Hospital, Jena, Germany
| | - Alessandro Contini
- Dipartimento di Scienze Farmaceutiche-Sezione di Chimica Generale e Organica "A. Marchesini", Università degli Studi di Milano, Milano, Italy
| | - Paola Luciani
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland. and Department of Pharmaceutical Technology, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
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20
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Haep N, Florentino RM, Squires JE, Bell A, Soto-Gutierrez A. The Inside-Out of End-Stage Liver Disease: Hepatocytes are the Keystone. Semin Liver Dis 2021; 41:213-224. [PMID: 33992030 PMCID: PMC8996333 DOI: 10.1055/s-0041-1725023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic liver injury results in cirrhosis and end-stage liver disease (ESLD) which represents a leading cause of death worldwide, affecting people in their most productive years of life. Medical therapy can extend life, but the only definitive treatment is liver transplantation (LT). However, LT remains limited by access to quality donor organs and suboptimal long-term outcomes. The degeneration from healthy-functioning livers to cirrhosis and ESLD involves a dynamic process of hepatocyte damage, diminished hepatic function, and adaptation. However, the mechanisms responsible for deterioration of hepatocyte function and ultimately hepatic failure in man are poorly understood. We review the current understanding of cirrhosis and ESLD as a dynamic process and outline the current mechanisms associated with the development of hepatic failure from the clinical manifestations to energy adaptations, regeneration, and regulation of nuclear transcription factors. A new generation of therapeutics could target stabilization of hepatocyte differentiation and function to avoid the need for transplantation in patients with cirrhosis and ESLD.
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Affiliation(s)
- Nils Haep
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - James E. Squires
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Aaron Bell
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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21
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Astragali Radix Contributes to the Inhibition of Liver Fibrosis via High-Mobility Group Box 1-Mediated Inflammatory Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5574010. [PMID: 33790974 PMCID: PMC7984916 DOI: 10.1155/2021/5574010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/20/2022]
Abstract
Astragali Radix (AR), the dried root of Astragali Radix membranaceus (Fisch.) Bge. or Astragali Radix membranaceus (Fisch.) Bge. var. mongholicus (Bge) Hsiao, is a commonly used traditional Chinese medicine for the treatment of liver diseases. This study aimed to comprehensively evaluate the pharmacological action and explore the potential mechanism of AR on liver fibrosis. Rats were administered with carbon tetrachloride for eight weeks, followed by oral treatment with AR for six weeks. The efficacy was confirmed by measuring liver function and liver fibrosis levels. The underlying mechanisms were explored by detecting the expression of related proteins. AR significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (COL-IV), hyaluronic acid (HA), laminin (LN), and precollagen type III (PCIII). In addition, AR inhibited the deposition of collagen and the activation of hepatic stellate cells. Those data strongly demonstrated that AR alleviated liver fibrosis by CCl4. In order to illustrate the potential inflammatory, the mRNA levels of IL-6, TNF-α, and IL-1β were detected. Subsequently, immunohistochemistry analysis was performed to further verify the expression of type I collagen. Finally, the expression of key proteins in the inflammatory signaling pathway was detected. AR significantly reduced the expression of high-mobility group box 1 (HMGB1), TLR4, Myd88, RAGE, and NF-κ B p65 genes and proteins. In addition, western blotting showed AR decreased the protein expression of RAGE, p-MEK1/2, p-ERK1/2, and p-c-Jun. Taken together, our data reveal that AR significantly inhibits liver fibrosis by intervening in the HMGB1-mediated inflammatory signaling pathway and secretion signaling pathway. This study will provide valuable references for the in-depth research and development of Astragali Radix against liver fibrosis.
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Zhou Y, Wu R, Cai FF, Zhou WJ, Lu YY, Zhang H, Chen QL, Su SB. Xiaoyaosan decoction alleviated rat liver fibrosis via the TGFβ/Smad and Akt/FoxO3 signaling pathways based on network pharmacology analysis. JOURNAL OF ETHNOPHARMACOLOGY 2021; 264:113021. [PMID: 32479885 DOI: 10.1016/j.jep.2020.113021] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 05/12/2020] [Accepted: 05/24/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver fibrosis is an outcome of many chronic liver diseases and often results in cirrhosis, liver failure, and even hepatocarcinoma. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to liver fibrosis in clinical practice while its mechanism is unclear. AIM OF THE STUDY The aim of this study was to investigate the anti-fibrosis effect of XYS and to explore the molecular mechanisms by combining network pharmacology and transcriptomic technologies. MATERIALS AND METHODS The carbon tetrachloride (CCl4)-induced liver fibrosis rat were treated with three doses of XYS. The liver fibrosis and function were evaluated by histopathological examination and serum biochemical detection. The fibrosis related protein a-SMA and collagen I were assessed by Western blot. Different expressed genes (DEGs) between XYS-treated group and model group were analyzed. The herb-component-target network was constructed combined the network pharmacology. The predict targets and pathways were validated by in vitro and in vivo experiments. RESULTS With XYS treatment, the liver function was significantly improved, and fibrotic changes were alleviated. The a-SMA and collagen I expression levels in the liver were also decreased in XYS-treated rats compared with CCl4 model rats. 108 active components and 42 targets from 8 herbs constituted herb-compound-target network by transcriptomics and network pharmacology analysis. The KEGG pathway and GO enrichment analyses showed that the FoxO, TGFβ, AMPK, MAPK, PPAR, and hepatitis B and C pathways were involved in the anti-fibrosis effects of XYS. In the liver tissues, p-FoxO3a and p-Akt expression levels were significantly increased in the CCl4 model group but decreased in the XYS-treated group. The TGFβ1/Smad pathway and Akt/FoxO3 pathway were verified in LX2 cells by inhibiting phosphorylation of Smad3 and Akt activity, respectively. CONCLUSIONS Our findings suggested that XYS markedly alleviated CCl4-induced liver fibrosis in histopathological and serum liver function analyses, and this effect may occur via the TGFβ1/Smad and Akt/FoxO signaling pathways.
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Affiliation(s)
- Yuan Zhou
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Rong Wu
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Fei-Fei Cai
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Wen-Jun Zhou
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yi-Yu Lu
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qi-Long Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, University of Traditional Chinese Medicine, Shanghai, 201203, China.
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23
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Claveria-Cabello A, Colyn L, Uriarte I, Latasa MU, Arechederra M, Herranz JM, Alvarez L, Urman JM, Martinez-Chantar ML, Banales JM, Sangro B, Rombouts K, Oyarzabal J, Marin JJG, Berasain C, Avila MA, Fernandez-Barrena MG. Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis. Cancers (Basel) 2020; 12:3748. [PMID: 33322158 PMCID: PMC7763137 DOI: 10.3390/cancers12123748] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 12/10/2020] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.
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Grants
- PI16/01126, PI16/00598, PI19/00819, PI15/01132, PI18/01075 Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
- Miguel Servet Program CON14/00129 Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
- CPII19/00008 Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
- Rare Cancers 2017 Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation)
- 58/17 Gobierno de Navarra Salud
- HEPACARE La Caixa Foundation
- 06119JB AMMF
- ESCALON project, grant number H2020-SC1-BHC-2018-2020 Horizon 2020 (H2020)
- EiTB Maratoia : BIO15/CA/016/BD, BIO15/CA/011 BIOEF (Basque Foundation for Innovation and Health Research
- 2017111010 Department of Health of the Basque Country
- 2016222001, 2017222014, 2018222029, 2019222054, 2020333010 Euskadi RIS3
- KK-2020/00008 Elkartek
- SA063P17 Junta de Castilla y Leon
- LCF/PR/HP17/52190004 La Caixa Foundation
- SAF2016-75197-R, SAF2017-88933-R, SAF2017-87301-R, PID2019-104878RB-100, PID2019-104265RB-100 Mineco-Feder
- Ayudas a Equipos de Investigación Científica Umbrella 2018 Fundación BBVA
- Severo Ochoa Excellence Accreditation SEV-2016-0644 MCIU
- Centro Internacional sobre el Envejecimiento MCIU
- OLD-HEPAMARKER, 0348_CIE_6_E Centro Internacional sobre el Envejecimiento
- PC-TCUE18-20_051 University of Salamanca Foundation
- 201916-31 Fundació Marato TV3
- RYC2018-024475-1 Ramón y Cajal Program
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Affiliation(s)
- Alex Claveria-Cabello
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
| | - Leticia Colyn
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
| | - Iker Uriarte
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
| | - Maria Ujue Latasa
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Jose M. Herranz
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
| | - Laura Alvarez
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
| | - Jesus M. Urman
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Department of Gastroenterology and Hepatology, Navarra University Hospital Complex, 31008 Pamplona, Spain
| | - Maria L. Martinez-Chantar
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Jesus M. Banales
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, 20014 San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
| | - Bruno Sangro
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Hepatology Unit, Department of Internal Medicine, University of Navarra Clinic, 31008 Pamplona, Spain
| | - Krista Rombouts
- Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK;
| | - Julen Oyarzabal
- Program of Molecular Therapeutics, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
| | - Jose J. G. Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Matias A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Maite G. Fernandez-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (I.U.); (M.U.L.); (M.A.); (J.M.H.); (L.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (M.L.M.-C.); (J.M.B.); (B.S.); (J.J.G.M.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
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Damiris K, Tafesh ZH, Pyrsopoulos N. Efficacy and safety of anti-hepatic fibrosis drugs. World J Gastroenterol 2020; 26:6304-6321. [PMID: 33244194 PMCID: PMC7656211 DOI: 10.3748/wjg.v26.i41.6304] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/30/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Recent progress in our understanding of the pathways linked to progression from hepatic insult to cirrhosis has led to numerous novel therapies being investigated as potential cures and inhibitors of hepatic fibrogenesis. Liver cirrhosis is the final result of prolonged fibrosis, which is an intimate balance between fibrogenesis and fibrinolysis. A number of these complex mechanisms are shared across the various etiologies of liver disease. Thankfully, investigation has yielded some promising results in regard to reversal of fibrosis, particularly the indirect benefits associated with antiviral therapy for the treatment of hepatitis B and C and the farnesoid receptor agonist for the treatment of primary biliary cholangitis and metabolic associated fatty liver disease. A majority of current clinical research is focused on targeting metabolic associated fatty liver disease and its progression to metabolic steatohepatitis and ultimately cirrhosis, with some hope of potential standardized therapeutics in the near future. With our ever-evolving understanding of the underlying pathophysiology, these therapeutics focus on either controlling the primary disease (the initial trigger of fibrogenesis), interrupting receptor ligand interactions and other intracellular communications, inhibiting fibrogenesis, or even promoting resolution of fibrosis. It is imperative to thoroughly test these potential therapies with the rigorous standards of clinical therapeutic trials in order to ensure the highest standards of patient safety. In this article we will briefly review the key pathophysiological pathways that lead to liver fibrosis and present current clinical and experimental evidence that has shown reversibility of liver fibrosis and cirrhosis, while commenting on therapeutic safety.
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Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Zaid H Tafesh
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
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25
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Radwan SAA, El-Maadawy WH, Yousry C, ElMeshad AN, Shoukri RA. Zein/Phospholipid Composite Nanoparticles for Successful Delivery of Gallic Acid into aHSCs: Influence of Size, Surface Charge, and Vitamin A Coupling. Int J Nanomedicine 2020; 15:7995-8018. [PMID: 33116514 PMCID: PMC7585553 DOI: 10.2147/ijn.s270242] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 09/12/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Zein/phospholipid composite nanoparticles (CNPs) were developed as a delivery platform for gallic acid (GA), a polyphenolic compound with reported preclinical antifibrotic activities. However, the therapeutic applicability of GA is hampered owing to its low bioavailability and rapid clearance. Accordingly, we developed GA-loaded CNPs. The effect of their size, surface charge and targeting strategies was investigated and optimized, with the aim of enhancing their ability to deliver GA to the activated hepatic stellate cells (aHSCs) in order to suppress hepatic fibrosis progression. METHODS Different CNP systems were prepared and characterized with regard to their particle size, zeta potential, and GA entrapment efficiency (EE%). Also, they were statistically optimized via response surface methodology. The optimized systems were investigated with regard to their in vitro GA release, in vitro efficacy on aHSCs, and in vivo biodistribution in healthy rats. RESULTS The GA-loaded cationic CNPs coupled with vitamin A (GA-CACNP/VA; 192 nm) showed high GA EE% (60% w/w), highest cellular internalization via active targeting, and more selective hepatic distribution, relative to free GA solution, GA-loaded anionic, and GA-loaded cationic systems. Furthermore, GA-CACNP/VA markedly triggered the apoptosis of aHSCs, repressed collagen deposition, and inhibited HSCs' activation to a lesser extent. CONCLUSION The GA-CACNP/VA was shown to be a promising candidate for specific and controlled delivery of GA to aHSCs, which may provide an effective antifibrotic therapeutic approach.
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Affiliation(s)
- Shaimaa Ali Ali Radwan
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Walaa H El-Maadawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Giza12411, Egypt
| | - Carol Yousry
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Aliaa Nabil ElMeshad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Raguia Aly Shoukri
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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26
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Gao Y, Xi B, Li J, Li Z, Xu J, Zhong M, Xu Q, Lian Y, Wei R, Wang L, Cao H, Jin L, Zhang K, Dong J. Scoparone alleviates hepatic fibrosis by inhibiting the TLR-4/NF-κB pathway. J Cell Physiol 2020; 236:3044-3058. [PMID: 33090488 DOI: 10.1002/jcp.30083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 01/15/2023]
Abstract
The aim of this study was to investigate the role of scoparone (SCO) in hepatic fibrosis. For this, we conducted in vivo and in vitro experiments. In vivo rats that were divided into six groups, control, carbon tetrachloride, and colchicine, as well as SCO groups, SCO50, SCO100, and SCO200 treated with 50, 100, and 200 mg/kg SCO doses, respectively. Furthermore, SCO was shown to inhibit Toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB; TLR-4/NF-κB) signals by inhibiting TLR-4, which in turn downregulates the expression of MyD88, promotes NF-κB inhibitor-α, NF-κB inhibitor-β, and NF-κB inhibitor-ε activation, while inhibiting NF-κB inhibitor-ζ. Subsequently, the decrease of phosphorylation of nuclear factor-κB levels leads to the downregulation of the downstream inflammatory factors' tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 beta, thus weakening hepatic fibrosis. Notably, the SCO200 treated group presented the most significant improvement. Hence, we conclude that SCO alleviates hepatic fibrosis by inhibiting TLR-4/NF-κB signals.
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Affiliation(s)
- Ya Gao
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Boting Xi
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Jiani Li
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Zimeng Li
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Jie Xu
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Mingli Zhong
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Qiongmei Xu
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Yuanyu Lian
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Riming Wei
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Liping Wang
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Houkang Cao
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Ling Jin
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Kefeng Zhang
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Jianghui Dong
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
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Critical role of estrogen in the progression of chronic liver diseases. Hepatobiliary Pancreat Dis Int 2020; 19:429-434. [PMID: 32299655 DOI: 10.1016/j.hbpd.2020.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Estrogens regulate sexual function and also have a significant role in various pathophysiological processes. Estrogens have a non-reproductive role as the modulators of the immune system, growth, neuronal function, and metabolism. Estrogen receptors are expressed in the liver and their impaired expression and function are implicated with obesity and liver associated metabolic dysfunctions. The purpose of the current review is to discuss the disparity role of estrogens on several forms of liver diseases. DATA SOURCES A comprehensive search in PubMed and EMBASE was conducted using the keywords "estrogens and liver diseases", "estradiol and liver diseases", "hormones and liver diseases", "endocrine function in liver diseases", and "female hormones in liver diseases". Relevant papers published before September 30, 2019 were included. RESULTS The present review confirms the imperative role of estrogen in various forms of chronic liver diseases. Estrogens play a key role in maintaining homeostasis and make the liver less susceptible to several forms of chronic liver diseases in healthy premenopausal individuals. In contrast, clinical studies also showed increased estrogen levels with chronic liver diseases. CONCLUSIONS Several studies reported the protective role of estrogens in chronic liver diseases and this has been widely accepted and confirmed in experimental studies using ovariectomized rat models. However, in a few clinical studies, increased estrogen levels are also implicated in chronic liver diseases. Therefore, further studies are warranted at molecular level to explore the role of estrogen in various forms of chronic liver diseases.
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Mojtahed A, Gee MS, Yokoo T. Pearls and Pitfalls of Metabolic Liver Magnetic Resonance Imaging in the Pediatric Population. Semin Ultrasound CT MR 2020; 41:451-461. [DOI: 10.1053/j.sult.2020.05.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Radwan SAA, El-Maadawy WH, ElMeshad AN, Shoukri RA, Yousry C. Impact of Reverse Micelle Loaded Lipid Nanocapsules on the Delivery of Gallic Acid into Activated Hepatic Stellate Cells: A Promising Therapeutic Approach for Hepatic Fibrosis. Pharm Res 2020; 37:180. [PMID: 32875435 DOI: 10.1007/s11095-020-02891-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Gallic acid (GA) is a polyphenolic compound with proven efficacy against hepatic fibrosis in experimental animals. However, it suffers from poor bioavailability and rapid clearance that hinders its clinical investigation. Accordingly, we designed and optimized reverse micelle-loaded lipid nanocapsules (RMLNC) using Box-Behnken design that can deliver GA directly into activated-hepatic stellate cells (aHSCs) aiming to suppress hepatic fibrosis progression. METHODS GA-RMLNC was prepared using soft energy, solvent free phase inversion temperature method. Effects of formulation variables on particle size, zeta potential, entrapment efficiency (EE%) and GA release were studied. In-vivo biodistribution of GA-RMLNC in rats and in-vitro activities on aHSCs were also explored. RESULTS Nano-sized GA-RMLNCs (30.35 ± 2.34 nm) were formulated with high GA-EE% (63.95 ± 2.98% w/w) and physical stability (9 months). The formulated system showed burst GA release in the first 2 h followed by sustained release profile. In-vivo biodistribution imaging revealed that RMLNC-loaded with rhodamine-B accumulated mainly in rats' livers. Relative to GA; GA-RMLNC displayed higher anti-proliferative activities, effective internalization into aHSCs, marked down-regulation in pro-fibrogenic biomarkers' expressions and elevated HSCs' apoptosis. CONCLUSIONS These findings emphasize the promising application of RMLNC as a delivery system in hepatic fibrosis treatment, where successful delivery of GA into aHSCs was ensured via increased cellular uptake and antifibrotic activities.
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Affiliation(s)
- Shaimaa Ali Ali Radwan
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Al Aini street, PO Box 11562, Cairo, Egypt.
| | - Walaa H El-Maadawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt
| | - Aliaa Nabil ElMeshad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Al Aini street, PO Box 11562, Cairo, Egypt
| | - Raguia Aly Shoukri
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Al Aini street, PO Box 11562, Cairo, Egypt
| | - Carol Yousry
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Al Aini street, PO Box 11562, Cairo, Egypt
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Tsai FJ, Yang PY, Chen CJ, Li JP, Li TM, Chiou JS, Cheng CF, Chuang PH, Lin TH, Liao CC, Huang SM, Ban B, Liang WM, Lin YJ. Decreased overall mortality rate with Chinese herbal medicine usage in patients with decompensated liver cirrhosis in Taiwan. BMC Complement Med Ther 2020; 20:221. [PMID: 32664975 PMCID: PMC7362535 DOI: 10.1186/s12906-020-03010-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 07/02/2020] [Indexed: 02/06/2023] Open
Abstract
Background Liver cirrhosis is one of the main causes of the morbidity and mortality in liver diseases. Chinese herbal medicine (CHM) has long been used for the clinical treatment of liver diseases. This study was designed to explore the usage frequency and prescription patterns of CHM for patients with decompensated liver cirrhosis and to evaluate the long-term effects of CHM on overall mortality. Methods Two thousand four hundred sixty-seven patients with decompensated liver cirrhosis (ICD-9-CM code: 571.2, 571.5, and 571.6) diagnosed between 2000 and 2009 in Taiwan were identified from the registry for catastrophic illness patients. Of these, 149 CHM users and 298 CHM non-users were matched for age, gender, and Charlson comorbidity index score. The chi-squared test, paired Student’s t-test, Cox proportional hazard model, and Kaplan–Meier method were applied for various comparisons between these groups of patients. Results CHM-treated patients showed a lower overall mortality risk compared with non-treated patients (Multivariable: p < 0.0001; HR: 0.54, 95% CI: 0.42–0.69). The cumulative incidence of overall mortality was lower in the CHM-treated group (stratified log-rank test, p = 0.0002). The strongest CHM co-prescription pattern- Yin-Chen-Hao-Tang (YCHT) → Long-Dan-Xie-Gan-Tang (LDXGT) had the highest support, followed by Zhi-Zi (ZZ) → Yin-Chen-Wu-Ling-San (YCWLS) and Bai-Hua-She-She-Cao (BHSSC) → Da-Huang (DaH). Conclusion CHM, as adjunct therapy, might decrease the risk of overall mortality in patients with decompensated liver cirrhosis. CHM co-prescription patterns and network analysis showed that comprehensive herbal medicines have a protective role against liver fibrosis. Further studies are required to enhance the knowledge of safety and efficacy of CHM in patients with decompensated liver cirrhosis.
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Affiliation(s)
- Fuu-Jen Tsai
- School of Chinese Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan.,Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,Asia University, Taichung, Taiwan
| | - Pei-Yuu Yang
- Department of Traditional Chinese Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chao-Jung Chen
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Ju-Pi Li
- School of Chinese Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan.,Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Te-Mao Li
- School of Chinese Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan
| | - Jian-Shiun Chiou
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan
| | - Chi-Fung Cheng
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Biostatistics, School of Public Health, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Hepato-gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ting-Hsu Lin
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chiu-Chu Liao
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Mei Huang
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Bo Ban
- Chinese Research Center for Behavior Medicine in Growth and Development, 89 Guhuai Road, Jining, Shandong, China
| | - Wen-Miin Liang
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan.
| | - Ying-Ju Lin
- School of Chinese Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan. .,Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
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Ma X, Tang M, Lu L, Zheng J, Huang J, Li J, Luo W. Effects of salvianolic acid B on liver fibrosis: A protocol for systematic review and meta analysis. Medicine (Baltimore) 2020; 99:e21036. [PMID: 32664111 PMCID: PMC7360269 DOI: 10.1097/md.0000000000021036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Liver fibrosis is a pathological change existing in most chronic liver diseases, which leads to abnormal changes in liver tissue structure and affects the normal physiological function of liver. Without effectively control, liver fibrosis can develop into cirrhosis and increase the risk of liver cancer. Salvianolic acid B (Sal B) is the main active component in the water-soluble extract from Salvia miltiorrhiza, which is a traditional Chinese medicine usually used for treating cardiovascular and liver diseases. It is reported that Sal B shown a good action against liver fibrosis via numerous signaling pathways, which indicate that Sal B is a potential candidate drug for the treatment of liver fibrosis. METHODS We searched the related researches from the following electronic databases: PubMed, EMBASE, Web of science, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan fang Database for Chinese Technical Periodicals and VIP Database. All the databases were searched from inception to December 2019. No restriction of language, publication date, or publication status. PICO of this systematic review are shown as flowing: P, preclinical studies which evaluated the effects of Sal B on the animal models of liver fibrosis with controlled studies; I, received Sal B as only treat in any dose; C, received normal saline, distilled water, or no treatment; O, the primary outcome include measure will be the decrease in liver fibrosis score, and the secondary outcomes include the index of liver fibrosis. All the included data will be analyzed with the software of Review Manager 5.2 and STATA 14.2. DISCUSSION The purpose of this study is to conduct a systematic review and meta-analysis to assess the effects on anti-liver fibrosis of Sal B, and this will be contribute to drug development and pathological mechanisms of clinical research. TRIAL REGISTRATION INPLASY202050101, registered on 28/5/2020.
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Affiliation(s)
- Xiaocong Ma
- Graduate School, Guangxi University of Chinese Medicine
| | - Meiwen Tang
- Graduate School, Guangxi University of Chinese Medicine
| | - Liying Lu
- Graduate School, Guangxi University of Chinese Medicine
| | - Jinghui Zheng
- Department of Geriatrics, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine
| | - Jingjing Huang
- The First Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Junhong Li
- The First Affiliated Hospital of Guangxi University of Chinese Medicine
| | - Weisheng Luo
- Department of Gastroenterology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Wu JS, Chiu V, Lan CC, Wang MC, Tzeng IS, Kuo CY, Hsieh PC. Chrysophanol Prevents Lipopolysaccharide-Induced Hepatic Stellate Cell Activation by Upregulating Apoptosis, Oxidative Stress, and the Unfolded Protein Response. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:8426051. [PMID: 32714424 PMCID: PMC7355365 DOI: 10.1155/2020/8426051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/27/2020] [Accepted: 06/06/2020] [Indexed: 12/14/2022]
Abstract
Hepatic stellate cell (HSC) activation is a vital driver of liver fibrosis. Recent research efforts have emphasized the clearance of activated HSCs by apoptosis, senescence, or reversion to the quiescent state. LPS induces human HSC activation directly and contributes to liver disease progression. Chrysophanol is an anthraquinone with hepatoprotective and anti-inflammatory effects. This study aimed to investigate the pharmacological effects and mechanisms of chrysophanol in an LPS-induced activated rat HSC cell line (HSC-T6). The fibrosis phenotype was identified from the expression of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and integrin β1 by western blot analysis. We examined DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. We detected the apoptotic markers p53 and cleaved caspase-3 by western blot analysis. Intracellular ROS were labeled with 2',7'-dichlorofluorescein diacetate (DCF-DA) and the levels were measured by flow cytometry. Finally, we evaluated the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP) by Western blot analysis. Our results showed that chrysophanol decreased HSC-T6 cell viability in LPS-induced activated HSCs. Chrysophanol increased the expression of α-SMA, CTGF, integrin βI, p53, cleaved caspase-3, and DNA fragmentation. Chrysophanol also elevated ROS levels and increased the expression of BiP and CHOP. Pretreatment with chrysophanol prevented LPS-induced HSC-T6 cell activation by upregulating apoptosis, ROS accumulation, unfolded protein response (UPR) activation, and the UPR proapoptotic effect.
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Affiliation(s)
- Jiunn-Sheng Wu
- Division of Infectious Diseases, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Valeria Chiu
- Division of Physical Medicine and Rehabilitation, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chou-Chin Lan
- Division of Pulmonary Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Ming-Chieh Wang
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - I.-Shiang Tzeng
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Po-Chun Hsieh
- Department of Chinese Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
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Abstract
PURPOSE OF REVIEW Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is an activation of fibroblast to a myofibroblast that secretes huge amounts of extracellular matrix. Currently, no treatment exists that modifies the fibrosis elements and new therapeutic targets are badly needed. This review examines the current state of treatments and emerging therapeutics. RECENT FINDINGS Nintedanib was found to significantly reduce the rate of decline in SSc associated FVC, although it has no benefit on skin fibrosis. New cannabinoid receptor2 agonist has shown superb effects in phase II and results in phase III are anticipated. Other targets are currently being tested in clinical trials and new targets that are yet to be tested are increasing in the SSc literature. Nintedanib is now licenced for SSc interstitial lung disease but this does not modify the skin fibrosis. Current ongoing trials will determine the role of various targets. New targets are emerging as we gain a deeper understanding of disease pathogenesis.
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Affiliation(s)
- Monique Hinchcliff
- Section of Rheumatology and allergy, Yale School of medicine, Yale University, New Haven, CT, USA
| | - Steven O'Reilly
- Department of Biosciences, Durham University, Stockton Road, Durham, UK. steven.o'
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Li H. Advances in anti hepatic fibrotic therapy with Traditional Chinese Medicine herbal formula. JOURNAL OF ETHNOPHARMACOLOGY 2020; 251:112442. [PMID: 31891799 DOI: 10.1016/j.jep.2019.112442] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The process of liver fibrogenesis includes a number of common and etiology-dependent or independent mechanisms and events. Up to now, there are still insufficient approved biological or chemical therapies directly targeting and reversing advanced fibrosis. The key is that once liver fibrosis is triggered, it presents a complex network control model with the activation of HSCs as the core, resulting in poor efficacy of treatment. Traditional Chinese medicine (TCM) has unique advantages in treating hepatic fibrosis because of its syndrome differentiation and treatment and comprehensive pharmacological effects of multi-channel, multi-level and multi-target. However, TCM's advantages were rarely discussed as previous reviews focused on the active ingredients of TCM and single Chinese Medicine. Therefore, this paper focuses on TCM herbal formulae's pharmacological role, target and related mechanisms in the treatment of liver fibrosis. AIM OF THE STUDY This paper will focus on the pharmacological role, target and related mechanisms of TCM herbal formulae in the treatment of liver fibrosis. MATERIALS AND METHODS We collect English literatures or Chinese literatures with English Abstract on the treatment of liver fibrosis with TCM herbal formulae from databases including PubMed, Wiley InterScience, Science Direct OnSite/Elsevier, Ovid, Excerpta Medica Database, SpringLink, CNKI and China Biomedical Literature Database. Based on previous literatures, we summarize the TCM herbal formulae with definite anti-hepatic fibrosis effects. RESULTS To some extent, classical or modern TCM herbal formulae including Yinchenhao Decoction (YCHD), Xiayuxue Decoction (XYXD), Xiaochaihutang (XCHT), Yiguanjian Decoction (YGJ), Huangqi Decoction (HQD), Dahuang Zhechong Pills (DHZC), Fuzheng Huayu Formula (FZHY), Fufang Biejia Ruangan Tablets (FFBJRG), Anluo Huaxian Pills (ALHX) and Compound 861 (Cpd861) have anti-hepatic fibrosis effect both on patients with liver fibrosis and animal models with liver fibrosis. CONCLUSION According to the principle of syndrome differentiation and treatment, Liver fibrosis patients with different syndromes are treated with different herbal formula, which increases the difficulty of clinical efficacy research. YCHD and XYXD research lack randomized and controlled clinical trials. XCHT, YGJ and HQD research has small sample sizes despite randomized and controlled clinical trials. In contrast, most modern herbal formulae have randomized and controlled clinical trials. For instance, FZHY and ALHX recently published the research results of the combination of entecavir in the treatment of patients with chronic hepatitis B liver fibrosis or cirrhosis. Compared to anti-viral treatment with entecavir alone, this method has improved the reversion rate of liver fibrosis but still needs syndrome classification therapy of TCM. TCM Herbal formulae have a good prospect in treating liver fibrosis, but its composition of multiple drugs and a wide range of targets intensify the difficulty of studying their anti-hepatic fibrosis mechanisms. Future research needs to further study the anti-hepatic fibrosis mechanisms and select corresponding TCM herbal formula to treat patients with different syndromes of liver fibrosis or the same patient with different syndromes at different stages to achieve better curative results.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
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Silva CM, Ferrari GD, Alberici LC, Malaspina O, Moraes KCM. Cellular and molecular effects of silymarin on the transdifferentiation processes of LX-2 cells and its connection with lipid metabolism. Mol Cell Biochem 2020; 468:129-142. [PMID: 32185674 DOI: 10.1007/s11010-020-03717-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/06/2020] [Indexed: 12/17/2022]
Abstract
Fibrosis process in the liver is a clinical condition established in response to chronic lesions and may be reversible in many situations. In this process, hepatic stellate cells (HSCs) activate and produce extracellular matrix compounds. During fibrosis, the lipid metabolism is also altered and contributes to the transdifferentiation of the HSCs. Thus, controlling lipid metabolism in HSCs is suggested as a method to control or reverse the fibrotic condition. In the search for therapies that modulate lipid metabolism and treat liver diseases, silymarin has been identified as a relevant natural compound to treat liver pathologies. The present study aimed to evaluate the cellular and molecular effects of silymarin in the transdifferentiation process of HSCs (LX-2) from activated phenotype to a more quiesced-like cells , also focusing on understanding the modulatory effects of silymarin on lipid metabolism of HSCs. In our analyses, 100 µM of silymarin reduced the synthesis of actin filaments in activated cells, the synthesis of the protein level of α-SMA, and other pro-fibrotic factors such as CTGF and PFGF. The concentration of 150 µM silymarin did not reverse the activation aspects of LX-2 cells. However, both evaluated concentrations of the natural compound protected the cells from the negative effects of dimethyl sulfoxide (DMSO). Furthermore, we evaluated lipid-related molecules correlated to the transdifferentiation process of LX-2, and 100 µM of silymarin demonstrated to control molecules associated with lipid metabolism such as FASN, MLYCD, ACSL4, CPTs, among others. In contrast, cellular incubation with 150 µM of silymarin increased the synthesis of long-chain fatty acids and triglycerides, regarding the higher presence of DMSO (v/v) in the solvent. In conclusion, silymarin acts as a hepatoprotective agent and modulates the pro-fibrogenic stimuli of LX-2 cells, whose effects depend on stress levels in the cellular environment.
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Affiliation(s)
- Caio Mateus Silva
- Laboratório de Biologia Molecular, Departamento de Biologia Geral e Aplicada, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, 13506-900, Brazil
| | - Gustavo Duarte Ferrari
- Departamento de Bioquímica E Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil
| | - Luciane Carla Alberici
- Departamento de Física E Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil
| | - Osmar Malaspina
- Centro de Estudos de Insetos Sociais, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
| | - Karen C M Moraes
- Laboratório de Biologia Molecular, Departamento de Biologia Geral e Aplicada, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, 13506-900, Brazil.
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Abstract
Hepatic fibrosis is a reparative response of diffuse over-deposition and abnormal distribution of extracellular matrix (collagen, glycoprotein and proteoglycans) after exposure to various kinds of liver injuries, and is a key step in the developmental process of various chronic liver diseases leading to cirrhosis. Recently, many advances in our understanding of hepatic fibrosis have been obtained through basic and clinical research. Therefore, this consensus summarizes and offers 15 evidence-based recommendations on the diagnosis and evaluation of hepatic fibrosis, its treatment, drug development and applications.
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Discovery of 9O-Substituted Palmatine Derivatives as a New Class of anti-COL1A1 Agents via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways. Molecules 2020; 25:molecules25040773. [PMID: 32054011 PMCID: PMC7070350 DOI: 10.3390/molecules25040773] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/07/2020] [Accepted: 02/08/2020] [Indexed: 12/18/2022] Open
Abstract
Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.
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Wang J, Ding Y, Zhou W. Albumin self-modified liposomes for hepatic fibrosis therapy via SPARC-dependent pathways. Int J Pharm 2019; 574:118940. [PMID: 31830578 DOI: 10.1016/j.ijpharm.2019.118940] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/17/2019] [Accepted: 12/06/2019] [Indexed: 12/16/2022]
Abstract
Activated hepatic stellate cells (HSCs) have a central role in the progression of liver fibrosis and express a large amount of secreted protein, acidic and rich in cysteine (SPARC), a specific protein-binding protein. In this study, we reported the preparation and evaluation of naringenin (Nar) -loaded albumin self-modified liposomes (NaAlLs), which delivered Nar, a specific Smad3 inhibitor that blocked the TGF-β/Smad3 signaling pathway and played an anti-fibrosis role. After a series of characterization, it was found that NaAlLs had favorable dispersion (PDI < 0.15) with an average particle size of about 120 nm and high entrapment efficiency (>85%), albumin coated the surface of liposomes or embedded in phospholipid bilayer by interaction with the encapsulated naringenin and phospholipid molecules during the preparation of liposomes. The amount of albumin modified to the surface of NaAlLs by this method is not only more than that of the physical adsorption method, but also the binding force between albumin and liposomes is stronger. The albumin modified to the surface of NaAlLs greatly reduced the aggregation of liposomes and drug leakage and increased the stability of liposomes. More importantly, the uptake of NaAlLs by activated HSCs was 1.5 times higher than that of Nar-loaded liposomes (NaLs), suggesting that NaAlLs specifically increased targeting of activated HSCs via albumin and SPARC-dependent pathways. As expected, NaAlLs was more effective in improving liver fibrosis than the NaLs or the inclusion complex solution of Nar and Hydroxypropyl-β-cyclodextrin (NaICS). The results suggested that NaAlLs was a promising drug delivery system, which could target drug delivery to activated HSC for the treatment of liver fibrosis.
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Affiliation(s)
- Jianzhu Wang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China; School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271016, China
| | - Yu Ding
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
| | - Wei Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
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Lachiondo-Ortega S, Mercado-Gómez M, Serrano-Maciá M, Lopitz-Otsoa F, Salas-Villalobos TB, Varela-Rey M, Delgado TC, Martínez-Chantar ML. Ubiquitin-Like Post-Translational Modifications (Ubl-PTMs): Small Peptides with Huge Impact in Liver Fibrosis. Cells 2019; 8:1575. [PMID: 31817258 PMCID: PMC6953033 DOI: 10.3390/cells8121575] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/29/2019] [Accepted: 12/01/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease. Even though our knowledge of the cellular and molecular mechanisms of liver fibrosis has deeply improved in the last years, therapeutic approaches for liver fibrosis remain limited. Profiling and characterization of the post-translational modifications (PTMs) of proteins, and more specifically NEDDylation and SUMOylation ubiquitin-like (Ubls) modifications, can provide a better understanding of the liver fibrosis pathology as well as novel and more effective therapeutic approaches. On this basis, in the last years, several studies have described how changes in the intermediates of the Ubl cascades are altered during liver fibrosis and how specific targeting of particular enzymes mediating these ubiquitin-like modifications can improve liver fibrosis, mainly in in vitro models of hepatic stellate cells, the main fibrogenic cell type, and in pre-clinical mouse models of liver fibrosis. The development of novel inhibitors of the Ubl modifications as well as novel strategies to assess the modified proteome can provide new insights into the overall role of Ubl modifications in liver fibrosis.
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Affiliation(s)
- Sofia Lachiondo-Ortega
- Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Spain; (S.L.-O.); (M.M.-G.); (M.S.-M.); (M.V.-R.); (M.L.M.-C.)
| | - Maria Mercado-Gómez
- Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Spain; (S.L.-O.); (M.M.-G.); (M.S.-M.); (M.V.-R.); (M.L.M.-C.)
| | - Marina Serrano-Maciá
- Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Spain; (S.L.-O.); (M.M.-G.); (M.S.-M.); (M.V.-R.); (M.L.M.-C.)
| | | | - Tanya B Salas-Villalobos
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo León, Monterrey, Nuevo León 66450, Mexico;
| | - Marta Varela-Rey
- Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Spain; (S.L.-O.); (M.M.-G.); (M.S.-M.); (M.V.-R.); (M.L.M.-C.)
| | - Teresa C. Delgado
- Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Spain; (S.L.-O.); (M.M.-G.); (M.S.-M.); (M.V.-R.); (M.L.M.-C.)
| | - María Luz Martínez-Chantar
- Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Spain; (S.L.-O.); (M.M.-G.); (M.S.-M.); (M.V.-R.); (M.L.M.-C.)
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The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis. Cells 2019; 8:cells8121503. [PMID: 31771248 PMCID: PMC6952767 DOI: 10.3390/cells8121503] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 01/09/2023] Open
Abstract
Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell–cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.
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Chen Z, Jain A, Liu H, Zhao Z, Cheng K. Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis. J Pharmacol Exp Ther 2019; 370:695-702. [PMID: 30886124 PMCID: PMC6806344 DOI: 10.1124/jpet.118.256156] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 03/04/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is caused by excessive accumulation of extracellular matrix during chronic liver injuries. Although clinical evidence suggests that liver fibrosis can be reversed, there is no standard therapy for liver fibrosis. Moreover, there is a lack of diagnostic tools to detect early-stage liver fibrosis. Activation of hepatic stellate cells (HSCs) is the key step during liver fibrogenesis, and its mechanism has been extensively studied by various cell culture and animal models. Targeted delivery of therapeutic agents to activated HSCs is therefore critical for the successful treatment of liver fibrosis. A number of protein markers have been found to be overexpressed in activated HSCs, and their ligands have been used to specifically deliver various antifibrotic agents. In this review, we summarize these HSC-specific protein markers and their ligands for targeted delivery of antifibrotic agents.
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Affiliation(s)
- Zhijin Chen
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Akshay Jain
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Hao Liu
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Zhen Zhao
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
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Wang D, Li R, Wei S, Gao S, Xu Z, Liu H, Wang R, Li H, Cai H, Wang J, Zhao Y. Metabolomics combined with network pharmacology exploration reveals the modulatory properties of Astragali Radix extract in the treatment of liver fibrosis. Chin Med 2019; 14:30. [PMID: 31467589 PMCID: PMC6712842 DOI: 10.1186/s13020-019-0251-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 08/14/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Astragali Radix (AR) is widely-used for improving liver fibrosis, but, the mechanism of action has not been systematically explained. This study aims to investigate the mechanism of AR intervention in liver fibrosis based on comprehensive metabolomics combined with network pharmacology approach. MATERIALS AND METHODS UPLC-Q-TOF/MS based metabolomics technique was used to explore the specific metabolites and possible pathways of AR affecting the pathological process of liver fibrosis. Network pharmacology analysis was introduced to explore the key targets of AR regarding the mechanisms on liver fibrosis. RESULTS AR significantly reduced the levels of ALT, AST and AKP in serum, and improved pathological characteristics. Metabolomics analysis showed that the therapeutic effect of AR was mainly related to the regulation of nine metabolites, including sphingosine, 6-keto-prostaglandin F1a, LysoPC (O-18:0), 3-dehydrosphinganine, 5,6-epoxy-8,11,14-eicosatrienoic acid, leukotriene C4, taurochenodesoxycholic acid, LysoPC (18:1 (9Z)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine. Pathway analysis indicated that the treatment of AR on liver fibrosis was related to arachidonic acid metabolism, ether lipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism and primary bile acid biosynthesis. Validation of the key targets by network pharmacology analysis of potential metabolic markers showed that AR significantly down-regulated the expression of CYP1B1 and up-regulated the expression of CYP1A2 and PCYT1A. CONCLUSION Metabolomics combined with network pharmacology was used for the first time to clarify that the treatment of AR on liver fibrosis, which is related to the regulation of arachidonic acid metabolism and ether lipid metabolism by modulating the expression of CYP1A2, CYP1B1 and PCYT1A. And the integrated approach can provide new strategies and ideas for the study of molecular mechanisms of traditional Chinese medicines in the treatment of liver fibrosis.
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Affiliation(s)
- Dan Wang
- Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Ruisheng Li
- Research Center for Clinical and Translational Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Shizhang Wei
- Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Sijia Gao
- Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Zhuo Xu
- Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Honghong Liu
- Integrative Medical Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Ruilin Wang
- Department of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Haotian Li
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Huadan Cai
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Jian Wang
- Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Yanling Zhao
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
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Arab JP, Roblero JP, Altamirano J, Bessone F, Chaves Araujo R, Higuera-De la Tijera F, Restrepo JC, Torre A, Urzua A, Simonetto DA, Abraldes JG, Méndez-Sánchez N, Contreras F, Lucey MR, Shah VH, Cortez-Pinto H, Bataller R. Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH). Ann Hepatol 2019; 18:518-535. [PMID: 31053546 DOI: 10.1016/j.aohep.2019.04.005] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/06/2019] [Indexed: 02/04/2023]
Abstract
Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.
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Affiliation(s)
- Juan P Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Juan P Roblero
- Instituto Chileno Japonés de Enfermedades Digestivas, Facultad de Medicina, Universidad de Chile, Hospital Clínico San Borja Arriarán, Santiago, Chile
| | - Jose Altamirano
- Liver Unit-Internal Medicine Department, Hospital Universitario Valle Hebron, Barcelona, Spain; Internal Medicine Department, Hospital Quiron Salud Barcelona, Barcelona, Spain
| | - Fernando Bessone
- Servicio de Gastroenterología y Hepatología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Roberta Chaves Araujo
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
| | | | - Juan Carlos Restrepo
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia; Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe, Medellin, Colombia
| | - Aldo Torre
- Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - Alvaro Urzua
- Departamento de Medicina Interna, Sección de Gastroenterología, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Juan G Abraldes
- Cirrhosis Care Clinic Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | | | | | - Michael R Lucey
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Helena Cortez-Pinto
- Departmento de Gastrenterologia e Hepatologia, Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Liver Research Center, Pittsburgh, PA, USA.
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A noninvasive indicator for the diagnosis of early hepatitis B virus-related liver fibrosis. Eur J Gastroenterol Hepatol 2019; 31:218-223. [PMID: 30277926 DOI: 10.1097/meg.0000000000001281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Liver stiffness measurement (LSM) detected by FibroScan, combined with biochemical indexes, has shown potential values for assessment of liver fibrosis pathological degrees. Here we aimed to investigate a noninvasive method for hepatitis B virus-related liver fibrosis. PATIENTS AND METHODS In all, 307 patients who underwent liver biopsy and LSM measurement were included. Inflammation grades and fibrosis stages were evaluated according to METAVIR scoring system. Spearman's rank correlation analysis, logistic regression analysis, and receiver operating characteristic (ROC) curves analysis were performed to assess the factors' role in inflammation grades/fibrosis stages. RESULTS Spearman's rank correlation analysis showed that LSM, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and AST-to-platelet ratio index were positively correlated with inflammation grades and histologic fibrosis stages; platelets showed negative correlation, and AST-to-ALT ratio was not related. Logistic regression analysis indicated that LSM and APRI were risk factors for inflammation grades; LSM was the independent risk factor for fibrosis stages, P<0.0001, odds ratio>1. ROC curve analysis found LSM cutoff values and areas under the curve for the diagnosis of fibrosis scores: 6.95 and 0.804, respectively, for the diagnosis of significant fibrosis (F≥F2); 10.35 and 0.856, respectively, for severe fibrosis (F≥F3); 11.35 and 0.897, respectively, for cirrhosis (F=F4). Considering ALT as a confounding factor, ROC analysis was repeated in patients with normal and elevated ALT separately; the results indicated that when ALT was up to 40 U/l, LSM cutoff value and areas under the curve for the diagnosis of significant fibrosis (F≥F2) were 6.55 and 0.748, respectively. CONCLUSION This study provided a noninvasive treatment and prevention indicator for early hepatitis B virus-related liver fibrosis.
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Jiang Y, Zhao Y, He F, Wang H. Artificial MicroRNA-Mediated Tgfbr2 and Pdgfrb Co-Silencing Ameliorates Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice. Hum Gene Ther 2018; 30:179-196. [PMID: 30024280 DOI: 10.1089/hum.2018.047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their receptors may achieve therapeutic effects. A novel RNAi strategy based on HSC-specific GFAP promoter-driven and lentiviral-expressed artificial microRNAs (amiRNAs) was devised that consists of an microRNA-30a backbone and effective shRNAs against mouse Pdgfrβ and Tgfbr2. Then, its antifibrotic efficacy was tested in primary and cultured HSCs and in mice affected with carbon tetrachloride-induced hepatic fibrosis. The study shows that amiRNA-mediated Pdgfrβ and Tgfbr2 co-silencing inhibits HSC activation and proliferation. After recombinant lentiviral particles were delivered into the liver via tail-vein injection, therapeutic amiRNAs were preferentially expressed in HSCs and efficiently co-knocked down in situ Tgfbr2 and Pdgfrβ expression, which correlates with downregulated expression of target or effector genes of their signaling, which include Pai-1, P70S6K, and D-cyclins. amiRNA-based HSC-specific co-silencing of Tgfbr2 and Pdgfrβ significantly suppressed hepatic expression of fibrotic markers α-Sma and Col1a1, extracellular matrix regulators Mmps and Timp1, and phenotypically ameliorated liver fibrosis, as indicated by reductions in serum alanine aminotransferase activity, collagen deposition, and α-Sma-positive staining. The findings provide proof of concept for the use of amiRNA-mediated co-silencing of two profibrogenic pathways in liver fibrosis treatment and highlight the therapeutic potential of concatenated amiRNAs for gene therapy.
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Affiliation(s)
- Yan Jiang
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Yuanyuan Zhao
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Fuchu He
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China.,2 State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Haijian Wang
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China
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Abstract
Chronic injury to the liver, such as viral hepatitis, alcoholism, non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), promotes extracellular matrix deposition and organ scarring, termed hepatic fibrosis. Fibrosis might progress to cirrhosis and predisposes to hepatocellular carcinoma (HCC), but is also associated with extrahepatic morbidity and mortality in NAFLD/NASH. The improved understanding of pathogenic mechanisms underlying chronic inflammation and fibrogenesis in the liver prompted recent advances in antifibrotic therapies. Areas covered: We review recent advances in antifibrotic therapy, of which most are currently tested in clinical trials for NAFLD or NASH. This explains the manifold metabolic pathways as antifibrotic targets, including farnesoid X receptor (FXR) agonism (obeticholic acid, nonsteroidal FXR agonists), acetyl-CoA carboxylase inhibition, peroxisome proliferator-activator receptor agonism (elafibranor, lanifibranor, saroglitazar), and fibroblast growth factor (FGF)-21 or FGF-19 activation. Other antifibrotic drug candidates target cell death or inflammation, such as caspase (emricasan) or ASK1 inhibitors (selonsertib), galectin-3 inhibitors and reducing inflammatory macrophage recruitment by blocking chemokine receptors CCR2/CCR5 (cenicriviroc). Expert commentary: The tremendous advances in translational and clinical research fuels the hope for efficacious antifibrotic therapies within the next 5 years. Very likely, a combination of etiology-specific, metabolic, anti-inflammatory, and direct antifibrotic interventions will be most effective.
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Affiliation(s)
- Frank Tacke
- a Deptartment of Medicine III , RWTH University Hospital Aachen , Aachen , Germany
| | - Ralf Weiskirchen
- b Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry , RWTH University Hospital Aachen , Aachen , Germany
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Qiao JB, Fan QQ, Xing L, Cui PF, He YJ, Zhu JC, Wang L, Pang T, Oh YK, Zhang C, Jiang HL. Vitamin A-decorated biocompatible micelles for chemogene therapy of liver fibrosis. J Control Release 2018; 283:113-125. [DOI: 10.1016/j.jconrel.2018.05.032] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/25/2018] [Accepted: 05/28/2018] [Indexed: 01/10/2023]
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Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Chalasani NP, Anstee QM, Kowdley KV, George J, Goodman ZD, Lindor K. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018; 68:361-371. [PMID: 29222911 PMCID: PMC6508084 DOI: 10.1002/hep.29724] [Citation(s) in RCA: 269] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/17/2017] [Accepted: 12/06/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long-term outcomes, and patient-reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies. CONCLUSION Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD. (Hepatology 2018;68:361-371).
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Affiliation(s)
- Zobair M. Younossi
- Department of Medicine and Betty and Guy Beatty Center for Integrated Research, Claude Moore, Inova Health Systems, Falls Church, VA
| | - Rohit Loomba
- Department of Gastroenterology, University of California at San Diego, La Jolla, CA
| | - Mary E. Rinella
- Department of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | | | | | | | - Francesco Negro
- Department of Gastroenterology, University Hospitals of Geneva, Geneva, Switzerland
| | - Stephen H. Caldwell
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA
| | - Vlad Ratziu
- Institute of Cardiometabolism and Nutrition and Hospital Pitié Salpêtrière, de L’Hopital, Paris, France
| | - Kathleen E. Corey
- Division of Gastroenterology, Massachusetts General Hospital, Cambridge, MA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | | | - Arun J. Sanyal
- Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA
| | - Joel E. Lavine
- Department of Pediatrics, Columbia College of Physicians and Surgeons, New York, NY
| | | | | | - Naga P. Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Quentin M. Anstee
- Institute of Cellular Medicine, Newcastle University, New Castle, UK
| | - Kris V. Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA
| | - Jacob George
- Department of Gastroenterology & Hepatology, Westmead Hospital and Sydney West Local Health District, Sydney, Australia
| | - Zachary D. Goodman
- Department of Medicine and Betty and Guy Beatty Center for Integrated Research, Claude Moore, Inova Health Systems, Falls Church, VA
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ
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Chen L, Chen R, Kemper S, Cong M, You H, Brigstock DR. Therapeutic effects of serum extracellular vesicles in liver fibrosis. J Extracell Vesicles 2018; 7:1461505. [PMID: 29696080 PMCID: PMC5912192 DOI: 10.1080/20013078.2018.1461505] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 04/02/2018] [Indexed: 12/15/2022] Open
Abstract
The lack of approved therapies for hepatic fibrosis seriously limits medical management of patients with chronic liver disease. Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti-fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl4)- or thioacetic acid-induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl4-treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST/ALT levels and hepatic or circulating pro-inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26-labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury-induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl4. In vitro, EVN decreased proliferation and fibrosis-associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl4 or ethanol on hepatocyte proliferation. In mice, microRNA-34c, -151-3p, -483-5p, -532-5p and -687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX-2 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR-34c, -151-3p, -483-5p or -532-5p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti-fibrogenic and anti-fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes. Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl4: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP-1: monocyte chemotactic protein-1; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT-PCR: quantitative real-time polymerase chain reaction; SDS-PAGE: sodium dodecyl sulphate – polyacrylamide gel electrophoresis; αSMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF-β: transforming growth factor beta; TEM: transmission electron microscopy; TNFα: tumour necrosis factor alpha.
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Affiliation(s)
- Li Chen
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Ruju Chen
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Sherri Kemper
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - David R Brigstock
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.,Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
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50
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Schuppan D, Ashfaq-Khan M, Yang AT, Kim YO. Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol 2018; 68-69:435-451. [PMID: 29656147 DOI: 10.1016/j.matbio.2018.04.006] [Citation(s) in RCA: 326] [Impact Index Per Article: 46.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/10/2018] [Accepted: 04/11/2018] [Indexed: 12/11/2022]
Abstract
Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases. Moreover, drugs that would speed up fibrosis reversal are needed for patients with cirrhosis, since even with effective causal therapy reversal is slow or the disease may further progress. Therefore, highly efficient and specific antifibrotic agents are needed that can address advanced fibrosis, i.e., the detrimental downstream result of all chronic liver diseases. This review discusses targeted antifibrotic therapies that address molecules and mechanisms that are central to fibrogenesis or fibrolysis, including strategies that allow targeting of activated hepatic stellate cells and myofibroblasts and other fibrogenic effector cells. Focus is on collagen synthesis, integrins and cells and mechanisms specific including specific downregulation of TGFbeta signaling, major extracellular matrix (ECM) components, ECM-crosslinking, and ECM-receptors such as integrins and discoidin domain receptors, ECM-crosslinking and methods for targeted delivery of small interfering RNA, antisense oligonucleotides and small molecules to increase potency and reduce side effects. With an increased understanding of the biology of the ECM and liver fibrosis and an improved preclinical validation, the translation of these approaches to the clinic is currently ongoing. Application to patients with liver fibrosis and a personalized treatment is tightly linked to the development of noninvasive biomarkers of fibrosis, fibrogenesis and fibrolysis.
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Affiliation(s)
- Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
| | - Muhammad Ashfaq-Khan
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
| | - Ai Ting Yang
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
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