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1
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Parfenyev SE, Daks AA, Shuvalov OY, Fedorova OA, Pestov NB, Korneenko TV, Barlev NA. Dualistic role of ZEB1 and ZEB2 in tumor progression. Biol Direct 2025; 20:32. [PMID: 40114235 PMCID: PMC11927373 DOI: 10.1186/s13062-025-00604-3] [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: 11/24/2024] [Accepted: 01/10/2025] [Indexed: 03/22/2025] Open
Abstract
It is generally accepted that ZEB1 and ZEB2 act as master regulators of the epithelial-mesenchymal transition, which arguably is the key mechanism of metastasis. Accordingly, they are deemed as negative predictors of the survival of cancer patients by promoting the emergence of secondary foci of the disease. Paradoxically, in some types of cancer types the opposite effect is observed, i.e. ZEB1 and ZEB2 are associated with better prognosis for cancer patients. In this review, we discuss the hypothesis that the tumorigenic effects of ZEB1/ZEB2 can be different in various tissues depending on the initial status of these proteins in the corresponding healthy tissues. Emerging evidence suggests that ZEB1 and ZEB2 are constitutively expressed in several healthy tissues, performing vital functions. Consequently, reducing the expression of ZEB1 and ZEB2 could negatively affect these tissues causing various diseases, including cancer. Finally, the dualistic role of ZEB1 and ZEB2 as immune modulators and their effect on tumor microenvironment is also discussed.
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Affiliation(s)
- Sergey E Parfenyev
- Laboratory of Gene Expression Regulation, Institute of Cytology RAS, Saint-Petersburg, 164064, Russia
| | - Alexandra A Daks
- Laboratory of Gene Expression Regulation, Institute of Cytology RAS, Saint-Petersburg, 164064, Russia
| | - Oleg Y Shuvalov
- Laboratory of Gene Expression Regulation, Institute of Cytology RAS, Saint-Petersburg, 164064, Russia
| | - Olga A Fedorova
- Laboratory of Gene Expression Regulation, Institute of Cytology RAS, Saint-Petersburg, 164064, Russia
| | - Nikolay B Pestov
- Vavilov Institute of General Genetics, Moscow, 119991, Russia.
- Laboratory of Tick-Borne Encephalitis and Other Viral Encephalitides, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow, 108819, Russia.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
| | - Tatyana V Korneenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia
| | - Nickolai A Barlev
- Laboratory of Gene Expression Regulation, Institute of Cytology RAS, Saint-Petersburg, 164064, Russia.
- Laboratory of Tick-Borne Encephalitis and Other Viral Encephalitides, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow, 108819, Russia.
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, 01000, Kazakhstan.
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2
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Ito T, Shinzato T. Liver Blood Stagnation: An Overlooked but Significant Factor in Intradialytic Hypotension. Kidney Blood Press Res 2025; 50:259-266. [PMID: 40058360 DOI: 10.1159/000545113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 03/04/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUND Intradialytic hypotension (IDH) occurs suddenly and without warning, although it is generally reversible. While ultrafiltration rate, cardiac function, and vascular resistance have been widely studied, more attention should be given to venous blood return to the heart in relation to blood stagnation. Both existing literature and clinical observations suggest that as a hemodialysis session progresses, the vascular bed of the liver expands, reducing venous return to the heart. This decrease in cardiac output may further increase hepatic blood volume, potentially playing a central role in the development of IDH. SUMMARY This review explores the role of reduced venous return to the heart, caused by liver blood stagnation, as a key contributor to IDH. KEY MESSAGES We tentatively name this pathophysiological mechanism "liver circulation jam." The clinical significance of this concept requires validation through future research.
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Affiliation(s)
- Takahito Ito
- Division of Nephrology, Minatonomori Hospital, Kobe, Japan
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3
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Yuasa H, Matsubara T, Urushima H, Daikoku A, Ikenaga H, Kadono C, Kinoshita M, Kimura K, Ishizawa T, Ohta K, Kawada N, Ikeda K. Cdc42 is crucial for the early regulation of hepatic stellate cell activation. Am J Physiol Cell Physiol 2025; 328:C757-C775. [PMID: 39871537 DOI: 10.1152/ajpcell.00987.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 12/28/2024] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The activation of hepatic stellate cells (HSCs) from a quiescent state is a cause of liver fibrosis and a therapeutic target. HSCs are resident mesenchymal cells located in the space of Disse, exhibiting specialized morphological characteristics such as a stellate shape, large lipid droplets, and direct adhesions to hepatocytes via microprojections called HSC spines. Morphological alterations in HSCs play a crucial role in initiating their activation. However, the mechanisms regulating these changes remain unexplored. In this study, we analyzed the morphological alterations associated with HSC activation in vivo using carbon tetrachloride treatment and identified the key factors regulating these changes in vitro. Following carbon tetrachloride treatment, HSCs exhibited shortened cell processes and HSC spines, adopting an oval shape. Subsequently, the HSCs underwent further morphological changes into two activated forms: flattened and complex shapes. In vitro, activation of cell division cycle 42 (Cdc42) maintained the morphological characteristics of quiescent HSCs. Cdc42 activation in HSC cell lines inhibited the expression of markers associated with activated HSCs. Cdc42 inhibitor treatment in vivo prevented quiescent HSCs from maintaining their morphological characteristics and hindered activated HSCs from reverting to the quiescent state. In addition, HSCs around fibrotic areas in the human liver exhibited morphological alterations indicative of early activation. These findings demonstrate that Cdc42 is a crucial regulator of morphological and molecular alterations associated with HSC activation, identifying it as a novel target for the development of therapeutic agents against liver fibrosis.NEW & NOTEWORTHY The activation of hepatic stellate cells from a quiescent state is a cause and a therapeutic target for liver fibrosis. Morphological alterations in the hepatic stellate cells play a critical role in initiating their activation. However, the mechanisms that regulate these alterations remain unexplored. Our results indicate that cell division cycle 42 is a crucial regulator of hepatic stellate cell activation and a novel target for the development of therapeutic agents against liver fibrosis.
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Affiliation(s)
- Hideto Yuasa
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Research Institute for Light-induced Acceleration System, Osaka Metropolitan University, Sakai, Japan
| | - Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsuko Daikoku
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Chiho Kadono
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masahiko Kinoshita
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kenjiro Kimura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Takeaki Ishizawa
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Keisuke Ohta
- Division Microscopic and Development Anatomy, Department of Anatomy, School of Medicine, Kurume University, Kurume, Japan
- Advanced Imaging Research Center, School of Medicine, Kurume University, Kurume, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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4
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Sattler A, Korzun T, Gupta K, Diba P, Kyprianou N, Eksi SE. Sympathetic nerve signaling rewires the tumor microenvironment: a shift in "microenvironmental-ity". Cancer Metastasis Rev 2025; 44:25. [PMID: 39831934 PMCID: PMC11753337 DOI: 10.1007/s10555-025-10241-x] [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: 09/11/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
Nerve signaling within the tumor microenvironment (TME) plays a critical role in the initiation, progression, and metastasis of solid tumors. Due to their highly responsive behavior and activation upon injury and cancer onset, this review specifically focuses on how sympathetic nerves rewire the TME. Within tumors, sympathetic nerves closely interact with various TME components, and their combined signaling often shifts tumor-intrinsic physiology toward tumor-supportive phenotypes. In turn, the TME components, such as myeloid cells, lymphoid cells, extracellular matrix (ECM), endothelial cells, cancer associated fibroblasts (CAFs), and Schwann cells, secrete neurotrophic and axon guidance factors that influence both sympathetic outgrowth and tumor cell behavior, further exacerbating tumor progression and metastasis. Here, we review the current evidence on the multidirectional impacts of sympathetic nerves and both immune and non-immune TME components, the nature of these communication processes, and how exploring these interactions may inform future therapeutics to impair cancer progression and metastasis.
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Affiliation(s)
- Ariana Sattler
- Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
- Cell, Development and Cancer Biology Department, Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Avenue, Portland, OR, 97201, USA
| | - Tetiana Korzun
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 S Moody Avenue, Portland, OR, 97201, USA
- Department of Biomedical Engineering, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR, 97239, USA
| | - Kasmira Gupta
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Parham Diba
- Department of Biomedical Engineering, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR, 97239, USA
| | - Natasha Kyprianou
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sebnem Ece Eksi
- Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
- Cell, Development and Cancer Biology Department, Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Avenue, Portland, OR, 97201, USA.
- Department of Biomedical Engineering, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR, 97239, USA.
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
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5
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Buakaew W, Krobthong S, Yingchutrakul Y, Khamto N, Sutana P, Potup P, Thongsri Y, Daowtak K, Ferrante A, Léon C, Usuwanthim K. In Vitro Investigation of the Anti-Fibrotic Effects of 1-Phenyl-2-Pentanol, Identified from Moringa oleifera Lam., on Hepatic Stellate Cells. Int J Mol Sci 2024; 25:8995. [PMID: 39201682 PMCID: PMC11354330 DOI: 10.3390/ijms25168995] [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: 06/15/2024] [Revised: 08/17/2024] [Accepted: 08/17/2024] [Indexed: 09/03/2024] Open
Abstract
Liver fibrosis, characterized by excessive extracellular matrix deposition, is driven by activated hepatic stellate cells (HSCs). Due to the limited availability of anti-fibrotic drugs, the research on therapeutic agents continues. Here we have investigated Moringa oleifera Lam. (MO), known for its various bioactive properties, for anti-fibrotic effects. This study has focused on 1-phenyl-2-pentanol (1-PHE), a compound derived from MO leaves, and its effects on LX-2 human hepatic stellate cell activation. TGF-β1-stimulated LX-2 cells were treated with MO extract or 1-PHE, and the changes in liver fibrosis markers were assessed at both gene and protein levels. Proteomic analysis and molecular docking were employed to identify potential protein targets and signaling pathways affected by 1-PHE. Treatment with 1-PHE downregulated fibrosis markers, including collagen type I alpha 1 chain (COL1A1), collagen type IV alpha 1 chain (COL4A1), mothers against decapentaplegic homologs 2 and 3 (SMAD2/3), and matrix metalloproteinase-2 (MMP2), and reduced the secretion of matrix metalloproteinase-9 (MMP-9). Proteomic analysis data showed that 1-PHE modulates the Wnt/β-catenin pathway, providing a possible mechanism for its effects. Our results suggest that 1-PHE inhibits the TGF-β1 and Wnt/β-catenin signaling pathways and HSC activation, indicating its potential as an anti-liver-fibrosis agent.
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Affiliation(s)
- Watunyoo Buakaew
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
- Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sucheewin Krobthong
- Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
- National Center for Genetic Engineering and Biotechnology, NSTDA, Pathum Thani 12120, Thailand
| | - Yodying Yingchutrakul
- National Center for Genetic Engineering and Biotechnology, NSTDA, Pathum Thani 12120, Thailand
| | - Nopawit Khamto
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Pornsuda Sutana
- Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Pachuen Potup
- Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Yordhathai Thongsri
- Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Krai Daowtak
- Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Antonio Ferrante
- Department of Immunopathology, South Australia (SA) Pathology, Women's and Children's Hospital, Adelaide, SA 5006, Australia
- The Adelaide Medical School, The School of Biological Science and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia
| | - Catherine Léon
- INSERM, UMR_S1255, Université de Strasbourg, Etablissement Français du Sang-GEST, 67000 Strasbourg, France
| | - Kanchana Usuwanthim
- Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
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Ma Y, Harris J, Li P, Jiang C, Sun H, Cao H. An Integrative Transcriptome Subtraction Strategy to Identify Human lncRNAs That Specifically Play a Role in Activation of Human Hepatic Stellate Cells. Noncoding RNA 2024; 10:34. [PMID: 38921831 PMCID: PMC11206700 DOI: 10.3390/ncrna10030034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/31/2024] [Accepted: 06/04/2024] [Indexed: 06/27/2024] Open
Abstract
Fibrotic liver features excessive deposition of extracellular matrix (ECM), primarily produced from "activated" hepatic stellate cells (HSCs). While targeting human HSCs (hHSCs) in fibrosis therapeutics shows promise, the overall understanding of hHSC activation remains limited, in part because it is very challenging to define the role of human long non-coding RNAs (lncRNAs) in hHSC activation. To address this challenge, we identified another cell type that acts via a diverse gene network to promote fibrogenesis. Then, we identified the lncRNAs that were differentially regulated in activated hHSCs and the other profibrotic cell. Next, we conducted concurrent analysis to identify those lncRNAs that were specifically involved in fibrogenesis. We tested and confirmed that transdifferentiation of vascular smooth muscle cells (VSMCs) represents such a process. By overlapping TGFβ-regulated lncRNAs in multiple sets of hHSCs and VSMCs, we identified a highly selected list of lncRNA candidates that could specifically play a role in hHSC activation. We experimentally characterized one human lncRNA, named CARMN, which was significantly regulated by TGFβ in all conditions above. CARMN knockdown significantly reduced the expression levels of a panel of marker genes for hHSC activation, as well as the levels of ECM deposition and hHSC migration. Conversely, gain of function of CARMN using CRISPR activation (CRISPR-a) yielded the completely opposite effects. Taken together, our work addresses a bottleneck in identifying human lncRNAs that specifically play a role in hHSC activation and provides a framework to effectively select human lncRNAs with significant pathophysiological role.
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Affiliation(s)
| | | | | | | | | | - Haiming Cao
- Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Sun J, Chen Y, Wang T, Ali W, Ma Y, Yuan Y, Gu J, Bian J, Liu Z, Zou H. Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 125:155337. [PMID: 38241915 DOI: 10.1016/j.phymed.2024.155337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/14/2023] [Accepted: 01/05/2024] [Indexed: 01/21/2024]
Abstract
(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N-Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6 J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism.
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Affiliation(s)
- Jian Sun
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China
| | - Yan Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China
| | - Tao Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China
| | - Waseem Ali
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China
| | - Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.
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Briggs EN, Lynch ME. The Role of Osteocytes in Pre-metastatic Niche Formation. Curr Osteoporos Rep 2024; 22:105-114. [PMID: 38198034 DOI: 10.1007/s11914-023-00857-9] [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] [Accepted: 12/22/2023] [Indexed: 01/11/2024]
Abstract
PURPOSE OF REVIEW The formation of a pre-metastatic niche (PMN), in which primary cancer cells prime the distant site to be favorable to their engraftment and survival, may help explain the strong osteotropism observed in multiple cancers, such as breast and prostate. PMN formation, which includes extracellular matrix remodeling, increased angiogenesis and vascular permeability, enhanced bone marrow-derived cell recruitment and immune suppression, has mostly been described in soft tissues. In this review, we summarize current literature of PMN formation in bone. We also present evidence of a potential role for osteocytes to be the primary mediators of PMN development. RECENT FINDINGS Osteocytes regulate the bone microenvironment in myriad ways beyond canonical bone tissue remodeling, including changes that contribute to PMN formation. Perilacunar tissue remodeling, which has been observed in both bone and non-bone metastatic cancers, is a potential mechanism by which osteocyte-cancer cell signaling stimulates changes to the bone microenvironment. Osteocytes also protect against endothelial permeability, including that induced by cancer cells, in a loading-mediated process. Finally, osteocytes are potent regulators of cells within the bone marrow, including progenitors and immune cells, and might be involved in this aspect of PMN formation. Osteocytes should be examined for their role in PMN formation.
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Affiliation(s)
- Emma N Briggs
- Department of Mechanical Engineering, University of Colorado, 427 UCB, Boulder, CO, 80309, USA
| | - Maureen E Lynch
- Department of Mechanical Engineering, University of Colorado, 427 UCB, Boulder, CO, 80309, USA.
- BioFrontiers Institute, University of Colorado, Boulder, CO, 80309, USA.
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9
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Abstract
Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow, stabilizing vessel walls, and maintaining the integrity of the blood-brain barrier. The loss of pericytes has been associated with the development and progression of various diseases, such as diabetes, Alzheimer's disease, sepsis, stroke, and traumatic brain injury. This review examines the detection of pericyte loss in different diseases, explores the methods employed to assess pericyte coverage, and elucidates the potential mechanisms contributing to pericyte loss in these pathological conditions. Additionally, current therapeutic strategies targeting pericytes are discussed, along with potential future interventions aimed at preserving pericyte function and promoting disease mitigation.
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Affiliation(s)
| | - Hongkuan Fan
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
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10
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Cao Z, Liu Y, Wang Y, Leng P. Research progress on the role of PDGF/PDGFR in type 2 diabetes. Biomed Pharmacother 2023; 164:114983. [PMID: 37290188 DOI: 10.1016/j.biopha.2023.114983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/10/2023] Open
Abstract
Platelet-derived growth factors (PDGFs) are basic proteins stored in the α granules of platelets. PDGFs and their receptors (PDGFRs) are widely expressed in platelets, fibroblasts, vascular endothelial cells, platelets, pericytes, smooth muscle cells and tumor cells. The activation of PDGFR plays a number of critical roles in physiological functions and diseases, including normal embryonic development, cellular differentiation, and responses to tissue damage. In recent years, emerging experimental evidence has shown that activation of the PDGF/PDGFR pathway is involved in the development of diabetes and its complications, such as atherosclerosis, diabetic foot ulcers, diabetic nephropathy, and retinopathy. Research on targeting PDGF/PDGFR as a treatment has also made great progress. In this mini-review, we summarized the role of PDGF in diabetes, as well as the research progress on targeted diabetes therapy, which provides a new strategy for the treatment of type 2 diabetes.
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Affiliation(s)
- Zhanqi Cao
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yijie Liu
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yini Wang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Ping Leng
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
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11
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Hu J, Liu Y, Pan Z, Huang X, Wang J, Cao W, Chen Z. Eupatilin Ameliorates Hepatic Fibrosis and Hepatic Stellate Cell Activation by Suppressing β-catenin/PAI-1 Pathway. Int J Mol Sci 2023; 24:ijms24065933. [PMID: 36983006 PMCID: PMC10054508 DOI: 10.3390/ijms24065933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
The activation of hepatic stellate cells (HSCs) has proved to be pivotal in hepatic fibrosis. Therefore, the suppression of HSC activation is an effective anti-fibrotic strategy. Although studies have indicated that eupatilin, a bioactive flavone found in Artemisia argyi, has anti-fibrotic properties, the effect of eupatilin on hepatic fibrosis is currently unclear. In this study, we used the human hepatic stellate cell line LX-2 and the classical CCl4-induced hepatic fibrosis mouse model for in vitro and vivo experiments. We found that eupatilin significantly repressed the levels of the fibrotic markers COL1α1 and α-SMA, as well as other collagens in LX-2 cells. Meanwhile, eupatilin markedly inhibited LX-2 cell proliferation, as verified by the reduced cell viability and down-regulation of c-Myc, cyclinB1, cyclinD1, and CDK6. Additionally, eupatilin decreased the level of PAI-1 in a dose-dependent manner, and knockdown of PAI-1 using PAI-1-specific shRNA significantly suppressed the levels of COL1α1, α-SMA, and the epithelial-mesenchymal transition (EMT) marker N-cadherin in LX-2 cells. Western blotting indicated that eupatilin reduced the protein level of β-catenin and its nuclear translocation, while the transcript level of β-catenin was not affected in LX-2 cells. Furthermore, analysis of histopathological changes in the liver and markers of liver function and fibrosis revealed that hepatic fibrosis in CCl4-treated mice was markedly alleviated by eupatilin. In conclusion, eupatilin ameliorates hepatic fibrosis and hepatic stellate cell activation by suppressing the β-catenin/PAI-1 pathway.
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Affiliation(s)
- Jinyuan Hu
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yuanyuan Liu
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zheng Pan
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xuekuan Huang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Traditional Chinese Medicine, Chongqing College of Traditional Chinese Medicine, Chongqing 402760, China
| | - Jianwei Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Traditional Chinese Medicine, Chongqing College of Traditional Chinese Medicine, Chongqing 402760, China
| | - Wenfu Cao
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Zhiwei Chen
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Traditional Chinese Medicine, Chongqing College of Traditional Chinese Medicine, Chongqing 402760, China
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12
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Wang S, He L, Xiao F, Gao M, Wei H, Yang J, Shu Y, Zhang F, Ye X, Li P, Hao X, Zhou X, Wei H. Upregulation of GLT25D1 in Hepatic Stellate Cells Promotes Liver Fibrosis via the TGF-β1/SMAD3 Pathway In Vivo and In vitro. J Clin Transl Hepatol 2023; 11:1-14. [PMID: 36406310 PMCID: PMC9647113 DOI: 10.14218/jcth.2022.00005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/23/2022] [Accepted: 04/12/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Collagen β(1-O) galactosyltransferase 25 domain 1 (GLT25D1) is associated with collagen production and glycosylation, and its knockout in mice results in embryonic death. However, its role in liver fibrosis remains elusive, particularly in hepatic stellate cells (HSCs), the primary collagen-producing cells associated with liver fibrogenesis. Herein, we aimed to elucidate the role of GLT25D1 in HSCs. METHODS Bile duct ligation (BDL)-induced mouse liver fibrosis models, primary mouse HSCs (mHSCs), and transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 human hepatic stellate cells were used in in vivo and in vitro studies. Stable LX-2 cell lines with either GLT25D1 overexpression or knockdown were established using lentiviral transfection. RNA-seq was performed to investigate the genomic differences. HPLC-MS/MS were used to identify glycosylation sites. Scanning electronic microscopy (SEM) and second-harmonic generation/two-photon excited fluorescence (SHG/TPEF) were used to image collagen fibril morphology. RESULTS GLT25D1 expression was upregulated in nonparenchymal cells in human cirrhotic liver tissues. Meanwhile, its knockdown attenuated collagen deposition in BDL-induced mouse liver fibrosis and inhibited mHSC activation. GLT25D1 was overexpressed in activated versus quiescence LX-2 cells and regulated in vitro LX-2 cell activation, including proliferation, contraction, and migration. GLT25D1 also significantly increased liver fibrogenic gene and protein expression. GLT25D1 upregulation promoted HSC activation and enhanced collagen expression through the TGF-β1/SMAD signaling pathway. Mass spectrometry showed that GLT25D1 regulated the glycosylation of collagen in HSCs, affecting the diameter of collagen fibers. CONCLUSIONS Collectively, the upregulation of GLT25D1 in HSCs promoted the progression of liver fibrosis by affecting HSCs activation and collagen stability.
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Affiliation(s)
- Shiwei Wang
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lingling He
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Fan Xiao
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Meixin Gao
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Herui Wei
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Junru Yang
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yang Shu
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Fuyang Zhang
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Ye
- Department of Gastroenterology, Beijing Huaxin Hospital, the First Affiliated Hospital of Tsinghua University, Beijing, China
| | - Ping Li
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaohua Hao
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xingang Zhou
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongshan Wei
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing, China
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13
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Niu L, Geyer PE, Gupta R, Santos A, Meier F, Doll S, Wewer Albrechtsen NJ, Klein S, Ortiz C, Uschner FE, Schierwagen R, Trebicka J, Mann M. Dynamic human liver proteome atlas reveals functional insights into disease pathways. Mol Syst Biol 2022; 18:e10947. [PMID: 35579278 PMCID: PMC9112488 DOI: 10.15252/msb.202210947] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/12/2022] Open
Abstract
Deeper understanding of liver pathophysiology would benefit from a comprehensive quantitative proteome resource at cell type resolution to predict outcome and design therapy. Here, we quantify more than 150,000 sequence-unique peptides aggregated into 10,000 proteins across total liver, the major liver cell types, time course of primary cell cultures, and liver disease states. Bioinformatic analysis reveals that half of hepatocyte protein mass is comprised of enzymes and 23% of mitochondrial proteins, twice the proportion of other liver cell types. Using primary cell cultures, we capture dynamic proteome remodeling from tissue states to cell line states, providing useful information for biological or pharmaceutical research. Our extensive data serve as spectral library to characterize a human cohort of non-alcoholic steatohepatitis and cirrhosis. Dramatic proteome changes in liver tissue include signatures of hepatic stellate cell activation resembling liver cirrhosis and providing functional insights. We built a web-based dashboard application for the interactive exploration of our resource (www.liverproteome.org).
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Affiliation(s)
- Lili Niu
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
| | - Philipp E Geyer
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
- Present address:
OmicEra Diagnostics GmbHPlaneggGermany
| | - Rajat Gupta
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Present address:
Pfizer Worldwide Research and DevelopmentSan DiegoCAUSA
| | - Alberto Santos
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Center for Health Data ScienceFaculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
- Big Data InstituteNuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Florian Meier
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
- Present address:
Functional ProteomicsJena University HospitalJenaGermany
| | - Sophia Doll
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
- Present address:
OmicEra Diagnostics GmbHPlaneggGermany
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Clinical BiochemistryRigshospitaletUniversity of CopenhagenCopenhagenDenmark
| | - Sabine Klein
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
| | - Cristina Ortiz
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
| | - Frank E Uschner
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
| | - Robert Schierwagen
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
| | - Jonel Trebicka
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
- European Foundation for the Study of Chronic Failure, EFCLIFBarcelonaSpain
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
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14
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Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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15
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Ji J, Feng M, Huang Y, Niu X. Liraglutide inhibits receptor for advanced glycation end products (RAGE)/reduced form of nicotinamide-adenine dinucleotide phosphate (NAPDH) signaling to ameliorate non-alcoholic fatty liver disease (NAFLD) in vivo and vitro. Bioengineered 2022; 13:5091-5102. [PMID: 35164657 PMCID: PMC8974036 DOI: 10.1080/21655979.2022.2036902] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The study was designed to investigate the effects of liraglutide and reveal its action mechanism associated with RAGE/NAPDH in NAFLD. The liver tissue was collected for HE, Masson, and ROS staining. Apoptosis levels were detected through TUNEL staining and ROS levels were evaluated through ROS staining. The expression levels of c-Jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β) were detected through Western blot. JNK and the expression of Collagenα1, Collagenα2 and connective tissue growth factor (CTGF) were detected through RT-qPCR and Western blot and the expression in mouse liver stellate cells (JS-1) cells were evaluated through immunofluorescence staining. We detected the effects of liraglutide on NAFLD in high-fat diet (HFD)-fed mice. Liraglutide treatment improved bridging fibrosis and liver function, as well as lessening ROS levels and the protein levels of RAGE, NOX1, NOX2 and NOX4. In PA and H2O2-induced AML12 cells, liraglutide treatment was able to decrease cell apoptosis, ROS levels and the levels of inflammatory factors including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, while it effects were reversed by the induction of RAGE overexpression or NOX2 overexpression. In JS-1 cells treated with medium culturing AML12 cells, liraglutide markedly suppressed cell proliferation and activation, while RAGE overexpression or NOX2 overexpression blunted these effects of liraglutide. Taken together, liraglutide exerts a protective role in improving liver injury caused by HFD, which could be related to decreased apoptosis and oxidative stress of liver cells, as well as decreased proliferation and activation of hepatic stellate cells through RAGE/NOX2.
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Affiliation(s)
- Jingquan Ji
- Department of Pathophysiology, Changzhi Medical College, Changzhi, Shanxi, China
| | - Ming Feng
- Department of Neurosurgery, Changzhi People's Hospital, Changzhi, Shanxi, China
| | - Yan Huang
- Department of Biochemistry, Changzhi Medical College, Changzhi, Shanxi, China
| | - Xiaohong Niu
- Department of Endocrinology, The Heji Affiliated Hospital of Changzhi Medical College, Changzhi, Shanxi, China
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16
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Schinagl M, Tomin T, Gindlhuber J, Honeder S, Pfleger R, Schittmayer M, Trauner M, Birner-Gruenberger R. Proteomic Changes of Activated Hepatic Stellate Cells. Int J Mol Sci 2021; 22:ijms222312782. [PMID: 34884585 PMCID: PMC8657869 DOI: 10.3390/ijms222312782] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatic stellate cells (HSC) are the major cellular drivers of liver fibrosis. Upon liver inflammation caused by a broad range of insults including non-alcoholic fatty liver, HSC transform from a quiescent into a proliferating, fibrotic phenotype. Although much is known about the pathophysiology of this process, exact cellular processes which occur in HSC and enable this transformation remain yet to be elucidated. In order to investigate this HSC transformation, we employed a simple, yet reliable model of HSC activation via an increase in growth medium serum concentration (serum activation). For that purpose, immortalized human LX-2 HSC were exposed to either 1% or 10% fetal bovine serum (FBS). Resulting quiescent (1% FBS) and activated (10% FBS) LX-2 cells were then subjected to in-depth mass spectrometry-based proteomics analysis as well as comprehensive phenotyping. Protein network analysis of activated LX-2 cells revealed an increase in the production of ribosomal proteins and proteins related to cell cycle control and migration, resulting in higher proliferation and faster migration phenotypes. Interestingly, we also observed a decrease in the expression of cholesterol and fatty acid biosynthesis proteins in accordance with a concomitant loss of cytosolic lipid droplets during activation. Overall, this work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analyses and presents an accessible model for HSC activation. Data are available via ProteomeXchange with identifier PXD029121.
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Affiliation(s)
- Maximilian Schinagl
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
| | - Tamara Tomin
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
| | - Juergen Gindlhuber
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
| | - Sophie Honeder
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
| | - Raphael Pfleger
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
| | - Matthias Schittmayer
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria;
| | - Ruth Birner-Gruenberger
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
- Correspondence:
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17
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Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview. Pharmacol Res 2021; 170:105739. [PMID: 34171492 DOI: 10.1016/j.phrs.2021.105739] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/07/2021] [Accepted: 06/19/2021] [Indexed: 02/08/2023]
Abstract
Fibrosis is characterized by an abnormal accumulation of extracellular matrix (ECM) constituents in the liver parenchyma that lead to hepatic cirrhosis. After liver injury, the hepatic stellate cells (HSCs) undergo a response called "activation", transforming the cells into proliferative, fibrogenic and contractile myofibroblasts, representing the main collagen-producing cells in the injured tissue. Activated HSCs are considered as pro-inflammatory cells producing cytokines and several hepatomatogens; they are additionally involved in the recruitment of Kupffer cells, circulating monocytes and macrophages through the production of chemokines. Moreover, HSC have been proposed as being involved in the development of insulin resistance mainly mediated by their inflammatory properties, which undeniably links their activation to the development of diabetes and Non-alcoholic fatty liver disease. In addition, when the liver is injured, a complex interaction between hepatocytes and HSCs occurs, inducing mitochondrial dysfunction, which contributes to the accumulation of fats in hepatocytes that trigger to liver lipotoxicity. These mechanisms underlying the activation of HSC suggest their major role in the development of metabolic disorders. It turns out that several molecules including MicroRNAs and proteins have the ability to inhibit the activation and the proliferation of HSCs, which makes them interesting therapeutic targets for the subsequent management of metabolic conditions. This review focuses on the mechanisms and molecular pathways underlying the initiation and onset of metabolic disorders following HSCs activation, as well as on molecular therapeutic targets, which could limit their fibrogenic transdifferentiation and therefore improve the liver condition in the course of metabolic imbalance.
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Affiliation(s)
- Nabila Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland.
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18
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Goddi A, Schroedl L, Brey EM, Cohen RN. Laminins in metabolic tissues. Metabolism 2021; 120:154775. [PMID: 33857525 DOI: 10.1016/j.metabol.2021.154775] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 03/13/2021] [Accepted: 04/08/2021] [Indexed: 12/16/2022]
Abstract
Laminins are extracellular matrix proteins that reside in the basement membrane and provide structural support in addition to promoting cellular adhesion and migration. Through interactions with cell surface receptors, laminins stimulate intracellular signaling cascades which direct specific survival and differentiation outcomes. In metabolic tissues such as the pancreas, adipose, muscle, and liver, laminin isoforms are expressed in discrete temporal and spatial patterns suggesting that certain isoforms may support the development and function of particular metabolic cell types. This review focuses on the research to date detailing the expression of laminin isoforms, their potential function, as well as known pathways involved in laminin signaling in metabolic tissues. We will also discuss the current biomedical therapies involving laminins in these tissues in addition to prospective applications, with the goal being to encourage future investigation of laminins in the context of metabolic disease.
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Affiliation(s)
- Anna Goddi
- Committee on Molecular Metabolism and Nutrition, The University of Chicago, 900 East 57th St, Chicago, IL 60637, USA
| | - Liesl Schroedl
- Pritzker School of Medicine, The University of Chicago, 924 E 57th St, Chicago, IL 60637, USA
| | - Eric M Brey
- Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
| | - Ronald N Cohen
- Committee on Molecular Metabolism and Nutrition, The University of Chicago, 900 East 57th St, Chicago, IL 60637, USA; Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 South Maryland Ave, Chicago, IL 60637, USA.
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19
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Kragh Petersen S, Bilkei‐Gorzo O, Govaere O, Härtlova A. Macrophages and scavenger receptors in obesity-associated non-alcoholic liver fatty disease (NAFLD). Scand J Immunol 2020; 92:e12971. [PMID: 32892401 PMCID: PMC7685160 DOI: 10.1111/sji.12971] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 08/28/2020] [Accepted: 08/30/2020] [Indexed: 12/20/2022]
Abstract
With an increase in sedentary lifestyle and dietary over nutrition, obesity has become one of the major public health problems worldwide and is a prevalent predisposing risk factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western developed countries. NAFLD represents a series of diseased states ranging from non-alcoholic fatty liver (NAFL) to steatohepatitis (NASH), which can lead to fibrosis and eventually to cirrhosis and hepatocellular carcinoma. Currently, the only effective treatment to cure end-stage liver disease is liver transplantation. Macrophages have been reported to play a crucial role in the progression of NAFLD, thereby are a potential target for therapy. In this review, we discuss the current knowledge on the role of macrophages and inflammatory signalling pathways associated with obesity and chronic liver inflammation, and their contribution to NAFLD development and progression.
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Affiliation(s)
- Sine Kragh Petersen
- Department of Microbiology and Immunology at Institute of BiomedicineWallenberg Centre for Molecular and Translational MedicineUniversity of GothenburgGothenburgSweden
| | - Orsolya Bilkei‐Gorzo
- Department of Microbiology and Immunology at Institute of BiomedicineWallenberg Centre for Molecular and Translational MedicineUniversity of GothenburgGothenburgSweden
| | - Olivier Govaere
- Translational and Clinical Research InstituteFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Anetta Härtlova
- Department of Microbiology and Immunology at Institute of BiomedicineWallenberg Centre for Molecular and Translational MedicineUniversity of GothenburgGothenburgSweden
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20
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Huang D, Gibeley SB, Xu C, Xiao Y, Celik O, Ginsberg HN, Leong KW. Engineering liver microtissues for disease modeling and regenerative medicine. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1909553. [PMID: 33390875 PMCID: PMC7774671 DOI: 10.1002/adfm.201909553] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Indexed: 05/08/2023]
Abstract
The burden of liver diseases is increasing worldwide, accounting for two million deaths annually. In the past decade, tremendous progress has been made in the basic and translational research of liver tissue engineering. Liver microtissues are small, three-dimensional hepatocyte cultures that recapitulate liver physiology and have been used in biomedical research and regenerative medicine. This review summarizes recent advances, challenges, and future directions in liver microtissue research. Cellular engineering approaches are used to sustain primary hepatocytes or produce hepatocytes derived from pluripotent stem cells and other adult tissues. Three-dimensional microtissues are generated by scaffold-free assembly or scaffold-assisted methods such as macroencapsulation, droplet microfluidics, and bioprinting. Optimization of the hepatic microenvironment entails incorporating the appropriate cell composition for enhanced cell-cell interactions and niche-specific signals, and creating scaffolds with desired chemical, mechanical and physical properties. Perfusion-based culture systems such as bioreactors and microfluidic systems are used to achieve efficient exchange of nutrients and soluble factors. Taken together, systematic optimization of liver microtissues is a multidisciplinary effort focused on creating liver cultures and on-chip models with greater structural complexity and physiological relevance for use in liver disease research, therapeutic development, and regenerative medicine.
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Affiliation(s)
- Dantong Huang
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Sarah B. Gibeley
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Cong Xu
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Yang Xiao
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Ozgenur Celik
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Henry N. Ginsberg
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Kam W. Leong
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
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Oxidative Stress in Chronic Liver Disease and Portal Hypertension: Potential of DHA as Nutraceutical. Nutrients 2020; 12:nu12092627. [PMID: 32872239 PMCID: PMC7551786 DOI: 10.3390/nu12092627] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/25/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease constitutes a growing public health issue worldwide, with no safe and effective enough treatment clinical scenarios. The present review provides an overview of the current knowledge regarding advanced chronic liver disease (ACLD), focusing on the major contributors of its pathophysiology: inflammation, oxidative stress, fibrosis and portal hypertension. We present the benefits of supplementation with docosahexaenoic acid triglycerides (TG-DHA) in other health areas as demonstrated experimentally, and explore its potential as a novel nutraceutical approach for the treatment of ACLD and portal hypertension based on published pre-clinical data.
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22
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Eubanks HB, Lavoie EG, Goree J, Kamykowski JA, Gokden N, Fausther M, Dranoff JA. Reduction in SNAP-23 Alters Microfilament Organization in Myofibrobastic Hepatic Stellate Cells. Gene Expr 2020; 20:25-37. [PMID: 31757226 PMCID: PMC7284106 DOI: 10.3727/105221619x15742818049365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Hepatic stellate cells (HSC) are critical effector cells of liver fibrosis. In the injured liver, HSC differentiate into a myofibrobastic phenotype. A critical feature distinguishing myofibroblastic from quiescent HSC is cytoskeletal reorganization. Soluble NSF attachment receptor (SNARE) proteins are important in trafficking of newly synthesized proteins to the plasma membrane for release into the extracellular environment. The goals of this project were to determine the expression of specific SNARE proteins in myofibroblastic HSC and to test whether their alteration changed the HSC phenotype in vitro and progression of liver fibrosis in vivo. We found that HSC lack the t-SNARE protein, SNAP-25, but express a homologous protein, SNAP-23. Downregulation of SNAP-23 in HSC induced reduction in polymerization and disorganization of the actin cytoskeleton associated with loss of cell movement. In contrast, reduction in SNAP-23 in mice by monogenic deletion delayed but did not prevent progression of liver fibrosis to cirrhosis. Taken together, these findings suggest that SNAP-23 is an important regular of actin dynamics in myofibroblastic HSC, but that the role of SNAP-23 in the progression of liver fibrosis in vivo is unclear.
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Affiliation(s)
- Haleigh B. Eubanks
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Elise G. Lavoie
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jessica Goree
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jeffrey A. Kamykowski
- †Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Neriman Gokden
- ‡Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Michel Fausther
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jonathan A. Dranoff
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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He X, Chen J, Mu Y, Zhang H, Chen G, Liu P, Liu W. The effects of inhibiting the activation of hepatic stellate cells by lignan components from the fruits of Schisandra chinensis and the mechanism of schisanhenol. J Nat Med 2020; 74:513-524. [PMID: 32193805 DOI: 10.1007/s11418-020-01394-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 03/06/2020] [Indexed: 12/15/2022]
Abstract
Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose-effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor β (TGF-β)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.
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Affiliation(s)
- Xiaoli He
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China.,TCM Department, Ningbo Huamei Hospital Affiliated to Chinese Academy of Sciences, 41 Xibei Road, Ningbo, 315010, 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, 528 Zhangheng Road, Shanghai, 201203, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, 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, 528 Zhangheng Road, Shanghai, 201203, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, 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, 528 Zhangheng Road, Shanghai, 201203, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Gaofeng 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, 528 Zhangheng Road, Shanghai, 201203, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, 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, 528 Zhangheng Road, Shanghai, 201203, China. .,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, 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, 528 Zhangheng Road, Shanghai, 201203, China. .,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
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24
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Effect of High-dose Vitamin A Supplementation in Children With Sickle Cell Disease: A Randomized, Double-blind, Dose-finding Pilot Study. J Pediatr Hematol Oncol 2020; 42:83-91. [PMID: 31764511 DOI: 10.1097/mph.0000000000001673] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Suboptimal vitamin A status (serum retinol <30 µg/dL) is associated with poor clinical outcomes in children with the hemoglobin-SS disease (HbSS), and supplementation with the recommended daily allowance of retinol is ineffective in improving vitamin A status. In a single-center randomized blinded dose-finding pilot study, we compared vitamin A and nutritional status in children with HbSS to healthy children and explored the impact of high-dose supplementation on the primary outcome serum vitamin A status. Exploratory outcomes included hematologic, nutritional, immunologic, and muscle function status in children with HbSS. A mixed-effects linear regression model evaluated associations between vitamin A dose, serum retinol, and exploratory outcomes. Twenty healthy children participated, and 22 subjects with HbSS were randomized to oral 3000 or 6000 IU/d retinol for 8 weeks; 21 subjects completed all evaluations. Serum retinol, growth, and nutritional status were all suboptimal in HbSS subjects at baseline, and supplementation did not change vitamin A status. Fetal hemoglobin (Δ=2.5, 95% confidence interval [CI], 0.5-4.3), mean corpuscular volume (Δ=2.7, 95% CI, 0.7-4.7), mean corpuscular hemoglobin (Δ=1.4, 95% CI, 0.5-2.3), and mean corpuscular hemoglobin concentration (Δ=0.5, 95% CI, 0.1-0.9) all improved with supplementation. Mild improvements in erythrocyte indices, growth status, and muscle function occurred independent of hydroxyurea use.
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25
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Zhao Z, Lin CY, Cheng K. siRNA- and miRNA-based therapeutics for liver fibrosis. Transl Res 2019; 214:17-29. [PMID: 31476281 PMCID: PMC6848786 DOI: 10.1016/j.trsl.2019.07.007] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/08/2019] [Accepted: 07/18/2019] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is a wound-healing process induced by chronic liver injuries, such as nonalcoholic steatohepatitis, hepatitis, alcohol abuse, and metal poisoning. The accumulation of excessive extracellular matrix (ECM) in the liver is a key characteristic of liver fibrosis. Activated hepatic stellate cells (HSCs) are the major producers of ECM and therefore play irreplaceably important roles during the progression of liver fibrosis. Liver fibrogenesis is highly correlated with the activation of HSCs, which is regulated by numerous profibrotic cytokines. Using RNA interference to downregulate these cytokines in activated HSCs is a promising strategy to reverse liver fibrosis. Meanwhile, microRNAs (miRNAs) have also been exploited for the treatment of liver fibrosis. This review focuses on the current siRNA- and miRNA-based liver fibrosis treatment strategies by targeting activated HSCs in the liver.
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Affiliation(s)
- Zhen Zhao
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Chien-Yu Lin
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri.
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26
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Lan YT, Wang ZL, Tian P, Gong XN, Fan YC, Wang K. Treg/Th17 imbalance and its clinical significance in patients with hepatitis B-associated liver cirrhosis. Diagn Pathol 2019; 14:114. [PMID: 31639000 PMCID: PMC6805395 DOI: 10.1186/s13000-019-0891-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 09/12/2019] [Indexed: 02/06/2023] Open
Abstract
Background Recent studies have shown that T cell-mediated cellular immune mechanisms play important roles in the progression of hepatitis B to liver cirrhosis, but the underlying mechanisms remain unclear. This present study was aimed to determine the relationship between Treg/Th17 and hepatitis B-associated liver cirrhosis. Methods The Treg and Th17 cell frequencies in the peripheral blood of all participants, including 93 patients with hepatitis B-associated liver cirrhosis and 40 healthy subjects, were measured by flow cytometer. Cox regression model and receiver operating characteristic(ROC) curves were applied to investigate the prognostic significance of Treg/Th17 ratio in decompensated liver cirrhosis. Results We observed the Treg/Th17 imbalance was present in patients with hepatitis B-associated liver cirrhosis, with reduced Treg cells in their peripheral blood, increased Th17 cells and decreased Treg/Th17 ratio. Treg and Th17 cells were negatively correlated. Treg/Th17 imbalance was closely related to the clinical stage of hepatitis B-associated liver cirrhosis. The Virus load, Treg frequencies and the Treg/Th17 ratio were independent factors predicting decompensated liver cirrhosis from a Cox regression model. The ROC analysis showed that the Treg/Th17 ratio was the best marker for predicting decompensated liver cirrhosis. Conclusions Treg/Th17 imbalance is involved in the pathogenesis of hepatitis B-associated liver cirrhosis and the Treg/Th17 ratio can be used as a potential marker for predicting decompensated liver cirrhosis.
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Affiliation(s)
- Yong-Ting Lan
- Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, People's Republic of China.,Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong, People's Republic of China
| | - Zhen-Li Wang
- Department of Hepatology, Qing Dao No. 6 People's Hospital, Qingdao, Shandong, People's Republic of China
| | - Peng Tian
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong, People's Republic of China
| | - Xiao-Na Gong
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong, People's Republic of China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, People's Republic of China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, People's Republic of China. .,Institute of Hepatology, Shandong University, Jinan, Shandong, People's Republic of China.
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27
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Elias MDB, Oliveira FL, Guma FCR, Martucci RB, Borojevic R, Teodoro AJ. Lycopene inhibits hepatic stellate cell activation and modulates cellular lipid storage and signaling. Food Funct 2019; 10:1974-1984. [PMID: 30889234 DOI: 10.1039/c8fo02369g] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatic stellate cells are liver-specific perivascular cells, identified as the major source of collagen in liver fibrosis, following their activation and conversion to myofibroblast-like cells. Lycopene is a carotenoid with biological activities and protective effects described in different pathologies, but little is known about its role in liver protection. We evaluated the influence of lycopene on the cell cycle and lipid metabolism and monitored the possible pathways involved in lycopene inhibition of stellate cell activation. Lycopene induced expression of the lipocyte phenotype, with an accumulation of fat droplets in cytoplasm, with high synthesis and turnover of phospholipids and triglycerides. Cell proliferation analysis showed that lycopene reduced the growth of GRX cells. Lycopene induced an arrest in the G0/G1 phase, followed by a decrease of cells in the G2/M phase, regardless of the concentration of lycopene used. Lycopene modulated relevant signaling pathways related to cholesterol metabolism, cellular proliferation, and lipid metabolism. Also, lycopene treatment increased the expression of RXR-α, RXR-β, and PPARγ, important biomarkers of liver regeneration. These results show that lycopene was able to negatively modulate events related to the activation of hepatic stellate cells through mechanisms that involve changes in expression of cellular lipid metabolism factors, and suggest that this compound might provide a novel pharmacological approach for the prevention and treatment of fibrotic liver diseases.
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Affiliation(s)
- Monique de Barros Elias
- Laboratory of Functional Foods, Universidade Federal do Estado do Rio de Janeiro, Av. Pastuer 296, Brazil.
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Di Benedetto P, Ruscitti P, Liakouli V, Del Galdo F, Giacomelli R, Cipriani P. Linking myofibroblast generation and microvascular alteration: The role of CD248 from pathogenesis to therapeutic target (Review). Mol Med Rep 2019; 20:1488-1498. [PMID: 31257535 DOI: 10.3892/mmr.2019.10429] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/29/2019] [Indexed: 11/06/2022] Open
Abstract
Fibrosis is characterized by excessive extracellular matrix (ECM) deposition, and is the pathological outcome of tissue injury in a number of disorders. Accumulation of the ECM may disrupt the structure and function of native tissues and organs, including the lungs, heart, liver and skin, resulting in significant morbidity and mortality. On this basis, multiple lines of evidence have focused on the molecular pathways and cellular mechanisms involved in fibrosis, which has led to the development of novel antifibrotic therapies. CD248 is one of several proteins identified to be localized to the stromal compartment in cancers and fibroproliferative disease, and may serve a key role in myofibroblast generation and accumulation. Numerous studies have supported the contribution of CD248 to tumour growth and fibrosis, stimulating interest in this molecule as a therapeutic target. In addition, it has been revealed that CD248 may be involved in pathological angiogenesis. The present review describes the current understanding of the structure and function of CD248 during angiogenesis and fibrosis, supporting the hypothesis that blocking CD248 signalling may prevent both myofibroblast generation and microvascular alterations during tissue fibrosis.
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Affiliation(s)
- Paola Di Benedetto
- Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila I‑67100, Italy
| | - Piero Ruscitti
- Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila I‑67100, Italy
| | - Vasiliki Liakouli
- Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila I‑67100, Italy
| | - Francesco Del Galdo
- Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK
| | - Roberto Giacomelli
- Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila I‑67100, Italy
| | - Paola Cipriani
- Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila I‑67100, Italy
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29
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Retinoids in Stellate Cells: Development, Repair, and Regeneration. J Dev Biol 2019; 7:jdb7020010. [PMID: 31137700 PMCID: PMC6630434 DOI: 10.3390/jdb7020010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 05/15/2019] [Accepted: 05/17/2019] [Indexed: 01/17/2023] Open
Abstract
Stellate cells, either hepatic (HSCs) or pancreatic (PSCs), are a type of interstitial cells characterized by their ability to store retinoids in lipid vesicles. In pathological conditions both HSCs and PSCs lose their retinoid content and transform into fibroblast-like cells, contributing to the fibrogenic response. HSCs also participate in other functions including vasoregulation, drug detoxification, immunotolerance, and maintenance of the hepatocyte population. PSCs maintain pancreatic tissue architecture and regulate pancreatic exocrine function. Recently, PSCs have attracted the attention of researchers due to their interactions with pancreatic ductal adenocarcinoma cells. PSCs promote tumour growth and angiogenesis, and their fibrotic activity increases the resistance of pancreatic cancer to chemotherapy and radiation. We are reviewing the current literature concerning the role played by retinoids in the physiology and pathophysiology of the stellate cells, paying attention to their developmental aspects as well as the function of stellate cells in tissue repair and organ regeneration.
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30
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Munguía-Reyes A, Balderas-Martínez YI, Becerril C, Checa M, Ramírez R, Ortiz B, Meléndez-Zajgla J, Pardo A, Selman M. R-Spondin-2 Is Upregulated in Idiopathic Pulmonary Fibrosis and Affects Fibroblast Behavior. Am J Respir Cell Mol Biol 2019; 59:65-76. [PMID: 29345973 DOI: 10.1165/rcmb.2017-0115oc] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by the expansion of the myofibroblast population, excessive extracellular matrix accumulation, and destruction of the lung parenchyma. The R-spondin family (RSPO) comprises a group of proteins essential for development. Among them, RSPO2 is expressed primarily in the lungs, and its mutations cause severe defects in the respiratory tract. Interestingly, RSPO2 participates in the canonical Wingless/int1 pathway, a critical route in the pathogenesis of IPF. Thus, the aim of this study was to examine the expression and putative role of RSPO2 in this disease. We found that RSPO2 and its receptor leucine-rich G protein-coupled receptor 6 were upregulated in IPF lungs, where they localized primarily in fibroblasts and epithelial cells. Stimulation of IPF and normal lung fibroblasts with recombinant human RSPO2 resulted in the deregulation of numerous genes, although the transcriptional response was essentially distinct. In IPF fibroblasts, RSPO2 stimulation induced the up- or downregulation of several genes involved in the Wingless/int1 pathway (mainly from noncanonical signaling). In both normal and IPF fibroblasts, RSPO2 modifies the expression of genes implicated in several pathways, including the cell cycle and apoptosis. In accordance with gene expression, the stimulation of normal and IPF fibroblasts with RSPO2 significantly reduced cell proliferation and induced cell death. RSPO2 also inhibited collagen production and increased the expression of matrix metalloproteinase 1. Silencing RSPO2 with shRNA induced the opposite effects. Our findings demonstrate, for the first time to our knowledge, that RSPO2 is upregulated in IPF, where it appears to have an antifibrotic role.
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Affiliation(s)
- Adrián Munguía-Reyes
- 1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico
| | - Yalbi I Balderas-Martínez
- 1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico.,2 Cátedra Consejo Nacional de Ciencia y Tecnología (CONACyT)-INER, Mexico City, Mexico
| | - Carina Becerril
- 1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico
| | - Marco Checa
- 1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico
| | - Remedios Ramírez
- 3 Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico; and
| | - Blanca Ortiz
- 1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico
| | | | - Annie Pardo
- 3 Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico; and
| | - Moisés Selman
- 1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico
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2-Methoxyestradiol attenuates liver fibrosis in mice: implications for M2 macrophages. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:381-391. [PMID: 30535572 DOI: 10.1007/s00210-018-1577-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a major health problem worldwide due to its serious complications including cirrhosis and liver cancer. 2-Methoxyestradiol (2-ME) is an end metabolite of estradiol with anti-proliferative, antioxidant, and anti-inflammatory activities. However, the protective role of 2-ME in liver fibrosis has not been fully investigated. The aim of this study was to determine the protective effect of 2-ME in carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Animals were injected intraperitoneally with CCl4 twice weekly for 6 weeks. 2-ME 50 mg/kg or 100 mg/kg was administrated intraperitoneally every day over the same period. Our data showed that 2-ME reduced the extent of liver toxicity and fibrosis due to CCl4 exposure. It restored the elevated serum liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels and ameliorated oxidative status. In addition, 2-ME significantly reduced collagen deposition and alpha-smooth muscle actin (α-SMA) protein expressions. Furthermore, 2-ME markedly lowered macrophage infiltration and macrophage alternative activation marker chitinase-like molecules (CHI3L3/YM1). The results of this study indicate an important protective activity of 2-ME in liver fibrosis and highlight the role of macrophage recruitment and alternative activation as a possible target.
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Ma Z, Liu X, Dong H, Xia D, Wang L, Chen Y, Xiong Y. Sorafenib and praziquantel synergistically attenuate Schistosoma japonicum-induced liver fibrosis in mice. Parasitol Res 2018; 117:2831-2839. [PMID: 29946766 DOI: 10.1007/s00436-018-5972-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 06/15/2018] [Indexed: 12/27/2022]
Abstract
Liver fibrosis is an important process that occurs in most types of chronic liver diseases and often results in the end stage of liver diseases, such as cirrhosis, portal hypertension, and hepatocellular carcinoma. Sorafenib, a multiple tyrosine kinase inhibitor, has been shown to inhibit liver fibrosis in multiple experimental fibrosis mouse and rat models. The aim of this study was to test the therapeutic effect of sorafenib on liver fibrosis induced by infection with a parasite, Schistosoma japonicum, in mice. Mice were percutaneously infected through the abdomen with Schistosoma cercariae to develop a schistosomula liver fibrosis model. Eight weeks after infection, infected mice were treated with the anti-parasitic agent praziquantel for 2 days and sorafenib for 2 weeks. Hepatic histopathological changes were assessed using hematoxylin and eosin (HE) and Masson's trichome staining. The hepatic expression levels of collagen I, collagen III, alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and PDGF receptor-beta (PDGFR-β) were analyzed by immunohistochemistry and western blot. Praziquantel administration alone but not sorafenib reduced liver fibrosis, and the combination of praziquantel and sorafenib significantly attenuated liver fibrosis in S. japonicum-infected mice. Moreover, sorafenib plus praziquantel markedly decreased the hepatic deposition of collagen and expression of fibrogenic genes in these mice. In conclusion, the use of sorafenib following praziquantel treatment may represent a potential therapeutic strategy for liver fibrosis induced by S. japonicum in patients.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, China
| | - Xia Liu
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, China
| | - Huifen Dong
- Department of Human Parasitology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Dong Xia
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Lixia Wang
- Hubei Provincial Academy of Preventive Medicine, Wuhan, 430079, China
| | - Yu Chen
- State Key Laboratory of Virology, Modern Virology Research Centre, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, China.
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Bersini S, Gilardi M, Mora M, Krol S, Arrigoni C, Candrian C, Zanotti S, Moretti M. Tackling muscle fibrosis: From molecular mechanisms to next generation engineered models to predict drug delivery. Adv Drug Deliv Rev 2018. [PMID: 29518415 DOI: 10.1016/j.addr.2018.02.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Muscle fibrosis represents the end stage consequence of different diseases, among which muscular dystrophies, leading to severe impairment of muscle functions. Muscle fibrosis involves the production of several growth factors, cytokines and proteolytic enzymes and is strictly associated to inflammatory processes. Moreover, fibrosis causes profound changes in tissue properties, including increased stiffness and density, lower pH and oxygenation. Up to now, there is no therapeutic approach able to counteract the fibrotic process and treatments directed against muscle pathologies are severely impaired by the harsh conditions of the fibrotic environment. The design of new therapeutics thus need innovative tools mimicking the obstacles posed by the fibrotic environment to their delivery. This review will critically discuss the role of in vivo and 3D in vitro models in this context and the characteristics that an ideal model should possess to help the translation from bench to bedside of new candidate anti-fibrotic agents.
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Liang L, Yang X, Yu Y, Li X, Wu Y, Shi R, Jiang J, Gao L, Ye F, Zhao Q, Li R, Wei L, Han Z. Babao Dan attenuates hepatic fibrosis by inhibiting hepatic stellate cells activation and proliferation via TLR4 signaling pathway. Oncotarget 2018; 7:82554-82566. [PMID: 27776340 PMCID: PMC5347713 DOI: 10.18632/oncotarget.12783] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/12/2016] [Indexed: 12/11/2022] Open
Abstract
Babao Dan (BBD), a traditional Chinese medicine, has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the protective effect of BBD on rat hepatic fibrosis induced by diethylnitrosamine (DEN) and explore it possible mechanism. BBD was administrated while DEN was given. After eight weeks, values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicated that BBD significantly protected liver from damaging by DEN and had no obvious side effect on normal rat livers. Meanwhile, BBD attenuated hepatic inflammation and fibrosis in DEN-induced rat livers through histopathological examination and hepatic hydroxyproline content. Furthermore, we found that BBD inhibited hepatic stellate cells activation and proliferation without altering the concentration of lipopolysaccharide (LPS) in portal vein. In vitro study, serum from BBD treated rats (BBD-serum) could also significantly suppress LPS-induced HSCs activation through TLR4/NF-κB pathway. In addition, BBD-serum also inhibited the proliferation of HSCs by regulating TLR4/ERK pathway. Our study demonstrated that BBD may provide a new therapy strategy of hepatic injury and hepatic fibrosis.
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Affiliation(s)
- Lei Liang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.,Medical College of Soochow University, Suzhou, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Yang Yu
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.,Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiaoyong Li
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.,Medical College of Soochow University, Suzhou, China
| | - Yechen Wu
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.,Medical College of Soochow University, Suzhou, China
| | - Rongyu Shi
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
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36
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Yang J, Liu Q, Cao S, Xu T, Li X, Zhou D, Pan L, Li C, Huang C, Meng X, Zhang L, Wang X. MicroRNA-145 Increases the Apoptosis of Activated Hepatic Stellate Cells Induced by TRAIL through NF-κB Signaling Pathway. Front Pharmacol 2018; 8:980. [PMID: 29375381 PMCID: PMC5770373 DOI: 10.3389/fphar.2017.00980] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 12/21/2017] [Indexed: 12/18/2022] Open
Abstract
During the liver fibrosis recovery stage tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can effectively induce apoptosis of activated hepatic stellate cells (HSCs). Normal hepatic stellate cells are resistant to TRAIL cytotoxicity. Therefore, enhancing the sensitivity of TRAIL-induced apoptosis of HSCs may be useful to treat hepatic fibrogenesis. Here, we demonstrated that miR-145 and TRAIL were down-regulated in both liver fibrosis tissue samples and transforming growth factor-β1 induced HSCs, concomitant with increased the expression of ZEB2. In addition, we found that mimics-mediated over-expression of miR-145 led to resistance to the ZEB2 expression and up-regulation of the TRAIL-induced apoptosis after treatment of LX-2 cells with TRAIL. Furthermore, ZEB2-siRNA transfected LX-2 cells showed the increased sensitivity to TRAIL-induced apoptosis. Whereas, opposite results were obtained in miR-145-inhibitor group or ZEB2 plasmid group. Moreover, miR-145 regulated ZEB2 gene expression by specifically interacting with the 3′-UTR of ZEB2 mRNA to inhibit the expression of ZEB2. Further studies showed that the over-expression of ZEB2 could inhibit TRAIL-induced apoptosis via inhibiting nuclear factor-κB (NF-κB) signaling pathway in LX-2 cells. Collectively, our data suggest that up-regulation of miR-145 can down-regulate ZEB2 expression, consequently promoting TRAIL-induced apoptosis in LX-2 cells through NF-κB signaling pathway, which facilitates the resolution of liver fibrosis.
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Affiliation(s)
- Junfa Yang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Qingxue Liu
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Shiyang Cao
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Tao Xu
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaofeng Li
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Dandan Zhou
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Linxin Pan
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Changyao Li
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaoming Meng
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiao Wang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Zhao Z, Li Y, Jain A, Chen Z, Liu H, Jin W, Cheng K. Development of a peptide-modified siRNA nanocomplex for hepatic stellate cells. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2018; 14:51-61. [PMID: 28890106 PMCID: PMC5742024 DOI: 10.1016/j.nano.2017.08.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 08/08/2017] [Accepted: 08/28/2017] [Indexed: 01/05/2023]
Abstract
Insulin-like growth factor 2 receptor (IGF2R) is overexpressed in activated hepatic stellate cells (HSCs) and therefore can be utilized for HSC-specific drug delivery. We recently discovered an IGF2R-specific peptide using a novel biopanning. Here, we adopted biotin-conjugated IGF2R-specific peptide, cholesterol, and vitamin A as the targeting ligands for the neutravidin-based siRNA nanocomplex to deliver PCBP2 siRNA, a potentially antifibrotic agent, to HSCs. Compared to vitamin A and cholesterol, the IGF2R-specific peptide exhibited the highest targeting effect to human LX-2 HSC, rat HSC-T6 cell line, and activated primary rat HSCs. Accordingly, the IGF2R-specific peptide coupled nanocomplex demonstrated higher silencing activity of PCBP2 and better inhibition on the migration of activated HSCs. Compared to free siRNA and the nanocomplexes coupled with vitamin A and cholesterol, the IGF2R-specific peptide coupled nanocomplex showed the highest uptake in the liver and lowest uptake in the lung and kidney of the rats with CCl4-induced liver fibrosis.
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Affiliation(s)
- Zhen Zhao
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Yuanke Li
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Akshay Jain
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Zhijin Chen
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Hao Liu
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Wei Jin
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Kun Cheng
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
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Upregulation of the actin cytoskeleton via myocardin leads to increased expression of type 1 collagen. J Transl Med 2017; 97:1412-1426. [PMID: 29035375 PMCID: PMC6437559 DOI: 10.1038/labinvest.2017.96] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 06/19/2017] [Accepted: 07/05/2017] [Indexed: 12/28/2022] Open
Abstract
Liver fibrosis, a model wound healing system, is characterized by excessive deposition of extracellular matrix (ECM) in the liver. Although many fibrogenic cell types may express ECM, the hepatic stellate cell (HSC) is currently considered to be the major effector. HSCs transform into myofibroblast-like cells, also known as hepatic myofibroblasts in a process known as activation; this process is characterized in particular by de novo expression of smooth muscle alpha actin (SM α-actin) and type 1 collagen. The family of actins, which form the cell's cytoskeleton, are essential in many cellular processes. β-actin and cytoplasmic γ-actin (γ-actin) are ubiquitously expressed, whereas SM α-actin defines smooth muscle cell and myofibroblast phenotypes. Thus, SM α-actin is tightly associated with multiple functional properties. However, the regulatory mechanisms by which actin isoforms might regulate type 1 collagen remain unclear. In primary HSCs from normal and fibrotic rat liver, we demonstrate that myocardin, a canonical SRF cofactor, is upregulated in hepatic myofibroblasts and differentially regulates SM α-actin, γ-actin, and β-actins through activation of an ATTA box in the SM α-actin and a CCAAT box in γ-actin and β-actin promoters, respectively; moreover, myocardin differentially activated serum response factor (SRF) in CArG boxes of actin promoters. In addition, myocardin-stimulated Smad2 phosphorylation and RhoA expression, leading to increased expression of type 1 collagen in an actin cytoskeleton-dependent manner. Myocardin also directly enhanced SRF expression and stimulated collagen 1α1 and 1α2 promoter activities. In addition, overexpression of myocardin in vivo during carbon tetrachloride-induced liver injury led to increased HSC activation and fibrogenesis. In summary, our data suggest that myocardin plays a critical role in actin cytoskeletal dynamics during HSC activation, in turn, specifically regulating type I collagen expression in hepatic myofibroblasts.
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39
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Zhan W, Liao X, Xie RJ, Tian T, Yu L, Liu X, Liu J, Li P, Han B, Yang T, Zhang B, Cai LJ, Li R, Yang Q. The effects of blueberry anthocyanins on histone acetylation in rat liver fibrosis. Oncotarget 2017; 8:96761-96773. [PMID: 29228569 PMCID: PMC5722521 DOI: 10.18632/oncotarget.17842] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 04/17/2017] [Indexed: 12/26/2022] Open
Abstract
To determine the effects ofanthocyanins from blueberries on hepatic stellate cell (HSCs-T6) and on histone acetylation during liver fibrosis induced by CCl4 in rats. Fifty male SD rats weighing 180 ± 20g were randomly placed into a control group, a hepatic fibrosis group, a blueberry treatment group, a blueberry intervention group, and a natural recovery group. After the rats were sacrificed, the livers and the liver indexes were measured, and the pathological changes were observed by HE staining and Masson staining. The blood was analyzed for the four indexes of liver fibrosis and liver function; nucleoprotein from liver tissues and karyoplasm were isolated to determine the expression of acH3K9, acH3K14, and acH3K18 by Western blotting. Compared with the lethal rate of the control group, the median lethal rate of HSCs-T6 cells treated with a the 50μmol/L concentration was 66.94% (P < 0.05). The protein expression on α-SMA, type I collagen, TIMP1 significantly decreased (P < 0.05) following treatment with 50 ug/ml of anthocyanin for 36 h; moreover, the expression of acH3K9, acH3K14 and acH3K18 modification were up-regulated (P < 0.05). Furthermore, compared with the liver in the model group, the liver in the intervention group showed the most obvious improvement (P < 0.01), and its karyoplasm had increased expression of acH3K9, acH3K14 and acH3K18 (P<0.01). Regulating histone acetylation could improve liver function and liver fibrosis indexes in rats with hepatic fibrosis. The mechanism might be related to certain genes that promote apoptosis, so as to inhibit the effect of anti hepatic fibrosis.
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Affiliation(s)
- Wei Zhan
- General Surgery of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Xin Liao
- Imaging Department of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Ru-Jia Xie
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Tian Tian
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Lei Yu
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Xing Liu
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Jing Liu
- Imaging Department of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Po Li
- Department of Pathology of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Bing Han
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Ting Yang
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Bei Zhang
- Ultrasonic Center of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Li-Jun Cai
- Department of Neurology of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Rui Li
- Department of Neurology of The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Qin Yang
- Department of Physiology of The Guizhou Medical University, Guiyang 550004, Guizhou Province, China
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40
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Zhou CL, Kong DL, Liu JF, Lu ZK, Guo HF, Wang W, Qiu JF, Liu XJ, Wang Y. MHC II -, but not MHC II +, hepatic Stellate cells contribute to liver fibrosis of mice in infection with Schistosoma japonicum. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1848-1857. [PMID: 28483578 DOI: 10.1016/j.bbadis.2017.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 04/12/2017] [Accepted: 05/04/2017] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cells (HSCs) are considered as the main effector cells in vitamin A metabolism and liver fibrosis, as well as in hepatic immune regulation. Recently, researches have revealed that HSCs have plasticity and heterogeneity, which depend on their lobular location and whether liver is normal or injured. This research aimed to explore the biological characteristics and heterogeneity of HSCs in mice with Schistosoma japonicum (S. japonicum) infection, and determine the subpopulation of HSCs in pathogenesis of hepatic fibrosis caused by S. japonicum infection. Results revealed that HSCs significantly increased the expressions of MHC II and fibrogenic genes after S. japonicum infection, and could be classified into MHC II+ HSCs and MHC II- HSCs subsets. Both two HSCs populations suppressed the proliferation of activated CD4+T cells, whereas only MHC II- HSCs displayed a myofibroblast-like phenotype. In response to IFN-γ, HSCs up-regulated the expressions of MHC II and CIITA, while down-regulated the expression of fibrogenic gene Col1. In addition, praziquantel treatment decreased the expressions of fibrogenic genes in MHC II- HSCs. These results confirmed that HSCs from S. japonicum-infected mice have heterogeneity. The MHC II- α-SMA+ HSCs were major subsets of HSCs contributing to liver fibrosis and could be considered as a potential target of praziquantel anti-fibrosis treatment.
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Affiliation(s)
- Chun-Lei Zhou
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - De-Long Kong
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Jin-Feng Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Zhong-Kui Lu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Hong-Fei Guo
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Wei Wang
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Jing-Fan Qiu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Xin-Jian Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Yong Wang
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China.
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Dykstra JA, Facile T, Patrick RJ, Francis KR, Milanovich S, Weimer JM, Kota DJ. Concise Review: Fat and Furious: Harnessing the Full Potential of Adipose-Derived Stromal Vascular Fraction. Stem Cells Transl Med 2017; 6:1096-1108. [PMID: 28186685 PMCID: PMC5388064 DOI: 10.1002/sctm.16-0337] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/14/2016] [Accepted: 11/07/2016] [Indexed: 12/28/2022] Open
Abstract
Due to their capacity to self-renew, proliferate and generate multi-lineage cells, adult-derived stem cells offer great potential for use in regenerative therapies to stop and/or reverse degenerative diseases such as diabetes, heart failure, Alzheimer's disease and others. However, these subsets of cells can be isolated from different niches, each with differing potential for therapeutic applications. The stromal vascular fraction (SVF), a stem cell enriched and adipose-derived cell population, has garnered interest as a therapeutic in regenerative medicine due to its ability to secrete paracrine factors that accelerate endogenous repair, ease of accessibility and lack of identified major adverse effects. Thus, one can easily understand the rush to employ adipose-derived SVF to treat human disease. Perhaps faster than any other cell preparation, SVF is making its way to clinics worldwide, while critical preclinical research needed to establish SVF safety, efficacy and optimal, standardized clinical procedures are underway. Here, we will provide an overview of the current knowledge driving this phenomenon, its regulatory issues and existing studies, and propose potential unmapped applications. Stem Cells Translational Medicine 2017;6:1096-1108.
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Affiliation(s)
- Jordan A. Dykstra
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
| | - Tiffany Facile
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
| | - Ryan J. Patrick
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
| | - Kevin R. Francis
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
- Department of PediatricsThe University of South Dakota Sanford School of MedicineVermillion, South DakotaUSA
| | - Samuel Milanovich
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
- Department of PediatricsThe University of South Dakota Sanford School of MedicineVermillion, South DakotaUSA
| | - Jill M. Weimer
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
- Department of PediatricsThe University of South Dakota Sanford School of MedicineVermillion, South DakotaUSA
| | - Daniel J. Kota
- Children's Health Research Center, Sanford Research, Sioux FallsSouth DakotaUSA
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The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
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43
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Kochan K, Kus E, Filipek A, Szafrańska K, Chlopicki S, Baranska M. Label-free spectroscopic characterization of live liver sinusoidal endothelial cells (LSECs) isolated from the murine liver. Analyst 2017; 142:1308-1319. [DOI: 10.1039/c6an02063a] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Imaging with the use of Raman spectroscopy enables the characterization and distinction of live cells that were freshly isolated from murine livers.
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Affiliation(s)
- K. Kochan
- Centre for Biospectroscopy and School of Chemistry
- Monash University
- Clayton
- Australia
- Jagiellonian Centre for Experimental Therapeutics (JCET)
| | - E. Kus
- Jagiellonian Centre for Experimental Therapeutics (JCET)
- Jagiellonian University
- Krakow
- Poland
| | - A. Filipek
- Jagiellonian Centre for Experimental Therapeutics (JCET)
- Jagiellonian University
- Krakow
- Poland
- Faculty of Chemistry
| | - K. Szafrańska
- Jagiellonian Centre for Experimental Therapeutics (JCET)
- Jagiellonian University
- Krakow
- Poland
| | - S. Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET)
- Jagiellonian University
- Krakow
- Poland
- Chair of Pharmacology
| | - M. Baranska
- Jagiellonian Centre for Experimental Therapeutics (JCET)
- Jagiellonian University
- Krakow
- Poland
- Faculty of Chemistry
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Pericytes: The Role of Multipotent Stem Cells in Vascular Maintenance and Regenerative Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1079:69-86. [PMID: 29282647 DOI: 10.1007/5584_2017_138] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Blood vessels consist of an inner endothelial cell layer lining the vessel wall and perivascular pericytes, also known as mural cells, which envelop the vascular tube surface. Pericytes have recently been recognized for their central role in blood vessel formation. Pericytes are multipotent cells that are heterogeneous in their origin, function, morphology and surface markers. Similar to other types of stem cells, pericytes act as a repair system in response to injury by maintaining the structural integrity of blood vessels. Several studies have shown that blood vessels lacking pericytes become hyperdilated and haemorrhagic, leading to vascular complications ranging from diabetic retinopathy to embryonic death. The role of pericytes is not restricted to the formation and development of the vasculature: they have been shown to possess stem cell-like characteristics and may differentiate into cell types from different lineages. Recent discoveries regarding the contribution of pericytes to tumour metastasis and the maintenance of tumour vascular supply and angiogenesis have led researchers to propose targeting pericytes with anti-angiogenic therapies. In this review, we will examine the different physiological roles of pericytes, their differentiation potential, and how they interact with surrounding cells to ensure the integrity of blood vessel formation and maintenance.
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Cai SP, Cheng XY, Chen PJ, Pan XY, Xu T, Huang C, Meng XM, Li J. Transmembrane protein 88 attenuates liver fibrosis by promoting apoptosis and reversion of activated hepatic stellate cells. Mol Immunol 2016; 80:58-67. [DOI: 10.1016/j.molimm.2016.11.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/14/2016] [Accepted: 11/01/2016] [Indexed: 01/27/2023]
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Human hepatic stellate cells and inflammation: A regulated cytokine network balance. Cytokine 2016; 90:130-134. [PMID: 27865205 DOI: 10.1016/j.cyto.2016.11.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 10/21/2016] [Accepted: 11/11/2016] [Indexed: 12/25/2022]
Abstract
AIM Uncertainty about the safety of cell therapy continues to be a major challenge to the medical community. Inflammation and the associated immune response represent a major safety concern hampering the development of long-term clinical therapy. In vivo interactions between the cell graft and the host immune system are mediated by functional environmental sensors and stressors that play significant roles in the immunobiology of the graft. Within this context, human liver stellate cells (HSC) demonstrated marked immunological plasticity that has main importance for future liver cell therapy application. METHODS By using qPCR technique, we established the cytokine gene expression profile of HSCs and investigated the effect of an inflammatory environment on the immunobiology of HSCs. RESULTS AND DISCUSSION HSCs present a specific immunological profile as demonstrated by the expression and modulation of major immunological cytokines. Under constitutive conditions, the cytokine pattern expressed by HSCs was characterized by the high expression of IL-6. Inflammation critically modulated the expression of major immunological cytokines. As evidenced by the induction of the expression of several inflammatory genes, HSCs acquire a pro-inflammatory profile that ultimately might have critical implications for their immunological shape. CONCLUSION These new observations have to be taken into account in any future liver cell therapy application based on the use of HSCs.
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Fernandez MC, Rayes R, Ham B, Wang N, Bourdeau F, Milette S, Lllemann M, Bird N, Majeed A, Xu J, Kisselova T, Brodt P. The type I insulin-like growth factor regulates the liver stromal response to metastatic colon carcinoma cells. Oncotarget 2016; 8:52281-52293. [PMID: 28881729 PMCID: PMC5581028 DOI: 10.18632/oncotarget.12595] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 09/20/2016] [Indexed: 12/21/2022] Open
Abstract
Hepatic stellate cells (HSC) play a major role in initiating the liver fibrogenic (wounding) response of the liver and can also orchestrate a pro-metastatic microenvironment in the liver in response to invading cancer cells. Here we explored the role of the hepatic stellate cells in colon carcinoma liver metastasis with emphasis on the contribution of the insulin-like growth factor (IGF) axis to their activation and function. To this end, we used mice with a Tamoxifen inducible liver IGF-I deficiency. We found that in mice with a sustained IGF-I deficiency, recruitment and activation of HSC into tumor-infiltrated areas of the liver were markedly diminished, resulting in decreased collagen deposition and reduced tumor expansion. In addition, IGF-I could rescue HSC from apoptosis induced by pro-inflammatory factors such as TNF-α known to be upregulated in the early stages of liver metastasis. Moreover, in surgical specimens, activated IGF-IR was observed on HSC-like stromal cells surrounding colorectal carcinoma liver metastases. Finally, IGF-targeting in vivo using an IGF-Trap caused a significant reduction in HSC activation in response to metastatic colon cancer cells. Therefore, our data identify IGF as a survival factor for HSC and thereby, a promoter of the pro-metastatic microenvironment in the liver. IGF-targeting could therefore provide a strategy for curtailing the pro-metastatic host response of the liver during the early stages of liver metastasis.
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Affiliation(s)
- Maria Celia Fernandez
- Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Roni Rayes
- Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Boram Ham
- Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Ni Wang
- Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - France Bourdeau
- Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Simon Milette
- Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Martin Lllemann
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nigel Bird
- Liver Research Group, Clinical Sciences, University of Sheffield, Yorkshire, UK
| | - Ali Majeed
- Department of Oncology, School of Medicine, Sheffield Teaching Hospitals, Yorkshire, UK
| | - Jun Xu
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
| | - Tatiana Kisselova
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
| | - Pnina Brodt
- Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada.,Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada.,Oncology, McGill University and the McGill University Health Centre, Montréal, QC, Canada
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Long live the liver: immunohistochemical and stereological study of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells of male and female rats throughout ageing. Cell Tissue Res 2016; 366:639-649. [DOI: 10.1007/s00441-016-2490-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 08/03/2016] [Indexed: 01/23/2023]
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Abstract
Cellular crosstalk is a process through which a message is transmitted within an individual cell (intracellular crosstalk) or between different cells (intercellular crosstalk). Intercellular crosstalk within the liver microenvironment is critical for the maintenance of normal hepatic functions and for cells survival. Hepatic cells are closely connected to each other, work in synergy, and produce molecules that modulate their differentiation and activity. This review summarises the current knowledge regarding paracrine communication networks in parenchymal and non-parenchymal cells in liver fibrosis due to chronic injury, and regeneration after partial hepatectomy.
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He L, Gubbins J, Peng Z, Medina V, Fei F, Asahina K, Wang J, Kahn M, Rountree CB, Stiles BL. Activation of hepatic stellate cell in Pten null liver injury model. FIBROGENESIS & TISSUE REPAIR 2016; 9:8. [PMID: 27307790 PMCID: PMC4908727 DOI: 10.1186/s13069-016-0045-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/31/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND Hepatic fibrosis is a prominent pathological feature associated with chronic liver disease including non-alcoholic hepatosteatosis (NASH), and a precursor for liver cancer development. We previously reported that PTEN loss in the liver, which leads to hyperactivated liver insulin signaling results in NASH development. Here we used the same mouse model to study the progression from steatosis to fibrosis. RESULTS The Pten null livers develop progressive liver fibrosis as indicated by Sirius Red staining and increased expression of collagen I, Timp 1, SMAα, and p75NTR. Consistently, hepatic stellate cells (HSCs) isolated from Pten null livers are readily activated when compared with that from mice with intact PTEN. Deletion of AKT2, the downstream target of PTEN signal, blocked NASH development, and alleviated fibrosis. HSCs from the Pten/Akt2 double null mice are quiescent like those isolated from the control livers. Our analysis shows that the activation of HSCs does not depend on the intrinsic signals regulated by PI3K/AKT, the target of PTEN, but does depend on steatosis and injury to the liver. During the progression of liver fibrosis in the Pten null model, Wnt ligands and signaling receptor are induced, concurrent with the reduction of sFRP5, a Wnt antagonist. We showed that treatment of HSCs with Wnt receptor antagonist blocks the observed morphological changes when HSCs undergo activation in culture. This signal appears to be mediated by β-catenin, as manipulating β-catenin signaling alters marker gene expressions of HSC activation. CONCLUSIONS Wnt/β-catenin activation serves as an important mediator for fibrosis development resulting from NASH using a mouse model where NASH is mimicked by PTEN loss.
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Affiliation(s)
- Lina He
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA
| | | | - Zhechu Peng
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA
| | - Vivian Medina
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA
| | - Fan Fei
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA
| | - Kinji Asahina
- Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
| | - Jiaohong Wang
- Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
| | - Michael Kahn
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA ; Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
| | - Carl B Rountree
- Department of Pediatrics and Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, H085, Hershey, PA 17033 USA
| | - Bangyan L Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA ; Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA ; Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy PSC402, 1985 Zonal Ave, Los Angeles, CA 90089 USA
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