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Sande-Melon M, Bergemann D, Fernández-Lajarín M, González-Rosa JM, Cox AG. Development of a hepatic cryoinjury model to study liver regeneration. Development 2024; 151:dev203124. [PMID: 38975841 PMCID: PMC11318111 DOI: 10.1242/dev.203124] [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: 05/29/2024] [Accepted: 06/20/2024] [Indexed: 07/09/2024]
Abstract
The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. After this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma within an individual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration.
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Affiliation(s)
- Marcos Sande-Melon
- Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3000, Australia
| | - David Bergemann
- Cardiovascular Research Centre, Massachusetts General Hospital Research Institute, Charlestown Navy Yard Campus, 149, 13th Street, MA 02129, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - Miriam Fernández-Lajarín
- Cardiovascular Research Centre, Massachusetts General Hospital Research Institute, Charlestown Navy Yard Campus, 149, 13th Street, MA 02129, USA
- Harvard Medical School, Boston, MA 02115, USA
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA 02467, USA
| | - Juan Manuel González-Rosa
- Cardiovascular Research Centre, Massachusetts General Hospital Research Institute, Charlestown Navy Yard Campus, 149, 13th Street, MA 02129, USA
- Harvard Medical School, Boston, MA 02115, USA
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA 02467, USA
| | - Andrew G. Cox
- Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3000, Australia
- Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria 3000, Australia
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2
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Chandrasegaran S, Sluka JP, Shanley D. Modelling the spatiotemporal dynamics of senescent cells in wound healing, chronic wounds, and fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.04.602041. [PMID: 39026713 PMCID: PMC11257496 DOI: 10.1101/2024.07.04.602041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Cellular senescence is known to drive age-related pathology through the senescence-associated secretory phenotype (SASP). However, it also plays important physiological roles such as cancer suppression, embryogenesis and wound healing. Wound healing is a tightly regulated process which when disrupted results in conditions such as fibrosis and chronic wounds. Senescent cells appear during the proliferation phase of the healing process where the SASP is involved in maintaining tissue homeostasis after damage. Interestingly, SASP composition and functionality was recently found to be temporally regulated, with distinct SASP profiles involved: a fibrogenic, followed by a fibrolytic SASP, which could have important implications for the role of senescent cells in wound healing. Given the number of factors at play a full understanding requires addressing the multiple levels of complexity, pertaining to the various cell behaviours, individually followed by investigating the interactions and influence each of these elements have on each other and the system as a whole. Here, a systems biology approach was adopted whereby a multi-scale model of wound healing that includes the dynamics of senescent cell behaviour and corresponding SASP composition within the wound microenvironment was developed. The model was built using the software CompuCell3D, which is based on a Cellular Potts modelling framework. We used an existing body of data on healthy wound healing to calibrate the model and validation was done on known disease conditions. The model provides understanding of the spatiotemporal dynamics of different senescent cell phenotypes and the roles they play within the wound healing process. The model also shows how an overall disruption of tissue-level coordination due to age-related changes results in different disease states including fibrosis and chronic wounds. Further specific data to increase model confidence could be used to explore senolytic treatments in wound disorders.
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Affiliation(s)
- Sharmilla Chandrasegaran
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - James P Sluka
- Department of Intelligent Systems Engineering and Biocomplexity Institute, Indiana University Bloomington, Bloomington, IN, USA
| | - Daryl Shanley
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
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3
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Sande-Melon M, Bergemann D, Fernández-Lajarín M, González-Rosa JM, Cox AG. Development of a hepatic cryoinjury model to study liver regeneration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.24.550437. [PMID: 38948752 PMCID: PMC11212901 DOI: 10.1101/2023.07.24.550437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. Following this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma with an individual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration.
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Affiliation(s)
- Marcos Sande-Melon
- Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, 3000, Australia
| | - David Bergemann
- Cardiovascular Research Centre, Massachusetts General Hospital Research Institute, Charlestown Navy Yard Campus, 149, 13 Street, 02129 MA, USA
- Harvard Medical School
| | - Miriam Fernández-Lajarín
- Cardiovascular Research Centre, Massachusetts General Hospital Research Institute, Charlestown Navy Yard Campus, 149, 13 Street, 02129 MA, USA
- Harvard Medical School
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA 02467
| | - Juan Manuel González-Rosa
- Cardiovascular Research Centre, Massachusetts General Hospital Research Institute, Charlestown Navy Yard Campus, 149, 13 Street, 02129 MA, USA
- Harvard Medical School
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA 02467
| | - Andrew G. Cox
- Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, 3000, Australia
- Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, 3000, Australia
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4
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Abouelezz HM, Shehatou GS, Shebl AM, Salem HA. A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling. Heliyon 2023; 9:e14256. [PMID: 36938469 PMCID: PMC10015255 DOI: 10.1016/j.heliyon.2023.e14256] [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: 07/29/2022] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/07/2023] Open
Abstract
This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-β1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-β1, and TIMP-1.
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Affiliation(s)
- Hadeer M. Abouelezz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Corresponding author.
| | - George S.G. Shehatou
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Egypt
| | - Abdelhadi M. Shebl
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem A. Salem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Fleming Martinez AK, Döppler HR, Bastea LI, Edenfield BH, Liou GY, Storz P. Ym1 + macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer. iScience 2022; 25:104327. [PMID: 35602933 PMCID: PMC9118688 DOI: 10.1016/j.isci.2022.104327] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/04/2022] [Accepted: 04/26/2022] [Indexed: 01/05/2023] Open
Abstract
Desmoplasia around pancreatic lesions is a barrier for immune cells and a hallmark of developing and established pancreatic cancer. However, the contribution of the innate immune system to this process is ill-defined. Using the KC mouse model and primary cells in vitro, we show that alternatively activated macrophages (AAM) crosstalk with pancreatic lesion cells and pancreatic stellate cells (PSCs) to mediate fibrosis and progression of lesions. TGFβ1 secreted by AAM not only drives activation of quiescent PSCs but also in activated PSCs upregulates expression of TIMP1, a factor previously shown as crucial in fibrosis. Once activated, PSCs auto-stimulate proliferation via CXCL12. Furthermore, we found that TIMP1/CD63 signaling mediates PanIN lesion growth and TGFβ1 contributes to a cadherin switch and drives structural collapse of lesions, indicating a potential progression step. Taken together, our data indicate TGFβ1 produced by Ym1+ AAM as a major driver of processes that initiate the development of pancreatic cancer.
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Affiliation(s)
| | - Heike R. Döppler
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Ligia I. Bastea
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Brandy H. Edenfield
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Geou-Yarh Liou
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA,Department of Biological Sciences, Center for Cancer Research & Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA,Corresponding author
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Rodríguez-Rodríguez DR, Lozano-Sepulveda SA, Delgado-Montemayor C, Waksman N, Cordero-Perez P, Rivas-Estilla AM. Turnera diffusa extract attenuates profibrotic, extracellular matrix and mitochondrial markers in activated human hepatic stellate cells (HSC). Ann Hepatol 2021; 22:100281. [PMID: 33220464 DOI: 10.1016/j.aohep.2020.10.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/21/2020] [Accepted: 10/23/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Hepatic fibrosis is characterized by the accumulation of extracellular matrix which includes the accumulation of α-smooth muscle actin (α-SMA), collagen type I (COL1α1), as well as remodeling induced by metalloproteinases and tissue inhibitor of metalloproteinase (TIMPs), where hepatic stellate cells (HSCs) play a central role. In addition, the transcription factor SNAI1 (which participates in epithelial-mesenchymal transition, EMT) and mitofusin 2 (MFN2, a mitochondrial marker) plays an important role in chronic liver disease. Turnera diffusa (TD), a Mexican endemic plant, has been shown to possess antioxidant and hepatoprotective activity in vitro. We treated human HSC (LX2 cells) with a methanolic extract of Turnera diffusa (METD) to evaluate the mechanism involved in its hepatoprotective effect measured as fibrosis modulation, EMT, and mitochondrial markers. MATERIALS AND METHODS HSC LX-2 cells were treated with METD (100 and 200ng/mL) alone or combined with TGF-β (10ng/mL) at different time points (24, 48, and 72h). α-SMA, COL1α1, MMP2, TIMP1, SNAI1, and MFN2 mRNAs and protein levels were determined by real-time quantitative PCR and Western Blot analysis. RESULTS We found that METD decreases COL1α1-mRNA, α-SMA, and TIMP1 protein expression in LX2 cells treated with and TGF-β. This treatment also decreases MFN2 and TIMP1 protein expression and induces overexpression of MMP2-mRNA. CONCLUSIONS Our results suggest that a methanolic extract of Turnera diffusa is associated with an antifibrotic effect by decreasing profibrotic and mitochondrial markers together with the possible induction of apoptosis through SNAI1 expression in activated HSC cells.
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Affiliation(s)
- Diana Raquel Rodríguez-Rodríguez
- Universidad Autonoma de Nuevo Leon, Deptartment of Biochemistry and Molecular Medicine, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Sonia Amelia Lozano-Sepulveda
- Universidad Autonoma de Nuevo Leon, Deptartment of Biochemistry and Molecular Medicine, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Cecilia Delgado-Montemayor
- Universidad Autonoma de Nuevo Leon, Department of Analytical Chemistry, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Noemí Waksman
- Universidad Autonoma de Nuevo Leon, Department of Analytical Chemistry, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Paula Cordero-Perez
- Universidad Autonoma de Nuevo Leon, Liver Unit, Department of Internal Medicine, University Hospital "Dr. José E. González", Monterrey, Nuevo León, Mexico
| | - Ana María Rivas-Estilla
- Universidad Autonoma de Nuevo Leon, Deptartment of Biochemistry and Molecular Medicine, School of Medicine, Monterrey, Nuevo León, Mexico.
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7
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An GH, Lee J, Jin X, Chung J, Kim JC, Park JH, Kim M, Han C, Kim JH, Woo DH. Truncated Milk Fat Globule-EGF-like Factor 8 Ameliorates Liver Fibrosis via Inhibition of Integrin-TGFβ Receptor Interaction. Biomedicines 2021; 9:biomedicines9111529. [PMID: 34829758 PMCID: PMC8615163 DOI: 10.3390/biomedicines9111529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/27/2021] [Accepted: 10/21/2021] [Indexed: 11/16/2022] Open
Abstract
Milk fat globule-EGF factor 8 (MFG-E8) protein is known as an immunomodulator in various diseases, and we previously demonstrated the anti-fibrotic role of MFG-E8 in liver disease. Here, we present a truncated form of MFG-E8 that provides an advanced therapeutic benefit in treating liver fibrosis. The enhanced therapeutic potential of the modified MFG-E8 was demonstrated in various liver fibrosis animal models, and the efficacy was further confirmed in human hepatic stellate cells and a liver spheroid model. In the subsequent analysis, we found that the modified MFG-E8 more efficiently suppressed transforming growth factor β (TGF-β) signaling than the original form of MFG-E8, and it deactivated the proliferation of hepatic stellate cells in the liver disease environment through interfering with the interactions between integrins (αvβ3 & αvβ5) and TGF-βRI. Furthermore, the protein preferentially delivered in the liver after administration, and the safety profiles of the protein were demonstrated in male and female rat models. Therefore, in conclusion, this modified MFG-E8 provides a promising new therapeutic strategy for treating fibrotic diseases.
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Affiliation(s)
- Geun Ho An
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
| | - Jaehun Lee
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Xiong Jin
- School of Pharmacy, Henan University, Jin Ming Ave, Kaifeng 475004, China;
| | - Jinwoo Chung
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Joon-Chul Kim
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Jung-Hyuck Park
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Minkyung Kim
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Choongseong Han
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
- Correspondence: (J.-H.K.); (D.-H.W.)
| | - Dong-Hun Woo
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
- Correspondence: (J.-H.K.); (D.-H.W.)
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8
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Campana L, Esser H, Huch M, Forbes S. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol 2021; 22:608-624. [PMID: 34079104 DOI: 10.1038/s41580-021-00373-7] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2021] [Indexed: 02/05/2023]
Abstract
Liver regeneration is a complex process involving the crosstalk of multiple cell types, including hepatocytes, hepatic stellate cells, endothelial cells and inflammatory cells. The healthy liver is mitotically quiescent, but following toxic damage or resection the cells can rapidly enter the cell cycle to restore liver mass and function. During this process of regeneration, epithelial and non-parenchymal cells respond in a tightly coordinated fashion. Recent studies have described the interaction between inflammatory cells and a number of other cell types in the liver. In particular, macrophages can support biliary regeneration, contribute to fibrosis remodelling by repressing hepatic stellate cell activation and improve liver regeneration by scavenging dead or dying cells in situ. In this Review, we describe the mechanisms of tissue repair following damage, highlighting the close relationship between inflammation and liver regeneration, and discuss how recent findings can help design novel therapeutic approaches.
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Affiliation(s)
- Lara Campana
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | - Hannah Esser
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | - Meritxell Huch
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Stuart Forbes
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
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Henderson J, O'Reilly S. The emerging role of metabolism in fibrosis. Trends Endocrinol Metab 2021; 32:639-653. [PMID: 34024695 DOI: 10.1016/j.tem.2021.05.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/04/2021] [Indexed: 12/21/2022]
Abstract
The metabolic shift that cancer cells undergo towards aerobic glycolysis was identified as a defining feature in tumours almost 100 years ago; however, it has only recently become apparent that similar metabolic reprogramming is a key feature in other diseases - with fibrosis now entering the fray. In this perspective, an overview of the recent evidence implicating increased glycolysis and glutaminolysis as mediators of fibrosis is presented, with a particular emphasis on the novel therapeutic possibilities this introduces. Furthermore, the impact that metabolic reprogramming has on redox homeostasis is discussed, providing an insight into how this often-overlooked mechanism may drive the pathogenesis.
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Affiliation(s)
- John Henderson
- Department of Applied Sciences, Northumbria University, Ellison Place, Newcastle upon Tyne NE1 8ST, UK
| | - Steven O'Reilly
- Biosciences, Durham University, South Road, Durham DH1 3LE, UK. steven.o'
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10
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Acharya P, Chouhan K, Weiskirchen S, Weiskirchen R. Cellular Mechanisms of Liver Fibrosis. Front Pharmacol 2021; 12:671640. [PMID: 34025430 PMCID: PMC8134740 DOI: 10.3389/fphar.2021.671640] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
The liver is a central organ in the human body, coordinating several key metabolic roles. The structure of the liver which consists of the distinctive arrangement of hepatocytes, hepatic sinusoids, the hepatic artery, portal vein and the central vein, is critical for its function. Due to its unique position in the human body, the liver interacts with components of circulation targeted for the rest of the body and in the process, it is exposed to a vast array of external agents such as dietary metabolites and compounds absorbed through the intestine, including alcohol and drugs, as well as pathogens. Some of these agents may result in injury to the cellular components of liver leading to the activation of the natural wound healing response of the body or fibrogenesis. Long-term injury to liver cells and consistent activation of the fibrogenic response can lead to liver fibrosis such as that seen in chronic alcoholics or clinically obese individuals. Unidentified fibrosis can evolve into more severe consequences over a period of time such as cirrhosis and hepatocellular carcinoma. It is well recognized now that in addition to external agents, genetic predisposition also plays a role in the development of liver fibrosis. An improved understanding of the cellular pathways of fibrosis can illuminate our understanding of this process, and uncover potential therapeutic targets. Here we summarized recent aspects in the understanding of relevant pathways, cellular and molecular drivers of hepatic fibrosis and discuss how this knowledge impact the therapy of respective disease.
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Affiliation(s)
- Pragyan Acharya
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Komal Chouhan
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
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11
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Rockey DC, Friedman SL. Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside. Gastroenterology 2021; 160:1502-1520.e1. [PMID: 33529675 PMCID: PMC8601597 DOI: 10.1053/j.gastro.2020.09.065] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/01/2020] [Accepted: 09/06/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection and its complications have been the major cause of cirrhosis and its complications for several decades in the Western world. Until recently, treatment for HCV with interferon-based regimens was associated with moderate success but was difficult to tolerate. More recently, however, an arsenal of novel and highly effective direct-acting antiviral (DAA) drugs has transformed the landscape by curing HCV in a broad range of patients, including those with established advanced fibrosis, cirrhosis, comorbidities, and even those with complications of cirrhosis. Fibrosis is a dynamic process comprising both extracellular matrix deposition, as well as its degradation. With almost universal sustained virologic response (SVR) (ie, elimination of HCV), it is timely to explore whether HCV eradication can reverse fibrosis and cirrhosis. Indeed, fibrosis in several types of liver disease is reversible, including HCV. However, we do not know with certainty in whom fibrosis regression can be expected after HCV elimination, how quickly it occurs, and whether antifibrotic therapies will be indicated in those with persistent cirrhosis. This review summarizes the evidence for reversibility of fibrosis and cirrhosis after HCV eradication, its impact on clinical outcomes, and therapeutic prospects for directly promoting fibrosis regression in patients whose fibrosis persists after SVR.
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Affiliation(s)
- Don C Rockey
- The Medical University of South Carolina, Charleston, South Carolina.
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
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12
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Sharawy MH, El-Awady MS, Makled MN. Protective effects of paclitaxel on thioacetamide-induced liver fibrosis in a rat model. J Biochem Mol Toxicol 2021; 35:e22745. [PMID: 33749060 DOI: 10.1002/jbt.22745] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 01/13/2021] [Accepted: 02/10/2021] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a public health burden that is highly associated with morbidity and mortality. Therefore, this study aims to explore the anti-fibrotic effects of low dose of paclitaxel (PTX) against thioacetamide (TAA)-induced liver fibrosis in rats and the possible mechanisms involved. TAA was administered at a dose of 200 mg/kg twice weekly for 6 weeks in rats to induce liver fibrosis similar to that in humans. Liver dysfunction was shown by increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase, along with histopathological changes. Liver fibrosis was confirmed by Masson's Trichome staining, increased collagen content, and elevated α-smooth muscle actin (α-SMA) protein expression. In addition, TAA induced liver apoptosis as indicated by the increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in liver tissues. This study demonstrated that the administration of PTX (0.3 mg/kg/i.p.) three times a week for 6 weeks significantly alleviated functional and biochemical changes induced by TAA in addition to improving the liver architecture. PTX attenuated liver fibrosis as reflected by the decreased collagen content and α-SMA protein expression. Additionally, PTX attenuated liver apoptosis as indicated by the decreased TUNEL-positive cells. Moreover, PTX prevented TAA-induced elevation of transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-BB (PDGF-BB), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in liver tissues. These findings suggest that the low dose of PTX prevented TAA-induced liver fibrosis in rats, possibly by inhibiting the expression of TGF-β1 and PDGF-BB and subsequently suppressing the apoptosis and the expression of TIMP-1.
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Affiliation(s)
- Maha H Sharawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohammed S El-Awady
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.,Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
| | - Mirhan N Makled
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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13
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Yuan Y, Naito H, Kitamori K, Hashimoto S, Asano T, Nakajima T. The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension. PLoS One 2020; 15:e0243846. [PMID: 33315911 PMCID: PMC7735612 DOI: 10.1371/journal.pone.0243846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 11/28/2020] [Indexed: 11/18/2022] Open
Abstract
Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
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Affiliation(s)
- Yuan Yuan
- College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan
| | - Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Kazuya Kitamori
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Sayuki Hashimoto
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Tomomi Asano
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Tamie Nakajima
- College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan
- * E-mail:
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14
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Cui Z, Huang N, Liu L, Li X, Li G, Chen Y, Wu Q, Zhang J, Long S, Wang M, Sun F, Shi Y, Pan Q. Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis. Epigenomics 2020; 12:1707-1723. [PMID: 33174480 DOI: 10.2217/epi-2019-0365] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim: To dynamically analyze the differential m6A methylation during the progression and reversal of hepatic fibrosis. Materials & methods: We induced hepatic fibrosis in C57/BL6 mice by intraperitoneal injection of CCl4. The reversal model of hepatic fibrosis was established by stopping drug after continuous injection of CCl4. Dynamic m6A methylation was evaluated using MeRIP-Seq in the progression and reversal of hepatic fibrosis at different stages. Result: During the hepatic fibrosis, differential m6A methylation was mainly enriched in processes associated with oxidative stress and cytochrome metabolism, while differential m6A methylation was mainly enriched in processes associated with immune response and apoptosis in the hepatic fibrosis reversal. Conclusion: m6A methylation plays an important role in the progression and reversal of hepatic fibrosis.
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Affiliation(s)
- Zhongqi Cui
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Nan Huang
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Li Liu
- Department of Clinical Laboratory, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200081, China
| | - Xue Li
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Guohui Li
- Institute of Life Sciences, Jiangsu University, 301# Xuefu Road, Zhenjiang 212013, China
| | - Yan Chen
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Qi Wu
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Jie Zhang
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Shuping Long
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Minyi Wang
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Fenyong Sun
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Yi Shi
- Department of Clinical Laboratory, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200081, China
| | - Qiuhui Pan
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
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15
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Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol 2020; 73:896-905. [PMID: 32376414 DOI: 10.1016/j.jhep.2020.04.037] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step of de novo lipogenesis and regulates fatty acid β-oxidation in hepatocytes. ACC inhibition reduces hepatic fat content and markers of liver injury in patients with NASH; however, the effect of ACC inhibition on liver fibrosis has not been reported. METHODS A direct role for ACC in fibrosis was evaluated by measuring de novo lipogenesis, procollagen production, gene expression, glycolysis, and mitochondrial respiration in hepatic stellate cells (HSCs) in the absence or presence of small molecule inhibitors of ACC. ACC inhibitors were evaluated in rodent models of liver fibrosis induced by diet or the hepatotoxin, diethylnitrosamine. Fibrosis and hepatic steatosis were evaluated by histological and biochemical assessments. RESULTS Inhibition of ACC reduced the activation of TGF-β-stimulated HSCs, as measured by both α-SMA expression and collagen production. ACC inhibition prevented a metabolic switch necessary for induction of glycolysis and oxidative phosphorylation during HSC activation. While the molecular mechanism by which inhibition of de novo lipogenesis blocks glycolysis and oxidative phosphorylation is unknown, we definitively show that HSCs require de novo lipogenesis for activation. Consistent with this direct antifibrotic mechanism in HSCs, ACC inhibition reduced liver fibrosis in a rat choline-deficient, high-fat diet model and in response to chronic diethylnitrosamine-induced liver injury (in the absence of hepatic lipid accumulation). CONCLUSIONS In addition to reducing lipid accumulation in hepatocytes, ACC inhibition also directly impairs the profibrogenic activity of HSCs. Thus, small molecule inhibitors of ACC may lessen fibrosis by reducing lipotoxicity in hepatocytes and by preventing HSC activation, providing a mechanistic rationale for the treatment of patients with advanced liver fibrosis due to NASH. LAY SUMMARY Hepatic fibrosis is the most important predictor of liver-related outcomes in patients with non-alcoholic steatohepatitis (NASH). Small molecule inhibitors of acetyl-CoA carboxylase (ACC) reduce hepatic fat content and markers of liver injury in patients with NASH. Herein, we report that inhibition of ACC and de novo lipogenesis also directly suppress the activation of hepatic stellate cells - the primary cell responsible for generating fibrotic scar in the liver - and thus fibrosis. These data provide further evidence for the use of ACC inhibitors to treat patients with NASH and advanced fibrosis.
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Affiliation(s)
| | | | - Sarani Ghoshal
- Massachusetts General Hospital, Boston, MA, USA; Synlogic Therapeutics, Cambridge, MA, USA
| | | | - Saili Yi
- Gilead Sciences, Foster City, CA, USA
| | | | | | | | | | - Kathy Liu
- Gilead Sciences, Foster City, CA, USA
| | | | - David Newstrom
- Gilead Sciences, Foster City, CA, USA; Advanced Cell Diagnostics (ACD), Newark, CA, USA
| | - Robert Brockett
- Gilead Sciences, Foster City, CA, USA; Visiopharm, Westminster, CO, USA
| | - Igor Mikaelian
- Gilead Sciences, Foster City, CA, USA; 23andMe, San Mateo, CA, USA
| | | | | | | | - Li Li
- Gilead Sciences, Foster City, CA, USA
| | - Bryan C Fuchs
- Massachusetts General Hospital, Boston, MA, USA; Ferring Pharmaceuticals, San Diego, CA, USA
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16
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Mohammed AT, Khalil SR, Mahmoud FA, Elmowalid GA, Ali HA, El-Serehy HA, Abdel-Daim MM. The role of sulpiride in attenuating the cardiac, renal, and immune disruptions in rats receiving clozapine: mRNA expression pattern of the genes encoding Kim-1, TIMP-1, and CYP isoforms. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:25404-25414. [PMID: 32350838 DOI: 10.1007/s11356-020-08914-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/16/2020] [Indexed: 06/11/2023]
Abstract
The present study was aimed to explore the cardio-, immuno-, and nephrotoxic effects of the antipsychotic agent clozapine (CLZ) and the alleviative potency of sulpiride (SPD) on these impairments in rats. For this purpose, 40 male rats were divided into four groups and were orally treated with saline (control), CLZ (0.5 mg/kg bw), SPD (28 mg/kg bw), or a combination of CLZ and SPD (CLZ+SPD), daily for 30 consecutive days. At necropsy, blood samples and specimens from the heart, kidneys, and spleen were collected for biochemical, molecular, and histopathological investigations. The results showed that CLZ administration was associated with significantly lower immune status indices and increased serum levels of pro-inflammatory cytokines, lactate dehydrogenase, malondialdehyde, cardiac, and renal tissues injury markers. Moreover, the mRNA expression levels of Kidney Injury Molecule-1 (Kim-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and cytochrome P450 (CYP) isoforms were markedly upregulated in CLZ-treated rats, compared to the control group. On the other hand, rats treated with SPD alone showed non-significant differences in terms of immune response indices, tissue injury markers, and mRNA expression levels of Kim-1, TIMP-1, and CYP isoforms. Finally, CLZ+SPD co-treatment significantly modulated almost all biochemical indices. Besides, Kim-1, TIMP-1, and CYP2C19 mRNA expression levels were significantly downregulated, while other CYP isoforms showed no modulation, compared with CLZ-treated group. Histopathologically, CLZ-treated rats showed severe lesions in renal, splenic, and cardiac tissues, compared with control rats, which were restored in CLZ+SPD-co-treated rats. Overall, these findings demonstrate that CLZ treatment induces significant cardiac, immune, and nephropathic alterations, which were reduced with CLZ+SPD co-treatment.
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Affiliation(s)
- Amany T Mohammed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt
| | - Samah R Khalil
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt.
| | - Fagr A Mahmoud
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt
| | - Gamal A Elmowalid
- Department of Microbiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt
| | - Haytham A Ali
- Department of Biochemistry. Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt
| | - Hamed A El-Serehy
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
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17
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El-Maadawy WH, Hammam OA, Seif el-Din SH, El-Lakkany NM. α-Lipoic acid modulates liver fibrosis: A cross talk between TGF-β1, autophagy, and apoptosis. Hum Exp Toxicol 2019; 39:440-450. [DOI: 10.1177/0960327119891212] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autophagy and apoptosis are important players in the progression of hepatic fibrosis via activation of hepatic stellate cells (HSCs). Despite the recently depicted antifibrotic effects of alpha-lipoic acid (ALA), however, its modulatory effects on HSCs autophagy remain unverified. Our study aimed to elucidate the underlying antifibrotic mechanisms through which ALA mediates HSC autophagy and apoptosis. Liver fibrosis was induced via thioacetamide (TAA) intoxication in rats; TAA-intoxicated rats were treated with either silymarin or ALA. Effect of ALA on biochemical parameters and immunohistopathological examinations was measured and compared to silymarin. ALA restored normal hepatic architecture (S1 vs. S4), liver functions, hepatic glutathione, and transforming growth factor-β1 levels. ALA ameliorated hepatic levels of malondialdehyde, platelet-derived growth factor, tissue inhibitor metalloproteinases-1, hydroxyproline, and expression of alpha-smooth muscle actin. Moreover, ALA significantly reduced messenger RNA expression of LC3-II genes and triggered caspase-3 expression. Interestingly, ALA exhibited superior activities over silymarin regarding suppression of proliferation, activation and autophagy of HSCs, collagen deposition, and induction of HSCs apoptosis. In conclusion, treatment of TAA-intoxicated rats with ALA inhibited autophagy and induced apoptotic clearance of activated HSCs. Accordingly, this study provides mechanistic insights into the possible applicability of ALA in the treatment of hepatic fibrosis.
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Affiliation(s)
- WH El-Maadawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Giza, Egypt
| | - OA Hammam
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt
| | - SH Seif el-Din
- Department of Pharmacology, Theodor Bilharz Research Institute, Giza, Egypt
| | - NM El-Lakkany
- Department of Pharmacology, Theodor Bilharz Research Institute, Giza, Egypt
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18
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Ding X, Cao Y, Xing Y, Ge S, Lin M, Li J. TIMP-1 Mediates Inflammatory and Immune Response to IL-6 in Adult Orbital Xanthogranulomatous Disease. Ocul Immunol Inflamm 2019; 28:288-297. [PMID: 30973282 DOI: 10.1080/09273948.2019.1581227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Purpose: To explore the pathogenesis that TIMP-1 mediated in adult orbital xanthogranulomatous disease (AOXGD), a rare type of non-Langerhans histiocytosis that damages the appearance and quality of life of patientsMethods: We reviewed 22 patients diagnosed with AOXGD based on clinical manifestations and histological analysis, and then investigated the expression of TIMP-1 and IL-6 with q-PCR and IHC in AOXGD tissues and the possible mechanism involved in the induction of TIMP-1 by IL-6.Results: IL-6 and TIMP-1 were significantly increased in AOXGD tissues. IL-6 promoted TIMP-1 production by M1 macrophages by stimulating the phosphorylation of JAK2 and STAT3. Moreover, IL-17 and IFN-γ, the classical markers of Th1 and Th17 cells, were increased in AOXGD.Conclusion: These data implied that the IL6~JAK2/STAT3-TIMP-1 signalling pathway is activated in AOXGD and that adaptive Th1 and Th17 responses are involved in the development of AOXGD.
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Affiliation(s)
- Xia Ding
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.,Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Yuan Cao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.,Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Yue Xing
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.,Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.,Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Ming Lin
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.,Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jin Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.,Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
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19
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Tsay HC, Yuan Q, Balakrishnan A, Kaiser M, Möbus S, Kozdrowska E, Farid M, Tegtmeyer PK, Borst K, Vondran FWR, Kalinke U, Kispert A, Manns MP, Ott M, Sharma AD. Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis. J Hepatol 2019; 70:722-734. [PMID: 30582979 DOI: 10.1016/j.jhep.2018.12.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 12/02/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive. METHODS Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. RESULTS Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis. CONCLUSIONS Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis. LAY SUMMARY Liver fibrosis majorly contributes to mortality resulting from various liver diseases. We discovered a small RNA known as miRNA-221-3p, whose downregulation in hepatocytes results in reduced liver fibrosis. Thus, inhibition of miRNA-221-3p may serve as one of the therapeutic approaches for treatment of liver fibrosis.
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Affiliation(s)
- Hsin-Chieh Tsay
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Qinggong Yuan
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Marina Kaiser
- Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
| | - Selina Möbus
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Emilia Kozdrowska
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marwa Farid
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Human Cytogenetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
| | - Pia-Katharina Tegtmeyer
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Katharina Borst
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Regenerative Medicine and Experimental Surgery (RedMediES), Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Ulrich Kalinke
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Andreas Kispert
- Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Ott
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
| | - Amar Deep Sharma
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
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20
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Dornas W, Glaise D, Bodin A, Sharanek A, Burban A, Le Guillou D, Robert S, Dutertre S, Aninat C, Corlu A, Lagente V. Endotoxin regulates matrix genes increasing reactive oxygen species generation by intercellular communication between palmitate-treated hepatocyte and stellate cell. J Cell Physiol 2018; 234:122-133. [PMID: 30191979 DOI: 10.1002/jcp.27175] [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: 05/16/2018] [Accepted: 07/16/2018] [Indexed: 12/19/2022]
Abstract
Previous studies have shown that gut-derived bacterial endotoxins contribute in the progression of simple steatosis to steatohepatitis, although the mechanism(s) remains inaccurate to date. As hepatic stellate cells (HSC) play a pivotal role in the accumulation of excessive extracellular matrix (ECM), leading to collagen deposition, fibrosis, and perpetuation of inflammatory response, an in vitro model was developed to investigate the crosstalk between HSC and hepatocytes (human hepatoma cell) pretreated with palmitate. Bacterial lipopolysaccharide (LPS) stimulated HSC with phosphorylation of the p38 mitogen-activated protein kinase/NF-κB pathway, while several important pro-inflammatory cytokines were upregulated in the presence of hepatocyte-HSC. Concurrently, fibrosis-related genes were regulated by palmitate and the inflammatory effect of endotoxin where cells were more exposed or sensitive to reactive oxygen species (ROS). This interaction was accompanied by increased expression of the mitochondrial master regulator, proliferator-activated receptor gamma coactivator alpha, and a cytoprotective effect of the agent N-acetylcysteine suppressing ROS production, transforming growth factor-β1, and tissue inhibitor of metalloproteinase-1. In summary, our results demonstrate that pro-inflammatory mediators LPS-induced promote ECM rearrangement in hepatic cells transcriptionally committed to the regulation of genes encoding enzymes for fatty acid metabolism in light of differences that might require an alternative therapeutic approach targeting ROS regulation.
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Affiliation(s)
- Waleska Dornas
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Denise Glaise
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Aude Bodin
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Ahmad Sharanek
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Audrey Burban
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Dounia Le Guillou
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Sacha Robert
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Stephanie Dutertre
- Microscopy Rennes Imaging Center UMS CNRS 3480/US INSERM 018, Biosit, Université de Rennes 1, Rennes, France
| | - Caroline Aninat
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Anne Corlu
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
| | - Vincent Lagente
- Nutrition Metabolisms and Cancer Institute, Institut National de la Santé et de la Recherche Médicale U1241, INRA, Université de Rennes 1, Université Bretagne Loire, Rennes, France
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21
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Petrescu AD, Grant S, Frampton G, McMillin M, Kain J, Kodali M, Shetty AK, DeMorrow S. Gulf war illness-related chemicals increase CD11b/c + monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model. Sci Rep 2018; 8:13147. [PMID: 30177688 PMCID: PMC6120951 DOI: 10.1038/s41598-018-31599-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 08/16/2018] [Indexed: 12/25/2022] Open
Abstract
Gulf War Illness (GWI) is a chronic multisymptom disorder affecting veterans of the 1990-91 Gulf war. GWI was linked with exposure to chemicals including the nerve gas prophylactic drug pyridostigmine-bromide (PB) and pesticides (DEET, permethrin). Veterans with GWI exhibit prolonged, low-level systemic inflammation, though whether this impacts the liver is unknown. While no evidence exists that GWI-related chemicals are hepatotoxic, the prolonged inflammation may alter the liver's response to insults such as cholestatic injury. We assessed the effects of GWI-related chemicals on macrophage infiltration and its subsequent influence on hepatic cholestasis. Sprague Dawley rats were treated daily with PB, DEET and permethrin followed by 15 minutes of restraint stress for 28 days. Ten weeks afterward, GWI rats or naïve age-matched controls underwent bile duct ligation (BDL) or sham surgeries. Exposure to GWI-related chemicals alone increased IL-6, and CD11b+F4/80- macrophages in the liver, with no effect on biliary mass or hepatic fibrosis. However, pre-exposure to GWI-related chemicals enhanced biliary hyperplasia and fibrogenesis caused by BDL, compared to naïve rats undergoing the same surgery. These data suggest that GWI patients could be predisposed to developing worse liver pathology due to sustained low-level inflammation of the liver when compared to patients without GWI.
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Affiliation(s)
- Anca D Petrescu
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
- Central Texas Veterans Healthcare System, Temple, 76504, USA
| | - Stephanie Grant
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
- Central Texas Veterans Healthcare System, Temple, 76504, USA
| | - Gabriel Frampton
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
- Central Texas Veterans Healthcare System, Temple, 76504, USA
| | | | - Jessica Kain
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA
| | - Maheedhar Kodali
- Central Texas Veterans Healthcare System, Temple, 76504, USA
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, 77843, USA
| | - Ashok K Shetty
- Central Texas Veterans Healthcare System, Temple, 76504, USA
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, 77843, USA
| | - Sharon DeMorrow
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, 76504, USA.
- Central Texas Veterans Healthcare System, Temple, 76504, USA.
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Balta C, Ciceu A, Herman H, Rosu M, Boldura OM, Hermenean A. Dose-Dependent Antifibrotic Effect of Chrysin on Regression of Liver Fibrosis: The Role in Extracellular Matrix Remodeling. Dose Response 2018; 16:1559325818789835. [PMID: 30108459 PMCID: PMC6083810 DOI: 10.1177/1559325818789835] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/04/2018] [Accepted: 06/12/2018] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis represents an overaccumulation of extracellular matrix (ECM). This study was designed to investigate the effect of chrysin on established ECM overproduction in carbon tetrachloride (CCl4) mouse liver fibrosis. Experimental fibrosis was induced by intraperitoneal injection of 2 mL/kg CCl4 twice a week, for 7 weeks. Mice were orally treated with 3 doses of chrysin (5,7-dihydroxyflavone). For the assessment of the spontaneous reversion of fibrosis, CCl4-treated mice were investigated after 2 weeks of recovery time. Silymarin was used as a standard of liver protection. In fibrotic livers, the results showed the upregulation of collagen I (Col I) and tissue inhibitors of metalloproteinase 1 (TIMP-1) and modulation of matrix metalloproteinases (MMPs), which led to an altered ECM enriched in Col, confirmed as well by electron microscopy investigations. Treatment with chrysin significantly reduced ultrastructural changes, downregulated Col I, and restored TIMP-1/MMP balance, whereas in the group observed for the spontaneous regression of fibrosis, they remained in the same pattern with fibrotic livers. In this study, we have shown chrysin efficacy to attenuate dose-dependent CCl4-stimulated liver ECM accumulation by regulation of MMP/TIMP imbalance and inhibition of Col production. We have shown the dose-dependent chrysin efficiency in attenuation of CCl4-induced liver ECM accumulation by regulation of MMP/TIMP imbalance and inhibition of Col production. Our findings suggest that chrysin oral administration may introduce a new strategy for treating liver fibrosis in humans.
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Affiliation(s)
- Cornel Balta
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Arad, Romania
| | - Alina Ciceu
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Arad, Romania
| | - Hildegard Herman
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Arad, Romania
| | - Marcel Rosu
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Arad, Romania
| | - Oana Maria Boldura
- Department of Chemistry, Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Banat University of Agricultural Sciences and Veterinary Medicine "King Mihai I of Romania," Timisoara, Romania
| | - Anca Hermenean
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Arad, Romania.,Department of Histology, Faculty of Medicine, Pharmacy and Dentistry, "Vasile Goldis" Western University of Arad, Arad, Romania
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23
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Al-Humadi H, Alhumadi A, Al-Saigh R, Strilakou A, Lazaris AC, Gazouli M, Liapi C. "Extracellular matrix remodelling in the liver of rats subjected to dietary choline deprivation and/or thioacetamide administration". Clin Exp Pharmacol Physiol 2018; 45:1245-1256. [PMID: 30019784 DOI: 10.1111/1440-1681.13013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 07/08/2018] [Accepted: 07/13/2018] [Indexed: 01/19/2023]
Abstract
Choline deprivation is a recognized experimental approach to nonalcoholic steatohepatitis, while thioacetamide (TAA)-induced liver fibrosis resembles alcoholic liver fibrogenesis. In order to elucidate the effect of TAA on liver extracellular matrix composition under choline deprivation due to choline-deficient diet (CDD) administration, we evaluated the transcriptional and immunohistochemical (IHC) pattern of major hepatic matrix metalloproteinases (namely, MMP-2, -9) and their tissue inhibitors (TIMP-1, -2) in adult male albino Wistar rats at 30, 60 and 90 days. In the CDD+TAA group, IHC showed an early progressive increase in MMP-2 expression, while MMP-9 initially exhibited a significant increase followed by a gradual decrease; TIMP-1 and TIMP-2 IHC expressions showed gradual increase throughout the experiment. The MMPs-TIMPs regulation at the transcriptional level was found to be increased in all groups throughout the experiment. The increased MMP-2/TIMP-2 and suppressed MMP-9/TIMP-1 ratios in IHC and in real-time polymerase chain reaction (RT-PCR) seemed to correlate with the degree of liver fibrosis. These results support the important role of MMPs and TIMPs in controlling the hepatic pathogenesis and shed more light on the recently described experimental approach to liver disease (steatohepatitis) under the impact of two insults (TAA and CDD).
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Affiliation(s)
- Hussam Al-Humadi
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Department of Pharmacology & Toxicology, College of Pharmacy, University of Babylon, Babylon, Iraq
| | - Ahmed Alhumadi
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Rafal Al-Saigh
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Department of Clinical & Laboratory Sciences, College of Pharmacy, University of Babylon, Babylon, Iraq
| | - Athina Strilakou
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas C Lazaris
- 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Gazouli
- Department of Basic Medical Science/Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece
| | - Charis Liapi
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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24
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Liu H, Zhang Z, Hu H, Zhang C, Niu M, Li R, Wang J, Bai Z, Xiao X. Protective effects of Liuweiwuling tablets on carbon tetrachloride-induced hepatic fibrosis in rats. Altern Ther Health Med 2018; 18:212. [PMID: 29986685 PMCID: PMC6038198 DOI: 10.1186/s12906-018-2276-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 06/28/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Liuweiwuling tablets (LWWL) are an herbal product that exerts remarkable effects on liver protection and aminotransferase levels, and they have been approved by the Chinese State Food and Drug Administration (CFDA). Clinical studies have found that LWWL can inhibit collagen production and reduce the levels of liver fibrosis markers in the serum. Thus, LWWL is expected to have beneficial effects in the treatment of liver fibrosis. The purpose of this study was to evaluate the pharmacological effects of LWWL. METHODS Hepatic fibrosis was induced in rats via carbon tetrachloride (CCl4) treatment. The rats were treated twice weekly for 8 weeks with either 2 mL·kg- 1 body weight of a 50% solution of CCl4 in olive oil or olive oil alone by oral gavage. A subset of rats received daily intraperitoneal injections of either colchicine (0.2 mg/kg per day), LWWL (0.4, 1.6, or 6.4 g/kg per day), or vehicle (N = 12 for all groups) during weeks 9-12. The rats were sacrificed after 12 weeks. Pathological changes in hepatic tissue were examined using hematoxylin and eosin (H&E) and Sirius Red staining. Immunohistochemistry was performed to observe α-smooth muscle actin (α-SMA) and collagen type I (collagen I) protein expression. Western blotting was also used to detect α-SMA protein expression. Real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) was used to detect transforming growth factor-1 (TGF-β1), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinase-1 (TIMP1), and tissue inhibitor of metalloproteinase-2 (TIMP2) mRNA expression. RESULTS LWWL significantly reversed histological fibrosis and liver injury, reduced the hydroxyproline content in liver tissue, and decreased α-SMA and collagen I expression. LWWL also suppressed hepatic stellate cell (HSC) activation by reducing the expression of the profibrogenic factors TGF-β1 and PDGF. The expression levels of TIMP1 and TIMP2, which regulate extracellular matrix (ECM) degradation, were decreased after CCl4 injury in LWWL-treated rats. CONCLUSIONS These data suggest that LWWL may serve as a promising therapeutic agent to reduce fibrogenesis.
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25
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Cordero-Espinoza L, Huch M. The balancing act of the liver: tissue regeneration versus fibrosis. J Clin Invest 2018; 128:85-96. [PMID: 29293095 DOI: 10.1172/jci93562] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epithelial cell loss alters a tissue's optimal function and awakens evolutionarily adapted healing mechanisms to reestablish homeostasis. Although adult mammalian organs have a limited regeneration potential, the liver stands out as one remarkable exception. Following injury, the liver mounts a dynamic multicellular response wherein stromal cells are activated in situ and/or recruited from the bloodstream, the extracellular matrix (ECM) is remodeled, and epithelial cells expand to replenish their lost numbers. Chronic damage makes this response persistent instead of transient, tipping the system into an abnormal steady state known as fibrosis, in which ECM accumulates excessively and tissue function degenerates. Here we explore the cellular and molecular switches that balance hepatic regeneration and fibrosis, with a focus on uncovering avenues of disease modeling and therapeutic intervention.
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26
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Thunbergia laurifolia Exhibits Antifibrotic Effects in Human Hepatic Stellate Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:3508569. [PMID: 29410686 PMCID: PMC5749275 DOI: 10.1155/2017/3508569] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 11/13/2017] [Indexed: 12/18/2022]
Abstract
Leaves of Thunbergia laurifolia (TL) have been reported to have antioxidation, anti-inflammatory, detoxifying, and hepatoprotective effects. However, studies relating to antifibrotic activity have not been reported. Currently, there is no standard treatment for hepatic fibrosis. This study aimed to investigate the antifibrotic activity of TL in human hepatic stellate LX-2 cells. Results from cell viability and cell death assays showed that the extract at high concentrations was toxic to LX-2 cells. TL extract reversed the transformation of LX-2 cells to myofibroblast-like characteristics in response to stimulation by transforming growth factor-beta 1. This action may be associated with the effect of TL in suppressing α-SMA and collagen-I production observed by immunofluorescence study and western blot analysis. Additionally, TL extract significantly decreased MMP-9 activity which is consistent with the reduction of MMP-9, MMP-2, and TIMP-1 gene expression. The effect of TL in suppressing fibrosis may be associated with its ability to inhibit the activation of p38 MAPK and Erk1/2 kinases as examined by western blot analysis. Our study provides convincing evidence that TL possesses antifibrotic activity which may be through the suppression of TGF-β1-mediated production of MMPs, collagen-1, and α-SMA in hepatic stellate cells.
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27
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Eulenberg VM, Lidbury JA. Hepatic Fibrosis in Dogs. J Vet Intern Med 2017; 32:26-41. [PMID: 29194760 PMCID: PMC5787209 DOI: 10.1111/jvim.14891] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/17/2017] [Accepted: 10/31/2017] [Indexed: 12/19/2022] Open
Abstract
Hepatic fibrosis is commonly diagnosed in dogs, often as a sequela to chronic hepatitis (CH). The development of fibrosis is a crucial event in the progression of hepatic disease that is of prognostic value. The pathophysiology of hepatic fibrosis in human patients and rodent models has been studied extensively. Although less is known about this process in dogs, evidence suggests that fibrogenic mechanisms are similar between species and that activation of hepatic stellate cells is a key step. Diagnosis and staging of hepatic fibrosis in dogs requires histopathological examination of a liver biopsy specimen. However, performing a liver biopsy is invasive and assessment of fibrotic stage is complicated by the absence of a universally accepted staging scheme in veterinary medicine. Serum biomarkers that can discriminate among different fibrosis stages are used in human patients, but such markers must be more completely evaluated in dogs before clinical use. When successful treatment of its underlying cause is feasible, reversal of hepatic fibrosis has been shown to be possible in rodent models and human patients. Reversal of fibrosis has not been well documented in dogs, but successful treatment of CH is possible. In human medicine, better understanding of the pathomechanisms of hepatic fibrosis is leading to the development of novel treatment strategies. In time, these may be applied to dogs. This article comparatively reviews the pathogenesis of hepatic fibrosis, its diagnosis, and its treatment in dogs.
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Affiliation(s)
- V M Eulenberg
- Gastrointestinal Laboratory, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX
| | - J A Lidbury
- Gastrointestinal Laboratory, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX
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28
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Perumal N, Perumal M, Halagowder D, Sivasithamparam N. Morin attenuates diethylnitrosamine-induced rat liver fibrosis and hepatic stellate cell activation by co-ordinated regulation of Hippo/Yap and TGF-β1/Smad signaling. Biochimie 2017; 140:10-19. [PMID: 28552397 DOI: 10.1016/j.biochi.2017.05.017] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/24/2017] [Indexed: 01/18/2023]
Abstract
Despite great progress in understanding the activation of hepatic stellate cells (HSCs) during liver fibrosis, therapeutic approaches to inhibit HSC activation remain very limited. Recent reports highlight Yes-associated protein (Yap) and transforming growth factor-β1 (TGF-β1) as critical regulators of HSC activation and henceforth a compound targeting Hippo/Yap and TGF-β1/Smad pathways would be a potential anti-fibrotic candidate. Morin, a dietary flavonoid, was earlier reported to inhibit HSC proliferation and induction of apoptosis of cultured HSCs, mainly by suppressing Wnt/β-catenin and NF-κB signaling, but its effect on Hippo/Yap and TGF-β1/Smad pathways was not determined. To address this concern, this study was carried out in cultured LX-2 cells and diethylnitrosamine-induced fibrotic rats. Morin activated hippo signaling through significantly increased expression of Mst1 and Lats1 with decreased expression of transcriptional effectors Yap/TAZ, thereby prevented HSC activation and also suppressed the expression of exacerbated TGF-β/Smad signaling molecules such as TGF-β1, p-Smad2/3, collagen-I, MMP-2, MMP-9 and TIMP-1 in cultured LX-2 and DEN induced fibrotic rats. Both the in vitro and in vivo results clearly showed that, morin by acting on Hippo/Yap and TGF-β1/Smad pathways, ameliorated experimental liver fibrosis, indicating that morin has potential for effective treatment of liver fibrosis.
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Affiliation(s)
- NaveenKumar Perumal
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India
| | - MadanKumar Perumal
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Devaraj Halagowder
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India
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Carvedilol Attenuates the Progression of Hepatic Fibrosis Induced by Bile Duct Ligation. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4612769. [PMID: 28396867 PMCID: PMC5370484 DOI: 10.1155/2017/4612769] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/07/2017] [Accepted: 01/30/2017] [Indexed: 01/06/2023]
Abstract
Background. The sympathetic nervous system (SNS) is responsible for hepatic stellate cells (HSCs) activation and the accumulation of collagen that occurs in hepatic fibrogenesis. Carvedilol has been widely used for the complication of hepatic cirrhosis in the clinic. Furthermore, it has powerful antioxidant properties. We assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may further enhance its clinical benefits. Methods. Using a bile duct ligation rat model of hepatic fibrosis, we studied the effects of carvedilol on the fibrosis, collagen deposition, and oxidative stress based on histology, immunohistochemistry, western blot, and RT-PCR analyses. Results. Carvedilol attenuated liver fibrosis, as evidenced by reduced hydroxyproline content and the accumulation of collagen, downregulated TIMP-1 and TIMP-2, and upregulated MMP-13. MMP-2 was an exception, which was decreased after carvedilol treatment for 2 weeks and upregulated after carvedilol treatment for 4 weeks. Carvedilol reduced the activation of HSCs, decreased the induction of collagen, transforming growth factor-β1, and MDA content, and strengthened the SOD activity. The antifibrotic effects were augmented as dosages increased. Conclusions. The study indicates that carvedilol attenuated hepatic fibrosis in a dose-dependent manner. It can decrease collagen accumulation and HSCs activation by the amelioration of oxidative stress.
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30
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Jung YK, Yim HJ. Reversal of liver cirrhosis: current evidence and expectations. Korean J Intern Med 2017; 32:213-228. [PMID: 28171717 PMCID: PMC5339475 DOI: 10.3904/kjim.2016.268] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 12/23/2016] [Indexed: 02/06/2023] Open
Abstract
In the past, liver cirrhosis was considered an irreversible phenomenon. However, many experimental data have provided evidence of the reversibility of liver fibrosis. Moreover, multiple clinical studies have also shown regression of fibrosis and reversal of cirrhosis on repeated biopsy samples. As various etiologies are associated with liver fibrosis via integrated signaling pathways, a comprehensive understanding of the pathobiology of hepatic fibrogenesis is critical for improving clinical outcomes. Hepatic stellate cells play a central role in hepatic fibrogenesis upon their activation from a quiescent state. Collagen and other extracellular material components from activated hepatic stellate cells are deposited on, and damage, the liver parenchyma and vascular structures. Hence, inactivation of hepatic stellate cells can lead to enhancement of fibrolytic activity and could be a potential target of antifibrotic therapy. In this regard, continued efforts have been made to develop better treatments for underlying liver diseases and antifibrotic agents in multiple clinical and therapeutic trials; the best results may be expected with the integration of such evidence. In this article, we present the underlying mechanisms of fibrosis, current experimental and clinical evidence of the reversibility of liver fibrosis/cirrhosis, and new agents with therapeutic potential for liver fibrosis.
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Affiliation(s)
| | - Hyung Joon Yim
- Correspondence to Hyung Joon Yim, M.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea Tel: +82-31-412-6565 Fax: +82-31-412-5582 E-mail:
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Huang Y, Deng X, Liang J. Modulation of hepatic stellate cells and reversibility of hepatic fibrosis. Exp Cell Res 2017; 352:420-426. [PMID: 28238836 DOI: 10.1016/j.yexcr.2017.02.038] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/19/2017] [Accepted: 02/21/2017] [Indexed: 12/21/2022]
Abstract
Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal.
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Affiliation(s)
- Yu Huang
- Faculty of Graduate Studies of Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region, PR China.
| | - Xin Deng
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, 10 East China Road, Nanning 530011, Guangxi Zhuang Autonomous Region, PR China.
| | - Jian Liang
- Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region, PR China.
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Noninvasive estimation of liver fibrosis in biopsy-proven hepatitis C virus-infected patients: angiogenic fibrogenic link. Eur J Gastroenterol Hepatol 2017; 29:199-207. [PMID: 27930387 DOI: 10.1097/meg.0000000000000775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM The assessment of liver fibrosis provides useful information not only for diagnosis but also for therapeutic decisions. This study aimed to develop and evaluate a predictive score named the angiogenic index (Angio-Index) for liver fibrosis staging and to compare Angio-Index by King, Gotebörg University Cirrhosis Index, Lok, FIB-4, and aspartate aminotranferase/alanine aminotranferase scores in hepatitis C virus-infected patients. PATIENTS AND METHODS Serum levels of angiopoietin-2, basic fibroblast growth factor, hepatocyte growth factor, and endostatin were assayed using an enzyme-linked immunosorbent assay in 122 HCV patients represented in two sets (estimation group and validation group). Stepwise linear discriminant analysis and area under receiver-operating characteristic curves (AUCs) were utilized to produce a predictive score comprising significant angiogenic biomarkers. RESULTS A novel score named the Angio-Index score was created on the basis of a combination of angiopoietin-2, basic fibroblast growth factor, hepatocyte growth factor, and endostatin. Angio-Index produces an AUC of 0.90 for significant fibrosis, 0.865 for advanced fibrosis, and 0.857 for cirrhosis. The Angio-Index score correctly classified 71% of the significant fibrosis (F2-F4) with a sensitivity of 93% and a specificity of 91%. The Angio-Index had a similar AUC in the validation study. The above six scores showed lower AUCs than Angio-Index. CONCLUSION Whereas liver biopsy is invasive, costly, and associated with complications, Angio-Index is simple, noninvasive, and more accurate; it may decrease the need for liver biopsy in Egyptian patients.
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Hung WL, Yang G, Wang YC, Chiou YS, Tung YC, Yang MJ, Wang BN, Ho CT, Wang Y, Pan MH. Protective effects of theasinensin A against carbon tetrachloride-induced liver injury in mice. Food Funct 2017; 8:3276-3287. [DOI: 10.1039/c7fo00700k] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
TSA markedly reduced the CCl4-induced liver injury in mice.
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Affiliation(s)
- Wei-Lun Hung
- Citrus Research and Education Center
- Department of Food Science and Human Nutrition
- University of Florida
- Lake Alfred
- USA
| | - Guliang Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization; Hubei Collaborative Innovation Center for the Characteristic Resources Exploitation of Dabie Mountains; Huanggang Normal University
- Huanggang
- China
| | - Yu-Chuan Wang
- Institute of Food Science and Technology
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Yi-Shiou Chiou
- Institute of Food Science and Technology
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Yen-Chen Tung
- Institute of Food Science and Technology
- National Taiwan University
- Taipei 10617
- Taiwan
| | | | - Bi-Ni Wang
- College of Food Engineering and Nutritional Science
- Shaanxi Normal University
- Xi'an 710119
- China
| | - Chi-Tang Ho
- Department of Food Science
- Rutgers University
- New Brunswick
- USA
| | - Yu Wang
- Citrus Research and Education Center
- Department of Food Science and Human Nutrition
- University of Florida
- Lake Alfred
- USA
| | - Min-Hsiung Pan
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization; Hubei Collaborative Innovation Center for the Characteristic Resources Exploitation of Dabie Mountains; Huanggang Normal University
- Huanggang
- China
- Institute of Food Science and Technology
- National Taiwan University
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Tai CJ, Choong CY, Lin YC, Shi YC, Tai CJ. The anti-hepatic fibrosis activity of ergosterol depended on upregulation of PPARgamma in HSC-T6 cells. Food Funct 2016; 7:1915-23. [PMID: 27040153 DOI: 10.1039/c6fo00117c] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Advanced glycation endproducts (AGEs) were shown to play an important role in metabolic syndrome and were suggested to contribute to the development of hepatic fibrosis. Evidence indicates that AGEs resulted in hepatic fibrosis coupled to the activation of the receptor for AGEs (RAGE) in hepatic stellate cells (HSCs). NADPH oxidase is downstream of the RAGE signaling pathway, resulting in an increase in reactive oxygen species (ROS), alpha-smooth muscle actin (alpha-SMA), RAGE, and matrix metalloproteinase-9 (MMP-9). This study was designed to evaluate the effects of ergosterol on RAGE signaling in HSC-T6 cells. Ergosterol suppressed the activation of HSC-T6 cells induced by AGEs, and attenuated overexpressions of alpha-SMA, MMP-9, and epithelial-mesenchymal transition (EMT) markers, including N-cadherin and vimentin. We also found that these inhibitory effects of ergosterol on the activation of HSCs were dependent on peroxisome proliferator-activated receptor-gamma (PPARgamma) confirmed by PPARgamma reporter assay and PPARgamma knockdown. In addition, ergosterol also showed an inhibitory effect on the generation of AGEs, fructosamine, and α-dicarbonyl compounds in this study. Our results show that ergosterol can be used as a protective agent against hepatic fibrosis caused by induction of AGEs.
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Affiliation(s)
- Chen-Jei Tai
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan and Department of Chinese Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Chen-Yen Choong
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Chun Lin
- Graduate Institute of Medical Sciences, Taipei Medical University Hospital, Taipei, Taipei 11031, Taiwan
| | - Yeu-Ching Shi
- Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medicine University Hospital, Taipei 11031, Taiwan. and Taiwan Indigena Botanica Co., Ltd, Taipei City 11494, Taiwan
| | - Cheng-Jeng Tai
- Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medicine University Hospital, Taipei 11031, Taiwan. and Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Hong Y, Han YQ, Wang YZ, Gao JR, Li YX, Liu Q, Xia LZ. Paridis Rhizoma Sapoinins attenuates liver fibrosis in rats by regulating the expression of RASAL1/ERK1/2 signal pathway. JOURNAL OF ETHNOPHARMACOLOGY 2016; 192:114-122. [PMID: 27396351 DOI: 10.1016/j.jep.2016.07.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 05/10/2016] [Accepted: 07/06/2016] [Indexed: 06/06/2023]
Abstract
ETHNO-PHARMACOLOGICAL RELEVANCE Paridis Rhizoma is a Chinese medicinal herb that has been used in liver disease treatment for thousands of years. Our previous studies found that Paridis Rhizoma saponins (PRS) are the critical components of Paridis Rhizoma which has good liver protection effect. However, the anti-hepatic fibrosis effect and the mechanism of PRS have seldom been reported. AIM OF THE STUDY To investigate the potential of PRS in the treatment of experimental liver fibrosis and the underlying mechanism. MATERIALS AND METHODS The chemical feature fingerprint of PRS was analyzed by UPLC-PDA. A total of 40 Male Sprague-Dawley (SD) rats were randomly divided into the control group, the model group, the PRS high dose group (PRS H) and the PRS low dose group (PRS L) with 10 rats in each group. The model, PRS H and L groups as liver fibrosis models were established with carbon tetrachloride (CCl4) method. PRS H and L groups were adopted PRS (300 and 150mg/kgd-1) treatment since the twelfth week of modeling till the sixteenth week. Pathological changes in hepatic tissue were examined using hematoxylin and eosin (H&E) and MASSON trichrome staining. Immunohistochemical analysis was performed to determine the protein expression of the RASAL1. RT-PCR and western blotting were used to detect the expression of ERK1/2 mRNA and protein. RESULTS Four saponins in PRS were identified from 19 detected chromatographic peaks on UPLC-PDA by comparing to the standard compounds. PRS can improve the degeneration and necrosis of hepatic tissue, reduce the extent of its fibrous hyperplasia according to H&E and MASSON staining detection. As was detected in PRS H and L groups, PRS down-regulated p-ERK1/2 mRNA and RASAL1 protein, and up-regulated the level of p-ERK1/2 mRNA and RASAL1 protein. CONCLUSION These results demonstrated that PRS can attenuate CCl4-induced liver fibrosis through the regulation of RAS/ERK1/2 signal pathway.
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MESH Headings
- Animals
- Blotting, Western
- Carbon Tetrachloride
- Chemical and Drug Induced Liver Injury/enzymology
- Chemical and Drug Induced Liver Injury/pathology
- Chemical and Drug Induced Liver Injury/prevention & control
- Chromatography, High Pressure Liquid
- Cytoprotection
- GTPase-Activating Proteins/genetics
- GTPase-Activating Proteins/metabolism
- Gene Expression Regulation, Enzymologic
- Hyperplasia
- Immunohistochemistry
- Liver/drug effects
- Liver/enzymology
- Liver/pathology
- Liver Cirrhosis, Experimental/chemically induced
- Liver Cirrhosis, Experimental/enzymology
- Liver Cirrhosis, Experimental/pathology
- Liver Cirrhosis, Experimental/prevention & control
- Male
- Melanthiaceae/chemistry
- Mitogen-Activated Protein Kinase 1/genetics
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/genetics
- Mitogen-Activated Protein Kinase 3/metabolism
- Necrosis
- Phosphorylation
- Phytotherapy
- Plant Extracts/isolation & purification
- Plant Extracts/pharmacology
- Plants, Medicinal
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats, Sprague-Dawley
- Reverse Transcriptase Polymerase Chain Reaction
- Saponins/isolation & purification
- Saponins/pharmacology
- Signal Transduction/drug effects
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Affiliation(s)
- Yan Hong
- Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
| | - Yan-Quan Han
- The First Affiliated Hospital, Anhui University of Chinese Medicine, Grade 3 Laboratory of TCM Preparation, State Administration of Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
| | - Yong-Zhong Wang
- The First Affiliated Hospital, Anhui University of Chinese Medicine, Grade 3 Laboratory of TCM Preparation, State Administration of Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
| | - Jia-Rong Gao
- The First Affiliated Hospital, Anhui University of Chinese Medicine, Grade 3 Laboratory of TCM Preparation, State Administration of Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
| | - Yu-Xin Li
- Anhui University of Chinese Medicine, Hefei, Anhui 230031, China; The First Affiliated Hospital, Anhui University of Chinese Medicine, Grade 3 Laboratory of TCM Preparation, State Administration of Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
| | - Qing Liu
- Anhui University of Chinese Medicine, Hefei, Anhui 230031, China; The First Affiliated Hospital, Anhui University of Chinese Medicine, Grade 3 Laboratory of TCM Preparation, State Administration of Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
| | - Lun-Zhu Xia
- The First Affiliated Hospital, Anhui University of Chinese Medicine, Grade 3 Laboratory of TCM Preparation, State Administration of Anhui University of Chinese Medicine, Hefei, Anhui 230031, China.
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Grünwald B, Harant V, Schaten S, Frühschütz M, Spallek R, Höchst B, Stutzer K, Berchtold S, Erkan M, Prokopchuk O, Martignoni M, Esposito I, Heikenwalder M, Gupta A, Siveke J, Saftig P, Knolle P, Wohlleber D, Krüger A. Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver. Gastroenterology 2016; 151:1011-1024.e7. [PMID: 27506299 DOI: 10.1053/j.gastro.2016.07.043] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 07/04/2016] [Accepted: 07/25/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) metastasizes to liver at early stages, making this disease highly lethal. Tissue inhibitor of metalloproteinases-1 (TIMP1) creates a metastasis-susceptible environment in the liver. We investigated the role of TIMP1 and its receptor CD63 in metastasis of early-stage pancreatic tumors using mice and human cell lines and tissue samples. METHODS We obtained liver and plasma samples from patients in Germany with chronic pancreatitis, pancreatic intra-epithelial neoplasia, or PDAC, as well as hepatic stellate cells (HSCs). We performed studies with Ptf1a+/Cre;Kras+/LSL-G12D;Trp53loxP/loxP (CPK) mice, Pdx-1+/Cre;Kras+/LSL-G12D;Trp53+/LSL-R172H (KPC) mice, and their respective healthy littermates as control, and Cd63-/- mice with their wild-type littermates. KPC mice were bred with Timp1-/- mice to produce KPCxTimp1-/- mice. TIMP1 was overexpressed and CD63 was knocked down in mice using adenoviral vectors AdTIMP1 or AdshCD63, respectively. Hepatic susceptibility to metastases was determined after intravenous inoculation of syngeneic 9801L pancreas carcinoma cells. Pancreata and liver tissues were collected and analyzed by histology, immunohistochemical, immunoblot, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction analyses. We analyzed the effects of TIMP1 overexpression or knockdown and CD63 knockdown in transduced human primary HSCs and HSC cell lines. RESULTS Chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients expressed higher levels of TIMP1 protein than normal pancreas. The premalignant pancreatic lesions that developed in KPC and CPK mice expressed TIMP1 and secreted it into the circulation. In vitro and in vivo, TIMP1 activated human or mouse HSCs, which required interaction between TIMP1 and CD63 and signaling via phosphatidylinositol 3-kinase, but not TIMP1 protease inhibitor activity. This signaling pathway induced expression of endogenous TIMP1. TIMP1 knockdown in HSCs reduced their activation. Cultured TIMP1-activated human and mouse HSCs began to express stromal-derived factor-1, which induced neutrophil migration, a marker of the premetastatic niche. Mice with pancreatic intra-epithelial neoplasia-derived systemic increases in TIMP1 developed more liver metastases after injections of pancreatic cancer cells than mice without increased levels of TIMP1. This increase in formation of liver metastases from injected pancreatic cancer cells was not observed in TIMP1 or CD63 knockout mice. CONCLUSIONS Expression of TIMP1 is increased in chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients. TIMP1 signaling via CD63 leads to activation of HSCs, which create an environment in the liver that increases its susceptibility to pancreatic tumor cells. Strategies to block TIMP1 signaling via CD63 might be developed to prevent PDAC metastasis to the liver.
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Affiliation(s)
- Barbara Grünwald
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Veronika Harant
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Susanne Schaten
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Monika Frühschütz
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Ria Spallek
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Bastian Höchst
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Katharina Stutzer
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Sonja Berchtold
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Mert Erkan
- Chirurgische Klinik Technische Universität München, München, Germany
| | - Olga Prokopchuk
- Chirurgische Klinik Technische Universität München, München, Germany
| | - Marc Martignoni
- Chirurgische Klinik Technische Universität München, München, Germany
| | - Irene Esposito
- Institut für Pathologie, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | | | - Aayush Gupta
- II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Jens Siveke
- II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Paul Saftig
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Percy Knolle
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Dirk Wohlleber
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany
| | - Achim Krüger
- Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany.
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Attia H, Al-Rasheed N, Mohamad R, Al-Rasheed N, Al-Amin M. The antifibrotic and fibrolytic properties of date fruit extract via modulation of genotoxicity, tissue-inhibitor of metalloproteinases and nuclear factor- kappa B pathway in a rat model of hepatotoxicity. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:414. [PMID: 27776513 PMCID: PMC5078931 DOI: 10.1186/s12906-016-1388-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 10/11/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND Hepatic fibrosis and its end point; cirrhosis, are the major cause of liver failure and death in patients with chronic liver disease. Therefore, the need for an effective treatment is evident. This study was designed to assess the potential effects of aqueous extract of date fruits, either flesh (DFE) or pits (DPE), on oxidative DNA damage and liver inflammation induced by carbon tetrachloride (CCl4) and whether they are related to inhibition of nuclear factor-κB pathway. In addition, the fibrolytic potential was evaluated via measuring matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases -1 and -2. METHODS Rats were divided into the following groups: normal control, model control (CCl4 only), CCl4 + DFE, CCl4 + DPE and CCl4 + coffee. Coffee was used as a positive control. Fibrosis was induced by chronic administration of CCl4 (0.4 ml/kg) 3× a week for 8 weeks, and rats were treated with 6 ml/kg/day of DFE or DPE for 8 weeks. Liver homogenate was prepared for evaluation of oxidative stress, DNA damage, inflammatory and fibrolytic markers. Data are analyzed using one-way analysis of variance followed by a Tukey-Kramer post hoc test. RESULTS Both DFE and DPE significantly attenuated CCl4-induced oxidative damage as indicated by reducing lipid, protein and DNA oxidation in addition to increasing the levels of hepatic catalase activity. Both extracts blocked the accumulation of collagen I in the liver and ameliorated the increased expression of collagen III and α-smooth muscle actin suggesting suppression of profibrotic response induced by CCl4. DFE and DPE also upregulated the expression of heme oxygenase-1 and attenuated the nuclear factor-κB activation and cycloxygenase-2 expression reflecting their anti-inflammatory potential. Additionally, both flesh and pits extracts attenuated the increase in the tissue inhibitor of metalloproteinases -1 and -2 suggesting their fibrolytic activity. CONCLUSION Our data suggest that DFE or DPE can prevent liver fibrosis by suppressing genotoxicity and nuclear factor-κB inflammatory pathway and by promoting collagen degradation.
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Affiliation(s)
- Hala Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia.
- Department of Biochemistry, College of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.
| | - Nouf Al-Rasheed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia
| | - Raeesa Mohamad
- Anatomy Department, Faculty of Medicine, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia
| | - Nawal Al-Rasheed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia
| | - Maha Al-Amin
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia
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Wang C, Zhang F, Cao Y, Zhang M, Wang A, Xu M, Su M, Zhang M, Zhuge Y. Etoposide Induces Apoptosis in Activated Human Hepatic Stellate Cells via ER Stress. Sci Rep 2016; 6:34330. [PMID: 27680712 PMCID: PMC5041150 DOI: 10.1038/srep34330] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 09/12/2016] [Indexed: 12/11/2022] Open
Abstract
The activation of hepatic stellate cells (HSCs) plays a vital role in the progression of liver fibrosis, and the induction of HSCs apoptosis may attenuate or reverse fibrogenesis. The therapeutic effects of etoposide(VP-16), a widely used anticancer agent, on HSCs apoptosis and liver fibrosis resolution are still unclear. Here, we report that VP-16 reduced the proliferation of LX-2 cells and led to significantly high levels of apoptosis, as indicated by Annexin V staining and the proteolytic cleavage of the executioner caspase-3 and PARP. Additionally, the unfolded protein response regulators CHOP, BIP, caspase-12, p-eIF2α and IRE1α, which are considered endoplasmic reticulum (ER) stress markers, were upregulated by VP-16. The strong inhibitory effect of VP-16 on LX-2 cells was mainly dependent on ER stress, which activated JNK signaling pathway. Remarkably, VP-16 treatment decreased the expression of α-SMA and type I collagen and simultaneously increased the ratio of matrix metalloproteinases (MMPs) to tissue inhibitor of matrix metalloproteinases (TIMPs). In contrast, VP-16 induced significantly more apoptosis in HSCs than in normal hepatocytes. Taken together, our findings demonstrate that VP-16 exerts a proapoptotic effect on LX-2 cells and has an antifibrogenic effect on collagen deposition, suggesting a new strategy for the treatment of liver fibrosis.
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Affiliation(s)
- Chen Wang
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feng Zhang
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yu Cao
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Mingming Zhang
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Aixiu Wang
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Mingcui Xu
- Department of Gastroenterology, Affiliated Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, China
| | - Min Su
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ming Zhang
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yuzheng Zhuge
- Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
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Haldar D, Henderson NC, Hirschfield G, Newsome PN. Mesenchymal stromal cells and liver fibrosis: a complicated relationship. FASEB J 2016; 30:3905-3928. [DOI: 10.1096/fj.201600433r] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 08/15/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Debashis Haldar
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Neil C. Henderson
- Medical Research Council (MRC) Centre for Inflammation ResearchQueens Medical Research Institute University of Edinburgh Edinburgh United Kingdom
| | - Gideon Hirschfield
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Philip N. Newsome
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
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40
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Takeuchi-Yorimoto A, Yamaura Y, Kanki M, Ide T, Nakata A, Noto T, Matsumoto M. MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease. Toxicol Lett 2016; 258:159-167. [DOI: 10.1016/j.toxlet.2016.06.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 05/18/2016] [Accepted: 06/12/2016] [Indexed: 12/25/2022]
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Habuchi H, Ushida T, Habuchi O. Mice deficient in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase exhibit enhanced liver fibrosis and delayed recovery from fibrosis in carbon tetrachloride-treated mice. Heliyon 2016; 2:e00138. [PMID: 27547834 PMCID: PMC4983273 DOI: 10.1016/j.heliyon.2016.e00138] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 08/01/2016] [Indexed: 01/18/2023] Open
Abstract
Background Chondroitin/dermatan sulfate (CS/DS) rich in N-acetylgalactosamine 4,6-bissulfate (GalNAc(4,6SO4)) residues is present as decorin and/or biglycan in mouse liver, and GalNAc(4,6SO4) residues disappeared completely in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) knockout (KO) mice. The aim of this study was to investigate whether CS/DS rich in GalNAc(4,6SO4) residues participate in the progression or resolution of liver fibrosis. Methods Wild type (WT) and GalNAc4S-6ST KO mice were treated with CCl4 for 5 weeks. After discontinuation of CCl4 administration, histochemical and biochemical changes and expression of genes related to matrix components were compared between WT and GalNAc4S-6ST KO mice. Results and conclusion On 2 days after cessation of CCl4 administration, higher fibrosis was observed in KO mice than in WT mice by Sirius Red staining. Serum alanine aminotransferase activity was higher in KO mice than in WT mice. Hydroxyproline contents and Sirius Red staining showed that repair of liver fibrosis in the recovery stages appeared to be delayed in KO mice. Expression of mRNA of matrix metalloproteinase (MMP)-2, MMP-13 and versican peaked at 2 days after cessation of CCl4 administration and was higher in KO mice than in WT mice. Expression of MMP-9 in the recovery stage was lower in KO mice than in WT mice. Our findings demonstrate that defect in GalNAc4S-6ST, which resulted in disappearance of CS/DS containing GalNAc(4,6SO4), appear to contribute to progression of liver fibrosis, delayed recovery from fibrosis, and various changes in the expression of proteoglycans and MMPs in carbon tetrachloride–treated mice.
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Affiliation(s)
- Hiroko Habuchi
- Advanced Medical Research Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan; Multidisciplinary Pain Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Takahiro Ushida
- Multidisciplinary Pain Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Osami Habuchi
- Advanced Medical Research Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan; Multidisciplinary Pain Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
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Sakiyama H, Fujiwara N, Yoneoka Y, Yoshihara D, Eguchi H, Suzuki K. Cu,Zn-SOD deficiency induces the accumulation of hepatic collagen. Free Radic Res 2016; 50:666-77. [PMID: 26981929 DOI: 10.3109/10715762.2016.1164856] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic diseases, and results in the development of fibrosis. Oxidative stress is thought to be one of the underlying causes of NAFLD. Copper/zinc superoxide dismutase (SOD1) is a primary antioxidative enzyme that scavenges superoxide anion radicals. Although SOD1 knockout (KO) mice have been reported to develop fatty livers, it is not known whether this lack of SOD1 leads to the development of fibrosis. Since the accumulation of collagen typically precedes liver fibrosis, we assessed the balance between the synthesis and degradation of collagen in liver tissue from SOD1 KO mice. We found a higher accumulation of collagen in the livers of SOD1 KO mice compared to wild type mice. The level of expression of HSP47, a chaperone of collagen, and a tissue inhibitor (TIMP1) of matrix metalloproteinases (a collagen degradating enzyme) was also increased in SOD1 KO mice livers. These results indicate that collagen synthesis is increased but that its degradation is inhibited in SOD1 KO mice livers. Moreover, SOD1 KO mice liver sections were extensively modified by advanced glycation end products (AGEs), which suggest that collagen in SOD1 KO mice liver might be also modified with AGEs and then would be more resistant to the action of collagen degrading enzymes. These findings clearly show that oxidative stress plays an important role in the progression of liver fibrosis.
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Affiliation(s)
- Haruhiko Sakiyama
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Noriko Fujiwara
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Yuka Yoneoka
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Daisaku Yoshihara
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Hironobu Eguchi
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Keiichiro Suzuki
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
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Versican: a novel modulator of hepatic fibrosis. J Transl Med 2016; 96:361-74. [PMID: 26752747 DOI: 10.1038/labinvest.2015.152] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/29/2015] [Accepted: 11/02/2015] [Indexed: 01/17/2023] Open
Abstract
Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE(1401) and G1-DPEAAE(441)). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.
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Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R. Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis. Front Pharmacol 2016; 7:33. [PMID: 26941644 PMCID: PMC4764688 DOI: 10.3389/fphar.2016.00033] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 02/08/2016] [Indexed: 12/17/2022] Open
Abstract
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.
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Affiliation(s)
- Hans-Theo Schon
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany
| | - Matthias Bartneck
- Department of Medicine III, University Hospital RWTH Aachen Aachen, Germany
| | - Erawan Borkham-Kamphorst
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn Bonn, Germany
| | - Twan Lammers
- Department for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany
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Louka ML, Ramzy MM. Involvement of fibroblast-specific protein 1 (S100A4) and matrix metalloproteinase-13 (MMP-13) in CCl4-induced reversible liver fibrosis. Gene 2015; 579:29-33. [PMID: 26721462 DOI: 10.1016/j.gene.2015.12.042] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/06/2015] [Accepted: 12/18/2015] [Indexed: 12/26/2022]
Abstract
INTRODUCTION The intense basic research on the molecular and cellular mechanisms of liver fibrosis regression intends to translate these findings into new therapies targeting such pathways in human liver disease. Fibrosis regression is rapidly initiated in mouse models of fibrosis within days after termination of the cause, so in this study, we investigated the expression of S100A4 and MMP-13 during liver fibrogenesis and remodeling. METHODS Thirty rats were divided into three groups: control group, fibrotic group, and fibrotic resolution group (10 each). The rats were sacrificed 48h and 96h after cessation of CCL-4, respectively. Liver tissue levels of S100A4 mRNA and S100A4 protein, MMP-13 mRNA and serum levels of serum TGF-β1, ALT and AST were determined. RESULTS Expression of S100A4 was increased during fibrotic stage and declined during resolution which was in correlation with the pro-fibrotic marker TGF-β1 with concordance about 90%, while MMP-13 expression increased in both stages reaching to 40 fold during resolution. CONCLUSION These findings suggested that S100A4 level in the liver tissue was related positively with liver fibrosis making it a good marker for liver fibrogenesis and also a good target for novel antifibrotic strategies.
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Affiliation(s)
- Manal L Louka
- Biochemistry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Maggie M Ramzy
- Biochemistry Department, Faculty of Medicine, Minia University, Minia, Egypt
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Ahn J, Son MK, Jung KH, Kim K, Kim GJ, Lee SH, Hong SS, Park SG. Aminoacyl-tRNA synthetase interacting multi-functional protein 1 attenuates liver fibrosis by inhibiting TGFβ signaling. Int J Oncol 2015; 48:747-55. [PMID: 26692190 DOI: 10.3892/ijo.2015.3303] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/07/2015] [Indexed: 11/05/2022] Open
Abstract
The aminoacyl-tRNA synthetase interacting multi-functional protein 1 (AIMP1) participates in a variety of cellular processes, including translation, cell proliferation, inflammation and wound healing. Previously, we showed that the N-terminal peptide of AIMP1 (6-46 aa) induced ERK phosphorylation. Liver fibrosis is characterized by excessive deposition of extracellular matrix, which is induced by TGFβ signaling, and activated ERK is known to induce the phosphorylation of SMAD, thereby inhibiting TGFβ signaling. We assessed whether the AIMP1 peptide can inhibit collagen synthesis in hepatic stellate cells (HSCs) by activating ERK. The AIMP1 peptide induced phosphorylation of SMAD2 via ERK activation, and inhibited the nuclear translocation of SMAD, resulting in a reduction of the synthesis of type I collagen. The AIMP1 peptide attenuated liver fibrosis induced by CCl4, in a dose-dependent manner. Masson-Trichrome staining showed that the AIMP1 peptide reduced collagen deposition. Immunohistochemical staining showed that the levels of α-SMA, TGFβ and type I collagen were all reduced by the AIMP1 peptide. Liver toxicity analysis showed that the AIMP1 peptide improved the levels of relevant biological parameters in the blood. These results suggest that AIMP1 peptide may have potential for development as a therapeutic agent to treat liver fibrosis.
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Affiliation(s)
- Jongchan Ahn
- Department of Biomedical Science, College of Life Science, CHA University, Gyunggido, Republic of Korea
| | - Mi Kwon Son
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Kyung Hee Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Kwangil Kim
- Department of Pathology, Bundang CHA General Hospital, CHA University, Gyunggido, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, College of Life Science, CHA University, Gyunggido, Republic of Korea
| | - Soo-Hong Lee
- Department of Biomedical Science, College of Life Science, CHA University, Gyunggido, Republic of Korea
| | - Soon-Sun Hong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Sang Gyu Park
- Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, Gyunggido, Republic of Korea
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Ye L, Yu H, Li C, Hirsch ML, Zhang L, Samulski RJ, Li W, Liu Z. Adeno-Associated Virus Vector Mediated Delivery of the HBV Genome Induces Chronic Hepatitis B Virus Infection and Liver Fibrosis in Mice. PLoS One 2015; 10:e0130052. [PMID: 26075890 PMCID: PMC4468063 DOI: 10.1371/journal.pone.0130052] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 05/15/2015] [Indexed: 01/04/2023] Open
Abstract
Liver cirrhosis and hepatocellular carcinomas are major health problems of chronic hepatitis B virus (HBV) infection. To date, rare model has reproduced liver fibrosis associated with long-term HBV infection which in turn has hindered both the understanding of HBV biology and the development of new treatment options. Here, using adeno-associated virus serotype 8 (AAV8) mediated delivery of a 1.2-kb HBV genome, we successfully generated a chronic HBV infectious mouse model that presents the associated liver fibrosis observed following human infection. After AAV8/HBV1.2 vector administration, mice demonstrated effective HBV replication and transcription which resulted in HBV antigen expression and viremia over 6 months. Although no obvious acute inflammatory response was noted, these mice still developed chronic liver disease and hepatic fibrogenesis as demonstrated by increased ground glass-like hepatocytes, an increasing trend of collagen deposition and upregulated fibrosis markers, including type I collagen, type III collagen, tissue inhibitor of metalloproteinase (TIMP), and transforming growth factor-β1(TGF-β1). Taken together, AAV-mediated HBV gene delivery to the mouse liver, induced HBV persistent infection accompanied by liver fibrosis which can serve as a model for investigating the precise mechanisms underlying liver fibrosis following chronic HBV infection as well as for the potential development of novel therapeutics.
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MESH Headings
- Animals
- Blotting, Northern
- Blotting, Southern
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/virology
- Cells, Cultured
- Dependovirus/genetics
- Disease Models, Animal
- Drug Delivery Systems
- Enzyme-Linked Immunosorbent Assay
- Genetic Vectors/administration & dosage
- Genome, Viral
- HEK293 Cells
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/virology
- Humans
- Liver Cirrhosis/genetics
- Liver Cirrhosis/virology
- Liver Neoplasms/genetics
- Liver Neoplasms/virology
- Mice
- Mice, Inbred C57BL
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Viremia/genetics
- Viremia/virology
- Virus Replication
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Affiliation(s)
- Lei Ye
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
| | - Haisheng Yu
- Key Laboratory of Immunity and Infection, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Chengwen Li
- Gene Therapy Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Matthew L. Hirsch
- Gene Therapy Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Liguo Zhang
- Key Laboratory of Immunity and Infection, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - R. Jude Samulski
- Gene Therapy Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Wuping Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- * E-mail:
| | - Zhong Liu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
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Tang Y. Curcumin targets multiple pathways to halt hepatic stellate cell activation: updated mechanisms in vitro and in vivo. Dig Dis Sci 2015; 60:1554-64. [PMID: 25532502 DOI: 10.1007/s10620-014-3487-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 12/07/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease, which is often accompanied by obese and/or type II diabetes mellitus. Approximately one-third of NASH patients develop hepatic fibrosis. Hepatic stellate cells are the major effector cells during liver fibrogenesis. Advanced liver fibrosis usually proceeds to cirrhosis and even hepatocellular carcinoma, leading to liver failure, portal hypertension and even death. Currently, there are no approved agents for treatment and prevention of liver fibrosis in human beings. Curcumin, the principal curcuminoid of turmeric, has been reported to show antitumor, antioxidant, and anti-inflammatory properties both in in vitro and in vivo systems. Accumulating data shows that curcumin plays a critical role in combating liver fibrogenesis. This review will discuss the inhibitory roles of curcumin and update the underlying mechanisms by which curcumin targets in inhibiting hepatic stellate cell activation.
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Affiliation(s)
- Youcai Tang
- Department of Pediatrics, The Second Affiliated Hospital, Zhengzhou University, 2 Jingba Road, Zhengzhou, 450014, Henan, China,
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Kantari-Mimoun C, Castells M, Klose R, Meinecke AK, Lemberger UJ, Rautou PE, Pinot-Roussel H, Badoual C, Schrödter K, Österreicher CH, Fandrey J, Stockmann C. Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis. Hepatology 2015; 61:2042-55. [PMID: 25475053 DOI: 10.1002/hep.27635] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 12/01/2014] [Indexed: 12/12/2022]
Abstract
UNLABELLED Angiogenesis is a key feature of liver fibrosis. Although sinusoidal remodeling is believed to contribute to fibrogenesis, the impact of sinusoidal angiogenesis on the resolution of liver fibrosis remains undefined. Myeloid cells, particularly macrophages, constantly infiltrate the fibrotic liver and can profoundly contribute to remodeling of liver sinusoids. We observe that the development of fibrosis is associated with decreased hepatic vascular endothelial growth factor (VEGF) expression as well as sinusoidal rarefication of the fibrotic scar. In contrast, the resolution of fibrosis is characterized by a rise in hepatic VEGF levels and revascularization of the fibrotic tissue. Genetic ablation of VEGF in myeloid cells or pharmacological inhibition of VEGF receptor 2 signaling prevents this angiogenic response and the resolution of liver fibrosis. We observe increased expression of matrix metalloproteases as well as decreased expression of tissue inhibitor of metalloproteases confined to sinusoidal endothelial cells in response to myeloid cell VEGF. Remarkably, reintroduction of myeloid cell-derived VEGF upon recovery restores collagenolytic acitivity and the resolution of fibrosis. CONCLUSION We identify myeloid cell-derived VEGF as a critical regulator of extracellular matrix degradation by liver endothelial cells, thereby unmasking an unanticipated link between angiogenesis and the resolution of fibrosis.
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Affiliation(s)
- Chahrazade Kantari-Mimoun
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France
| | - Magali Castells
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France
| | - Ralph Klose
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France
| | - Anna-Katharina Meinecke
- Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Duisburg, Germany
| | - Ursula J Lemberger
- Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Pierre-Emmanuel Rautou
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.,DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
| | - Hélène Pinot-Roussel
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.,Service d'Anatomie et Pathologie, Hôpital Européen Georges Pompidou, APHP, Paris, France
| | - Cécile Badoual
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.,Service d'Anatomie et Pathologie, Hôpital Européen Georges Pompidou, APHP, Paris, France
| | - Katrin Schrödter
- Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Duisburg, Germany
| | - Christoph H Österreicher
- Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Joachim Fandrey
- Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Duisburg, Germany
| | - Christian Stockmann
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France
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Atta HM. Reversibility and heritability of liver fibrosis: Implications for research and therapy. World J Gastroenterol 2015; 21:5138-5148. [PMID: 25954087 PMCID: PMC4419054 DOI: 10.3748/wjg.v21.i17.5138] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Revised: 02/20/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis continues to be a major health problem worldwide due to lack of effective therapy. If the etiology cannot be eliminated, liver fibrosis progresses to cirrhosis and eventually to liver failure or malignancy; both are associated with a fatal outcome. Liver transplantation, the only curative therapy, is still mostly unavailable. Liver fibrosis was shown to be a reversible process; however, complete reversibility remains debatable. Recently, the molecular markers of liver fibrosis were shown to be transmitted across generations. Epigenetic mechanisms including DNA methylation, histone posttranslational modifications and noncoding RNA have emerged as major determinants of gene expression during liver fibrogenesis and carcinogenesis. Furthermore, epigenetic mechanisms have been shown to be transmitted through mitosis and meiosis to daughter cells and subsequent generations. However, the exact epigenetic regulation of complete liver fibrosis resolution and inheritance has not been fully elucidated. This communication will highlight the recent advances in the search for delineating the mechanisms governing resolution of liver fibrosis and the potential for multigenerational and transgenerational transmission of fibrosis markers. The fact that epigenetic changes, unlike genetic mutations, are reversible and can be modulated pharmacologically underscores the unique opportunity to develop effective therapy to completely reverse liver fibrosis, to prevent the development of malignancy and to regulate heritability of fibrosis phenotype.
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