|
1
|
Wang SQ, Meng YQ, Wu YL, Nan JX, Jin CH, Lian LH. Imidazole-Based ALK5 Inhibitor Attenuates TGF-β/Smad-Mediated Hepatic Stellate Cell Activation and Hepatic Fibrogenesis. Chem Res Toxicol 2025; 38:930-941. [PMID: 40211771 DOI: 10.1021/acs.chemrestox.5c00036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Liver fibrosis resulting from severe liver damage is a major clinical problem for which effective pharmacological drugs and treatment strategies are lacking. TGF-β, a hallmark of liver fibrosis, has been shown to promote ALK5 phosphorylation in an activated state. Hence, the suppression of ALK5 signal transduction has emerged as a promising therapeutic strategy for the treatment of liver fibrosis. In this study, the imidazole derivative J-1149, which exhibited inhibitory activity against ALK5, was synthesized to exert antifibrotic effects, and the inhibition mechanisms were uncovered. Our findings suggested that J-1149 significantly attenuated HSC activation and liver fibrogenesis by acting on the TGF-β/Smad signaling pathway. Concurrently, the potential of J-1149 to impede the P2X7R/NLRP3 axis, curtail the infiltration of macrophages and neutrophils, and reduce liver fibrogenesis was also highlighted. These results demonstrated that J-1149 is a promising candidate for the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Si-Qi Wang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
- Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yu-Qing Meng
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
- Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
- Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
- Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Cheng-Hua Jin
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
- Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
- Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| |
Collapse
|
|
2
|
Elison W, Chang L, Xie Y, Miciano C, Yang Q, Mummey H, Lancione R, Corban S, Sakane S, Lucero J, Mamde S, Kim HY, Kim MJ, Melton R, Tucciarone L, Lie A, Loe T, Vashist T, Dang K, Elgamal R, Li D, Vu M, Farah EN, Seng C, Djulamsah J, Yang B, Buchanan J, Miller M, Tran M, Birrueta JO, Chi NC, Wang T, D’Antonio-Chronowska A, Wang A, Kisseleva T, Brenner D, Ren B, Gaulton KJ. Single cell multiomics reveals drivers of metabolic dysfunction-associated steatohepatitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.05.09.25327043. [PMID: 40385416 PMCID: PMC12083587 DOI: 10.1101/2025.05.09.25327043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has limited treatments, and cell type-specific regulatory networks driving MASLD represent therapeutic avenues. We assayed five transcriptomic and epigenomic modalities in 2.4M cells from 86 livers across MASLD stages. Integrating modalities increased annotation of the genome in liver cell types several-fold over previous catalogs. We identified cell type regulatory networks of MASLD progression, including distinct hepatocyte networks driving MASL and mild and severe fibrosis MASH. Our single cell atlas annotated 88% of MASH-associated loci, including a third affecting hepatocyte regulation which we linked to distal target genes. Finally, we characterized hepatocyte heterogeneity, including MASH-enriched populations with altered repression, localization, and signaling. Overall, our results provide high-resolution maps of liver cell types and revealed novel targets for anti-MASH therapy.
Collapse
Affiliation(s)
- Weston Elison
- Biomedical Sciences program, University of California San Deigo; La Jolla CA
| | - Lei Chang
- Department of Cellular and Molecular Medicine, University of California San Diego; La Jolla, CA
| | - Yang Xie
- Department of Cellular and Molecular Medicine, University of California San Diego; La Jolla, CA
| | - Charlene Miciano
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Qian Yang
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Hannah Mummey
- Bioinformatics and Systems Biology program, University of California San Diego; La Jolla CA
| | - Ryan Lancione
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Sierra Corban
- Department of Pediatrics, University of California San Diego; La Jolla CA
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego; La Jolla CA USA
| | - Jacinta Lucero
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Sainath Mamde
- Department of Cellular and Molecular Medicine, University of California San Diego; La Jolla, CA
| | - Hyun Young Kim
- Department of Medicine, University of California San Diego; La Jolla CA USA
| | - Matthew J Kim
- Department of Pediatrics, University of California San Diego; La Jolla CA
| | - Rebecca Melton
- Biomedical Sciences program, University of California San Deigo; La Jolla CA
| | - Luca Tucciarone
- Department of Pediatrics, University of California San Diego; La Jolla CA
| | - Audrey Lie
- Department of Cellular and Molecular Medicine, University of California San Diego; La Jolla, CA
| | - Timothy Loe
- Department of Cellular and Molecular Medicine, University of California San Diego; La Jolla, CA
| | - Tanmayi Vashist
- Biomedical Sciences program, University of California San Deigo; La Jolla CA
| | - Kelsey Dang
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Ruth Elgamal
- Biomedical Sciences program, University of California San Deigo; La Jolla CA
| | - Daofeng Li
- Department of Genetics, Washington University in St. Louis; St. Louis MO USA
| | - Melissa Vu
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Diego, La Jolla, CA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA
| | - Elie N Farah
- Department of Medicine, University of California San Diego; La Jolla CA USA
| | - Chad Seng
- Department of Genetics, Washington University in St. Louis; St. Louis MO USA
| | - Jovina Djulamsah
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Bing Yang
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Justin Buchanan
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Michael Miller
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Mai Tran
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | | | - Neil C Chi
- Department of Medicine, University of California San Diego; La Jolla CA USA
| | - Ting Wang
- Department of Genetics, Washington University in St. Louis; St. Louis MO USA
| | | | - Allen Wang
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego; La Jolla CA USA
| | - David Brenner
- Department of Medicine, University of California San Diego; La Jolla CA USA
- Sanford Burnham Prebys Medical Discovery Institute; La Jolla CA USA
| | - Bing Ren
- Department of Cellular and Molecular Medicine, University of California San Diego; La Jolla, CA
- Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Deigo; La Jolla CA
- Institute for Genomic Medicine, University of California; San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego; La Jolla, CA, USA
- New York Genome Center; New York, NY, USA
- Department of Genetics and Development, Systems Biology, Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center; New York, NY, USA
| | - Kyle J Gaulton
- Department of Pediatrics, University of California San Diego; La Jolla CA
- Institute for Genomic Medicine, University of California; San Diego, La Jolla, CA, USA
| |
Collapse
|
|
3
|
Aabis M, Tiwari P, Kumar V, Singh G, Panghal A, Jena G. Pentadecanoic acid attenuates thioacetamide-induced liver fibrosis by modulating oxidative stress, inflammation, and ferroptosis pathways in rat. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04143-6. [PMID: 40310526 DOI: 10.1007/s00210-025-04143-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 04/03/2025] [Indexed: 05/02/2025]
Abstract
Pentadecanoic acid (PDA) has been reported as a histone deacetylase 6 inhibitor. Numerous studies have shown that Histone deacetylases (HDACs) are significantly involved in the development of fibrosis. The present study focused on assessing the anti-fibrotic properties of PDA in ameliorating hepatic fibrosis induced by thioacetamide (TAA) in Wistar rats. PDA was administered orally at the doses of 10, 20 and 40 mg/kg daily, whereas TAA was administered intraperitoneally at a dose of 200 mg/kg twice weekly, for a period of 9 weeks. Administration of TAA significantly increased the relative and absolute liver weight, alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (γ-GT), myeloperoxidase (MPO), malondialdehyde (MDA) and reduced the glutathione (GSH) levels and PDA intervention restored the same. PDA treatment ameliorated TAA-induced collagen deposition and infiltration of inflammatory cells as revealed by Sirius red and H&E staining. Additionally, histopathological analysis revealed lymphocyte infiltration, collagen build up, development of bridging fibrosis, degeneration of the portal triad, iron accumulation, and necrosis in TAA-treated rats. The intervention with PDA significantly mitigated these pathological changes. PDA treatment significantly downregulated the expressions of TGF-β1, α-SMA, NLRP3, NF-κB and HDAC6 against TAA-induced liver damage. The present study clearly demonstrated that PDA treatment significantly alleviated TAA-induced hepatic fibrosis by ameliorating the inflammatory markers.
Collapse
Affiliation(s)
- Mohammad Aabis
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, 160062, India
| | - Priyanka Tiwari
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, 160062, India
| | - Vinod Kumar
- High resolution Transmission electron microscopy Facility, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Mohali (near to Chandigarh), Punjab, 160062, India
| | - Gurpreet Singh
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, 160062, India
| | - Archana Panghal
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, 160062, India
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, 160062, India.
| |
Collapse
|
|
4
|
Li L, Liu Y, Wang K, Mo J, Weng Z, Jiang H, Jin C. Stem cell exosomes: new hope and future potential for relieving liver fibrosis. Clin Mol Hepatol 2025; 31:333-349. [PMID: 39510097 PMCID: PMC12016649 DOI: 10.3350/cmh.2024.0854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/15/2024] Open
Abstract
Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.
Collapse
Affiliation(s)
- Lihua Li
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Yongjie Liu
- Department of Cell biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, P. R. China
- Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, P. R. China
| | - Kunpeng Wang
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Jinggang Mo
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Zhiyong Weng
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Hao Jiang
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Chong Jin
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| |
Collapse
|
|
5
|
Bases E, El-Sheekh MM, El Shafay SM, El-Shenody R, Nassef M. Therapeutic anti-inflammatory immune potentials of some seaweeds extracts on chemically induced liver injury in mice. Sci Rep 2025; 15:4370. [PMID: 39910080 PMCID: PMC11799325 DOI: 10.1038/s41598-025-87379-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 01/20/2025] [Indexed: 02/07/2025] Open
Abstract
Carbon tetrachloride (CCl4) is a well-known hepatotoxin. This work aimed to assess the therapeutic anti-inflammatory immune potentials of the seaweeds Padina pavonia and Jania rubens extracts on carbon tetrachloride (CCL4)-caused liver damage in mice. Our experimentation included two testing regimens: pre-treatment and post-treatment of P. pavonia and J. rubens extracts in CCL4/mice. Pre-treatment and post-treatment of P. pavonia and J. rubens extracts in CCL4/mice increased WBCs count and lymphocytes relative numbers and reduced the neutrophils and monocytes relative numbers. Pre-treatment and post-treatment of CCL4/mice with P. pavonia and J. rubens extracts significantly reduced the release amounts of pro-inflammatory cytokines TNF-α and IL-6 and significantly inhibited the increased CRP level. Furthermore, pre-treatment and post-treatment of CCL4/mice with P. pavonia and J. rubens extracts recovered the activities of GSH, and significantly decreased MDA level. CCL4/mice pre-treated and post-treated with P. pavonia and J. rubens extracts decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Pre- and post-treatment of CCL4/mice with the P. pavonia and J. rubens extracts ameliorated the liver damages caused by CCl4 and significantly inhibited the necrotic area, indicating hepatic cell death and decreased periportal hepatic degeneration, fibrosis, and inflammation.
Collapse
Affiliation(s)
- Eman Bases
- Botany Department, Faculty of Science, Tanta University, Tanta, Egypt
| | | | | | - Rania El-Shenody
- Botany Department, Faculty of Science, Tanta University, Tanta, Egypt
| | - Mohamed Nassef
- Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
| |
Collapse
|
|
6
|
Roy S, Chakrabarti M, Mondal T, Das TK, Sarkar T, Datta S, Kundu M, Banerjee M, Kulkarni OP. Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2- a] Pyrimidin-5(8 H)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats. ACS Pharmacol Transl Sci 2024; 7:2662-2676. [PMID: 39296254 PMCID: PMC11406694 DOI: 10.1021/acsptsci.4c00066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/21/2024]
Abstract
The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-β, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.
Collapse
Affiliation(s)
- Subhasis Roy
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Monali Chakrabarti
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Trisha Mondal
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Tapas Kumar Das
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Tonmoy Sarkar
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Sebak Datta
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Mrinalkanti Kundu
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Manish Banerjee
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Onkar Prakash Kulkarni
- Metabolic Disorders and Neuroscience Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Hyderabad 500078, India
| |
Collapse
|
|
7
|
Ji G, Zhang Z, Wang X, Guo Q, Zhang E, Li C. Comprehensive evaluation of the mechanism of human adipose mesenchymal stem cells ameliorating liver fibrosis by transcriptomics and metabolomics analysis. Sci Rep 2024; 14:20035. [PMID: 39198546 PMCID: PMC11358327 DOI: 10.1038/s41598-024-70281-1] [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: 05/04/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Liver fibrosis is a chronic liver disease with progressive wound healing reaction caused by liver injury. Currently, there is no FDA approved drugs for liver fibrosis. Human adipose mesenchymal stem cells (hADSCs) have shown remarkable therapeutic effects in liver diseases. However, few studies have evaluated the therapeutic role of hADSCs in liver fibrosis, and the detailed mechanism of action is unknown. Here, we investigated the in vitro and in vivo anti-fibrosis efficacy of hADSCs and identified important metabolic changes and detailed mechanisms through transcriptomic and metabolomic analyses. We found that hADSCs could inhibit the proliferation of activated hepatic stellate cells (HSCs), promote their apoptosis, and effectively inhibit the expression of pro-fibrotic protein. It can significantly reduce collagen deposition and liver injury, improve liver function and alleviate liver inflammation in cirrhotic mouse models. In addition, transcriptome analysis revealed that the key mechanism of hADSCs against liver fibrosis is the regulation of AGE-RAGE signaling pathway. Metabolic analysis showed that hADSCs influenced changes of metabolites in lipid metabolism. Therefore, our study shows that hADSCs could reduce the activation of hepatic stellate cells and inhibit the progression of liver fibrosis, which has important potential in the treatment of liver fibrosis as well as other refractory chronic liver diseases.
Collapse
Affiliation(s)
- Guibao Ji
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Department of Hepatobiliary-Pancreatic and Hernia Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Zilong Zhang
- Department of Hepatobiliary-Pancreatic and Hernia Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Xinze Wang
- Department of Trauma and Orthopedics, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Qiuxia Guo
- Department of Gastroenterology Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Erlei Zhang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
| | - Chuanjiang Li
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
| |
Collapse
|
|
8
|
Breitkopf-Heinlein K, Martinez-Chantar ML. Targeting hepatic stellate cells to combat liver fibrosis: where do we stand? Gut 2024; 73:1411-1413. [PMID: 38684236 DOI: 10.1136/gutjnl-2023-331785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/16/2024] [Indexed: 05/02/2024]
Affiliation(s)
- Katja Breitkopf-Heinlein
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany
| | | |
Collapse
|
|
9
|
Elblová P, Lunova M, Dejneka A, Jirsa M, Lunov O. Impact of mechanical cues on key cell functions and cell-nanoparticle interactions. DISCOVER NANO 2024; 19:106. [PMID: 38907808 PMCID: PMC11193707 DOI: 10.1186/s11671-024-04052-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 06/14/2024] [Indexed: 06/24/2024]
Abstract
In recent years, it has been recognized that mechanical forces play an important regulative role in living organisms and possess a direct impact on crucial cell functions, ranging from cell growth to maintenance of tissue homeostasis. Advancements in mechanobiology have revealed the profound impact of mechanical signals on diverse cellular responses that are cell type specific. Notably, numerous studies have elucidated the pivotal role of different mechanical cues as regulatory factors influencing various cellular processes, including cell spreading, locomotion, differentiation, and proliferation. Given these insights, it is unsurprising that the responses of cells regulated by physical forces are intricately linked to the modulation of nanoparticle uptake kinetics and processing. This complex interplay underscores the significance of understanding the mechanical microenvironment in shaping cellular behaviors and, consequently, influencing how cells interact with and process nanoparticles. Nevertheless, our knowledge on how localized physical forces affect the internalization and processing of nanoparticles by cells remains rather limited. A significant gap exists in the literature concerning a systematic analysis of how mechanical cues might bias the interactions between nanoparticles and cells. Hence, our aim in this review is to provide a comprehensive and critical analysis of the existing knowledge regarding the influence of mechanical cues on the complicated dynamics of cell-nanoparticle interactions. By addressing this gap, we would like to contribute to a detailed understanding of the role that mechanical forces play in shaping the complex interplay between cells and nanoparticles.
Collapse
Affiliation(s)
- Petra Elblová
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic
- Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16, Prague 2, Czech Republic
| | - Mariia Lunova
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic
- Institute for Clinical & Experimental Medicine (IKEM), 14021, Prague, Czech Republic
| | - Alexandr Dejneka
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic
| | - Milan Jirsa
- Institute for Clinical & Experimental Medicine (IKEM), 14021, Prague, Czech Republic
| | - Oleg Lunov
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic.
| |
Collapse
|
|
10
|
Zhao B, Liu K, Liu X, Li Q, Li Z, Xi J, Xie F, Li X. Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis. Phytother Res 2024; 38:3122-3145. [PMID: 38613172 DOI: 10.1002/ptr.8193] [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: 09/07/2023] [Revised: 02/28/2024] [Accepted: 03/10/2024] [Indexed: 04/14/2024]
Abstract
Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.
Collapse
Affiliation(s)
- Bolin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kai Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhibei Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingjing Xi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Xie
- Hospital of Chengdu University of Traditional Chinese Medicine 610032, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
11
|
Shinde SS, Chakole S, Humane S. Understanding Alcohol Relapse in Liver Transplant Patients With Alcohol-Related Liver Disease: A Comprehensive Review. Cureus 2024; 16:e54052. [PMID: 38481880 PMCID: PMC10934278 DOI: 10.7759/cureus.54052] [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: 10/30/2023] [Accepted: 02/12/2024] [Indexed: 11/02/2024] Open
Abstract
Alcohol-related liver disease (ALD) presents a significant global health concern, with liver transplantation being a crucial intervention for patients in the advanced stages of the disease. However, the persistent risk of alcohol relapse in transplant recipients with ALD remains a formidable challenge. This comprehensive review explores the multifaceted nature of alcohol relapse, from its underlying factors to strategies for prevention. It highlights the importance of rigorous pre-transplant assessments, effective post-transplant interventions, and the role of multidisciplinary care teams in mitigating the risk of relapse. Furthermore, the review underscores the significance of adopting a holistic approach to ALD and transplantation, acknowledging the interconnectedness of medical, psychosocial, and psychological factors. With this holistic approach, we aim to enhance patient outcomes, reduce relapse rates, and ultimately improve the overall quality of life for individuals affected by ALD.
Collapse
Affiliation(s)
- Shreyashee S Shinde
- Pediatrics, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Swarupa Chakole
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sonal Humane
- Mental Health Nursing, Smt. Radhikabai Meghe Memorial College of Nursing, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| |
Collapse
|
|
12
|
Di Fazio P, Mielke S, Böhm IT, Buchholz M, Matrood S, Schuppan D, Wissniowski T. Toll-like receptor 5 tunes hepatic and pancreatic stellate cells activation. BMJ Open Gastroenterol 2023; 10:e001148. [PMID: 37433685 PMCID: PMC10347502 DOI: 10.1136/bmjgast-2023-001148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
OBJECTIVE Stellate cells are responsible for liver and pancreas fibrosis and strictly correlate with tumourigenesis. Although their activation is reversible, an exacerbated signalling triggers chronic fibrosis. Toll-like receptors (TLRs) modulate stellate cells transition. TLR5 transduces the signal deriving by the binding to bacterial flagellin from invading mobile bacteria. DESIGN Human hepatic and pancreatic stellate cells were activated by the administration of transforming growth factor-beta (TGF-β). TLR5 was transiently knocked down by short-interference RNA transfection. Reverse Transcription-quantitativePCR and western blot were performed to analyse the transcript and protein level of TLR5 and the transition players. Fluorescence microscopy was performed to identify these targets in spheroids and in the sections of murine fibrotic liver. RESULTS TGF-β-activated human hepatic and pancreatic stellate cells showed an increase of TLR5 expression. TLR5 knockdown blocked the activation of those stellate cells. Furthermore, TLR5 busted during murine liver fibrosis and co-localised with the inducible Collagen I. Flagellin suppressed TLR5, COL1A1 and ACTA2 expression after the administration of TGF-β. Instead, the antagonist of TLR5 did not block the effect of TGF-β. Wortmannin, a specific AKT inhibitor, induced TLR5 but not COL1A1 and ACTA2 transcript and protein level. CONCLUSION TGF-β-mediated activation of hepatic and pancreatic stellate cells requires the over-expression of TLR5. Instead, its autonomous signalling inhibits the activation of the stellate cells, thus prompting a signalling through different regulatory pathways.
Collapse
Affiliation(s)
- Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Sophia Mielke
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Isabell T Böhm
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Malte Buchholz
- Department of Gastroenterology, Philipps-Universität Marburg, Marburg, Germany
| | - Sami Matrood
- Department of Visceral Thoracic and Vascular Surgery, Philipps-Universität Marburg, Marburg, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, Johannes Gutenberg Universitat Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | |
Collapse
|
|
13
|
Lauer SM, Omar MH, Golkowski MG, Kenerson HL, Pascual BC, Forbush K, Smith FD, Gordan J, Ong SE, Yeung RS, Scott JD. Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.28.546958. [PMID: 37425703 PMCID: PMC10327129 DOI: 10.1101/2023.06.28.546958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
The DNAJ-PKAc fusion kinase is a defining feature of the adolescent liver cancer fibrolamellar carcinoma (FLC). A single lesion on chromosome 19 generates this mutant kinase by creating a fused gene encoding the chaperonin binding domain of Hsp40 (DNAJ) in frame with the catalytic core of protein kinase A (PKAc). FLC tumors are notoriously resistant to standard chemotherapies. Aberrant kinase activity is assumed to be a contributing factor. Yet recruitment of binding partners, such as the chaperone Hsp70, implies that the scaffolding function of DNAJ- PKAc may also underlie pathogenesis. By combining proximity proteomics with biochemical analyses and photoactivation live-cell imaging we demonstrate that DNAJ-PKAc is not constrained by A-kinase anchoring proteins. Consequently, the fusion kinase phosphorylates a unique array of substrates. One validated DNAJ-PKAc target is the Bcl-2 associated athanogene 2 (BAG2), a co-chaperone recruited to the fusion kinase through association with Hsp70. Immunoblot and immunohistochemical analyses of FLC patient samples correlate increased levels of BAG2 with advanced disease and metastatic recurrences. BAG2 is linked to Bcl-2, an anti-apoptotic factor that delays cell death. Pharmacological approaches tested if the DNAJ- PKAc/Hsp70/BAG2 axis contributes to chemotherapeutic resistance in AML12 DNAJ-PKAc hepatocyte cell lines using the DNA damaging agent etoposide and the Bcl-2 inhibitor navitoclax. Wildtype AML12 cells were susceptible to each drug alone and in combination. In contrast, AML12 DNAJ-PKAc cells were moderately affected by etoposide, resistant to navitoclax, but markedly susceptible to the drug combination. These studies implicate BAG2 as a biomarker for advanced FLC and a chemotherapeutic resistance factor in DNAJ-PKAc signaling scaffolds.
Collapse
|
|
14
|
Fitzgerald H, Bonin JL, Sadhu S, Lipscomb M, Biswas N, Decker C, Nabage M, Bossardi R, Marinello M, Mena AH, Gilliard K, Spite M, Adam A, MacNamara KC, Fredman G. The Resolvin D2-GPR18 Axis Enhances Bone Marrow Function and Limits Hepatic Fibrosis in Aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.05.522881. [PMID: 36711905 PMCID: PMC9881918 DOI: 10.1101/2023.01.05.522881] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Aging is associated with non-resolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a pro-resolving ligand that acts through the G-protein coupled receptor (GPCR) called GRP18. Using an unbiased screen, we report increased Gpr18 expression in macrophages from old mice and in livers from elderly humans that is associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, monocyte-derived macrophages and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly upon the bone marrow to increase monocyte-macrophage progenitors. Using a transplantation assay we further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice, and transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, our study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.
Collapse
|
|
15
|
Rao J, Wang H, Ni M, Wang Z, Wang Z, Wei S, Liu M, Wang P, Qiu J, Zhang L, Wu C, Shen H, Wang X, Cheng F, Lu L. FSTL1 promotes liver fibrosis by reprogramming macrophage function through modulating the intracellular function of PKM2. Gut 2022; 71:2539-2550. [PMID: 35140065 PMCID: PMC9664121 DOI: 10.1136/gutjnl-2021-325150] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 01/23/2022] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Follistatin-like protein 1 (FSTL1) is widely recognised as a secreted glycoprotein, but its role in modulating macrophage-related inflammation during liver fibrosis has not been documented. Herein, we aimed to characterise the roles of macrophage FSTL1 in the development of liver fibrosis. DESIGN Expression analysis was conducted with human liver samples obtained from 33 patients with liver fibrosis and 18 individuals without fibrosis serving as controls. Myeloid-specific FSTL1-knockout (FSTL1M-KO) mice were constructed to explore the function and mechanism of macrophage FSTL1 in 3 murine models of liver fibrosis induced by carbon tetrachloride injection, bile duct ligation or a methionine-deficient and choline-deficient diet. RESULTS FSTL1 expression was significantly elevated in macrophages from fibrotic livers of both humans and mice. Myeloid-specific FSTL1 deficiency effectively attenuated the progression of liver fibrosis. In FSTL1M-KO mice, the microenvironment that developed during liver fibrosis showed relatively less inflammation, as demonstrated by attenuated infiltration of monocytes/macrophages and neutrophils and decreased expression of proinflammatory factors. FSTL1M-KO macrophages exhibited suppressed proinflammatory M1 polarisation and nuclear factor kappa B pathway activation in vivo and in vitro. Furthermore, this study showed that, through its FK domain, FSTL1 bound directly to the pyruvate kinase M2 (PKM2). Interestingly, FSTL1 promoted PKM2 phosphorylation and nuclear translocation, reduced PKM2 ubiquitination to enhance PKM2-dependent glycolysis and increased M1 polarisation. Pharmacological activation of PKM2 (DASA-58) partially countered FSTL1-mediated glycolysis and inflammation. CONCLUSION Macrophage FSTL1 promotes the progression of liver fibrosis by inducing M1 polarisation and inflammation based on the intracellular PKM2 reprogramming function of macrophages.
Collapse
Affiliation(s)
- Jianhua Rao
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, Jiangsu, China
| | - Hao Wang
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Ni
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zeng Wang
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ziyi Wang
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Song Wei
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Mu Liu
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peng Wang
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiannan Qiu
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Zhang
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chen Wu
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongbing Shen
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuehao Wang
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feng Cheng
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, Jiangsu, China
| | - Ling Lu
- Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, Jiangsu, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
16
|
Dai Q, Ain Q, Rooney M, Song F, Zipprich A. Role of IQ Motif-Containing GTPase-Activating Proteins in Hepatocellular Carcinoma. Front Oncol 2022; 12:920652. [PMID: 35785216 PMCID: PMC9243542 DOI: 10.3389/fonc.2022.920652] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/10/2022] [Indexed: 11/21/2022] Open
Abstract
IQ motif-containing GTPase-activating proteins (IQGAPs) are a class of scaffolding proteins, including IQGAP1, IQGAP2, and IQGAP3, which govern multiple cellular activities by facilitating cytoskeletal remodeling and cellular signal transduction. The role of IQGAPs in cancer initiation and progression has received increasing attention in recent years, especially in hepatocellular carcinoma (HCC), where the aberrant expression of IQGAPs is closely related to patient prognosis. IQGAP1 and 3 are upregulated and are considered oncogenes in HCC, while IQGAP2 is downregulated and functions as a tumor suppressor. This review details the three IQGAP isoforms and their respective structures. The expression and role of each protein in different liver diseases and mainly in HCC, as well as the underlying mechanisms, are also presented. This review also provides a reference for further studies on IQGAPs in HCC.
Collapse
Affiliation(s)
- Qingqing Dai
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
- Else Kröner Graduate School for Medical Students “Jena School for Ageing Medicine (JSAM)”, Jena University Hospital, Jena, Germany
| | - Quratul Ain
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Michael Rooney
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Fei Song
- Department of Urology, Jena University Hospital, Jena, Germany
| | - Alexander Zipprich
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
- *Correspondence: Alexander Zipprich,
| |
Collapse
|
|
17
|
Chiabotto G, Ceccotti E, Tapparo M, Camussi G, Bruno S. Human Liver Stem Cell-Derived Extracellular Vesicles Target Hepatic Stellate Cells and Attenuate Their Pro-fibrotic Phenotype. Front Cell Dev Biol 2021; 9:777462. [PMID: 34796180 PMCID: PMC8593217 DOI: 10.3389/fcell.2021.777462] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis occurs in response to chronic liver injury and is characterized by an excessive deposition of extracellular matrix. Activated hepatic stellate cells are primarily responsible for this process. A possible strategy to counteract the development of hepatic fibrosis could be the reversion of the activated phenotype of hepatic stellate cells. Extracellular vesicles (EVs) are nanosized membrane vesicles involved in intercellular communication. Our previous studies have demonstrated that EVs derived from human liver stem cells (HLSCs), a multipotent population of adult stem cells of the liver with mesenchymal-like phenotype, exert in vivo anti-fibrotic activity in the liver. However, the mechanism of action of these EVs remains to be determined. We set up an in vitro model of hepatic fibrosis using a human hepatic stellate cell line (LX-2) activated by transforming growth factor-beta 1 (TGF-β1). Then, we investigated the effect of EVs obtained from HLSCs and from human bone marrow-derived mesenchymal stromal cells (MSCs) on activated LX-2. The incubation of activated LX-2 with HLSC-EVs reduced the expression level of alpha-smooth muscle actin (α-SMA). Conversely, MSC-derived EVs induced an increase in the expression of pro-fibrotic markers in activated LX-2. The analysis of the RNA cargo of HLSC-EVs revealed the presence of several miRNAs involved in the regulation of fibrosis and inflammation. Predictive target analysis indicated that several microRNAs (miRNAs) contained into HLSC-EVs could possibly target pro-fibrotic transcripts. In particular, we demonstrated that HLSC-EVs shuttled miR-146a-5p and that treatment with HLSC-EVs increased miR-146a-5p expression in LX-2. In conclusion, this study demonstrates that HLSC-EVs can attenuate the activated phenotype of hepatic stellate cells and that their biological effect may be mediated by the delivery of anti-fibrotic miRNAs, such as miR-146a-5p.
Collapse
Affiliation(s)
- Giulia Chiabotto
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Elena Ceccotti
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Marta Tapparo
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| |
Collapse
|
|
18
|
Kartasheva-Ebertz DM, Pol S, Lagaye S. Retinoic Acid: A New Old Friend of IL-17A in the Immune Pathogeny of Liver Fibrosis. Front Immunol 2021; 12:691073. [PMID: 34211477 PMCID: PMC8239722 DOI: 10.3389/fimmu.2021.691073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
Despite all the medical advances mortality due to cirrhosis and hepatocellular carcinoma, the end stages of fibrosis, continuously increases. Recent data suggest that liver fibrosis is guided by type 3 inflammation with IL-17A at the top of the line. The storage of vitamin A and its active metabolites, as well as genetics, can influence the development and progression of liver fibrosis and inflammation. Retinoic acid (active metabolite of vitamin A) is able to regulate the differentiation of IL-17A+/IL-22–producing cells as well as the expression of profibrotic markers. IL-17A and its pro-fibrotic role in the liver is the most studied, while the interaction and communication between IL-17A, IL-22, and vitamin A–active metabolites has not been investigated. We aim to update what is known about IL-17A, IL-22, and retinoic acid in the pathobiology of liver diseases.
Collapse
Affiliation(s)
| | - Stanislas Pol
- Institut Pasteur, INSERM U1223, Paris, France.,Université de Paris, Paris, France.,APHP, Groupe Hospitalier Cochin, Département d'Hépatologie, Paris, France
| | | |
Collapse
|
|
19
|
Liu Y, Wu X, Wang Y, Guo Y. Endoplasmic reticulum stress and autophagy are involved in adipocyte-induced fibrosis in hepatic stellate cells. Mol Cell Biochem 2021; 476:2527-2538. [PMID: 33638026 DOI: 10.1007/s11010-020-03990-6] [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: 05/05/2020] [Accepted: 11/16/2020] [Indexed: 11/28/2022]
Abstract
Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF β/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.
Collapse
Affiliation(s)
- Yingjuan Liu
- Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.,Medical College, Qingdao University, Qingdao, 266071, China
| | - Xiaolin Wu
- Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yue Wang
- Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yunliang Guo
- Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. .,Medical College, Qingdao University, Qingdao, 266071, China.
| |
Collapse
|
|
20
|
Negro F. Natural History of Hepatic and Extrahepatic Hepatitis C Virus Diseases and Impact of Interferon-Free HCV Therapy. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036921. [PMID: 31636094 DOI: 10.1101/cshperspect.a036921] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The hepatitis C virus (HCV) infects 71.1 million persons and causes 400,000 deaths annually worldwide. HCV mostly infects the liver, causing acute and chronic necroinflammatory damage, which may progress toward cirrhosis and hepatocellular carcinoma. In addition, HCV has been associated with several extrahepatic manifestations. The advent of safe and effective direct-acting antivirals (DAAs) has made the dream of eliminating this public health scourge feasible in the medium term. Prospective studies using DAA-based regimens have shown the benefit of HCV clearance in terms of both liver- and non-liver-related mortality.
Collapse
Affiliation(s)
- Francesco Negro
- Divisions of Clinical Pathology and of Gastroenterology and Hepatology, University Hospital, 1211 Genève 4, Switzerland
| |
Collapse
|
|
21
|
Protective Effect of Phaleria macrocarpa Water Extract (Proliverenol) against Carbon Tetrachloride-Induced Liver Fibrosis in Rats: Role of TNF- α and TGF- β1. J Toxicol 2018; 2018:2642714. [PMID: 30631351 PMCID: PMC6304574 DOI: 10.1155/2018/2642714] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/27/2018] [Accepted: 11/11/2018] [Indexed: 01/25/2023] Open
Abstract
Phaleria macrocarpa is one of the Indonesian herbal plants which has been shown to have a hepatoprotective effect. This study was conducted to evaluate the protective effect of water extract of mahkota dewa (Phaleria macrocarpa) in liver fibrosis and to elucidate its mechanism of action. Male Sprague-Dawley rats were treated with carbon tetrachloride (CCl4) for 8 weeks to induce liver fibrosis. Rats were randomly divided into 6 groups (n=5), i.e., control group, CCl4 group, CCl4 + NAC group, CCl4 + various doses of water extract of Phaleria macrocarpa (50, 100, and 150 mg/kg body weight). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), liver histopathology, malondialdehyde (MDA), ratio GSH/GSSG, Tumor Necrosis Factor- (TNF-) α, and Transforming Growth Factor- (TGF-) β 1 were analyzed. This study demonstrated that water extract of Phaleria macrocarpa and NAC significantly protected CCl4-induced liver injury as demonstrated by reduced AST, ALT, ALP, and fibrosis percentage compared with the CCl4-only group. In addition, water extract of Phaleria macrocarpa and NAC significantly reduced the levels of MDA, TNF-α, and TGF-β 1 as well as increasing the ratio of GSH/GSSG. Water extract of Phaleria macrocarpa prevents CCl4-induced fibrosis in rats. The prevention of liver fibrosis was at least in part through its antioxidant and anti-inflammatory activities and through its capacity to inhibit hepatic stellate cells (HSC) activation by reducing fibrogenic cytokine TGF-β 1.
Collapse
|
|
22
|
Alpha Mangostin Inhibits the Proliferation and Activation of Acetaldehyde Induced Hepatic Stellate Cells through TGF- β and ERK 1/2 Pathways. J Toxicol 2018; 2018:5360496. [PMID: 30538742 PMCID: PMC6261236 DOI: 10.1155/2018/5360496] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/07/2018] [Accepted: 10/24/2018] [Indexed: 12/20/2022] Open
Abstract
Liver fibrosis is characterized by excessive accumulation of extracellular matrix in chronic liver injury. Alcohol-induced fibrosis may develop into cirrhosis, one of the major causes of liver disease mortality. Previous studies have shown that alpha mangostin can decrease ratio of pSmad/Smad and pAkt/Akt in TGF-β-induced liver fibrosis model in vitro. Further investigation of the mechanism of action of alpha mangostin in liver fibrosis model still needs to be done. The present study aimed to analyze the mechanism of action of alpha mangostin on acetaldehyde induced liver fibrosis model on TGF-β and ERK 1/2 pathways. Immortalized HSCs, LX-2 cells, were incubated with acetaldehyde, acetaldehyde with alpha mangostin (10 and 20 μM), or alpha mangostin only (10 μM). Sorafenib 10 μM was used as positive control. LX-2 viability was counted using trypan blue exclusion method. The effect of alpha mangostin on hepatic stellate cells proliferation and activation markers and its possible mechanism of action via TGF-β and ERK1/2 were studied. Acetaldehyde was shown to increase proliferation and expression of profibrogenic and migration markers on HSC, while alpha mangostin treatment resulted in a reduced proliferation and migration of HSC and decreased Ki-67 and pERK 1/2 expressions. These findings were followed with decreased expressions and concentrations of TGF-β; decreased expression of Col1A1, TIMP1, and TIMP3; increased expression of MnSOD and GPx; and reduction in intracellular reactive oxygen species. These effects were shown to be dose dependent. Therefore, we conclude that alpha mangostin inhibits hepatic stellate cells proliferation and activation through TGF-β and ERK 1/2 pathways.
Collapse
|
|
23
|
Schyman P, Printz RL, Estes SK, Boyd KL, Shiota M, Wallqvist A. Identification of the Toxicity Pathways Associated With Thioacetamide-Induced Injuries in Rat Liver and Kidney. Front Pharmacol 2018; 9:1272. [PMID: 30459623 PMCID: PMC6232954 DOI: 10.3389/fphar.2018.01272] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/18/2018] [Indexed: 12/25/2022] Open
Abstract
Ingestion or exposure to chemicals poses a serious health risk. Early detection of cellular changes induced by such events is vital to identify appropriate countermeasures to prevent organ damage. We hypothesize that chemically induced organ injuries are uniquely associated with a set (module) of genes exhibiting significant changes in expression. We have previously identified gene modules specifically associated with organ injuries by analyzing gene expression levels in liver and kidney tissue from rats exposed to diverse chemical insults. Here, we assess and validate our injury-associated gene modules by analyzing gene expression data in liver, kidney, and heart tissues obtained from Sprague-Dawley rats exposed to thioacetamide, a known liver toxicant that promotes fibrosis. The rats were injected intraperitoneally with a low (25 mg/kg) or high (100 mg/kg) dose of thioacetamide for 8 or 24 h, and definite organ injury was diagnosed by histopathology. Injury-associated gene modules indicated organ injury specificity, with the liver being most affected by thioacetamide. The most activated liver gene modules were those associated with inflammatory cell infiltration and fibrosis. Previous studies on thioacetamide toxicity and our histological analyses supported these results, signifying the potential of gene expression data to identify organ injuries.
Collapse
Affiliation(s)
- Patric Schyman
- DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD, United States
| | - Richard L Printz
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Shanea K Estes
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Kelli L Boyd
- Division of Comparative Medicine, Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Masakazu Shiota
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Anders Wallqvist
- DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD, United States
| |
Collapse
|
|
24
|
Dwivedi DK, Jena GB. Glibenclamide protects against thioacetamide-induced hepatic damage in Wistar rat: investigation on NLRP3, MMP-2, and stellate cell activation. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2018; 391:1257-1274. [PMID: 30066023 DOI: 10.1007/s00210-018-1540-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 07/13/2018] [Indexed: 02/07/2023]
Abstract
Glibenclamide (GLB), most widely used in the treatment of type II diabetes mellitus, inhibits K+ATP channel in pancreatic-β cells and releases insulin, while thioacetamide (TAA) is a well-known hepatotoxicant and most recommended for the induction of acute and chronic liver disease. The purpose of this study was to evaluate the hepatoprotective potential of GLB against TAA-induced hepatic damage in Wistar rats. TAA (200 mg/kg, ip, twice weekly) and GLB (1.25, 2.5, and 5 mg/kg/day, po) were administered for 6 consecutive weeks. Different biochemical, DNA damage, histopathological, TEM, immunohistochemical, and western blotting parameters were evaluated. GLB treatment has no effects on the TAA-induced significant decrease in body and liver weights. TAA treatment significantly increased liver index and treatment with GLB has no effect the same. TAA treatment altered the liver morphology, whereas treatment with GLB normalized the alteration in morphology. Further, significant increase in oxidative stress, apoptosis, and DNA damage was found in TAA-treated animals and GLB treatment significantly reduced these effects. TAA-induced plasma transaminases and serum ALP levels were significantly restored by GLB. Furthermore, histopathological findings showed the presence of lymphocyte infiltration, collagen deposition, bridging fibrosis, degeneration of portal triad, and necrosis in TAA-treated animals and GLB intervention significantly reduced the same. TEM images revealed that GLB significantly normalized the hepatic stellate cell morphology as well as restored the number of lipid droplets. GLB treatment significantly downregulated the expressions of TGF-β1, α-SMA, NLRP3, ASC, caspase-1, and IL-1β, and upregulated MMP-2 and catalase against TAA-induced liver damage. The outcomes of the present study confirmed that GLB ameliorated the liver damage induced by TAA.
Collapse
Affiliation(s)
- Durgesh Kumar Dwivedi
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S., Nagar, Punjab, 160062, India
| | - G B Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S., Nagar, Punjab, 160062, India.
| |
Collapse
|
|
25
|
Grouix B, Sarra-Bournet F, Leduc M, Simard JC, Hince K, Geerts L, Blais A, Gervais L, Laverdure A, Felton A, Richard J, Ouboudinar J, Gagnon W, Leblond FA, Laurin P, Gagnon L. PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway. J Pharmacol Exp Ther 2018; 367:71-81. [PMID: 30093459 DOI: 10.1124/jpet.118.250068] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/12/2018] [Indexed: 12/30/2022] Open
Abstract
Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We previously showed that 2-(3-pentylphenyl)acetic acid (PBI-4050) is a dual G protein-coupled receptor GPR40 agonist/GPR84 antagonist that exerts antifibrotic, anti-inflammatory, and antiproliferative action. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The antifibrotic effect of PBI-4050 was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation-induced liver fibrosis rodent models. Treatment with PBI-4050 suppressed CCl4-induced serum aspartate aminotransferase levels, inflammatory marker nitric oxide synthase, epithelial to mesenchymal transition transcription factor Snail, and multiple profibrotic factors. PBI-4050 also decreased GPR84 mRNA expression in CCl4-induced injury, while restoring peroxisome proliferator-activated receptor γ (PPARγ) to the control level. Collagen deposition and α-smooth muscle actin (α-SMA) protein levels were also attenuated by PBI-4050 treatment in the bile duct ligation rat model. Transforming growth factor-β-activated primary HSCs were used to examine the effect of PBI-4050 and its mechanism of action in vitro. PBI-4050 inhibited HSC proliferation by arresting cells in the G0/G1 cycle phase. Subsequent analysis demonstrated that PBI-4050 signals through a reduction of intracellular ATP levels, activation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), and blockade of mammalian target of rapamycin (mTOR), resulting in reduced protein and mRNA levels of α-SMA and connective tissue growth factor and restored PPARγ mRNA expression. Our findings suggest that PBI-4050 may exert antifibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway in stellate cells, and PBI-4050 may be a promising agent for treating liver fibrosis.
Collapse
Affiliation(s)
| | | | - Martin Leduc
- Prometic BioSciences Inc., Laval, Québec, Canada
| | | | - Kathy Hince
- Prometic BioSciences Inc., Laval, Québec, Canada
| | | | | | | | | | | | | | | | | | | | | | - Lyne Gagnon
- Prometic BioSciences Inc., Laval, Québec, Canada
| |
Collapse
|
|
26
|
Xiang DM, Sun W, Ning BF, Zhou TF, Li XF, Zhong W, Cheng Z, Xia MY, Wang X, Deng X, Wang W, Li HY, Cui XL, Li SC, Wu B, Xie WF, Wang HY, Ding J. The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut 2018; 67:1704-1715. [PMID: 28754776 DOI: 10.1136/gutjnl-2016-313392] [Citation(s) in RCA: 169] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 06/07/2017] [Accepted: 06/11/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear. METHODS The fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism. RESULTS Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis. CONCLUSIONS In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.
Collapse
Affiliation(s)
- Dai-Min Xiang
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Nelson Institute of Environmental Medicine, New York University School of Medicine, New York, USA.,National Center for Liver Cancer, Shanghai, China
| | - Wen Sun
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Bei-Fang Ning
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Teng-Fei Zhou
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiao-Feng Li
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wei Zhong
- Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Zhuo Cheng
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ming-Yang Xia
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xue Wang
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xing Deng
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Wang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China.,Department of Gastroenterology, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, China
| | - Heng-Yu Li
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiu-Liang Cui
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shi-Chao Li
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Bin Wu
- Department of Gastroenterology and Endoscopy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Wei-Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hong-Yang Wang
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jin Ding
- The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| |
Collapse
|
|
27
|
Wu Y, Wang W, Peng XM, He Y, Xiong YX, Liang HF, Chu L, Zhang BX, Ding ZY, Chen XP. Rapamycin Upregulates Connective Tissue Growth Factor Expression in Hepatic Progenitor Cells Through TGF-β-Smad2 Dependent Signaling. Front Pharmacol 2018; 9:877. [PMID: 30135653 PMCID: PMC6092675 DOI: 10.3389/fphar.2018.00877] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 07/19/2018] [Indexed: 12/15/2022] Open
Abstract
Rapamycin (sirolimus) is a mTOR kinase inhibitor and is widely used as an immunosuppressive drug to prevent graft rejection in organ transplantation currently. However, some recent investigations have reported that it had profibrotic effect in the progression of organ fibrosis, and its precise role in the liver fibrosis is still poorly understood. Here we showed that rapamycin upregulated connective tissue growth factor (CTGF) expression at the transcriptional level in hepatic progenitor cells (HPCs). Using lentivirus-mediated small hairpin RNA (shRNA) we demonstrated that knockdown of mTOR, Raptor, or Rictor mimicked the effect of rapamycin treatment. Mechanistically, inhibition of mTOR activity with rapamycin resulted in a hyperactive PI3K-Akt pathway, whereas this activation inhibited the expression of CTGF in HPCs. Besides, rapamycin activated the TGF-β-Smad signaling, and TGF-β receptor type I (TGFβRI) serine/threonine kinase inhibitors completely blocked the effects of rapamycin on HPCs. Moreover, Smad2 was involved in the induction of CTGF through rapamycin-activated TGF-β-Smad signaling as knockdown completely blocked CTGF induction, while knockdown of Smad4 expression partially inhibited induction, whereas Smad3 knockdown had no effect. Rapamycin also induced ROS generation and latent TGF-β activation which contributed to TGF-β-Smad signaling. In conclusion, this study demonstrates that rapamycin upregulates CTGF in HPCs and suggests that rapamycin has potential fibrotic effect in liver.
Collapse
Affiliation(s)
- Yu Wu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang-mei Peng
- Department of Nephrology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi He
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-xiao Xiong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui-fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-xiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ze-yang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
28
|
Prasad B, Bhatt DK, Johnson K, Chapa R, Chu X, Salphati L, Xiao G, Lee C, Hop CECA, Mathias A, Lai Y, Liao M, Humphreys WG, Kumer SC, Unadkat JD. Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study. Drug Metab Dispos 2018; 46:943-952. [PMID: 29695616 PMCID: PMC5987995 DOI: 10.1124/dmd.118.080523] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/13/2018] [Indexed: 01/12/2023] Open
Abstract
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers (n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
Collapse
Affiliation(s)
- Bhagwat Prasad
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Deepak Kumar Bhatt
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Katherine Johnson
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Revathi Chapa
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Xiaoyan Chu
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Laurent Salphati
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Guangqing Xiao
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Caroline Lee
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Cornelis E C A Hop
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Anita Mathias
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Yurong Lai
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Mingxiang Liao
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - William G Humphreys
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Sean C Kumer
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| | - Jashvant D Unadkat
- University of Washington, Seattle, Washington (B.P., D.K.B., K.J., R.C., J.D.U.); Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C.); Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Biogen, Cambridge, Massachusetts (G.X.); Ardea Biosciences, Inc., San Diego, California (C.L.); Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and University of Kansas Medical Center, Kansas City, Kansas (S.C.K.)
| |
Collapse
|
|
29
|
|
|
30
|
Astragaloside Inhibits Hepatic Fibrosis by Modulation of TGF- β1/Smad Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:3231647. [PMID: 29853950 PMCID: PMC5952439 DOI: 10.1155/2018/3231647] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 02/24/2018] [Accepted: 03/15/2018] [Indexed: 12/19/2022]
Abstract
Activation of HSC is a pivotal step in hepatic fibrosis. In the activation of HSC, the TGF-β1 plays a key role that can promote the occurrence of hepatic fibrosis by combining with Smad proteins. Astragaloside is the main active component extracted from Radix Astragali that has the effect of antioxidation and hepatoprotection. In the present study, we investigated the mechanism of astragalosides inhibiting hepatic fibrosis in vitro and in vivo. In vitro, astragalosides inhibited the activation of HSC and regulated the expression of MMP-2 and TIMP-2 and reduced the formation of collagen fibers. In vivo, administration of astragalosides decreased the serum ALT, AST, and TBiL in rats by reducing oxidative stress. Astragalosides also attenuated hepatic fibrosis by reducing the concentration of hydroxyproline and inhibiting the formation of collagen fibers. The expressions of TGF-β1, TβR-I, p-Smad 2, and p-Smad 3 were downregulated after astragalosides treatments, while Smad 7 was upregulated compared to the control group. The results indicated that the effect of astragaloside on hepatic fibrosis was related to the inhibition of HSC activation and the modulation of the TGF-β1/Smad signaling pathway.
Collapse
|
|
31
|
Emodin Alleviates Liver Fibrosis of Mice by Reducing Infiltration of Gr1 hi Monocytes. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:5738101. [PMID: 29743924 PMCID: PMC5884281 DOI: 10.1155/2018/5738101] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 12/14/2017] [Accepted: 01/01/2018] [Indexed: 12/23/2022]
Abstract
Emodin, as a major active component of Rheum palmatum L. and Polygonum cuspidatum, has been reported to have antifibrotic effect. However, the mechanism of emodin on antifibrotic effect for liver fibrosis was still obscure. In the present study, we aimed to investigate whether emodin can alleviate carbon tetrachloride- (CCl4-) induced liver fibrosis through reducing infiltration of Gr1hi monocytes. Liver fibrosis was induced by intraperitoneal CCl4 injection in mice. Mice in the emodin group received emodin treatment by gavage. Pretreatment with emodin significantly protected mice from liver inflammation and fibrosis revealed by the decreased elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as reduced hepatic necrosis and fibrosis by analysis of hematoxylin-eosin (HE) staining, Masson staining, α-smooth muscle actin (α-SMA), and collagen-I immunohistochemistry staining. Further, compared to CCl4 group, mice in the emodin group showed significantly less intrahepatic infiltration of Gr1hi monocytes. Moreover, emodin significantly inhibited hepatic expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), granulin (GRN), monocyte chemoattractant protein 1 (MCP-1), and chemokine ligand 7 (CCL7), which was in line with the decreased numbers of intrahepatic Gr1hi monocytes. In conclusion, emodin can alleviate the degree of liver fibrosis by reducing infiltration of Gr1hi monocytes. These results suggest that emodin is a promising candidate to prevent and treat liver fibrosis.
Collapse
|
|
32
|
PPAR γ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling. PPAR Res 2018; 2018:6970407. [PMID: 29686697 PMCID: PMC5852857 DOI: 10.1155/2018/6970407] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 12/20/2017] [Indexed: 12/12/2022] Open
Abstract
Background and Aims Accumulating evidence reveals that PPARγ plays a unique role in the regulation of hepatic fibrosis and hepatic stellate cells (HSCs) activation. This study was aimed at investigating the role of PPARγ in hypoxia-induced hepatic fibrogenesis and its possible mechanism. Methods Rats used for CCl4-induced hepatic fibrosis model were exposed to hypoxia for 8 hours each day. Rats exposed to hypoxia were treated with or without the PPARγ agonist rosiglitazone. Liver sections were stained with HE and Sirius red staining 8 weeks later. HSCs were exposed to hypoxic environment in the presence or absence of rosiglitazone, and expression of PPARγ and two fibrosis markers, α-SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPARγ, α-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor. Results Hypoxia promoted the induction and progress of hepatic fibrosis and HSCs activation. Meanwhile, rosiglitazone significantly antagonized the effects induced by hypoxia. Signaling by sGC/cGMP/PKG promoted the inhibitory effect of PPARγ on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPARγ. Conclusion sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation.
Collapse
|
|
33
|
Billington S, Ray AS, Salphati L, Xiao G, Chu X, Humphreys WG, Liao M, Lee CA, Mathias A, Hop CECA, Rowbottom C, Evers R, Lai Y, Kelly EJ, Prasad B, Unadkat JD. Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC-MS/MS Proteomics. Drug Metab Dispos 2018; 46:189-196. [PMID: 29138286 PMCID: PMC5776333 DOI: 10.1124/dmd.117.077289] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/19/2017] [Indexed: 12/11/2022] Open
Abstract
Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, n = 8) and adjacent noncancerous (NC, n = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from noninfected, noncirrhotic (control, n = 36) and HCV-cirrhotic (n = 30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers. In comparison with control livers, with the exception of NTCP, MRP2, and MATE1, transporter expression decreased in NC (38%-76%) and C (56%-96%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP expression increased (113%), MATE1 expression decreased (58%), and MRP2 expression was unchanged relative to control livers. In C HCV-HCC tissues, NTCP and MRP2 expression decreased (63%, 56%) and MATE1 expression was unchanged relative to control livers. Compared with HCV-cirrhotic livers, aside from NTCP, OCT1, BSEP, and MRP2, transporter expression decreased in NC (41%-71%) and C (54%-89%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP and MRP2 expression increased (362%, 142%), whereas OCT1 and BSEP expression was unchanged. In C HCV-HCC tissues, OCT1 and BSEP expression decreased (90%, 80%) relative to HCV-cirrhotic livers, whereas NTCP and MRP2 expression was unchanged. Expression of OATP2B1, BSEP, MRP2, and MRP3 decreased (56%-72%) in C HCV-HCC tissues in comparison with matched NC tissues (n = 8), but the expression of other transporters was unchanged. These data will be helpful in the future to predict transporter-mediated hepatocellular drug concentrations in patients with HCV-HCC.
Collapse
Affiliation(s)
- Sarah Billington
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Adrian S Ray
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Laurent Salphati
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Guangqing Xiao
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Xiaoyan Chu
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - W Griffith Humphreys
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Mingxiang Liao
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Caroline A Lee
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Anita Mathias
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Cornelis E C A Hop
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Christopher Rowbottom
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Raymond Evers
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Yurong Lai
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Edward J Kelly
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Bhagwat Prasad
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Jashvant D Unadkat
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| |
Collapse
|
|
34
|
Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis. Can J Gastroenterol Hepatol 2018; 2018:4197857. [PMID: 29670867 PMCID: PMC5833156 DOI: 10.1155/2018/4197857] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
Collapse
|
|
35
|
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.
Collapse
|
|
36
|
Rivera P, Pastor A, Arrabal S, Decara J, Vargas A, Sánchez-Marín L, Pavón FJ, Serrano A, Bautista D, Boronat A, de la Torre R, Baixeras E, Lucena MI, de Fonseca FR, Suárez J. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver. Front Pharmacol 2017; 8:705. [PMID: 29056914 PMCID: PMC5635604 DOI: 10.3389/fphar.2017.00705] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Accepted: 09/21/2017] [Indexed: 12/11/2022] Open
Abstract
Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5-5-10-20 mM) and time-course (2-6-24 h) study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1)-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response.
Collapse
Affiliation(s)
- Patricia Rivera
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.,Department of Endocrinology, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Antoni Pastor
- Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.,CIBER Fisiopatología Obesidad y Nutrición, Instituto Salud Carlos III, Madrid, Spain
| | - Sergio Arrabal
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Juan Decara
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Antonio Vargas
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Laura Sánchez-Marín
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Francisco J Pavón
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Antonia Serrano
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Dolores Bautista
- Unidad de Gestión Clínica de Anatomía Patológica, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Anna Boronat
- Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - Rafael de la Torre
- Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.,CIBER Fisiopatología Obesidad y Nutrición, Instituto Salud Carlos III, Madrid, Spain
| | - Elena Baixeras
- Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - M Isabel Lucena
- Servicio de Farmacología Clínica, Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Salud Carlos III, Madrid, Spain
| | - Fernando R de Fonseca
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Juan Suárez
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.,Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| |
Collapse
|
|
37
|
Koh EK, Kim JE, Song SH, Sung JE, Lee HA, Kim KS, Hong JT, Hwang DY. Ethanol extracts collected from the Styela clava tunic alleviate hepatic injury induced by carbon tetrachloride (CCl 4) through inhibition of hepatic apoptosis, inflammation, and fibrosis. J Toxicol Pathol 2017; 30:291-306. [PMID: 29097839 PMCID: PMC5660951 DOI: 10.1293/tox.2017-0021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 06/29/2017] [Indexed: 02/07/2023] Open
Abstract
The Styela clava tunic (SCT) is known as a good raw material for preparing anti-inflammatory compounds, wound healing films, guided bone regeneration, and food additives. To investigate whether ethanol extracts of the SCT (EtSCT) could protect against hepatic injury induced by carbon tetrachloride (CCl4) in ICR mice, alterations in serum biochemical indicators, histopathology, hepatic apoptosis, inflammation, and fibrosis were observed in ICR mice pretreated with EtSCT for 5 days before CCl4 injection. EtSCT contained 15.6 mg/g of flavonoid and 37.5 mg/g phenolic contents with high 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (93.3%) and metal chelation activity (46.5%). The EtSCT+CCl4-treated groups showed decreased levels of ALT, LDH, and AST, indicating toxicity and a necrotic area in the liver, while the level of ALP remained constant. The formation of active caspase-3 and enhancement of Bax/Bcl-2 expression was effectively inhibited in the EtSCT+CCl4-treated groups. Furthermore, the levels of pro- and anti-inflammatory cytokines and the phosphorylation of p38 in the TNF-α downstream signaling pathway rapidly recovered in the EtSCT+CCl4-treated groups. The EtSCT+CCl4-treated groups showed a significant decrease in hepatic fibrosis markers including collagen accumulation, MMP-2 expression, TGF-β1 concentration, and phosphorylation of Smad2/3. Moreover, a significant decline in malondialdehyde (MDA) concentration and enhancement of superoxide dismutase (SOD) expression were observed in the EtSCT+CCl4-treated groups. Taken together, these results indicate that EtSCT can protect against hepatic injury induced by CCl4-derived reactive intermediates through the suppression of hepatic apoptosis, inflammation, and fibrosis.
Collapse
Affiliation(s)
- Eun Kyoung Koh
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, 1268-50 Samnangjin-ro, Samnangjin-eup, Miryang-si, Gyeongsangnam-do 50463, Republic of Korea
| | - Ji Eun Kim
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, 1268-50 Samnangjin-ro, Samnangjin-eup, Miryang-si, Gyeongsangnam-do 50463, Republic of Korea
| | - Sung Hwa Song
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, 1268-50 Samnangjin-ro, Samnangjin-eup, Miryang-si, Gyeongsangnam-do 50463, Republic of Korea
| | - Ji Eun Sung
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, 1268-50 Samnangjin-ro, Samnangjin-eup, Miryang-si, Gyeongsangnam-do 50463, Republic of Korea
| | - Hyun Ah Lee
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, 1268-50 Samnangjin-ro, Samnangjin-eup, Miryang-si, Gyeongsangnam-do 50463, Republic of Korea
| | - Kil Soo Kim
- College of Veterinary Medicine, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju-si, Chungcheongbuk-do 28644, Republic of Korea
| | - Dae Youn Hwang
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, 1268-50 Samnangjin-ro, Samnangjin-eup, Miryang-si, Gyeongsangnam-do 50463, Republic of Korea
| |
Collapse
|
|
38
|
Pingitore P, Dongiovanni P, Motta BM, Meroni M, Lepore SM, Mancina RM, Pelusi S, Russo C, Caddeo A, Rossi G, Montalcini T, Pujia A, Wiklund O, Valenti L, Romeo S. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum Mol Genet 2017; 25:5212-5222. [PMID: 27742777 PMCID: PMC5886043 DOI: 10.1093/hmg/ddw341] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 09/28/2016] [Indexed: 01/22/2023] Open
Abstract
Liver fibrosis is a pathological scarring response to chronic hepatocellular injury and hepatic stellate cells (HSCs) are key players in this process. PNPLA3 I148M is a common variant robustly associated with liver fibrosis but the mechanisms underlying this association are unknown. We aimed to examine a) the effect of fibrogenic and proliferative stimuli on PNPLA3 levels in HSCs and b) the role of wild type and mutant PNPLA3 overexpression on markers of HSC activation and fibrosis. Here, we show that PNPLA3 is upregulated by the fibrogenic cytokine transforming growth factor-beta (TGF-β), but not by platelet-derived growth factor (PDGF), and is involved in the TGF-β-induced reduction in lipid droplets in primary human HSCs. Furthermore, we show that retinol release from human HSCs ex vivo is lower in cells with the loss-of-function PNPLA3 148M compared with 148I wild type protein. Stable overexpression of PNPLA3 148I wild type, but not 148M mutant, in human HSCs (LX-2 cells) induces a reduction in the secretion of matrix metallopeptidase 2 (MMP2), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2), which is mediated by retinoid metabolism. In conclusion, we show a role for PNPLA3 in HSC activation in response to fibrogenic stimuli. Moreover, we provide evidence to indicate that PNPLA3-mediated retinol release may protect against liver fibrosis by inducing a specific signature of proteins involved in extracellular matrix remodelling.
Collapse
Affiliation(s)
- Piero Pingitore
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden
| | - Paola Dongiovanni
- Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy
| | | | - Marica Meroni
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Saverio Massimo Lepore
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | | | - Serena Pelusi
- Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy
| | - Cristina Russo
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Andrea Caddeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden
| | - Giorgio Rossi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.,Liver Surgery and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy
| | - Tiziana Montalcini
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Arturo Pujia
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Olov Wiklund
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.,Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Luca Valenti
- Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.,Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.,Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
| |
Collapse
|
|
39
|
Natarajan V, Harris EN, Kidambi S. SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4097205. [PMID: 28293634 PMCID: PMC5331310 DOI: 10.1155/2017/4097205] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 11/16/2016] [Indexed: 01/17/2023]
Abstract
Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.
Collapse
Affiliation(s)
- Vaishaali Natarajan
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE, USA
| | - Edward N. Harris
- Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska, Lincoln, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Nebraska Center for the Prevention of Obesity Diseases, University of Nebraska, Lincoln, NE, USA
| | - Srivatsan Kidambi
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE, USA
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska, Lincoln, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Nebraska Center for the Prevention of Obesity Diseases, University of Nebraska, Lincoln, NE, USA
- Nebraska Center for Materials and Nanoscience, University of Nebraska, Lincoln, NE, USA
- Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
40
|
Müller A, Hochrath K, Stroeder J, Hittatiya K, Schneider G, Lammert F, Buecker A, Fries P. Effects of Liver Fibrosis Progression on Tissue Relaxation Times in Different Mouse Models Assessed by Ultrahigh Field Magnetic Resonance Imaging. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8720367. [PMID: 28194423 PMCID: PMC5286538 DOI: 10.1155/2017/8720367] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 12/14/2016] [Indexed: 01/06/2023]
Abstract
Recently, clinical studies demonstrated that magnetic resonance relaxometry with determination of relaxation times T1 and T2⁎ may aid in staging and management of liver fibrosis in patients suffering from viral hepatitis and steatohepatitis. In the present study we investigated T1 and T2⁎ in different models of liver fibrosis to compare alternate pathophysiologies in their effects on relaxation times and to further develop noninvasive quantification methods of liver fibrosis. MRI was performed with a fast spin echo sequence for measurement of T1 and a multigradient echo sequence for determination of T2⁎. Toxic liver fibrosis was induced by injections of carbon tetrachloride (1.4 mL CCl4 per kg bodyweight and week, for 3 or 6 weeks) in BALB/cJ mice. Chronic sclerosing cholangitis was mimicked using the ATP-binding cassette transporter B4 knockout (Abcb4 -/-) mouse model. Untreated BALB/cJ mice served as controls. To assess hepatic fibrosis, we ascertained collagen contents and fibrosis scores after Sirius red staining. T1 and T2⁎ correlate differently to disease severity and etiology of liver fibrosis. T2⁎ shows significant decrease correlating with fibrosis in CCl4 treated animals, while demonstrating significant increase with disease severity in Abcb4 -/- mice. Measurements of T1 and T2⁎ may therefore facilitate discrimination between different stages and causes of liver fibrosis.
Collapse
Affiliation(s)
- Andreas Müller
- Clinic for Diagnostic and Interventional Radiology, Saarland University Medical Center, Kirrberger Str. 100, Bdg. 50.1, 66421 Homburg, Germany
| | - Katrin Hochrath
- Department of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
- Department of Internal Medicine II, Saarland University, Saarland University Medical Center, Bdg. 77, Kirrberger Str. 100, 66421 Homburg, Germany
| | - Jonas Stroeder
- Clinic for Diagnostic and Interventional Radiology, Saarland University Medical Center, Kirrberger Str. 100, Bdg. 50.1, 66421 Homburg, Germany
| | - Kanishka Hittatiya
- Institute of Pathology, University Hospital Bonn, Bdg. 62, Sigmund-Freud Str. 25, 53127 Bonn, Germany
| | - Günther Schneider
- Clinic for Diagnostic and Interventional Radiology, Saarland University Medical Center, Kirrberger Str. 100, Bdg. 50.1, 66421 Homburg, Germany
| | - Frank Lammert
- Department of Internal Medicine II, Saarland University, Saarland University Medical Center, Bdg. 77, Kirrberger Str. 100, 66421 Homburg, Germany
| | - Arno Buecker
- Clinic for Diagnostic and Interventional Radiology, Saarland University Medical Center, Kirrberger Str. 100, Bdg. 50.1, 66421 Homburg, Germany
| | - Peter Fries
- Clinic for Diagnostic and Interventional Radiology, Saarland University Medical Center, Kirrberger Str. 100, Bdg. 50.1, 66421 Homburg, Germany
| |
Collapse
|
|
41
|
Bellan M, Pogliani G, Marconi C, Minisini R, Franzosi L, Alciato F, Magri A, Avanzi GC, Pirisi M, Sainaghi PP. Gas6 as a putative noninvasive biomarker of hepatic fibrosis. Biomark Med 2016; 10:1241-1249. [PMID: 27924629 DOI: 10.2217/bmm-2016-0210] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
AIM To evaluate serum growth arrest-specific gene 6 (Gas6) concentration as a biomarker of liver fibrosis progression. MATERIALS & METHODS One hundred and thirteen consecutive patients affected by chronic liver disease underwent transient elastography, Gas6 measurement and, if clinically indicated, liver biopsy. RESULTS Gas6 concentration was directly correlated to liver stiffness (r = 0.67; p < 0.0001) and was significantly higher in patients with advanced fibrosis (Ishak 4-5; p < 0.001). A plasma concentration <30 ng/ml Gas6 ruled out fibrosis with 84% sensitivity and 56% specificity, while values >42 ng/ml identified severe fibrosis with a sensitivity of 64% and a specificity of 95%; the diagnostic accuracy was comparable to that of transient elastography. CONCLUSION Gas6 is a novel biomarker of liver fibrosis, with a potential clinical and pathophysiological relevance.
Collapse
Affiliation(s)
- Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy
| | - Gabriele Pogliani
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy
| | - Cecilia Marconi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy
| | - Lisa Franzosi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy
| | - Federica Alciato
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy
| | - Andrea Magri
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy
| | - Gian Carlo Avanzi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Emergency Medicine Department, "AOU Maggiore della Carità", Corso Mazzini 18, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy.,Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy.,IRCAD, Interdisciplinary Research Center of Autoimmune Diseases, via Solaroli 17, Novara, Italy
| | - Pier Paolo Sainaghi
- Division of Internal Medicine, "AOU Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy.,IRCAD, Interdisciplinary Research Center of Autoimmune Diseases, via Solaroli 17, Novara, Italy
| |
Collapse
|
|
42
|
Clinical Advancements in the Targeted Therapies against Liver Fibrosis. Mediators Inflamm 2016; 2016:7629724. [PMID: 27999454 PMCID: PMC5143744 DOI: 10.1155/2016/7629724] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 10/11/2016] [Accepted: 10/19/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.
Collapse
|
|
43
|
Schisandrin B: A Double-Edged Sword in Nonalcoholic Fatty Liver Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:6171658. [PMID: 27847552 PMCID: PMC5101399 DOI: 10.1155/2016/6171658] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/13/2016] [Accepted: 09/28/2016] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver lesions ranging from hepatic steatosis, nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. The high global prevalence of NAFLD has underlined the important public health implications of this disease. The pathogenesis of NAFLD involves the abnormal accumulation of free fatty acids, oxidative stress, endoplasmic reticulum (ER) stress, and a proinflammatory state in the liver. Schisandrin B (Sch B), an active dibenzooctadiene lignan isolated from the fruit of Schisandra chinensis (a traditional Chinese herb), was found to possess antihyperlipidemic, antioxidant, anti-ER stress, and anti-inflammatory activities in cultured hepatocytes in vitro and in rodent livers in vivo. Whereas a long-term, low dose regimen of Sch B induces an antihyperlipidemic response in obese mice fed a high fat diet, a single bolus high dose of Sch B increases serum/hepatic lipid levels in mice. This differential action of Sch B is likely related to a dose/time-dependent biphasic response on lipid metabolism in mice. The hepatoprotection afforded by Sch B against oxidative stress, ER stress, and inflammation has been widely reported. The ensemble of results suggests that Sch B may offer potential as a therapeutic agent for NAFLD. The optimal dose and duration of Sch B treatment need to be established in order to ensure maximal efficacy and safety when used in humans.
Collapse
|
|
44
|
Magee N, Zou A, Zhang Y. Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5170402. [PMID: 27822476 PMCID: PMC5086374 DOI: 10.1155/2016/5170402] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 09/22/2016] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.
Collapse
Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - An Zou
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| |
Collapse
|
|
45
|
Saneyasu T, Akhtar R, Sakai T. Molecular Cues Guiding Matrix Stiffness in Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:2646212. [PMID: 27800489 PMCID: PMC5075297 DOI: 10.1155/2016/2646212] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 08/28/2016] [Indexed: 12/14/2022]
Abstract
Tissue and matrix stiffness affect cell properties during morphogenesis, cell growth, differentiation, and migration and are altered in the tissue remodeling following injury and the pathological progression. However, detailed molecular mechanisms underlying alterations of stiffness in vivo are still poorly understood. Recent engineering technologies have developed powerful techniques to characterize the mechanical properties of cell and matrix at nanoscale levels. Extracellular matrix (ECM) influences mechanical tension and activation of pathogenic signaling during the development of chronic fibrotic diseases. In this short review, we will focus on the present knowledge of the mechanisms of how ECM stiffness is regulated during the development of liver fibrosis and the molecules involved in ECM stiffness as a potential therapeutic target for liver fibrosis.
Collapse
Affiliation(s)
- Takaoki Saneyasu
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
| | - Riaz Akhtar
- Centre for Materials and Structures, School of Engineering, University of Liverpool, Liverpool L69 3GE, UK
| | - Takao Sakai
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
| |
Collapse
|
|
46
|
Bader El Din NG, Farouk S, El-Shenawy R, Ibrahim MK, Dawood RM, Elhady MM, Salem AM, Zayed N, Khairy A, El Awady MK. Tumor necrosis factor-α -G308A polymorphism is associated with liver pathological changes in hepatitis C virus patients. World J Gastroenterol 2016; 22:7767-7777. [PMID: 27678360 PMCID: PMC5016377 DOI: 10.3748/wjg.v22.i34.7767] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 07/05/2016] [Accepted: 07/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association of tumor necrosis factor alpha (TNFα) -G308A polymorphism with different liver pathological changes in treatment-naïve Egyptian patients infected with hepatitis C virus (HCV) genotype 4. METHODS This study included 180 subjects, composed of 120 treatment-naïve chronic HCV patients with different fibrosis grades (F0-F4) and 60 healthy controls. The TNFα -G308A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα -G308A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence. RESULTS Current data showed that the TNFα -G308A SNP frequency was significantly different between controls and HCV infected patients (P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients (F2-F4, n = 60) than in early fibrosis patients (F0-F1, n = 60) (P = 0.05, 0.04 respectively). Moreover, the GA or AA genotypes increased the TNFα serum level greater than the GG genotype (P = 0.002). The results showed a clear association between severe liver pathological conditions (inflammation, steatosis and fibrosis) and (GA + AA) genotypes (P = 0.035, 0.03, 0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes (GA + AA) were significantly associated with liver inflammation (OR = 3.776, 95%CI: 1.399-10.194, P = 0.009), severe steatosis (OR = 4.49, 95%CI: 1.441-14.0, P = 0.010) and fibrosis progression (OR = 2.84, 95%CI: 1.080-7.472, P = 0.034). Also, the A allele was an independent risk factor for liver inflammation (P = 0.003), steatosis (P = 0.003) and fibrosis (P = 0.014). CONCLUSION TNFα SNP at nucleotide -308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected patients.
Collapse
|
|
47
|
Norona LM, Nguyen DG, Gerber DA, Presnell SC, LeCluyse EL. Editor's Highlight: Modeling Compound-Induced Fibrogenesis In Vitro Using Three-Dimensional Bioprinted Human Liver Tissues. Toxicol Sci 2016; 154:354-367. [PMID: 27605418 DOI: 10.1093/toxsci/kfw169] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate- and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1β) during the early culture time period is followed by concentration- and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-β1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.
Collapse
Affiliation(s)
- Leah M Norona
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 .,Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, North Carolina 27599.,The Institute for Drug Safety Sciences, Research Triangle Park, North Carolina 27709
| | - Deborah G Nguyen
- Research and Development, Organovo, Inc, San Diego, California 92121
| | - David A Gerber
- Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
| | - Sharon C Presnell
- Research and Development, Organovo, Inc, San Diego, California 92121
| | - Edward L LeCluyse
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.,The Institute for Drug Safety Sciences, Research Triangle Park, North Carolina 27709
| |
Collapse
|
|
48
|
Lee SB, Kim HG, Kim HS, Lee JS, Im HJ, Kim WY, Son CG. Ethyl Acetate Fraction of Amomum xanthioides Exerts Antihepatofibrotic Actions via the Regulation of Fibrogenic Cytokines in a Dimethylnitrosamine-Induced Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:6014380. [PMID: 27594891 PMCID: PMC4995331 DOI: 10.1155/2016/6014380] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/08/2016] [Accepted: 07/16/2016] [Indexed: 01/18/2023]
Abstract
Amomum xanthioides has been traditionally used to treat diverse digestive system disorders in the Asian countries. We investigated antihepatofibrotic effects of ethyl acetate fraction of Amomum xanthioides (EFAX). Liver fibrosis is induced by dimethylnitrosamine (DMN) injection (intraperitoneally, 10 mg/kg of DMN for 4 weeks to Sprague-Dawley rats). EFAX (25 or 50 mg/kg), silymarin (50 mg/kg), or distilled water was orally administered every day. The DMN injection drastically altered body and organ mass, serum biochemistry, and platelet count, while EFAX treatment significantly attenuated this alteration. Severe liver fibrosis is determined by trichrome staining and measurement of hydroxyproline contents. EFAX treatment significantly attenuated these symptoms as well as the increase in oxidative by-products of lipid and protein metabolism in liver tissues. DMN induced a dramatic activation of hepatic stellate cells and increases in the levels of protein and gene expression of transforming growth factor-beta (TGF-β), platelet derived growth factor-beta (PDGF-β), and connective tissue growth factor (CTGF). Immunohistochemical analyses revealed increases in the levels of protein and gene expression of α-smooth muscle actin. These alterations were significantly normalized by EFAX treatment. Our findings demonstrate the potent antihepatofibrotic properties of EFAX via modulation of fibrogenic cytokines, especially TGF-β in the liver fibrosis rat model.
Collapse
Affiliation(s)
- Sung-Bae Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Hyeong-Geug Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Hyo-Seon Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Jin-Seok Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Hwi-Jin Im
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Won-Yong Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| |
Collapse
|
|
49
|
Chen J, Pan J, Wang J, Song K, Zhu D, Huang C, Duan Y. Soluble egg antigens of Schistosoma japonicum induce senescence in activated hepatic stellate cells by activation of the STAT3/p53/p21 pathway. Sci Rep 2016; 6:30957. [PMID: 27489164 PMCID: PMC4973244 DOI: 10.1038/srep30957] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/12/2016] [Indexed: 12/27/2022] Open
Abstract
Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. Based on previously observed anti-fibrotic effects of soluble egg antigens from Schistosoma japonicum in vitro, we hypothesized that SEA might play a crucial role in alleviating liver fibrosis through promoting senescence of activated HSCs. We show here that SEA inhibited expression of α-SMA and pro-collagen I and promoted senescence of activated HSCs in vitro. In addition, SEA induced an increased expression of P-p53 and p21. Knockdown of p53 inhibited the expression of p21 and failed to induce senescence of activated-HSCs. Phosphorylated STAT3 was elevated upon SEA stimulation, while loss of STAT3 decreased the level of p53 and senescence of HSCs. Results from immunoprecipitation analysis demonstrated that SOCS3 might be involved in the SEA-induced senescence in HSCs through its interaction with p53. This study demonstrates the potential capacity of SEA in restricting liver fibrosis through promoting senescence in HSCs. Furthermore, a novel STAT3-p53-p21 pathway might participate in the observed SEA-mediated senescence of HSCs. Our results suggest that SEA might carry potential therapeutic effects of restraining liver fibrosis through promoting senescence.
Collapse
Affiliation(s)
- Jinling Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Jing Pan
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Jianxin Wang
- Laboratory Medicine Center, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Ke Song
- Orthopedics and Traumatology Center of PLA, The 153rd Central Hospital of People's Liberation Army, Zhengzhou 450042, Henan, People's Republic of China
| | - Dandan Zhu
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Caiqun Huang
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Yinong Duan
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| |
Collapse
|
|
50
|
ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation. Sci Rep 2016; 6:30029. [PMID: 27435808 PMCID: PMC4951777 DOI: 10.1038/srep30029] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 06/28/2016] [Indexed: 12/15/2022] Open
Abstract
Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis.
Collapse
|