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Maher S, Atta S, Kamel M, A. Hammam O, Okasha H. Therapeutic Potential and Mechanistic Insights of a Novel Synthetic α-Lactalbumin-Derived Peptide for the Treatment of Liver Fibrosis. J Clin Exp Hepatol 2025; 15:102488. [PMID: 39868009 PMCID: PMC11755051 DOI: 10.1016/j.jceh.2024.102488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 12/09/2024] [Indexed: 01/28/2025] Open
Abstract
Background Liver fibrosis is a serious global health issue, but current treatment options are limited due to a lack of approved therapies capable of preventing or reversing established fibrosis. Aim This study investigated the antifibrotic effects of a synthetic peptide derived from α-lactalbumin in a mouse model of thioacetamide (TAA)-induced liver fibrosis. Methods In silico analyses were conducted to assess the physicochemical properties, pharmacophore features, and docking interactions of the peptide. Mice with induced fibrosis were treated with three different doses of the synthetic peptide (2.5, 5, or 10 μg/kg, twice weekly for 8 weeks). Immunohistochemistry, antioxidant enzyme levels, IGF-1 levels, and expression of fibrosis-related genes were assessed. Results Peptide interacted with human prothrombin's many sites with varying binding affinities. Besides, ligand similarity analysis identified 26 thrombin inhibitors with high Tanimoto scores. The peptide exhibited antifibrotic effects with dose-dependent improvements. The upregulated expression of IGF-1 in all treated groups compared with the pathological untreated group. In contrast, fibrotic markers such as TIMP, PDGF-α, and TGF-β were upregulated in the untreated pathological group but downregulated in the peptide-treated groups. The assessment of IGF-1 concentration in sera demonstrated that the peptide-treated groups exhibited an increase in IGF-1 levels. Histopathological examination of peptide-treated groups showed normal hepatic architecture with hepatocytes arranged in thin plates. Immunohistochemical results of high dose peptide-treated group showed a few numbers of positive αSMA with mild proliferating cell nuclear antigen expression. Conclusion The synthetic α-lactalbumin peptide shows promise as an antifibrotic therapy. Its safety and effectiveness are supported by in silico and in vivo analyses. The peptide's pharmacophore characteristics and potential as a thrombin inhibitor combine with its ability to downregulate fibrotic markers and maintain liver tissue integrity. These findings concluded the potential of this peptide as a promising therapeutic candidate for liver fibrosis, warranting further investigation.
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Affiliation(s)
- Sara Maher
- Immunology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Shimaa Atta
- Immunology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Manal Kamel
- Immunology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Olfat A. Hammam
- Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Hend Okasha
- Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Giza, Egypt
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2
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Bagheri L, Javanbakht M, Malekian S, Ghahderijani BH, Taghipour S, Tanha FD, Ranjkesh M, Cegolon L, Zhao S. Antifibrotic therapeutic strategies in systemic sclerosis: Critical role of the Wnt/β-catenin and TGF-β signal transduction pathways as potential targets. Eur J Pharmacol 2025; 999:177607. [PMID: 40209848 DOI: 10.1016/j.ejphar.2025.177607] [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: 11/14/2024] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
Systemic sclerosis (SSc) is a prototypic fibrosing disorder characterized by widespread fibrosis and immune dysregulation. Current evidence highlights the intricate cross-talk between the canonical Wnt/β-catenin signaling pathway and transforming growth factor-beta (TGF-β) signaling, both of which play fundamental roles in the pathogenesis of fibrosis. This review aims to elucidate the central role of the Wnt/β-catenin-TGF-β pathway and TGF-β signal transduction pathway in fibrotic diseases, focusing on SSc. We summarized evidence from cellular biology studies, animal model investigations and clinical observations to provide a comprehensive view of the mechanisms causing pathological fibrosis. In addition, we explore the possibilities of antifibrotic therapeutic strategies against Wnt/β-catenin-TGF-β signaling to counteract fibrosis, delineating approaches for treatment of SSc patients by targeting these interconnected signaling pathways.
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Affiliation(s)
- Leyla Bagheri
- Department of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sheida Malekian
- Department of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Sadra Taghipour
- Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fatemeh Davari Tanha
- Department of Infertility, Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Luca Cegolon
- Department of Medical, Surgical & Health Sciences, University of Trieste, 34128, Trieste, Italy; Public Health Unit, University Health Agency Giuliano-Isontina (ASUGI), 34148, Trieste, Italy
| | - Shi Zhao
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
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Yousefi Z, Nourbakhsh M, Sahebghadam Lotfi A. Pirfenidone Downregulates eIF6, P311, and TGF-β Expression and Improves Liver Fibrosis Induced by Bile Duct Ligation in Wistar Rats: Evidence for Liver Regeneration. DNA Cell Biol 2025; 44:109-124. [PMID: 39681345 DOI: 10.1089/dna.2024.0194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024] Open
Abstract
Liver fibrosis (LF) is a clinical disorder characterized by inflammation and excessive accumulation of extracellular matrix (ECM). This study investigates the effects of the antifibrotic compound pirfenidone (PFD) on improving LF through histological changes and modulation of eukaryotic translation initiation factor 6 (eIF6), P311, and transforming growth factor beta (TGF-β) in rats with bile duct ligation (BDL)-induced LF. Rats received daily doses of PFD (200 and 500 mg/kg) for 4 weeks. The study encompassed biochemical, pathological, and immunohistochemical (IHC) analyses. mRNA levels of eIF6, P311, TGF-β, ECM deposition, hepatic stellate cell (HSC) activation, and inflammatory mediator genes were measured by RT-qPCR. Protein levels of eIF6, P311, and TGF-β were detected by western blotting. Compared with the BDL group, PFD dose-dependently reduced hydroxyproline content, liver index, biochemical parameters, fibrosis score, and fibrosis area. PFD also modulated BDL-induced hepatic inflammation, ECM accumulation, and HSC activation. IHC staining of Ki-67 and hepatocyte paraffin-1 revealed that PFD enhanced liver regeneration. The research confirmed that PFD gradually downregulated elevated eIF6, P311, and TGF-β levels in BDL-induced LF. These findings suggest that PFD could be a potential treatment for LF, as it may help attenuate fibrosis and enhance liver regeneration, possibly through the modulation of these specific markers.
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Affiliation(s)
- Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mitra Nourbakhsh
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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4
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Durazzo M, Ferro A, Navarro-Tableros VM, Gaido A, Fornengo P, Altruda F, Romagnoli R, Moestrup SK, Calvo PL, Fagoonee S. Current Treatment Regimens and Promising Molecular Therapies for Chronic Hepatobiliary Diseases. Biomolecules 2025; 15:121. [PMID: 39858515 PMCID: PMC11763965 DOI: 10.3390/biom15010121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/06/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Chronic hepatobiliary damage progressively leads to fibrosis, which may evolve into cirrhosis and/or hepatocellular carcinoma. The fight against the increasing incidence of liver-related morbidity and mortality is challenged by a lack of clinically validated early-stage biomarkers and the limited availability of effective anti-fibrotic therapies. Current research is focused on uncovering the pathogenetic mechanisms that drive liver fibrosis. Drugs targeting molecular pathways involved in chronic hepatobiliary diseases, such as inflammation, hepatic stellate cell activation and proliferation, and extracellular matrix production, are being developed. Etiology-specific treatments, such as those for hepatitis B and C viruses, are already in clinical use, and efforts to develop new, targeted therapies for other chronic hepatobiliary diseases are ongoing. In this review, we highlight the major molecular changes occurring in patients affected by metabolic dysfunction-associated steatotic liver disease, viral hepatitis (Delta virus), and autoimmune chronic liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis). Further, we describe how this knowledge is linked to current molecular therapies as well as ongoing preclinical and clinical research on novel targeting strategies, including nucleic acid-, mesenchymal stromal/stem cell-, and extracellular vesicle-based options. Much clinical development is obviously still missing, but the plethora of promising potential treatment strategies in chronic hepatobiliary diseases holds promise for a future reversal of the current increase in morbidity and mortality in this group of patients.
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Affiliation(s)
- Marilena Durazzo
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy; (M.D.); (A.F.); (A.G.); (P.F.)
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy; (M.D.); (A.F.); (A.G.); (P.F.)
| | - Victor Manuel Navarro-Tableros
- 2i3T, Società per la Gestione dell’Incubatore di Imprese e per il Trasferimento Tecnologico, University of Turin, 10126 Turin, Italy;
| | - Andrea Gaido
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy; (M.D.); (A.F.); (A.G.); (P.F.)
| | - Paolo Fornengo
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy; (M.D.); (A.F.); (A.G.); (P.F.)
| | - Fiorella Altruda
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre “Guido Tarone”, University of Turin, 10126 Turin, Italy;
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy;
| | - Søren K. Moestrup
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark;
- Department of Clinical Biochemistry, Aarhus University Hospital, 8000 Aarhus, Denmark
| | - Pier Luigi Calvo
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Città della Salute e della Scienza, 10126 Turin, Italy;
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Centre “Guido Tarone”, 10126 Turin, Italy
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Di X, Li Y, Wei J, Li T, Liao B. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410416. [PMID: 39665319 PMCID: PMC11744640 DOI: 10.1002/advs.202410416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/27/2024] [Indexed: 12/13/2024]
Abstract
As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.
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Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Ya Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Jingwen Wei
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Tianyue Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Banghua Liao
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
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Zhang Y, Ren L, Tian Y, Guo X, Wei F, Zhang Y. Signaling pathways that activate hepatic stellate cells during liver fibrosis. Front Med (Lausanne) 2024; 11:1454980. [PMID: 39359922 PMCID: PMC11445071 DOI: 10.3389/fmed.2024.1454980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Liver fibrosis is a complex process driven by various factors and is a key feature of chronic liver diseases. Its essence is liver tissue remodeling caused by excessive accumulation of collagen and other extracellular matrix. Activation of hepatic stellate cells (HSCs), which are responsible for collagen production, plays a crucial role in promoting the progression of liver fibrosis. Abnormal expression of signaling pathways, such as the TGF-β/Smads pathway, contributes to HSCs activation. Recent studies have shed light on these pathways, providing valuable insights into the development of liver fibrosis. Here, we will review six signaling pathways such as TGF-β/Smads that have been studied more in recent years.
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Affiliation(s)
- Youtian Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Long Ren
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yinting Tian
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaohu Guo
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Fengxian Wei
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yawu Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
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7
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Huang Y, Peng M, Yu W, Li H. Activation of Wnt/β-catenin signaling promotes immune evasion via the β-catenin/IKZF1/CCL5 axis in hepatocellular carcinoma. Int Immunopharmacol 2024; 138:112534. [PMID: 38941667 DOI: 10.1016/j.intimp.2024.112534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/10/2024] [Accepted: 06/18/2024] [Indexed: 06/30/2024]
Abstract
Immune checkpoint therapy (ICT) has been shown to produce durable responses in various cancer patients. However, its efficacy is notably limited in hepatocellular carcinoma (HCC), with only a small percentage of patients responding positively to treatment. The mechanism underlying resistance to ICT in HCC remains poorly understood. Here, we showed that combination treatment of ICG-001, an inhibitor of the Wnt/β-catenin signaling pathway, with anti-PD-1 antibody effectively suppresses tumor growth and promotes the infiltration of immune cells such as DCs and CD8+ T cells in the tumor microenvironment (TME). By inhibiting the activity of β-catenin and blocking its binding to the transcription factor IKAROS family zinc finger 1 (IKZF1), ICG-001 upregulated the expression of CCL5. Moreover, IKZF1 regulated the activity of the CCL5 promoter and its endogenous expression. Through inhibition of the WNT/β-catenin signaling pathway, upregulation of the expression of CCL5 was achieved, which subsequently recruited more DCs into the TME via C-C motif chemokine receptor 5 (CCR5). This, in turn, resulted in an increase in the infiltration of CD8+ T cells in the TME, thereby enhancing the antitumor immune response. Analysis of a tissue microarray derived from HCC patient samples revealed a positive correlation between survival rate and prognosis and the expression levels of CCL5/CD8. In conclusion, our findings suggest that combined application of ICG-001 and anti-PD-1 antibody exhibits significantly enhanced antitumor efficacy. Hence, combining a WNT/β-catenin signaling pathway inhibitor with anti-PD-1 therapy may be a promising treatment strategy for patients with HCC.
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Affiliation(s)
- Yamei Huang
- Department of Pathology and Pathophysiology, Medical School of Southeast University, China
| | - Min Peng
- Department of Pathogenic Biology and Immunology, Medical School of Southeast University, China
| | - Weiping Yu
- Department of Pathology and Pathophysiology, Medical School of Southeast University, China.
| | - Hui Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, China.
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Liu Y, Wang X, Wang Z, Gao X, Xu H, Gao Y, Niu J. System analysis based on weighted gene co-expression analysis identifies SOX7 as a novel regulator of hepatic stellate cell activation and liver fibrosis. FASEB J 2024; 38:e23495. [PMID: 39126242 DOI: 10.1096/fj.202302379r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/19/2024] [Accepted: 02/05/2024] [Indexed: 08/12/2024]
Abstract
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
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Affiliation(s)
- Yuwei Liu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaomei Wang
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhongfeng Wang
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiuzhu Gao
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongqin Xu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhang Gao
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
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9
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Somanader DVN, Zhao P, Widdop RE, Samuel CS. The involvement of the Wnt/β-catenin signaling cascade in fibrosis progression and its therapeutic targeting by relaxin. Biochem Pharmacol 2024; 223:116130. [PMID: 38490518 DOI: 10.1016/j.bcp.2024.116130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/06/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
Organ scarring, referred to as fibrosis, results from a failed wound-healing response to chronic tissue injury and is characterised by the aberrant accumulation of various extracellular matrix (ECM) components. Once established, fibrosis is recognised as a hallmark of stiffened and dysfunctional tissues, hence, various fibrosis-related diseases collectively contribute to high morbidity and mortality in developed countries. Despite this, these diseases are ineffectively treated by currently-available medications. The pro-fibrotic cytokine, transforming growth factor (TGF)-β1, has emerged as the master regulator of fibrosis progression, owing to its ability to promote various factors and processes that facilitate rapid ECM synthesis and deposition, whilst negating ECM degradation. TGF-β1 signal transduction is tightly controlled by canonical (Smad-dependent) and non-canonical (MAP kinase- and Rho-associated protein kinase-dependent) intracellular protein activity, whereas its pro-fibrotic actions can also be facilitated by the Wnt/β-catenin pathway. This review outlines the pathological sequence of events and contributing roles of TGF-β1 in the progression of fibrosis, and how the Wnt/β-catenin pathway contributes to tissue repair in acute disease settings, but to fibrosis and related tissue dysfunction in synergy with TGF-β1 in chronic diseases. It also outlines the anti-fibrotic and related signal transduction mechanisms of the hormone, relaxin, that are mediated via its negative modulation of TGF-β1 and Wnt/β-catenin signaling, but through the promotion of Wnt/β-catenin activity in acute disease settings. Collectively, this highlights that the crosstalk between TGF-β1 signal transduction and the Wnt/β-catenin cascade may provide a therapeutic target that can be exploited to broadly treat and reverse established fibrosis.
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Affiliation(s)
- Deidree V N Somanader
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia
| | - Peishen Zhao
- Drug Discovery Biology Program, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Robert E Widdop
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Victoria 3052, Australia.
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10
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Kimura K, Tanuma J, Kimura M, Imamura J, Yanase M, Ieiri I, Kurosaki M, Watanabe T, Endo T, Yotsuyanagi H, Gatanaga H. Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study. BMJ Open Gastroenterol 2024; 11:e001341. [PMID: 38677720 PMCID: PMC11057312 DOI: 10.1136/bmjgast-2023-001341] [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: 01/07/2024] [Accepted: 03/18/2024] [Indexed: 04/29/2024] Open
Abstract
OBJECTIVE Patients with haemophilia and HIV who acquire hepatitis C virus (HCV) after receiving contaminated blood products can experience accelerated progression of liver fibrosis and a poor prognosis, making liver disease a prominent cause of mortality among these patients. In the current study, we aimed to evaluate the safety and tolerability of the potential antifibrotic agent OP-724-a CREB-binding protein/β-catenin inhibitor-in this patient subset. DESIGN In this single-centre, open-label, non-randomised, phase I trial, we sequentially enrolled patients with cirrhosis following HIV/HCV coinfection classified as Child-Pugh (CP) class A or B. Five patients received an intravenous infusion of OP-724 at doses of 140 or 280 mg/m2 for 4 hours two times weekly over 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). Secondary endpoints included the incidence of AEs and improved liver stiffness measure (LSM), as determined by vibration-controlled transient elastography. This study was registered at ClinicalTrials.gov (NCT04688034). RESULTS Between 9 February 2021 and 5 July 2022, five patients (median age: 51 years) were enrolled. All five patients completed 12 cycles of treatment. SAEs were not observed. The most common AEs were fever (60%) and gastrointestinal symptoms (diarrhoea: 20%, enterocolitis: 20%). Improvements in LSM and serum albumin levels were also observed. CONCLUSION In this preliminary assessment, intravenous administration of 140 or 280 mg/m2/4 hours OP-724 over 12 weeks was well tolerated by patients with haemophilia combined with cirrhosis due to HIV/HCV coinfection. Hence, the antifibrotic effects of OP-724 warrant further assessment in patients with cirrhosis. TRIAL REGISTRATION NUMBER NCT04688034.
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Affiliation(s)
- Kiminori Kimura
- Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Junko Tanuma
- AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
| | - Masamichi Kimura
- Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Jun Imamura
- Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Mikio Yanase
- Department of Gastroenterology, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Tomoyuki Endo
- Department of Hematology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan
| | - Hiroyuki Gatanaga
- AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
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11
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Li X, Feng L, Kuang Q, Wang X, Yang J, Niu X, Gao L, Huang L, Luo P, Li L. Microplastics cause hepatotoxicity in diabetic mice by disrupting glucolipid metabolism via PP2A/AMPK/HNF4A and promoting fibrosis via the Wnt/β-catenin pathway. ENVIRONMENTAL TOXICOLOGY 2024; 39:1018-1030. [PMID: 38064261 DOI: 10.1002/tox.24034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 01/09/2024]
Abstract
In recent years, microplastics (MPs) have gained significant attention as a persistent environmental pollutant resulting from the decomposition of plastics, leading to their accumulation in the human body. The liver, particularly of individuals with type 2 diabetes mellitus (T2DM), is known to be more susceptible to the adverse effects of environmental pollutants. Therefore, to investigate the potential impact of MPs on the liver of diabetic mice and elucidate the underlying toxicological mechanisms, we exposed db/db mice to 0.5 μm MPs for 3 months. Our results revealed that MPs exposure resulted in several harmful effects, including decreased body weight, disruption of liver structure and function, elevated blood glucose levels, impaired glucose tolerance, and increased glycogen accumulation in the hepatic tissue of the mice. Furthermore, MPs exposure was found to promote hepatic gluconeogenesis by perturbing the PP2A/AMPK/HNF4A signaling pathway. In addition, MPs disrupt redox balance, leading to oxidative damage in the liver. This exposure also disrupted hepatic lipid metabolism, stimulating lipid synthesis while inhibiting catabolism, ultimately resulting in the development of fatty liver. Moreover, MPs were found to induce liver fibrosis by activating the Wnt/β-catenin signaling pathway. Furthermore, MPs influenced adaptive thermogenesis in brown fat by modulating the expression of uncoupling protein 1 (UCP1) and genes associated with mitochondrial oxidative respiration thermogenesis in brown fat. In conclusion, our study demonstrates that MPs induce oxidative damage in the liver, disturb glucose and lipid metabolism, promote hepatic fibrosis, and influence adaptive thermogenesis in brown fat in diabetic mice. These findings underscore the potential adverse effects of MPs on liver health in individuals with T2DM and highlight the importance of further research in this area.
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Affiliation(s)
- Xinxin Li
- Department of Urology, Wuhan Third Hospital, Medical School of Wuhan University, Wuhan, China
| | - Lixiang Feng
- Department of Urology, Wuhan Third Hospital, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qihui Kuang
- Department of Urology, Wuhan Third Hospital, Medical School of Wuhan University, Wuhan, China
| | - Xiong Wang
- Department of Pharmacy, Wuhan Third Hospital, Medical School of Wuhan University, Wuhan, China
| | - Jun Yang
- Department of Urology, Wuhan Third Hospital, Medical School of Wuhan University, Wuhan, China
| | - Xuan Niu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Likun Gao
- Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Lizhi Huang
- School of Civil Engineering, Wuhan University, Wuhan, China
| | - Pengcheng Luo
- Department of Urology, Wuhan Third Hospital, Medical School of Wuhan University, Wuhan, China
| | - Lili Li
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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12
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Luo H, Lou KC, Xie LY, Zeng F, Zou JR. Pharmacotherapy of urethral stricture. Asian J Androl 2024; 26:1-9. [PMID: 37738151 PMCID: PMC10846832 DOI: 10.4103/aja202341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/21/2023] [Indexed: 09/24/2023] Open
Abstract
Urethral stricture is characterized by the chronic formation of fibrous tissue, leading to the narrowing of the urethral lumen. Despite the availability of various endoscopic treatments, the recurrence of urethral strictures remains a common challenge. Postsurgery pharmacotherapy targeting tissue fibrosis is a promising option for reducing recurrence rates. Although drugs cannot replace surgery, they can be used as adjuvant therapies to improve outcomes. In this regard, many drugs have been proposed based on the mechanisms underlying the pathophysiology of urethral stricture. Ongoing studies have obtained substantial progress in treating urethral strictures, highlighting the potential for improved drug effectiveness through appropriate clinical delivery methods. Therefore, this review summarizes the latest researches on the mechanisms related to the pathophysiology of urethral stricture and the drugs to provide a theoretical basis and new insights for the effective use and future advancements in drug therapy for urethral stricture.
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Affiliation(s)
- Hui Luo
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Ke-Cheng Lou
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Ling-Yu Xie
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Fei Zeng
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
| | - Jun-Rong Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
- Institute of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
- Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou 341000, China
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13
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Shree Harini K, Ezhilarasan D, Mani U. Molecular insights on intracellular Wnt/β-catenin signaling in alcoholic liver disease. Cell Biochem Funct 2024; 42:e3916. [PMID: 38269515 DOI: 10.1002/cbf.3916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/27/2023] [Accepted: 12/10/2023] [Indexed: 01/26/2024]
Abstract
Alcoholic liver disease (ALD) is one of the most common health problems worldwide, especially in developing countries caused by chronic consumption of alcohol on a daily basis. The ALD spectrum is initiated with the early stages of alcoholic fatty liver (steatosis), progressing to alcoholic steatohepatitis, followed by the later stages of fibrosis and in some cases, cirrhosis and hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling required for healthy liver development, function, and regeneration is found to be aberrated in ALD, attributed to its progression. This review is to elucidate the association of Wnt/β-catenin signaling with various stages of ALD progression. Alcohol causes downregulation of Wnt/β-catenin signaling components and thereby suppressing the pathway. Reports have been published that aberrated Wnt/β-catenin signaling, especially the absence of β-catenin, results in decreased alcohol metabolism, causing steatosis followed by steatohepatitis via lipid accumulation, lipid peroxidation, liver injury, increased oxidative stress and apoptosis of hepatocytes, contributing to the advancement of ALD. Contrastingly, the progression of later stages of ALD like fibrosis and HCC depends on the increased activation of Wnt/β-catenin signaling and its components. Existing studies reveal the varied expression of Wnt/β-catenin signaling in ALD. However, the dual role of the Wnt/β-catenin pathway in earlier and later stages of ALD is not clear. Therefore, studies on the Wnt/β-catenin pathway and its components in various manifestations of ALD might provide insight in targeting the Wnt/β-catenin pathway in ALD treatment.
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Affiliation(s)
- Karthik Shree Harini
- Department of Pharmacology, Hepatology & Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Hepatology & Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Uthirappan Mani
- Animal House Division, CSIR-Central Leather Research Institute, Chennai, India
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14
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Li Q, Fan J, Zhou Z, Ma Z, Che Z, Wu Y, Yang X, Liang P, Li H. AID-induced CXCL12 upregulation enhances castration-resistant prostate cancer cell metastasis by stabilizing β-catenin expression. iScience 2023; 26:108523. [PMID: 38162032 PMCID: PMC10755053 DOI: 10.1016/j.isci.2023.108523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 11/14/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Prostate cancer (PCa) is one of the most common malignant diseases of urinary system and has poor prognosis after progression to castration-resistant prostate cancer (CRPC), and increased cytosine methylation heterogeneity is associated with the more aggressive phenotype of PCa cell line. Activation-induced cytidine deaminase (AID) is a multifunctional enzyme and contributes to antibody diversification. However, the dysregulation of AID participates in the progression of multiple diseases and related with certain oncogenes through demethylation. Nevertheless, the role of AID in PCa remains elusive. We observed a significant upregulation of AID expression in PCa samples, which exhibited a negative correlation with E-cadherin expression. Furthermore, AID expression is remarkably higher in CRPC cells than that in HSPC cells, and AID induced the demethylation of CXCL12, which is required to stabilize the Wnt signaling pathway executor β-catenin and EMT procedure. Our study suggests that AID drives CRPC metastasis by demethylation and can be a potential therapeutic target for CRPC.
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Affiliation(s)
- Qi Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Department of Urology, TianYou Hospital affiliated to Wuhan University of Science & Technology, Wuhan, Hubei Province, China
| | - Jinfeng Fan
- Department of Urology, the First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province, China
| | - Zhiyan Zhou
- Department of Urology, the First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province, China
| | - Zhe Ma
- The First Hospital of Tsinghua University, Beijing, China
| | - Zhifei Che
- Department of Urology, the First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province, China
| | - Yaoxi Wu
- Department of Urology, the First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province, China
| | - Xiangli Yang
- Department of Urology, TianYou Hospital affiliated to Wuhan University of Science & Technology, Wuhan, Hubei Province, China
| | - Peiyu Liang
- Department of Urology, the First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province, China
| | - Haoyong Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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15
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Yang B, Lin Y, Huang Y, Zhu N, Shen YQ. Extracellular vesicles modulate key signalling pathways in refractory wound healing. BURNS & TRAUMA 2023; 11:tkad039. [PMID: 38026441 PMCID: PMC10654481 DOI: 10.1093/burnst/tkad039] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 05/10/2023] [Accepted: 06/22/2023] [Indexed: 12/01/2023]
Abstract
Chronic wounds are wounds that cannot heal properly due to various factors, such as underlying diseases, infection or reinjury, and improper healing of skin wounds and ulcers can cause a serious economic burden. Numerous studies have shown that extracellular vesicles (EVs) derived from stem/progenitor cells promote wound healing, reduce scar formation and have significant advantages over traditional treatment methods. EVs are membranous particles that carry various bioactive molecules from their cellular origins, such as cytokines, nucleic acids, enzymes, lipids and proteins. EVs can mediate cell-to-cell communication and modulate various physiological processes, such as cell differentiation, angiogenesis, immune response and tissue remodelling. In this review, we summarize the recent advances in EV-based wound healing, focusing on the signalling pathways that are regulated by EVs and their cargos. We discuss how EVs derived from different types of stem/progenitor cells can promote wound healing and reduce scar formation by modulating the Wnt/β-catenin, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, vascular endothelial growth factor, transforming growth factor β and JAK-STAT pathways. Moreover, we also highlight the challenges and opportunities for engineering or modifying EVs to enhance their efficacy and specificity for wound healing.
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Affiliation(s)
- Bowen Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Yumeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Yibo Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Nanxi Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
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16
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Mohammed OS, Attia HG, Mohamed BMSA, Elbaset MA, Fayed HM. Current investigations for liver fibrosis treatment: between repurposing the FDA-approved drugs and the other emerging approaches. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2023; 26:11808. [PMID: 38022905 PMCID: PMC10662312 DOI: 10.3389/jpps.2023.11808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Long-term liver injuries lead to hepatic fibrosis, often progressing into cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. There is currently no effective therapy available for liver fibrosis. Thus, continuous investigations for anti-fibrotic therapy are ongoing. The main theme of anti-fibrotic investigation during recent years is the rationale-based selection of treatment molecules according to the current understanding of the pathology of the disease. The research efforts are mainly toward repurposing current FDA-approved drugs targeting etiological molecular factors involved in developing liver fibrosis. In parallel, investigations also focus on experimental small molecules with evidence to hinder or reverse the fibrosis. Natural compounds, immunological, and genetic approaches have shown significant encouraging effects. This review summarizes the efficacy and safety of current under-investigation antifibrosis medications targeting various molecular targets, as well as the properties of antifibrosis medications, mainly in phase II and III clinical trials.
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Affiliation(s)
- Omima S. Mohammed
- Department of Microbiology, College of Medicine, Najran University, Najran, Saudi Arabia
| | - Hany G. Attia
- Department of Pharmacognosy, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Bassim M. S. A. Mohamed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Marawan A. Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Hany M. Fayed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
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17
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Siapoush S, Rezaei R, Alavifard H, Hatami B, Zali MR, Vosough M, Lorzadeh S, Łos MJ, Baghaei K, Ghavami S. Therapeutic implications of targeting autophagy and TGF-β crosstalk for the treatment of liver fibrosis. Life Sci 2023; 329:121894. [PMID: 37380126 DOI: 10.1016/j.lfs.2023.121894] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/19/2023] [Accepted: 06/25/2023] [Indexed: 06/30/2023]
Abstract
Liver fibrosis is characterized by the excessive deposition and accumulation of extracellular matrix components, mainly collagens, and occurs in response to a broad spectrum of triggers with different etiologies. Under stress conditions, autophagy serves as a highly conserved homeostatic system for cell survival and is importantly involved in various biological processes. Transforming growth factor-β1 (TGF-β1) has emerged as a central cytokine in hepatic stellate cell (HSC) activation and is the main mediator of liver fibrosis. A growing body of evidence from preclinical and clinical studies suggests that TGF-β1 regulates autophagy, a process that affects various essential (patho)physiological aspects related to liver fibrosis. This review comprehensively highlights recent advances in our understanding of cellular and molecular mechanisms of autophagy, its regulation by TGF-β, and the implication of autophagy in the pathogenesis of progressive liver disorders. Moreover, we evaluated crosstalk between autophagy and TGF-β1 signalling and discussed whether simultaneous inhibition of these pathways could represent a novel approach to improve the efficacy of anti-fibrotic therapy in the treatment of liver fibrosis.
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Affiliation(s)
- Samaneh Siapoush
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramazan Rezaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100 Gliwice, Poland; Autophagy Research Center, Department of Biochemistry; Shiraz University of Medical Sciences, Shiraz, Iran; LinkoCare Life Sciences AB, Linkoping, Sweden
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada.
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18
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Shree Harini K, Ezhilarasan D. Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases. Hepatobiliary Pancreat Dis Int 2023; 22:333-345. [PMID: 36448560 DOI: 10.1016/j.hbpd.2022.10.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 10/13/2022] [Indexed: 11/04/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as "two-hit hypothesis", advancing with a "third hit" of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/β-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/β-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.
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Affiliation(s)
- Karthik Shree Harini
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600 077, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600 077, India.
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19
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Ishikane S, Arioka M, Takahashi-Yanaga F. Promising small molecule anti-fibrotic agents: Newly developed or repositioned drugs targeting myofibroblast transdifferentiation. Biochem Pharmacol 2023; 214:115663. [PMID: 37336252 DOI: 10.1016/j.bcp.2023.115663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/21/2023]
Abstract
Fibrosis occurs in all organs and tissues except the brain, and its progression leads to dysfunction of affected organs. Fibrosis-induced organ dysfunction results from the loss of elasticity, strength, and functionality of tissues due to the extracellular matrix secreted by myofibroblasts that express smooth muscle-type actin as a marker. Myofibroblasts, which play a major role in fibrosis, were once thought to originate exclusively from activated fibroblasts; however, it is now clear that myofibroblasts are diverse in origin, from epithelial cells, endothelial cells, adipocytes, macrophages, and other cells. Fibrosis of vital organs, such as the heart, lungs, kidneys, and liver, is a serious chronic disease that ultimately leads to death. Currently, anti-cancer drugs have made remarkable progress, as evidenced by the development of many molecular-targeted drugs, and are making a significant contribution to improving the prognosis of cancer treatment. However, the development of anti-fibrotic agents, which also play an important role in prognosis, has lagged. In this review, the current knowledge regarding myofibroblasts is summarized, with particular attention given to their origin and transdifferentiation signaling pathways (e.g., TGF-β, Wnt/β-catenin, YAP/TAZ and AMPK signaling pathways). The development of new small molecule anti-fibrotic agents and the repositioning of existing drugs targeting myofibroblast transdifferentiation are discussed.
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Affiliation(s)
- Shin Ishikane
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan
| | - Masaki Arioka
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan
| | - Fumi Takahashi-Yanaga
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
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20
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Zhao X, Zhang Z, Zhu Q, Luo Y, Ye Q, Shi S, He X, Zhu J, Zhang D, Xia W, Zhang Y, Jiang L, Cui L, Ye Y, Xiang Y, Hu J, Zhang J, Lin CP. Modeling human ectopic pregnancies with trophoblast and vascular organoids. Cell Rep 2023; 42:112546. [PMID: 37224015 DOI: 10.1016/j.celrep.2023.112546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 04/15/2023] [Accepted: 05/04/2023] [Indexed: 05/26/2023] Open
Abstract
Ruptured ectopic pregnancy (REP), a pregnancy complication caused by aberrant implantation, deep invasion, and overgrowth of embryos in fallopian tubes, could lead to rupture of fallopian tubes and accounts for 4%-10% of pregnancy-related deaths. The lack of ectopic pregnancy phenotypes in rodents hampers our understanding of its pathological mechanisms. Here, we employed cell culture and organoid models to investigate the crosstalk between human trophoblast development and intravillous vascularization in the REP condition. Compared with abortive ectopic pregnancy (AEP), the size of REP placental villi and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion in the REP condition. Our results reveal the important role of WNT-mediated angiogenesis and an organoid co-culture model for investigating intricate communications between trophoblasts and endothelial/endothelial progenitor cells.
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Affiliation(s)
- Xiaoya Zhao
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Zhenwu Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Qian Zhu
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Yurui Luo
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Qinying Ye
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Shuxiang Shi
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xueyang He
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Jing Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Duo Zhang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Wei Xia
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Yiqin Zhang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Linlin Jiang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Long Cui
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Yinghui Ye
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Yangfei Xiang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Junhao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Jian Zhang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China.
| | - Chao-Po Lin
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
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21
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Awadalla A, Hamam ET, Mostafa SA, Mahmoud SA, Elazab KM, El Nakib AM, Eldesoqui M, El-Sherbiny M, Ammar OA, Al-Serwi RH, Saleh MA, Sarhan A, Ali M. Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway. Cells 2023; 12:1526. [PMID: 37296647 PMCID: PMC10252276 DOI: 10.3390/cells12111526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/30/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Doxorubicin (DOX) is widely used to treat a variety of malignancies in both adults and children, including those of the bladder, breast, stomach, and ovaries. Despite this, it has been reported to cause hepatotoxicity. The recent discovery of bone marrow-derived mesenchymal stem cells' (BMSCs) therapeutic effects in the context of liver diseases suggests that their administration plays a part in the mitigation and rehabilitation of drug-induced toxicities. OBJECTIVES This study investigated whether bone BMSCs could reduce DOX-induced liver damage by blocking the Wnt/β-catenin pathway that causes fibrotic liver. MATERIALS AND METHODS BMSCs were isolated and treated with hyaluronic acid (HA) for 14 days before injection. Thirty-five mature male SD rats were categorized into four groups; group one (control) rats were supplemented with saline 0.9% for 28 days, group two (DOX) rats were injected with DOX (20 mg/kg), group three (DOX + BMSCs) rats were injected with 2 × 106 BMSCs after 4 days of DOX injection, group four (DOX + BMSCs + HA) rats were injected with 0.1 mL BMSCs pretreated with HA after 4 days of DOX. After 28 days the rats were sacrificed, and blood and liver tissue samples were subjected to biochemical and molecular analysis. Morphological and immunohistochemical observations were also carried out. RESULTS In terms of liver function and antioxidant findings, cells treated with HA showed considerable improvement compared to the DOX group (p < 0.05). Moreover, the expression of inflammatory markers (TGFβ1, iNos), apoptotic markers (Bax, Bcl2), cell tracking markers (SDF1α), fibrotic markers (β-catenin, Wnt7b, FN1, VEGF, and Col-1), and ROS markers (Nrf2, HO-1) was improved in BMSCs conditioned with HA in contrast to BMSCs alone (p < 0.05). CONCLUSION Our findings proved that BMSCs treated with HA exert their paracrine therapeutic effects via their secretome, suggesting that cell-based regenerative therapies conditioned with HA may be a viable alternative to reduce hepatotoxicity.
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Affiliation(s)
- Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Eman T. Hamam
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Sally Abdallah Mostafa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Seham Ahmed Mahmoud
- Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Khalid Mohamed Elazab
- Department of Biology, Faculty of Science, Jazan University, Jazan 82511, Saudi Arabia
| | - Ahmed Mohamed El Nakib
- Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mamdouh Eldesoqui
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Omar A. Ammar
- Basic Science Department, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Rasha Hamed Al-Serwi
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourahbint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Mohamed A. Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amira Sarhan
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed Ali
- Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
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22
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Zhang W, Cui Y, Du Y, Yang Y, Fang T, Lu F, Kong W, Xiao C, Shi J, Reid LM, He Z. Liver cell therapies: cellular sources and grafting strategies. Front Med 2023; 17:432-457. [PMID: 37402953 DOI: 10.1007/s11684-023-1002-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/27/2023] [Indexed: 07/06/2023]
Abstract
The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver's cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.
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Affiliation(s)
- Wencheng Zhang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yangyang Cui
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
- Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yuan Du
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yong Yang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Ting Fang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Fengfeng Lu
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Weixia Kong
- Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Canjun Xiao
- Department of General Surgery, Ji'an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji'an, 343006, China
| | - Jun Shi
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Department of General Surgery, Ji'an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji'an, 343006, China
| | - Lola M Reid
- Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA.
| | - Zhiying He
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China.
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China.
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23
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Huang Y, Ma J, Fan Y, Yang L. Mechanisms of human umbilical cord mesenchymal stem cells-derived exosomal lncRNA GAS5 in alleviating EMT of HPMCs via Wnt/β-catenin signaling pathway. Aging (Albany NY) 2023; 15:204719. [PMID: 37229651 DOI: 10.18632/aging.204719] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 05/01/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Prolonged peritoneal dialysis (PD) can result in epithelial-to-mesenchymal transition (EMT) and peritoneal fibrosis (PF), which can cause patients to discontinue PD. It is imperative to urgently investigate effective measures to mitigate PF. This study aims to reveal mechanisms of exosomal lncRNA GAS5 derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) on EMT of human peritoneal mesothelial cells (HPMCs) under high glucose (HG) conditions. METHODS HPMCs were stimulated with 2.5% glucose. The effects on EMT of HPMCs were observed by using an hUC-MSC conditioned medium (hUC-MSC-CM) and extracted exosomes. After hUC-MSCs were transfected with GAS5 siRNA, exosomes were extracted to act on HPMCs for detecting EMT markers, PTEN, and Wnt/β-catenin pathway, lncRNA GAS5 and miR-21 expressions in HPMCs. RESULTS We found that HG could induce the EMT of HPMCs. Compared with the HG group, the hUC-MSC-CM could alleviate the EMT of HPMCs induced by HG through exosomes. Exosomes in the hUC-MSC-CM entered HPMCs, by transferring lncRNA GAS5 to HPMCs, which down-regulates miR-21 and up-regulates PTEN, thus finally alleviating EMT of HPMCs. The Wnt/β-catenin pathway plays an essential role in alleviating EMT of HPMCs by exosomes in the hUC-MSC-CM. By transferring lncRNA GAS5 to HPMCs, exosomes derived from hUC-MSCs may competitively bind to miR-21 to regulate suppression on target PTEN genes and alleviate EMT of HPMCs through the Wnt/β-catenin pathway. CONCLUSIONS Exosomes from the hUC-MSCs-CM could alleviate the EMT of HPMCs induced by HG via regulating lncRNA GAS5/miR-21/PTEN through the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Yuling Huang
- Department of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jianfei Ma
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yi Fan
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Lina Yang
- Department of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
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24
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Xu X, Zhang B, Wang Y, Shi S, Lv J, Fu Z, Gao X, Li Y, Wu H, Song Q. Renal fibrosis in type 2 cardiorenal syndrome: An update on mechanisms and therapeutic opportunities. Biomed Pharmacother 2023; 164:114901. [PMID: 37224755 DOI: 10.1016/j.biopha.2023.114901] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/13/2023] [Accepted: 05/16/2023] [Indexed: 05/26/2023] Open
Abstract
Cardiorenal syndrome (CRS) is a state of coexisting heart failure and renal insufficiency in which acute or chronic dysfunction of the heart or kidney lead to acute or chronic dysfunction of the other organ.It was found that renal fibrosis is an important pathological process in the progression of type 2 CRS to end-stage renal disease, and progressive renal impairment accelerates the deterioration of cardiac function and significantly increases the hospitalization and mortality rates of patients. Previous studies have found that Hemodynamic Aiteration, RAAS Overactivation, SNS Dysfunction, Endothelial Dysfunction and Imbalance of natriuretic peptide system contribute to the development of renal disease in the decompensated phase of heart failure, but the exact mechanisms is not clear. Therefore, in this review, we focus on the molecular pathways involved in the development of renal fibrosis due to heart failure and identify the canonical and non-canonical TGF-β signaling pathways and hypoxia-sensing pathways, oxidative stress, endoplasmic reticulum stress, pro-inflammatory cytokines and chemokines as important triggers and regulators of fibrosis development, and summarize the therapeutic approaches for the above signaling pathways, including SB-525334 Sfrp1, DKK1, IMC, rosarostat, 4-PBA, etc. In addition, some potential natural drugs for this disease are also summarized, including SQD4S2, Wogonin, Astragaloside, etc.
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Affiliation(s)
- Xia Xu
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bingxuan Zhang
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yajiao Wang
- College of Traditional Chinese Medicine, China Academy of Chinese Medical Science, Beijing, China
| | - Shuqing Shi
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiayu Lv
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhenyue Fu
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xiya Gao
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Yumeng Li
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Huaqin Wu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qingqiao Song
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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25
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Caven LT, Carabeo RA. The role of infected epithelial cells in Chlamydia-associated fibrosis. Front Cell Infect Microbiol 2023; 13:1208302. [PMID: 37265500 PMCID: PMC10230099 DOI: 10.3389/fcimb.2023.1208302] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 05/08/2023] [Indexed: 06/03/2023] Open
Abstract
Ocular, genital, and anogenital infection by the obligate intracellular pathogen Chlamydia trachomatis have been consistently associated with scar-forming sequelae. In cases of chronic or repeated infection of the female genital tract, infection-associated fibrosis of the fallopian tubes can result in ectopic pregnancy or infertility. In light of this urgent concern to public health, the underlying mechanism of C. trachomatis-associated scarring is a topic of ongoing study. Fibrosis is understood to be an outcome of persistent injury and/or dysregulated wound healing, in which an aberrantly activated myofibroblast population mediates hypertrophic remodeling of the basement membrane via deposition of collagens and other components of the extracellular matrix, as well as induction of epithelial cell proliferation via growth factor signaling. Initial study of infection-associated immune cell recruitment and pro-inflammatory signaling have suggested the cellular paradigm of chlamydial pathogenesis, wherein inflammation-associated tissue damage and fibrosis are the indirect result of an immune response to the pathogen initiated by host epithelial cells. However, recent work has revealed more direct routes by which C. trachomatis may induce scarring, such as infection-associated induction of growth factor signaling and pro-fibrotic remodeling of the extracellular matrix. Additionally, C. trachomatis infection has been shown to induce an epithelial-to-mesenchymal transition in host epithelial cells, prompting transdifferentiation into a myofibroblast-like phenotype. In this review, we summarize the field's current understanding of Chlamydia-associated fibrosis, reviewing key new findings and identifying opportunities for further research.
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Affiliation(s)
- Liam T. Caven
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA, United States
| | - Rey A. Carabeo
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
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26
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β-catenin/TCF4 inhibitors ICG-001 and LF3 alleviate BDL-induced liver fibrosis by suppressing LECT2 signaling. Chem Biol Interact 2023; 371:110350. [PMID: 36639009 DOI: 10.1016/j.cbi.2023.110350] [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: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Liver fibrosis can be characterized by the over-deposition of extracellular matrix (ECM). It has been reported that β-catenin/TCF4 interaction was enhanced in bile duct ligation (BDL) model, which implicated the critical role of β-catenin/TCF4 interaction during the progression of fibrosis. However, whether inhibiting β-catenin/TCF4 signaling attenuates liver fibrosis remains unknown. In the current study, we used ICG-001, an inhibitor that disrupts the interaction between CREB binding protein (CBP) and β-catenin, to inhibit β-catenin/TCF4 transcriptional activity. We also used LF3, a small molecule antagonist, to inhibit β-catenin/TCF4 interaction. The antifibrotic effect of ICG-001 and LF3 was assessed on BDL-induced liver fibrosis model. The results indicated both ICG-001 and LF3 significantly reduced the positive staining area of Sirius Red and α-SMA. The protein expression levels of α-SMA, Collagen Ⅰ and CD31 were also significantly downregulated in BDL + ICG-001 and BDL + LF3 groups. Besides, ICG-001 and LF3 promoted portal angiogenesis and inhibited sinusoids capillarization in fibrotic livers. For mechanistic study, we measured the level of leukocyte cell-derived chemotaxin 2 (LECT2), a direct target of β-catenin/TCF4, which was recently reported to participate in hepatic fibrosis by regulating angiogenesis. The results showed that both ICG-001 and LF3 reduced LECT2 expression in BDL mice. LF3 also downregulated pSer 675 β-catenin and nuclear β-catenin. In conclusion, this study demonstrated that inhibiting β-catenin/TCF4 signaling by ICG-001 or LF3 mitigated liver fibrosis by downregulating LECT2, promoting portal angiogenesis and inhibiting sinusoids capillarization, which provided new evidence that β-catenin/TCF4 signaling might be a target for the treatment of liver fibrosis.
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27
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Macrophages and Wnts in Tissue Injury and Repair. Cells 2022; 11:cells11223592. [PMID: 36429021 PMCID: PMC9688352 DOI: 10.3390/cells11223592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/16/2022] Open
Abstract
Macrophages are important players in the immune system that sense various tissue challenges and trigger inflammation. Tissue injuries are followed by inflammation, which is tightly coordinated with tissue repair processes. Dysregulation of these processes leads to chronic inflammation or tissue fibrosis. Wnt ligands are present both in homeostatic and pathological conditions. However, their roles and mechanisms regulating inflammation and tissue repair are being investigated. Here we aim to provide an overview of overarching themes regarding Wnt and macrophages by reviewing the previous literature. We aim to gain future insights into how tissue inflammation, repair, regeneration, and fibrosis events are regulated by macrophages.
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28
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Zhang D, Zhang Y, Sun B. The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application. Int J Mol Sci 2022; 23:ijms232012572. [PMID: 36293428 PMCID: PMC9604031 DOI: 10.3390/ijms232012572] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/27/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.
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Affiliation(s)
- Danyan Zhang
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
| | - Bing Sun
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
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29
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Wang R, Guo T, Li J. Mechanisms of Peritoneal Mesothelial Cells in Peritoneal Adhesion. Biomolecules 2022; 12:1498. [PMID: 36291710 PMCID: PMC9599397 DOI: 10.3390/biom12101498] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/24/2022] Open
Abstract
A peritoneal adhesion (PA) is a fibrotic tissue connecting the abdominal or visceral organs to the peritoneum. The formation of PAs can induce a variety of clinical diseases. However, there is currently no effective strategy for the prevention and treatment of PAs. Damage to peritoneal mesothelial cells (PMCs) is believed to cause PAs by promoting inflammation, fibrin deposition, and fibrosis formation. In the early stages of PA formation, PMCs undergo mesothelial-mesenchymal transition and have the ability to produce an extracellular matrix. The PMCs may transdifferentiate into myofibroblasts and accelerate the formation of PAs. Therefore, the aim of this review was to understand the mechanism of action of PMCs in PAs, and to offer a theoretical foundation for the treatment and prevention of PAs.
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Affiliation(s)
- Ruipeng Wang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730030, China
| | - Tiankang Guo
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730030, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
| | - Junliang Li
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730030, China
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730030, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
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30
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Tang K, Jiao LM, Qi YR, Wang TC, Li YL, Xu JL, Wang ZW, Yu B, Liu HM, Zhao W. Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK- 129 and Its Protective Effects on Myocardial Remodeling and Fibrosis. J Med Chem 2022; 65:12979-13000. [DOI: 10.1021/acs.jmedchem.2c00797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Kai Tang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Le-Min Jiao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Yu-Ruo Qi
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Tian-Ci Wang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Ya-Lan Li
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Jia-Le Xu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Zi-Wei Wang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Bin Yu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Wen Zhao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
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31
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Booijink R, Salgado‐Polo F, Jamieson C, Perrakis A, Bansal R. A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis. EMBO Mol Med 2022; 14:e16333. [PMID: 35833384 PMCID: PMC9449594 DOI: 10.15252/emmm.202216333] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/09/2022] Open
Abstract
The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement of the ATX-LPA signaling axis in human and murine diseased livers. Then, we evaluated the effects of Cpd17, in comparison with the classic type I inhibitor PF8380, in vitro, where Cpd17 showed higher efficacy. Thereafter, we characterized the mechanism-of-action of both inhibitors and found that Cpd17 was more potent in inhibiting RhoA-mediated cytoskeletal remodeling, and phosphorylation of MAPK/ERK and AKT/PKB. Finally, the therapeutic potential of Cpd17 was investigated in CCl4 -induced acute liver injury and diet-induced nonalcoholic steatohepatitis, demonstrating an excellent potential of Cpd17 in reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases.
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Affiliation(s)
- Richell Booijink
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and TechnologyUniversity of TwenteEnschedeThe Netherlands
- Oncode Institute, Division of BiochemistryNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Fernando Salgado‐Polo
- Oncode Institute, Division of BiochemistryNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Craig Jamieson
- Department of Pure and Applied ChemistryUniversity of StrathclydeGlasgowUK
| | - Anastassis Perrakis
- Oncode Institute, Division of BiochemistryNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and TechnologyUniversity of TwenteEnschedeThe Netherlands
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Targeting fibrosis, mechanisms and cilinical trials. Signal Transduct Target Ther 2022; 7:206. [PMID: 35773269 PMCID: PMC9247101 DOI: 10.1038/s41392-022-01070-3] [Citation(s) in RCA: 227] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.
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Fleming Martinez AK, Döppler HR, Bastea LI, Edenfield BH, Liou GY, Storz P. Ym1 + macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer. iScience 2022; 25:104327. [PMID: 35602933 PMCID: PMC9118688 DOI: 10.1016/j.isci.2022.104327] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/04/2022] [Accepted: 04/26/2022] [Indexed: 01/05/2023] Open
Abstract
Desmoplasia around pancreatic lesions is a barrier for immune cells and a hallmark of developing and established pancreatic cancer. However, the contribution of the innate immune system to this process is ill-defined. Using the KC mouse model and primary cells in vitro, we show that alternatively activated macrophages (AAM) crosstalk with pancreatic lesion cells and pancreatic stellate cells (PSCs) to mediate fibrosis and progression of lesions. TGFβ1 secreted by AAM not only drives activation of quiescent PSCs but also in activated PSCs upregulates expression of TIMP1, a factor previously shown as crucial in fibrosis. Once activated, PSCs auto-stimulate proliferation via CXCL12. Furthermore, we found that TIMP1/CD63 signaling mediates PanIN lesion growth and TGFβ1 contributes to a cadherin switch and drives structural collapse of lesions, indicating a potential progression step. Taken together, our data indicate TGFβ1 produced by Ym1+ AAM as a major driver of processes that initiate the development of pancreatic cancer.
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Affiliation(s)
| | - Heike R. Döppler
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Ligia I. Bastea
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Brandy H. Edenfield
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Geou-Yarh Liou
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA,Department of Biological Sciences, Center for Cancer Research & Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA,Corresponding author
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Choi KH, Kim DK, Kim AR, Lee SR. Prevention of urethral fibrosis induced by transforming growth factor beta 1 using selective Wnt/β-catenin signaling inhibitors in a rat model. Int J Urol 2022; 29:764-771. [PMID: 35381618 DOI: 10.1111/iju.14884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 03/21/2022] [Indexed: 01/08/2023]
Abstract
OBJECTIVES To determine the anti-fibrotic effects of Wnt/β-catenin signaling inhibitors on urethral stricture. METHODS Human fibroblasts were exposed to transforming growth factor beta 1 combined with various concentrations of Wnt/β-catenin inhibitors (ICG-001, IWR-1, and PRI-724), and cell proliferation and migration were evaluated. Urethral fibrosis was induced in male Sprague-Dawley rats by urethral injection of transforming growth factor beta 1 and co-treatement with inhibitors. Urethral tissues were harvested 2 weeks after the injection. The messenger ribonucleic acid and protein expression was examined for fibrosis markers Axin-1, collagen type 1, alpha smooth muscle actin, and β-catenin. Histological analysis of fibrosis and collagen deposition was also performed. RESULTS Cell migration was ameliorated by ICG-001 and PRI-724. Protein and messenger ribonucleic acid expression of collagen type 1 and alpha smooth muscle actin in transforming growth factor beta 1-treated fibroblasts decreased in a concentration-dependent manner with the ICG-001 and PRI-724 treatments (P < 0.05). However, there were no significant changes with the IWR-1 treatment. Collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression were both significantly increased in the urethral tissues of rats with transforming growth factor beta 1-induced urethral fibrosis. Rats co-treated with ICG-001 or PRI-724 showed relatively mild fibrosis and significantly reduced collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression (P < 0.05). CONCLUSIONS ICG-001 and PRI-724 significantly ameliorated urethral fibrosis induced by transforming growth factor beta 1 in rats. These results suggest that ICG-001 and PRI-724 can be developed as therapeutics for treating urethral stricture.
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Affiliation(s)
- Kyung Hwa Choi
- Department of Urology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Dae Keun Kim
- Department of Urology, CHA Fertility Center Seoul Station, CHA University School of Medicine, Seoul, Korea
| | - A Ram Kim
- Department of Dermatology, School of Medicine, CHA University School of Medicine, Pocheon, Korea
| | - Seung-Ryeol Lee
- Department of Urology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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Li H, Li K, Zhu Q, Tang Z, Wang Z. Transcriptomic analysis of bladder tissue in a rat model of ketamine-induced bladder fibrosis. Neurourol Urodyn 2022; 41:765-776. [PMID: 35170809 DOI: 10.1002/nau.24892] [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: 09/12/2021] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 11/10/2022]
Abstract
INTRODUCTION Ketamine-induced cystitis (KIC) is a disease caused by ketamine that can cause lower urinary tract symptoms (LUTS). Its end-stage is bladder contracture, which is related to bladder fibrosis and poses a serious burden to patient lives. METHODS We established a KIC model in female Sprague Dawley rats and verified bladder fibrosis in the model by Masson trichrome staining and western blot analysis. The bladders of the rats from the ketamine and control groups were used to perform transcriptome analysis. In particular, association analysis with metabolomics was also used to determine the potential mechanisms of ketamine-induced bladder fibrosis. RESULTS A total of 685 differentially expressed messenger RNAs, 71 differentially expressed long noncoding RNAs, 23 differentially expressed microRNAs, and 68 differentially expressed circular RNAs were identified. We found that ribosome, Wnt signaling, vascular endothelial growth factor signaling, cytoskeleton organization, and cytoskeletal protein binding may be potential pathways in ketamine-induced bladder fibrosis as identified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. In addition, the mitogen-activated protein kinase pathway appeared to be closely related to the development of ketamine-induced bladder fibrosis according to association analysis. CONCLUSIONS In this study, using transcriptomic and correlation analyses of metabolomics, we identified pathways that may be potential targets for the prevention and treatment of ketamine-induced bladder fibrosis.
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Affiliation(s)
- Haozhen Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Urology, The second hospital of Dalian medical university, Dalian, Liaoning, China
| | - Kaixuan Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Quan Zhu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhengyan Tang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhao Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Chang YM, Chen PC, Hsu CP, Ma PF, Chen HL, Hsu SH. Loss of hepatic miR-194 promotes liver regeneration and protects from acetaminophen-induced acute liver injury. Biochem Pharmacol 2022; 195:114862. [PMID: 34843716 DOI: 10.1016/j.bcp.2021.114862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 11/26/2022]
Abstract
The two microRNAs miR-192 and miR-194 are abundantly expressed in the liver and are considered serum biomarkers of liver injury. However, their role in the development of liver injury has not yet been determined. In this study, we generated miR-192/194 mutant mice and determined the effect of miR-192/194 loss on acetaminophen (APAP)-induced acute liver injury. With genetic depletion of miR-192/194, mutant mice were fertile and normally developed. No spontaneous liver injuries were observed in mutant mice. After APAP administration, mutant mice developed less severe liver damage than control mice. Specifically, mutant mice exhibited significantly lower serum alanine transaminase (ALT) levels and pericentral necrosis/apoptosis than control mice receiving APAP. β-catenin signaling was activated during the early phase of liver injury. Activated β-catenin signaling led to faster cellular proliferation and higher expression of AXIN2 and glutamine synthetases. After partial hepatectomy, the miR-192/194 mutant hepatocytes were more regenerative than control hepatocytes (as shown by BrdU incorporation). Moreover, in vitro experiments indicated that miR-194, but not miR-192, specifically repressed β-catenin signaling, while animal experiments revealed that chemical-mediated knockdown of β-catenin signaling compromised APAP resistance that liver protected from miR-192/194 genetic depletion. Collectively, our data indicated that the loss of miR-194 promoted liver regeneration and protected the liver from APAP-induced injury.
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Affiliation(s)
- Yi-Ming Chang
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Po-Chun Chen
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan; Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chien-Peng Hsu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Peng-Fang Ma
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Shu-Hao Hsu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan.
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Duspara K, Bojanic K, Pejic JI, Kuna L, Kolaric TO, Nincevic V, Smolic R, Vcev A, Glasnovic M, Curcic IB, Smolic M. Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update. J Clin Transl Hepatol 2021; 9:960-971. [PMID: 34966659 PMCID: PMC8666372 DOI: 10.14218/jcth.2021.00065] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 06/23/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a life-threatening disease, with challenging morbidity and mortality for healthcare systems worldwide. It imparts an enormous economic burden to societies, making continuous research and informational updates about its pathogenesis and treatment crucial. This review's focus is on the current knowledge about the Wnt signaling pathway, serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells (HSCs). Two types of Wnt pathways are distinguished, namely the ß-catenin-dependent canonical and non-canonical Ca2+ or planar cell polarity (PCP)-dependent pathway. The dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver injuries. Activation of the ß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix (ECM), leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes, lacking the original function of healthy hepatocytes. Therefore, liver function is reduced due to the severely advanced disease. Selective inhibition of ß-catenin inhibits inflammatory processes (since chemokines and pro-inflammatory cytokines are produced during Wnt activation), reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis, thereby reducing the progression of liver fibrosis in vivo. While the canonical Wnt pathway is usually inactive in a physiologically healthy liver, it shows activity during cell regeneration or renewal and in certain pathophysiological conditions, such as liver diseases and cancer. Targeted blocking of some of the basic components of the Wnt pathway is a therapeutic approach. These include the frizzled transmembrane receptor (Fz) receptors using the secreted frizzled-related protein family (sFRP), Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1 (DKK1) or niclosamide, glycogen kinase-3 beta (GSK-3β) using SB-216763, cyclic-AMP response element-binding protein (CBP) using PRI-724 and ICG-001, the lymphoid enhancer binding factor (LEF)/T cell-specific transcription factor (TCF) system as well as Wnt inhibitory factor 1 (WIF1) and miR-17-5p using pinostilbene hydrate (PSH). Significant progress has been made in inhibiting Wnt and thus stopping the progression of liver fibrosis by diminishing key components for its action. Comprehending the role of the Wnt signaling pathway in liver fibrosis may lead to discovery of novel targets in liver fibrosis therapeutic strategies' development.
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Affiliation(s)
- Kristina Duspara
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Kristina Bojanic
- Department of Biophysics and Radiology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Biophysics and Radiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Radiology, Health Center Osijek, Osijek, Croatia
| | - Josipa Ivanusic Pejic
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Lucija Kuna
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Tea Omanovic Kolaric
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Vjera Nincevic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Robert Smolic
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pathophysiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Aleksandar Vcev
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pathophysiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Marija Glasnovic
- Department of Medicine, Family Medicine and History of Medicine, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Ines Bilic Curcic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Medicine, Division of Endocrinology, University Hospital Osijek, Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
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Koui Y, Himeno M, Mori Y, Nakano Y, Saijou E, Tanimizu N, Kamiya Y, Anzai H, Maeda N, Wang L, Yamada T, Sakai Y, Nakato R, Miyajima A, Kido T. Development of human iPSC-derived quiescent hepatic stellate cell-like cells for drug discovery and in vitro disease modeling. Stem Cell Reports 2021; 16:3050-3063. [PMID: 34861166 PMCID: PMC8693663 DOI: 10.1016/j.stemcr.2021.11.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic stellate cells (HSCs) play a central role in the progression of liver fibrosis by producing extracellular matrices. The development of drugs to suppress liver fibrosis has been hampered by the lack of human quiescent HSCs (qHSCs) and an appropriate in vitro model that faithfully recapitulates HSC activation. In the present study, we developed a culture system to generate qHSC-like cells from human-induced pluripotent stem cells (hiPSCs) that can be converted into activated HSCs in culture. To monitor the activation process, a red fluorescent protein (RFP) gene was inserted in hiPSCs downstream of the activation marker gene actin alpha 2 smooth muscle (ACTA2). Using qHSC-like cells derived from RFP reporter iPSCs, we screened a repurposing chemical library and identified therapeutic candidates that prevent liver fibrosis. Hence, hiPSC-derived qHSC-like cells will be a useful tool to study the mechanism of HSC activation and to identify therapeutic agents.
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Affiliation(s)
- Yuta Koui
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Misao Himeno
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Yusuke Mori
- Bio Science & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, 577 Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa 258-8577, Japan
| | - Yasuhiro Nakano
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Eiko Saijou
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Naoki Tanimizu
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan
| | - Yoshiko Kamiya
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Hiroko Anzai
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Natsuki Maeda
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Luyao Wang
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Tadanori Yamada
- Bio Science & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, 577 Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa 258-8577, Japan
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Ryuichiro Nakato
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Taketomo Kido
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
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Zhang J, Liu Q, He J, Li Y. Novel Therapeutic Targets in Liver Fibrosis. Front Mol Biosci 2021; 8:766855. [PMID: 34805276 PMCID: PMC8602792 DOI: 10.3389/fmolb.2021.766855] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
Liver fibrosis is end-stage liver disease that can be rescued. If irritation continues due to viral infection, schistosomiasis and alcoholism, liver fibrosis can progress to liver cirrhosis and even cancer. The US Food and Drug Administration has not approved any drugs that act directly against liver fibrosis. The only treatments currently available are drugs that eliminate pathogenic factors, which show poor efficacy; and liver transplantation, which is expensive. This highlights the importance of clarifying the mechanism of liver fibrosis and searching for new treatments against it. This review summarizes how parenchymal, nonparenchymal cells, inflammatory cells and various processes (liver fibrosis, hepatic stellate cell activation, cell death and proliferation, deposition of extracellular matrix, cell metabolism, inflammation and epigenetics) contribute to liver fibrosis. We highlight discoveries of novel therapeutic targets, which may provide new insights into potential treatments for liver fibrosis.
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Affiliation(s)
- Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China.,Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
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40
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Tan Z, Sun H, Xue T, Gan C, Liu H, Xie Y, Yao Y, Ye T. Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy. Front Cell Dev Biol 2021; 9:730176. [PMID: 34621747 PMCID: PMC8490799 DOI: 10.3389/fcell.2021.730176] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/31/2021] [Indexed: 02/05/2023] Open
Abstract
Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.
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Affiliation(s)
- Zui Tan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongbao Sun
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Taixiong Xue
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Cailing Gan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongyao Liu
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuting Xie
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuqin Yao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tinghong Ye
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Fan Y, Zhao X, Ma J, Yang L. LncRNA GAS5 Competitively Combined With miR-21 Regulates PTEN and Influences EMT of Peritoneal Mesothelial Cells via Wnt/β-Catenin Signaling Pathway. Front Physiol 2021; 12:654951. [PMID: 34526907 PMCID: PMC8435904 DOI: 10.3389/fphys.2021.654951] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022] Open
Abstract
Objective Epithelial-mesenchymal transition (EMT) is an important factor leading to peritoneal fibrosis (PF) in end-stage renal disease (ESRD) patients. The current research aimed to evaluate the effect of long non-coding RNA growth arrest-specific 5 (lncRNA GAS5) in human peritoneal mesothelial cells (HPMCs) EMT and explore the potential molecular mechanisms. Materials and Methods HPMCs were cultured under control conditions or with high glucose (HG). The cells were then treated with lncRNA GAS5, lncRNA GAS5 siRNA, with or without miR-21 inhibitor and PTEN transfection. Expression of lncRNA GAS5, miR-21, α-SMA, Vimentin, E-cadherin, phosphatase and tensin homolog deleted on chromosome ten (PTEN), Wnt3a, and β-catenin were measured by real time PCR and Western blotting. Bioinformatics analyses were used to test the specific binding sites between the 3' UTR of the PTEN gene, miR-21, and lncRNA GAS5. Rescue experiments were performed to confirm the lncRNA GAS5/miR-21/PTEN axis in HPMC EMT. Results We found that HG-induced EMT decreased lncRNA GAS5 and that overexpression of lncRNA GAS5 can attenuate EMT in HPMCs. In addition, lncRNA GAS5 regulated HG-induced EMT through miR-21/PTEN. Cotransfection of miR-21 inhibitors remarkably increased PTEN expression and attenuated EMT in lncRNA GAS5 knockdown HPMCs. Moreover, rescue experiments showed that overexpression of PTEN attenuated the EMT effects of lncRNA GAS5 siRNA in HPMCs. We also confirmed that the Wnt/β-catenin pathway was stimulated in lncRNA GAS5/miR-21/PTEN-mediated EMT. Conclusion Our research showed that lncRNA GAS5 competitively combined with miR-21 to regulate PTEN expression and influence EMT of HPMCs via the Wnt/β-catenin signaling pathway. This study provides novel evidence that lncRNA GAS5 may be a potential therapeutic target for HPMC EMT.
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Affiliation(s)
- Yi Fan
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xingxu Zhao
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jianfei Ma
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lina Yang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
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Li SS, Sun Q, Hua MR, Suo P, Chen JR, Yu XY, Zhao YY. Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis. Front Pharmacol 2021; 12:719880. [PMID: 34483931 PMCID: PMC8415231 DOI: 10.3389/fphar.2021.719880] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/03/2021] [Indexed: 12/15/2022] Open
Abstract
The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.
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Affiliation(s)
- Shan-Shan Li
- Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi’an, China
- The First School of Clinical Medicine, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
| | - Qian Sun
- Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi’an, China
- The First School of Clinical Medicine, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
| | - Meng-Ru Hua
- Faculty of Life Science and Medicine, Northwest University, Xi’an, China
| | - Ping Suo
- Faculty of Life Science and Medicine, Northwest University, Xi’an, China
| | - Jia-Rong Chen
- Department of Clinical Pharmacy, Affiliated Hospital of Chengdu University, Chengdu, China
| | - Xiao-Yong Yu
- Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi’an, China
| | - Ying-Yong Zhao
- Faculty of Life Science and Medicine, Northwest University, Xi’an, China
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Geervliet E, Moreno S, Baiamonte L, Booijink R, Boye S, Wang P, Voit B, Lederer A, Appelhans D, Bansal R. Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis. J Control Release 2021; 332:594-607. [PMID: 33737203 DOI: 10.1016/j.jconrel.2021.03.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.
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Affiliation(s)
- Eline Geervliet
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands
| | - Silvia Moreno
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany
| | - Luca Baiamonte
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany
| | - Richell Booijink
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands
| | - Susanne Boye
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany
| | - Peng Wang
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany; Technische Universität Dresden, Organic Chemistry of Polymers, 01062 Dresden, Germany
| | - Brigitte Voit
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany; Technische Universität Dresden, Organic Chemistry of Polymers, 01062 Dresden, Germany
| | - Albena Lederer
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany; Department of Chemistry and Polymer Science, Stellenbosch University, Matieland 7602, South Africa.
| | - Dietmar Appelhans
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany.
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands.
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Lai KKY, Kahn M. Pharmacologically Targeting the WNT/β-Catenin Signaling Cascade: Avoiding the Sword of Damocles. Handb Exp Pharmacol 2021; 269:383-422. [PMID: 34463849 DOI: 10.1007/164_2021_523] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
WNT/β-catenin signaling plays fundamental roles in numerous developmental processes and in adult tissue homeostasis and repair after injury, by controlling cellular self-renewal, activation, division, differentiation, movement, genetic stability, and apoptosis. As such, it comes as no surprise that dysregulation of WNT/β-catenin signaling is associated with various diseases, including cancer, fibrosis, neurodegeneration, etc. Although multiple agents that specifically target the WNT/β-catenin signaling pathway have been studied preclinically and a number have entered clinical trials, none has been approved by the FDA to date. In this chapter, we provide our insights as to the reason(s) it has been so difficult to safely pharmacologically target the WNT/β-catenin signaling pathway and discuss the significant efforts undertaken towards this goal.
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Affiliation(s)
- Keane K Y Lai
- Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Michael Kahn
- Beckman Research Institute, City of Hope, Duarte, CA, USA.
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46
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Zhao L, Yao C, Xing X, Jing T, Li P, Zhu Z, Yang C, Zhai J, Tian R, Chen H, Luo J, Liu N, Deng Z, Lin X, Li N, Fang J, Sun J, Wang C, Zhou Z, Li Z. Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells. Nat Commun 2020; 11:5683. [PMID: 33173058 PMCID: PMC7655944 DOI: 10.1038/s41467-020-19414-4] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 10/09/2020] [Indexed: 12/21/2022] Open
Abstract
Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA pathogenesis and normal spermatogenic microenvironment. Here, we profile >80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. We show that Sertoli cells, which form the scaffold in the testicular microenvironment, are severely damaged in NOA patients and identify the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature, but exhibit abnormal immune responses, while the cells in idiopathic NOA (iNOA) are physiologically immature. Furthermore, we find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA. Non-obstructive azoospermia affects 1% of men. Here, authors perform single-cell transcriptomic analysis of human testicular cells from healthy donors and non-obstructive azoospermia patients and find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from patients.
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Affiliation(s)
- LiangYu Zhao
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - ChenCheng Yao
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - XiaoYu Xing
- Department of Urology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China
| | - Tao Jing
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.,Department of Andrology, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Peng Li
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - ZiJue Zhu
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chao Yang
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Jing Zhai
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - RuHui Tian
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - HuiXing Chen
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - JiaQiang Luo
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - NaChuan Liu
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - ZhiWen Deng
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - XiaoHan Lin
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Na Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Jing Fang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.,Shanghai Advanced Research Institute, Stem Cell and Reproductive Biology Laboratory, Chinese Academy of Sciences, Shanghai, 201210, China
| | - Jie Sun
- Department of Urology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China.
| | - ChenChen Wang
- Shanghai Advanced Research Institute, Stem Cell and Reproductive Biology Laboratory, Chinese Academy of Sciences, Shanghai, 201210, China.
| | - Zhi Zhou
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
| | - Zheng Li
- Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
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Yang J, Tao D, Ma W, Liu S, Liao Y, Shu L, Zhang S, Li C, Du N, Shi Z. Sijunzi, Lizhong, and Fuzilizhong Decoction Alleviate Nonalcoholic Fatty Liver Disease through Activation of PPAR Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:6363748. [PMID: 33178320 PMCID: PMC7648686 DOI: 10.1155/2020/6363748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 09/23/2020] [Accepted: 10/16/2020] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Sijunzi, Lizhong, and Fuzilizhong decoction were traditional Chinese classic formulations, which are widely used in clinical treatment, and the underlying mechanism is unclear. In this study, we aim to investigate the molecular mechanisms underlying the protective effects of Sijunzi, Lizhong, and Fuzilizhong on nonalcoholic fatty liver disease (NAFLD). METHODS Male Wistar rats were fed a high-fat diet for four weeks to induce NAFLD and were thereafter administered Sijunzi (8 g/kg/d), Lizhong (10 g/kg/d), or Fuzilizhong (10 g/kg/d) by gavage for four weeks. Hepatic damage, lipid accumulation, inflammation, autophagy, and peroxisome proliferator-activated receptor-α signaling were evaluated. RESULTS The high-fat diet-fed rats showed typical symptoms of NAFLD, including elevated levels of hepatic damage indicators, increased hepatic lipid deposition and fibrosis, severe liver inflammation, and prominent autophagy. Upon administration of Sijunzi, Lizhong, and Fuzilizhong, liver health was improved remarkably, along with ameliorated symptoms of NAFLD. In addition, NAFLD-suppressed peroxisome proliferator-activated receptor-α signaling was reactivated after treatment with the three types of decoctions. CONCLUSIONS The results collectively signify the effective therapeutic and protective functions of Sijunzi, Lizhong, and Fuzilizhong against NAFLD and demonstrate the potential of Chinese herbal medication in mitigating the symptoms of liver diseases. Novelty of the Work. Traditional Chinese herbal medicine has been used for centuries to treat various diseases, but the molecular mechanisms of individual ingredients have rarely been studied. The novelty of our work lies in elucidating the specific signaling pathways involved in the control of NAFLD using three common Chinese herbal decoctions. We suggest that natural herbal formulations can be effective therapeutic agents to combat against NAFLD.
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Affiliation(s)
- Jiayao Yang
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Dongqing Tao
- Department of Endocrinology, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Wei Ma
- Department of Center Laboratory, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Song Liu
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Yan Liao
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Lei Shu
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Shu Zhang
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Chenyu Li
- Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Nianlong Du
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Zhaohong Shi
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
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Cheikhi AM, Johnson ZI, Julian DR, Wheeler S, Feghali-Bostwick C, Conley YP, Lyons-Weiler J, Yates CC. Prediction of severity and subtype of fibrosing disease using model informed by inflammation and extracellular matrix gene index. PLoS One 2020; 15:e0240986. [PMID: 33095822 PMCID: PMC7584227 DOI: 10.1371/journal.pone.0240986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/06/2020] [Indexed: 11/19/2022] Open
Abstract
Fibrosis is a chronic disease with heterogeneous clinical presentation, rate of progression, and occurrence of comorbidities. Systemic sclerosis (scleroderma, SSc) is a rare rheumatic autoimmune disease that encompasses several aspects of fibrosis, including highly variable fibrotic manifestation and rate of progression. The development of effective treatments is limited by these variabilities. The fibrotic response is characterized by both chronic inflammation and extracellular remodeling. Therefore, there is a need for improved understanding of which inflammation-related genes contribute to the ongoing turnover of extracellular matrix that accompanies disease. We have developed a multi-tiered method using Naïve Bayes modeling that is capable of predicting level of disease and clinical assessment of patients based on expression of a curated 60-gene panel that profiles inflammation and extracellular matrix production in the fibrotic disease state. Our novel modeling design, incorporating global and parametric-based methods, was highly accurate in distinguishing between severity groups, highlighting the importance of these genes in disease. We refined this gene set to a 12-gene index that can accurately identify SSc patient disease state subsets and informs knowledge of the central regulatory pathways in disease progression.
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Affiliation(s)
- Amin M. Cheikhi
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States of America
| | - Zariel I. Johnson
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States of America
| | - Dana R. Julian
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States of America
- Department of Health Promotion and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA, United States of America
| | - Sarah Wheeler
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Carol Feghali-Bostwick
- Department of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States of America
| | - Yvette P. Conley
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States of America
| | - James Lyons-Weiler
- Genomic and Proteomic Core Laboratories, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Cecelia C. Yates
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States of America
- Department of Health Promotion and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA, United States of America
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
- * E-mail:
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49
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Claveria-Cabello A, Colyn L, Arechederra M, Urman JM, Berasain C, Avila MA, Fernandez-Barrena MG. Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target? Cells 2020; 9:cells9102321. [PMID: 33086678 PMCID: PMC7589994 DOI: 10.3390/cells9102321] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/15/2020] [Accepted: 10/17/2020] [Indexed: 12/13/2022] Open
Abstract
Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
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Affiliation(s)
- Alex Claveria-Cabello
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
| | - Leticia Colyn
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Jesus M. Urman
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Department of Gastroenterology and Hepatology, Navarra University Hospital Complex, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Matias A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Correspondence: (M.A.A.); (M.G.F.-B.); Tel.: +34-94-819-4700 (M.A.A.); +34-94-819-4700 (M.G.F.-B.)
| | - Maite G. Fernandez-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Correspondence: (M.A.A.); (M.G.F.-B.); Tel.: +34-94-819-4700 (M.A.A.); +34-94-819-4700 (M.G.F.-B.)
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Zhu M, Meng P, Ling X, Zhou L. Advancements in therapeutic drugs targeting of senescence. Ther Adv Chronic Dis 2020; 11:2040622320964125. [PMID: 33133476 PMCID: PMC7576933 DOI: 10.1177/2040622320964125] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022] Open
Abstract
Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects. In this review, we summarize different types of drugs promoting healthy aging – such as senolytics, senescence-associated secretory phenotype (SASP) inhibitors, and nutrient signaling regulators – and provide an update on their potential therapeutic merits. Taken together, our review synthesizes recent advancements in the therapeutic potentialities of drugs promoting healthy aging with regard to their clinical implications.
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Affiliation(s)
- Mingsheng Zhu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ping Meng
- Department of Nephrology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China
| | - Xian Ling
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lili Zhou
- Division of Nephrology, Nanfang Hospital, 1838 North Guangzhou Ave, Guangzhou 510515, China
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