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Huang R, Han B, Peng J, Jiao H. PTB Regulates Keloid Fibroblast Migration and Proliferation Through Autophagy. Aesthetic Plast Surg 2025; 49:897-907. [PMID: 39402202 DOI: 10.1007/s00266-024-04375-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/03/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Keloid disease is a chronic fibroproliferative disease that occurs after tissue injury, and the currently available treatments are unsatisfactory. OBJECTIVES We aimed to explore the level of autophagy in keloid fibroblasts (KFbs) and adjacent normal fibroblasts (NFbs). In addition, whether polypyrimidine tract-binding protein (PTB) regulates the biological functions of KFbs via autophagy was also investigated. METHODS The morphology of fibroblasts in normal skin and keloids was observed transmission electron microscopy. We silenced PTB with PTB-specific siRNA to determine whether PTB-regulated KFb proliferation. Acridine orange and LysoTracker Red staining was performed to label acidic compartments. Interestingly, when autophagy was inhibited by wortmannin, the PTB knockdown-mediated decrease in KFb migration and proliferation was abolished, while the collagen I and III levels were not altered; these results indicated that PTB regulated the migration and proliferation of KFbs via autophagy, while collagen synthesis occurred independently of PTB regulation. RESULTS Many activities related to the survival and function of KFbs are controlled by PTB. Transmission electron microscopy revealed more autophagosomes and autolysosomes in KFbs than in NFbs. PTB induced autophagy in KFbs, as demonstrated by the significantly greater number of autophagosomes in KFbs after PTB knockdown, which was revealed by acridine orange and LysoTracker staining. CONCLUSIONS Our study is the first to show that PTB regulates the migration and proliferation of KFbs via autophagy and that PTB regulates collagen synthesis in KFbs in an autophagy-independent manner. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Rong Huang
- Department of Dermatology, Hangzhou Third People's Hospital, 38, West Lake Avenue, Hangzhou, 310009, Zhejiang, China
| | - Bing Han
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, 100144, China
| | - Jianzhong Peng
- Department of Dermatology, Hangzhou Third People's Hospital, 38, West Lake Avenue, Hangzhou, 310009, Zhejiang, China.
| | - Hu Jiao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, 100144, China.
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Wang Z, Chen G, Li H, Liu J, Yang Y, Zhao C, Li Y, Shi J, Chen H, Chen G. Zotarolimus alleviates post-trabeculectomy fibrosis via dual functions of anti-inflammation and regulating AMPK/mTOR axis. Int Immunopharmacol 2024; 142:113176. [PMID: 39303539 DOI: 10.1016/j.intimp.2024.113176] [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: 07/24/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024]
Abstract
OBJECTIVE Postoperative scar formation is the primary cause of uncontrolled intraocular pressure following trabeculectomy failure. This study aimed to evaluate the efficacy of zotarolimus as an adjuvant anti-scarring agent in the experimental trabeculectomy. METHODS We performed differential gene and Gene Ontology enrichment analysis on rabbit follicular transcriptome sequencing data (GSE156781). New Zealand white Rabbits were randomly assigned into three groups: Surgery only, Surgery with mitomycin-C treatment, Surgery with zotarolimus treatment. Rabbits were euthanized 3 days or 28 days post-trabeculectomy. Pathological sections were analyzed using immunohistochemistry, immunofluorescence, and Masson staining. In vitro, primary human tenon's capsule fibroblasts (HTFs) were stimulated by transforming growth factor-β1 (TGF-β1) and treated with either mitomycin-C or zotarolimus. Cell proliferation and migration were evaluated using cell counting kit-8, cell cycle, and scratch assays. Mitochondrial membrane potential was detected with the JC-1 probe, and reactive oxygen species were detected using the DCFH-DA probe. RNA and protein expressions were quantified using RT-qPCR and immunofluorescence. RESULTS Transcriptome sequencing analysis revealed the involvement of complex immune factors and metabolic disorders in trabeculectomy outcomes. Zotarolimus effectively inhibited fibrosis, reduced proinflammatory factor release and immune cell infiltration, and improved the surgical outcomes of trabeculectomy. In TGF-β1-induced HTFs, zotarolimus reduced fibrosis, proliferation, and migration without cytotoxicity via the dual regulation of the TGF-β1/Smad2/3 and AMPK/AKT/mTOR pathways. CONCLUSION Our study demonstrates that zotarolimus mitigates fibrosis by reducing immune infiltration and correcting metabolic imbalances, offering a potential treatment for improving trabeculectomy surgical outcomes.
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Affiliation(s)
- Zhiruo Wang
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Gong Chen
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Haoyu Li
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Jingyuan Liu
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Yuanyuan Yang
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Cong Zhao
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Yunping Li
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Jingming Shi
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Huihui Chen
- Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China; Clinical Immunology Research Center of Central South University, Changsha, China.
| | - Guochun Chen
- Clinical Immunology Research Center of Central South University, Changsha, China; Department of Nephrology, the Second Xiangya Hospital of Central South University, Changsha, China
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Pallares RM, Abergel RJ. New insights into the toxicity of lanthanides with functional genomics. Toxicology 2024; 509:153967. [PMID: 39384009 DOI: 10.1016/j.tox.2024.153967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 09/30/2024] [Accepted: 10/07/2024] [Indexed: 10/11/2024]
Abstract
As the use of lanthanides increases in many industries, concerns regarding their impact on human health rise. However, until recently, the toxicological profile of these elements had been incompletely characterized, with most studies relying on biodistribution assessments and lethal dose determinations in different animal models. In the last few years, the f-element field has started to pivot towards other examination types that identify cellular and molecular mechanisms of toxicity in a high-throughput manner. Under this new paradigm, functional genomics techniques, which rely on genetically modified cells or model organisms with missing genes or proteins, are becoming fundamental to gain novel insights into the genetic and proteomic bases of lanthanide toxicity, as well as to identify potential therapeutic targets to minimize the harmful effects of the metals. This review aims to provide an updated perspective on current efforts using functional genomics to characterize the toxicity and biological impact of lanthanides and improve their safety in different industrial applications.
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Affiliation(s)
- Roger M Pallares
- Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen 52074, Germany; Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
| | - Rebecca J Abergel
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Nuclear Engineering and Department of Chemistry, University of California, Berkeley, CA, 94720, USA.
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Quintero Bernabeu J, Juamperez Goñi J, Mercadal Hally M, Padrós Fornieles C, Ortega López J, Larrarte King M, Molino Gahete JA, Salcedo Allende MT, Hidalgo Llompart E, Bilbao Aguirre I, Charco Torra R. Sirolimus to treat chronic and steroid-resistant allograft rejection-related fibrosis in pediatric liver transplantation. J Pediatr Gastroenterol Nutr 2024; 79:962-968. [PMID: 38973300 DOI: 10.1002/jpn3.12286] [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: 10/31/2023] [Revised: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 07/09/2024]
Abstract
This study aimed to report our experience with the use of Sirolimus (SRL) in pediatric liver transplant patients with chronic rejection or steroid-resistant rejection with hepatic fibrosis, focusing on their histological evolution. All pediatric liver transplant recipients who received off-label treatment with SRL for chronic ductopenic rejection or cortico-resistant rejection between July 2003 and July 2022 were included in the study. All nine patients included in the study showed improvement in liver enzymes and cholestasis parameters as soon as 1-month after post-SRL introduction. A decrease in fibrosis stage was observed in 7/9 (77.7%) patients at 36 months. All but one patient experienced an improvement in the Rejection Activity Index and ductopenia at 12 months. A single patient had to discontinue SRL treatment owing to nephrotic proteinuria. In conclusion, SRL may be a safe and effective treatment for chronic and steroid-resistant rejection and may improve allograft rejection-related fibrosis and ductal damage.
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Affiliation(s)
- Jesús Quintero Bernabeu
- Pediatric Hepatology and Liver Transplant Department, ERN Rare Liver - ERN TrasplantChild, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Javier Juamperez Goñi
- Pediatric Hepatology and Liver Transplant Department, ERN Rare Liver - ERN TrasplantChild, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Maria Mercadal Hally
- Pediatric Hepatology and Liver Transplant Department, ERN Rare Liver - ERN TrasplantChild, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Cristina Padrós Fornieles
- Pediatric Hepatology and Liver Transplant Department, ERN Rare Liver - ERN TrasplantChild, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Juan Ortega López
- Pediatric Intensive Care Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Mauricio Larrarte King
- Pediatric Hepatology and Liver Transplant Department, ERN Rare Liver - ERN TrasplantChild, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - José A Molino Gahete
- Pediatric Surgery Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | | | | | | | - Ramon Charco Torra
- HPB Surgery and Transplants, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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5
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Wen J, Li H, Zhou Y, Du H, Hu G, Wen Z, Tang D, Wang Y, Cui X, Zhou Z, Wang DW, Chen C. Immunoglobin attenuates fulminant myocarditis by inhibiting overactivated innate immune response. Br J Pharmacol 2024. [PMID: 39442535 DOI: 10.1111/bph.17372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 09/08/2024] [Accepted: 09/16/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND AND PURPOSE Fulminant myocarditis (FM) is a myocardial inflammatory disease that can result from either viral diseases or autoimmune diseases. In this study, we have determined the treatment effects of immunomodulatory drugs on FM. EXPERIMENTAL APPROACH FM was induced in A/JGpt mice by intraperitoneal administration of coxsackievirus B3, after which immunoglobins were administered daily by intraperitoneal injection. On the seventh day, the cardiac structure and function were determined using echocardiography and cardiac catheterisation. Single-cell RNA sequencing (scRNA-seq) was performed to evaluate CD45+ cells in the heart. KEY RESULTS Immunoglobin, a typical immunomodulatory drug, dramatically reduced mortality and significantly improved cardiac function in mice with FM. ScRNA-seq revealed that immunoglobin treatment effectively modulated cardiac immune homeostasis, particularly by attenuating overactivated innate immune responses. At the cellular level, immunoglobin predominantly targeted Plac8+ monocytes and S100a8+ neutrophils, suppressing their proinflammatory activities, and enhancing antigen processing and presentation capabilities, thereby amplifying the efficiency and potency of the immune response against the virus. Immunoglobin benefits are mediated by the modulation of multiple signalling pathways, including relevant receptors on immune cells, direction of inflammatory cell chemotaxis, antigen presentation and anti-viral effects. Subsequently, Bst2-ILT7 ligand-receptor-mediated cellular interactions manipulated by immunoglobin were further confirmed in vivo. CONCLUSIONS AND IMPLICATIONS Immunoglobin treatment significantly attenuated FM-induced cardiac inflammation and improved cardiac function by inhibiting overactivated innate immune responses.
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Affiliation(s)
- Jianpei Wen
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Huihui Li
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Yufei Zhou
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Hengzhi Du
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guo Hu
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Zheng Wen
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Du Tang
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Yanwen Wang
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Xinwu Cui
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhou Zhou
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
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Bosselmann EA, Engel B, Hartleben B, Wedemeyer H, Jaeckel E, Maasoumy B, Potthoff A, Zender S, Taubert R. Prospective comparison of liver stiffness measurement methods in surveillance biopsies after liver transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1148195. [PMID: 38993851 PMCID: PMC11235307 DOI: 10.3389/frtra.2023.1148195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 11/03/2023] [Indexed: 07/13/2024]
Abstract
Background Liver stiffness measurements (LSMs) have proven useful for non-invasive detection of fibrosis. Previous studies of LSMs after transplantation were performed in cohorts dominated by hepatitis C reinfections and indication biopsies for the evaluation of graft dysfunction. However, the diagnostic fidelity of LSMs for fibrosis is biased by inflammation e.g., during replicative hepatitis C or rejection. Materials and methods The current study aimed for a head-to-head comparison of two different LSMs, acoustic radiation force impulse (ARFI) and transient elastography (TE), and a determination of cut-off values for the detection of advanced fibrosis (any LAF score component ≥2) in grafts undergoing surveillance biopsies (svLbx) without recurrent hepatitis C. Results 103 svLbx were paired with valid LSMs at time of biopsy. AUROC analyses showed significant positive correlation with fibrosis for both methods (TE: AUROC = 0.819 (p < 0.001; 95%CI: 0.717-0.921); ARFI: AUROC = 0.771 (p = 0.001; 95%CI: 0.652-0.890). Patients were randomly assigned to training and validation cohorts for both LSM methods. Cut-off values were determined at 1.29 m/s (ARFI) and at 7.5 kPa (TE) in training cohorts. Sensitivity and specificity in training and validation cohorts were: TE: SEN 0.818 and 0.5; SPE 0.742 and 0.885; ARFI: SEN 0.818 and 1.0; SPE 0.75 and 0.586. LSMs were not associated with BANFF criteria for relevant graft injury. Conclusion LSM is a good non-invasive tool to screen for advanced graft fibrosis but not for relevant graft injury in patients with (near) normal liver enzymes. Fibrosis cut-off values identified and validated in svLbx were lower than in previous cohorts using indication biopsies.
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Affiliation(s)
- Emily A Bosselmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Steffen Zender
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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Winans T, Oaks Z, Choudhary G, Patel A, Huang N, Faludi T, Krakko D, Nolan J, Lewis J, Blair S, Lai Z, Landas SK, Middleton F, Asara JM, Chung SK, Wyman B, Azadi P, Banki K, Perl A. mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency. J Autoimmun 2023; 140:103112. [PMID: 37742509 PMCID: PMC10957505 DOI: 10.1016/j.jaut.2023.103112] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 09/26/2023]
Abstract
Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.
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Affiliation(s)
- T Winans
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - Z Oaks
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - G Choudhary
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - A Patel
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - N Huang
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - T Faludi
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - D Krakko
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - J Nolan
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - J Lewis
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - Sarah Blair
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - Z Lai
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - S K Landas
- Departments of Pathology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - F Middleton
- Departments of Neuroscience, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - J M Asara
- Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - S K Chung
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau
| | - B Wyman
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - P Azadi
- University of Georgia, Athens, GA 30602, USA
| | - K Banki
- Departments of Pathology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA
| | - A Perl
- Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Microbiology and Immunology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
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8
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Arora M, Pavlíková Z, Kučera T, Kozlík P, Šopin T, Vacík T, Ľupták M, Duda M, Slanař O, Kutinová Canová N. Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression. Biomed Pharmacother 2023; 167:115447. [PMID: 37683589 DOI: 10.1016/j.biopha.2023.115447] [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: 06/30/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/10/2023] Open
Abstract
Knowledge of the benefits of mTOR inhibition concerning adipogenesis and inflammation has recently encouraged the investigation of a new generation of mTOR inhibitors for non-alcoholic steatohepatitis (NASH). We investigated whether treatment with a specific mTORC1/C2 inhibitor (Ku-0063794; KU) exerted any beneficial impacts on experimentally-induced NASH in vitro and in vivo. The results indicated that KU decreases palmitic acid-induced lipotoxicity in cultivated primary hepatocytes, thus emerging as a successful candidate for testing in an in vivo NASH dietary model, which adopted the intraperitoneal KU dosing route rather than oral application due to its significantly greater bioavailability in mice. The pharmacodynamics experiments commenced with the feeding of male C57BL/6 mice with a high-fat atherogenic western-type diet (WD) for differing intervals over several weeks aimed at inducing various phases of NASH. In addition to the WD, the mice were treated with KU for 3 weeks or 4 months. Acute and chronic KU treatments were observed to be safe at the given concentrations with no toxicity indications in the mice. KU was found to alleviate NASH-related hepatotoxicity, mitochondrial and oxidative stress, and decrease the liver triglyceride content and TNF-α mRNA in at least one set of in vivo experiments. The KU modulated liver expression of selected metabolic and oxidative stress-related genes depended upon the length and severity of the disease. Although KU failed to completely reverse the histological progression of NASH in the mice, we demonstrated the complexity of mTORC1/C2 signaling regulation and suggest a stratified therapeutic management approach throughout the disease course.
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Affiliation(s)
- Mahak Arora
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Zuzana Pavlíková
- Institute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech Republic
| | - Tomáš Kučera
- Institute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Kozlík
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Tijana Šopin
- Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Tomáš Vacík
- Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Matej Ľupták
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Matthias Duda
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Ondřej Slanař
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Nikolina Kutinová Canová
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
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Gong S, Li C, Leng Q, Liu C, Zhu Y, Zhang H, Li X. Inhibition of the mTORC1 pathway alleviates adipose tissue fibrosis. Heliyon 2023; 9:e21526. [PMID: 38034664 PMCID: PMC10681937 DOI: 10.1016/j.heliyon.2023.e21526] [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: 07/25/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023] Open
Abstract
Background Adipose fibrosis is a major factor of adipose dysfunction, which causes metabolic dysfunction during obesity, but its molecular mechanisms are poorly understood. This study investigated the role and potential mechanisms of mTORC1 in obesity-induced adipose fibrosis. Methods ob/ob mice were injected with rapamycin or the same volume of normal saline. The level of fibrosis in epididymal adipose tissue (EAT) was detected by observing aberrant deposition of extracellular matrix. Expression of fibrotic related genes was analysed using RNA-seq. 3T3-L1 preadipocytes were treated with cobalt chloride (CoCl2) and TGF-β1 to induce preadipocyte fibrosis. The fibrosis-related gene expression and protein levels were determined by RT-PCR, WB, and immunofluorescence in two types of fibrotic preadipocytes with or without rapamycin. Results Compared with vehicle treatment, EAT fibrosis-related aberrant deposition of extracellular matrix proteins and fibrotic gene expression were reduced in ob/ob mice treated with rapamycin. Both CoCl2-induced hypoxia and TGF-β1 successfully promoted adipocyte fibrosis, and the upregulated fibrosis-related genes expression was inhibited after the mTORC1 pathway was inhibited by rapamycin. Conclusion Inhibition of the mTORC1 pathway ameliorates adipose fibrosis by suppressing fibrosis-related genes in hypoxia- and TGF-β-induced fibrotic preadipocytes.
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Affiliation(s)
- Sa Gong
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
- Shanghai Songjiang District Fangta Hospital of Traditional Chinese Medicine, Shanghai, 201600, China
| | - Chang Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Qingyang Leng
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Chongxiao Liu
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Yi Zhu
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Hongli Zhang
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Xiaohua Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
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Yue C, Li D, Fan S, Tao F, Yu Y, Lu W, Chen Q, Yuan A, Wu J, Zhao G, Dong H, Hu Y. Long-term and liver-selected ginsenoside C-K nanoparticles retard NAFLD progression by restoring lipid homeostasis. Biomaterials 2023; 301:122291. [PMID: 37619263 DOI: 10.1016/j.biomaterials.2023.122291] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 07/25/2023] [Accepted: 08/19/2023] [Indexed: 08/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent hepatic disease characterized as lipid accumulation, yet without any approved drug. And development of therapeutic molecules is obstructed by low efficiency and organ toxicity. Herein, we develop a long-term, low-toxic and liver-selected nano candidate, nabCK, to alleviate NAFLD. NabCK is simply composed by natural compound ginsenoside compound K (CK) and albumin. As a major metabolite of ginseng, ginsenoside CK has excellently modulating functions for lipid metabolism, but accompanied by an extremely poor bioavailability <1%. Albumin is a key lipid carrier secreted and metabolized by livers. Thereby, it can improve solubility and liver-localization of CK. In adipocytes and hepatocytes, nabCK prevents lipid deposition and eliminates lipid droplets. Transcriptomic analysis reveals that nabCK rectifies various pathways that involved in steatosis development, including lipid absorption, lipid export, fatty acid biosynthesis, lipid storage and inflammation. All these pathways are modulated by mTOR, the pivotal feedback sensor that is hyperactive in NAFLD. NabCK suppresses mTOR activation to restores lipid homeostasis. In high-fat diet (HFD) induced NAFLD mice, nabCK retards development of steatosis and fibrosis, coupling a protective effect on cardiac tissues from lipotoxicity. Together, nabCK is a safe and potent candidate to offer benefits for NAFLD treatment.
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Affiliation(s)
- Chunyan Yue
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Dandan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Shuxin Fan
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Feng Tao
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yue Yu
- Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, China
| | - Wenjing Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Qian Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Ahu Yuan
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Jinhui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China
| | - Guoping Zhao
- Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Hong Dong
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China.
| | - Yiqiao Hu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China.
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11
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Engel B, Falk Villesen I, Fisker Nielsen MJ, Karsdal M, Taubert R, Jaeckel E, Leeming DJ. Quantification of extracellular matrix remodeling for the non-invasive identification of graft fibrosis after liver transplantation. Sci Rep 2023; 13:6103. [PMID: 37055472 PMCID: PMC10101979 DOI: 10.1038/s41598-023-33100-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 04/07/2023] [Indexed: 04/15/2023] Open
Abstract
Detecting patients with early post-transplant fibrosis after liver transplantation (LT) is very important. Non-invasive tests are needed to avoid liver biopsies. We aimed to detect fibrosis in liver transplant recipients (LTR) using extracellular matrix (ECM) remodeling biomarkers. ECM biomarkers for type III (PRO-C3), IV (PRO-C4), VI (PRO-C6) and XVIII (PRO-C18L) collagen formation and type IV collagen degradation (C4M) were measured by ELISA in prospectively collected, cryopreserved plasma samples (n = 100) of LTR with paired liver biopsies from a protocol biopsy program. Fibrosis ≥ F2 was present in 29% of patients (median 44 months post-LT). APRI and FIB-4 neither identified significant fibrosis nor were correlated with histopathological fibrosis scores, while ECM biomarkers (AUCs 0.67-0.74) did. The median levels of PRO-C3 (15.7 vs. 11.6 ng/ml; p = 0.002) and C4M (22.9 vs. 11.6 ng/ml; p = 0.006) levels were elevated in T-cell-mediated rejection compared to normal graft function. The median levels of PRO-C4 (178.9 vs. 151.8 ng/ml; p = 0.009) and C4M (18.9 vs. 16.8 ng/ml; p = 0.004) levels were increased if donor-specific antibodies were present. PRO-C6 had the highest sensitivity (100%), NPV (100%) and negative likelihood-ratio (0) for graft fibrosis. To conclude, ECM biomarkers are helpful in identifying patients at risk of relevant graft fibrosis.
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Affiliation(s)
- Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
| | | | | | - Morten Karsdal
- Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany
- Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada
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Molecular and therapeutic insights of rapamycin: a multi-faceted drug from Streptomyces hygroscopicus. Mol Biol Rep 2023; 50:3815-3833. [PMID: 36696023 PMCID: PMC9875782 DOI: 10.1007/s11033-023-08283-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 01/13/2023] [Indexed: 01/26/2023]
Abstract
The advancement in pharmaceutical research has led to the discovery and development of new combinatorial life-saving drugs. Rapamycin is a macrolide compound produced from Streptomyces hygroscopicus. Rapamycin and its derivatives are one of the promising sources of drug with broad spectrum applications in the medical field. In recent times, rapamycin has gained significant attention as of its activity against cytokine storm in COVID-19 patients. Rapamycin and its derivatives have more potency when compared to other prevailing drugs. Initially, it has been used exclusively as an anti-fungal drug. Currently rapamycin has been widely used as an immunosuppressant. Rapamycin is a multifaceted drug; it has anti-cancer, anti-viral and anti-aging potentials. Rapamycin has its specific action on mTOR signaling pathway. mTOR has been identified as a key regulator of different pathways. There will be an increased demand for rapamycin, because it has lesser adverse effects when compared to steroids. Currently researchers are focused on the production of effective rapamycin derivatives to combat the growing demand of this wonder drug. The main focus of the current review is to explore the origin, development, molecular mechanistic action, and the current therapeutic aspects of rapamycin. Also, this review article revealed the potential of rapamycin and the progress of rapamycin research. This helps in understanding the exact potency of the drug and could facilitate further studies that could fill in the existing knowledge gaps. The study also gathers significant data pertaining to the gene clusters and biosynthetic pathways involved in the synthesis and production of this multi-faceted drug. In addition, an insight into the mechanism of action of the drug and important derivatives of rapamycin has been expounded. The fillings of the current review, aids in understanding the underlying molecular mechanism, strain improvement, optimization and production of rapamycin derivatives.
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13
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Wang Z, Zhou H, Cheng F, Zhang Z, Long S. MiR-21 regulates epithelial-mesenchymal transition in intestinal fibrosis of Crohn's disease by targeting PTEN/mTOR. Dig Liver Dis 2022; 54:1358-1366. [PMID: 35504804 DOI: 10.1016/j.dld.2022.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Previous studies suggested miR-21 regulated epithelial-mesenchymal transition (EMT) and fibrosis in organs. The aim of this study was to explore the role and mechanism of miR-21 in EMT process of CD(Crohn's disease)-associated intestinal fibrosis. METHODS Tissue biopsies from fibrotic and nonfibrotic intestine of CD patients, and non-CD patients were obtained; chronic intestinal fibrosis model established by TNBS was treated with antagonist of miR-21; human intestinal epithelial cell, NCM460, were transfected with miR-21 mimics or inhibitor. The expressions of PTEN and mTOR, EMT-related markers and severity of colitis and fibrosis were examined. RESULTS Compared to the controls, miR-21 was significantly upregulated in the intestinal tissues from CD patients with fibro stenosis, followed by decreased PTEN expression, increased EMT markers, and mTOR expression, and imbalanced ratio of MMP9(matrix metalloproteinase 9)/TIMP1(tissue inhibitor of metalloproteinase 1). MiR-21 downregulated the expression of PTEN and upregulated mTOR signal in NCM460 cell. Also, knocking miR-21 down reduced EMT in vitro. Inhibiting miR-21 with antagonists reversed TNBS-induced intestinal fibrosis in vivo, through suppressing EMT and balancing MMPs/TIMPs. CONCLUSION We identified the involvement of miR-21 in EMT during intestinal fibrosis via targeting PTEN and mTOR, and miR-21 inhibition relieved intestinal fibrosis by regulating extracellular matrix (ECM) remodeling . Our results indicated miR-21 as a potential new target for the treatment of fibrosis complication in CD.
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Affiliation(s)
- Zhizhi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University and China Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Huihui Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University and China Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Fei Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University and China Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Zhendong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University and China Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Shunhua Long
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University and China Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China.
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14
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Prevalence of fatty liver disease after liver transplantation and risk factors for recipients and donors. Ann Hepatol 2022; 27:100670. [PMID: 35051631 DOI: 10.1016/j.aohep.2022.100670] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/09/2022] [Accepted: 01/11/2022] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVES Fatty liver disease (FLD) may develop in liver transplant recipients. We investigated the recipient and donor risk factors for FLD development after liver transplantation (LT). METHODS A total of 108 liver transplant recipients (54 men [50.0%]; median age, 52 [20-68] years) treated from 2011-2020 was enrolled. Three recipients died at < 3 months as a result of infection or blood flow impairment, and were excluded from the long-term FLD study. On evaluation of 88 prospective living donors, fatty liver was observed in 21. The prevalence and risk factors for FLD and survival were evaluated. RESULTS After LT, 28 of 105 recipients (26.7%) developed FLD. FLD was more common in patients with a high body mass index (BMI) and dyslipidemia (both p < 0.01), primary nonalcoholic steatohepatitis (p = 0.02), after living-donor LT (p = 0.03) and everolimus (EVL) use (p = 0.08). Factors predictive of FLD included EVL use and a high BMI (hazard ratios = 3.00 and 1.34; p = 0.05 and p < 0.01, respectively). Sixteen donors lost 6.5 kg (range: 2.0-16.0 kg) of body weight prior to LT. However, there were no cases of primary non-function, which did not affect the FLD prevalence. Development of FLD did not have a negative impact on LT outcome; the 5-year survival rate was 92.6%. CONCLUSIONS Recipient factors were more important than donor factors for FLD onset after LT.
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15
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Saunders EA, Engel B, Höfer A, Hartleben B, Vondran FWR, Richter N, Potthoff A, Zender S, Wedemeyer H, Jaeckel E, Taubert R. Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation. Am J Transplant 2022; 22:519-531. [PMID: 34455702 DOI: 10.1111/ajt.16817] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/08/2021] [Accepted: 08/19/2021] [Indexed: 01/25/2023]
Abstract
Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.
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Affiliation(s)
- Emily A Saunders
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anne Höfer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Nicolas Richter
- Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Steffen Zender
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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16
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Pallares RM, An DD, Hébert S, Faulkner D, Loguinov A, Proctor M, Villalobos JA, Bjornstad KA, Rosen CJ, Vulpe C, Abergel RJ. Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium. Mol Omics 2022; 18:237-248. [PMID: 35040455 DOI: 10.1039/d1mo00267h] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gadolinium is a metal used in contrast agents for magnetic resonance imaging. Although gadolinium is widely used in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent administration have been raised and published over the last decade. To date, most toxicological studies have focused on identifying acute effects following gadolinium exposure, rather than investigating associated toxicity mechanisms. In this study, we employ functional toxicogenomics to assess mechanistic interactions of gadolinium with Saccharomyces cerevisiae. Furthermore, we determine which mechanisms are conserved in humans, and their implications for diseases related to the use of gadolinium-based contrast agents in medicine. A homozygous deletion pool of 4291 strains were screened to identify biological functions and pathways disturbed by the metal. Gene ontology and pathway enrichment analyses showed endocytosis and vesicle-mediated transport as the main yeast response to gadolinium, while certain metabolic processes, such as glycosylation, were the primary disrupted functions after the metal treatments. Cluster and protein-protein interaction network analyses identified proteins mediating vesicle-mediated transport through the Golgi apparatus and the vacuole, and vesicle cargo exocytosis as key components to reduce the metal toxicity. Moreover, the metal seemed to induce cytotoxicity by disrupting the function of enzymes (e.g. transferases and proteases) and chaperones involved in metabolic processes. Several of the genes and proteins associated with gadolinium toxicity are conserved in humans, suggesting that they may participate in pathologies linked to gadolinium-based contrast agent exposures. We thereby discuss the potential role of these conserved genes and gene products in gadolinium-induced nephrogenic systemic fibrosis, and propose potential prophylactic strategies to prevent its adverse health effects.
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Affiliation(s)
- Roger M Pallares
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Dahlia D An
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Solène Hébert
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - David Faulkner
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Alex Loguinov
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Michael Proctor
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Jonathan A Villalobos
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Kathleen A Bjornstad
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Chris J Rosen
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Christopher Vulpe
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Rebecca J Abergel
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. .,Department of Nuclear Engineering, University of California, Berkeley, CA, 94720, USA
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Chen Y, Que R, Zhang N, Lin L, Zhou M, Li Y. Saikosaponin-d alleviates hepatic fibrosis through regulating GPER1/autophagy signaling. Mol Biol Rep 2021; 48:7853-7863. [PMID: 34714484 PMCID: PMC8604865 DOI: 10.1007/s11033-021-06807-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 10/05/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatic fibrosis is the final pathway of chronic liver disease characterized by excessive accumulation of extracellular matrix (ECM), which eventually develop into cirrhosis and liver cancer. Emerging studies demonstrated that Saikosaponin-d (SSd) exhibits a protective role in liver fibrosis. However, the mechanism underlying anti-liver fibrosis of SSd in vivo and in vitro remains unclear. METHODS AND RESULTS Transforming growth factor (TGF)-β and carbon tetrachloride (CCl4) were used for creating liver fibrosis model in vitro and in vivo, respectively. The role of SSd in regulating liver fibrosis was assessed through Sirius red and Masson staining, and IHC assay. We found that SSd attenuated remarkably CCl4-induced liver fibrosis as evidenced by decreased collagen level, and decreased expression of fibrotic markers Col 1 and α-SMA. Meanwhile, SSd repressed autophagy activation as suggested by decreased BECN1 expression and increased p62 expression. Compared with HSCs from CCl4-treated group, the primary HSCs from SSd-treated mice exhibited a marked inactivation of autophagy. Mechanistically, SSd treatment enhanced the expression of GPER1 in primary HSCs and in TGF-β-treated LX-2 cells. GPER1 agonist G1 repressed autophagy activation, whereas GPER1 antagonist G15 activated autophagy and G15 also damaged the function of SSd on suppressing autophagy, leading to subsequent increased levels of fibrotic marker level in LX-2 cells. CONCLUSIONS Our findings highlight that SSd alleviates hepatic fibrosis by regulating GPER1/autophagy pathway.
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Affiliation(s)
- Yirong Chen
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274 Zhijiang Road, Shanghai, 200071, China
| | - Renye Que
- Department of Gastroenterology, Shanghai TCM Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200082, China
| | - Na Zhang
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274 Zhijiang Road, Shanghai, 200071, China
| | - Liubing Lin
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274 Zhijiang Road, Shanghai, 200071, China
| | - Mengen Zhou
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274 Zhijiang Road, Shanghai, 200071, China
| | - Yong Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274 Zhijiang Road, Shanghai, 200071, China.
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Dong XC, Chowdhury K, Huang M, Kim HG. Signal Transduction and Molecular Regulation in Fatty Liver Disease. Antioxid Redox Signal 2021; 35:689-717. [PMID: 33906425 PMCID: PMC8558079 DOI: 10.1089/ars.2021.0076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Recent Advances: Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease. Multiple signaling pathways have been implicated in the development of fatty liver disease, including AMP-activated protein kinase, mechanistic target of rapamycin kinase, endoplasmic reticulum stress, oxidative stress, inflammation, transforming growth factor β, and yes1-associated transcriptional regulator/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In addition, critical molecular regulations at the transcriptional and epigenetic levels have been linked to the pathogenesis of fatty liver disease. Critical Issues: Some critical issues remain to be solved so that research findings can be translated into clinical applications. Robust and reliable biomarkers are needed for diagnosis of different stages of the fatty liver disease. Effective and safe molecular targets remain to be identified and validated. Prevention strategies require solid scientific evidence and population-wide feasibility. Future Directions: As more data are generated with time, integrative approaches are needed to comprehensively understand the disease pathophysiology and mechanisms at multiple levels from population, organismal system, organ/tissue, to cell. The interactions between genes and environmental factors require deeper investigation for the purposes of prevention and personalized treatment of fatty liver disease. Antioxid. Redox Signal. 35, 689-717.
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Affiliation(s)
- Xiaocheng Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA
| | - Kushan Chowdhury
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Devaux CA, Melenotte C, Piercecchi-Marti MD, Delteil C, Raoult D. Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19? Front Med (Lausanne) 2021; 8:663708. [PMID: 34552938 PMCID: PMC8450353 DOI: 10.3389/fmed.2021.663708] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 08/04/2021] [Indexed: 12/22/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.
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Affiliation(s)
- Christian A. Devaux
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
- CNRS, Marseille, France
| | - Cléa Melenotte
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Marie-Dominique Piercecchi-Marti
- Department of Legal Medicine, Hôpital de la Timone, Marseille University Hospital Center, Marseille, France
- Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France
| | - Clémence Delteil
- Department of Legal Medicine, Hôpital de la Timone, Marseille University Hospital Center, Marseille, France
- Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France
| | - Didier Raoult
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
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20
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Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis. Hepatobiliary Pancreat Dis Int 2021; 20:207-214. [PMID: 33972160 DOI: 10.1016/j.hbpd.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 04/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αβ) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.
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21
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Tan Q, Link PA, Meridew JA, Pham TX, Caporarello N, Ligresti G, Tschumperlin DJ. Spontaneous Lung Fibrosis Resolution Reveals Novel Antifibrotic Regulators. Am J Respir Cell Mol Biol 2021; 64:453-464. [PMID: 33493091 DOI: 10.1165/rcmb.2020-0396oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Fibroblast activation is transient in successful wound repair but persistent in fibrotic pathologies. Understanding fibroblast deactivation during successful wound healing may provide new approaches to therapeutically reverse fibroblast activation. To characterize the gene programs that accompany fibroblast activation and reversal during lung fibrosis resolution, we used RNA sequencing analysis of flow sorted Col1α1-GFP-positive and CD45-, CD31-, and CD326-negative cells isolated from the lungs of young mice exposed to bleomycin. We compared fibroblasts isolated from control mice with those isolated at Days 14 and 30 after bleomycin exposure, representing the peak of extracellular matrix deposition and an early stage of fibrosis resolution, respectively. Bleomycin exposure dramatically altered fibroblast gene programs at Day 14. Principal component and differential gene expression analyses demonstrated the predominant reversal of these trends at Day 30. Upstream regulator and pathway analyses of reversing "resolution" genes identified novel candidate antifibrotic genes and pathways. Two genes from these analyses that were decreased in expression at Day 14 and reversed at Day 30, Aldh2 and Nr3c1, were selected for further analysis. Enhancement of endogenous expression of either gene by CRISPR activation in cultured human idiopathic pulmonary fibrosis fibroblasts was sufficient to reduce profibrotic gene expression, fibronectin deposition, and collagen gel compaction, consistent with roles for these genes in fibroblast deactivation. This combination of RNA sequencing analysis of freshly sorted fibroblasts and hypothesis testing in cultured idiopathic pulmonary fibrosis fibroblasts offers a path toward identification of novel regulators of lung fibroblast deactivation, with potential relevance to understanding fibrosis resolution and its failure in human disease.
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Affiliation(s)
- Qi Tan
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Patrick A Link
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Jeffrey A Meridew
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Tho X Pham
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Nunzia Caporarello
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Giovanni Ligresti
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and.,Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Daniel J Tschumperlin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
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22
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van Haaften WT, Blokzijl T, Hofker HS, Olinga P, Dijkstra G, Bank RA, Boersema M. Intestinal stenosis in Crohn's disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets. Therap Adv Gastroenterol 2020; 13:1756284820952578. [PMID: 32922514 PMCID: PMC7457685 DOI: 10.1177/1756284820952578] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 07/31/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Crohn's disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss which drugs might be suitable to inhibit excessive extracellular matrix formation targeting these pathways. METHODS Human fibrotic and non-fibrotic terminal ileum was obtained from patients with CD undergoing ileocecal resection due to stenosis. Genes involved in collagen metabolism were analyzed using a microfluidic low-density TaqMan array. A literature search was performed to find potential anti-fibrotic drugs that target proteins/enzymes involved in collagen synthesis, its degradation and its recognition. RESULTS mRNA expression of collagen type I (COL1A1, 0.76 ± 0.28 versus 37.82 ± 49.85, p = 0.02) and III (COL3A1, 2.01 ± 2.61 versus 68.65 ± 84.07, p = 0.02) was increased in fibrotic CD compared with non-fibrotic CD. mRNA expression of proteins involved in both intra- and extracellular post-translational modification of collagens (prolyl- and lysyl hydroxylases, lysyl oxidases, chaperones), collagen-degrading enzymes (MMPs and cathepsin-K), and collagen receptors were upregulated in the fibrosis-affected part. A literature search on the upregulated genes revealed several potential anti-fibrotic drugs. CONCLUSION Expression of genes involved in collagen metabolism in intestinal fibrosis affected terminal ileum of patients with CD reveals a plethora of drug targets. Inhibition of post-translational modification and altering collagen metabolism might attenuate fibrosis formation in the intestine in CD. Which compound has the highest potential depends on a combination anti-fibrotic efficacy and safety, especially since some of the enzymes play key roles in the physiology of collagen.
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Affiliation(s)
- Wouter Tobias van Haaften
- Department of Gastroenterology and Hepatology,
University Medical Center Groningen, University of Groningen, Groningen, the
Netherlands
- Department of Pharmaceutical Technology and
Biopharmacy, University of Groningen, Groningen, the Netherlands
| | - Tjasso Blokzijl
- Department of Laboratory Medicine, University of
Groningen, University Medical Center Groningen, Groningen, The
Netherlands
| | - Hendrik Sijbrand Hofker
- Department of Surgery, University Medical Center
Groningen, University of Groningen, Groningen, the Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and
Biopharmacy, University of Groningen, Ant. Deusinglaan 1, Groningen, 9713
AV, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology,
University Medical Center Groningen, University of Groningen, Groningen, the
Netherlands
| | - Ruud A. Bank
- Department of Pathology and Medical Biology,
University Medical Center Groningen, University of Groningen, Groningen, the
Netherlands
| | - Miriam Boersema
- Department of Pharmaceutical Technology and
Biopharmacy, University of Groningen, Groningen, the Netherlands
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23
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Penke LR, Peters-Golden M. Molecular determinants of mesenchymal cell activation in fibroproliferative diseases. Cell Mol Life Sci 2019; 76:4179-4201. [PMID: 31563998 PMCID: PMC6858579 DOI: 10.1007/s00018-019-03212-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 06/01/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Uncontrolled scarring, or fibrosis, can interfere with the normal function of virtually all tissues of the body, ultimately leading to organ failure and death. Fibrotic diseases represent a major cause of death in industrialized countries. Unfortunately, no curative treatments for these conditions are yet available, highlighting the critical need for a better fundamental understanding of molecular mechanisms that may be therapeutically tractable. The ultimate indispensable effector cells responsible for deposition of extracellular matrix proteins that comprise scars are mesenchymal cells, namely fibroblasts and myofibroblasts. In this review, we focus on the biology of these cells and the molecular mechanisms that regulate their pertinent functions. We discuss key pro-fibrotic mediators, signaling pathways, and transcription factors that dictate their activation and persistence. Because of their possible clinical and therapeutic relevance, we also consider potential brakes on mesenchymal cell activation and cellular processes that may facilitate myofibroblast clearance from fibrotic tissue-topics that have in general been understudied.
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Affiliation(s)
- Loka R Penke
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109-5642, USA
| | - Marc Peters-Golden
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109-5642, USA.
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24
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Han B, Chu C, Su X, Zhang N, Zhou L, Zhang M, Yang S, Shi L, Zhao B, Niu Y, Zhang R. N 6-methyladenosine-dependent primary microRNA-126 processing activated PI3K-AKT-mTOR pathway drove the development of pulmonary fibrosis induced by nanoscale carbon black particles in rats. Nanotoxicology 2019; 14:1-20. [PMID: 31502903 DOI: 10.1080/17435390.2019.1661041] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The pulmonary fibrosis could be caused by long-term inhalation of carbon black (CB) particles. Studies on the mechanisms of pulmonary fibrosis induced by CB are required to develop the stratagem of prevention and treatment on fibrosis. The RNA-binding protein DiGeorge syndrome critical region gene 8 (DGCR8)-dependent pri-miRNAs processing is regulated by N6-methyladenosine (m6A) modification, which targets the downstream signal pathway. However, its role in pulmonary fibrosis has not been known clearly. In the present study, rats inhaled CB at dose of 0, 5 or 30 mg/m3 for 28 days, 6 h/day, respectively. The rats inhaled CB at dose of 0 or 30 mg/m3 for 14 days, 28 days and 90 days, respectively. In vitro experiments, the normal human bronchial epithelial cell line (16HBE) was treated with CB (0, 50, 100 and 200 μg/mL) for 24 h. In vitro and vivo study, the levels of fibrosis indicators including α-SMA, vimentin, collagen-I and hydroxyproline in CB treatment groups statistically increased in dose- or time- dependent manners compared with the control. After CB treatment, PI3K-AKT-mTOR pathway was activated and regulated by miRNA-126. We found that both of m6A modifications of pri-miRNA-126 and its binding with DGCR8 were decreased after CB treatment, which resulted in the reduction of mature miRNA-126 accompanied by accumulation of unprocessed pri-miRNA-126. This work demonstrated that m6A modification of pri-miRNA-126 and its binding with DGCR8 decreases blocked miRNA-126 maturation, and then activated the PI3K/AKT/mTOR pathway, which drove the fibro genesis in the lung after CB exposure.
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Affiliation(s)
- Bin Han
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Chen Chu
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Xuan Su
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Ning Zhang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lixiao Zhou
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Mengyue Zhang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Shuaishuai Yang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lei Shi
- Occupational Health and Environmental Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Bo Zhao
- Department of Laboratory Diagnosis, Hebei Medical University, Shijiazhuang, China
| | - Yujie Niu
- Occupational Health and Environmental Health, School of Public Health, Hebei Medical University, Shijiazhuang, China.,Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang, China
| | - Rong Zhang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China.,Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang, China
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25
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Peng S, Yang K, Xu Z, Chen S, Ji Y. Vincristine and sirolimus in the treatment of kaposiform haemangioendothelioma. J Paediatr Child Health 2019; 55:1119-1124. [PMID: 30604513 DOI: 10.1111/jpc.14370] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 12/01/2018] [Accepted: 12/13/2018] [Indexed: 02/05/2023]
Abstract
AIM Kaposiform haemangioendothelioma (KHE) is a rare, potentially life-threatening vascular tumour that is often associated with thrombocytopenia and coagulopathy, known as the Kasabach-Merritt phenomenon (KMP). Because of the rarity and complexity of KHE, the optimal paradigm for treating KHE has yet to be elucidated. We aim to assess the efficacy and safety of vincristine and sirolimus for the treatment of KHE. METHODS A comprehensive review of the literature was conducted from January 1993 to June 2018. A total of 15 studies were selected for the meta-analysis. Five studies included 75 individuals and reported the response and side effects to vincristine in the treatment of KHE with or without KMP. A total of 10 studies that included 127 individuals reported the response and safety of sirolimus for treating KHE with or without KMP. RESULTS The pooled odds ratio (OR) for the effectiveness of vincristine was 0.72. The pooled OR for the effectiveness of sirolimus was 0.91. The side effects associated with vincristine during the treatment included neuropathy, abdominal pain, loss of appetite and mild elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The side effects associated with sirolimus therapy included bronchitis; lymphopenia; elevated AST, ALT and platelets; hyperlipidaemia; opportunistic infection; mild reversible leukopenia; mucositis; fever; pain and skin rash/vomiting and diarrhoea. CONCLUSIONS This systematic review showed a high efficacy of vincristine and sirolimus in the treatment of KHE. Based on the available data in the literature, it appears that sirolimus is potentially an efficacious and safe treatment option for KHE. Further randomised, controlled trials are recommended.
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Affiliation(s)
- Suhua Peng
- Division of Oncology, Department of Paediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Kaiying Yang
- Division of Oncology, Department of Paediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Zhicheng Xu
- Division of Oncology, Department of Paediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Siyuan Chen
- Paediatric Intensive Care Unit, Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Yi Ji
- Division of Oncology, Department of Paediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
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26
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Zhang Z, Wen H, Weng J, Feng L, Liu H, Hu X, Zeng F. Silencing of EPCAM suppresses hepatic fibrosis and hepatic stellate cell proliferation in mice with alcoholic hepatitis via the PI3K/Akt/mTOR signaling pathway. Cell Cycle 2019; 18:2239-2254. [PMID: 31378124 PMCID: PMC6738525 DOI: 10.1080/15384101.2019.1642067] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Alcoholic hepatitis (AH) is a severe condition developed in patients with underlying alcoholic liver disease. Epithelial cell adhesion molecule (EPCAM) plays a role in hepatitis. Therefore, the current study aimed to explore the effect of EPCAM and its potential mechanism in AH. Bioinformatic analysis was performed to screen differentially expressed genes associated with AH. AH mouse models were established through a Lieber-DeCarli liquid diet containing 4% ethanol, which were co-treated with siRNA against EPCAM or the PI3K/Akt/mTOR signaling pathway inhibitor in order to investigate the effects of EPCAM and the PI3K/Akt/mTOR signaling pathway on hepatic fibrosis, hepatic stellate cell (HSC) proliferation and apoptosis. The relationship between EPCAM and the PI3K/Akt/mTOR signaling pathway was investigated for the purposes of elucidating the potential mechanism of EPCAM in AH. EPCAM was predicted to regulate AH progression through the PI3K/Akt/mTOR signaling pathway. Silencing EPCAM or inhibition of the PI3K/Akt/mTOR signaling pathway inhibited the hepatic fibrosis and HSC proliferation yet induced HSC apoptosis. Moreover, silencing EPCAM was found to repress the PI3K/Akt/mTOR signaling pathway as evidenced by decreased levels of Bcl2 yet increased levels of caspase-3. Collectively, silencing EPCAM could hinder AH progression by inhibiting the PI3K/Akt/mTOR signaling pathway, which might serve as a potential therapeutic target for AH treatment.
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Affiliation(s)
- Zhi Zhang
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China,CONTACT Zhi Zhang
| | - Huiqing Wen
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Lei Feng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Hongya Liu
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Xiaojun Hu
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Fanhong Zeng
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
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27
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Expression of neuropeptide Y is increased in an activated human HSC cell line. Sci Rep 2019; 9:9500. [PMID: 31263154 PMCID: PMC6602956 DOI: 10.1038/s41598-019-45932-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 06/20/2019] [Indexed: 01/20/2023] Open
Abstract
Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian central and peripheral nervous systems. Transgenic mice overexpressing NPY in noradrenergic neurons have increased level of hepatic triglycerides, fatty acids and cholesterol, which contributed to the development of hepatosteatosis. However, the roles of NPY in the activation of hepatic stellate cells (HSCs) and the underlying mechanisms remain unclear. This study aimed to investigate the expression and secretion of NPY in human immortalized HSC LX-2 cells and the regulatory function of NPY on the fibrogenic response in LX-2 cells, to explore the potential association between NPY and LX-2 activation. The results showed an increase in the expression and secretion of NPY(1–36) in activated LX-2 cells. Both endogenous and exogenous NPY(1–36) induced the phosphorylation of mTOR, p70S6K, and 4EBP1 and promoted the fibrogenic response via NPY Y1 receptor subtype (NPY1R), as these responses were blocked by either an NPY1R antagonist (BIBP3226) or NPY1R knockdown. Moreover, NPY(1–36) serum levels were increased in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) and presented a positive relationship with MELD scores in LC patients. These findings suggest that immortalized HSCs LX-2 have the potential to produce NPY(1–36). High serum levels of NPY(1–36) is correlated with hepatic dysfunction in cirrhotic patients.
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28
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The Alisma and Rhizoma decoction abates nonalcoholic steatohepatitis-associated liver injuries in mice by modulating oxidative stress and autophagy. Altern Ther Health Med 2019; 19:92. [PMID: 31035991 PMCID: PMC6489313 DOI: 10.1186/s12906-019-2488-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 03/24/2019] [Indexed: 02/07/2023]
Abstract
Background To investigate the effects of the Alisma and Rhizoma decoction on nonalcoholic steatohepatitis (NASH) and to further shed light on the underlying mechanisms of the actions of the Alisma and Rhizoma decoction. Methods Plasma alanine aminotransferase (ALT) content was determined and liver inflammation and fibrosis were evaluated. Intrahepatocellular malondialdehyde and superoxide dismutase contents were determined using commercially available kits Furthermore, α-SMA expression in liver tissues was examined by immunohistochemistry and LC3-II was detected by immunoblotting assays. Results Mice receiving the Alisma and Rhizoma decoction by gastric lavage had significantly lower plasma ALT content and markedly higher hepatic superoxide dismutase activity than mice receiving the methionine-choline deficient (MCD) diet. Furthermore, the decoction aborted MCD-induced increase in liver malondialdehyde content. Immunohistochemistry showed that the decoction suppressed hepatic α-SMA expression. Our transmission electronic microscopy revealed that the decoction markedly reduced the number of autophagosomes and immunoblotting assays showed that the decoction caused a dose-dependent decrease in LC3-II in hepatic tissues. Conclusion The Alisma and Rhizoma decoction lessens NASH-associated liver injuries by modulating oxidative stress and autophagy in hepatocytes of mice fed with MCD. Electronic supplementary material The online version of this article (10.1186/s12906-019-2488-6) contains supplementary material, which is available to authorized users.
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29
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Pan Q, Qin T, Gao Y, Li S, Li D, Peng M, Zhai H, Xu G. Hepatic mTOR-AKT2-Insig2 signaling pathway contributes to the improvement of hepatic steatosis after Roux-en-Y Gastric Bypass in mice. Biochim Biophys Acta Mol Basis Dis 2019; 1865:525-534. [DOI: 10.1016/j.bbadis.2018.12.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/26/2018] [Accepted: 12/12/2018] [Indexed: 12/18/2022]
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30
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Wei R, Liu H, Chen R, Sheng Y, Liu T. Astragaloside IV combating liver cirrhosis through the PI3K/Akt/mTOR signaling pathway. Exp Ther Med 2018; 17:393-397. [PMID: 30651810 PMCID: PMC6307369 DOI: 10.3892/etm.2018.6966] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 10/23/2018] [Indexed: 01/18/2023] Open
Abstract
Astragaloside IV (AS-IV) in improving liver cirrhosis injury in rats and its effect on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway were observed. Rat model of liver cirrhosis was induced by injection of carbon tetrachloride (CCl4). A total of 36 Sprague-Dawley (SD) rats were randomly divided into three groups: the normal control group (n=10), the model control group (n=13), and the AS-IV group (n=13). The normal control group was injected with olive oil and given carboxymethyl cellulose (CMC)-Na (10 ml/kg/day), the model control group was given CMC-Na (10 ml/kg/day), and the AS-IV group underwent intragastric administration of AS-IV (20 ml/kg/day). The content of alanine transaminase (ALT) and aspartate transaminase (AST) of rats was detected. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in serum were detected via enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) staining was applied to observe morphological changes in liver tissues. The expression of collagens in liver tissues was detected via Masson's trichrome staining. Additionally, the expression of proteins in liver tissues was detected via western blotting. Compared with those in the blank group, the levels of AST, ALT, TNF-α, IL-6 and IL-1β were higher, the expression level of collagens in liver tissues was increased, and the expression ratios of phosphorylated (p)-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR proteins were increased in the model group. Compared with the model group, AS-IV could significantly decrease the content of AST, ALT, TNF-α, IL-6 and IL-β in serum of rats, obviously inhibit the expression of collagens in liver tissues and decrease the expression ratios of p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR proteins in liver tissues. AS-IV can inhibit the inflammatory response so as to reduce the expression of collagens, and its mechanism may play a key role by inhibiting the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Rendong Wei
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
| | - Haidong Liu
- Department of Digestive Diseases, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
| | - Ru Chen
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
| | - Yunjian Sheng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Tao Liu
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
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Abstract
The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of calcineurin inhibitor (CNI) therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy. However, concomitant mycophenolic acid is advisable to avoid an increase in mild biopsy-proven acute rejection, and induction with an interleukin-2 receptor antagonist may also be helpful. High-quality robust data regarding prevention of posttransplant malignancies under mTOR inhibitors is lacking in liver transplantation, although there are some indications of benefit. In maintenance patients, robust data are limited regarding mTOR inhibitor initiation in response to deteriorating renal function or other indications but late conversion (>1 year) appears ineffective. Rates of mTOR inhibitor discontinuation due to adverse events are high, affecting at least a quarter of patients. In conclusion, the evidence base for use of mTOR inhibitors early posttransplant to support CNI reduction now convincingly demonstrates a renal advantage, but adequate adjunctive immunosuppression is essential to preserve efficacy.
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Xu W, Liu P, Mu YP. Research progress on signaling pathways in cirrhotic portal hypertension. World J Clin Cases 2018; 6:335-343. [PMID: 30283796 PMCID: PMC6163134 DOI: 10.12998/wjcc.v6.i10.335] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/27/2018] [Accepted: 08/04/2018] [Indexed: 02/05/2023] Open
Abstract
Portal hypertension (PHT) is an important consequence of liver cirrhosis, which can lead to complications that adversely affect a patient’s quality of life and survival, such as upper gastrointestinal bleeding, ascites, and portosystemic encephalopathy. In recent years, advances in molecular biology have led to major discoveries in the pathological processes of PHT, including the signaling pathways that may be involved: PI3K-AKT-mTOR, RhoA/Rho-kinase, JAK2/STAT3, and farnesoid X receptor. However, the pathogenesis of PHT is complex and there are numerous pathways involved. Therefore, the targeting of signaling pathways for medical management is lagging. This article summarizes the progress that has been made in understanding the signaling pathways in PHT, and provides ideas for treatment of the disorder.
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Affiliation(s)
- Wen Xu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
| | - Yong-Ping Mu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
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Eberhardt W, Nasrullah U, Pfeilschifter J. Activation of renal profibrotic TGFβ controlled signaling cascades by calcineurin and mTOR inhibitors. Cell Signal 2018; 52:1-11. [PMID: 30145216 DOI: 10.1016/j.cellsig.2018.08.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 12/11/2022]
Abstract
The calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus represent potent immunosuppressive agents frequently used for solid organ transplantation and treatment of autoimmune disorders. Despite of their immense therapeutic benefits, residual fibrosis mainly in the kidney represents a common side effect of long-term therapy with CNI. Regardless of the immunosuppressive action, an increasing body of evidence implicates that a drug-induced increase in TGFβ and subsequent activation of TGFβ-initiated signaling pathways is closely associated with the development and progression of CNI-induced nephropathy. Mechanistically, an increase in reactive oxygen species (ROS) generation due to drug-induced changes in the intracellular redox homeostasis functions as an important trigger of the profibrotic signaling cascades activated under therapy with CNI. Although, inhibitors of the mechanistic target of rapamycin (mTOR) kinase have firmly been established as alternative compounds with a lower nephrotoxic potential, an activation of fibrogenic signaling cascades has been reported for these drugs as well. This review will comprehensively summarize recent advances in the understanding of profibrotic signaling events modulated by these widely used compounds with a specific focus put on mechanisms occurring independent of their respective immunosuppressive action. Herein, the impact of redox modulation, the activation of canonical TGFβ and non-Smad pathways and modulation of autophagy by both classes of immunosuppressive drugs will be highlighted and discussed in a broader perspective. The comprehensive knowledge of profibrotic signaling events specifically accompanying the immunomodulatory activity of these widely used drugs is needed for a reliable benefit-risk assessment under therapeutic regimens.
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Affiliation(s)
- Wolfgang Eberhardt
- Pharmazentrum frankfurt/ZAFES, Universitätsklinikum und Goethe-Universität, Frankfurt am Main, Germany.
| | - Usman Nasrullah
- Pharmazentrum frankfurt/ZAFES, Universitätsklinikum und Goethe-Universität, Frankfurt am Main, Germany
| | - Josef Pfeilschifter
- Pharmazentrum frankfurt/ZAFES, Universitätsklinikum und Goethe-Universität, Frankfurt am Main, Germany
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Wu Y, Wang W, Peng XM, He Y, Xiong YX, Liang HF, Chu L, Zhang BX, Ding ZY, Chen XP. Rapamycin Upregulates Connective Tissue Growth Factor Expression in Hepatic Progenitor Cells Through TGF-β-Smad2 Dependent Signaling. Front Pharmacol 2018; 9:877. [PMID: 30135653 PMCID: PMC6092675 DOI: 10.3389/fphar.2018.00877] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 07/19/2018] [Indexed: 12/15/2022] Open
Abstract
Rapamycin (sirolimus) is a mTOR kinase inhibitor and is widely used as an immunosuppressive drug to prevent graft rejection in organ transplantation currently. However, some recent investigations have reported that it had profibrotic effect in the progression of organ fibrosis, and its precise role in the liver fibrosis is still poorly understood. Here we showed that rapamycin upregulated connective tissue growth factor (CTGF) expression at the transcriptional level in hepatic progenitor cells (HPCs). Using lentivirus-mediated small hairpin RNA (shRNA) we demonstrated that knockdown of mTOR, Raptor, or Rictor mimicked the effect of rapamycin treatment. Mechanistically, inhibition of mTOR activity with rapamycin resulted in a hyperactive PI3K-Akt pathway, whereas this activation inhibited the expression of CTGF in HPCs. Besides, rapamycin activated the TGF-β-Smad signaling, and TGF-β receptor type I (TGFβRI) serine/threonine kinase inhibitors completely blocked the effects of rapamycin on HPCs. Moreover, Smad2 was involved in the induction of CTGF through rapamycin-activated TGF-β-Smad signaling as knockdown completely blocked CTGF induction, while knockdown of Smad4 expression partially inhibited induction, whereas Smad3 knockdown had no effect. Rapamycin also induced ROS generation and latent TGF-β activation which contributed to TGF-β-Smad signaling. In conclusion, this study demonstrates that rapamycin upregulates CTGF in HPCs and suggests that rapamycin has potential fibrotic effect in liver.
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Affiliation(s)
- Yu Wu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang-mei Peng
- Department of Nephrology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi He
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-xiao Xiong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui-fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-xiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ze-yang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Effects of the Mammalian Target of Rapamycin Inhibitor Everolimus on Hepatitis C Virus Replication In Vitro and In Vivo. Transplant Proc 2018; 49:1947-1955. [PMID: 28923653 DOI: 10.1016/j.transproceed.2017.04.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/28/2017] [Accepted: 04/27/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND The influence of immunosuppressants on hepatitis C virus (HCV) re-infection after liver transplantation, particularly mammalian target of rapamycin inhibitors, remains unclear. The aim of our study was to analyze the influence of everolimus (EVR) on HCV replication activity in the context of underlying molecular mechanisms, with focus on the pro-myelocytic leukemia protein (PML). METHODS HCV viral load was recorded in 40 patients with post-transplant HCV re-infection before and 8 weeks after introduction of EVR. An HCV cell culture replicon system for genotype (GT) 1b, GT2b, and GT3a was used to compare the influence of EVR on HCV replication for the respective genotypes in vitro. Fluorescence-activated cell-sorting analysis was used to test for effects on cell proliferation. PML expression was silenced with the use of small hairpin RNA constructs, and PML expression was quantified by means of quantitative real-time polymerase chain reaction. RESULTS In patients with HCV, the viral load of GT1a and GT1b was hardly affected by EVR, whereas the viral load was reduced in patients with GT2a (P ≤ .0001) or GT3 infection (P ≤ .05). In vitro EVR impairs HCV replication activity of GT2a and GT3a up to 60% (P ≤ .0005), whereas in GT1b cells, HCV replication activity is increased by 50% (P ≤ .005). Replicon cell viability was not impaired. HCV replication activity is impaired in the absence of PML, which can be reversed by overexpression of PML isoforms. Furthermore, in the absence of PML, the effect of EVR on HCV replication activity is nearly abrogated. CONCLUSIONS The mammalian target of rapamycin inhibitor EVR influences HCV replication via PML. The herein presented results suggest a genotype-dependent benefit for an EVR-based immunosuppressive regimen in patients with GT2a or GT3 re-infection after liver transplantation.
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In-vitro assessment of antimicrobial properties and lymphocytotoxicity assay of benzoisochromanequinones polyketide from Streptomyces sp JRG-04. Microb Pathog 2017; 110:117-127. [DOI: 10.1016/j.micpath.2017.06.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 05/11/2017] [Accepted: 06/22/2017] [Indexed: 11/21/2022]
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Xu L, Yin L, Tao X, Qi Y, Han X, Xu Y, Song S, Li L, Sun P, Peng J. Dioscin, a potent ITGA5 inhibitor, reduces the synthesis of collagen against liver fibrosis: Insights from SILAC-based proteomics analysis. Food Chem Toxicol 2017; 107:318-328. [PMID: 28689917 DOI: 10.1016/j.fct.2017.07.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/04/2017] [Accepted: 07/05/2017] [Indexed: 11/26/2022]
Abstract
Inhibiting collagen generation is one effective method to treat liver fibrosis. Dioscin showed protective effect against liver fibrosis in our previous studies, and in the present work, SILAC-based proteomics was employed to test the underlying mechanism. A total of 121 differentially expressed proteins caused by dioscin in LX-2 cells were found, and dioscin significantly decreased the expression levels of FN, FAK1, ITGA5, p-PI3K/PI3K, p-Akt/Akt, p-mTOR/mTOR, Col1a1, Col1a2, Col2a1, Col5a1, Col6a1, and increased 2ABB level in vivo and in vitro. Thus, we elucidated that dioscin specifically suppressed collagen synthesis through modulating PI3K/Akt pathway. In addition, we found that dioscin directly targeted with ITGA5 by molecular docking assay. SiRNA and overexpression transfection tests showed that ITGA5 siRNA plus dioscin slightly altered the effect of ITGA5 siRNA, and ITGA5 DNA transfection reversed the inhibitory effect of dioscin on collagen expressions via PI3K/Akt pathway. Our data explicated that dioscin should be considered as a novel and potent ITGA5 inhibitor to suppress collagen synthesis, which can also be developed as an effective food and healthcare product against hepatic fibrosis.
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Affiliation(s)
- Lina Xu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Lianhong Yin
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Xufeng Tao
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Yan Qi
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Xu Han
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Youwei Xu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Shasha Song
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Lei Li
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Pengyuan Sun
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Jinyong Peng
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
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Temmerman F, Chen F, Libbrecht L, Vander Elst I, Windmolders P, Feng Y, Ni Y, De Smedt H, Nevens F, van Pelt J. Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease. World J Gastroenterol 2017; 23:5499-5507. [PMID: 28852309 PMCID: PMC5558113 DOI: 10.3748/wjg.v23.i30.5499] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 05/16/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly.
METHODS Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) (n = 10) or everolimus (EVR: 1 mg/kg per day) (n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated.
RESULTS LV determination by MRI correlated excellent with the ex vivo measurements (r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis (P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels.
CONCLUSION Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression.
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Li L, Duan M, Chen W, Jiang A, Li X, Yang J, Li Z. The spleen in liver cirrhosis: revisiting an old enemy with novel targets. J Transl Med 2017; 15:111. [PMID: 28535799 PMCID: PMC5442653 DOI: 10.1186/s12967-017-1214-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/16/2017] [Indexed: 12/15/2022] Open
Abstract
The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.
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Affiliation(s)
- Liang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Mubing Duan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
| | - Weisan Chen
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
| | - An Jiang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Department of General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Xiaoming Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Jun Yang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Department of Pathology, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease that can progress to end-stage liver disease, cirrhosis and cholangiocarcinoma. PSC is an uncommon and highly heterogeneous disease, associated with inflammatory bowel disease and a complex pathophysiology. To date, no medical therapies have proved effective. The only available treatment for end-stage PSC is liver transplant, but recurrence is a significant complication. Areas covered: This review will explore previously tested treatments, discuss current treatment strategies and present viewpoints about future emerging therapies in PSC. We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: The development of new therapies in PSC has been challenging. However, with greater awareness of the disease nowadays, new insights into the disease may help in the design of future therapeutic agents in PSC and ultimately in effective therapies.
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Affiliation(s)
- Eduardo A Rodriguez
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA
| | - Elizabeth J Carey
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA
| | - Keith D Lindor
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.,b College of Health Solutions , Arizona State University , Phoenix , AZ , USA
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Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis. Dig Dis Sci 2017; 62:968-978. [PMID: 28194671 DOI: 10.1007/s10620-017-4470-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 01/20/2017] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS Hyperinsulinemia and insulin resistance are hallmark features of nonalcoholic fatty liver disease and steatohepatitis (NASH). It remains unclear whether and how insulin contributes to the development of fibrosis in NASH. In this study, we explored insulin signaling in the regulation of hepatic stellate cell (HSC) activation and the progression of NASH-fibrosis. METHODS Phosphorylation of Akt and p70S6K were examined in primary HSC and in a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet for 24 weeks. HSC activation was analyzed for the changes in cell morphology, intracellular lipid droplets, expression of α-SMA and cell proliferation. The serum markers and histology for NASH-fibrosis were also characterized in animals. RESULTS Insulin enhanced the expression of smooth muscle actin-α in quiescent but not in activated HSC in culture. Insulin-mediated activation of the PI3K/Akt-p70S6K pathway was involved in the regulation of profibrogenic effects of insulin. Although insulin did not stimulate HSC proliferation directly, the insulin-PI3K/Akt-p70S6K pathway was necessary for serum-enhanced cell proliferation during initial HSC activation. In a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet, hyperinsulinemia is associated with the activation of p70S6K and enhanced fibrosis. CONCLUSION The insulin-PI3K/Akt-p70S6K pathway plays an important role in the early activation of HSC. The profibrogenic effect of insulin is dependent on the activation stage of HSC. Dysregulation of the insulin pathway likely correlates with the development of fibrosis in NASH, suggesting a potentially novel antifibrotic target of inhibiting insulin signaling in HSC.
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Love S, Mudasir MA, Bhardwaj SC, Singh G, Tasduq SA. Long-term administration of tacrolimus and everolimus prevents high cholesterol-high fructose-induced steatosis in C57BL/6J mice by inhibiting de-novo lipogenesis. Oncotarget 2017; 8:113403-113417. [PMID: 29371918 PMCID: PMC5768335 DOI: 10.18632/oncotarget.15194] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 11/02/2016] [Indexed: 12/15/2022] Open
Abstract
Aim To investigate the effects of tacrolimus (TC) and everolimus (EV) on non-alcoholic steatohepatitis (NASH) induced by high fat, high cholesterol and fructose (fast food) diet in C57BL/6J mice. Materials and Methods C57BL/6J mice were divided into four groups (n=8). 1) Standard Chow (SC); 2) Fast food (FF) diet; 3) FF + Tacrolimus (TC, 1mg/kg) and; 4) FF + Everolimus (EV, 1mg/kg) and treated for 16 weeks. Serum and tissue samples were analyzed for evidence of inflammation, fibrosis, lipogenesis, and apoptosis. Results TC and EV treatments significantly reduced the hepatic lipid accumulation, improved liver-body weight ratio, blood biochemistry, and insulin resistance in mice fed with FF diet. However, inflammation, enlarged portal tracts, and fibrosis were pronounced in EV treated group. The lipogenic parameters, Peroxisome proliferator-activated receptor gamma (PPAR-γ), Sterol regulatory element-binding protein 1(SREBP-1), mammalian target of rapamycin (m-TOR), Stearoyl-CoA desaturase-1 (SCD-1) and fatty acid translocase (CD36) were significantly down-regulated in livers of TC and EV treated groups as compared to FF group. TC improved Bcl2/Bax ratio, decreased apoptosis, CYP2E1 protein expression and liver fibrosis levels, however, EV offered no such protection. Further, in an In-vitro model of lipotoxicity using the mouse hepatocyte (AML-12) cell line, treatment with TC and EV significantly reduced lipid accumulation and lipogenic and apoptotic markers induced with palmitic acid. Conclusion In FF diet induced model of NASH, both TC and EV inhibited hepatic lipid accumulation and improved metabolic parameters such as insulin resistance and dyslipidemia. However, mice administered with EV exhibited inflammatory and fibrotic responses despite reduced hepatic steatosis.
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Affiliation(s)
- Sharma Love
- PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India.,Academy of Scientific and Innovative Research (AcSIR), Chennai, India
| | - Malik A Mudasir
- PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Subhash C Bhardwaj
- Department of Pathology, Government Medical College, Jammu, Jammu and Kashmir, India
| | - Gurdarshan Singh
- PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India.,Academy of Scientific and Innovative Research (AcSIR), Chennai, India
| | - Sheikh A Tasduq
- PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India.,Academy of Scientific and Innovative Research (AcSIR), Chennai, India
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Ge MX, He HW, Shao RG, Liu H. Recent progression in the utilization of autophagy-regulating nature compound as anti-liver fibrosis agents. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2017; 19:109-113. [PMID: 28133978 DOI: 10.1080/10286020.2016.1276168] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 12/20/2016] [Indexed: 06/06/2023]
Abstract
Hepatic fibrosis is a wound-healing response to chronic liver injury caused by various pathogenesis, such as hepatitis virus infection, drugs toxicity and autoimmune imbalances. Autophagy, a cellular process degrading damaged organelles or aggregative proteins, participates in multiple human diseases including hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is yet to be elucidated. Accumulated evidences indicate that several nature compounds exhibit anti-fibrotic potential through modulating autophagy activity. For a better understanding of the relationships among autophagy, hepatic fibrosis, and autophagy-regulating nature compounds, this review highlights the recent advancement of nature compounds treating hepatic fibrosis through regulating autophagy.
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Affiliation(s)
- Mao-Xu Ge
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
| | - Hong-Wei He
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
| | - Rong-Guang Shao
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
| | - Hong Liu
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
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Dang L, Liu J, Wang C, Liu H, Wen J. Enhancement of rapamycin production by metabolic engineering in Streptomyces hygroscopicus based on genome-scale metabolic model. ACTA ACUST UNITED AC 2017; 44:259-270. [DOI: 10.1007/s10295-016-1880-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/26/2016] [Indexed: 12/18/2022]
Abstract
Abstract
Rapamycin, as a macrocyclic polyketide with immunosuppressive, antifungal, and anti-tumor activity produced by Streptomyces hygroscopicus, is receiving considerable attention for its significant contribution in medical field. However, the production capacity of the wild strain is very low. Hereby, a computational guided engineering approach was proposed to improve the capability of rapamycin production. First, a genome-scale metabolic model of Streptomyces hygroscopicus ATCC 29253 was constructed based on its annotated genome and biochemical information. The model consists of 1003 reactions, 711 metabolites after manual refinement. Subsequently, several potential genetic targets that likely guaranteed an improved yield of rapamycin were identified by flux balance analysis and minimization of metabolic adjustment algorithm. Furthermore, according to the results of model prediction, target gene pfk (encoding 6-phosphofructokinase) was knocked out, and target genes dahP (encoding 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase) and rapK (encoding chorismatase) were overexpressed in the parent strain ATCC 29253. The yield of rapamycin increased by 30.8% by knocking out gene pfk and increased by 36.2 and 44.8% by overexpression of rapK and dahP, respectively, compared with parent strain. Finally, the combined effect of the genetic modifications was evaluated. The titer of rapamycin reached 250.8 mg/l by knockout of pfk and co-expression of genes dahP and rapK, corresponding to a 142.3% increase relative to that of the parent strain. The relationship between model prediction and experimental results demonstrates the validity and rationality of this approach for target identification and rapamycin production improvement.
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Affiliation(s)
- Lanqing Dang
- grid.419897.a 0000 0004 0369 313X Key Laboratory of System Bioengineering (Tianjin University), Ministry of Education 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 School of Chemical Engineering and Technology Tianjin University 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) 300072 Tianjin People’s Republic of China
| | - Jiao Liu
- grid.419897.a 0000 0004 0369 313X Key Laboratory of System Bioengineering (Tianjin University), Ministry of Education 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 School of Chemical Engineering and Technology Tianjin University 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) 300072 Tianjin People’s Republic of China
| | - Cheng Wang
- grid.419897.a 0000 0004 0369 313X Key Laboratory of System Bioengineering (Tianjin University), Ministry of Education 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 School of Chemical Engineering and Technology Tianjin University 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) 300072 Tianjin People’s Republic of China
| | - Huanhuan Liu
- grid.419897.a 0000 0004 0369 313X Key Laboratory of System Bioengineering (Tianjin University), Ministry of Education 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 School of Chemical Engineering and Technology Tianjin University 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) 300072 Tianjin People’s Republic of China
| | - Jianping Wen
- grid.419897.a 0000 0004 0369 313X Key Laboratory of System Bioengineering (Tianjin University), Ministry of Education 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 School of Chemical Engineering and Technology Tianjin University 300072 Tianjin People’s Republic of China
- grid.33763.32 0000000417612484 SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) 300072 Tianjin People’s Republic of China
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Sun K, Xu L, Jing Y, Han Z, Chen X, Cai C, Zhao P, Zhao X, Yang L, Wei L. Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. Cancer Lett 2016; 388:198-207. [PMID: 28011320 DOI: 10.1016/j.canlet.2016.12.004] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 11/17/2016] [Accepted: 12/06/2016] [Indexed: 02/07/2023]
Abstract
As a cellular degradation mechanism, autophagy exerts crucial and complicated effects on HCC development. Liver non-parenchymal cells, including hepatic resident macrophage Kupffer cells, also play important roles in this process. However, most associated studies have focused on the influence of the autophagy level in hepatic cells and HCC cells, but not liver non-parenchymal cells. Based on our previous study, we confirmed that Atg5 silence in the liver during the preneoplastic stage facilitated liver fibrosis, inflammation and, ultimately, tumorigenesis. We further found that autophagy deficiency promotes the production of inflammatory and fibrogenic factors in macrophages. Moreover, Kupffer cell depletion rescued the tumor-promoting effect of autophagy deficiency during the preneoplastic stage. In autophagy-deficient macrophages, mitochondrial ROS mediated inflammation- and fibrosis-promoting effects by increasing IL1α/β production via enhancing NF-κB-associated pathways. Both blocking of mitochondrial ROS and blocking the IL1 receptor stopped the promotion of fibrosis, inflammation and tumorigenesis resulting from Atg5 knockdown during the preneoplastic stage. In conclusion, autophagy-deficient Kupffer cells promote liver fibrosis, inflammation and, finally, hepatocarcinogenesis during the preneoplastic stage by enhancing mitochondrial ROS- NF-κB-IL1α/β pathways.
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Affiliation(s)
- Kai Sun
- Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lingyun Xu
- Department of Pediatrics, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yingying Jing
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Xiaojing Chen
- Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenlei Cai
- Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Peipei Zhao
- Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xue Zhao
- Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Liqun Yang
- Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
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Clinical Advancements in the Targeted Therapies against Liver Fibrosis. Mediators Inflamm 2016; 2016:7629724. [PMID: 27999454 PMCID: PMC5143744 DOI: 10.1155/2016/7629724] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 10/11/2016] [Accepted: 10/19/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.
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Shan L, Ding Y, Fu Y, Zhou L, Dong X, Chen S, Wu H, Nai W, Zheng H, Xu W, Bai X, Jia C, Dai M. mTOR Overactivation in Mesenchymal cells Aggravates CCl 4- Induced liver Fibrosis. Sci Rep 2016; 6:36037. [PMID: 27819329 PMCID: PMC5098141 DOI: 10.1038/srep36037] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 10/10/2016] [Indexed: 01/22/2023] Open
Abstract
Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl4, oil or CCl4+ rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl4− induced liver fibrosis and the rapamycin prevent its occurance.
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Affiliation(s)
- Lanlan Shan
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yan Ding
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - You Fu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Ling Zhou
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xiaoying Dong
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Shunzhi Chen
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Hongyuan Wu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Wenqing Nai
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Hang Zheng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Xiaochun Bai
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Chunhong Jia
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Meng Dai
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
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CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis. Oncogene 2016; 36:2446-2456. [PMID: 27819676 PMCID: PMC5408319 DOI: 10.1038/onc.2016.400] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 09/16/2016] [Accepted: 09/23/2016] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ-/- mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuates the compensatory proliferation of hepatocytes in CAMK2γ-/- livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
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50
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Nasser SA, Sabra R, Elmallah AI, El-Din MMM, Khedr MM, El-Mas MM. Facilitation by the renin-angiotensin system of cyclosporine-evoked hypertension in rats: Role of arterial baroreflexes and vasoreactivity. Life Sci 2016; 163:1-10. [DOI: 10.1016/j.lfs.2016.08.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/16/2016] [Accepted: 08/25/2016] [Indexed: 12/25/2022]
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