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Wijayasiri P, Astbury S, Needham G, Kaye P, Bhat M, Piccinini AM, Aravinthan AD. Role of hepatocellular senescence in the development of hepatocellular carcinoma and the potential for therapeutic manipulation. Hum Cell 2025; 38:70. [PMID: 40100482 PMCID: PMC11920335 DOI: 10.1007/s13577-025-01201-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/04/2025] [Indexed: 03/20/2025]
Abstract
Accumulation of senescent hepatocytes is universal in chronic liver disease (CLD). This study investigates an association between hepatocyte senescence and hepatocellular carcinoma (HCC) and explores the therapeutic role of sirolimus. Background liver biopsies from 15 patients with cirrhosis and HCC and 45 patients with cirrhosis were stained for p16, a marker of cell senescence. STAM™ mice were randomized into 3 groups of 5 at 4 weeks of age and administered vehicle ± sirolimus intraperitoneally, thrice weekly, from 4 to 18 weeks of age. Placebo group was an administered vehicle, early sirolimus group was an administered vehicle with sirolimus, late sirolimus group was an administered vehicle from 4 to 12 weeks then vehicle with sirolimus from 12 to 18 weeks. The primary outcome was HCC nodule development. Senescent hepatocyte burden and senescence-associated secretory phenotype (SASP) factors were assessed in mice livers. In the human study, age (OR 1.282, 95% CI 1.086-1.513, p = 0.003) and p16 (OR 1.429, 95% CI 1.112-1.838, p = 0.005) were independently associated with HCC. In the animal study, all three groups exhibited similar MASLD activity scores (p = 0.39) and fibrosis area (p = 0.92). The number and the maximum diameter of HCC nodules were significantly lower in the early sirolimus group compared to placebo and late sirolimus group. The gene expression of SASP factors was similar in all groups. Protein levels of some SASP factors (TNFα, IL1β, IL-2, CXCL15) were significantly lower in sirolimus administered groups compared to placebo group. The study demonstrates an independent association between senescent hepatocyte burden and HCC. It indicates a potential chemoprophylactic role for sirolimus through SASP factor inhibition. These early results could inform a future human clinical trial.
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Affiliation(s)
- Pramudi Wijayasiri
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, E Floor, West Block, QMC Campus, Derby Road, Nottingham, NG7 2UH, UK
| | - Stuart Astbury
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, E Floor, West Block, QMC Campus, Derby Road, Nottingham, NG7 2UH, UK
| | - Grace Needham
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Philip Kaye
- Department of Pathology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Mamatha Bhat
- Multiorgan Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Canada
| | | | - Aloysious D Aravinthan
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, E Floor, West Block, QMC Campus, Derby Road, Nottingham, NG7 2UH, UK.
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Liu X, Fang C, Yu H, Huang L, Feng J, Luo S, Song L, Wu M, Tan Y, Dong J, Gong T, Xiao P. Chondroitin Sulfate-Based Imatinib Nanoparticles Targeting Activated Hepatic Stellate Cells Against Hepatic Fibrosis. Pharmaceutics 2025; 17:351. [PMID: 40143016 PMCID: PMC11944399 DOI: 10.3390/pharmaceutics17030351] [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: 01/06/2025] [Revised: 02/16/2025] [Accepted: 02/28/2025] [Indexed: 03/28/2025] Open
Abstract
Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis.
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Affiliation(s)
- Xunzhi Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Changlong Fang
- Department of Pharmacy, Chongqing University Fuling Hospital, Chongqing University, Chongqing 408099, China;
| | - Hongling Yu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Lu Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Jiaxing Feng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Shiqin Luo
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Li Song
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China;
| | - Mengying Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Yulu Tan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Jianxia Dong
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (X.L.); (H.Y.); (L.H.); (J.F.); (S.L.); (M.W.); (Y.T.); (T.G.)
| | - Peihong Xiao
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China;
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Al Saihati HA, Badr OA, Dessouky AA, Mostafa O, Samir Farid A, Aborayah NH, Abdullah Aljasir M, Baioumy B, Mahmoud Taha N, El-Sherbiny M, Hamed Al-Serwi R, Ramadan MM, Salim RF, Shaheen D, E M Ali F, Ebrahim N. Exploring the cytoprotective role of mesenchymal stem Cell-Derived exosomes in chronic liver Fibrosis: Insights into the Nrf2/Keap1/p62 signaling pathway. Int Immunopharmacol 2024; 141:112934. [PMID: 39178516 DOI: 10.1016/j.intimp.2024.112934] [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: 06/01/2024] [Revised: 08/03/2024] [Accepted: 08/12/2024] [Indexed: 08/26/2024]
Abstract
Hepatic fibrosis is a common pathology present in most chronic liver diseases. Autophagy is a lysosome-mediated intracellular catabolic and recycling process that plays an essential role in maintaining normal hepatic functions. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor responsible for the regulation of cellular anti-oxidative stress response. This study was designed to assess the cytoprotective effect of mesenchymal stem cell-derived exosomes (MSC-exos) on endothelial-mesenchymal transition (EMT) in Carbon Tetrachloride (CCL4) induced liver fibrosis. Rats were treated with 0.1 ml of CCL4 twice weekly for 8 weeks, followed by administration of a single dose of MSC-exos. Rats were then sacrificed after 4 weeks, and liver samples were collected for gene expression analyses, Western blot, histological studies, immunohistochemistry, and transmission electron microscopy. Our results showed that MSC-exos administration decreased collagen deposition, apoptosis, and inflammation. Exosomes modulate the Nrf2/Keap1/p62 pathway, restoring autophagy and Nrf2 levels through modulation of the non-canonical pathway of Nrf2/Keap1/p62. Additionally, MSC-exos regulated miR-153-3p, miR-27a, miR-144 and miRNA-34a expression. In conclusion, the present study shed light on MSC-exos as a cytoprotective agent against EMT and tumorigenesis in chronic liver inflammation.
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Affiliation(s)
- Hajir A Al Saihati
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Saudi Arabia.
| | - Omnia A Badr
- Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Egypt.
| | - Arigue A Dessouky
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, 44519 Zagazig, Egypt.
| | - Ola Mostafa
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt.
| | - Ayman Samir Farid
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh 13736, Qalyubia, Egypt.
| | - Nashwa H Aborayah
- Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Egypt, Department of Pharmacology, Mutah University, Mutah 61710, Jordan.
| | - Mohammad Abdullah Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
| | - Bodour Baioumy
- Department of Anatomy and Embryology, Faculty of Medicine, Benha University, Egypt.
| | | | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Egypt.
| | - Rasha Hamed Al-Serwi
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Mahmoud M Ramadan
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah City, United Arab Emirates; Department of Cardiology, Faculty of Medicine, Mansoura University, Mansoura City, Egypt.
| | - Rabab F Salim
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha Universit, Egypt.
| | - Dalia Shaheen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Nesrine Ebrahim
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Stem Cell Unit, Egypt.
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Su L, Rao K, Wang L, Pu L, Zhang Z, Li H, Li R, Liu D. Prenylated Dihydroflavonol from Sophora flavescens Regulate the Polarization and Phagocytosis of Macrophages In Vitro. Molecules 2024; 29:4741. [PMID: 39407669 PMCID: PMC11477850 DOI: 10.3390/molecules29194741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/04/2024] [Accepted: 10/05/2024] [Indexed: 10/20/2024] Open
Abstract
As an important member of innate immunity, macrophages show remarkable plasticity and heterogeneity, and play an important role in immune regulation, tissue development, homeostasis of the internal environment and injury repair. However, the excessive activation of macrophages is closely related to the occurrence and development of many diseases. The prenylated flavonoid structure is one of the characteristic structures isolated from Sophora flavescens, with anti-inflammatory, anti-tumor, anti-allergy and other effects. In this study, the effects of (2R)-3β,7,4'-trihydroxy-5-methoxy-8-prenylflavanone (TMP), a prenylated dihydroflavonol, on the polarization and phagocytosis of macrophages were systematically studied. In LPS-induced M1-type macrophages, TMP dose-dependently inhibited the expression of COX-2, iNOS and the secretion of NO, IL-1β, IL-6 and IL-18, showing an inhibitory effect on M1 polarization. Further experiments revealed that it was related to the inhibition of TLR4-related AKT/mTOR, MAPK and NF-κB signaling pathways; in IL-4-induced M2-type macrophages, TMP down-regulated the expression of M2-related Arg1, IL-10, TGF-β, CD206 and CD163, as well as the phosphorylation levels of AKT1 and STAT6. For macrophages in a physiological state, it was very important for cells to return from a stress state to a phenotypic stability in the M0 state. These results indicated that TMP negatively regulated the M1/M2 polarization of macrophages, and made them tend to M0 homeostasis, which might provide new theoretical and data support for explaining the anti-inflammatory immunoregulatory activity of Sophora flavescens.
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Affiliation(s)
| | | | | | | | | | | | - Rongtao Li
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Dan Liu
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
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Stanciu SM, Jinga M, Miricescu D, Stefani C, Nica RI, Stanescu-Spinu II, Vacaroiu IA, Greabu M, Nica S. mTOR Dysregulation, Insulin Resistance, and Hypertension. Biomedicines 2024; 12:1802. [PMID: 39200267 PMCID: PMC11351979 DOI: 10.3390/biomedicines12081802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.
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Affiliation(s)
- Silviu Marcel Stanciu
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania; (S.M.S.); (M.J.)
| | - Mariana Jinga
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania; (S.M.S.); (M.J.)
| | - Daniela Miricescu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania;
| | - Constantin Stefani
- Department of Family Medicine and Clinical Base, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania;
| | - Remus Iulian Nica
- Surgery Department, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania;
- Discipline of General Surgery, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanotari Blvd, 054474 Bucharest, Romania
| | - Iulia-Ioana Stanescu-Spinu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Ileana Adela Vacaroiu
- Department of Nephrology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Maria Greabu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania;
| | - Silvia Nica
- Emergency Discipline, University Hospital of Bucharest, 050098 Bucharest, Romania;
- Department of Emergency and First Aid, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
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Shamsan E, Almezgagi M, Gamah M, Khan N, Qasem A, Chuanchuan L, Haining F. The role of PI3k/AKT signaling pathway in attenuating liver fibrosis: a comprehensive review. Front Med (Lausanne) 2024; 11:1389329. [PMID: 38590313 PMCID: PMC10999701 DOI: 10.3389/fmed.2024.1389329] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 03/11/2024] [Indexed: 04/10/2024] Open
Abstract
Excessive accumulation of extracellular matrix (ECM) components within the liver leads to a pathological condition known as liver fibrosis. Alcohol abuse, non-alcoholic fatty liver disease (NAFLD), autoimmune issues, and viral hepatitis cause chronic liver injury. Exploring potential therapeutic targets and understanding the molecular mechanisms involved in liver fibrosis are essential for the development of effective interventions. The goal of this comprehensive review is to explain how the PI3K/AKT signaling pathway contributes to the reduction of liver fibrosis. The potential of this pathway as a therapeutic target is investigated through a summary of results from in vivo and in vitro studies. Studies focusing on PI3K/AKT activation have shown a significant decrease in fibrosis markers and a significant improvement in liver function. The review emphasizes how this pathway may prevent ECM synthesis and hepatic stellate cell (HSC) activation, ultimately reducing the fibrotic response. The specific mechanisms and downstream effectors of the PI3K/AKT pathway in liver fibrosis constitute a rapidly developing field of study. In conclusion, the PI3K/AKT signaling pathway plays a significant role in attenuating liver fibrosis. Its complex role in regulating HSC activation and ECM production, demonstrated both in vitro and in vivo, underscores its potential as a effective therapeutic approach for managing liver fibrosis and slowing disease progression. A comprehensive review of this field provides valuable insights into its future developments and implications for clinical applications.
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Affiliation(s)
- Emad Shamsan
- College of Clinical Medicine, Qinghai University, Xining, China
- College of Medical Science, Taiz University, Taiz, Yemen
| | - Maged Almezgagi
- College of Clinical Medicine, Qinghai University, Xining, China
| | - Mohammed Gamah
- College of Clinical Medicine, Qinghai University, Xining, China
| | - Naveed Khan
- College of Clinical Medicine, Qinghai University, Xining, China
| | | | - Liu Chuanchuan
- College of Clinical Medicine, Qinghai University, Xining, China
- Qinghai University Affiliated Hospital, Xining, China
| | - Fan Haining
- College of Clinical Medicine, Qinghai University, Xining, China
- Qinghai University Affiliated Hospital, Xining, China
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Soto A, Spongberg C, Martinino A, Giovinazzo F. Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond. Biomedicines 2024; 12:397. [PMID: 38397999 PMCID: PMC10886580 DOI: 10.3390/biomedicines12020397] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease's range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids.
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Affiliation(s)
- Allison Soto
- Department of Surgery, University of Illinois College of Medicine, Chicago, IL 60607, USA;
| | - Colby Spongberg
- Touro College of Osteopathic Medicine, Great Falls, MT 59405, USA
| | | | - Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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Yang J, Li S, Liu S, Zhang Y, Shen D, Wang P, Dang X. Metformin ameliorates liver fibrosis induced by congestive hepatopathy via the mTOR/HIF-1α signaling pathway. Ann Hepatol 2023; 28:101135. [PMID: 37451514 DOI: 10.1016/j.aohep.2023.101135] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/22/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023]
Abstract
INTRODUCTION AND OBJECTIVES Congestive hepatopathy (CH) is a hepatic vascular disease that results in chronic liver congestion, which can lead to liver fibrosis. New uses of metformin have been discovered over the years. However, the function of metformin in congestive liver fibrosis is not yet fully understood. This study aimed to investigate the effect of metformin on liver fibrosis in a mouse model of CH. MATERIALS AND METHODS Partial ligation of the inferior vena cava (pIVCL) was used to establish a mouse model of liver congestion. Metformin (0.1%) was added to the daily drinking water of the animals, and the effect of metformin on liver tissue was studied after 6 weeks. Hepatic stellate cells (HSCs) were also stimulated with CoCl2 to investigate the inhibitory impact of metformin on the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) pathway. RESULTS Metformin attenuated liver congestion; decreased the expression of collagen, fibronectin, α-smooth muscle actin (α-SMA), and HIF-1α; and ameliorated liver fibrosis in pIVCL mice. The proliferation and migration of HSCs were inhibited by metformin in vitro, which prevented α-SMA expression and restrained HSC activation. The expression levels of phosphorylated-mTOR, HIF-1α, and vascular endothelial growth factor were also decreased. CONCLUSIONS Metformin inhibits CH-induced liver fibrosis. Functionally, this beneficial effect may be the result of inhibition of HSC activation and of the mTOR/HIF-1α signaling pathway.
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Affiliation(s)
- Jing Yang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Suxin Li
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Shengyan Liu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yuehui Zhang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Dongqi Shen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Peiju Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xiaowei Dang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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9
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Liu P, Li H, Xu H, Gong J, Jiang M, Xu Z, Shi J. Aggravated hepatic fibrosis induced by phenylalanine and tyrosine was ameliorated by chitooligosaccharides supplementation. iScience 2023; 26:107754. [PMID: 37731617 PMCID: PMC10507131 DOI: 10.1016/j.isci.2023.107754] [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: 07/05/2022] [Revised: 03/21/2023] [Accepted: 08/24/2023] [Indexed: 09/22/2023] Open
Abstract
Hepatic fibrosis is a classic pathological manifestation of metabolic chronic hepatopathy. The pathological process might either gradually deteriorate into cirrhosis and ultimately liver cancer with inappropriate nutrition supply, or be slowed down by several multifunctional nutrients, alternatively. Herein, we found diet with excessive phenylalanine (Phe) and tyrosine (Tyr) exacerbated hepatic fibrosis symptoms of liver dysfunction and gut microflora dysbiosis in mice. Chitooligosaccharides (COS) could ameliorate hepatic fibrosis with the regulation of amino acid metabolism by downregulating the mTORC1 pathway, especially that of Phe and Tyr, and also with the alleviation of the dysbiosis of gut microbiota, simultaneously. Conclusively, this work presents new insight into the role of Phe and Tyr in the pathologic process of hepatic fibrosis, while revealing the effectiveness and molecular mechanism of COS in improving hepatic fibrosis from the perspective of metabolites.
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Affiliation(s)
- Peng Liu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, 1000 Jinqi Road, Shanghai 201403, China
| | - Heng Li
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Hongyu Xu
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi 214122, China
| | - Jinsong Gong
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Min Jiang
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Zhenghong Xu
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi 214122, China
| | - Jinsong Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
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10
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Han DW, Xu K, Jin ZL, Xu YN, Li YH, Wang L, Cao Q, Kim KP, Ryu D, Hong K, Kim NH. Customized liver organoids as an advanced in vitro modeling and drug discovery platform for non-alcoholic fatty liver diseases. Int J Biol Sci 2023; 19:3595-3613. [PMID: 37497008 PMCID: PMC10367556 DOI: 10.7150/ijbs.85145] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/12/2023] [Indexed: 07/28/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) have presented a major and common health concern worldwide due to their increasing prevalence and progressive development of severe pathological conditions such as cirrhosis and liver cancer. Although a large number of drug candidates for the treatment of NASH have entered clinical trial testing, all have not been released to market due to their limited efficacy, and there remains no approved treatment for NASH available to this day. Recently, organoid technology that produces 3D multicellular aggregates with a liver tissue-like cytoarchitecture and improved functionality has been suggested as a novel platform for modeling the human-specific complex pathophysiology of NAFLD and NASH. In this review, we describe the cellular crosstalk between each cellular compartment in the liver during the pathogenesis of NAFLD and NASH. We also summarize the current state of liver organoid technology, describing the cellular diversity that could be recapitulated in liver organoids and proposing a future direction for liver organoid technology as an in vitro platform for disease modeling and drug discovery for NAFLD and NASH.
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Affiliation(s)
- Dong Wook Han
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
- International Healthcare Innovation Institute (Jiangmen), Jianghai, Jiangmen, Guangdong Province, China
- Research and Development, Qingdao Haier Biotech Co. Ltd, Qingdao, China
- Guangdong ORGANOID Biotechnology Co. Ltd, Jiangmen, China
| | - KangHe Xu
- Department of Surgery, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Zhe-Long Jin
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
- International Healthcare Innovation Institute (Jiangmen), Jianghai, Jiangmen, Guangdong Province, China
- Guangdong ORGANOID Biotechnology Co. Ltd, Jiangmen, China
| | - Yong-Nan Xu
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
- International Healthcare Innovation Institute (Jiangmen), Jianghai, Jiangmen, Guangdong Province, China
| | - Ying-Hua Li
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
- International Healthcare Innovation Institute (Jiangmen), Jianghai, Jiangmen, Guangdong Province, China
| | - Lin Wang
- Research and Development, Qingdao Haier Biotech Co. Ltd, Qingdao, China
| | - Qilong Cao
- Research and Development, Qingdao Haier Biotech Co. Ltd, Qingdao, China
| | - Kee-Pyo Kim
- Department of Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - DongHee Ryu
- Department of Surgery, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Kwonho Hong
- Department of Stem Cell and Regenerative Biotechnology, The institute of advanced regenerative science, Konkuk University, Seoul, Republic of Korea
| | - Nam-Hyung Kim
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
- International Healthcare Innovation Institute (Jiangmen), Jianghai, Jiangmen, Guangdong Province, China
- Research and Development, Qingdao Haier Biotech Co. Ltd, Qingdao, China
- Guangdong ORGANOID Biotechnology Co. Ltd, Jiangmen, China
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11
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Felli E, Nulan Y, Selicean S, Wang C, Gracia-Sancho J, Bosch J. Emerging Therapeutic Targets for Portal Hypertension. CURRENT HEPATOLOGY REPORTS 2023; 22:51-66. [PMID: 36908849 PMCID: PMC9988810 DOI: 10.1007/s11901-023-00598-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/18/2023] [Indexed: 02/13/2023]
Abstract
Purpose of Review Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. Recent Findings Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. Summary New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated.
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Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Yelidousi Nulan
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
- Liver Vascular Biology Research Group, CIBEREHD, IDIBAPS Research Institute, 08036 Barcelona, Spain
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
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12
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Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression. Cells 2022; 11:cells11142221. [PMID: 35883664 PMCID: PMC9322633 DOI: 10.3390/cells11142221] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this ‘proof of concept’ study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.
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13
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Abdelrahman SA, Abdelfatah MM, Keshta AT. Rapamycin-filgrastim combination therapy ameliorates portal hypertension-induced splenomegaly: Role of β actin and S100A9 proteins modulation. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:732-744. [PMID: 35949314 PMCID: PMC9320204 DOI: 10.22038/ijbms.2022.64034.14101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/07/2022] [Indexed: 11/06/2022]
Abstract
Objectives Thioacetamide (TAA) was administered to induce an animal model of liver disease with secondary splenomegaly to assess the mechanisms underlying the effects of rapamycin and filgrastim when taken separately or in combination on the biochemical and histopathological aspects of the liver and spleen. Materials and Methods Thirty adult male albino rats were divided into five groups (control, TAA-treated group, TAA+rapamycin, TAA+filgrastim, and TAA+rapamycin+filgrastim group). We measured relative liver and spleen weights, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin. Molecular docking modeling and histopathological examination of liver and spleen sections with hematoxylin and eosin and Masson trichrome staining with immunohistochemical detection of splenic CD3 and CD20 lymphocytes, S100A9 and β actin antibodies were detected. Morphometric and statistical analyses of the results were performed. Results TAA administration altered the histological structure of the liver and spleen and impaired liver function. It increased the expression of splenic CD3, CD20 lymphocytes, and S100A9 while diminishing the expression of β actin. Each of rapamycin and filgrastim, when administered separately, improved liver and spleen indices and liver function, but rapamycin did not affect the albumin level. They lowered splenic B and T lymphocyte levels. Expression levels of S100A9 showed down-regulation while β actin levels were up-regulated when compared with TAA. Combination therapy improved liver and spleen tissue pathology and significantly ameliorated the expression of splenic lymphocytes through regulation of S100A9 and β actin expression. Conclusion The synergistic effect of combination therapy was dependent on the regulation of splenic S100A9 and β actin levels.
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Affiliation(s)
- Shaimaa A. Abdelrahman
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt,Corresponding author: Shaimaa A. Abdelrahman. Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Mohammed M. Abdelfatah
- Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Akaber T. Keshta
- Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
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14
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Huang WQ, Zou Y, Tian Y, Ma XF, Zhou QY, Li ZY, Gong SX, Wang AP. Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future. J Cardiovasc Pharmacol 2022; 79:444-455. [PMID: 34983907 DOI: 10.1097/fjc.0000000000001208] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/16/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT The abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key pathological characteristic of vascular proliferative diseases. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays an important role in regulating cell growth, motility, proliferation, and survival, as well as gene expression in response to hypoxia, growth factors, and nutrients. Increasing evidence shows that mTOR also regulates VSMC proliferation in vascular proliferative diseases and that mTOR inhibitors, such as rapamycin, effectively restrain VSMC proliferation. However, the molecular mechanisms linking mTOR to vascular proliferative diseases remain elusive. In our review, we summarize the key roles of the mTOR and the recent discoveries in vascular proliferative diseases, focusing on the therapeutic potential of mTOR inhibitors to target the mTOR signaling pathway for the treatment of vascular proliferative diseases. In this study, we discuss mTOR inhibitors as promising candidates to prevent VSMC-associated vascular proliferative diseases.
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Affiliation(s)
- Wen-Qian Huang
- Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
| | - Yan Zou
- Department of Hand and Foot Surgery, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China ; and
| | - Ying Tian
- Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
| | - Xiao-Feng Ma
- Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
| | - Qin-Yi Zhou
- Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
| | - Zhen-Yu Li
- Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
| | - Shao-Xin Gong
- Department of Pathology, First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
| | - Ai-Ping Wang
- Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
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15
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Al-Hashem F, Al Humayed S, Haidara MA, Abdel Latif NS, Al-Ani B. Captopril suppresses hepatic mammalian target of rapamycin cell signaling and biomarkers of inflammation and oxidative stress in thioacetamide-induced hepatotoxicity in rats. Arch Physiol Biochem 2021; 127:414-421. [PMID: 31364422 DOI: 10.1080/13813455.2019.1647249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 07/16/2019] [Accepted: 07/18/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND The potential inhibitory effects of captopril, the angiotensin-converting enzyme inhibitor, on thioacetamide (TAA)-induced hepatic mammalian target of rapamycin (mTOR), liver injury enzymes, blood pressure, and biomarkers of inflammation and oxidative stress have not been investigated before. MATERIALS AND METHODS Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (model group) or were pretreated with captopril (150 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment (protective group). RESULTS Captopril significantly (p < .05) inhibited TAA-induced hypertension, liver tissue levels of mTOR, TIMP-1, TNF-α, IL-6, MDA; and blood levels of lipids, ALT, and AST. We further demonstrated a significant (p < .01) positive correlation between mTOR scoring and the levels of inflammatory, oxidative and liver injury biomarkers. CONCLUSIONS Captopril protects against TAA-induced mTOR, liver injury enzymes, dyslipidemia, hypertension, inflammation, and oxidative stress.
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Affiliation(s)
- Fahaid Al-Hashem
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Suliman Al Humayed
- Department of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohamed A Haidara
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha S Abdel Latif
- Medical Pharmacology Department, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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16
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Cai J, Hu M, Chen Z, Ling Z. The roles and mechanisms of hypoxia in liver fibrosis. J Transl Med 2021; 19:186. [PMID: 33933107 PMCID: PMC8088569 DOI: 10.1186/s12967-021-02854-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis occurs in response to any etiology of chronic liver injury. Lack of appropriate clinical intervention will lead to liver cirrhosis or hepatocellular carcinoma (HCC), seriously affecting the quality of life of patients, but the current clinical treatments of liver fibrosis have not been developed yet. Recent studies have shown that hypoxia is a key factor promoting the progression of liver fibrosis. Hypoxia can cause liver fibrosis. Liver fibrosis can, in turn, profoundly further deepen the degree of hypoxia. Therefore, exploring the role of hypoxia in liver fibrosis will help to further understand the process of liver fibrosis, and provide the theoretical basis for its diagnosis and treatment, which is of great significance to avoid further deterioration of liver diseases and protect the life and health of patients. This review highlights the recent advances in cellular and molecular mechanisms of hypoxia in developments of liver fibrosis.
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Affiliation(s)
- Jingyao Cai
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Min Hu
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China.
| | - Zhiyang Chen
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Zeng Ling
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
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17
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Shu Y, Liu X, Huang H, Wen Q, Shu J. Research progress of natural compounds in anti-liver fibrosis by affecting autophagy of hepatic stellate cells. Mol Biol Rep 2021; 48:1915-1924. [PMID: 33609264 PMCID: PMC7925445 DOI: 10.1007/s11033-021-06171-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022]
Abstract
Chronic liver diseases caused by various pathogenesis are marked by inflammatory infiltration and wound healing reaction, while their normal regeneration ability is impaired. The unbalance between the generation and the degradation of extracellular matrix (ECM) leads to collagen accumulation and develops into liver fibrosis. Inflammation, oxidative stress, and autophagy interact closely in the pathogenesis of hepatic fibrosis. Reactive Oxygen Species (ROS) can not only stimulate Kupffer cells to release massive inflammatory factors, but induce autophagy. However, the latter may suppress inflammatory reaction by inhibiting proinflammatory complex formation directly, and removing damaged organelles or pathogenic microorganism indirectly. At present, effective anti-fibrosis drugs are still lacking. Previous studies have found various natural compounds enabled liver protection through anti-inflammatory, antioxidant, and other mechanisms. In recent years, autophagy, a vital life activity, has been found to be involved in the mechanism of liver fibrosis. As a new target, developing anti-liver fibrosis drugs that regulate the activity of autophagy is very promising. In this review, we summarize the latest studies about natural compounds in the treatment of liver fibrosis by regulating autophagy.
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Affiliation(s)
- Yongxiang Shu
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Xuyou Liu
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Haifeng Huang
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Qi Wen
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
| | - Jianchang Shu
- Department of Gastroenterology, GuangZhou Red Cross Hospital, Jinan University, Guangzhou, 510220 China
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18
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Yan C, Koda S, Wu J, Zhang BB, Yu Q, Netea MG, Tang RX, Zheng KY. Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target. Hepatology 2020; 72:1838-1850. [PMID: 32463941 DOI: 10.1002/hep.31395] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/21/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Chao Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Stephane Koda
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Jing Wu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Bei-Bei Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Qian Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.,Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Ren-Xian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Kui-Yang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
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19
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Novel therapeutics for portal hypertension and fibrosis in chronic liver disease. Pharmacol Ther 2020; 215:107626. [DOI: 10.1016/j.pharmthera.2020.107626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023]
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20
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Chang CC, Chuang CL, Hsin IF, Hsu SJ, Huang HC, Lee FY, Lee SD. A high-dose rapamycin treatment alleviates hepatopulmonary syndrome in cirrhotic rats. J Chin Med Assoc 2020; 83:32-40. [PMID: 31567652 DOI: 10.1097/jcma.0000000000000194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Rapamycin is a type of immunosuppressive agent that acts through inhibition of mammalian target of rapamycin (mTOR). Hepatopulmonary syndrome (HPS) is a lethal complication in cirrhotic patients. It is characterized by hypoxia and increased intrapulmonary shunts, in which pulmonary inflammation and angiogenesis play important roles. The current study aimed to evaluate the effect of rapamycin on HPS using the experimental model of common bile duct ligation (CBDL)-induced cirrhosis in rats. METHODS The rats received low-dose (0.5 mg/kg), high-dose (2 mg/kg) rapamycin, or vehicle from the 15th to the 28th day post CBDL. Then the mortality rate, hemodynamics, biochemistry parameters, arterial blood gas and plasma levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-α were evaluated on the 28th day post CBDL. Pulmonary histopathological stains were performed, and protein expression was examined. In parallel groups, the intrapulmonary shunts of CBDL rats were measured. RESULTS Compared with the control, a high-dose rapamycin treatment decreased portal pressure and improved hypoxia in CBDL rats. It also reduced the plasma level of VEGF and TNF-α and decreased intrapulmonary shunts. Meanwhile, it ameliorated pulmonary inflammation and angiogenesis and downregulated the protein expression of mTOR, P70S6K, nuclear factor kappa B (NFκB), VEGF, and VEGF receptor 2. In contrast, low-dose rapamycin did not attenuate intrapulmonary shunts despite ameliorating portal hypertension. CONCLUSION High-dose rapamycin ameliorates HPS in cirrhotic rats as evidenced by the alleviated hypoxia and decreased intrapulmonary shunts. Downregulation of the mTOR/P70S6K, NFκB, and VEGF signaling pathways might play a key role.
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Affiliation(s)
- Ching-Chih Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Chiao-Lin Chuang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - I-Fang Hsin
- Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Endoscopy Center for Diagnosis and Treatment, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Hui-Chun Huang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
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21
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Ma JQ, Sun YZ, Ming QL, Tian ZK, Yang HX, Liu CM. Ampelopsin attenuates carbon tetrachloride-induced mouse liver fibrosis and hepatic stellate cell activation associated with the SIRT1/TGF-β1/Smad3 and autophagy pathway. Int Immunopharmacol 2019; 77:105984. [DOI: 10.1016/j.intimp.2019.105984] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/13/2019] [Accepted: 10/16/2019] [Indexed: 02/07/2023]
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22
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Fancher IS, Rubinstein I, Levitan I. Potential Strategies to Reduce Blood Pressure in Treatment-Resistant Hypertension Using Food and Drug Administration-Approved Nanodrug Delivery Platforms. Hypertension 2019; 73:250-257. [PMID: 30624988 DOI: 10.1161/hypertensionaha.118.12005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Ibra S Fancher
- From the Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois at Chicago (I.S.F., I.R., I.L.)
| | - Israel Rubinstein
- From the Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois at Chicago (I.S.F., I.R., I.L.).,Jesse Brown VA Medical Center, Chicago, Illinois (I.R.)
| | - Irena Levitan
- From the Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois at Chicago (I.S.F., I.R., I.L.)
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23
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A Nutraceutical Rich in Docosahexaenoic Acid Improves Portal Hypertension in a Preclinical Model of Advanced Chronic Liver Disease. Nutrients 2019; 11:nu11102358. [PMID: 31623374 PMCID: PMC6835927 DOI: 10.3390/nu11102358] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/25/2019] [Accepted: 09/29/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.
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Al-Hashem F, Al-Humayed S, Amin SN, Kamar SS, Mansy SS, Hassan S, Abdel-Salam LO, Ellatif MA, Alfaifi M, Haidara MA, Al-Ani B. Metformin inhibits mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers in thioacetamide-induced hepatic tissue alterations. J Cell Physiol 2019; 234:9328-9337. [PMID: 30334569 DOI: 10.1002/jcp.27616] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 09/24/2018] [Indexed: 02/05/2023]
Abstract
The potential inhibitory effect of the antidiabetic and anti-inflammatory drug, metformin on thioacetamide (TAA)-induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA-induced HIF-1α, mTOR, the profibrogenic biomarker α-smooth muscle actin, tissue inhibitor of metalloproteinases-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF-1α) and the serum levels of TNF-α ( r = 0.797), IL-6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA-induced hepatic injuries in rats, which is associated with the inhibition of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans.
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Affiliation(s)
- Fahaid Al-Hashem
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Suliman Al-Humayed
- Department of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Shaimaa N Amin
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Samaa S Kamar
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Soheir S Mansy
- Electron Microscopy Research Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Sarah Hassan
- Electron Microscopy Research Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Lubna O Abdel-Salam
- Department of Pathology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Abd Ellatif
- Department of Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohammed Alfaifi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Mohamed A Haidara
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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25
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Yang W, Shao L, Zhu S, Li H, Zhang X, Ding C, Wu X, Xu R, Yue M, Tang J, Kuang B, Fan G, Zhu Q, Zeng H. Transient Inhibition of mTORC1 Signaling Ameliorates Irradiation-Induced Liver Damage. Front Physiol 2019; 10:228. [PMID: 30984007 PMCID: PMC6449701 DOI: 10.3389/fphys.2019.00228] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 02/21/2019] [Indexed: 12/25/2022] Open
Abstract
Recurrent liver cancer after surgery is often treated with radiotherapy, which induces liver damage. It has been documented that activation of the TGF-β and NF-κB signaling pathways plays important roles in irradiation-induced liver pathologies. However, the significance of mTOR signaling remains undefined after irradiation exposure. In the present study, we investigated the effects of inhibiting mTORC1 signaling on irradiated livers. Male C57BL/6J mice were acutely exposed to 8.0 Gy of X-ray total body irradiation and subsequently treated with rapamycin. The effects of rapamycin treatment on irradiated livers were examined at days 1, 3, and 7 after exposure. The results showed that 8.0 Gy of irradiation resulted in hepatocyte edema, hemorrhage, and sinusoidal congestion along with a decrease of ALB expression. Exposure of mice to irradiation significantly activated the mTORC1 signaling pathway determined by pS6 and p-mTOR expression via western blot and immunostaining. Transient inhibition of mTORC1 signaling by rapamycin treatment consistently accelerated liver recovery from irradiation, which was evidenced by decreasing sinusoidal congestion and increasing ALB expression after irradiation. The protective role of rapamycin on irradiated livers might be mediated by decreasing cellular apoptosis and increasing autophagy. These data suggest that transient inhibition of mTORC1 signaling by rapamycin protects livers against irradiation-induced damage.
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Affiliation(s)
- Wuping Yang
- Medical College of Nanchang University, Nanchang, China
| | - Lijian Shao
- Medical College of Nanchang University, Nanchang, China
| | - Sihong Zhu
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Health Vocational College, Nanchang, China
| | - Huan Li
- Medical College of Nanchang University, Nanchang, China
| | - Xinxin Zhang
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Congcong Ding
- Medical College of Nanchang University, Nanchang, China
| | - Xincheng Wu
- Medical College of Nanchang University, Nanchang, China
| | - Rui Xu
- Medical College of Nanchang University, Nanchang, China
| | - Mengzhen Yue
- Medical College of Nanchang University, Nanchang, China
| | - Jiahui Tang
- Medical College of Nanchang University, Nanchang, China
| | - Bohai Kuang
- Medical College of Nanchang University, Nanchang, China
| | - Guangqin Fan
- Medical College of Nanchang University, Nanchang, China
| | - Qingxian Zhu
- Medical College of Nanchang University, Nanchang, China
| | - Huihong Zeng
- Medical College of Nanchang University, Nanchang, China
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26
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Muir AB, Wang JX, Nakagawa H. Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis. J Gastroenterol 2019; 54:10-18. [PMID: 30101408 PMCID: PMC6314980 DOI: 10.1007/s00535-018-1498-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 07/29/2018] [Indexed: 02/07/2023]
Abstract
Eosinophilic esophagitis (EoE) is a food allergen-induced inflammatory disorder. EoE is increasingly recognized as a cause of swallowing dysfunction, food impaction and esophageal stricture. Inflammation of the esophageal mucosa involves immune cell infiltrate, reactive epithelial changes and fibroblast activation, culminating in robust tissue remodeling toward esophageal fibrosis characterized by excess collagen deposition in the subepithelial lamina propria. Fibrosis contributes to a unique mechanical property of the EoE-affected esophagus that is substantially stiffer than the normal esophagus. There is a great need to better understand the processes behind esophageal fibrosis in order to foster improved diagnostic tools and novel therapeutics for EoE-related esophageal fibrosis. In this review, we discuss the role of esophageal inflammatory microenvironment that promotes esophageal fibrosis, with specific emphasis upon cytokines-mediated functional epithelial-stromal interplays, recruitment and activation of a variety of effector cells, and tissue stiffness. We then explore the current state of clinical methodologies to detect and treat the EoE-related esophageal stricture.
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Affiliation(s)
- Amanda B. Muir
- 0000 0001 0680 8770grid.239552.aDivision of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104-6160 USA ,0000 0004 1936 8972grid.25879.31Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Joshua X. Wang
- 0000 0001 0680 8770grid.239552.aDivision of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104-6160 USA ,0000 0004 1936 8972grid.25879.31Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Hiroshi Nakagawa
- 0000 0004 1936 8972grid.25879.31Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 956 Biomedical Research Building, 421 Curie Boulevard, Philadelphia, PA 19104-6160 USA ,0000 0004 1936 8972grid.25879.31Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104 USA
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27
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Vilaseca M, Guixé-Muntet S, Fernández-Iglesias A, Gracia-Sancho J. Advances in therapeutic options for portal hypertension. Therap Adv Gastroenterol 2018; 11:1756284818811294. [PMID: 30505350 PMCID: PMC6256317 DOI: 10.1177/1756284818811294] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/15/2018] [Indexed: 02/04/2023] Open
Abstract
Portal hypertension represents one of the major clinical consequences of chronic liver disease, having a deep impact on patients' prognosis and survival. Its pathophysiology defines a pathological increase in the intrahepatic vascular resistance as the primary factor in its development, being subsequently aggravated by a paradoxical increase in portal blood inflow. Although extensive preclinical and clinical research in the field has been developed in recent decades, no effective treatment targeting its primary mechanism has been defined. The present review critically summarizes the current knowledge in portal hypertension therapeutics, focusing on those strategies driven by the disease pathophysiology and underlying cellular mechanisms.
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Affiliation(s)
- Marina Vilaseca
- Hepatic Hemodynamic Laboratory, IDIBAPS
Biomedical Research Institute, Barcelona, Spain
| | - Sergi Guixé-Muntet
- Department of Biomedical Research, University of
Bern, Bern, Switzerland
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona
Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute,
CIBEREHD, Rosselló 149, 4th floor, 08036 Barcelona, Spain
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28
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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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29
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Effect of sirolimus on liver cirrhosis and hepatic encephalopathy of common bile duct-ligated rats. Eur J Pharmacol 2018; 824:133-139. [PMID: 29444470 DOI: 10.1016/j.ejphar.2018.02.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 02/09/2018] [Accepted: 02/09/2018] [Indexed: 01/16/2023]
Abstract
Cirrhosis is often associated with portal hypertension and portal-systemic collateral vessels formation attributed to angiogenesis, which leads to severe complications as hepatic encephalopathy. Sirolimus has anti-fibrosis and anti-angiogenesis effects, but whether it influences the severity of portal-systemic collaterals and hepatic encephalopathy is unknown. This study was thus designed to address this issue in rats with common bile duct ligation-induced liver cirrhosis. Sham-operated rats were surgical controls. Rats were intraperitoneally administered with 0.5 and 2 mg/kg/day sirolimus or vehicle for 2 weeks. Four weeks post operations, motor activities, body weight, biochemistry and hemodynamic data were measured. The liver was dissected for histopathology, immunohistochemical stains and protein analysis. On the parallel cirrhotic groups, the portal-systemic shunting was determined. The results showed that the body weight gain was significantly lower in sirolimus-treated rats. Sirolimus reduced portal pressure and plasma levels of alanine aminotransferase, aspartate aminotransferase and ammonia, and attenuated hepatic inflammation and fibrosis in cirrhotic rats. In addition, the hepatic phosphorylated mammalian target of rapamycin (mTOR) and P70S6K protein expressions were significantly downregulated and endothelial nitric oxide synthase (eNOS) expression upregulated by sirolimus. Sirolimus did not influence portal-systemic shunting and motor activities of cirrhotic rats. In conclusion, sirolimus significantly improved hepatic inflammation and fibrosis accompanied by portal pressure reduction in cirrhotic rats, in which down-regulated mTOR/P70S6K and up-regulated eNOS expressions might play a role. However, sirolimus did not significantly change the severity of portal-systemic collaterals and motor activities, suggesting that the multifactorial pathogenesis of hepatic encephalopathy could not be fully overcome by sirolimus.
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Kikuchi A, Pradhan-Sundd T, Singh S, Nagarajan S, Loizos N, Monga SP. Platelet-Derived Growth Factor Receptor α Contributes to Human Hepatic Stellate Cell Proliferation and Migration. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2273-2287. [PMID: 28734947 DOI: 10.1016/j.ajpath.2017.06.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/19/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023]
Abstract
Platelet-derived growth factor receptor α (PDGFRα), a tyrosine kinase receptor, is up-regulated in hepatic stellate cells (HSCs) during chronic liver injury. HSCs mediate hepatic fibrosis through their activation from a quiescent state partially in response to profibrotic growth factors. HSC activation entails enhanced expression of profibrotic genes, increase in proliferation, and increase in motility, which facilitates migration within the hepatic lobule. We show colocalization of PDGFRα in murine carbon tetrachloride, bile duct ligation, and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine models of chronic liver injury, and investigate the role of PDGFRα on proliferation, profibrotic gene expression, and migration in primary human HSCs (HHSteCs) using the PDGFRα-specific inhibitory monoclonal antibody olaratumab. Although lacking any effects on HHSteC transdifferentiation assessed by gene expression of ACTA2, TGFB1, COL1A1, SYP1, and FN1, olaratumab specifically reduced HHSteC proliferation (AlamarBlue assay) and cell migration (transwell migration assays). Using phospho-specific antibodies, we show that olaratumab attenuates PDGFRα activation in response to PDGF-BB, and reduced phosphorylation of extracellular signal-regulated kinase 1 and 2, Elk-1, p38, Akt, focal adhesion kinase, mechanistic target of rapamycin, C10 regulator of kinase II, and C10 regulator of kinase-like, suggesting that PDGFRα contributes to mitogenesis and actin reorganization through diverse downstream effectors. Our findings support a distinct contribution of PDGFRα signaling to HSC proliferation and migration and provide evidence that inhibition of PDGFRα signaling could alter the pathogenesis of hepatic fibrosis.
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Affiliation(s)
- Alexander Kikuchi
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Tirthadipa Pradhan-Sundd
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sucha Singh
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shanmugam Nagarajan
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nick Loizos
- Department of Immunology, Eli Lilly and Company, New York, New York
| | - Satdarshan P Monga
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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31
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Zhou B, Leng Y, Lei SQ, Xia ZY. AMPK activation restores ischemic post-conditioning cardioprotection in STZ-induced type 1 diabetic rats: Role of autophagy. Mol Med Rep 2017; 16:3648-3656. [DOI: 10.3892/mmr.2017.7033] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 04/07/2017] [Indexed: 12/31/2022] Open
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32
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Yang N, Dang S, Shi J, Wu F, Li M, Zhang X, Li Y, Jia X, Zhai S. Caffeic acid phenethyl ester attenuates liver fibrosis via inhibition of TGF-β1/Smad3 pathway and induction of autophagy pathway. Biochem Biophys Res Commun 2017; 486:22-28. [PMID: 28193525 DOI: 10.1016/j.bbrc.2017.02.057] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 02/09/2017] [Indexed: 02/06/2023]
Abstract
Caffeic acid phenethyl ester (CAPE) has been reported to possess the hepatoprotective effect. This study was to investigate the mechanism underlying CAPE against liver fibrosis in a liver fibrosis model induced by toxic carbon tetrachloride (CCl4) in male Sprague-Dawley rats and in vitro in CAPE (5 μM, 10 μM, 15 μM) treated hepatic stellate cells (HSC-T6). We found that CAPE treatment remarkably attenuated CCl4-induced liver fibrosis by blocking the activation of HSCs as determined by the expression alternation of transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3), collage I, α-smooth muscle actin (α-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1. The hepatoprotective effects of CAPE were also associated with upregulation of autophasomes in HSCs as determined by transmission electron microscopy (TEM) detection. The in vitro study further confrimed that CAPE attenuated liver fibrogenesis via inducing authophagic markers including LC3, ATG5, Beclin 1 expressions, while inhibiting AKT/mTOR signaling in HSC-T6 cells. Thus, the protective effects of CAPE against liver fibrosis might due to the inhibition of TGF-β1/Smad3 signaling and induction of authophagy in HSCs.
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Affiliation(s)
- Ning Yang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
| | - Juanjuan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Fengping Wu
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Mei Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Song Zhai
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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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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Shi H, Shi H, Ren F, Chen D, Chen Y, Duan Z. Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti-fibrosis effect by inhibition of mammalian target of rapamycin. J Cell Mol Med 2017; 21:500-509. [PMID: 27687505 PMCID: PMC5323881 DOI: 10.1111/jcmm.12994] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 08/19/2016] [Indexed: 12/30/2022] Open
Abstract
A previous study has demonstrated that Ganshuang granule (GSG) plays an anti-fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)-autophagy plays an important role. We attempted to investigate the role of mTOR-autophagy in anti-fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti-fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti-fibrotic effect. 3-methyladenine (3-MA) and Insulin-like growth factor-1 (IGF-1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti-fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3-MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF-1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti-fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.
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Affiliation(s)
- Hongbo Shi
- Beijing Youan HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Honglin Shi
- Beijing Youan HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Feng Ren
- Beijing Youan HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Dexi Chen
- Beijing Youan HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Yu Chen
- Beijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Zhongping Duan
- Beijing Youan HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of HepatologyBeijingChina
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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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Gao Y, Chu S, Shao Q, Zhang M, Xia C, Wang Y, Li Y, Lou Y, Huang H, Chen N. Antioxidant activities of ginsenoside Rg1 against cisplatin-induced hepatic injury through Nrf2 signaling pathway in mice. Free Radic Res 2016; 51:1-13. [PMID: 27931128 DOI: 10.1080/10715762.2016.1234710] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oxidative stress is mainly caused by reactive oxygen species (ROS). The damage causes a net stress on normal organs, leading to a gradual loss of vital physiological function. ROS, such as free radicals, represent a class of molecules which are derived from the metabolism of oxygen and exist inherently. However, excessive produced ROS can damage all aerobic organisms. Ginseng is one of the most commonly used alternative herbal medicines, also as a traditional Chinese medicine. The aim of this study is to investigate the antioxidant potential function of ginsenoside Rg1 against cisplatin-caused hepatic damage. Male mice were treated with cisplatin to induce oxidative stress to mimic the side effect of anti-cancer drug cisplatin. Ginsenoside Rg1 effectively prevented against cisplatin-induced hepatotoxicity, alleviating histological lesions. Antioxidant functions of Rg1 were restrained by the activation of p62-Keap1-Nrf2 signaling pathway, simultaneously accompanied with expression of protein products. Accumulative p62 and increased activation of JNK in hepatocytes promoted the activation of Nrf2. For the other, degradation of Nrf2 was guided by tyrosine phosphorylation, ubiquitin, and Keap1. In summary, Rg1 prevents hepatotoxicity mainly by inhibiting the binding of Keap1 and Nrf2, partly by p62 accumulation, and more importantly by increasing the production of antioxidative proteins associated to Nrf2. Pharmacological activation of Nrf2 is an effective way in combating against liver injury.
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Affiliation(s)
- Yan Gao
- a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Shifeng Chu
- b College of Pharmacy , Hunan University of Chinese Medicine , Changsha , China
| | - Qianhang Shao
- a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Meijin Zhang
- a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Congyuan Xia
- a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Yingying Wang
- a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Yueting Li
- c Beijing Hospital of Integrated Traditional and Western Medicine , Beijing , China
| | - Yuxia Lou
- d Tianjin University of Traditional Chinese Medicine , Tianjin , China
| | - Huiyong Huang
- b College of Pharmacy , Hunan University of Chinese Medicine , Changsha , China
| | - Naihong Chen
- a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China.,b College of Pharmacy , Hunan University of Chinese Medicine , Changsha , China
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Chen G, Dong Z, Liu H, Liu Y, Duan S, Liu Y, Liu F, Chen H. mTOR Signaling Regulates Protective Activity of Transferred CD4+Foxp3+ T Cells in Repair of Acute Kidney Injury. THE JOURNAL OF IMMUNOLOGY 2016; 197:3917-3926. [DOI: 10.4049/jimmunol.1601251] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 09/21/2016] [Indexed: 12/16/2022]
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Huang SL, Fu DL, Li HC, Zhang P, Chong T. The effect of rapamycin on TGFβ1 and MMP1 expression in a rabbit model of urethral stricture. Int Urol Nephrol 2016; 48:717-23. [PMID: 26837772 DOI: 10.1007/s11255-016-1227-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 01/22/2016] [Indexed: 11/25/2022]
Abstract
PURPOSE To investigate the effect of rapamycin on TGFβ1 and MMP1 expression in a rabbit model of urethral stricture. METHODS Twenty-four adult New Zealand male rabbits underwent an electrocoagulation of the bulbar urethra with a 13Fr pediatric resectoscope. Then rabbits were randomly divided into three groups: (1) normal control group: normal saline (NS), (2) the vehicle control group: dimethyl sulfoxide (DMSO), and (3) the treatment group: effective-dose rapamycin in DMSO (Ra), with 12, 6, and 6 rabbits in each group, respectively. Drugs were given by urethral irrigation daily for 4 weeks. Urethral tissue was harvested for histological and molecular analyses. TGFβ1 and MMP1 expression levels were evaluated by real-time quantitative PCR and immunohistochemistry. RESULTS Ten, six, and six rabbits were evaluated finally in Ra, DMSO, and NS group, respectively. Histological examination revealed the distribution of fibrosis and the degree of collagen deposition in the Ra group were smaller and slighter than the two control groups. Collagen content was significantly less in the Ra group than in the DMSO group (P < 0.001) and the NS group (P < 0.001). qRT-PCR analysis showed a higher expression of MMP1 mRNA in the Ra group than in the DMSO group (P < 0.001) and the NS group (P < 0.001). Immunohistochemistry showed the protein levels of MMP1 in the Ra group were significantly increased when compared with the DMSO group (P < 0.01) and the NS group (P < 0.01). On the other hand, no statistical difference could be found between every two groups in both mRNA and protein levels of TGFβ1. CONCLUSIONS Rapamycin enhances the expression of MMP1 in a rabbit model of urethral stricture, but has no direct effect on the expression of TGFβ1.
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Affiliation(s)
- S L Huang
- Department of Urology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, 710004, Shaanxi Province, People's Republic of China
| | - D L Fu
- Department of Urology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, 710004, Shaanxi Province, People's Republic of China
| | - H C Li
- Department of Urology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, 710004, Shaanxi Province, People's Republic of China
| | - P Zhang
- Department of Urology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, 710004, Shaanxi Province, People's Republic of China
| | - T Chong
- Department of Urology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, 710004, Shaanxi Province, People's Republic of China.
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Chen Y, Wang W, Wang H, Li Y, Shi M, Li H, Yan J. Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway. PLoS One 2016; 11:e0141159. [PMID: 26734934 PMCID: PMC4703391 DOI: 10.1371/journal.pone.0141159] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/03/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. METHODS Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. RESULTS We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure. CONCLUSIONS This study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly.
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Affiliation(s)
- Yunyang Chen
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Weijie Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Huakai Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yongjian Li
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Minmin Shi
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongwei Li
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiqi Yan
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail:
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Wu T, Yao C, Tsang F, Huang L, Zhang W, Jiang J, Mao Y, Shao Y, Kong B, Singh P, Fu Z. Facilitated physiological adaptation to prolonged circadian disruption through dietary supplementation with essence of chicken. Chronobiol Int 2015; 32:1458-68. [DOI: 10.3109/07420528.2015.1105252] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Zhang HM, Fu J, Hamilton R, Diaz V, Zhang Y. The mammalian target of rapamycin modulates the immunoproteasome system in the heart. J Mol Cell Cardiol 2015; 86:158-67. [PMID: 26239133 DOI: 10.1016/j.yjmcc.2015.07.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 07/11/2015] [Accepted: 07/28/2015] [Indexed: 12/16/2022]
Abstract
The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-κB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFγ and TNFα, by suppressing NF-κB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy.
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Affiliation(s)
- Hong-Mei Zhang
- Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
| | - Jianliang Fu
- Department of Neurology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ryan Hamilton
- Barshop Institute, The University of Texas Health Science Center at San Antonio, TX 78249, United States
| | - Vivian Diaz
- Barshop Institute, The University of Texas Health Science Center at San Antonio, TX 78249, United States
| | - Yiqiang Zhang
- Barshop Institute, The University of Texas Health Science Center at San Antonio, TX 78249, United States; Department of Physiology, The University of Texas Health Science Center at San Antonio, TX 78249, United States
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Garbuzenko DV. Contemporary concepts of the medical therapy of portal hypertension under liver cirrhosis. World J Gastroenterol 2015; 21:6117-6126. [PMID: 26034348 PMCID: PMC4445090 DOI: 10.3748/wjg.v21.i20.6117] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/20/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023] Open
Abstract
Severe complications of liver cirrhosis are mostly related to portal hypertension. At the base of the pathogenesis of portal hypertension is the increase in hepatic vascular resistance to portal blood flow with subsequent development of hyperdynamic circulation, which, despite of the formation of collateral circulation, promotes progression of portal hypertension. An important role in its pathogenesis is played by the rearrangement of vascular bed and angiogenesis. As a result, strategic directions of the therapy of portal hypertension under liver cirrhosis include selectively decreasing hepatic vascular resistance with preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis, while striving to reduce the hepatic venous pressure gradient to less than 12 mmHg or 20% of the baseline. Over the last years, substantial progress in understanding the pathophysiological mechanisms of hemodynamic disorders under liver cirrhosis has resulted in the development of new drugs for their correction. Although the majority of them have so far been investigated only in animal experiments, as well as at the molecular and cellular level, it might be expected that the introduction of the new methods in clinical practice will increase the efficacy of the conservative approach to the prophylaxis and treatment of portal hypertension complications. The purpose of the review is to describe the known methods of portal hypertension pharmacotherapy and discuss the drugs that may affect the basic pathogenetic mechanisms of its development.
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Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells Exposed to Lipid Peroxidations. BIOMED RESEARCH INTERNATIONAL 2015; 2015:240210. [PMID: 26064888 PMCID: PMC4434176 DOI: 10.1155/2015/240210] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 01/09/2015] [Indexed: 02/05/2023]
Abstract
Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.
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Wang W, Du Z, Yan J, Ma D, Shi M, Zhang M, Peng C, Li H. Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: involvement of C-Jun N-terminal kinase, cyclin D1, and NF-κB. PLoS One 2014; 9:e112532. [PMID: 25479410 PMCID: PMC4257551 DOI: 10.1371/journal.pone.0112532] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 10/07/2014] [Indexed: 12/16/2022] Open
Abstract
Background The therapeutic potential of mesenchymal stem cells (MSCs) has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT). Methods SFSLT model was established with a 30% partial liver transplantation (30PLT) in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot. Results MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group. Conclusion These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.
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Affiliation(s)
- Weijie Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou University School of Medicine, Zhengzhou, Henan Province, China
| | - Zhiyong Du
- Department of Hepatobiliary Surgery, Central Hospital of Wuhan, Wuhan, Hubei Province, China
| | - Jiqi Yan
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail:
| | - Di Ma
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Minmin Shi
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mingjun Zhang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chenghong Peng
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongwei Li
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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