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He J, Li L, Yan X, Li Y, Wang Y, Huang J, Li C, Liu W, Qi J. Sappanone A enhances hepatocyte proliferation in lipopolysaccharide-induced acute liver injury in mice by promoting injured hepatocyte apoptosis and regulating macrophage polarization. Int Immunopharmacol 2024; 142:113055. [PMID: 39243556 DOI: 10.1016/j.intimp.2024.113055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 08/03/2024] [Accepted: 08/29/2024] [Indexed: 09/09/2024]
Abstract
OBJECTIVES Lipopolysaccharide (LPS), also known as endotoxin, is the main toxic component of the cell wall of gram negative bacteria, which is released after bacterial death and widely exists in the living environment. Human exposure to endotoxin may cause sepsis. The occurrence of septic liver injury is a prominent factor contributing to mortality in patients with sepsis. The purpose of this study is to explore the role of Sappanone A (SA), a homoisoflavonoid isolated from the heartwood of Caesalpinia sappan Linn., in LPS-induced acute liver injury (ALI). METHODS An LPS-induced ALI mouse model was used to evaluate the effects of SA on septic ALI, and murine cells were treated with LPS to explore the mechanisms underlying SA-provided effects. RESULTS Treating SA substantially improved LPS-induced ALI. We also performed in silico prediction and RNA-seq analysis to elucidate SA's potential mechanisms of action. The terms generated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of predicted target proteins of SA include inflammation, oxidative stress, and apoptosis; protein-protein interaction network (PPI) analysis indicated that fas binding protein 1 (Fbf1) has the strongest correlation with SA. Consistently, RNA-seq analysis displayed that SA administration regulates cell apoptosis and inflammatory responses, which was further confirmed by checking related markers in livers of mice and murine cells challenged with LPS. Of note, SA significantly decreased the expression of Fbf1 in mouse livers, and promoted apoptosis of injured hepatocytes and hepatocyte proliferation, which were substantially abolished by Fbf1 knockdown in AML12 cells. Besides, SA could increase M2 phenotype polarization but inhibit M1 macrophage polarization in LPS-induced ALI in mice. CONCLUSION SA enhances hepatocyte proliferation and liver repair in LPS-induced ALI in mcie by promoting injured hepatocyte apoptosis through Fbf1 inhibition and regulating macrophage polarization.
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Affiliation(s)
- Jiale He
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Lanqian Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Xueqing Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Yehaomin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Yufei Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Jiabin Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Chutao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Wenwen Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
| | - Jing Qi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian, China.
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Yang GH, Yoon YI, Hwang S, Kim KH, Ahn CS, Moon DB, Ha TY, Song GW, Jung DH, Park GC, Lee SG. Clinical significance and outcomes of adult living donor liver transplantation for acute liver failure: a retrospective cohort study based on 15-year single-center experience. Ann Surg Treat Res 2024; 107:167-177. [PMID: 39282101 PMCID: PMC11390282 DOI: 10.4174/astr.2024.107.3.167] [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: 05/22/2024] [Revised: 07/01/2024] [Accepted: 07/01/2024] [Indexed: 09/18/2024] Open
Abstract
Purpose This study aimed to describe adult living donor liver transplantation (LDLT) for acute liver failure and evaluate its clinical significance by comparing its surgical and survival outcomes with those of deceased donor liver transplantation (DDLT). Methods We retrospectively reviewed the medical records of 267 consecutive patients (161 LDLT recipients and 106 DDLT recipients) aged 18 years or older who underwent liver transplantation between January 2006 and December 2020. Results The mean periods from hepatic encephalopathy to liver transplantation were 5.85 days and 8.35 days for LDLT and DDLT, respectively (P = 0.091). Among these patients, 121 (45.3%) had grade III or IV hepatic encephalopathy (living, 34.8% vs. deceased, 61.3%; P < 0.001), and 38 (14.2%) had brain edema (living, 16.1% vs. deceased, 11.3%; P = 0.269) before liver transplantation. There were no significant differences in in-hospital mortality (living, 11.8% vs. deceased, 15.1%; P = 0.435), 10-year overall survival (living, 90.8% vs. deceased, 84.0%; P = 0.096), and graft survival (living, 83.5% vs. deceased, 71.3%; P = 0.051). However, postoperatively, the mean intensive care unit stay was shorter in the LDLT group (5.0 days vs. 9.5 days, P < 0.001). In-hospital mortality was associated with vasopressor use (odds ratio [OR], 3.40; 95% confidence interval [CI], 1.45-7.96; P = 0.005) and brain edema (OR, 2.75; 95% CI, 1.16-6.52; P = 0.022) of recipient at the time of transplantation. However, LDLT (OR, 1.26; 95% CI, 0.59-2.66; P = 0.553) was not independently associated with in-hospital mortality. Conclusion LDLT is feasible for acute liver failure when organs from deceased donors are not available.
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Affiliation(s)
- Geun-Hyeok Yang
- Division of Hepatobiliary Surgery and Transplantation, Department of Surgery, Kyunghee University Hospital at Gangdong, Kyunghee University College of Medicine, Seoul, Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Li F, Wang X, Shi J, Wu S, Xing W, He Y. Anti-inflammatory effect of dental pulp stem cells. Front Immunol 2023; 14:1284868. [PMID: 38077342 PMCID: PMC10701738 DOI: 10.3389/fimmu.2023.1284868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Dental pulp stem cells (DPSCs) have received a lot of attention as a regenerative medicine tool with strong immunomodulatory capabilities. The excessive inflammatory response involves a variety of immune cells, cytokines, and has a considerable impact on tissue regeneration. The use of DPSCs for controlling inflammation for the purpose of treating inflammation-related diseases and autoimmune disorders such as supraspinal nerve inflammation, inflammation of the pulmonary airways, systemic lupus erythematosus, and diabetes mellitus is likely to be safer and more regenerative than traditional medicines. The mechanism of the anti-inflammatory and immunomodulatory effects of DPSCs is relatively complex, and it may be that they themselves or some of the substances they secrete regulate a variety of immune cells through inflammatory immune-related signaling pathways. Most of the current studies are still at the laboratory cellular level and animal model level, and it is believed that through the efforts of more researchers, DPSCs/SHED are expected to be transformed into excellent drugs for the clinical treatment of related diseases.
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Affiliation(s)
- FenYao Li
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - XinXin Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Jin Shi
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - ShuTing Wu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - WenBo Xing
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
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Amer K, Flikshteyn B, Lingiah V, Tafesh Z, Pyrsopoulos NT. Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 2023; 27:563-579. [PMID: 37380283 DOI: 10.1016/j.cld.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Affiliation(s)
- Kamal Amer
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Ben Flikshteyn
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Vivek Lingiah
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Zaid Tafesh
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 53, Newark, NJ 07101-1709, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 536, Newark, NJ 07101-1709, USA.
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Gong X, Zhang F, Li Y, Peng C. Study on the mechanism of acute liver injury protection in Rhubarb anthraquinone by metabolomics based on UPLC-Q-TOF-MS. Front Pharmacol 2023; 14:1141147. [PMID: 36950014 PMCID: PMC10025310 DOI: 10.3389/fphar.2023.1141147] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
As a traditional Chinese medicine, rhubarb has been used in a variety of liver diseases and it is widely used in clinic to prevent and treat acute liver injury. Anthraquinone, as the main medicinal component of rhubarb, can reverse the further development of liver fibrosis caused by acute liver injury. In this study, metabonomics was used to explore the mechanism of different doses of rhubarb anthraquinone on acute liver injury in rats. Rhubarb anthraquinone was administered intragastric to rats at doses of 3.9, 7.8 and 15.6 mg/kg, respectively, for 7 days, and then 30% CCl4 was injected intraperitoneally at the dose of 1 ml/kg to replicate the acute liver injury model. The biochemical indicators content of ALT, AST, ALP, γ-GT, TG, TC, LDL, HDL in serum and GSH, Hyp, SOD, TNF-α, IL-6 and IL-8 in liver tissue extract were tested respectively, and liver tissue was histopathologically analysis. At the same time, UPLC-Q-TOF-MS combined with non-targeted metabolomics were used to study the metabolites and metabolic pathways of rhubarb anthraquinone in treating acute liver injury. Compared with normal rats, the contents of ALT, AST, ALP, TG, TC, LDL, γ-GT in serum and Hyp, MDA, IL-6, IL-8, TNF-α in the liver tissue extract were significantly increased in model rats (p < 0.05, p < 0.01), and the content of HDL in the serum was significantly decreased (p < 0.05); the activities of GSH and SOD in liver tissue extract were also significantly decreased (p < 0.05). After administration of rhubarb anthraquinone, compared with the model group, with the increase of dosage, some biochemical indexes showed opposite changes, and gradually approached to normal rats. 12 different metabolites were identified by metabonomics, and the biosynthesis and metabolism of phenylalanine, tyrosine and tryptophan, the metabolism of amino sugars, nucleotide sugars and pyrimidines metabolism, and the biosynthesis of steroid hormone were identified based on the biomarker analysis. Based on the biochemical analysis and metabonomics analysis of rats with acute liver injury treated with different doses of rhubarb anthraquinone, combined with histopathological observation, the results show that the protective effect of rhubarb anthraquinone on acute liver injury is related to the dosage; Meanwhile, the metabolic pathway analysis suggested that rhubarb anthraquinone alleviate acute liver injury by regulating inflammation, oxidative stress and fibrosis disorders. This study explained the therapeutic effect of rhubarb anthraquinone on acute liver injury from both material basis and action pathway, and provided safe and effective research ideas for clinical application of rhubarb.
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Affiliation(s)
| | | | - Yunxia Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Wang J, Shi K, An N, Li S, Bai M, Wu X, Shen Y, Du R, Cheng J, Wu X, Xu Q. Direct Inhibition of GSDMD by PEITC Reduces Hepatocyte Pyroptosis and Alleviates Acute Liver Injury in Mice. Front Immunol 2022; 13:825428. [PMID: 35173734 PMCID: PMC8841757 DOI: 10.3389/fimmu.2022.825428] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/06/2022] [Indexed: 12/14/2022] Open
Abstract
Acute liver injury (ALI), often caused by viruses, alcohol, drugs, etc., is one of the most common clinical liver diseases. Although pyroptosis plays an important role in ALI, there is still a lack of effective clinical drugs related to this mechanism. Here, we show that phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, can significantly alleviate concanavalin A (ConA)-induced inflammatory liver damage and carbon tetrachloride (CCl4)-induced chemical liver damage in a dose-dependent manner. PEITC dose-dependently reversed the ALI-induced increase in plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and reduced the protein levels of hepatocyte pyroptosis markers such as Nod-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and cleaved gasdermin D (GSDMD). In vitro experiments have also verified the inhibitory effect of PEITC on hepatocyte pyroptosis. Furthermore, PEITC inhibits pyroptosis by interacting with cysteine 191 of GSDMD. In summary, our findings establish a role for PEITC in rescuing hepatocyte pyroptosis via direct inhibition of GSDMD, which may provide a new potential therapeutic strategy for ALI.
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7
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Ali AL, Nailwal NP, Doshi GM. Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases. Endocr Metab Immune Disord Drug Targets 2021; 22:371-382. [PMID: 34819013 DOI: 10.2174/1871530321666211124102837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The most common liver diseases are fibrosis, alcoholic liver disease, non-alcoholic fatty disease, viral hepatitis, and hepatocellular carcinoma. These liver diseases account for approximately 2 million deaths per year worldwide, with cirrhosis accounting for 2.1% of the worldwide burden. The most widely used liver function tests for diagnosis are alanine transaminase, aspartate transaminase, serum proteins, serum albumin, and serum globulins, whereas antivirals and corticosteroids have been proven to be useful for the treatment of liver diseases. A major disadvantage of these diagnostic measures is the lack of specificity to a particular tissue or cell type, as these enzymes are common to one or more tissues. The major adverse effect of current treatment methods is drug resistance. To overcome these issues, interleukins have been investigated. The balance of these interleukins determines the outcome of an immune response. Interleukins are considered interesting therapeutic targets for the treatment of liver diseases. In this review, we summarize the current state of knowledge regarding interleukins in the diagnosis, treatment, and pathogenesis of different acute and chronic liver diseases. OBJECTIVE To understand the role of interleukins in the assessment and treatment of different types of liver diseases. METHODS A literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: Interleukins, Acute Liver Failure, Alcoholic Liver Disease, Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, Hepatocellular Carcinoma, Inflammation, Liver injury, Hepatoprotective effect. Clinical trial data on these interleukins have been searched on Clinicaltrials.gov. RESULTS Existing literature and preclinical and clinical trial data demonstrate that interleukins play a crucial role in the pathogenesis of liver diseases. CONCLUSION Our findings indicate that IL-1, IL-6, IL-10, IL-17, IL-22, IL-35, and IL-37 are involved in the progression and control of various liver conditions via the regulation of cell signaling pathways. However, further investigation on the involvement of these interleukins is necessary for their use as a targeted therapy in liver diseases.
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Affiliation(s)
- Aaliya L Ali
- Department of Pharmacology, SVKM'S Dr. Bhanuben Nanavati College of Pharmacy, Mithibai Campus, Vile Parle (W), Mumbai-400056. India
| | - Namrata P Nailwal
- Department of Pharmacology, SVKM'S Dr. Bhanuben Nanavati College of Pharmacy, Mithibai Campus, Vile Parle (W), Mumbai-400056. India
| | - Gaurav M Doshi
- Department of Pharmacology, SVKM'S Dr. Bhanuben Nanavati College of Pharmacy, Mithibai Campus, Vile Parle (W), Mumbai-400056. India
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Liver transplantation in acute liver failure due to Hepatitis B. Two clinical cases. Ann Hepatol 2021; 21:100107. [PMID: 31623992 DOI: 10.1016/j.aohep.2019.06.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 05/30/2019] [Accepted: 06/03/2019] [Indexed: 02/04/2023]
Abstract
Hepatitis B virus (HBV) related acute liver failure (ALF) is uncommon in our region, and there is limited HBV literature regarding the optimal management of these cases. In this article, we report two clinical cases of young men who have sex with men (MSM), both developed severe acute hepatitis caused by HBV, progressed to ALF and afterward required liver transplantation. Antiviral post-transplant treatment included entecavir without Hepatitis B Immunoglobulin (HBIG), and immunosuppression therapy with steroids, tacrolimus, and mycophenolate. Serologic follow-up showed early Hepatitis B surface Antigen (HBsAg) seroconversion, undetectable HBV viral load, and positive Anti-HBs titers. During later follow-up, Anti-HBs titers gradually fell (<10mUI/L after six months), with normal liver function. DISCUSSION: In cases of HBV-related ALF, the liver develops a robust immune response, leading to, an early undetectable viral load and seroconversion, with loss of HBsAg, and the appearance of Anti-HBs as a result of the inflammatory response. The management varies depending on whether this is a de novo acute infection or a reactivation of a previous chronic infection. In both cases, the use of antiviral therapy is recommended, with entecavir or tenofovir, among others, but the use of specific HBIG is supported only in ALF related to chronic HBV infection. The optimal length of the antiviral therapy after liver transplantation is still under discussion. CONCLUSION: These cases of HBV related ALF with an early HBsAg seroconversion demonstrates the relevance of requesting IgM antibody against hepatitis B core antigen (anti-HBc IgM) for the etiological study of ALF with negative HBsAg. Usage of HBIG does not seem essential during the post-transplantation period in these cases.
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Wang F, Tang L, Liang B, Jin C, Gao L, Li Y, Li Z, Shao J, Zhang Z, Tan S, Zhang F, Zheng S. Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro. Front Pharmacol 2021; 12:658811. [PMID: 33967802 PMCID: PMC8102982 DOI: 10.3389/fphar.2021.658811] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is described as a characteristic of acute jaundice and coagulation dysfunction. Effective treatments for ACLF are unavailable and hence are urgently required. We aimed to define the effect of Yi-Qi-Jian-Pi Formula (YQJPF) on liver injury and further examine the molecular mechanisms. In this study, we established CCl4-, LPS-, and d-galactosamine (D-Gal)-induced ACLF rat models in vivo and LPS- and D-Gal-induced hepatocyte injury models in vitro. We found that YQJPF significantly ameliorates liver injury in vivo and in vitro that is associated with the regulation of hepatocyte necroptosis. Specifically, YQJPF decreased expression of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and pseudokinase mixed lineage kinase domain-like (MLKL) to inhibit the migration of RIPK1 and RIPK3 into necrosome. YQJPF also reduces the expression of inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α, which were regulated by RIPK3 mediates cell death. RIPK1 depletion was found to enhance the protective effect of YQJPF. Furthermore, we showed that YQJPF significantly downregulates the mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization, with ROS scavenger, 4-hydroxy-TEMPO treatment recovering impaired RIPK1-mediated necroptosis and reducing the expression of IL-6, IL-8, IL-1β, and TNF-α. In summary, our study revealed the molecular mechanism of protective effect of YQJPF on hepatocyte necroptosis, targeting RIPK1/RIPK3-complex-dependent necroptosis via ROS signaling. Overall, our results provided a novel perspective to indicate the positive role of YQJPF in ACLF.
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Affiliation(s)
- Feixia Wang
- Department of Integrated TCM and Western Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Tang
- Department of Integrated TCM and Western Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Baoyu Liang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chun Jin
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Liyuan Gao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yujia Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhanghao Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shanzhong Tan
- Department of Integrated TCM and Western Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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Hu C, Zhao L, Zhang L, Bao Q, Li L. Mesenchymal stem cell-based cell-free strategies: safe and effective treatments for liver injury. Stem Cell Res Ther 2020; 11:377. [PMID: 32883343 PMCID: PMC7469278 DOI: 10.1186/s13287-020-01895-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/17/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023] Open
Abstract
Various hepatoxic factors, such as viruses, drugs, lipid deposition, and autoimmune responses, induce acute or chronic liver injury, and 3.5% of all worldwide deaths result from liver cirrhosis, liver failure, or hepatocellular carcinoma. Liver transplantation is currently limited by few liver donors, expensive surgical costs, and severe immune rejection. Cell therapy, including hepatocyte transplantation and stem cell transplantation, has recently become an attractive option to reduce the overall need for liver transplantation and reduce the wait time for patients. Recent studies showed that mesenchymal stem cell (MSC) administration was a promising therapeutic approach for promoting liver regeneration and repairing liver injury by the migration of cells into liver sites, hepatogenic differentiation, immunoregulation, and paracrine mechanisms. MSCs secrete a large number of molecules into the extracellular space, and soluble proteins, free nucleic acids, lipids, and extracellular vesicles (EVs) effectively repair tissue injury in response to fluctuations in physiological states or pathological conditions. Cell-free-based therapies avoid the potential tumorigenicity, rejection of cells, emboli formation, undesired differentiation, and infection transmission of MSC transplantation. In this review, we focus on the potential mechanisms of MSC-based cell-free strategies for attenuating liver injury in various liver diseases. Secretome-mediated paracrine effects participate in the regulation of the hepatic immune microenvironment and promotion of hepatic epithelial repair. We look forward to completely reversing liver injury through an MSC-based cell-free strategy in regenerative medicine in the near future.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lingfei Zhao
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lingjian Zhang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Qiongling Bao
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China. .,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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11
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Cheng FS, Pan D, Chang B, Jiang M, Sang LX. Probiotic mixture VSL#3: An overview of basic and clinical studies in chronic diseases. World J Clin Cases 2020; 8:1361-1384. [PMID: 32368530 PMCID: PMC7190945 DOI: 10.12998/wjcc.v8.i8.1361] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 04/08/2020] [Indexed: 02/05/2023] Open
Abstract
Probiotics are known as “live microorganisms” and have been proven to have a health effect on hosts at the proper dose. Recently, a kind of probiotic mixture including eight live bacterial strains, VSL#3, has attracted considerable attention for its combined effect. VSL#3 is the only probiotic considered as a kind of medical food; it mainly participates in the regulation of the intestinal barrier function, including improving tight junction protein function, balancing intestinal microbial composition, regulating immune-related cytokine expression and so on. The objective of this review is to discuss the treatment action and mechanism for the administration of VSL#3 in chronic diseases of animals and humans (including children). We found that VSL#3 has a therapeutic or preventive effect in various systemic diseases per a large number of studies, including digestive systemic diseases (gastrointestinal diseases and hepatic diseases), obesity and diabetes, allergic diseases, nervous systemic diseases, atherosclerosis, bone diseases, and female reproductive systemic diseases.
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Affiliation(s)
- Fang-Shu Cheng
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Class 85 of 101k, China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, the First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, the First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
| | - Min Jiang
- Department of Gastroenterology, the First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, the First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
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12
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Comparative Analysis of Expression Profiles of Reg Signaling Pathways-Related Genes Between AHF and HCC. Biochem Genet 2019; 57:382-402. [PMID: 30600408 DOI: 10.1007/s10528-018-9900-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022]
Abstract
Regenerating islet-derived protein (Reg) could participate in the occurrence of diabetes mellitus, inflammation, tumors, and other diseased or damaged tissues. However, the correlation of Reg with acute hepatic failure (AHF) and hepatocellular carcinoma (HCC) is poorly defined. To reveal the expression profiles of Reg family and their possible regulatory roles in AHF and HCC, rat models of HCC and AHF were separately established, and Rat Genome 230 2.0 was used to detect expression profiles of Reg-mediated signaling pathways-associated genes from liver tissues in AHF and HCC. The results showed that a total of 79 genes were significantly changed. Among these genes, 67 genes were the AHF-specific genes, 45 genes were the HCC-specific genes, and 33 genes were the common genes. Then, K-means clustering classified these genes into 4 clusters based on the gene expression similarity, and DAVID analysis showed that the above altered genes were mainly associated with stress response, inflammatory response, and cell cycle regulation. Thereafter, IPA software was used to analyze potential effects of these genes, and the predicted results suggested that the Reg-mediated JAK/STAT, NF-κB, MAPK (ERK1/2, P38 and JNK), PLC, and PI3K/AKT signaling pathways may account for the activated inflammation and cell proliferation, and the attenuated apoptosis and cell death during the occurrence of AHF and HCC.
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Abstract
Acute liver failure (ALF) is a rare life-threatening condition characterized by rapid progression and death. Causes vary according to geographic region, with acetaminophen and drug-induced ALF being the most common causes in the United States. Determining the cause aids in predicting the prognosis and the presentation of manifestations and guides providers to perform cause-specific management. At initial presentation, nonspecific symptoms are present but may progress to complications, including cerebral edema, infection, coagulopathy, renal failure, cardiopulmonary failure, and acid-base and/or metabolic disturbances. Although some cases of ALF resolve with conservative measures, liver transplantation is the ultimate treatment in many cases.
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Affiliation(s)
- Sarah Zahra Maher
- Internal Medicine, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
| | - Ian Roy Schreibman
- Division of Gastroenterology and Hepatology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
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14
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Yang Y, Zhong Z, Ding Y, Zhang W, Ma Y, Zhou L. Bioinformatic identification of key genes and pathways that may be involved in the pathogenesis of HBV-associated acute liver failure. Genes Dis 2018; 5:349-357. [PMID: 30591937 PMCID: PMC6303483 DOI: 10.1016/j.gendis.2018.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 02/13/2018] [Indexed: 02/07/2023] Open
Abstract
In order to explore the molecular mechanisms behind the pathogenesis of acute liver failure (ALF) associated with hepatitis B virus (HBV) infection, the present study aimed to identify potential key genes and pathways involved using samples from patients with HBV-associated ALF. The GSE38941 array dataset was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between 10 liver samples from 10 healthy donors and 17 liver specimens from 4 patients with HBV-associated ALF were analyzed using the Linear Models for Microarray Data package. Gene Ontology and KEGG pathway enrichment analyses of the DEGs were performed, followed by functional annotation of the genes and construction of a protein–protein interaction (PPI) network. Subnetwork modules were subsequently identified and analyzed. In total, 3142 DEGs were identified, of which 1755 were upregulated and 1387 were downregulated. The extracellular exosome, immune response, and inflammatory response pathways may potentially be used as biomarkers of ALF pathogenesis. In total, 17 genes (including CCR5, CXCR4, ALB, C3, VGEFA, and IGF1) were identified as hub genes in the PPI network and may therefore be potential marker genes for HBV-associated ALF.
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Key Words
- ALF, acute liver failure
- BP, biological processes
- CC, cell components
- DEGs, differentially expressed genes
- Differentially expressed genes
- Function enrichment analysis
- GEO, Gene Expression Omnibus
- GO, Gene Ontology
- HBV, Hepatitis B Virus
- HBV-associated ALF
- HSPC, hepatic stem/progenitor cells
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- MF, molecular functions
- Module analysis
- OLT, orthotopic liver transplantation
- PPI, protein–protein interaction
- Protein–protein interaction network
- STRING, the Search Tool for the Retrieval of Interacting Genes
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Affiliation(s)
- Yalan Yang
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Zhaohui Zhong
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Yubin Ding
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Wanfeng Zhang
- Department of Bioinformatics, Chongqing Medical University, Chongqing, 400016, China
| | - Yang Ma
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Li Zhou
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
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15
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Lin H, Zhang Q, Li X, Wu Y, Liu Y, Hu Y. Identification of key candidate genes and pathways in hepatitis B virus-associated acute liver failure by bioinformatical analysis. Medicine (Baltimore) 2018; 97:e9687. [PMID: 29384847 PMCID: PMC5805419 DOI: 10.1097/md.0000000000009687] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 12/31/2017] [Accepted: 01/02/2018] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus-associated acute liver failure (HBV-ALF) is a rare but life-threatening syndrome that carried a high morbidity and mortality. Our study aimed to explore the possible molecular mechanisms of HBV-ALF by means of bioinformatics analysis. In this study, genes expression microarray datasets of HBV-ALF from Gene Expression Omnibus were collected, and then we identified differentially expressed genes (DEGs) by the limma package in R. After functional enrichment analysis, we constructed the protein-protein interaction (PPI) network by the Search Tool for the Retrieval of Interacting Genes online database and weighted genes coexpression network by the WGCNA package in R. Subsequently, we picked out the hub genes among the DEGs. A total of 423 DEGs with 198 upregulated genes and 225 downregulated genes were identified between HBV-ALF and normal samples. The upregulated genes were mainly enriched in immune response, and the downregulated genes were mainly enriched in complement and coagulation cascades. Orosomucoid 1 (ORM1), orosomucoid 2 (ORM2), plasminogen (PLG), and aldehyde oxidase 1 (AOX1) were picked out as the hub genes that with a high degree in both PPI network and weighted genes coexpression network. The weighted genes coexpression network analysis found out 3 of the 5 modules that upregulated genes enriched in were closely related to immune system. The downregulated genes enriched in only one module, and the genes in this module majorly enriched in the complement and coagulation cascades pathway. In conclusion, 4 genes (ORM1, ORM2, PLG, and AOX1) with immune response and the complement and coagulation cascades pathway may take part in the pathogenesis of HBV-ALF, and these candidate genes and pathways could be therapeutic targets for HBV-ALF.
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Affiliation(s)
- Huapeng Lin
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing
| | - Qian Zhang
- Department of Infectious Disease, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan
| | - Xiaocheng Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing
| | - Yushen Wu
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing
| | - Ye Liu
- Department of Paediatrics, Chidren's Hospital Chongqing Medical University, Chongqing, Chongqing
| | - Yingchun Hu
- Department of Emergency, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Liu YM, Lv J, Zeng QL, Shen S, Xing JY, Zhang YY, Zhang ZH, Yu ZJ. AMPK activation ameliorates D-GalN/LPS-induced acute liver failure by upregulating Foxo3A to induce autophagy. Exp Cell Res 2017; 358:335-342. [PMID: 28689811 DOI: 10.1016/j.yexcr.2017.07.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 06/30/2017] [Accepted: 07/05/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIM Acute liver failure (ALF) is an uncommon but serious disease still carrying a high mortality. This study aimed to investigate the mechanism of AMPK on D-GalN/LPS-induced ALF. METHODS In this study, we utilized intraperitoneal injection of D-GalN/LPS to induce ALF model, and analyzed the expression of AMPK, inflammatory cytokines (TNF-α, IL-1β and IL-6), Foxo3A and autophagy-related genes (Atg-5, Beclin-1, Atg-7) by real-time quantitative polymerase chain reaction (RT-PCR) in liver tissue. We also examined the level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of ALF mice. AMPK activation and inhibition of autophagy were induced by AICAR and 3-MA, respectively. Silence and overexpression of Foxo3A were performed by si-Foxo3A and pcDNA-Foxo3A, respectively. Lastly, the BMDM-conditioned medium (BMDM-CM) derived from BMDMs treated with AICAR and LPS were used to explore the effect of AMPK and Foxo3A on hepatocytes. RESULT The expression of AMPK was decreased in liver tissue and the level of ALT and AST were increased in serum of D-GalN/LPS-induced ALF mice. AMPK activation ameliorated ALF by inhibiting inflammation (downregulated TNF-α, IL-1β and IL-6 expression), activating autophagy (increased Atg-5, Beclin-1 and Atg-7 expression) and upregulating Foxo3A expression. Silence of Foxo3A decreased AMPK-activated autophagy, but overexpressing Foxo3A attenuated liver failure by activating autophagy. In addition, AMPK activation alleviated liver failure in vitro. CONCLUSION Thus, AMPK/Foxo3A/autophagy pathway may be an effective treatment approach to ameliorate ALF.
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Affiliation(s)
- Yan-Min Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Jun Lv
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Qing-Lei Zeng
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Shen Shen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Ji-Yuan Xing
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Ying-Ying Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Zhi-Hao Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China.
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17
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Zhang X, Jiang W, Zhou AL, Zhao M, Jiang DR. Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3β signaling pathway. World J Gastroenterol 2017; 23:3839-3849. [PMID: 28638224 PMCID: PMC5467070 DOI: 10.3748/wjg.v23.i21.3839] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/09/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of oxymatrine (OMT) on hepatocyte apoptosis in rats with lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver failure (ALF).
METHODS LPS/D-GalN was used to establish a model of ALF in rats. To evaluate the effect of OMT, we assessed apoptosis by transmission electron microscopy, and the pathological changes in the liver by light microscopy with hematoxylin and eosin staining. An automated biochemical analyzer was used to measure serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Enzyme-linked immunosorbent assay was used to determine the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Western blotting was used to detect protein levels in liver tissues. Streptavidin peroxidase immunohistochemistry was used to observe expression of Toll-like receptor (TLR)4, active caspase-3, Bax and Bcl-2.
RESULTS All rats in the normal control and OMT-pretreated groups survived. The mortality rate in the model group was 30%. OMT preconditioning down-regulated apoptosis of hepatocytes and ameliorated pathological changes in liver tissue. The levels of AST, ALT, TNF-α and IL-1β in the model group increased significantly, and were significantly reduced by OMT pretreatment. OMT pretreatment down-regulated expression of TLR4 and active caspase-3 and the Bax/Bcl-2 ratio, and up-regulated expression of P-AktSer473 (Akt phosphorylated at serine 473) and P-GSK3βSer9 (glycogen synthase kinase 3β phosphorylated at serine 9) induced by LPS/D-GalN.
CONCLUSION OMT inhibits hepatocyte apoptosis by suppressing the TLR4/PI3K/Akt/GSK-3β signaling pathway, which suggests that OMT is an effective candidate for ameliorating acute liver failure.
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18
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Wu YL, Lian LH, Nan JX. Protective effects of Chinese traditional medicine against liver injury and liver fibrosis and mechanisms involved. Shijie Huaren Xiaohua Zazhi 2016; 24:4144-4150. [DOI: 10.11569/wcjd.v24.i30.4144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver injury and liver fibrosis are clinically common, and there is currently a lack of ideal drugs for these conditions. Recent studies have indicated that the effective components of traditional Chinese medicine show certain efficacy in prevention and treatment of liver injury and liver fibrosis, and the mechanisms are related to the protection of liver cells, anti-oxidation and anti-inflammation. This paper discusses the protective effects of the effective components of traditional Chinese medicine against liver injury and liver fibrosis and the mechanisms involved, with an aim to promote the development of therapeutic drugs for liver injury and liver fibrosis.
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19
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Zhang L, Ren F, Zhang X, Wang X, Shi H, Zhou L, Zheng S, Chen Y, Chen D, Li L, Zhao C, Duan Z. Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure. Dis Model Mech 2016; 9:799-809. [PMID: 27482818 PMCID: PMC4958306 DOI: 10.1242/dmm.023242] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 04/28/2016] [Indexed: 12/25/2022] Open
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF.
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Affiliation(s)
- Li Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang 050051, China Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Feng Ren
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Xiangying Zhang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Xinxin Wang
- Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Hongbo Shi
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Li Zhou
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Sujun Zheng
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yu Chen
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Liying Li
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Caiyan Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang 050051, China
| | - Zhongping Duan
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
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Manka P, Verheyen J, Gerken G, Canbay A. Liver Failure due to Acute Viral Hepatitis (A-E). Visc Med 2016; 32:80-5. [PMID: 27413724 PMCID: PMC4926881 DOI: 10.1159/000444915] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Viral hepatitis is still one of the key causes of acute liver failure (ALF) in the world. METHODS A selective literature search of the PubMed database was conducted, including current studies, reviews, meta-analyses, and guidelines. We obtained an overview of ALF due to viral hepatitis in terms of epidemiology, course, and treatment options. RESULTS Most fulminant viral courses are reported after infection with hepatitis A, B, and B/D, but not with hepatitis C. Hepatitis E is also known to cause ALF but has not gained much attention in recent years. However, more and more autochthonous hepatitis E virus infections have been recently observed in Europe. Reactivation of hepatitis B virus (HBV) under immunosuppressive conditions, such as after intensive chemotherapy, is also an increasing problem. For most viral-induced cases of ALF, liver transplantation represented the only therapeutic option in the past. Today, immediate treatment of HBV-induced ALF with nucleotide or nucleoside analogs is well tolerated and beneficially affects the course of the disease. CONCLUSION Although numbers in Western European countries are decreasing rapidly, reliable diagnostic screening for hepatitis A-E is necessary to identify the etiology and to determine those most at risk of developing ALF.
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Affiliation(s)
- Paul Manka
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
- Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK
- Division of Transplantation Immunology and Mucosal Biology, King's College, London, UK
| | - Jens Verheyen
- Institute of Virology, University Hospital, University Duisburg-Essen, Essen, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Ali Canbay
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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21
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Role of TLR4-Mediated PI3K/AKT/GSK-3β Signaling Pathway in Apoptosis of Rat Hepatocytes. BIOMED RESEARCH INTERNATIONAL 2015; 2015:631326. [PMID: 26770978 PMCID: PMC4685073 DOI: 10.1155/2015/631326] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/09/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023]
Abstract
We investigated the mechanism of the Toll-like receptor 4- (TLR4-) mediated PI3K/AKT/GSK-3β signaling pathway in rat hepatocytes apoptosis induced by LPS. The cultured rat hepatocytes were treated with LPS alone or first pretreated with TLR4 inhibitor, AKT inhibitor, and GSK-3β inhibitor, respectively, and then stimulated with the same dose of LPS. Cell viability, cell apoptotic rate, and apoptosis morphology were assessed; the level of P-AKTSer473, P-GSK-3βSer9, and active Caspase-3 and the ratio of Bax/Bcl-2 were evaluated. The results indicated that cell viability decreased, while cell apoptotic rate increased with time after LPS stimulation. The expression of P-AKTSer473 and P-GSK-3βSer9 in the LPS group decreased compared with the control, while the level of active Caspase-3 and the ratio of Bax/Bcl-2 were significantly increased. These effects were attenuated by pretreatment with CLI-095. In addition, the apoptotic ratio decreased after pretreatment with LiCl but increased following pretreatment with LY294002. The expression of P-AKTSer473 further decreased following pretreatment with LY294002 and the expression of P-GSK-3βSer9 increased following pretreatment with LiCl. Moreover, pretreatment with CLI-095 weakened LPS-induced nuclear translocation of GSK-3β. Our findings suggest that the TLR4-mediated PI3K/AKT/GSK-3β signaling pathway is present in rat hepatocytes and participates in apoptosis of BRL-3A cells.
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22
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Matsushita Y, Ishigami M, Matsubara K, Kondo M, Wakayama H, Goto H, Ueda M, Yamamoto A. Multifaceted therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for acute liver failure in rats. J Tissue Eng Regen Med 2015; 11:1888-1896. [DOI: 10.1002/term.2086] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Revised: 05/06/2015] [Accepted: 07/14/2015] [Indexed: 12/13/2022]
Affiliation(s)
- Yoshihiro Matsushita
- Department of Oral and Maxillofacial Surgery; Nagoya University Graduate School of Medicine; Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology; Nagoya University Graduate School of Medicine; Japan
| | - Kohki Matsubara
- Department of Oral and Maxillofacial Surgery; Nagoya University Graduate School of Medicine; Japan
| | - Megumi Kondo
- Department of Oral and Maxillofacial Surgery; Nagoya University Graduate School of Medicine; Japan
| | - Hirotaka Wakayama
- Department of Oral and Maxillofacial Surgery; Nagoya University Graduate School of Medicine; Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology; Nagoya University Graduate School of Medicine; Japan
| | - Minoru Ueda
- Department of Oral and Maxillofacial Surgery; Nagoya University Graduate School of Medicine; Japan
| | - Akihito Yamamoto
- Department of Oral and Maxillofacial Surgery; Nagoya University Graduate School of Medicine; Japan
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Endoplasmic Reticulum Stress-Activated Glycogen Synthase Kinase 3β Aggravates Liver Inflammation and Hepatotoxicity in Mice with Acute Liver Failure. Inflammation 2015; 38:1151-65. [DOI: 10.1007/s10753-014-0080-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Duarte S, Baber J, Fujii T, Coito AJ. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol 2015; 44-46:147-56. [PMID: 25599939 PMCID: PMC4495728 DOI: 10.1016/j.matbio.2015.01.004] [Citation(s) in RCA: 351] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 01/09/2015] [Accepted: 01/10/2015] [Indexed: 01/18/2023]
Abstract
The liver is a large highly vascularized organ with a central function in metabolic homeostasis, detoxification, and immunity. Due to its roles, the liver is frequently exposed to various insults which can cause cell death and hepatic dysfunction. Alternatively, the liver has a remarkable ability to self-repair and regenerate after injury. Liver injury and regeneration have both been linked to complex extracellular matrix (ECM) related pathways. While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases. Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation. MMPs not only remodel the ECM, but also regulate immune responses. In this review, we highlight some of the MMP-attributed roles in acute and chronic liver injury and emphasize the need for further experimentation to better understand their functions during hepatic physiological conditions and disease progression.
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Affiliation(s)
- Sergio Duarte
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - John Baber
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Takehiro Fujii
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Ana J Coito
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
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Hu C, Shen S, Zhang A, Ren B, Lin F. The liver protective effect of methylprednisolone on a new experimental acute-on-chronic liver failure model in rats. Dig Liver Dis 2014; 46:928-35. [PMID: 25022338 DOI: 10.1016/j.dld.2014.06.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/24/2014] [Accepted: 06/18/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure is a severe, life-threatening entity and the comprehension of this disease is incomplete. Currently, a reasonable surgical model of acute-on-chronic liver failure is still lacking. The aim of this study was to establish a new model of acute-on-chronic liver failure in rats and to investigate the protective effects of methylprednisolone on this model. METHODS An obstructive jaundice model in rats was established. Two weeks later, the animals were subjected to a choledochoduodenostomy and a reduced-size hepatic ischaemia/reperfusion injury. Animals were randomly divided into a control group, a methylprednisolone injected via the tail vein group and a methylprednisolone injected via the portal vein group. The survival rates and serum levels of alanine transaminase, aspartate aminotransferase, total bilirubin, tumour necrosis factor alpha, and interferon gamma of the rats were measured and the pathological changes in liver tissues were observed. RESULTS The survival rate was significantly improved in the methylprednisolone treatment groups. Serum levels of the biochemical indexes were the lowest in the portal vein injection group. Liver tissues under microscopy presented severe pathological injury in the control group. CONCLUSION This model could be useful for further research into acute-on-chronic liver failure and methylprednisolone may be a potential therapeutic agent for this disease.
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Affiliation(s)
- Chao Hu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Shiqiang Shen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
| | - Aimin Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Bo Ren
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Fusheng Lin
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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Jiao M, Ren F, Zhou L, Zhang X, Zhang L, Wen T, Wei L, Wang X, Shi H, Bai L, Zhang X, Zheng S, Zhang J, Chen Y, Han Y, Zhao C, Duan Z. Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway. Cell Death Dis 2014; 5:e1397. [PMID: 25165883 PMCID: PMC4454331 DOI: 10.1038/cddis.2014.361] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Revised: 07/19/2014] [Accepted: 07/21/2014] [Indexed: 12/11/2022]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.
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Affiliation(s)
- M Jiao
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - F Ren
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - L Zhou
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - X Zhang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - L Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - T Wen
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - L Wei
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - X Wang
- Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - H Shi
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - L Bai
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - X Zhang
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - S Zheng
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - J Zhang
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Y Chen
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Y Han
- Sichuan University, The College of Life Sciences, Chengdu, China
| | - C Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Z Duan
- Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Jin YJ, Lee JW, Park SW, Lee JI, Lee DH, Kim YS, Cho SG, Jeon YS, Lee KY, Ahn SI. Survival outcome of patients with spontaneously ruptured hepatocellular carcinoma treated surgically or by transarterial embolization. World J Gastroenterol 2013; 19:4537-4544. [PMID: 23901230 PMCID: PMC3725379 DOI: 10.3748/wjg.v19.i28.4537] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 03/27/2013] [Accepted: 06/10/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate clinical outcomes of patients that underwent surgery, transarterial embolization (TAE), or supportive care for spontaneously ruptured hepatocellular carcinoma (HCC).
METHODS: A consecutive 54 patients who diagnosed as spontaneously ruptured HCC at our institution between 2003 and 2012 were retrospectively enrolled. HCC was diagnosed based on the diagnostic guidelines issued by the 2005 American Association for the Study of Liver Diseases. HCC rupture was defined as disruption of the peritumoral liver capsule with enhanced fluid collection in the perihepatic area adjacent to the HCC by dynamic liver computed tomography, and when abdominal paracentesis showed an ascitic red blood cell count of > 50000 mm3/mL in bloody fluid.
RESULTS: Of the 54 patients, 6 (11.1%) underwent surgery, 25 (46.3%) TAE, and 23 (42.6%) supportive care. The 2-, 4- and 6-mo cumulative survival rates at 2, 4 and 6 mo were significantly higher in the surgery (60%, 60% and 60%) or TAE (36%, 20% and 20%) groups than in the supportive care group (8.7%, 0% and 0%), respectively (each, P < 0.01), and tended to be higher in the surgical group than in the TAE group. Multivariate analysis showed that serum bilirubin (HR = 1.09, P < 0.01), creatinine (HR = 1.46, P = 0.04), and vasopressor requirement (HR = 2.37, P = 0.02) were significantly associated with post-treatment mortality, whereas surgery (HR = 0.41, P < 0.01), and TAE (HR = 0.13, P = 0.01) were inversely associated with post-treatment mortality.
CONCLUSION: Post-treatment survival after surgery or TAE was found to be better than after supportive care, and surgery tended to provide better survival benefit than TAE.
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Sundaram V, Shneider BL, Dhawan A, Ng VL, Im K, Belle S, Squires RH. King's College Hospital Criteria for non-acetaminophen induced acute liver failure in an international cohort of children. J Pediatr 2013; 162:319-23.e1. [PMID: 22906509 PMCID: PMC3504621 DOI: 10.1016/j.jpeds.2012.07.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Revised: 05/09/2012] [Accepted: 07/05/2012] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To validate King's College Hospital criteria (KCHC) in children with non-acetaminophen induced pediatric acute liver failure (PALF) and to determine whether re-optimizing the KCHC would improve predictive accuracy. STUDY DESIGN We used the PALF study group database. Primary outcomes were survival without liver transplantation vs death at 21 days following enrollment. Classification and regression tree analysis was used to determine if modification of KCHC parameters would improve classification of death vs survival. RESULTS Among 163 patients who met KCHC, 54 patients (33.1%) died within 21 days. Sensitivity of KCHC in this cohort was significantly lower than in the original study (61% vs 91%, P = .002), and specificity did not differ significantly. The positive predictive value (PPV) and negative predictive value (NPV) of KCHC for this cohort was 33% and 88% respectively. Classification and regression tree analysis yielded the following optimized parameters to predict death: grade 2-4 encephalopathy, international normalized ratio >4.02, and total bilirubin >2.02 mg/dL. These parameters did not improve PPV, but NPV was significantly better (88% vs 92%, P < .0001). CONCLUSIONS KCHC does not reliably predict death in PALF. With a PPV of 33%, twice as many participants who met KCHC recovered spontaneously than died, indicating that using KCHC may cause over utilization of liver transplantation. Re-optimized cutpoints for KCHC parameters improved NPV, but not PPV. Parameters beyond the KCHC should be evaluated to create a predictive model for PALF.
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Affiliation(s)
- Vinay Sundaram
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | - Benjamin L. Shneider
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | - Anil Dhawan
- Paediatric Liver Center, King’s College Hospital, London, United Kingdom
| | - Vicky L. Ng
- Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, Toronto, ON, Canada
| | - Kyungah Im
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Steven Belle
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Robert H. Squires
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA
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Villano G, Lunardi F, Turato C, Schiff S, Tono N, Campagna F, Gatta A, Amodio P, Calabrese F, Pontisso P. Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure. Exp Biol Med (Maywood) 2012; 237:1474-82. [DOI: 10.1258/ebm.2012.012135] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Acute liver failure (ALF) is characterized by severe neurological complications, known as acute hepatic encephalopathy, where brain ammonia and inflammatory processes play a dominant role. In experimental models of acute liver failure SERPINB3 was found significantly increased in microglia, the intrinsic immune cells of the central nervous system. The aim of the present study was to investigate the extent of brain tissue damage and the inflammatory milieu in experimental acute liver failure using a SERPINB3-transgenic mouse model. C57BL/6J wild-type and transgenic mice were inoculated with acetaminophen or phosphate-buffered saline and sacrificed 20 h postinjection. Proliferation and apoptotic activity were analyzed in brain tissue by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique. The expression of cytokines was analysed in brain and liver tissue by real time polymerase chain reaction and in the corresponding serum samples using a Bio-Plex system. Acetaminophen induced a significantly lower body temperature and shorter survival in transgenic than in wild-type mice, despite liver function was similar in both groups. The brain of transgenic mice, expressing SERPINB3 positivity in microglia, showed increased glial cell number, associated to significant lower apoptotic death events, compared with wild-type mice. In mice injected with acetaminophen, remarkably higher values of cytokines mRNA were observed in the liver of both groups, with a trend toward higher values in transgenic animals. In brain tissue similar increase of tumor necrosis factor-αwas detected in transgenic and wild-type mice, while IL-10 mRNA increased only in the wild-type group. A remarkable increase of circulating Th1 cytokines was detected in serum of transgenic mice, while in the wild-type group they remained rather unchanged. These figures were associated with lower levels of granulocyte macropage colony-stimulating factor, despite similar increase of IL-10 values in both groups. In conclusion, in acute liver failure SERPINB3 determines an enhanced inflammatory background, mainly mediated by higher levels of Th1 proinflammatory cytokines.
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Affiliation(s)
- Gianmarco Villano
- Clinica Medica 5, Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova
| | - Francesca Lunardi
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Via Gabelli, 61 - 35128 Padova
| | - Cristian Turato
- Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata, 64-35128 Padova, Italy
| | - Sami Schiff
- Clinica Medica 5, Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova
| | - Natascia Tono
- Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata, 64-35128 Padova, Italy
| | - Francesca Campagna
- Clinica Medica 5, Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova
| | - Angelo Gatta
- Clinica Medica 5, Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova
| | - Piero Amodio
- Clinica Medica 5, Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Via Gabelli, 61 - 35128 Padova
| | - Patrizia Pontisso
- Clinica Medica 5, Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova
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Mouloudi E, Vasiliadis T, Aslanidis T, Karapanagiotou A, Papanikolaou V, Gritsi-Gerogianni N. Preterm Delivery in a Parturient Candidate for Emergency Liver Transplantation After Hepatitis B Virus Infection Related Fulminant Liver Failure. Transplant Proc 2012; 44:2765-7. [DOI: 10.1016/j.transproceed.2012.09.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Jin YJ, Lim YS, Han S, Lee HC, Hwang S, Lee SG. Predicting survival after living and deceased donor liver transplantation in adult patients with acute liver failure. J Gastroenterol 2012; 47:1115-24. [PMID: 22526269 DOI: 10.1007/s00535-012-0570-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Accepted: 02/20/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Post-transplant outcomes for acute liver failure (ALF) are unsatisfactory, and there are debates about the most suitable type of graft. Given the critical shortage of donor organs, accurate assessment of post-transplant outcome in ALF patients is crucial to avoid a futile liver transplantation (LT). METHODS A database of 160 consecutive adult ALF patients who underwent primary LT between 2000 and 2009 in a tertiary LT center was analyzed. RESULTS The most common causes of ALF were hepatitis B virus infection (30%) and herbal/folk medicine use (30%). Thirty-six (22.5%) and 124 (77.5%) patients underwent deceased-donor LT (DDLT) and adult-to-adult living-donor LT (LDLT), respectively. During a median follow-up period of 38 (range 1-132) months, the DDLT and LDLT groups showed similar patient (P = 0.99) and graft (P = 0.97) survival rates. The overall 1- and 3-year patient survival rates were 78.8 and 74.6%, respectively. Five predictors of patient survival were identified by bootstrapping and multivariate analysis: vasopressor requirement, estimated glomerular filtration rate, serum sodium concentration, recipient age, and donor age, at the time of transplant. By summing scores weighted in each of these predictor categories, we designed a prognostic scoring system (scores from -2 to 20) that estimated 1-year post-transplant mortality from 0 to 100% (c statistic 0.79). CONCLUSIONS Long-term outcomes after LDLT and DDLT were comparable in adult patients with ALF. A simple prognostic scoring system that includes 5 predictive variables at the time of LT may help estimate post-transplant survival in ALF patients, regardless of the type of transplant.
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Affiliation(s)
- Young-Joo Jin
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 138-736, Republic of Korea
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Abdel-Salam BKA, Sayed AAAA. Beneficial effect of garlic on D-galactosamine and lipopolysaccharide-induced acute hepatic failure in male albino rats. Allergol Immunopathol (Madr) 2012; 40:238-43. [PMID: 22280552 DOI: 10.1016/j.aller.2011.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Revised: 10/05/2011] [Accepted: 10/11/2011] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS Activation of the pro-inflammatory and anti-inflammatory cytokine cascade, including tumour necrosis factor (TNF)-alpha and interleukin (IL)-4, is considered to play an important role in severe liver injury. Kupffer cells, resident macrophages of the liver, activated with lipopolysaccharide (LPS) release pro-inflammatory cytokine. D-Galactosamine (D-GalN), a hepatocyte-specific inhibitor of RNA synthesis, is known to sensitise animals to the lethal effects of LPS. In the present study we seek to reverse some altered parameters, immunological and histopathological, to normal values of rats pre-treated with garlic. METHODS Acute hepatic failure was induced in male albino rats by the intraperitoneal injection of 500 mg D-GalN and 50 μg LPS/kg body weight. Expression levels of TNF-α and IL-4 were detected by ELISA. Leukocytes proliferation was carried out by differential count. For histopathology, liver sections were stained with haematoxylin and eosin. Data were analysed by SPSS program version 13.0. RESULTS The data showed significant increase in the numbers of granulocytes, but with significant decreases in lymphocyte and monocytes proliferation and the TNF-alpha and IL-4 levels in D-GalN/LPS-induced group. Garlic pre-treatment of liver-injured rats induced significant amelioration in the numbers of monocytes and lymphocytes, with significant increase in granulocytes numbers, TNF-α level and IL-4 level. CONCLUSIONS Results of this study revealed that garlic could afford a significant protection in the alleviation of D-GalN/LPS-induced hepatocellular injury.
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Eftekhari MH, Ershad M, Oryan A. Hepatoprotective effects of soy protein isolate against dimethylnitrosamine-induced acute liver injury in Sprague Dawley rat. MEDITERRANEAN JOURNAL OF NUTRITION AND METABOLISM 2012. [DOI: 10.1007/s12349-012-0099-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Hassan MH, Edfawy M, Mansour A, Hamed AA. Antioxidant and antiapoptotic effects of capsaicin against carbon tetrachloride-induced hepatotoxicity in rats. Toxicol Ind Health 2011; 28:428-38. [DOI: 10.1177/0748233711413801] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The aim of the study was to evaluate the potential hepatoprotective utility of capsaicin against carbon tetrachloride (CCl4)-induced liver injury and to explore the possible mechanisms whereby this agent mediated its beneficial effects. We randomized 40 rats into four groups for treatment with corn oil, CCl4, capsaicin and both CCl4 and capsaicin, respectively, for 8 weeks. At the end of the experiment, blood samples were collected and used for determination of aspartylaminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin, while the liver tissues were subjected to hematoxylin and eosin examination; evaluation of malondialdehyde (MDA), reduced glutathione (GSH) and active caspase-3 contents; and evaluation of superoxide dismutase (SOD), catalase (CAT) and glutathione- S-transferase (GST) activities. Animals treated with CCl4 exhibited significant elevation in AST, ALT, total bilirubin and caspase-3 and exhibited significant decrease in activities of SOD, CAT, GST and GSH contents. The combination (both capsaicin and CCl4) group has preserved the liver histology, liver enzymes and bilirubin close to normal, exhibited significant induction in the activities of CAT, SOD and GST, increased the liver content of GSH and active caspase-3 and conversely showed significant decrease in liver MDA content compared to CCl4 challenged rats. Capsaicin confers an appealing hepatoprotective effect which might be explained partially via diminishing the generation of MDA, induction of antioxidant systems and inhibition of active caspase-3.
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Affiliation(s)
- Memy H Hassan
- Department of Pharmacy, Faculty of Health Sciences, Taibah University, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azahr University, Egypt
| | - Mohamed Edfawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Egypt
| | - Ahmed Mansour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azahr University, Egypt
| | - Abdel-Aziz Hamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azahr University, Egypt
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Zhang L, Kang W, Lei Y, Han Q, Zhang G, Lv Y, Li Z, Lou S, Liu Z. Granulocyte colony-stimulating factor treatment ameliorates liver injury and improves survival in rats with D-galactosamine-induced acute liver failure. Toxicol Lett 2011; 204:92-99. [PMID: 21550386 DOI: 10.1016/j.toxlet.2011.04.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 04/14/2011] [Accepted: 04/19/2011] [Indexed: 12/14/2022]
Abstract
Only liver transplantation is currently available therapy for the patients with acute liver failure (ALF). This study was designed to determine whether administration of granulocyte colony-stimulating factor (G-CSF) has therapeutic efficacy in animals with ALF. Female Sprague-Dawley (SD) rats were intraperitoneally injected with a single dose of d-galactosamine (d-GalN, 1.4g/kg) to induce ALF. After 2h, the rats were randomized to receive G-CSF (50μg/kg/day), or saline vehicle injection for 5 days. Rats were observed for survival and assessed for liver injury by serum alanine transaminase (ALT) measurement and histological analysis. CD34+ cells in bone marrow were assessed by flow cytometry. CD34+ cells and Ki-67+ hepatocytes in liver tissue were evaluated by immunohistochemistry. In the ALF model, 5-day survival after d-GalN injection was 33.3% (10/30), while G-CSF administration following d-GalN resulted in 53.3% (16/30) survival (p=0.027). G-CSF treated rats had lower ALT level and less hepatic injury compared with saline vehicle rats. The increases of CD34+ cells in bone marrow and liver tissue and Ki-67+ cells in liver tissue in G-CSF treated rats were higher than those in saline rats. No correlation was observed between CD34+ cells and Ki-67+ hepatocytes in liver tissue in both G-CSF and vehicle rats. It is suggested that G-CSF increases survival rate, decreases liver injury and enhances hepatocyte proliferation in rats with d-GalN-induced ALF possibly through actions including but not limiting to CD34+ cell mobilization, and that G-CSF may be of potential value in treating ALF.
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Affiliation(s)
- Lei Zhang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, #277 Yanta West Road, Xi'an 710061, Shaanxi Province, People's Republic of China
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Al Sibae MR, Cappell MS. Accuracy of MELD scores in predicting mortality in decompensated cirrhosis from variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, or acute liver failure as well as mortality after non-transplant surgery or TIPS. Dig Dis Sci 2011; 56:977-987. [PMID: 20844956 DOI: 10.1007/s10620-010-1390-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Accepted: 08/05/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND To systematically review literature on use of model for end-stage liver disease (MELD) score to determine severity and prognosis of liver disease in various clinical situations and to evaluate its use in decisions regarding therapeutic interventions. METHODS Computerized literature searches using key medical terms; review of authors' extensive files on this subject; and personal clinical experience. RESULTS The MELD score, a prospectively developed and validated scale for severity of end-stage liver disease, utilizes serum bilirubin, serum creatinine, and international normalized ratio to predict mortality in cirrhotic patients. It has proven clinically useful in increasingly varied clinical situations. The United Network for Organ Sharing uses MELD scores, with bonus points assigned for hepatocellular cancer, to prioritize allocation of deceased donor livers for liver transplantation. This work reviews recent data demonstrating that MELD scores relatively accurately predict mortality in patients with variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, and acute liver failure, as well as assess risks of non-liver transplantation surgery or transjugular intrahepatic portosystemic shunts in cirrhotic patients. MELD scores fail to predict mortality in about 15% of patients with end-stage liver disease. Incorporation of additional parameters, including serum sodium level, serum albumin level, glucose intolerance, or APACHE II score, may potentially improve prognostic accuracy. CONCLUSIONS MELD scores relatively accurately assess severity of liver disease and prognosis in patients with advanced liver disease in general, and in patients with individual complications of liver disease. It is useful in making decisions on potential therapies. Incorporating additional parameters may further improve its prognostic accuracy.
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Affiliation(s)
- Mohamad R Al Sibae
- Division of Transplantation, Department of Surgery, William Beaumont Hospital, Royal Oak, MI 48073, USA
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Dechêne A, Sowa JP, Gieseler RK, Jochum C, Bechmann LP, El Fouly A, Schlattjan M, Saner F, Baba HA, Paul A, Dries V, Odenthal M, Gerken G, Friedman SL, Canbay A. Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Hepatology 2010; 52:1008-16. [PMID: 20684020 DOI: 10.1002/hep.23754] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
UNLABELLED Acute liver failure (ALF) is associated with massive short-term cell death, whereas chronic liver injury is accompanied by continuous cell death. Hepatic stellate cells (HSCs) contribute to tissue repair and liver fibrosis in chronic liver injury, although their role in ALF remains unexplained. Twenty-nine patients (median age = 43 years, 17 females and 12 males) with ALF according to the Acute Liver Failure Study Group criteria were included. Upon the diagnosis of ALF and after 7 days, we determined liver stiffness (LS) with FibroScan, standard laboratory parameters, and serum levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, hyaluronic acid, and markers of overall cell death (M65) and apoptosis (M30). Stellate cell activation and progenitor response were analyzed immunohistochemically in biopsy samples of 12 patients with alpha-smooth muscle actin (alpha-SMA), keratin-17, and keratin-19 staining, respectively. Cell death markers (M30 level = 2243 +/- 559.6 U/L, M65 level = 3732 +/- 839.9 U/L) and fibrosis markers (TIMP-1 level = 629.9 +/- 69.4 U/mL, MMP-2 level = 264 +/- 32.5 U/mL, hyaluronic acid level = 438.5 +/- 69.3 microg/mL) were significantly increased in patients versus healthy controls. This was paralleled by collagen deposition, elevated alpha-SMA expression, and higher LS (25.6 +/- 3.0 kPa). ALF was associated with ductular progenitor proliferation. CONCLUSION Our results demonstrate HSC activation and a progenitor response in ALF. Positive correlations between LS, the degree of liver cell damage, and the intensity of HSC activation suggest that fibrosis is a response to ALF in an attempt to repair damaged tissue.
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Affiliation(s)
- Alexander Dechêne
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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Bémeur C, Vaquero J, Desjardins P, Butterworth RF. N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis 2010; 25:241-9. [PMID: 20431929 DOI: 10.1007/s11011-010-9201-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Accepted: 11/04/2009] [Indexed: 12/11/2022]
Abstract
N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2 g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.
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Nevens F, Katoonizadeh A, Roskams T. Hepatic progenitor cells in acute and chronic liver disease: Clinical aspects. Arab J Gastroenterol 2010. [DOI: 10.1016/j.ajg.2009.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Bémeur C, Desjardins P, Butterworth RF. Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse. Metab Brain Dis 2010; 25:23-9. [PMID: 20198438 DOI: 10.1007/s11011-010-9186-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2009] [Accepted: 01/06/2010] [Indexed: 12/19/2022]
Abstract
Previous studies have demonstrated protective effects of mild hypothermia following acetaminophen (APAP)-induced acute liver failure (ALF). However, effects of this treatment in ALF due to other toxins have not yet been fully investigated. In the present study, the effects of mild hypothermia in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines were assessed in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stages of encephalopathy in parallel with AOM mice maintained mildly hypothermic (35 degrees C). AOM treatment led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels, and brain GSH/GSSG ratios as well as selective increases in expression of plasma proinflammatory cytokines. Mild hypothermia resulted in reduced hepatic damage, improvement in neurological function, normalization of glutathione levels, and selective attenuation in expression of circulating proinflammatory cytokines. These findings demonstrate that the beneficial effects of mild hypothermia in experimental AOM-induced ALF involve both antioxidant and anti-inflammatory mechanisms.
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Affiliation(s)
- Chantal Bémeur
- Neuroscience Research Unit, St-Luc Hospital (CHUM), University of Montreal, 1058 St-Denis Street, Montreal, Quebec, Canada, H2X 3J4
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Wu YL, Lian LH, Jiang YZ, Nan JX. Hepatoprotective effects of salidroside on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice. J Pharm Pharmacol 2010. [DOI: 10.1211/jpp.61.10.0015] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Abstract
Objectives
The aim was to investigate the protective effect of salidroside isolated from Rhodiola sachalinensis A. Bor. (Crassulaceae) on d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.
Methods
Hepatotoxicity was induced by an intraperitoneal injection of d-galactosamine (700 mg/kg) and lipopolysaccharide (10 μg/kg); salidroside (20, 50 and 100 mg/kg) was administered intraperitoneally 1 h before induction of hepatoxicity. Liver injury was assessed biochemically and histologically.
Key findings
Salidroside attenuated the induced acute increase in serum aspartate aminotransferase and alanine aminotransferase activities, and levels of tumour necrosis factor-alpha levels and serum nitric oxide. It restored depleted hepatic glutathione, superoxide dismutase, catalase and glutathione peroxidase activities, decreased malondialdehyde levels and considerably reduced histopathological changes. Histopathological, immunohistochemical and Western blot analyses also demonstrated that salidroside could reduce the appearance of necrotic regions and expression of caspase-3 and hypoxia-inducible factor-1α in liver tissue.
Conclusions
Salidroside protected liver tissue from the oxidative stress elicited by d-galactosamine and lipopolysaccharide. The hepatoprotective mechanism of salidroside appear to be related to antioxidant activity and inhibition of hypoxia-inducible factor-1α.
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Affiliation(s)
- Yan-Ling Wu
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Jilin Province, China
| | - Li-Hua Lian
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Jilin Province, China
| | - Ying-Zi Jiang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Jilin Province, China
| | - Ji-Xing Nan
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Jilin Province, China
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Kitzberger R, Funk GC, Holzinger U, Miehsler W, Kramer L, Kaider A, Ferenci P, Madl C. Severity of organ failure is an independent predictor of intracranial hypertension in acute liver failure. Clin Gastroenterol Hepatol 2009; 7:1000-1006. [PMID: 19465152 DOI: 10.1016/j.cgh.2009.05.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2008] [Revised: 04/05/2009] [Accepted: 05/13/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Ionized ammonia (NH(3)) and partial pressure of the gaseous ammonia (pNH(3)) are associated with hepatic encephalopathy and intracranial hypertension in patients with acute liver failure; NH(3) is also believed to contribute to extrahepatic organ failure. We investigated whether the severity of organ failure was associated with intracranial hypertension and evaluated the correlation between NH(3) and pNH(3) and grade of hepatic encephalopathy. METHODS In 87 patients with acute liver failure admitted to the intensive care unit, we simultaneously evaluated arterial ammonia, pNH(3), clinical grade of hepatic encephalopathy, the sequential organ failure assessment score (SOFA score), and evidence of intracranial hypertension. RESULTS In comparing patients with intracranial hypertension (n = 37) with patients without intracranial hypertension (n = 50), the highest NH(3) and pNH(3) levels and SOFA scores before onset of intracranial hypertension were independent predictors of intracranial hypertension (P < .001). Among patients with NH(3) levels less than 146 mumol/L, those with intracranial hypertension had a higher SOFA score than those without intracranial hypertension (median, 10 vs 5.5; P = .004), despite the patients' similar levels of NH(3). NH(3) (r = 0.68, P < .0001) and pNH(3) (r = 0.78, P < .0001) both correlated with grade of hepatic encephalopathy. However, in multiple regression analysis, only pNH(3) (P < .0001) was shown to be a significant independent parameter for predicting grade of hepatic encephalopathy (P = .27). CONCLUSIONS SOFA score and ammonia levels are independent predictors of intracranial hypertension. In patients with acute liver failure admitted to the intensive care unit, pNH(3) level is a better predictor of clinical grade of hepatic encephalopathy than arterial NH(3) level.
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Affiliation(s)
- Reinhard Kitzberger
- Department of Gastroenterology, Hepatology and Medical Intensive Care Medicine, Medical University Hospital Vienna, Vienna, Austria.
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Naringenin-loaded nanoparticles improve the physicochemical properties and the hepatoprotective effects of naringenin in orally-administered rats with CCl(4)-induced acute liver failure. Pharm Res 2008; 26:893-902. [PMID: 19034626 DOI: 10.1007/s11095-008-9791-0] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Accepted: 11/07/2008] [Indexed: 02/07/2023]
Abstract
PURPOSE A novel naringenin-loaded nanoparticles system (NARN) was developed to resolve the restricted bioavailability of naringenin (NAR) and to enhance its hepatoprotective effects in vivo on oral administration. MATERIALS AND METHODS Physicochemical characterizations of NARN included assessment of particle size and morphology, powder X-ray diffraction, fourier transform infrared spectroscopy, and dissolution study. In addition, to evaluate its bioactivities and its oral treatment potential against liver injuries, we compared the hepatoprotective, antioxidant, and antiapoptotic effects of NARN and NAR on carbon tetrachloride (CCl(4))-induced hepatotoxicity in rats. RESULTS NARN had a significantly higher release rate than NAR and improved its solubility. NARN also exhibited more liver-protective effects compared to NAR with considerable reduction in liver function index and lipid peroxidation, in conjunction to a substantial increase in the levels of the antioxidant enzymes (P < 0.05). Moreover, NARN was able to significantly inhibit the activation of caspase-3, -8, and -9 signaling, whereas NAR only markedly inhibited caspase-3 and -9 (P < 0.05). CONCLUSION NARN effectively improved the release of NAR which resulted in more hepatoprotective effects mediated by its antioxidant and antiapoptotic properties. These observations also suggest that nanoformulation can improve the free drug's bioactivity on oral administration.
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Abstract
Acute liver failure caused by viruses, drugs, or liver resection, is marked by a massive degree of hepatocyte apoptosis and impaired hepatocyte proliferation, the mechanisms of which, however, still remain to be understood. The choice between life and death is associated with events in regulation of the immune system. The liver is continuously exposed to a large antigenic load that includes pathogens, toxins and dietary antigens. Bacterial toxins, including endotoxin and staphylococcal enterotoxin, have been implicated in the pathogenesis of multi-organ failure associated with liver damage through production of cytokines and chemokines. Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Among pro-inflammatory mediators, tumor necrosis factor-alpha (TNF-alpha)/TNF receptor (TNFR) systems play central roles in the physiological regulation of apoptosis as well as inflammation and immunity. These pleiotropic biological effects of TNF-alpha result from its ability to initiate different intracellular signaling pathways, which induce both pro-apoptotic and anti-apoptotic molecules. Hepatocytes appear to be poorly responsive to pro-apoptotic stimuli by TNF-alpha. Tumor necrosis factor-alpha, however, induces excessive hepatocyte apoptosis, once cells are sensitized by D-galactosamine or actinomycin D, suggesting that TNF-alpha itself also induces molecules that protect cells from apoptosis by TNF-alpha. Besides the apoptosis-inducing signal, the binding of TNF-alpha to TNFR1 triggers a series of intracellular events that result in the activation of nuclear factor-kappaB (NF-kappaB), phosphatidylinositol 3-kinase (PI3K)/Akt, and c-Jun NH(2)-terminal kinase (JNK). Inhibition of NF-kappaB may be a two-edged sword against liver injury, which inhibits pro-inflammatory gene expression in leukocytes and causes the sensitization of hepatocytes to TNF-alpha-induced apoptosis. A variety of mechanisms exist to modulate the activity of intracellular molecules and thereby affect the ultimate outcome of a liver cell's fate.
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Affiliation(s)
- Masahito Nagaki
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan
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Tran TT, Groben P, Pisetsky DS. The release of DNA into the plasma of mice following hepatic cell death by apoptosis and necrosis. Biomarkers 2008; 13:184-200. [DOI: 10.1080/13547500701791719] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Kitazawa T, Tsujimoto T, Kawaratani H, Fujimoto M, Fukui H. Expression of Toll-like receptor 4 in various organs in rats with D-galactosamine-induced acute hepatic failure. J Gastroenterol Hepatol 2008; 23:e494-8. [PMID: 18070011 DOI: 10.1111/j.1440-1746.2007.05246.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Activation of the pro-inflammatory cytokine cascade, including tumor necrosis factor alpha (TNF-alpha) is considered to play an important role in the pathophysiology and clinical outcome of severe liver injury. Kupffer cells, resident macrophages of the liver, have a transmembrane protein Toll-like receptor 4 (TLR4), which recognizes endotoxin (lipopolysaccharide; LPS) or LPS-CD14 complex and mediates macrophage activation and pro-inflammatory cytokine release. D-Galactosamine (GalN), a hepatocyte-specific inhibitor of RNA synthesis, is known to sensitize animals to the lethal effects of LPS and TNF-alpha. In the present study we seek to address TLR4-signaling in the development of GalN-induced acute hepatic failure (AHF) and explore the expression of TLR4 mRNA as compared to TNF-alpha mRNA and CD14 mRNA in the liver, spleen and lung of rats with GalN-induced hepatitis. METHODS AHF was induced in male Wistar rats by the intraperitoneal injection of 1 g/kg bodyweight GalN. Expression levels of TNF-alpha, TLR4 and CD14 mRNA in the whole liver, spleen and lung of rats were detected by reverse transcription-polymerase chain reaction analysis. RESULTS Expression level of TLR4 mRNA in the liver of rats with GalN-induced AHF was increased parallel with that of TNF-alpha and CD14 mRNA as compared to the control rats. However, expression levels of TNF-alpha, TLR4 and CD14 mRNA in the whole spleen and lung were not different between rats with AHF and control. CONCLUSIONS There may be a difference of stimulatory effects of endotoxin on the innate immunity between the liver and other organs of rats with GalN-induced AHF.
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Affiliation(s)
- Toshiyuki Kitazawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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Mechanism of the suppression against d-galactosamine-induced hepatic injury by dietary amino acids in rats. Amino Acids 2008; 37:239-47. [DOI: 10.1007/s00726-008-0139-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2008] [Accepted: 06/23/2008] [Indexed: 01/08/2023]
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Liu LM, Zhang JX, Luo J, Guo HX, Deng H, Chen JY, Sun SL. A role of cell apoptosis in lipopolysaccharide (LPS)-induced nonlethal liver injury in D-galactosamine (D-GalN)-sensitized rats. Dig Dis Sci 2008; 53:1316-1324. [PMID: 17934810 DOI: 10.1007/s10620-007-9994-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2007] [Accepted: 08/20/2007] [Indexed: 02/06/2023]
Abstract
Lipopolysaccharide (LPS) is implicated in the pathology of acute liver injury and can induce lethal liver failure when simultaneously administered with D-galactosamine (D-GalN). At the present time, nonlethal liver failure, the liver injury of clinical implication, is incompletely understood following challenge by low-dose LPS/D-GalN. We report here our investigation of the effects of liver injury following a nonlethal dose LPS/D-GalN and the role of apoptosis in this disorder. Blood biochemistry indexes, including those of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), had risen by 6 h post-LPS/D-GalN injection, reached a peak at 24 h and sustained high levels at 48 h. An abnormal liver appearance was found at 24 and 48 h post-injection. Histopathological changes of hepatic injuries accompanied by hepatocellular death, inflammatory infiltration and hemorrhage began to appear at 6 h and were markedly aggravated at 24 and 48 h. Cell apoptosis was significantly induced by the nonlethal dose LPS/D-GalN challenge, and the apoptotic indexes (AIs) in 24 h- and 48 h-treated rats were approximately 70%, as estimated by the terminal transferase dUTP nick end labeling (TUNEL) assay. The mRNA levels of the inflammatory cytokine IL-1beta rose markedly at 6 h and maintained high levels at 24 and 48 h; however, TNF-alpha levels were normal in the liver tissues of 6-, 24- and 48-h-treated rats. mRNA expression of the damage gene nitric oxide synthase (NOS) was also induced early by the LPS/D-GalN challenge, reaching a peak at 6 h, then gradually decreasing in a stepwise manner; conversely, high expression levels of the apoptosis-inducing gene p53 mRNA were not found in the early post-injection period (6 h) but emerged in the crest-time of liver apoptosis (24 h) and were maintained at this level until the late stage (48 h). We also observed that in 24 h-treated rats, caspase-3, -8, -9 and -12 were markedly activated by LPS/D-GalN challenge. These results suggest that a challenge with low-dose LPS in conjunction with D-GalN can induce nonlethal but marked liver failure, the main morphological feature of which is hepatic apoptosis, which may be associated with a high expression of inducible (i)NOS (early post-injection period) and p53 genes (in the mid and late stages) and at least three apoptosis pathways participate in the pathogenesis.
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Affiliation(s)
- Liang-Ming Liu
- Department of Gastroenterology, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province, China
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Hetz H, Hoetzenecker K, Hacker S, Faybik P, Pollreisz A, Moser B, Roth G, Hoetzenecker W, Lichtenauer M, Klinger M, Krenn CG, Ankersmit HJ. Caspase-cleaved cytokeratin 18 and 20 S proteasome in liver degeneration. J Clin Lab Anal 2007; 21:277-81. [PMID: 17847110 PMCID: PMC6648973 DOI: 10.1002/jcla.20180] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Apoptosis of epithelial hepatocytes plays a pivotal role in acute as well as in chronic liver diseases. The cleavage of cytokeratin-18 (CK-18) by caspases is an early event in the apoptotic process. We therefore sought to investigate serum levels of CK-18 and 20S proteasome in patients with liver cirrhosis, primary graft dysfunction (PDF), and acute liver failure (ALF), and in healthy volunteers. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the concentration of M30, a fragment of CK-18 cleaved at Asp396 (M30 neoantigen), and the concentration of 20S proteasome. Serum levels of the CK-18 neoepitope M30 were significantly increased in ALF, primary graft dysfunction, and liver cirrhosis vs. healthy controls (1,993.6+/-124.7 U/L, 2,238.1+/-235.9 U/L, and 673.6+/-86.5 U/L vs. 66.8+/-29.1 U/L, respectively, P<0.001). Similar results were detected with the evaluation of 20S proteasome (124,014.5+/-13,235.6 ng/mL, 76,993.2+/-15,720.1 ng/mL, and 2,395.9+/-1,098.2 ng/mL vs. 1,074.5+/-259.4 ng/mL, respectively; P<0.001). Detection of CK-18 neoepitope M30 and 20S proteasome may represent a novel marker of tracing apoptotic epithelium, respectively mirroring degenerative liver processes in affected patient population.
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Affiliation(s)
- Hubert Hetz
- Department of Anesthesiology and Intensive Care, General Hospital Vienna, Medical University of Vienna, Austria
| | - Konrad Hoetzenecker
- Department of CT‐Surgery, General Hospital Vienna, Medical University of Vienna, Austria
| | - Stefan Hacker
- Department of CT‐Surgery, General Hospital Vienna, Medical University of Vienna, Austria
| | - Peter Faybik
- Department of Anesthesiology and Intensive Care, General Hospital Vienna, Medical University of Vienna, Austria
| | - Andreas Pollreisz
- Department of CT‐Surgery, General Hospital Vienna, Medical University of Vienna, Austria
| | - Bernhard Moser
- Department of CT‐Surgery, General Hospital Vienna, Medical University of Vienna, Austria
| | - Georg Roth
- Department of Anesthesiology and Intensive Care, General Hospital Vienna, Medical University of Vienna, Austria
| | | | - Michael Lichtenauer
- Department of CT‐Surgery, General Hospital Vienna, Medical University of Vienna, Austria
| | - Markus Klinger
- Department of Surgery, General Hospital Vienna, Medical University of Vienna, Austria
| | - Claus Georg Krenn
- Department of Anesthesiology and Intensive Care, General Hospital Vienna, Medical University of Vienna, Austria
| | - Hendrik Jan Ankersmit
- Department of CT‐Surgery, General Hospital Vienna, Medical University of Vienna, Austria
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