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1
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Krasnenkova SF, Zayratyants OV, Midiber KY, Mikhaleva LM. [Liver pathology in COVID-19]. Arkh Patol 2025; 87:53-59. [PMID: 39943730 DOI: 10.17116/patol20258701153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
The literature review presents an analysis of the pathogenesis and pathological anatomy of liver damage in COVID-19. Liver damage with the steatosis, vascular disorders, mild portal and lobular inflammatory infiltration, cholestasis and clinically - liver failure is observed in majority of the patients with COVID-19. Chronic liver diseases with infection SARS-CoV-2 tend to decompensate, which significantly worsens the prognosis of the disease. Pathogenesis of liver damage in COVID19 is unclear. There was no convincing evidence for the hypothesis of cytotoxicity for hepatocytes or cholangiocytes by SARS-CoV-2. Similar liver morphological changes described by different authors suggest their nonspecific nature and multifactorial pathogenesis related to hypoxia, cytokin storm, systemic inflammatory response syndrome, sepsis and shock, Covid-associated angio- and coagulopathy, as well as drug-induced hepatotoxicity. Further research is needed to clarify the pathogenesis and pathological anatomy of the liver pathology in COVID-19.
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Affiliation(s)
- S F Krasnenkova
- Russian University of Medicine, Moscow, Russia
- Research Institute of Organization of Medicine and Medicine Management, Moscow, Russia
| | - O V Zayratyants
- Russian University of Medicine, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
| | - K Yu Midiber
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
- Peoples' Friendship University of Russia named after Patrice Lumumba, Moscow, Russia
| | - L M Mikhaleva
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
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2
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Zhang Y, Chen S, Tian Y, Fu X. Host factors of SARS-CoV-2 in infection, pathogenesis, and long-term effects. Front Cell Infect Microbiol 2024; 14:1407261. [PMID: 38846354 PMCID: PMC11155306 DOI: 10.3389/fcimb.2024.1407261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/08/2024] [Indexed: 06/09/2024] Open
Abstract
SARS-CoV-2 is the causative virus of the devastating COVID-19 pandemic that results in an unparalleled global health and economic crisis. Despite unprecedented scientific efforts and therapeutic interventions, the fight against COVID-19 continues as the rapid emergence of different SARS-CoV-2 variants of concern and the increasing challenge of long COVID-19, raising a vast demand to understand the pathomechanisms of COVID-19 and its long-term sequelae and develop therapeutic strategies beyond the virus per se. Notably, in addition to the virus itself, the replication cycle of SARS-CoV-2 and clinical severity of COVID-19 is also governed by host factors. In this review, we therefore comprehensively overview the replication cycle and pathogenesis of SARS-CoV-2 from the perspective of host factors and host-virus interactions. We sequentially outline the pathological implications of molecular interactions between host factors and SARS-CoV-2 in multi-organ and multi-system long COVID-19, and summarize current therapeutic strategies and agents targeting host factors for treating these diseases. This knowledge would be key for the identification of new pathophysiological aspects and mechanisms, and the development of actionable therapeutic targets and strategies for tackling COVID-19 and its sequelae.
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Affiliation(s)
| | | | - Yan Tian
- Department of Endocrinology and Metabolism, Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Medical School, West China Hospital and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, Chengdu, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Medical School, West China Hospital and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, Chengdu, China
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3
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Liguori A, Calvez V, D’Ambrosio F, Sciarra A, Marrone G, Biolato M, Grieco A, Gasbarrini A, Alisi A, Miele L. The bidirectional relationship between fatty liver disease and COVID-19. METABOLISM AND TARGET ORGAN DAMAGE 2023; 3. [DOI: 10.20517/mtod.2022.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
COVID-19 and nonalcoholic fatty liver disease (NAFLD) have emerged as global pandemics affecting millions of people worldwide over the past three years. NAFLD is particularly prevalent in individuals with metabolic comorbidities, such as diabetes and obesity, which have been strongly linked to a severe course of Sars-CoV-2 infection. Recently, due to the close association between metabolic abnormalities and NAFLD, the disease has been redefined as metabolic dysfunction-associated fatty liver disease (MAFLD). This review offers an overview of the biological and cellular mechanisms by which COVID-19 can cause liver damage, with a specific focus on the influence of fatty liver in these mechanisms. Additionally, it explores how fatty liver can exacerbate a COVID-19 infection and, conversely, if the presence of COVID-19 may accelerate the development and progression of fatty liver. Finally, the review examines the existing evidence suggesting that NAFLD or MAFLD independently contributes to a heightened severity of COVID-19, while also considering other factors such as age and metabolic comorbidities that may play a role in the disease’s progression.
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4
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Martínez JA, Alonso-Bernáldez M, Martínez-Urbistondo D, Vargas-Nuñez JA, Ramírez de Molina A, Dávalos A, Ramos-Lopez O. Machine learning insights concerning inflammatory and liver-related risk comorbidities in non-communicable and viral diseases. World J Gastroenterol 2022; 28:6230-6248. [PMID: 36504554 PMCID: PMC9730439 DOI: 10.3748/wjg.v28.i44.6230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/07/2022] [Accepted: 11/16/2022] [Indexed: 11/25/2022] Open
Abstract
The liver is a key organ involved in a wide range of functions, whose damage can lead to chronic liver disease (CLD). CLD accounts for more than two million deaths worldwide, becoming a social and economic burden for most countries. Among the different factors that can cause CLD, alcohol abuse, viruses, drug treatments, and unhealthy dietary patterns top the list. These conditions prompt and perpetuate an inflammatory environment and oxidative stress imbalance that favor the development of hepatic fibrogenesis. High stages of fibrosis can eventually lead to cirrhosis or hepatocellular carcinoma (HCC). Despite the advances achieved in this field, new approaches are needed for the prevention, diagnosis, treatment, and prognosis of CLD. In this context, the scientific com-munity is using machine learning (ML) algorithms to integrate and process vast amounts of data with unprecedented performance. ML techniques allow the integration of anthropometric, genetic, clinical, biochemical, dietary, lifestyle and omics data, giving new insights to tackle CLD and bringing personalized medicine a step closer. This review summarizes the investigations where ML techniques have been applied to study new approaches that could be used in inflammatory-related, hepatitis viruses-induced, and coronavirus disease 2019-induced liver damage and enlighten the factors involved in CLD development.
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Affiliation(s)
- J Alfredo Martínez
- Precision Nutrition and Cardiometabolic Health, Madrid Institute of Advanced Studies-Food Institute, Madrid 28049, Spain
| | - Marta Alonso-Bernáldez
- Precision Nutrition and Cardiometabolic Health, Madrid Institute of Advanced Studies-Food Institute, Madrid 28049, Spain
| | | | - Juan A Vargas-Nuñez
- Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Madrid 28222, Majadahonda, Spain
| | - Ana Ramírez de Molina
- Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Madrid 28049, Spain
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute of Advanced Studies-Food Institute, Madrid 28049, Spain
| | - Omar Ramos-Lopez
- Medicine and Psychology School, Autonomous University of Baja California, Tijuana 22390, Baja California, Mexico
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5
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Wu HHL, Athwal VS, Kalra PA, Chinnadurai R. COVID-19 and hepatorenal syndrome. World J Gastroenterol 2022; 28:5666-5678. [PMID: 36338894 PMCID: PMC9627428 DOI: 10.3748/wjg.v28.i39.5666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 09/21/2022] [Accepted: 10/02/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a highly infectious disease which emerged into a global pandemic. Although it primarily causes respiratory symptoms for affected patients, COVID-19 was shown to have multi-organ manifestations. Elevated liver enzymes appear to be commonly observed during the course of COVID-19, and there have been numerous reports of liver injury secondary to COVID-19 infection. It has been established that patients with pre-existing chronic liver disease (CLD) are more likely to have poorer outcomes following COVID-19 infection compared to those without CLD. Co-morbidities such as diabetes, hypertension, obesity, cardiovascular and chronic kidney disease frequently co-exist in individuals living with CLD, and a substantial population may also live with some degree of frailty. The mechanisms of how COVID-19 induces liver injury have been postulated. Hepatorenal syndrome (HRS) is the occurrence of kidney dysfunction in patients with severe CLD/fulminant liver failure in the absence of another identifiable cause, and is usually a marker of severe decompensated liver disease. Select reports of HRS following acute COVID-19 infection have been presented, although the risk factors and pathophysiological mechanisms leading to HRS in COVID-19 infection or following COVID-19 treatment remain largely unestablished due to the relative lack and novelty of published data. Evidence discussing the management of HRS in high-dependency care and intensive care contexts is only emerging. In this article, we provide an overview on the speculative pathophysiological mechanisms of COVID-19 induced HRS and propose strategies for clinical diagnosis and management to optimize outcomes in this scenario.
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Affiliation(s)
- Henry H L Wu
- Renal Research, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney 2065, New South Wales, Australia
| | - Varinder S Athwal
- Faculty of Biology, Medicine & Health (Division of Diabetes, Metabolism & Gastroenterology), The University of Manchester, Manchester M13 9PL, United Kingdom
| | - Philip A Kalra
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, United Kingdom
| | - Rajkumar Chinnadurai
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, United Kingdom
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6
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Chen H, Chen Q. COVID-19 Pandemic: Insights into Interactions between SARS-CoV-2 Infection and MAFLD. Int J Biol Sci 2022; 18:4756-4767. [PMID: 35874945 PMCID: PMC9305262 DOI: 10.7150/ijbs.72461] [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: 02/28/2022] [Accepted: 06/23/2022] [Indexed: 01/08/2023] Open
Abstract
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an ongoing global health pandemic. Since 2019, the pandemic continues to cast a long shadow on all aspects of our lives, bringing huge health and economic burdens to all societies. With our in-depth understanding of COVID-19, from the initial respiratory tract to the later gastrointestinal tract and cardiovascular systems, the multiorgan involvement of this infectious disease has been discovered. Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named nonalcoholic fatty liver disease (NAFLD), is a major health issue closely related to metabolic dysfunctions, affecting a quarter of the world's adult population. The association of COVID-19 with MAFLD has received increasing attention, as MAFLD is a potential risk factor for SARS-CoV-2 infection and severe COVID-19 symptoms. In this review, we provide an update on the interactions between COVID-19 and MAFLD and its underlying mechanisms.
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Affiliation(s)
- Hanfei Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.,Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Qiang Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.,Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.,MOE Frontier Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China
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7
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Chen Y, Xu Y, Zhang K, Shen L, Deng M. Ferroptosis in COVID-19-related liver injury: A potential mechanism and therapeutic target. Front Cell Infect Microbiol 2022; 12:922511. [PMID: 35967872 PMCID: PMC9363633 DOI: 10.3389/fcimb.2022.922511] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/01/2022] [Indexed: 01/08/2023] Open
Abstract
The outbreak and worldwide spread of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a threat to global public health. SARS-CoV-2 infection not only impacts the respiratory system but also causes hepatic injury. Ferroptosis, a distinct iron-dependent form of non-apoptotic cell death, has been investigated in various pathological conditions, such as cancer, ischemia/reperfusion injury, and liver diseases. However, whether ferroptosis takes part in the pathophysiological process of COVID-19-related liver injury has not been evaluated yet. This review highlights the pathological changes in COVID-19-related liver injury and presents ferroptosis as a potential mechanism in the pathological process. Ferroptosis, as a therapeutic target for COVID-19-related liver injury, is also discussed. Discoveries in these areas will improve our understanding of strategies to prevent and treat hepatic injuries caused by COVID-19.
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Affiliation(s)
- Yunqing Chen
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
- *Correspondence: Yunqing Chen,
| | - Yan Xu
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Kan Zhang
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Liang Shen
- Department of Cardiology, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Min Deng
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
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8
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Cai Y, Ye LP, Song YQ, Mao XL, Wang L, Jiang YZ, Que WT, Li SW. Liver injury in COVID-19: Detection, pathogenesis, and treatment. World J Gastroenterol 2021; 27:3022-3036. [PMID: 34168405 PMCID: PMC8192279 DOI: 10.3748/wjg.v27.i22.3022] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/24/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
In the early December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 was first reported in Wuhan, China, followed by an outbreak that spread around the world. Numerous studies have shown that liver injury is common in patients with coronavirus disease 2019 (COVID-19), and may aggravate the severity of the disease. However, the exact cause and specific mechanism of COVID-associated liver injury needs to be elucidated further. In this review, we present an analysis of the clinical features, potential mechanisms, and treatment strategies for liver injury associated with COVID-19. We hope that this review would benefit clinicians in devising better strategies for management of such patients.
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Affiliation(s)
- Yue Cai
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Li-Ping Ye
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Ya-Qi Song
- School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Li Mao
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Li Wang
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010000, Inner Mongolia Autonomous Region, China
| | - Yan-Zhi Jiang
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
| | - Wei-Tao Que
- Department of Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
| | - Shao-Wei Li
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
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9
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Nardo AD, Schneeweiss-Gleixner M, Bakail M, Dixon ED, Lax SF, Trauner M. Pathophysiological mechanisms of liver injury in COVID-19. LIVER INTERNATIONAL : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION FOR THE STUDY OF THE LIVER 2020. [PMID: 33190346 DOI: 10.1111/liv.14730.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a world-wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID-19. Although liver failure does not seem to occur in the absence of pre-existing liver disease, hepatic involvement in COVID-19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID-19 may range from direct infection by SARS-CoV-2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS-CoV-2 hepatic tropism as well as acute and possibly long-term liver injury in COVID-19.
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Affiliation(s)
- Alexander D Nardo
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mathias Schneeweiss-Gleixner
- Medical Intensive Care Unit 13H1. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - May Bakail
- Campus IT, Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Emmanuel D Dixon
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Sigurd F Lax
- Department of Pathology, Hospital Graz II, Academic Teaching Hospital of the Medical University of Graz, Graz, Austria.,School of Medicine, Johannes Kepler University, Linz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Medical Intensive Care Unit 13H1. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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10
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Tiao MM, Lin YJ, Yu HR, Sheen JM, Lin IC, Lai YJ, Tain YL, Huang LT, Tsai CC. Resveratrol ameliorates maternal and post-weaning high-fat diet-induced nonalcoholic fatty liver disease via renin-angiotensin system. Lipids Health Dis 2018; 17:178. [PMID: 30055626 PMCID: PMC6064630 DOI: 10.1186/s12944-018-0824-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/11/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD. METHODS Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120. RESULTS We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group. CONCLUSION Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.
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Affiliation(s)
- Mao-Meng Tiao
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Yu-Ju Lin
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 83301, Taiwan, Republic of China
| | - Hong-Ren Yu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - I-Chun Lin
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Yun-Ju Lai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 83301, Taiwan, Republic of China
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Ching-Chou Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 83301, Taiwan, Republic of China.
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11
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Wu HT, Chuang YW, Huang CP, Chang MH. Loss of angiotensin converting enzyme II (ACE2) accelerates the development of liver injury induced by thioacetamide. Exp Anim 2017; 67:41-49. [PMID: 28845018 PMCID: PMC5814313 DOI: 10.1538/expanim.17-0053] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue
that displays antagonist effects on ACE/angiotensin II (Ang II) axis in renin-angiotensin
system (RAS), could play a protective role against liver damages. The purpose of this
study is to investigate whether inflammation-mediated liver injury could be affected by
ACE2 derived pathways in the RAS. Eight-weeks-old wild-type (WT; C57BL/6) and
Ace2 KO (hemizygous Ace2-/y) male mice were
used to induce liver fibrosis by thioacetamide (TAA) administration (0, 100, and 200 mg/kg
BW). The mice administrated with TAA could be successfully induced liver fibrosis in a
TAA-dose dependent manner. Compared to WT mice, the results show that
Ace2 KO mice have high sensitive, and developed more serious reaction
of hepatic inflammation and fibrosis by TAA administration. The physiological and
pathological examinations demonstrated higher serum aspartate aminotransferase (AST),
alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels, infiltration of
white blood cells and fibrotic lesions within liver in the Ace2 KO mice.
The severe liver damage of Ace2 KO mice were also confirmed by the
evidence of higher expression of hepatic inflammation-related genes (IL-6
and Tnf) and fibrosis-related genes (Col1a1,
Timp1 and Mmp9). Ace2 gene deficiency
could lead to a severe inflammation and collagen remodeling in the liver administrated by
TAA, and the responses lead the pathogenesis of liver fibrosis. Our studies provided the
main messages and favorable study directions of relationship of Ace2 and
liver disease.
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Affiliation(s)
- Hsi-Tien Wu
- Department of BioAgricultural Science, National Chia Yi University, 300 Syuefu Road, Chiayi 60004, Taiwan
| | - Ya-Wen Chuang
- Department of BioAgricultural Science, National Chia Yi University, 300 Syuefu Road, Chiayi 60004, Taiwan
| | - Cheng-Pu Huang
- Department of BioAgricultural Science, National Chia Yi University, 300 Syuefu Road, Chiayi 60004, Taiwan
| | - Ming-Huang Chang
- Department of Veterinary Medicine, National Chia Yi University, 580 Xinmin Road, Chiayi 60054, Taiwan
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12
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Schrom E, Huber M, Aneja M, Dohmen C, Emrich D, Geiger J, Hasenpusch G, Herrmann-Janson A, Kretzschmann V, Mykhailyk O, Pasewald T, Oak P, Hilgendorff A, Wohlleber D, Hoymann HG, Schaudien D, Plank C, Rudolph C, Kubisch-Dohmen R. Translation of Angiotensin-Converting Enzyme 2 upon Liver- and Lung-Targeted Delivery of Optimized Chemically Modified mRNA. MOLECULAR THERAPY. NUCLEIC ACIDS 2017; 7:350-365. [PMID: 28624211 PMCID: PMC5423349 DOI: 10.1016/j.omtn.2017.04.006] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 04/07/2017] [Accepted: 04/07/2017] [Indexed: 02/06/2023]
Abstract
Changes in lifestyle and environmental conditions give rise to an increasing prevalence of liver and lung fibrosis, and both have a poor prognosis. Promising results have been reported for recombinant angiotensin-converting enzyme 2 (ACE2) protein administration in experimental liver and lung fibrosis. However, the full potential of ACE2 may be achieved by localized translation of a membrane-anchored form. For this purpose, we advanced the latest RNA technology for liver- and lung-targeted ACE2 translation. We demonstrated in vitro that transfection with ACE2 chemically modified messenger RNA (cmRNA) leads to robust translation of fully matured, membrane-anchored ACE2 protein. In a second step, we designed eight modified ACE2 cmRNA sequences and identified a lead sequence for in vivo application. Finally, formulation of this ACE2 cmRNA in tailor-made lipidoid nanoparticles and in lipid nanoparticles led to liver- and lung-targeted translation of significant amounts of ACE2 protein, respectively. In summary, we provide evidence that RNA transcript therapy (RTT) is a promising approach for ACE2-based treatment of liver and lung fibrosis to be tested in fibrotic disease models.
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Affiliation(s)
- Eva Schrom
- Department of Pediatrics, LMU Munich, 80802 Munich, Germany; Ethris GmbH, 82152 Planegg, Germany
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- Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum Munich, 81377 Munich, Germany
| | - Anne Hilgendorff
- Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum Munich, 81377 Munich, Germany
| | - Dirk Wohlleber
- Institute of Molecular Immunology and Experimental Oncology, TU Munich, 81675 Munich, Germany
| | - Heinz-Gerd Hoymann
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | - Dirk Schaudien
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | - Christian Plank
- Ethris GmbH, 82152 Planegg, Germany; Institute of Molecular Immunology and Experimental Oncology, TU Munich, 81675 Munich, Germany
| | - Carsten Rudolph
- Department of Pediatrics, LMU Munich, 80802 Munich, Germany; Ethris GmbH, 82152 Planegg, Germany.
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Wu L, Zhou PQ, Xie JW, Zhu R, Zhou SC, Wang G, Wu ZX, Hao S. Effects of Yinchenhao decoction on self-regulation of renin-angiotensin system by targeting angiotensin converting enzyme 2 in bile duct-ligated rat liver. ACTA ACUST UNITED AC 2015. [PMID: 26223920 DOI: 10.1007/s11596-015-1463-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In order to investigate whether Yinchenhao decoction (YCHD) attenuates hepatic fibrogenesis in the bile duct ligation (BDL) model via recovering and restoring the self-regulation and balance of the renin-angiotensin system (RAS), 33 specific-pathogen-free (SPF) male Sprague-Dawley rats with common BDL and scission were randomly divided into five groups as follows: G1, the sham group (n=4); G2, BDL 7-day group (n=5); G3, BDL+YCHD 430 mg/mL (n=8); G4, BDL+losartan 0.65 mg/mL (ARB group, n=8); G5, model group (BDL without any treatment, n=8). YCHD and losartan (10 mL·kg(-1)·day(-1)) were given by gastric gavage for 16 days following BDL in G3 and G4 groups, respectively. The effect of YCHD on liver fibrosis and the detailed molecular mechanisms were assessed by liver function including total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IDBIL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological changes were observed by transmission electron microscopy (TEM) and Masson trichrome staining. Western blotting was used to detect the protein expression level of the renin-angiotensin system (RAS) components including angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), ACE2, angiotensin II (AngII) as well as transforming growth factor β1 (TGFβ1). The experimental data were analyzed by principle component analytical method of pattern recognition. The results showed that biochemically, serum TBIL, DBIL, IDBIL, ALT and AST levels were markedly increased following BDL as compared with the sham group (P<0.05). Serum TBIL, IDBIL and DBIL levels in G3 group were dramatically decreased as compared with G5 and G4 groups (P<0.05). Serum AST level in G3 was significantly lowered than in G5 group (P<0.05), but there was no significant difference in ALT among G3, G4 and G5 groups (P>0.05). Histologically, livers in G3 group showed less hepatocytes necrosis, less bile duct hyperplasia and less collagen formation than in G4 and G5 groups. The protein expression levels of ACE2, ACE, AngII, AT1R and TGFβ1 in G2, G3 and G4 groups were significantly higher than in sham group (P<0.05), and lower than in G5 group (P<0.05). However, the differences among G2, G3 and G4 groups were not significant (P>0.05). ACE2 protein expression in G3 group was significantly higher than in G2 group (P<0.05) and there was no significant difference in comparison with G4 group (P>0.05). Moreover, the protein expression of TGFβ1 in G3 group was significantly lower than in G5 and G4 groups (P<0.05). Our findings suggest that the antifibrotic effects of YCHD may be associated with the decreased classical RAS pathway components and TGFβ1 downexpression so as to recover and rebuild self-regulation of the RAS by elevating the protein expression of ACE2.
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Affiliation(s)
- Lin Wu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pi-Qi Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ji-Wen Xie
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rui Zhu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Sun-Chang Zhou
- Animal Experiment Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Geng Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhong-Xu Wu
- Department of Gastroenterology, Xianning Central Hospital, Xianning, 437100, China
| | - Sha Hao
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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14
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Up-regulation of components of the renin-angiotensin system in liver fibrosis in the rat induced by CCL₄. Res Vet Sci 2013; 95:54-8. [PMID: 23433841 PMCID: PMC7111816 DOI: 10.1016/j.rvsc.2013.01.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Revised: 01/22/2013] [Accepted: 01/25/2013] [Indexed: 12/16/2022]
Abstract
The purpose of this study was to investigate the components of renin-angiotensin system (RAS), liver function and histology in liver fibrogenesis in the rats induced by low-dose chronic carbon tetrachloride (CCL4) administration and evaluate the relationship between biochemical variables and components of RAS. Male Sprague-Dawley (SD) rats were randomly divided into the CCL4 group which received intraperitoneal injection of 40% CCL4 dissolved in olive oil every three days for four consecutive weeks (Initial dose was 5 mL/kg, other dose: 3 mL/kg) and the control group which received the same dose of olive oil. The micro-structure of the liver was examined by H&E. Hepatic Ang II and Ang(1-7) was detected. Real-time PCR and Western-blot were performed to determine the gene and protein expression of the RAS. The components of RAS were all up-regulated in CCL4 group, and the increased extent of ACE-Ang II-AT1 axis was higher than the ACE2-Ang(1-7)-Mas axis. There was a significant correlation between ACE and ACE2 gene expression, AT1 and MAS gene expression, Ang II and Ang(1-7) in the liver of rats. ACE (or ACE2) gene expression strongly correlated with the index of liver injury significantly. These results suggest hepatic fibrogenesis induced by chronic CCL4 administration may be associated with the relationship of ACE-Ang II-AT1 axis and ACE2-Ang(1-7)-MAS axis.
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Ferrario CM, Varagic J. The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function. Am J Physiol Renal Physiol 2010; 298:F1297-305. [PMID: 20375118 DOI: 10.1152/ajprenal.00110.2010] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The study of experimental hypertension and the development of drugs with selective inhibitory effects on the enzymes and receptors constituting the components of the circulating and tissue renin-angiotensin systems have led to newer concepts of how this system participates in both physiology and pathology. Over the last decade, a renewed emphasis on understanding the role of angiotensin-(1-7) and angiotensin-converting enzyme 2 in the regulation of blood pressure and renal function has shed new light on the complexity of the mechanisms by which these components of the renin angiotensin system act in the heart and in the kidneys to exert a negative regulatory influence on angiotensin converting enzyme and angiotensin II. The vasodepressor axis composed of angiotensin-(1-7)/angiotensin-converting enzyme 2/mas receptor emerges as a site for therapeutic interventions within the renin-angiotensin system. This review summarizes the evolving knowledge of the counterregulatory arm of the renin-angiotensin system in the control of nephron function and renal disease.
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Affiliation(s)
- Carlos M Ferrario
- Hypertension and Vascular Disease Research Center and Department of Surgery, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA.
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