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1
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Ali SA, Datusalia AK. Berberine Inhibits the Disruption of the Blood-Brain Barrier and Glial Cell Activation in a Rat Model of Acute Hepatic Encephalopathy. Phytother Res 2025; 39:1422-1437. [PMID: 39791947 DOI: 10.1002/ptr.8430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 11/25/2024] [Accepted: 12/08/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND AND AIM Hepatic encephalopathy (HE) is a complex neurological disorder in individuals with liver diseases, necessitating effective neuroprotective interventions to alleviate its adverse outcomes. Berberine (BBR), a natural compound with well-established anti-fibrotic and neuroprotective properties, has not been extensively studied in the context of glial activation under hyperammonaemic conditions. This study evaluates the neuroprotective potential of BBR in a thioacetamide (TAA)-induced HE rat model, focusing on its effects on glial activation and NLRP3 inflammasome signalling. METHODS Neurological impairments were assessed using open field tests and sensory analysis. Western blotting was performed to evaluate the expression of glial and neuronal markers, tight junction proteins and NLRP3 inflammasome components in the cortex and hippocampus. Histopathological and molecular changes were further examined using H&E, immunohistochemistry and immunofluorescence staining. KEY RESULTS BBR treatment significantly improved behavioural abnormalities and reduced systemic ammonia levels in TAA-exposed rats. It restored blood-brain barrier integrity, as evidenced by reduced tight junction protein degradation. BBR inhibited the expression of NLRP3 inflammasome markers, including caspase-1, IL-1β, ASC, and NF-κB, while reducing glial cell activation (IBA-1 and GFAP). Notably, BBR diminished NLRP3 expression in glial cells, indicating its potent anti-inflammatory effects. Additionally, BBR preserved neuronal integrity, as demonstrated by the maintained expression of MAP-2 and NeuN and reduced cleaved Gasdermin D levels. CONCLUSIONS These findings suggest that BBR alleviates behavioural and molecular abnormalities in HE through NLRP3 inflammasome inhibition, highlighting its potential as a therapeutic agent for managing HE.
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Affiliation(s)
- Syed Afroz Ali
- Laboratory of Molecular NeuroTherapeutics, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, India
| | - Ashok Kumar Datusalia
- Laboratory of Molecular NeuroTherapeutics, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, India
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, India
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2
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Choi K, Cho Y, Chae Y, Cheon SY. Cell-cell communications in the brain of hepatic encephalopathy: The neurovascular unit. Life Sci 2025; 363:123413. [PMID: 39863020 DOI: 10.1016/j.lfs.2025.123413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/07/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025]
Abstract
Many patients with liver diseases are exposed to the risk of hepatic encephalopathy (HE). The incidence of HE in liver patients is high, showing various symptoms ranging from mild symptoms to coma. Liver transplantation is one of the ways to overcome HE. However, not all patients can receive liver transplantation. Moreover, patients who have received liver transplantation have limitations in that they are vulnerable to hepatocellular carcinoma, allograft rejection, and infection. To find other therapeutic strategies, it is important to understand pathological factors and mechanisms that lead to HE after liver disease. Oxidative stress, inflammatory response, hyperammonaemia and metabolic disorders seen after liver diseases have been reported as risk factors of HE. These are known to affect the brain and cause HE. These peripheral pathological factors can impair the blood-brain barrier, cause it to collapse and damage the neurovascular unit component of multiple cells, including vascular endothelial cells, astrocytes, microglia, and neurons, leading to HE. Many previous studies on HE have suggested the impairment of neurovascular unit and cell-cell communication in the pathogenesis of HE. This review focuses on pathological factors that appear in HE, cell type-specific pathological mechanisms, miscommunication/incorrect relationships, and therapeutic candidates between brain cells in HE. This review suggests that regulating communications and interactions between cells may be important in overcoming HE.
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Affiliation(s)
- Kyuwan Choi
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yena Cho
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yerin Chae
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - So Yeong Cheon
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea; Research Institute for Biomedical & Health Science (RIBHS), Konkuk University, Chungju, Republic of Korea.
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3
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He X, Hu M, Xu Y, Xia F, Tan Y, Wang Y, Xiang H, Wu H, Ji T, Xu Q, Wang L, Huang Z, Sun M, Wan Y, Cui P, Liang S, Pan Y, Xiao S, He Y, Song R, Yan J, Quan X, Wei Y, Hong C, Liao W, Li F, El-Omar E, Chen J, Qi X, Gao J, Zhou H. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nat Med 2025; 31:627-638. [PMID: 39779925 DOI: 10.1038/s41591-024-03405-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025]
Abstract
Up to 50-70% of patients with liver cirrhosis develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with an unclear mechanism. Here, by constructing gut-brain modules to assess bacterial neurotoxins from metagenomic datasets, we found that phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus, increased approximately tenfold in patients with cirrhosis and higher in patients with HE. Cirrhotic, not healthy, mice colonized with R. gnavus showed brain phenylethylamine (PEA) accumulation, along with memory impairment, symmetrical tremors and cortex-specific neuron loss, typically found in patients with HE. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B activity in both the liver and serum due to cirrhosis. Targeting PDC or PEA reversed the neurological symptoms induced by R. gnavus. Furthermore, fecal microbiota transplantation from patients with HE to germ-free cirrhotic mice replicated these symptoms and further corroborated the efficacy of targeting PDC or PEA. Clinically, high baseline PEA levels were linked to a sevenfold increased risk of HE after intrahepatic portosystemic shunt procedures. Our findings expand the understanding of the gut-liver-brain axis and identify a promising therapeutic and predictive target for HE.
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Affiliation(s)
- Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Mengyao Hu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fangbo Xia
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Tan
- Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao C1 Refinery Engineering Research Center, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
| | - Yuqing Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huiling Xiang
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tengfei Ji
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhenhe Huang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Meiling Sun
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Wan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Cui
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shaocong Liang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Pan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Siyu Xiao
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China
| | - Ruixin Song
- The Third Central Clinical College of Tianjin Medical University, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Junqing Yan
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Xin Quan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yingge Wei
- Department of Hepatology, Third People's Hospital of Linfen City, Linfen, China
| | - Changze Hong
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weizuo Liao
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Fuli Li
- Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao C1 Refinery Engineering Research Center, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
| | - Emad El-Omar
- UNSW Microbiome Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW SYDNEY, Sydney, New South Wales, Australia
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
| | - Jie Gao
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China.
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
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Gallego JJ, Ballester MP, Fiorillo A, Casanova-Ferrer F, López-Gramaje A, Urios A, Arenas YM, Ríos MP, Durbán L, Megías J, San-Miguel T, Benlloch S, Lluch P, Jalan R, Montoliu C. Ammonia and beyond - biomarkers of hepatic encephalopathy. Metab Brain Dis 2025; 40:100. [PMID: 39812958 PMCID: PMC11735499 DOI: 10.1007/s11011-024-01512-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with liver cirrhosis, leading to neurotoxic effects and hepatic encephalopathy (HE). HE manifestations can range from mild, subclinical disturbances in cognition, or minimal HE (mHE) to gross disorientation and coma, a condition referred to as overt HE. Many blood-based biomarkers reflecting these neurotoxic effects of ammonia and liver disease can be measured in the blood allowing the development of new biomarkers to diagnose cirrhosis patients at risk of developing HE. The effect of ammonia on the brain is modulated by severity of systemic inflammation, and both hyperammonemia and inflammation can induce oxidative stress, which may mediate the neurological alterations associated to HE. This review aims to provide the latest evidence on biomarkers of HE beyond ammonia. We present different approaches to predict overt HE based on the combination of blood ammonia with some analytical and clinical parameters. Magnetic resonance analysis of brain images could also provide sensitive diagnostic biomarkers based on neuroimaging parameters. Some reports suggest that markers of systemic inflammation, oxidative stress, and central nervous system-derived components, may serve as additional biomarkers of HE. The involvement of extracellular vesicles and microbiota in the pathophysiology of mHE and HE has recently acquired importance and it would be interesting to explore their usefulness as early biomarkers of the disease. It is important to have a biomarker or a combination of them for early diagnosis of mHE to improve its treatment and prevent progression to overt HE.
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Affiliation(s)
- Juan-José Gallego
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ballester
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Alessandra Fiorillo
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Franc Casanova-Ferrer
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | | | - Amparo Urios
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Yaiza María Arenas
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ríos
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Lucía Durbán
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Javier Megías
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Teresa San-Miguel
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Salvador Benlloch
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
- CIBERehd. Instituto de Salud Carlos III, Madrid, 28029, Spain
- Universidad Cardenal Herrera-CEU Universities, Valencia, 46115, Spain
| | - Paloma Lluch
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, 08021, Spain.
| | - Carmina Montoliu
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain.
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain.
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5
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Zielińska M, Popek M, Albrecht J. Neuroglia in hepatic encephalopathy. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:191-212. [PMID: 40148045 DOI: 10.1016/b978-0-443-19102-2.00011-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Neuroglia contribute to the pathophysiology of hepatic encephalopathy (HE) either beneficially or detrimentally. Pathogenesis of HE is linked to damage triggered by blood-derived toxins, with ammonia being the main causative factor. Neuroglial cells, especially astrocytes and microglia, respond to HE-associated systemic and central signals and undergo complex and variable changes in their metabolism, morphology, and function, which include ion and water dyshomeostasis in conjunction with neurotransmission imbalance and neuroinflammation. HE-induced alterations of astrocytes are defined as astrocytopathy, with aberrant astrocytes resulting in either gain or loss of functions. In the chronic HE, the presence of Alzheimer type II cells is a histologic hallmark, with asthenic astrocytes emerging as a newcomer. In acute HE, rapid swelling of astrocytes is a primary cause of cerebral edema and mortality. This chapter reviews the dominant role of astrocytes in the pathogenesis of HE resulting from acute and chronic liver failure, mainly in experimental models. The focus is on the loss of homeostatic function bearing upon the functioning of the glymphatic system, aberrant neurotransmission as a consequence of astrocyte-neuron miscommunication, and the concordant neuroinflammatory response of astrocytes and microglia. The chapter concludes with a delineation of concepts for future research.
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Affiliation(s)
- Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
| | - Mariusz Popek
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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6
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Ortega-Ribera M, Zhuang Y, Babuta M, Brezani V, Joshi RS, Zsengeller Z, Thevkar Nagesh P, Wang Y, Bronson R, Szabo G. A Novel Multi-organ Male Model of Alcohol-induced Acute-on-chronic Liver Failure Reveals NET-mediated Hepatocellular Death, Which is Prevented by RIPK3 Inhibition. Cell Mol Gastroenterol Hepatol 2024; 19:101446. [PMID: 39710168 PMCID: PMC11874871 DOI: 10.1016/j.jcmgh.2024.101446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND & AIMS Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms. METHODS ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis murine model. Liver, kidney, and brain tissues and behavior were assessed in mice. Livers from patients with sclerosing cholangitis with and without ACLF were also evaluated. RESULTS In advanced fibrosis induced by BDL, an alcohol binge induced features of ACLF, including significant liver damage, systemic inflammation (increased endotoxin and pro-inflammatory cytokines), and hepatocyte dysfunction compared with BDL alone. ACLF was associated with extrahepatic manifestations, including increased blood urea nitrogen and creatinine, impaired coagulation, and features of encephalopathy. We discovered significantly increased neutrophil count and neutrophil extracellular traps (NETs) in the liver, kidney, and brain in murine ACLF. Livers from ACLF mice showed increased pyroptosis (gasdermin D) and necroptosis (receptor-interacting protein kinase 3 [RIPK3]), when compared with BDL. In vitro, cell-free NETs were induced by alcohol and/or bile acids and triggered pyro-/necroptotic death in hepatocytes. NETosis, pyroptosis, and RIPK3 activation were validated in human livers with ACLF. Moreover, pharmacological inhibition of necroptosis with a RIPK3 inhibitor-ameliorated inflammation, NETs, and liver fibrosis, improving multi-organ ACLF pathophysiology. CONCLUSIONS Our novel ACLF model triggered by alcohol binge mimics key features of pathophysiology and multi-organ impairment in human ACLF. Our results indicate that neutrophil infiltration and NETs contribute to hepatocyte cell death via pyroptosis and necroptosis in ACLF, identifying RIPK3 as a potential therapeutic target.
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Affiliation(s)
- Martí Ortega-Ribera
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Yuan Zhuang
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Mrigya Babuta
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Veronika Brezani
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Radhika S Joshi
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Zsuzsanna Zsengeller
- Department of Medicine, Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Prashanth Thevkar Nagesh
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Yanbo Wang
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | | | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Broad Institute, Cambridge, Massachusetts.
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7
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Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metab Brain Dis 2024; 39:1689-1703. [PMID: 39212845 PMCID: PMC11535002 DOI: 10.1007/s11011-024-01402-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.
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Affiliation(s)
- Yevedzo Ntuli
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Debbie L Shawcross
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK.
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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8
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Thu VTA, Hoang TX, Park JK, Kim JY. Induction of Innate Immune Memory in LPS-Primed Microglial Cells by Water-Soluble Chitosan. BIOMED RESEARCH INTERNATIONAL 2024; 2024:8027006. [PMID: 39654846 PMCID: PMC11628173 DOI: 10.1155/bmri/8027006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 09/24/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024]
Abstract
Innate immune memory or trained immunity refers to a long-lasting response of the innate immune cells against repeated exposure to the homogenous or heterogenous infectious agent. The trained immunity is induced through epigenetic modification and is characterized by the change of both intracellular immunological signaling and cellular metabolism. Recently, different groups have tried to establish protocols to generate trained innate immune cells. However, the molecular basis of innate memory induction remains poorly understood. Here, we evaluated the impact of water-soluble chitosan on the innate immune memory induction in microglial cells primed with LPS. The trained-immune response was accessed by measuring proinflammatory markers, metabolic change, and epigenetic modification. We showed that the stimulation/restimulation with LPS only caused a robust reduction of iNOS, and proinflammatory cytokines, indicating induced immune tolerance. In contrast, the treatment of chitosan induces long-lasting memory microglial cells accompanied by a high level of iNOS, increased lactate production, induced epigenetic modification, and the upregulation of proinflammatory cytokines upon further exposure to the same stimulus. These findings suggest that chitosan induces microglial-trained immunity by targeting distinct epigenetic and metabolic pathways; therefore, chitosan treatment may provide a novel approach for targeting innate immunity towards a memory-like response in an in vitro model.
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Affiliation(s)
- Vo Thuy Anh Thu
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
| | - Thi Xoan Hoang
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
| | - Jae Kweon Park
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
| | - Jae Young Kim
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
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9
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Sørensen M, Andersen JV, Bjerring PN, Vilstrup H. Hepatic encephalopathy as a result of ammonia-induced increase in GABAergic tone with secondary reduced brain energy metabolism. Metab Brain Dis 2024; 40:19. [PMID: 39560844 PMCID: PMC11576828 DOI: 10.1007/s11011-024-01473-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 09/02/2024] [Indexed: 11/20/2024]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver insufficiency and/or portosystemic shunting. HE is mostly episodic and as such reversible. Hyperammonemia clearly plays a key role in the pathophysiology, but the precise detrimental events in the brain leading to HE remain equivocal. Several pathogenic models have been proposed, but few have been linked to clinical studies and observations. Decreased oxygen metabolism is observed in both type A and C HE and in this review, we advocate that this reflects an actual reduced oxygen demand and not a primary cause of HE. As driving force, we propose that the hyperammonemia via astrocytic glutamine synthetase causes an increased γ-aminobutyric acid (GABA) mediated neuro-inhibition which subsequently leads to an overall decreased energy demand of the brain, something that can be enhanced by concomitant neuroinflammation. This also explains the reversibility of the condition.
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Affiliation(s)
- Michael Sørensen
- Department of Internal Medicine, Viborg Regional Hospital, Viborg, Denmark.
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | - Jens Velde Andersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Nissen Bjerring
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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10
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Kleidonas D, Hilfiger L, Lenz M, Häussinger D, Vlachos A. Ammonium chloride reduces excitatory synaptic transmission onto CA1 pyramidal neurons of mouse organotypic slice cultures. Front Cell Neurosci 2024; 18:1410275. [PMID: 39411004 PMCID: PMC11473415 DOI: 10.3389/fncel.2024.1410275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
Acute liver dysfunction commonly leads to rapid increases in ammonia concentrations in both the serum and the cerebrospinal fluid. These elevations primarily affect brain astrocytes, causing modifications in their structure and function. However, its impact on neurons is not yet fully understood. In this study, we investigated the impact of elevated ammonium chloride levels (NH4Cl, 5 mM) on synaptic transmission onto CA1 pyramidal neurons in mouse organotypic entorhino-hippocampal tissue cultures. We found that acute exposure to NH4Cl reversibly reduced excitatory synaptic transmission and affected CA3-CA1 synapses. Notably, NH4Cl modified astrocytic, but not CA1 pyramidal neuron, passive intrinsic properties. To further explore the role of astrocytes in NH4Cl-induced attenuation of synaptic transmission, we used methionine sulfoximine to target glutamine synthetase, a key astrocytic enzyme for ammonia clearance in the central nervous system. Inhibition of glutamine synthetase effectively prevented the downregulation of excitatory synaptic activity, underscoring the significant role of astrocytes in adjusting excitatory synapses during acute ammonia elevation.
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Affiliation(s)
- Dimitrios Kleidonas
- Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Louis Hilfiger
- Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maximilian Lenz
- Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Andreas Vlachos
- Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center BrainLinks-BrainTools, University of Freiburg, Freiburg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Chéry SL, O'Buckley TK, Boero G, Balan I, Morrow AL. Neurosteroid [3α,5α]3-hydroxypregnan-20-one inhibition of chemokine monocyte chemoattractant protein-1 in alcohol-preferring rat brain neurons, microglia, and astroglia. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:1693-1703. [PMID: 38991981 DOI: 10.1111/acer.15404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/21/2024] [Accepted: 06/26/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND Neuroimmune dysfunction in alcohol use disorder (AUD) is associated with activation of myeloid differentiation primary response 88 (MyD88)-dependent Toll-like receptors (TLR) resulting in overexpression of the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). MCP-1 overexpression in the brain is linked to anxiety, higher alcohol intake, neuronal death, and activation of microglia observed in AUD. The neurosteroid [3α,5α][3-hydroxypregnan-20-one (3α,5α-THP) has been reported as an inhibitor of MyD88-dependent TLR activation and MCP-1 overexpression in mouse and human macrophages and the brain of alcohol-preferring (P) rats. METHODS We investigated how 3α,5α-THP regulates MCP-1 expression at the cellular level in P rat nucleus accumbens (NAc) and central amygdala (CeA). We focused on neurons, microglia, and astrocytes, examining the individual voxel density of MCP-1, neuronal marker NeuN, microglial marker IBA1, astrocytic marker GFAP, and their shared voxel density, defined as intersection. Ethanol-naïve male and female P rats were perfused 1 h after IP injections of 15 mg/kg of 3α,5α-THP, or vehicle. The NAc and CeA were imaged using confocal microscopy following double-immunofluorescence staining for MCP-1 with NeuN, IBA1, and GFAP, respectively. RESULTS MCP-1 intersected with NeuN predominantly and IBA1/GFAP negligibly. 3α,5α-THP reduced MCP-1 expression in NeuN-labeled cells by 38.27 ± 28.09% in male and 56.11 ± 21.46% in female NAc, also 37.99 ± 19.53% in male and 54.96 ± 30.58% in female CeA. In females, 3α,5α-THP reduced the MCP-1 within IBA1 and GFAP-labeled voxels in the NAc and CeA. Conversely, in males, 3α,5α-THP did not significantly alter the MCP-1 within IBA1 in NAc or with GFAP in the CeA. Furthermore, 3α,5α-THP decreased levels of IBA1 in both regions and sexes with no impact on GFAP or NeuN levels. Secondary analysis performed on data normalized to % control values indicated that no significant sex differences were present. CONCLUSIONS These data suggest that 3α,5α-THP inhibits neuronal MCP-1 expression and decreases the proliferation of microglia in P rats. These results increase our understanding of potential mechanisms for 3α,5α-THP modulation of ethanol consumption.
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Affiliation(s)
- Samantha Lucenell Chéry
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Neuroscience Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Todd K O'Buckley
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Giorgia Boero
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Irina Balan
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - A Leslie Morrow
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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12
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Zou J, Li J, Wang X, Tang D, Chen R. Neuroimmune modulation in liver pathophysiology. J Neuroinflammation 2024; 21:188. [PMID: 39090741 PMCID: PMC11295927 DOI: 10.1186/s12974-024-03181-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 07/19/2024] [Indexed: 08/04/2024] Open
Abstract
The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.
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Affiliation(s)
- Ju Zou
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jie Li
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiaoxu Wang
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ruochan Chen
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Li D, Yu SF, Lin L, Guo JR, Huang SM, Wu XL, You HL, Cheng XJ, Zhang QY, Zeng YQ, Pan XD. Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice. J Neuroinflammation 2024; 21:123. [PMID: 38725082 PMCID: PMC11084037 DOI: 10.1186/s12974-024-03125-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 05/05/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.
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Affiliation(s)
- Dan Li
- Department of Gastroenterology, Fujian Medical University Union Hospital, 29, Xinquan Road, Fujian, 350001, China.
- Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fujian, 350001, China.
| | - Shu-Fang Yu
- Department of Gastroenterology, Fujian Medical University Union Hospital, 29, Xinquan Road, Fujian, 350001, China
| | - Lin Lin
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
- Fujian Key Laboratory of Vascular Aging, Fujian Medical University, Fuzhou, 350001, Fujian, China
| | - Jie-Ru Guo
- Department of Gastroenterology, Fujian Medical University Union Hospital, 29, Xinquan Road, Fujian, 350001, China
| | - Si-Mei Huang
- Department of Gastroenterology, Fujian Medical University Union Hospital, 29, Xinquan Road, Fujian, 350001, China
| | - Xi-Lin Wu
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
- Institute of Clinical Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
| | - Han-Lin You
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
| | - Xiao-Juan Cheng
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
| | - Qiu-Yang Zhang
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - Yu-Qi Zeng
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
| | - Xiao-Dong Pan
- Department of Neurology, Fujian Institute of Geriatrics, Center for Cognitive Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.
- Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
- Fujian Key Laboratory of Vascular Aging, Fujian Medical University, Fuzhou, 350001, Fujian, China.
- Institute of Clinical Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
- Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province, Fuzhou, 350001, China.
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Yu Z, Shi H, Zhang J, Ma C, He C, Yang F, Zhao L. ROLE OF MICROGLIA IN SEPSIS-ASSOCIATED ENCEPHALOPATHY PATHOGENESIS: AN UPDATE. Shock 2024; 61:498-508. [PMID: 38150368 DOI: 10.1097/shk.0000000000002296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
ABSTRACT Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, which is characterized by cognitive dysfunction, a poor prognosis, and high incidences of morbidity and mortality. Substantial levels of systemic inflammatory factors induce neuroinflammatory responses during sepsis, ultimately disrupting the central nervous system's (CNS) homeostasis. This disruption results in brain dysfunction through various underlying mechanisms, contributing further to SAE's development. Microglia, the most important macrophage in the CNS, can induce neuroinflammatory responses, brain tissue injury, and neuronal dysregulation, resulting in brain dysfunction. They serve an important regulatory role in CNS homeostasis and can be activated through multiple pathways. Consequently, activated microglia are involved in several pathogenic mechanisms related to SAE and play a crucial role in its development. This article discusses the role of microglia in neuroinflammation, dysfunction of neurotransmitters, disruption of the blood-brain barrier, abnormal control of cerebral blood flow, mitochondrial dysfunction, and reduction in the number of good bacteria in the gut as main pathogenic mechanisms of SAE and focuses on studies targeting microglia to ameliorate SAE to provide a theoretical basis for targeted microglial therapy for SAE.
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Affiliation(s)
| | - Hui Shi
- Department of Critical Care Medicine, Chifeng Municipal Hospital, Chifeng Clinical Medical College of Inner Mongolia Medical University, Chifeng, China
| | - Jingjing Zhang
- Department of Central Laboratory, Chifeng Municipal Hospital, Chifeng Clinical Medical College of Inner Mongolia Medical University, Chifeng, China
| | - Chunhan Ma
- Chifeng Clinical Medical College of Inner Mongolia Medical University, Hohhot, China
| | - Chen He
- Chifeng Clinical Medical College of Inner Mongolia Medical University, Hohhot, China
| | - Fei Yang
- Department of Critical Care Medicine, Chifeng Municipal Hospital, Chifeng Clinical Medical College of Inner Mongolia Medical University, Chifeng, China
| | - Lina Zhao
- Department of Critical Care Medicine, General Hospital of Tianjin Medical University, Tianjin, China
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El-Mansoury B, Smimih K, El Khiat A, Draoui A, Aimrane A, Chatoui R, Ferssiwi A, Bitar A, Gamrani H, Jayakumar AR, El Hiba O. Short Working Memory Impairment Associated with Hippocampal Microglia Activation in Chronic Hepatic Encephalopathy. Metabolites 2024; 14:193. [PMID: 38668321 PMCID: PMC11052478 DOI: 10.3390/metabo14040193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 01/03/2024] [Accepted: 01/06/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatic encephalopathy (HE) is a major neuropsychological condition that occursas a result of impaired liver function. It is frequently observed in patients with advanced liver disease or cirrhosis. Memory impairment is among the symptoms of HE; the pathophysiologic mechanism for this enervating condition remains unclear. However, it is possible that neuroinflammation may be involved, as recent studies have emphasized such phenomena. Therefore, the aim of the present study is to assess short working memory (SWM) and examine the involvement of microglia in a chronic model of HE. The study was carried out with male Wistar rats that were induced by repeated thioacetamide (TAA) administration (100 mg/kg i.p injection for 10 days). SWM function was assessed through Y-maze, T-Maze, and novel object recognition (NOR) tests, together with an immunofluorescence study of microglia activation within the hippocampal areas. Our data showed impaired SWM in TAA-treated rats that was associated with microglial activation in the three hippocampal regions, and which contributed to cognitive impairment.
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Affiliation(s)
- Bilal El-Mansoury
- Laboratory of Anthropogenic, Biotechnology and Health, Nutritional Physiopathologies, Neurosciences and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av. Des Facultés, El Jadida 24000, Morocco; (B.E.-M.); (A.E.K.); (A.A.); (A.F.); (A.B.)
| | - Kamal Smimih
- Laboratory of Genie-Biology, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Beni Mellal 23000, Morocco; (K.S.); (R.C.)
| | - Abdelaati El Khiat
- Laboratory of Anthropogenic, Biotechnology and Health, Nutritional Physiopathologies, Neurosciences and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av. Des Facultés, El Jadida 24000, Morocco; (B.E.-M.); (A.E.K.); (A.A.); (A.F.); (A.B.)
- Higher Institute of Nursing Professions and Health Techniques, Ministry of Health, Ouarzazate 45000, Morocco
- Laboratory of Clinical and Experimental Neurosciences and Environment, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40000, Morocco
| | - Ahmed Draoui
- Laboratory of Clinical and Experimental Neurosciences and Environment, Faculty of Science Semlalia, Cadi Ayyad University, Marrakech 40000, Morocco; (A.D.); (H.G.)
| | - Abdelmohcine Aimrane
- Laboratory of Anthropogenic, Biotechnology and Health, Nutritional Physiopathologies, Neurosciences and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av. Des Facultés, El Jadida 24000, Morocco; (B.E.-M.); (A.E.K.); (A.A.); (A.F.); (A.B.)
| | - Redouane Chatoui
- Laboratory of Genie-Biology, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Beni Mellal 23000, Morocco; (K.S.); (R.C.)
| | - Abdesslam Ferssiwi
- Laboratory of Anthropogenic, Biotechnology and Health, Nutritional Physiopathologies, Neurosciences and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av. Des Facultés, El Jadida 24000, Morocco; (B.E.-M.); (A.E.K.); (A.A.); (A.F.); (A.B.)
| | - Abdelali Bitar
- Laboratory of Anthropogenic, Biotechnology and Health, Nutritional Physiopathologies, Neurosciences and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av. Des Facultés, El Jadida 24000, Morocco; (B.E.-M.); (A.E.K.); (A.A.); (A.F.); (A.B.)
| | - Halima Gamrani
- Laboratory of Clinical and Experimental Neurosciences and Environment, Faculty of Science Semlalia, Cadi Ayyad University, Marrakech 40000, Morocco; (A.D.); (H.G.)
| | | | - Omar El Hiba
- Laboratory of Anthropogenic, Biotechnology and Health, Nutritional Physiopathologies, Neurosciences and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av. Des Facultés, El Jadida 24000, Morocco; (B.E.-M.); (A.E.K.); (A.A.); (A.F.); (A.B.)
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Izadi S, Abdolrezaei M, Soukhaklari R, Moosavi M. Memory impairment induced by aluminum nanoparticles is associated with hippocampal IL-1 and IBA-1 upregulation in mice. Neurol Res 2024; 46:284-290. [PMID: 38145565 DOI: 10.1080/01616412.2023.2298137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 12/18/2023] [Indexed: 12/27/2023]
Abstract
OBJECTIVES Increasing evidence indicates a link between aluminum (Al) intake and Alzheimer's disease (AD). The main entry of Al into the human body is through oral route, and in the digestive tract, under the influence of the pH change, Al can be transformed into Al nanoparticles (Al-NP). However, studies related to the effect of Al-NP on the brain are limited and need further investigation. Neuro-inflammation is considered as one of the principal features of AD. Microglial activation and expression of the inflammatory cytokine IL-1β (interleukin-1β) in the brain have been used as hallmarks of brain inflammation. Therefore, in the present study, the hippocampal levels of ionized calcium-binding adaptor molecule 1 (IBA-1), as the marker of microglia activation, and IL-1β were assessed. METHODS Adult male NMRI mice were treated with Al-NP (5 or 10 mg/kg) for 5 days. A novel object recognition (NOR) test was used to assess memory. Following cognitive assessments, the hippocampal tissues were isolated to analyze the levels of IL-1β and IBA-1 as well as beta actin proteins using western blot technique. RESULTS Al-NP in both doses of 5 and 10 mg/kg impaired NOR memory in mice. In addition, Al-NP increased IL-1β and IBA-1 in the hippocampus. DISCUSSION These findings indicate that the memory impairing effect of Al-NP coincides with hippocampal inflammation. According to the proposed relationship between AD and Al toxicity, this study can increase the knowledge about the toxic effects of Al-NP and highlight the need to limit the use of this nanoparticle.
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Affiliation(s)
- Sadegh Izadi
- Clinical Neurology Research Center and Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Abdolrezaei
- Clinical Neurology Research Center and Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roksana Soukhaklari
- Shiraz Neuroscience Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Cardiology, Medical University of Graz, Graz, Austria
| | - Maryam Moosavi
- Nanomedicine and Nanobiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Yang H, You L, Wang Z, Yang L, Wang X, Wu W, Zhi H, Rong G, Sheng Y, Liu X, Liu L. Bile duct ligation elevates 5-HT levels in cerebral cortex of rats partly due to impairment of brain UGT1A6 expression and activity via ammonia accumulation. Redox Biol 2024; 69:103019. [PMID: 38163420 PMCID: PMC10794929 DOI: 10.1016/j.redox.2023.103019] [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: 09/27/2023] [Revised: 12/19/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024] Open
Abstract
Hepatic encephalopathy (HE) is often associated with endogenous serotonin (5-HT) disorders. However, the reason for elevated brain 5-HT levels due to liver failure remains unclear. This study aimed to investigate the mechanism by which liver failure increases brain 5-HT levels and the role in behavioral abnormalities in HE. Using bile duct ligation (BDL) rats as a HE model, we verified the elevated 5-HT levels in the cortex but not in the hippocampus and striatum, and found that this cortical 5-HT overload may be caused by BDL-mediated inhibition of UDP-glucuronosyltransferase 1A6 (UGT1A6) expression and activity in the cortex. The intraventricular injection of the UGT1A6 inhibitor diclofenac into rats demonstrated that the inhibition of brain UGT1A6 activity significantly increased cerebral 5-HT levels and induced HE-like behaviors. Co-immunofluorescence experiments demonstrated that UGT1A6 is primarily expressed in astrocytes. In vitro studies confirmed that NH4Cl activates the ROS-ERK pathway to downregulate UGT1A6 activity and expression in U251 cells, which can be reversed by the oxidative stress antagonist N-acetyl-l-cysteine and the ERK inhibitor U0126. Silencing Hepatocyte Nuclear Factor 4α (HNF4α) suppressed UGT1A6 expression whilst overexpressing HNF4α increased Ugt1a6 promotor activity. Meanwhile, both NH4Cl and the ERK activator TBHQ downregulated HNF4α and UGT1A6 expression. In the cortex of hyperammonemic rats, we also found activation of the ROS-ERK pathway, decreases in HNF4α and UGT1A6 expression, and increases in brain 5-HT content. These results prove that the ammonia-mediated ROS-ERK pathway activation inhibits HNF4α expression to downregulate UGT1A6 expression and activity, thereby increasing cerebral 5-HT content and inducing manic-like HE symptoms. This is the first study to reveal the mechanism of elevated cortical 5-HT concentration in a state of liver failure and elucidate its association with manic-like behaviors in HE.
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Affiliation(s)
- Hanyu Yang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Linjun You
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, 210009, Nanjing, China
| | - Zhongyan Wang
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Lu Yang
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xun Wang
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Wenhan Wu
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hao Zhi
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Guangmei Rong
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yun Sheng
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaodong Liu
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Li Liu
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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Li J, Yang D, Ge S, Liu L, Huo Y, Hu Z. Identifying hub genes of sepsis-associated and hepatic encephalopathies based on bioinformatic analysis-focus on the two common encephalopathies of septic cirrhotic patients in ICU. BMC Med Genomics 2024; 17:19. [PMID: 38212812 PMCID: PMC10785360 DOI: 10.1186/s12920-023-01774-7] [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: 03/25/2023] [Accepted: 12/12/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND In the ICU ward, septic cirrhotic patients are susceptible to suffering from sepsis-associated encephalopathy and/or hepatic encephalopathy, which are two common neurological complications in such patients. However, the mutual pathogenesis between sepsis-associated and hepatic encephalopathies remains unclear. We aimed to identify the mutual hub genes, explore effective diagnostic biomarkers and therapeutic targets for the two common encephalopathies and provide novel, promising insights into the clinical management of such septic cirrhotic patients. METHODS The precious human post-mortem cerebral tissues were deprived of the GSE135838, GSE57193, and GSE41919 datasets, downloaded from the Gene Expression Omnibus database. Furthermore, we identified differentially expressed genes and screened hub genes with weighted gene co-expression network analysis. The hub genes were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analyses, and protein-protein interaction networks were constructed. Receiver operating characteristic curves and correlation analyses were set up for the hub genes. Finally, we explored principal and common signaling pathways by using Gene Set Enrichment Analysis and the association between the hub genes and immune cell subtype distribution by using CIBERSORT algorithm. RESULTS We identified seven hub genes-GPR4, SOCS3, BAG3, ZFP36, CDKN1A, ADAMTS9, and GADD45B-by using differentially expressed gene analysis and weighted gene co-expression network analysis method. The AUCs of these genes were all greater than 0.7 in the receiver operating characteristic curves analysis. The Gene Set Enrichment Analysis results demonstrated that mutual signaling pathways were mainly enriched in hypoxia and inflammatory response. CIBERSORT indicated that these seven hub genes were closely related to innate and adaptive immune cells. CONCLUSIONS We identified seven hub genes with promising diagnostic value and therapeutic targets in septic cirrhotic patients with sepsis-associated encephalopathy and/or hepatic encephalopathy. Hypoxia, inflammatory, and immunoreaction responses may share the common downstream pathways of the two common encephalopathies, for which earlier recognition and timely intervention are crucial for management of such septic cirrhotic patients in ICU.
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Affiliation(s)
- Juan Li
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Dong Yang
- Department of Emergency (Xiangjiang Hospital), The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, China
| | - Shengmei Ge
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Lixia Liu
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Yan Huo
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Zhenjie Hu
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
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Mittal S, Bhardwaj M, Shekhrajka P, Goyal VK, Nimje GR, Kanoji S, Danduri SK, Vishnoi A. An overview of unresolved issues in the perioperative management of liver transplant patients. KOREAN JOURNAL OF TRANSPLANTATION 2023; 37:221-228. [PMID: 38115164 PMCID: PMC10772275 DOI: 10.4285/kjt.23.0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/21/2023] Open
Abstract
Over the past decade, the field of solid organ transplantation has undergone significant changes, with some of the most notable advancements occurring in liver transplantation. Recent years have seen substantial progress in preoperative patient optimization protocols, anesthesia monitoring, coagulation management, and fluid management, among other areas. These improvements have led to excellent perioperative outcomes for all surgical patients, including those undergoing liver transplantation. In the last few decades, there have been numerous publications in the field of liver transplantation, but controversies related to perioperative management of liver transplant recipients persist. In this review article, we address the unresolved issues surrounding the anesthetic management of patients scheduled for liver transplantation.
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Affiliation(s)
- Saurabh Mittal
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Medha Bhardwaj
- Department of Neuro-Anaesthesia, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | | | - Vipin Kumar Goyal
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Ganesh Ramaji Nimje
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Sakshi Kanoji
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Suma Katyaeni Danduri
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Anshul Vishnoi
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
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Cheon SY, Kim MY, Kim J, Kim EJ, Kam EH, Cho I, Koo BN, Kim SY. Hyperammonemia induces microglial NLRP3 inflammasome activation via mitochondrial oxidative stress in hepatic encephalopathy. Biomed J 2023; 46:100593. [PMID: 37059364 PMCID: PMC10498413 DOI: 10.1016/j.bj.2023.04.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/10/2023] [Accepted: 04/04/2023] [Indexed: 04/16/2023] Open
Abstract
BACKGROUND The role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of hepatic encephalopathy (HE) is unclear. Mitochondrial reactive oxygen species (mtROS) is a signal for NLRP3 inflammasome activation. Therefore, we aimed to determine whether mtROS-dependent NLRP3 inflammasome activation is involved in HE, using in vivo and in vitro models. METHODS Bile duct ligation (BDL) in C57/BL6 mice was used as an in vivo HE model. NLRP3 activation was assessed in the hippocampus. Immunofluorescence staining was performed to determine the cellular source of NLRP3 in the hippocampal tissue. For the in vitro experiment, BV-2 microglial cells were primed with lipopolysaccharide (LPS), followed by ammonia treatment. NLRP3 activation and mitochondrial dysfunction were measured. Mito-TEMPO was used to suppress mtROS production. RESULTS BDL mice showed cognitive impairment with hyperammonemia. Both the priming and activation steps of NLRP3 inflammasome activation were processed in the hippocampus of BDL mice. Moreover, intracellular ROS levels increased in the hippocampus, and NLRP3 was mainly expressed in the microglia of the hippocampus. In LPS-primed BV-2 cells, ammonia treatment induced NLRP3 inflammasome activation and pyroptosis, with elevation of mtROS and altered mitochondrial membrane potential. Pretreatment with Mito-TEMPO suppressed mtROS production and the subsequent NLRP3 inflammasome activation and pyroptosis under LPS and ammonia treatment in BV-2 cells. CONCLUSIONS Hyperammonemia in HE may be involved in mtROS overproduction and subsequent NLRP3 inflammasome activation. Further studies using NLRP3-specific inhibitor or NLRP3 knockout mice are needed to elucidate the important role of NLRP3 inflammasome in HE development.
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Affiliation(s)
- So Yeong Cheon
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Min-Yu Kim
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeongmin Kim
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Jung Kim
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Hee Kam
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Inja Cho
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bon-Nyeo Koo
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - So Yeon Kim
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Leone P, Arenas YM, Balzano T, Mincheva G, Martinez-Garcia M, Montoliu C, Llansola M, Felipo V. Patients who died with steatohepatitis or liver cirrhosis show neuroinflammation and neuronal loss in hippocampus. Eur J Neurol 2023; 30:3032-3046. [PMID: 37340928 DOI: 10.1111/ene.15935] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 06/08/2023] [Accepted: 06/13/2023] [Indexed: 06/22/2023]
Abstract
BACKGROUND Neuroinflammation in the cerebral cortex of patients who died with liver cirrhosis and neuroinflammation, and neuronal death in the cerebellum of patients who died with steatohepatitis or cirrhosis, were reported. Hippocampal neuroinflammation could contribute to cognitive decline in patients with liver disease, but this has yet to be studied. The study aims were to assess if hippocampus from patients who died with steatohepatitis or cirrhosis showed: (i) glial activation, (ii) altered cytokine content, (iii) immune cell infiltration, (iv) neuronal apoptosis and (v) neuronal loss. METHODS Post-mortem hippocampus was obtained from 6 controls, 19 patients with steatohepatitis (SH) and 4 patients with liver cirrhosis. SH patients were divided into SH1 (n = 9), SH2 (n = 6) and SH3 (n = 4) groups depending on disease severity. Glial activation, IL-1β and TNFα content, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss were analyzed by immunohistochemistry. RESULTS Patients who died in SH1 showed astrocyte activation, whereas those who died in SH2 also showed microglial activation, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss. These changes remained in patients in SH3, who also showed increased IL-1β and TNFα. Patients who died of liver cirrhosis did not show CD4 lymphocyte infiltration, neuronal apoptosis or increase in TNFα, but still showed glial activation, increased IL-1β and neuronal loss. CONCLUSIONS Patients with steatohepatitis showed glial activation, immune cell infiltration, apoptosis and neuronal loss. Glial activation and neuronal loss remained in cirrhotic patients. This may explain the irreversibility of some cognitive alterations in hepatic encephalopathy. Cognitive reserve may contribute to different grades of cognitive impairment despite similar neuronal loss.
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Affiliation(s)
- Paola Leone
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Yaiza M Arenas
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Tiziano Balzano
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Centro Integral de Neurociencias, Hospital Universitario Puerta del Sur CINAC, Madrid, Spain
| | - Gergana Mincheva
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Mar Martinez-Garcia
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Carmina Montoliu
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
- Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
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Sepehrinezhad A, Shahbazi A, Joghataei MT, Larsen FS, Sahab Negah S. Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut-liver-brain axis: an experimental and bioinformatic study. Cell Death Dis 2023; 14:490. [PMID: 37528089 PMCID: PMC10394058 DOI: 10.1038/s41419-023-06022-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/19/2023] [Accepted: 07/26/2023] [Indexed: 08/03/2023]
Abstract
There is accumulating evidence that the circulatory levels of autotaxin (ATX) and lysophosphatidic acid (LPA) are increased in patients with severe liver disease. However, the potential role of the ATX-LPA axis in hepatic encephalopathy (HE) remains unclear. Our study aimed to investigate the role of the ATX-LPA signaling pathway in mice with thioacetamide (TAA) induced acute HE. To show the role of the ATX-LPA axis in the context of HE, we first measured the involvement of ATX-LPA in the pathogenesis of TAA-induced acute HE. Then, we compared the potential effects of ATX inhibitor (HA130) on astrocyte responses at in vitro and gut-liver-brain axis at in vivo levels. The inflammatory chemokine (C-C motif) ligand 3 was significantly increased in the hyperammonemic condition and could be prevented by ATX inhibition in astrocytes at in vitro level. Further statistical tests revealed that plasma and tissue pro-inflammatory cytokines were inhibited by HA130 in mice. Furthermore, the stage of HE was significantly improved by HA130. The most surprising result was that HA130 alleviated immune infiltrating cells in the liver and intestine and decreased mucus-secreting cells in the intestine. Further analysis showed that the levels of liver enzymes in serum were significantly decreased in response to ATX inhibition. Surprisingly, our data indicated that HA130 could recover permeabilization of the blood-brain barrier, neuroinflammation, and recognition memory. Besides that, we found that the changes of Interleukin-1 (IL-1) and aquaporin-4 (AQP4) in HE might have a connection with the glymphatic system based on bioinformatics analyses. Taken together, our data showed that the ATX-LPA axis contributes to the pathogenesis of HE and that inhibition of ATX improves HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | | | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
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Li Y, Li C, Luo T, Yue T, Xiao W, Yang L, Zhang Z, Han F, Long P, Hu Y. Progress in the Treatment of High Altitude Cerebral Edema: Targeting REDOX Homeostasis. J Inflamm Res 2023; 16:2645-2660. [PMID: 37383357 PMCID: PMC10296571 DOI: 10.2147/jir.s415695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/15/2023] [Indexed: 06/30/2023] Open
Abstract
With the increasing of altitude activities from low-altitude people, the study of high altitude cerebral edema (HACE) has been revived. HACE is a severe acute mountain sickness associated with exposure to hypobaric hypoxia at high altitude, often characterized by disturbance of consciousness and ataxia. As for the pathogenesis of HACE, previous studies suggested that it might be related to the disorder of cerebral blood flow, the destruction of blood-brain barrier and the injury of brain parenchyma cells caused by inflammatory factors. In recent years, studies have confirmed that the imbalance of REDOX homeostasis is also involved in the pathogenesis of HACE, which mainly leads to abnormal activation of microglia and destruction of tight junction of vascular endothelial cells through the excessive production of mitochondrial-related reactive oxygen species. Therefore, this review summarizes the role of REDOX homeostasis and the potential of the treatment of REDOX homeostasis in HACE, which is of great significance to expand the understanding of the pathogenesis of HACE. Moreover, it will also be helpful to further study the possible therapy of HACE related to the key link of REDOX homeostasis.
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Affiliation(s)
- Yubo Li
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, People’s Republic of China
- Basic Medical Laboratory, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Chengming Li
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, People’s Republic of China
- Basic Medical Laboratory, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Tao Luo
- Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Tian Yue
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China
| | - Wenjing Xiao
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Ling Yang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, People’s Republic of China
- Basic Medical Laboratory, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Zaiyuan Zhang
- College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China
| | - Fei Han
- Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Pan Long
- Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China
| | - Yonghe Hu
- College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China
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Giuli L, Maestri M, Santopaolo F, Pompili M, Ponziani FR. Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease. Metabolites 2023; 13:772. [PMID: 37367929 DOI: 10.3390/metabo13060772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/25/2023] [Accepted: 06/10/2023] [Indexed: 06/28/2023] Open
Abstract
Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marta Maestri
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Mendoza Vasquez LE, Payne S, Zamper R. Intracranial pressure monitoring in the perioperative period of patients with acute liver failure undergoing orthotopic liver transplantation. World J Transplant 2023; 13:122-128. [PMID: 37388394 PMCID: PMC10303411 DOI: 10.5500/wjt.v13.i4.122] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/28/2023] [Accepted: 04/12/2023] [Indexed: 06/16/2023] Open
Abstract
Acute liver failure (ALF) may result in severe neurological complications caused by cerebral edema and elevated intracranial pressure (ICP). Multiple pathogenic mechanisms explain the elevated ICP, and newer hypotheses have been descri bed. While invasive ICP monitoring (ICPM) may have a role in ALF management, these patients are typically coagulopathic and at risk for intracranial hemorrhage. ICPM is the subject of much debate, and significant heterogeneity exists in clinical practice regarding its use. Contemporary ICPM techniques and coagulopathy reversal strategies may be associated with a lower risk of hemor rhage; however, most of the evidence is limited by its retrospective nature and relatively small sample size.
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Affiliation(s)
- Luis Eduardo Mendoza Vasquez
- Department of Anesthesia and Perioperative Medicine, London Health Science Centre, London N6A 5A5, Ontario, Canada
| | - Sonja Payne
- Department of Anesthesia and Perioperative Medicine, London Health Science Centre, London N6A 5A5, Ontario, Canada
| | - Raffael Zamper
- Department of Anesthesia and Perioperative Medicine, London Health Science Centre, London N6A 5A5, Ontario, Canada
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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Cellular Pathogenesis of Hepatic Encephalopathy: An Update. Biomolecules 2023; 13:biom13020396. [PMID: 36830765 PMCID: PMC9953810 DOI: 10.3390/biom13020396] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/01/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions.
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28
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Luo M, Xin RJ, Hu FR, Yao L, Hu SJ, Bai FH. Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis. World J Gastroenterol 2023; 29:144-156. [PMID: 36683714 PMCID: PMC9850958 DOI: 10.3748/wjg.v29.i1.144] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/23/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety; however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.
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Affiliation(s)
- Ming Luo
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Rui-Juan Xin
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Fang-Rui Hu
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Li Yao
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Sheng-Juan Hu
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Fei-Hu Bai
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
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Zhang C, Luo G, Lin J, Zhao Z, Luo M, Li H. Identification of significant modules and hub genes involved in hepatic encephalopathy using WGCNA. Eur J Med Res 2022; 27:264. [PMID: 36424620 PMCID: PMC9685938 DOI: 10.1186/s40001-022-00898-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/11/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a reversible syndrome of brain dysfunction caused by advanced liver disease. Weighted gene co-expression network analysis (WGCNA) could establish a robust co-expression network to identify the hub genes and underlying biological functions. This study was aimed to explore the potential therapeutic targets in HE by WGCNA. RESULTS The green and brown modules were found to be significantly associated with the development of HE. Functional enrichment analyses suggested the neuroinflammation, neuroimmune, extracellular matrix (ECM), and coagulation cascade were involved in HE. CYBB and FOXO1 were calculated as hub genes, which were upregulated in the HE patients. Tamibarotene and vitamin E were suggested as possible drug candidates to alleviate HE. CONCLUSIONS It is the first time to analyze transcriptomic data of HE by WGCNA. Our study not only promoted the current understanding of neuroinflammation in HE, but also provided the first evidence that CYBB and FOXO1 played pivotal roles in the pathogenesis of HE, which might be potential biomarkers and therapeutic targets. Tamibarotene might be a novel drug compound against HE.
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Affiliation(s)
- Chihao Zhang
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011 China
| | - Guqing Luo
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011 China
| | - Jiayun Lin
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011 China
| | - Zhifeng Zhao
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011 China
| | - Meng Luo
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011 China
| | - Hongjie Li
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011 China
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Reactive Microgliosis in Sepsis-Associated and Acute Hepatic Encephalopathies: An Ultrastructural Study. Int J Mol Sci 2022; 23:ijms232214455. [PMID: 36430933 PMCID: PMC9696099 DOI: 10.3390/ijms232214455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/17/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022] Open
Abstract
Sepsis and acute liver failure are associated with severe endogenous intoxication. Microglia, which are the resident immune brain cells, play diverse roles in central nervous system development, surveillance, and defense, as well as contributing to neuroinflammatory reactions. In particular, microglia are fundamental to the pathophysiology of reactive toxic encephalopathies. We analyzed microglial ultrastructure, morphotypes, and phagocytosis in the sensorimotor cortex of cecal ligation and puncture (CLP) and acetaminophen-induced liver failure (AILF) Wistar rats. A CLP model induced a gradual shift of ~50% of surveillant microglia to amoeboid hypertrophic-like and gitter cell-like reactive phenotypes with active phagocytosis and frequent contacts with damaged neurons. In contrast, AILF microglia exhibited amoeboid, rod-like, and hypertrophic-like reactive morphotypes with minimal indications for efficient phagocytosis, and were mostly in contact with edematous astrocytes. Close interactions of reactive microglia with neurons, astrocytes, and blood-brain barrier components reflect an active contribution of these cells to the tissue adaptation and cellular remodeling to toxic brain damage. Partial disability of reactive microglia may affect the integrity and metabolism in all tissue compartments, leading to failure of the compensatory mechanisms in acute endogenous toxic encephalopathies.
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31
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Mikkelsen ACD, Thomsen KL, Mookerjee RP, Hadjihambi A. The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy. Metab Brain Dis 2022; 38:1707-1716. [PMID: 36326976 DOI: 10.1007/s11011-022-01105-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022]
Abstract
Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.
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Affiliation(s)
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- UCL Institute of Liver and Digestive Health, University College London, London, UK
| | - Rajeshwar Prosad Mookerjee
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- UCL Institute of Liver and Digestive Health, University College London, London, UK
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, SE5 9NT, UK.
- Faculty of Life Sciences and Medicine, King's College London, London, UK.
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Host-microbiome interactions: Gut-Liver axis and its connection with other organs. NPJ Biofilms Microbiomes 2022; 8:89. [PMID: 36319663 PMCID: PMC9626460 DOI: 10.1038/s41522-022-00352-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/18/2022] [Indexed: 11/26/2022] Open
Abstract
An understanding of connections between gut microbiome and liver has provided important insights into the pathophysiology of liver diseases. Since gut microbial dysbiosis increases gut permeability, the metabolites biosynthesized by them can reach the liver through portal circulation and affect hepatic immunity and inflammation. The immune cells activated by these metabolites can also reach liver through lymphatic circulation. Liver influences immunity and metabolism in multiple organs in the body, including gut. It releases bile acids and other metabolites into biliary tract from where they enter the systemic circulation. In this review, the bidirectional communication between the gut and the liver and the molecular cross talk between the host and the microbiome has been discussed. This review also provides details into the intricate level of communication and the role of microbiome in Gut-Liver-Brain, Gut-Liver-Kidney, Gut-Liver-Lung, and Gut-Liver-Heart axes. These observations indicate a complex network of interactions between host organs influenced by gut microbiome.
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A mouse model of hepatic encephalopathy: bile duct ligation induces brain ammonia overload, glial cell activation and neuroinflammation. Sci Rep 2022; 12:17558. [PMID: 36266427 PMCID: PMC9585018 DOI: 10.1038/s41598-022-22423-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 10/14/2022] [Indexed: 01/13/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common complication of chronic liver disease, characterized by an altered mental state and hyperammonemia. Insight into the brain pathophysiology of HE is limited due to a paucity of well-characterized HE models beyond the rat bile duct ligation (BDL) model. Here, we assess the presence of HE characteristics in the mouse BDL model. We show that BDL in C57Bl/6j mice induces motor dysfunction, progressive liver fibrosis, liver function failure and hyperammonemia, all hallmarks of HE. Swiss mice however fail to replicate the same phenotype, underscoring the importance of careful strain selection. Next, in-depth characterisation of metabolic disturbances in the cerebrospinal fluid of BDL mice shows glutamine accumulation and transient decreases in taurine and choline, indicative of brain ammonia overload. Moreover, mouse BDL induces glial cell dysfunction, namely microglial morphological changes with neuroinflammation and astrocyte reactivity with blood-brain barrier (BBB) disruption. Finally, we identify putative novel mechanisms involved in central HE pathophysiology, like bile acid accumulation and tryptophan-kynurenine pathway alterations. Our study provides the first comprehensive evaluation of a mouse model of HE in chronic liver disease. Additionally, this study further underscores the importance of neuroinflammation in the central effects of chronic liver disease.
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Roy S, Chakrabarti M, Dasgupta H, Mahale A, Tripathi S, Sharma V, Banerjee M, Kulkarni OP. Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy. ACS Chem Neurosci 2022; 13:2829-2841. [PMID: 36112416 DOI: 10.1021/acschemneuro.2c00046] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1β (interleukin-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1β, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH4CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.
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Affiliation(s)
- Subhasis Roy
- TCG Life Sciences Private Ltd., Biolab, Bengal Intelligent Park Ltd., Block EP and GP, Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Monali Chakrabarti
- TCG Life Sciences Private Ltd., Biolab, Bengal Intelligent Park Ltd., Block EP and GP, Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Hemantika Dasgupta
- TCG Life Sciences Private Ltd., Biolab, Bengal Intelligent Park Ltd., Block EP and GP, Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Ashutosh Mahale
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Hyderabad 500078, India
| | - Shraddha Tripathi
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Ranga Reddy District, Hyderabad 500078, India
| | - Vivek Sharma
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Ranga Reddy District, Hyderabad 500078, India
| | - Manish Banerjee
- TCG Life Sciences Private Ltd., Biolab, Bengal Intelligent Park Ltd., Block EP and GP, Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Onkar Prakash Kulkarni
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Hyderabad 500078, India
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Ramos A, Joshi RS, Szabo G. Innate immune activation: Parallels in alcohol use disorder and Alzheimer’s disease. Front Mol Neurosci 2022; 15:910298. [PMID: 36157070 PMCID: PMC9505690 DOI: 10.3389/fnmol.2022.910298] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/18/2022] [Indexed: 11/16/2022] Open
Abstract
Alcohol use disorder is associated with systemic inflammation and organ dysfunction especially in the liver and the brain. For more than a decade, studies have highlighted alcohol abuse-mediated impairment of brain function and acceleration of neurodegeneration through inflammatory mechanisms that directly involve innate immune cells. Furthermore, recent studies indicate overlapping genetic risk factors between alcohol use and neurodegenerative disorders, specifically regarding the role of innate immunity in the pathomechanisms of both areas. Considering the pressing need for a better understanding of the relevance of alcohol abuse in dementia progression, here we summarize the molecular mechanisms of neuroinflammation observed in alcohol abuse and Alzheimer’s disease, the most common cause of dementia. In addition, we highlight mechanisms that are already established in the field of Alzheimer’s disease that may be relevant to explore in alcoholism to better understand alcohol mediated neurodegeneration and dementia, including the relevance of the liver-brain axis.
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Affiliation(s)
- Adriana Ramos
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Radhika S. Joshi
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- *Correspondence: Gyongyi Szabo,
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36
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Zhao L, Li Y, Wang Y, Ge Z, Zhu H, Zhou X, Li Y. Non-hepatic Hyperammonemia: A Potential Therapeutic Target for Sepsis-associated Encephalopathy. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2022; 21:738-751. [PMID: 34939553 DOI: 10.2174/1871527321666211221161534] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/10/2021] [Accepted: 10/26/2021] [Indexed: 11/22/2022]
Abstract
Sepsis-Associated Encephalopathy (SAE) is a common complication in the acute phase of sepsis, and patients who develop SAE have a higher mortality rate, longer hospital stay, and worse quality of life than other sepsis patients. Although the incidence of SAE is as high as 70% in sepsis patients, no effective treatment is available for this condition. To develop an effective treatment for SAE, it is vital to explore its pathogenesis. It is known that hyperammonemia is a possible factor in the pathogenesis of hepatic encephalopathy as ammonia is a potent neurotoxin. Furthermore, our previous studies indicate that non-hepatic hyperammonemia seems to occur more often in sepsis patients; it was also found that >50% of sepsis patients with non-hepatic hyperammonemia exhibited encephalopathy and delirium. Substatistical analyses indicate that non-hepatic hyperammonemia is an independent risk factor for SAE. This study updates the definition, clinical manifestations, and diagnosis of SAE; it also investigates the possible treatment options available for non-hepatic hyperammonemia in patients with sepsis and the mechanisms by which non-hepatic hyperammonemia causes encephalopathy.
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Affiliation(s)
- Lina Zhao
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yun Li
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng Clinical Medical College of Inner Mongolia Medical University, Chifeng 024000, China
| | - Yunying Wang
- Department of Critical Care Medicine, Chifeng Municipal Hospital, Chifeng Clinical Medical College of Inner Mongolia Medical University, Chifeng 024000, China
| | - Zengzheng Ge
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Huadong Zhu
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiuhua Zhou
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yi Li
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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37
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Simicic D, Cudalbu C, Pierzchala K. Overview of oxidative stress findings in hepatic encephalopathy: From cellular and ammonium-based animal models to human data. Anal Biochem 2022; 654:114795. [PMID: 35753389 DOI: 10.1016/j.ab.2022.114795] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/26/2022] [Accepted: 06/15/2022] [Indexed: 11/30/2022]
Abstract
Oxidative stress is a natural phenomenon in the body. Under physiological conditions intracellular reactive oxygen species (ROS) are normal components of signal transduction cascades, and their levels are maintained by a complex antioxidants systems participating in the in-vivo redox homeostasis. Increased oxidative stress is present in several chronic diseases and interferes with phagocytic and nervous cell functions, causing an up-regulation of cytokines and inflammation. Hepatic encephalopathy (HE) occurs in both acute liver failure (ALF) and chronic liver disease. Increased blood and brain ammonium has been considered as an important factor in pathogenesis of HE and has been associated with inflammation, neurotoxicity, and oxidative stress. The relationship between ROS and the pathophysiology of HE is still poorly understood. Therefore, sensing ROS production for a better understanding of the relationship between oxidative stress and functional outcome in HE pathophysiology is critical for determining the disease mechanisms, as well as to improve the management of patients. This review is emphasizing the important role of oxidative stress in HE development and documents the changes occurring as a consequence of oxidative stress augmentation based on cellular and ammonium-based animal models to human data.
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Affiliation(s)
- D Simicic
- CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland
| | - C Cudalbu
- CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - K Pierzchala
- CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland.
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38
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Häussinger D, Dhiman RK, Felipo V, Görg B, Jalan R, Kircheis G, Merli M, Montagnese S, Romero-Gomez M, Schnitzler A, Taylor-Robinson SD, Vilstrup H. Hepatic encephalopathy. Nat Rev Dis Primers 2022; 8:43. [PMID: 35739133 DOI: 10.1038/s41572-022-00366-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 01/18/2023]
Abstract
Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.
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Affiliation(s)
- Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Radha K Dhiman
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, (Uttar Pradesh), India
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain
| | - Boris Görg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Rajiv Jalan
- Liver Failure Group ILDH, Division of Medicine, UCL Medical School, Royal Free Campus, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Gerald Kircheis
- Department of Gastroenterology, Diabetology and Hepatology, University Hospital Brandenburg an der Havel, Brandenburg Medical School, Brandenburg an der Havel, Germany
| | - Manuela Merli
- Department of Translational and Precision Medicine, Universita' degli Studi di Roma - Sapienza, Roma, Italy
| | | | - Manuel Romero-Gomez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Seville, Spain
| | - Alfons Schnitzler
- Institute of Clinical Neuroscience and Medical Psychology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Simon D Taylor-Robinson
- Department of Surgery and Cancer, St. Mary's Hospital Campus, Imperial College London, London, UK
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Leone P, Mincheva G, Balzano T, Malaguarnera M, Felipo V, Llansola M. Rifaximin Improves Spatial Learning and Memory Impairment in Rats with Liver Damage-Associated Neuroinflammation. Biomedicines 2022; 10:1263. [PMID: 35740285 PMCID: PMC9219896 DOI: 10.3390/biomedicines10061263] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/23/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022] Open
Abstract
Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment.
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Affiliation(s)
- Paola Leone
- Mar Lab Department of Neuroscience, NYU Grossman School of Medicine Science Building, New York, NY 10016, USA;
| | - Gergana Mincheva
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; (G.M.); (M.L.)
| | - Tiziano Balzano
- Centro Integral de Neurociencias, A.C. HM Hospital Universitario Puerta del Sur CINAC, 28938 Madrid, Spain;
| | - Michele Malaguarnera
- Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, 46010 Valencia, Spain;
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; (G.M.); (M.L.)
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; (G.M.); (M.L.)
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40
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Olate-Briones A, Escalona E, Salazar C, Herrada MJ, Liu C, Herrada AA, Escobedo N. The meningeal lymphatic vasculature in neuroinflammation. FASEB J 2022; 36:e22276. [PMID: 35344212 DOI: 10.1096/fj.202101574rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/08/2022] [Accepted: 03/14/2022] [Indexed: 12/13/2022]
Abstract
The lymphatic vasculature is a unidirectional network of lymphatic endothelial cells, whose main role is to maintain fluid homeostasis along with the absorption of dietary fat in the gastrointestinal organs and management and coordination of immune cell trafficking into lymph nodes during homeostasis and under inflammatory conditions. In homeostatic conditions, immune cells, such as dendritic cells, macrophages, or T cells can enter into the lymphatic vasculature and move easily through the lymph reaching secondary lymph nodes where immune cell activation or peripheral tolerance can be modulated. However, under inflammatory conditions such as pathogen infection, increased permeabilization of lymphatic vessels allows faster immune cell migration into inflamed tissues following a chemokine gradient, facilitating pathogen clearance and the resolution of inflammation. Interestingly, since the re-discovery of lymphatic vasculature in the central nervous system, known as the meningeal lymphatic vasculature, the role of these lymphatics as a key player in several neurological disorders has been described, with emphasis on the neurodegenerative process. Alternatively, less has been discussed about meningeal lymphatics and its role in neuroinflammation. In this review, we discuss current knowledge about the anatomy and function of the meningeal lymphatic vasculature and specifically analyze its contribution to different neuroinflammatory processes, highlighting the potential therapeutic target of meningeal lymphatic vasculature in these pathological conditions.
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Affiliation(s)
- Alexandra Olate-Briones
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Emilia Escalona
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Celia Salazar
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | | | - Chaohong Liu
- Department of Microbiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Andrés A Herrada
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Noelia Escobedo
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
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Weng ZB, Chen YR, Lv JT, Wang MX, Chen ZY, Zhou W, Shen XC, Zhan LB, Wang F. A Review of Bile Acid Metabolism and Signaling in Cognitive Dysfunction-Related Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4289383. [PMID: 35308170 PMCID: PMC8933076 DOI: 10.1155/2022/4289383] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/14/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022]
Abstract
Bile acids are commonly known as one of the vital metabolites derived from cholesterol. The role of bile acids in glycolipid metabolism and their mechanisms in liver and cholestatic diseases have been well studied. In addition, bile acids also serve as ligands of signal molecules such as FXR, TGR5, and S1PR2 to regulate some physiological processes in vivo. Recent studies have found that bile acids signaling may also play a critical role in the central nervous system. Evidence showed that some bile acids have exhibited neuroprotective effects in experimental animal models and clinical trials of many cognitive dysfunction-related diseases. Besides, alterations in bile acid metabolisms well as the expression of different bile acid receptors have been discovered as possible biomarkers for prognosis tools in multiple cognitive dysfunction-related diseases. This review summarizes biosynthesis and regulation of bile acids, receptor classification and characteristics, receptor agonists and signaling transduction, and recent findings in cognitive dysfunction-related diseases.
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Affiliation(s)
- Ze-Bin Weng
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan-Rong Chen
- College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
| | - Jin-Tao Lv
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min-Xin Wang
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zheng-Yuan Chen
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wen Zhou
- School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin-Chun Shen
- College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
| | - Li-Bin Zhan
- The Innovation Engineering Technology Center of Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Fang Wang
- College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
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Sun CP, Zhou JJ, Yu ZL, Huo XK, Zhang J, Morisseau C, Hammock BD, Ma XC. Kurarinone alleviated Parkinson's disease via stabilization of epoxyeicosatrienoic acids in animal model. Proc Natl Acad Sci U S A 2022; 119:e2118818119. [PMID: 35217618 PMCID: PMC8892522 DOI: 10.1073/pnas.2118818119] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 01/19/2022] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing bradykinesia and rest tremors. Although the molecular mechanism of PD is still not fully understood, neuroinflammation has a key role in the damage of dopaminergic neurons. Herein, we found that kurarinone, a unique natural product from Sophora flavescens, alleviated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic neurotoxicity, including the losses of neurotransmitters and tyrosine hydroxylase (TH)-positive cells (SN and striatum [STR]). Furthermore, kurarinone attenuated the MPTP-mediated neuroinflammation via suppressing the activation of microglia involved in the nuclear factor kappa B signaling pathway. The proteomics result of the solvent-induced protein precipitation and thermal proteome profiling suggest that the soluble epoxide hydrolase (sEH) enzyme, which is associated with the neuroinflammation of PD, is a promising target of kurarinone. This is supported by the increase of plasma epoxyeicosatrienoic acids (sEH substrates) and the decrease of dihydroxyeicosatrienoic acids (sEH products), and the results of in vitro inhibition kinetics, surface plasmon resonance, and cocrystallization of kurarinone with sEH revealed that this natural compound is an uncompetitive inhibitor. In addition, sEH knockout (KO) attenuated the progression of PD, and sEH KO plus kurarinone did not further reduce the protection of PD in MPTP-induced PD mice. These findings suggest that kurarinone could be a potential natural candidate for the treatment of PD, possibly through sEH inhibition.
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Affiliation(s)
- Cheng-Peng Sun
- College of Pharmacy, The Second Affiliated Hospital, Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Jun-Jun Zhou
- College of Pharmacy, The Second Affiliated Hospital, Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Zhen-Long Yu
- College of Pharmacy, The Second Affiliated Hospital, Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Xiao-Kui Huo
- College of Pharmacy, The Second Affiliated Hospital, Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Juan Zhang
- College of Pharmacy, The Second Affiliated Hospital, Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Christophe Morisseau
- Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616
| | - Bruce D Hammock
- Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616
| | - Xiao-Chi Ma
- College of Pharmacy, The Second Affiliated Hospital, Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China;
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Ismail FS, Corvace F, Faustmann PM, Faustmann TJ. Pharmacological Investigations in Glia Culture Model of Inflammation. Front Cell Neurosci 2022; 15:805755. [PMID: 34975415 PMCID: PMC8716582 DOI: 10.3389/fncel.2021.805755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 11/26/2021] [Indexed: 12/11/2022] Open
Abstract
Astrocytes and microglia are the main cell population besides neurons in the central nervous system (CNS). Astrocytes support the neuronal network via maintenance of transmitter and ion homeostasis. They are part of the tripartite synapse, composed of pre- and postsynaptic neurons and perisynaptic astrocytic processes as a functional unit. There is an increasing evidence that astroglia are involved in the pathophysiology of CNS disorders such as epilepsy, autoimmune CNS diseases or neuropsychiatric disorders, especially with regard to glia-mediated inflammation. In addition to astrocytes, investigations on microglial cells, the main immune cells of the CNS, offer a whole network approach leading to better understanding of non-neuronal cells and their pathological role in CNS diseases and treatment. An in vitro astrocyte-microglia co-culture model of inflammation was developed by Faustmann et al. (2003), which allows to study the endogenous inflammatory reaction and the cytokine expression under drugs in a differentiated manner. Commonly used antiepileptic drugs (e.g., levetiracetam, valproic acid, carbamazepine, phenytoin, and gabapentin), immunomodulatory drugs (e.g., dexamethasone and interferon-beta), hormones and psychotropic drugs (e.g., venlafaxine) were already investigated, contributing to better understanding mechanisms of actions of CNS drugs and their pro- or anti-inflammatory properties concerning glial cells. Furthermore, the effects of drugs on glial cell viability, proliferation and astrocytic network were demonstrated. The in vitro astrocyte-microglia co-culture model of inflammation proved to be suitable as unique in vitro model for pharmacological investigations on astrocytes and microglia with future potential (e.g., cancer drugs, antidementia drugs, and toxicologic studies).
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Affiliation(s)
- Fatme Seval Ismail
- Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany
| | - Franco Corvace
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
| | - Pedro M Faustmann
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
| | - Timo Jendrik Faustmann
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Pierzchala K, Simicic D, Sienkiewicz A, Sessa D, Mitrea S, Braissant O, McLin VA, Gruetter R, Cudalbu C. Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy. Free Radic Biol Med 2022; 178:295-307. [PMID: 34890769 DOI: 10.1016/j.freeradbiomed.2021.12.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/12/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023]
Abstract
The role and coexistence of oxidative stress (OS) and inflammation in type C hepatic encephalopathy (C HE) is a subject of intense debate. Under normal conditions the physiological levels of intracellular reactive oxygen species are controlled by the counteracting antioxidant response to maintain redox homeostasis. Our previous in-vivo1H-MRS studies revealed the longitudinal impairment of the antioxidant system (ascorbate) in a bile-duct ligation (BDL) rat model of type C HE. Therefore, the aim of this work was to examine the course of central nervous system (CNS) OS and systemic OS, as well as to check for their co-existence with inflammation in the BDL rat model of type C HE. To this end, we implemented a multidisciplinary approach, including ex-vivo and in-vitro electron paramagnetic resonance spectroscopy (EPR) spin-trapping, which was combined with UV-Vis spectroscopy, and histological assessments. We hypothesized that OS and inflammation act synergistically in the pathophysiology of type C HE. Our findings point to an increased CNS- and systemic-OS and inflammation over the course of type C HE progression. In particular, an increase in the CNS OS was observed as early as 2-weeks post-BDL, while the systemic OS became significant at week 6 post-BDL. The CNS EPR measurements were further validated by a substantial accumulation of 8-Oxo-2'-deoxyguanosine (Oxo-8-dG), a marker of oxidative DNA/RNA modifications on immunohistochemistry (IHC). Using IHC, we also detected increased synthesis of antioxidants, glutathione peroxidase 1 (GPX-1) and superoxide dismutases (i.e.Cu/ZnSOD (SOD1) and MnSOD (SOD2)), along with proinflammatory cytokine interleukin-6 (IL-6) in the brains of BDL rats. The presence of systemic inflammation was observed already at 2-weeks post-surgery. Thus, these results suggest that CNS OS is an early event in type C HE rat model, which seems to precede systemic OS. Finally, our results suggest that the increase in CNS OS is due to enhanced formation of intra- and extra-cellular ROS rather than due to reduced antioxidant capacity, and that OS in parallel with inflammation plays a significant role in type C HE.
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Affiliation(s)
- K Pierzchala
- Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland.
| | - D Simicic
- Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland
| | - A Sienkiewicz
- Laboratory for Quantum Magnetism, Institute of Physics, EPFL, Lausanne, Switzerland; ADSresonances Sàrl, Préverenges, Switzerland
| | - D Sessa
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
| | - S Mitrea
- Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - O Braissant
- Service of Clinical Chemistry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - V A McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
| | - R Gruetter
- Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland
| | - C Cudalbu
- Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules 2021; 12:biom12010056. [PMID: 35053205 PMCID: PMC8774162 DOI: 10.3390/biom12010056] [Citation(s) in RCA: 151] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.
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Zoratti C, Moretti R, Rebuzzi L, Albergati IV, Di Somma A, Decorti G, Di Bella S, Crocè LS, Giuffrè M. Antibiotics and Liver Cirrhosis: What the Physicians Need to Know. Antibiotics (Basel) 2021; 11:31. [PMID: 35052907 PMCID: PMC8772826 DOI: 10.3390/antibiotics11010031] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
The liver is the primary site of drug metabolism, which can be altered by a variety of diseases affecting the liver parenchyma, especially in patients with liver cirrhosis. The use of antibiotics in patients with cirrhosis is usually a matter of concern for physicians, given the lack of practical knowledge for drug choice and eventual dose adjustments in several clinical scenarios. The aim of the current narrative review is to report, as broadly as possible, basic, and practical knowledge that any physician should have when approaching a patient with liver cirrhosis and an ongoing infection to efficiently choose the best antibiotic therapy.
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Affiliation(s)
- Caterina Zoratti
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Rita Moretti
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Lisa Rebuzzi
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Irma Valeria Albergati
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Antonietta Di Somma
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Giuliana Decorti
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137 Trieste, Italy;
| | - Stefano Di Bella
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Lory Saveria Crocè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
- Italian Liver Foundation, 34149 Trieste, Italy
| | - Mauro Giuffrè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
- Italian Liver Foundation, 34149 Trieste, Italy
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Quincozes-Santos A, Santos CL, de Souza Almeida RR, da Silva A, Thomaz NK, Costa NLF, Weber FB, Schmitz I, Medeiros LS, Medeiros L, Dotto BS, Dias FRP, Sovrani V, Bobermin LD. Gliotoxicity and Glioprotection: the Dual Role of Glial Cells. Mol Neurobiol 2021; 58:6577-6592. [PMID: 34581988 PMCID: PMC8477366 DOI: 10.1007/s12035-021-02574-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023]
Abstract
Glial cells (astrocytes, oligodendrocytes and microglia) are critical for the central nervous system (CNS) in both physiological and pathological conditions. With this in mind, several studies have indicated that glial cells play key roles in the development and progression of CNS diseases. In this sense, gliotoxicity can be referred as the cellular, molecular, and neurochemical changes that can mediate toxic effects or ultimately lead to impairment of the ability of glial cells to protect neurons and/or other glial cells. On the other hand, glioprotection is associated with specific responses of glial cells, by which they can protect themselves as well as neurons, resulting in an overall improvement of the CNS functioning. In addition, gliotoxic events, including metabolic stresses, inflammation, excitotoxicity, and oxidative stress, as well as their related mechanisms, are strongly associated with the pathogenesis of neurological, psychiatric and infectious diseases. However, glioprotective molecules can prevent or improve these glial dysfunctions, representing glial cells-targeting therapies. Therefore, this review will provide a brief summary of types and functions of glial cells and point out cellular and molecular mechanisms associated with gliotoxicity and glioprotection, potential glioprotective molecules and their mechanisms, as well as gliotherapy. In summary, we expect to address the relevance of gliotoxicity and glioprotection in the CNS homeostasis and diseases.
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Affiliation(s)
- André Quincozes-Santos
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil.
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil.
- Programa de Pós-Graduação Em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil.
| | - Camila Leite Santos
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Rômulo Rodrigo de Souza Almeida
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Amanda da Silva
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Natalie K Thomaz
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Naithan Ludian Fernandes Costa
- Programa de Pós-Graduação Em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Fernanda Becker Weber
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Izaviany Schmitz
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Lara Scopel Medeiros
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Lívia Medeiros
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Bethina Segabinazzi Dotto
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Filipe Renato Pereira Dias
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Vanessa Sovrani
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Larissa Daniele Bobermin
- Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
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Kronsten VT, Shawcross DL. Hepatic encephalopathy and depression in chronic liver disease: is the common link systemic inflammation? Anal Biochem 2021; 636:114437. [PMID: 34715068 DOI: 10.1016/j.ab.2021.114437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/26/2021] [Accepted: 10/22/2021] [Indexed: 02/08/2023]
Abstract
Hepatic encephalopathy and depression share a number of clinical features, such as cognitive impairment and psychomotor retardation, and are highly prevalent in patients with chronic liver disease. Both conditions signify a poor prognosis, carry an increased mortality and are major determinants of reduced health related quality of life. The pathophysiology of hepatic encephalopathy is complex. Whilst cerebral accumulation of ammonia is well-recognised as being central to the development of hepatic encephalopathy, systemic inflammation, which acts in synergy with hyperammonaemia, is emerging as a key driver in its development. The pro-inflammatory state is also widely documented in depression, and peripheral to brain communication occurs resulting in central inflammation, behavioural changes and depressive symptoms. Gut dysbiosis, with a similar reduction in beneficial bacteria, increase in pathogens and decreased bacterial diversity, has been observed in both hepatic encephalopathy and depression, and it may be that the resultant increased bacterial translocation causes their shared inflammatory pathophysiology. Whilst the literature on a positive association between hepatic encephalopathy and depression in cirrhosis remains to be substantiated, there is evolving evidence that treatment with psychobiotics may be of dual benefit, improving cognition and mood in cirrhosis.
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Affiliation(s)
- Victoria Tatiana Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK.
| | - Debbie Lindsay Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
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Role of SIRT1 in Hepatic Encephalopathy: In Vivo and In Vitro Studies Focusing on the NLRP3 Inflammasome. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5522708. [PMID: 34676022 PMCID: PMC8526203 DOI: 10.1155/2021/5522708] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/25/2021] [Accepted: 09/09/2021] [Indexed: 11/25/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric disorder resulting from acute or chronic liver failure. This study is aimed at investigating the therapeutic effects and mechanisms of SIRT1 in thioacetamide- (TAA-) induced rat HE models. A selective activator (CAY10602) and inhibitor (EX527) of SIRT1 were used in this study. All male rats were separated into control, TAA, CAY10602+TAA, and EX527+TAA groups. Histological damage, liver function, serum ammonia, behavioral changes, and brain oxidative stress were measured in each group. Western blotting was used to measure SIRT1, NLRP3, ASC, and IL-1β protein expression. The results showed that CAY10602 alleviated liver injury, improved neurological decline, reduced microglial activation and brain oxidative stress, and improved the survival rates of HE rats. Moreover, CAY10602 inhibited activation of the NLRP3 inflammasome in microglia of the brain cortex in HE rats. Next, cell experiments confirmed that CAY10602 inhibited activation of the NLRP3 inflammasome in BV2 microglial cells. However, inhibition of SIRT1 by EX527 or lentivirus could enhance activation of the NLRP3 inflammasome in this process. Finally, CAY10602 reduced the neurotoxicity induced by high levels of ammonia in HT22 cells. Taken together, CAY10602 alleviates TAA-induced HE by suppressing microglial activation and the NLRP3 inflammasome and reducing the neurotoxicity of NH4Cl in HT22 cells. A pharmacologic activator of SIRT1 may be a promising approach for the treatment of HE.
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Claeys W, Van Hoecke L, Lefere S, Geerts A, Verhelst X, Van Vlierberghe H, Degroote H, Devisscher L, Vandenbroucke RE, Van Steenkiste C. The neurogliovascular unit in hepatic encephalopathy. JHEP Rep 2021; 3:100352. [PMID: 34611619 PMCID: PMC8476774 DOI: 10.1016/j.jhepr.2021.100352] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/14/2021] [Accepted: 07/23/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of hepatic dysfunction and portosystemic shunting. It is highly prevalent in patients with cirrhosis and is associated with poor outcomes. New insights into the role of peripheral origins in HE have led to the development of innovative treatment strategies like faecal microbiota transplantation. However, this broadening of view has not been applied fully to perturbations in the central nervous system. The old paradigm that HE is the clinical manifestation of ammonia-induced astrocyte dysfunction and its secondary neuronal consequences requires updating. In this review, we will use the holistic concept of the neurogliovascular unit to describe central nervous system disturbances in HE, an approach that has proven instrumental in other neurological disorders. We will describe HE as a global dysfunction of the neurogliovascular unit, where blood flow and nutrient supply to the brain, as well as the function of the blood-brain barrier, are impaired. This leads to an accumulation of neurotoxic substances, chief among them ammonia and inflammatory mediators, causing dysfunction of astrocytes and microglia. Finally, glymphatic dysfunction impairs the clearance of these neurotoxins, further aggravating their effect on the brain. Taking a broader view of central nervous system alterations in liver disease could serve as the basis for further research into the specific brain pathophysiology of HE, as well as the development of therapeutic strategies specifically aimed at counteracting the often irreversible central nervous system damage seen in these patients.
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Key Words
- ABC, ATP-binding cassette
- ACLF, acute-on-chronic liver failure
- AD, acute decompensation
- ALF, acute liver failure
- AOM, azoxymethane
- AQP4, aquaporin 4
- Acute Liver Failure
- Ammonia
- BBB, blood-brain barrier
- BCRP, breast cancer resistance protein
- BDL, bile duct ligation
- Blood-brain barrier
- Brain edema
- CCL, chemokine ligand
- CCR, C-C chemokine receptor
- CE, cerebral oedema
- CLD, chronic liver disease
- CLDN, claudin
- CNS, central nervous system
- CSF, cerebrospinal fluid
- Cirrhosis
- Energy metabolism
- GS, glutamine synthetase
- Glymphatic system
- HE, hepatic encephalopathy
- HO-1, heme oxygenase 1
- IL-, interleukin
- MMP-9, matrix metalloproteinase 9
- MRP, multidrug resistance associated protein
- NGVU
- NGVU, neurogliovascular unit
- NKCC1, Na-K-2Cl cotransporter 1
- Neuroinflammation
- OCLN, occludin
- ONS, oxidative and nitrosative stress
- Oxidative stress
- P-gp, P-glycoprotein
- PCA, portacaval anastomosis
- PSS, portosystemic shunt
- S1PR2, sphingosine-1-phosphate receptor 2
- SUR1, sulfonylurea receptor 1
- Systemic inflammation
- TAA, thioacetamide
- TGFβ, transforming growth factor beta
- TJ, tight junction
- TNF, tumour necrosis factor
- TNFR1, tumour necrosis factor receptor 1
- ZO, zonula occludens
- mPT, mitochondrial pore transition
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Affiliation(s)
- Wouter Claeys
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
- Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Lien Van Hoecke
- Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent; Ghent University, Ghent, Belgium
| | - Anja Geerts
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Xavier Verhelst
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Helena Degroote
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent; Ghent University, Ghent, Belgium
| | - Roosmarijn E. Vandenbroucke
- Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Christophe Van Steenkiste
- Antwerp University, Department of Gastroenterology and Hepatology, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium
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