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Miao Z, Zhang X, Xu Y, Liu Y, Yang Q. Unveiling the nexus: pyroptosis and its crucial implications in liver diseases. Mol Cell Biochem 2025; 480:2159-2176. [PMID: 39477911 DOI: 10.1007/s11010-024-05147-1] [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: 06/12/2024] [Accepted: 10/22/2024] [Indexed: 04/02/2025]
Abstract
Pyroptosis, a distinctive form of programmed cell death orchestrated by gasdermin proteins, manifests as cellular rupture, accompanied by the release of inflammatory factors. While pyroptosis is integral to anti-infection immunity, its aberrant activation has been implicated in tumorigenesis. The liver, as the body's largest metabolic organ, is rich in various enzymes and governs metabolism. It is also the primary site for protein synthesis. Recent years have witnessed the emergence of pyroptosis as a significant player in the pathogenesis of specific liver diseases, exerting a pivotal role in both physiological and pathological processes. A comprehensive exploration of pyroptosis can unveil its contributions to the development and regression of conditions such as hepatitis, cirrhosis, and hepatocellular carcinoma, offering innovative perspectives for clinical prevention and treatment. This review consolidates current knowledge on key molecules involved in cellular pyroptosis and delineates their roles in liver diseases. Furthermore, we discuss the potential of leveraging pyroptosis as a novel or existing anti-cancer strategy.
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Affiliation(s)
- Zeyu Miao
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Xiaorong Zhang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yang Xu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yan Liu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China.
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2
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Mata-Martínez E, Ramírez-Ledesma MG, Vázquez-Victorio G, Hernández-Muñoz R, Díaz-Muñoz M, Vázquez-Cuevas FG. Purinergic Signaling in Non-Parenchymal Liver Cells. Int J Mol Sci 2024; 25:9447. [PMID: 39273394 PMCID: PMC11394727 DOI: 10.3390/ijms25179447] [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: 08/15/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Purinergic signaling has emerged as an important paracrine-autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions.
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Affiliation(s)
- Esperanza Mata-Martínez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - María Guadalupe Ramírez-Ledesma
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Genaro Vázquez-Victorio
- Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Ciudad Universitaria, Mexico City 04510, Mexico
| | - Rolando Hernández-Muñoz
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Francisco G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
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3
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McGill MR. The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans. Drug Metab Dispos 2024; 52:729-739. [PMID: 37918967 PMCID: PMC11257692 DOI: 10.1124/dmd.123.001281] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/18/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023] Open
Abstract
Our understanding of the fundamental molecular mechanisms of acetaminophen (APAP) hepatotoxicity began in 1973 to 1974, when investigators at the US National Institutes of Health published seminal studies demonstrating conversion of APAP to a reactive metabolite that depletes glutathione and binds to proteins in the liver in mice after overdose. Since then, additional groundbreaking experiments have demonstrated critical roles for mitochondrial damage, oxidative stress, nuclear DNA fragmentation, and necrotic cell death as well. Over the years, some investigators have also attempted to translate these mechanisms to humans using human specimens from APAP overdose patients. This review presents those studies and summarizes what we have learned about APAP hepatotoxicity in humans so far. Overall, the mechanisms of APAP hepatotoxicity in humans strongly resemble those discovered in experimental mouse and cultured hepatocyte models, and emerging biomarkers also suggest similarities in liver repair. The data not only validate the first mechanistic studies of APAP-induced liver injury performed 50 years ago but also demonstrate the human relevance of numerous studies conducted since then. SIGNIFICANCE STATEMENT: Human studies using novel translational, mechanistic biomarkers have confirmed that the fundamental mechanisms of acetaminophen (APAP) hepatotoxicity discovered in rodent models since 1973 are the same in humans. Importantly, these findings have guided the development and understanding of treatments such as N-acetyl-l-cysteine and 4-methylpyrazole over the years. Additional research may improve not only our understanding of APAP overdose pathophysiology in humans but also our ability to predict and treat serious liver injury in patients.
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Affiliation(s)
- Mitchell R McGill
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health; Department of Pharmacology and Toxicology, College of Medicine; and Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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4
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Yu SM, Zheng HC, Wang SC, Rong WY, Li P, Jing J, He TT, Li JH, Ding X, Wang RL. Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury. World J Gastroenterol 2024; 30:2454-2466. [PMID: 38764769 PMCID: PMC11099387 DOI: 10.3748/wjg.v30.i18.2454] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/05/2024] [Accepted: 04/18/2024] [Indexed: 05/11/2024] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.
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Affiliation(s)
- Si-Miao Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hao-Cheng Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Si-Ci Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wen-Ya Rong
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ping Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jing Jing
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
| | - Ting-Ting He
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
| | - Jia-Hui Li
- The First Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Rui-Lin Wang
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
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Ghrayeb A, Finney AC, Agranovich B, Peled D, Anand SK, McKinney MP, Sarji M, Yang D, Weissman N, Drucker S, Fernandes SI, Fernández-García J, Mahan K, Abassi Z, Tan L, Lorenzi PL, Traylor J, Zhang J, Abramovich I, Chen YE, Rom O, Mor I, Gottlieb E. Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD. Cell Metab 2024; 36:116-129.e7. [PMID: 38171331 PMCID: PMC10777734 DOI: 10.1016/j.cmet.2023.12.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 10/27/2023] [Accepted: 12/08/2023] [Indexed: 01/05/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
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Affiliation(s)
- Alia Ghrayeb
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Alexandra C Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
| | - Bella Agranovich
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Daniel Peled
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Sumit Kumar Anand
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
| | - M Peyton McKinney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
| | - Mahasen Sarji
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Dongshan Yang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Natan Weissman
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Shani Drucker
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Sara Isabel Fernandes
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Jonatan Fernández-García
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Kyle Mahan
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Zaid Abassi
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Lin Tan
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Philip L Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - James Traylor
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ifat Abramovich
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
| | - Inbal Mor
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
| | - Eyal Gottlieb
- Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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6
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Kara A, Ozkanlar S. Blockade of P2X7 receptor-mediated purinergic signaling with A438079 protects against LPS-induced liver injury in rats. J Biochem Mol Toxicol 2023; 37:e23443. [PMID: 37365769 DOI: 10.1002/jbt.23443] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 02/05/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023]
Abstract
The study aimed to investigate the hepatoprotective effects of purinergic receptor (P2X7R) antagonism by A438079 in liver damage. An experimental model of inflammation was performed by intraperitoneal (i.p.) lipopolysaccharide (LPS) administration in the rat. The groups were Control, A438079, dimethyl sulfoxide (DMSO), LPS, LPS + DMSO, and LPS + A438079. Following LPS (8 mg/kg) injection, A438079 (15 mg/kg) and DMSO (0.1 mL) were administrated (i.p) in the study groups. The blood and the liver tissues were removed for histological, biochemical, and western blot analyses. In the biochemical analysis, serum aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, the tissue glutathione (GSH) level, and superoxide dismutase (SOD) activity dramatically decreased and malondialdehyde (MDA) level increased in the LPS and LPS + DMSO groups compared to the LPS + A438079 group. In the histological analysis, severe sinusoidal dilatation, necrotic hepatocytes, and inflammatory cell infiltration were observed in the LPS and LPS + DMSO groups while these effects were lessened in the LPS + A438079 group. The relative protein expression levels of P2X7R, Nf-kB-p65, IL-6, and Caspase-3 were significantly higher in the LPS and the LPS + DMSO groups than in the LPS + A438079 group. On the other hand, these protein expressions were considerably lower in the Control, A438079, and DMSO groups compared to the LPS + A438079 group. In addition, Bcl-2 protein expression was significantly lower in the LPS and the LPS + DMSO groups and higher in the LPS + A438079 group compared to the other groups. The protective effect of A438079 against LPS-induced hepatic inflammation may be related to P2X7R antagonism, inflammatory mediators, and apoptotic cell death.
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Affiliation(s)
- Adem Kara
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Seckin Ozkanlar
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
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Shaker ME, Gomaa HAM, Hazem SH, Abdelgawad MA, El-Mesery M, Shaaban AA. Mitigation of acetaminophen-induced liver toxicity by the novel phosphatidylinositol 3-kinase inhibitor alpelisib. Front Pharmacol 2023; 14:1212771. [PMID: 37608890 PMCID: PMC10441125 DOI: 10.3389/fphar.2023.1212771] [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: 04/26/2023] [Accepted: 07/26/2023] [Indexed: 08/24/2023] Open
Abstract
The sterile inflammatory response mediated by Toll-like receptors (TLRs) 4 and 9 is implicated in the massive hepatic damage caused by acetaminophen (APAP)-overdose. There is a crosstalk between TLR-dependent signaling with other intracellular kinases like phosphatidylinositol 3-kinases (PI3Ks). Nevertheless, the detailed role of PI3Kα is still unknown in hepatic sterile inflammation. Accordingly, the effect of the novel PI3Kα inhibitor alpelisib was investigated in the setting of APAP-driven sterile inflammation in the liver. This was examined by pretreating mice with alpelisib (5 and 10 mg/kg, oral) 2 h before APAP (500 mg/kg, i.p.)-intoxication. The results indicated that alpelisib dose-dependently lowered APAP-induced escalation in serum liver function biomarkers and hepatic necroinflammation score. Alpelisib also attenuated APAP-induced rise in cleaved caspase 3 and proliferating cell nuclear antigen (PCNA) in the liver hepatocytes, as indices for apoptosis and proliferation. Mechanistically, inhibition of PI3Kα by alpelisib limited APAP-induced overproduction of the pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the blood circulation via switching off the activation of several signal transduction proteins, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription-3 (Stat-3), glycogen Synthase Kinase (GSK)-3β and nuclear factor (NF)-κB. Alpelisib also impaired APAP-instigated immune cell infiltration in the liver via reducing systemic granulocyte/macrophage-colony stimulating factor (GM-CSF) release and reversed APAP-induced abnormalities in the systemic and hepatic levels of the anti-inflammatory IL-10 and IL-22. In conclusion, selective modulation of the PI3Kα activity by alpelisib can hinder the inflammatory response and infiltration of immune cells occurring by APAP-hepatotoxicity.
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Affiliation(s)
- Mohamed E. Shaker
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Hesham A. M. Gomaa
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Sara H. Hazem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed A. Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al-Jawf, Saudi Arabia
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Ahmed A. Shaaban
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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8
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Parthasarathy G, Hirsova P, Kostallari E, Sidhu GS, Ibrahim SH, Malhi H. Extracellular Vesicles in Hepatobiliary Health and Disease. Compr Physiol 2023; 13:4631-4658. [PMID: 37358519 PMCID: PMC10798368 DOI: 10.1002/cphy.c210046] [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] [Indexed: 06/27/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
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Affiliation(s)
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guneet S. Sidhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H. Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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9
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Li JH, Hepworth MR, O'Sullivan TE. Regulation of systemic metabolism by tissue-resident immune cell circuits. Immunity 2023; 56:1168-1186. [PMID: 37315533 PMCID: PMC10321269 DOI: 10.1016/j.immuni.2023.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/11/2023] [Accepted: 05/02/2023] [Indexed: 06/16/2023]
Abstract
Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
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Affiliation(s)
- Joey H Li
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA; Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Matthew R Hepworth
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA.
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10
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Li X, Bai X, Tang Y, Qiao C, Zhao R, Peng X. Research progress on the P2X7 receptor in liver injury and hepatocellular carcinoma. Chem Biol Drug Des 2023; 101:794-808. [PMID: 36403102 DOI: 10.1111/cbdd.14182] [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: 09/21/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
Purinergic ligand-gated ion channel 7 receptor (P2X7 receptor) is an adenosine triphosphate (ATP)-gated ion channel that is widely distributed on the surfaces of immune cells and tissues such as those in the liver, kidney, lung, intestine, and nervous system. Hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing incidence and mortality. Although many treatments for liver cancer have been studied, the prognosis for liver cancer is still very poor. Therefore, new liver cancer treatments are urgently needed. P2X7 receptor activation can secrete proinflammatory factors through the P2X7 receptor-NLRP3 signaling pathway, thereby affecting the progression of liver injury. The P2X7 receptor may be a target for growth inhibition of HCC cells and may affect the invasion and migration of HCC cells through the PI3K/AKT and AMPK signaling pathways. In recent years, P2X7 receptor antagonists or inhibitors have attracted widespread attention as therapeutic targets for hepatocellular carcinoma and liver injury. Therefore, this review covers the basic concepts of the P2X7 receptor and role of the P2X7 receptor in liver cancer and liver injury, providing new potential therapeutic targets for hepatocellular carcinoma and liver injury.
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Affiliation(s)
- Xinyu Li
- School of Medical Laboratory, Weifang Medical University, Weifang, China.,Institutional Key Laboratory of clinical laboratory Diagnostics, 12th 5-Year project of Shandong Province, Weifang Medical University, Weifang, China
| | - Xue Bai
- School of Medical Laboratory, Weifang Medical University, Weifang, China.,Institutional Key Laboratory of clinical laboratory Diagnostics, 12th 5-Year project of Shandong Province, Weifang Medical University, Weifang, China
| | - Yiqing Tang
- School of Medical Laboratory, Weifang Medical University, Weifang, China.,Institutional Key Laboratory of clinical laboratory Diagnostics, 12th 5-Year project of Shandong Province, Weifang Medical University, Weifang, China
| | - Cuicui Qiao
- School of Medical Laboratory, Weifang Medical University, Weifang, China.,Institutional Key Laboratory of clinical laboratory Diagnostics, 12th 5-Year project of Shandong Province, Weifang Medical University, Weifang, China
| | - Ronglan Zhao
- School of Medical Laboratory, Weifang Medical University, Weifang, China.,Institutional Key Laboratory of clinical laboratory Diagnostics, 12th 5-Year project of Shandong Province, Weifang Medical University, Weifang, China
| | - Xiaoxiang Peng
- School of Medical Laboratory, Weifang Medical University, Weifang, China.,Institutional Key Laboratory of clinical laboratory Diagnostics, 12th 5-Year project of Shandong Province, Weifang Medical University, Weifang, China
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11
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Ghrayeb A, Agranovich B, Peled D, Finney AC, Abramovich I, Garcia JF, Traylor J, Drucker S, Fernandes SI, Weissman N, Chen YE, Rom O, Mor I, Gottlieb E. Fatty liver-mediated glycine restriction impairs glutathione synthesis and causes hypersensitization to acetaminophen. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.16.524043. [PMID: 36711913 PMCID: PMC9882121 DOI: 10.1101/2023.01.16.524043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Understanding metabolic pathways involved can provide insights into disease progression. Untargeted metabolomics of livers from mice with early-stage steatosis indicated a decrease in methylated metabolites suggesting altered one carbon metabolism. The levels of glycine, a central component of one carbon metabolism, were lower in steatotic mice, in line with clinical evidence. Isotope tracing studies demonstrated that increased synthesis of serine from glycine is the underlying cause for glycine limitation in fatty livers. Consequently, the low glycine availability in steatotic livers impaired glutathione (GSH) synthesis under oxidative stress induced by acetaminophen (APAP), enhancing hepatic toxicity. Glycine supplementation mitigated acute liver damage and overall toxicity caused by APAP in fatty livers by supporting de novo GSH synthesis. Thus, early metabolic changes in NAFLD that lead to glycine depletion sensitize mice to xenobiotic toxicity even at a reversible stage of NAFLD.
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12
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Xia GQ, Fang Q, Cai JN, Li ZX, Zhang FZ, Lv XW. P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis. J Clin Transl Hepatol 2022; 10:1205-1212. [PMID: 36381094 PMCID: PMC9634783 DOI: 10.14218/jcth.2022.00022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/12/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Alcoholic liver disease is one of the most common chronic liver diseases in the world. It is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea, vomiting, enlargement of the liver, and jaundice. Recent studies suggest that Kupffer cell-mediated inflammatory response is a core driver in the development of alcoholic steatohepatitis and alcoholic liver fibrosis. As a danger signal, extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor, the activated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in KCs. Active caspase-1 promotes the conversion of pro-IL-1β to IL-1β, which further enhances the inflammatory response. Here, we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver fibrosis. Regulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.
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Affiliation(s)
- Guo-Qing Xia
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Qian Fang
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Jun-Nan Cai
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Zi-Xuan Li
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Feng-Zhi Zhang
- Wannan Medical College, Yijishan Hospital, Affiliated Hospital 1, Wuhu, Anhui, China
| | - Xiong-Wen Lv
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
- Correspondence to: Xiong-Wen Lv, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui 230032, China. ORCID: https://orcid.org/0000-0003-2354-0168. Tel: +86-13515519961, Fax: +86-551-63633742, E-mail:
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13
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Inhibition of Vascular Endothelial Growth Factor Protects against the Development of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Wild-Type but Not in CD39-Null Mice. Cancers (Basel) 2022; 14:cancers14235992. [PMID: 36497474 PMCID: PMC9739893 DOI: 10.3390/cancers14235992] [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: 09/18/2022] [Revised: 11/19/2022] [Accepted: 11/20/2022] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model. (2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma. (3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition. (4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2.
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14
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Woolbright BL, Nguyen NT, McGill MR, Sharpe MR, Curry SC, Jaeschke H. Generation of pro-and anti-inflammatory mediators after acetaminophen overdose in surviving and non-surviving patients. Toxicol Lett 2022; 367:59-66. [PMID: 35905941 PMCID: PMC9849076 DOI: 10.1016/j.toxlet.2022.07.813] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 01/21/2023]
Abstract
Acetaminophen (APAP) overdose causes liver injury in animals and humans. Although well-studied in animals, limited longitudinal data exist on cytokine release after APAP overdose in patients. The purpose of this study was to quantify concentrations of cytokines in APAP overdose patients to determine if early cytokine or complement measurements can distinguish between surviving and non-surviving patients. Plasma was obtained from healthy controls, APAP overdose patients with no increase in liver transaminases, and surviving and non-surviving APAP overdose patients with severe liver injury. Interleukin-10 (IL-10), and CC chemokine ligand-2 (CCL2, MCP-1) were substantially elevated in surviving and non-surviving patients, whereas IL-6 and CXC chemokine ligand-8 (CXCL8, IL-8) had early elevations in a subset of patients only with liver injury. Day 1 IL-10 and IL-6 levels, and Day 2 CCL2, levels correlated positively with survival. There was no significant increase in IL-1α, IL-1β or TNF-α in any patient during the first week after APAP. Monitoring cytokines such as CCL2 may be a good indicator of patient prognosis; furthermore, these data indicate the inflammatory response after APAP overdose in patients is not mediated by a second phase of inflammation driven by the inflammasome.
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Affiliation(s)
| | - Nga T Nguyen
- Department of Pharmacology, Toxicology & Therapeutics, USA
| | | | - Matthew R Sharpe
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Steven C Curry
- Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, AZ, USA; Department of Medicine, and Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ, USA
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15
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Sapidolide A alleviates acetaminophen-induced acute liver injury by inhibiting NLRP3 inflammasome activation in macrophages. Acta Pharmacol Sin 2022; 43:2016-2025. [PMID: 35022542 PMCID: PMC9343373 DOI: 10.1038/s41401-021-00842-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023]
Abstract
Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5-20 μM) suppressed the phosphorylated activation of NF-κB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 μM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients.
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16
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Yang T, Wang H, Wang X, Li J, Jiang L. The Dual Role of Innate Immune Response in Acetaminophen-Induced Liver Injury. BIOLOGY 2022; 11:biology11071057. [PMID: 36101435 PMCID: PMC9312699 DOI: 10.3390/biology11071057] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 05/27/2023]
Abstract
Acetyl-para-aminophenol (APAP), a commonly used antipyretic analgesic, is becoming increasingly toxic to the liver, resulting in a high rate of acute hepatic failure in Europe and the United States. Excessive APAP metabolism in the liver develops an APAP-protein adduct, which causes oxidative stress, MPTP opening, and hepatic necrosis. HMGB-1, HSP, nDNA, mtDNA, uric acid, and ATP are DMAPs released during hepatic necrosis. DMAPs attach to TLR4-expressing immune cells such KCs, macrophages, and NK cells, activating them and causing them to secrete cytokines. Immune cells and their secreted cytokines have been demonstrated to have a dual function in acetaminophen-induced liver injury (AILI), with a role in either proinflammation or pro-regeneration, resulting in contradicting findings and some research confusion. Neutrophils, KCs, MoMFs, NK/NKT cells, γδT cells, DCs, and inflammasomes have pivotal roles in AILI. In this review, we summarize the dual role of innate immune cells involved in AILI and illustrate how these cells initiate innate immune responses that lead to persistent inflammation and liver damage. We also discuss the contradictory findings in the literature and possible protocols for better understanding the molecular regulatory mechanisms of AILI.
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Affiliation(s)
- Tao Yang
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; (T.Y.); (H.W.); (X.W.)
- Department of Respiratory and Critical Care Medicine, The Affiliated People’s Hospital of Jiangsu University, The Zhenjiang Clinical Medical College of Nanjing Medical University, Zhenjiang 212001, China
| | - Han Wang
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; (T.Y.); (H.W.); (X.W.)
| | - Xiao Wang
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; (T.Y.); (H.W.); (X.W.)
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; (T.Y.); (H.W.); (X.W.)
| | - Longfeng Jiang
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; (T.Y.); (H.W.); (X.W.)
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17
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Guo FF, Meng FG, Zhang XN, Zeng T. Spermidine inhibits LPS-induced pro-inflammatory activation of macrophages by acting on Nrf2 signaling but not autophagy. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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18
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Wang J, Zhang L, Shi Q, Yang B, He Q, Wang J, Weng Q. Targeting innate immune responses to attenuate acetaminophen-induced hepatotoxicity. Biochem Pharmacol 2022; 202:115142. [PMID: 35700755 DOI: 10.1016/j.bcp.2022.115142] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/02/2022]
Abstract
Acetaminophen (APAP) hepatotoxicity is an important cause of acute liver failure, resulting in massive deaths in many developed countries. Currently, the metabolic process of APAP in the body has been well studied. However, the underlying mechanism of APAP-induced liver injury remains elusive. Increasing clinical and experimental evidences indicate that the innate immune responses are involved in the pathogenesis of APAP-induced acute liver injury (AILI), in which immune cells have dual roles of inducing inflammation to exacerbate hepatotoxicity and removing dead cells and debris to help liver regeneration. In this review, we summarize the latest findings of innate immune cells involved in AILI, particularly emphasizing the activation of innate immune cells and their different roles during the injury and repair phases. Moreover, current available treatments are discussed according to the different roles of innate immune cells in the development of AILI. This review aims to update the knowledge about innate immune responses in the pathogenesis of AILI, and provide potential therapeutic interventions for AILI.
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Affiliation(s)
- Jincheng Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lulu Zhang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qi Shi
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bo Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jiajia Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Qinjie Weng
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
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19
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An Q, Yue G, Yang X, Lou J, Shan W, Ding J, Jin Z, Hu Y, Du Q, Liao Q, Xie R, Xu J. Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases. Front Physiol 2022; 12:781069. [PMID: 35002763 PMCID: PMC8740087 DOI: 10.3389/fphys.2021.781069] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/01/2021] [Indexed: 11/16/2022] Open
Abstract
P2X receptors (P2XRs) are trimeric, non-selective cation channels activated by extracellular ATP and widely distributed in the digestive system. P2XRs have an important role in the physiological function of the digestive system, such as neurotransmission, ion transports, proliferation and apoptosis, muscle contraction, and relaxation. P2XRs can be involved in pain mechanisms both centrally and in the periphery and confirmed the association of P2XRs with visceral pain. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X(3)R or heteromeric P2X(2/3)R. Thus, peripheral P2XRs, and homomeric P2X(3) and/or heteromeric P2X(2/3)R in particular, constitute attractive targets for analgesic drugs. Recently studies have shown that P2XRs have made significant advances in inflammation and cancer. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. It is believed that with the further study of P2XRs and its subtypes, P2XRs and its specific antagonists will be expected to be widely used in the treatment of human digestive diseases in the future.
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Affiliation(s)
- Qimin An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Gengyu Yue
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xiaoxu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Weixi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jianhong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yanxia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qiushi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
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20
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Liu J, Jiang M, Jin Q, Wu YL, Cui ZY, Cui BW, Shang Y, Zhan ZY, Lin YC, Jiao JY, Piao MH, Zhang ZH, Sun RH, Nan JX, Lian LH. Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation. Front Pharmacol 2021; 12:723881. [PMID: 34366873 PMCID: PMC8333615 DOI: 10.3389/fphar.2021.723881] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/12/2021] [Indexed: 11/13/2022] Open
Abstract
Acetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently needed. The aim of this study was to explore the inflammatory exact mechanism of APAP, especially on neutrophils, and to study the intervention effect of Chikusetsusaponin V (CKV) derived from Panax japonicus. Establishment of hepatotoxicity model of APAP in vitro and in vivo. In vitro, HepG2 cells, AML12 cells, primary mouse hepatocytes and neutrophils were used to mimic APAP-affected hepatocytes and neutrophil. In vivo, C57BL/6 mice were administrated overdose of APAP with or without neutrophil depletion or abolishing neutrophil extracellular traps (NETs) formation. In this study, APAP stimulation increased the level of HMGB1, IL-1β and Caspase-1 in mouse liver, especially hepatocytes, which had a synergistic effect with LPS/ATP combination. NETs were formatted at early stage of APAP or HMGB1-stimulated neutrophils’ damage. Conditioned mediums from APAP-treated hepatocytes induced more significant NETs than direct APAP stimulation. Neutrophil depletion or abolishing NETs formation decreased HMGB1 level, eventually blocked hepatocytes necrosis. CKV pretreatment interfered Caspase-1 activation and HMGB1 release in APAP-damaged hepatocytes. CKV also prevented NETs formation. These results indicate that the production of HMGB1 may depend on the activation of Caspase-1 and play a key role in liver inflammation caused by APAP. The cross-dialogue between hepatocytes and neutrophils can be mediated by HMGB1. Therefore, CKV has a positive intervention effect on NETs-related inflammation in APAP-damaged liver, targeting Caspase-1-HMGB1.
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Affiliation(s)
- Jian Liu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Min Jiang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Quan Jin
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Zhen-Yu Cui
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Ben-Wen Cui
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Yue Shang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Zi-Ying Zhan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Yong-Ce Lin
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Jing-Ya Jiao
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Mei-Hua Piao
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Zhi-Hong Zhang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Rong-Hui Sun
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.,Clinical Research Centre, Yanbian University Hospital, Yanji, China
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, China.,Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
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21
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Abstract
The purine nucleotide ATP is a fundamental unit in cellular energy metabolism. Extracellular ATP and its metabolites are also ligands for a family of receptors, known as purinergic receptors, which are expressed ubiquitously in almost every cell type. In the immune system, extracellular ATP and its signals regulate the migration and activation of immune cells to orchestrate the induction and resolution of inflammation. In this review, we provide an overview of purinergic receptors and their downstream signaling related to macrophage activation. We also discuss the roles of purinergic signaling for macrophage functions in physiological and pathological conditions.
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Affiliation(s)
- Jing Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
| | - Naoki Takemura
- Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University
| | - Tatsuya Saitoh
- Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University
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22
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Wei S, Ma W, Zhang B, Li W. NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity. Front Cell Dev Biol 2021; 9:634607. [PMID: 33912556 PMCID: PMC8072389 DOI: 10.3389/fcell.2021.634607] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
Drug-induced toxicity, which impairs human organ function, is a serious problem during drug development that hinders the clinical use of many marketed drugs, and the underlying mechanisms are complicated. As a sensor of infections and external stimuli, nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in the pathological process of various diseases. In this review, we specifically focused on the role of NLRP3 inflammasome in drug-induced diverse organ toxicities, especially the hepatotoxicity, nephrotoxicity, and cardiotoxicity. NLRP3 inflammasome is involved in the initiation and deterioration of drug-induced toxicity through multiple signaling pathways. Therapeutic strategies via inhibiting NLRP3 inflammasome for drug-induced toxicity have made significant progress, especially in the protective effects of the phytochemicals. Growing evidence collected in this review indicates that NLRP3 is a promising therapeutic target for drug-induced toxicity.
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Affiliation(s)
- Shanshan Wei
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wanjun Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wenqun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
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23
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Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury. Sci Rep 2021; 11:5192. [PMID: 33664289 PMCID: PMC7933178 DOI: 10.1038/s41598-021-83144-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented d-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury.
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24
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Longhi MS, Feng L, Robson SC. Targeting ectonucleotidases to treat inflammation and halt cancer development in the gut. Biochem Pharmacol 2021; 187:114417. [PMID: 33460629 DOI: 10.1016/j.bcp.2021.114417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/30/2020] [Accepted: 01/11/2021] [Indexed: 01/28/2023]
Abstract
CD39 and CD73 control cell immunity by hydrolyzing proinflammatory ATP and ADP (CD39) into AMP, subsequently converted into anti-inflammatory adenosine (CD73). By regulating the balance between effector and regulatory cells, these ectonucleotidases promote immune homeostasis in acute and chronic inflammation; while also appearing to limit antitumor effector immunity in gut cancer. This manuscript focuses on the pivotal role of CD39 and CD73 ectonucleotidase function in shaping immune responses in the gut. We focus on those mechanisms deployed by these critical and pivotal ectoenzymes and the regulation in the setting of gastrointestinal tract infections, inflammatory bowel disease and tumors of the gastrointestinal tract. We will highlight translational and clinical implications of the latest and most innovative basic research discoveries of these important players of the purinergic signaling. Immunotherapeutic strategies that have been developed to either boost or control ectonucleotidase expression and activity in important disease settings are also reviewed and the in vivo effects discussed.
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Affiliation(s)
- Maria Serena Longhi
- Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, 02215 Boston, USA.
| | - Lili Feng
- Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, 02215 Boston, USA; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Simon C Robson
- Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, 02215 Boston, USA; Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, 02215 Boston, USA.
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25
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Hasuzawa N, Tatsushima K, Tokubuchi R, Kabashima M, Nomura M. [VNUT Is a Therapeutic Target for Type 2 Diabetes and NASH]. YAKUGAKU ZASSHI 2021; 141:517-526. [PMID: 33790119 DOI: 10.1248/yakushi.20-00204-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
ATP, used in cells as an energy currency, also acts as an extracellular signaling molecule. Studies of purinergic receptor subtypes have revealed that purinergic chemical transmission plays important roles in various cell types. The vesicular nucleotide transporter (VNUT), the ninth transporter in the SLC17 organic anion transporter family, is essential for vesicular ATP storage and its subsequent release. The VNUT is localized on the membrane of secretory vesicles and actively transports ATP into vesicles using an electrochemical gradient of protons supplied by vacuolar proton ATPase (V-ATPase) as a driving force. ATP acts as a damage-associated molecular pattern (DAMPs), contributing to the persistence of chronic inflammation. Chronic inflammation induces systemic insulin resistance, which is the underlying pathology of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). We previously demonstrated that ATP transported in insulin granules via the VNUT negatively regulates insulin secretion. We also found that hepatocytes release ATP in a VNUT-dependent manner, which elicits hepatic insulin resistance and inflammation. VNUT-knockout mice exhibited improved glucose tolerance and were resistant to the development of high fat diet-induced NAFLD. In this article, we summarize recent advances in our understanding of the mechanism of the VNUT, the development of inhibitors, and its pathological involvement in type 2 diabetes and NAFLD. The pharmacological inhibition of the VNUT may represent a potential therapeutic approach for the treatment of metabolic diseases.
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Affiliation(s)
- Nao Hasuzawa
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine
| | | | - Rie Tokubuchi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine
| | - Masaharu Kabashima
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine
| | - Masatoshi Nomura
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine
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26
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Zou J, Wang SP, Wang YT, Wan JB. Regulation of the NLRP3 inflammasome with natural products against chemical-induced liver injury. Pharmacol Res 2020; 164:105388. [PMID: 33359314 DOI: 10.1016/j.phrs.2020.105388] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/24/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022]
Abstract
The past decades have witnessed significant progress in understanding the process of sterile inflammation, which is dependent on a cytosolic complex termed the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome. Activation of NLRP3 inflammasome requires two steps, including the activation of Toll-like receptor (TLR) by its ligands, resulting in transcriptional procytokine and inflammasome component activation, and the assembly and activation of NLRP3 inflammasome triggered by various danger signals, leading to caspase-1 activation, which could subsequently cleave procytokines into their active forms. Metabolic disorders, ischemia and reperfusion, viral infection and chemical insults are common pathogenic factors of liver-related diseases that usually cause tissue damage and cell death, providing numerous danger signals for the activation of NLRP3 inflammasome. Currently, natural products have attracted much attention as potential agents for the prevention and treatment of liver diseases due to their multitargets and nontoxic natures. A great number of natural products have been shown to exhibit beneficial effects on liver injury induced by various chemicals through regulating NLRP3 inflammasome pathways. In this review, the roles of the NLRP3 inflammasome in chemical-induced liver injury (CILI) and natural products that exhibit beneficial effects in CILI through the regulation of inflammasomes were systematically summarized.
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Affiliation(s)
- Jian Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China
| | - Sheng-Peng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China
| | - Yi-Tao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China
| | - Jian-Bo Wan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China.
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27
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Larrouyet-Sarto ML, Tamura AS, Alves VS, Santana PT, Ciarlini-Magalhães R, Rangel TP, Siebert C, Hartwig JR, Dos Santos TM, Wyse ATS, Takiya CM, Coutinho-Silva R, Savio LEB. P2X7 receptor deletion attenuates oxidative stress and liver damage in sepsis. Purinergic Signal 2020; 16:561-572. [PMID: 33090332 PMCID: PMC7855213 DOI: 10.1007/s11302-020-09746-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/12/2020] [Indexed: 02/08/2023] Open
Abstract
Sepsis is a severe disease characterized by an uncontrolled systemic inflammation and consequent organ dysfunction generated in response to an infection. Extracellular ATP acting through the P2X7 receptor induces the maturation and release of pro-inflammatory cytokines (i.e., IL-1β) and the production of reactive nitrogen and oxygen species that lead to oxidative tissue damage. Here, we investigated the role of the P2X7 receptor in inflammation, oxidative stress, and liver injury in sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type (WT) and P2X7 knockout (P2X7-/-) mice. The oxidative stress in the liver of septic mice was assessed by 2',7'-dichlorofluorescein oxidation reaction (DCF), thiobarbituric acid-reactive substances (TBARS), and nitrite levels dosage. The status of the endogenous defense system was evaluated through catalase (CAT) and superoxide dismutase (SOD) activities. The inflammation was assessed histologically and by determining the expression of inflammatory cytokines and chemokines by RT-qPCR. We observed an increase in the reactive species and lipid peroxidation in the liver of septic WT mice, but not in the liver from P2X7-/- animals. We found an imbalance SOD/CAT ratio, also only WT septic animals. The number of inflammatory cells and the gene expression of IL-1 β, IL-6, TNF-α, IL-10, CXCL1, and CXCL2 were higher in the liver of WT septic mice in comparison to P2X7-/- septic animals. In summary, our results suggest that the P2X7 receptor might be a therapeutic target to limit oxidative stress damage and liver injury during sepsis.
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Affiliation(s)
- Maria Luciana Larrouyet-Sarto
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Augusto Shuiti Tamura
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Vinícius Santos Alves
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Patrícia T Santana
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Roberta Ciarlini-Magalhães
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Thuany Prado Rangel
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Cassiana Siebert
- Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Josiane R Hartwig
- Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Tiago Marcon Dos Santos
- Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Angela T S Wyse
- Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Christina Maeda Takiya
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Robson Coutinho-Silva
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil.
| | - Luiz Eduardo Baggio Savio
- Edifício do Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Bloco G. Av. Carlos Chagas Filho, 373. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil.
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28
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Shi L, Zhang S, Huang Z, Hu F, Zhang T, Wei M, Bai Q, Lu B, Ji L. Baicalin promotes liver regeneration after acetaminophen-induced liver injury by inducing NLRP3 inflammasome activation. Free Radic Biol Med 2020; 160:163-177. [PMID: 32682928 DOI: 10.1016/j.freeradbiomed.2020.05.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/26/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023]
Abstract
Liver regeneration has become a new hotspot in the study of drug-induced liver injury (DILI). Baicalin has already been reported to alleviate acetaminophen (APAP)-induced acute liver injury in our previous study. This study aims to observe whether baicalin also promotes liver regeneration after APAP-induced liver injury and to elucidate its engaged mechanism. Baicalin alleviated APAP-induced hepatic parenchymal cells injury and enhanced the number of mitotic and proliferating cell nuclear antigen (PCNA)-positive hepatocytes in APAP-intoxicated mice. Baicalin increased hepatic PCNA and cyclinD1 expression in APAP-intoxicated mice. Baicalin induced the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to the increased hepatic expression of interleukin-18 (IL-18) and IL-1β in APAP-intoxicated mice. The results in vitro demonstrated that IL-18 promoted the proliferation of human normal liver L-02 cells. Moreover, the baicalin-provided promotion on liver regeneration in APAP-intoxicated mice was diminished after the application of NLRP3 inhibitor MCC950 and the recombinant mouse IL-18 binding protein (rmIL-18BP). Baicalin induced the cytosolic accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), and increased the interaction between Nrf2 with Nlrp3, ASC and pro-caspase-1 in livers from APAP-intoxicated mice. Furthermore, the baicalin-provided NLRP3 inflammasome activation and promotion on liver regeneration after APAP-induced liver injury in wild-type mice were diminished in Nrf2 knockout mice. In conclusion, baicalin promoted liver regeneration after APAP-induced acute liver injury in mice via inducing Nrf2 accumulation in cytoplasm that led to NLRP3 inflammasome activation, and then caused the increased expression of IL-18, which induced hepatocytes proliferation.
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Affiliation(s)
- Liang Shi
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shaobo Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Feifei Hu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Tianyu Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qingyun Bai
- School of Chemical and Biological Engineering, Yichun University, Jiangxi, 336000, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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29
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Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol 2020; 18:45-56. [PMID: 33041338 DOI: 10.1038/s41423-020-00558-8] [Citation(s) in RCA: 401] [Impact Index Per Article: 80.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.
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Affiliation(s)
- Yankai Wen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Joeri Lambrecht
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.
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30
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Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity. Int J Mol Sci 2020; 21:ijms21175998. [PMID: 32825435 PMCID: PMC7504458 DOI: 10.3390/ijms21175998] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/05/2020] [Accepted: 08/13/2020] [Indexed: 12/19/2022] Open
Abstract
Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.
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31
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Wang P, Jia J, Zhang D. Purinergic signalling in liver diseases: Pathological functions and therapeutic opportunities. JHEP Rep 2020; 2:100165. [PMID: 33103092 PMCID: PMC7575885 DOI: 10.1016/j.jhepr.2020.100165] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/24/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
Extracellular nucleotides, including ATP, are essential regulators of liver function and serve as danger signals that trigger inflammation upon injury. Ectonucleotidases, which are expressed by liver-resident cells and recruited immune cells sequentially hydrolyse nucleotides to adenosine. The nucleotide/nucleoside balance orchestrates liver homeostasis, tissue repair, and functional restoration by regulating the crosstalk between liver-resident cells and recruited immune cells. In this review, we discuss our current knowledge on the role of purinergic signals in liver homeostasis, restriction of inflammation, stimulation of liver regeneration, modulation of fibrogenesis, and regulation of carcinogenesis. Moreover, we discuss potential targeted therapeutic strategies for liver diseases based on purinergic signals involving blockade of nucleotide receptors, enhancement of ectonucleoside triphosphate diphosphohydrolase activity, and activation of adenosine receptors.
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Key Words
- A1, adenosine receptor A1
- A2A, adenosine receptor A2A
- A2B, adenosine receptor A2B
- A3, adenosine receptor A3
- AIH, autoimmune hepatitis
- ALT, alanine aminotransferase
- APAP, acetaminophen
- APCP, α,β-methylene ADP
- Adenosine receptors
- BDL, bile duct ligation
- CCl4, carbon tetrachloride
- CD73, ecto-5ʹ-nucleotidase
- ConA, concanavalin A
- DCs, dendritic cells
- DMN, dimethylnitrosamine
- Ecto-5ʹ-nucleotidase
- Ectonucleoside triphosphate diphosphohydrolases 1
- HCC, hepatocellular carcinoma
- HFD, high-fat diet
- HGF, hepatocyte growth factor
- HSCs, hepatic stellate cells
- IFN, interferon
- IL-, interleukin-
- IPC, ischaemic preconditioning
- IR, ischaemia-reperfusion
- Liver
- MAPK, mitogen-activating protein kinase
- MCDD, methionine- and choline-deficient diet
- MHC, major histocompatibility complex
- NAFLD, non-alcoholic fatty liver disease
- NK, natural killer
- NKT, natural killer T
- NTPDases, ectonucleoside triphosphate diphosphohydrolases
- Nucleotide receptors
- P1, purinergic type 1
- P2, purinergic type 2
- PBC, primary biliary cholangitis
- PH, partial hepatectomy
- PKA, protein kinase A
- PPADS, pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonate
- Purinergic signals
- ROS, reactive oxygen species
- TAA, thioacetamide
- TNF, tumour necrosis factor
- Tregs, regulatory T cells
- VEGF, vascular endothelial growth factor
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Affiliation(s)
- Ping Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation & National Clinical Research Center for Digestive Diseases, Beijing 100050, China
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Baeza-Raja B, Goodyear A, Liu X, Lam K, Yamamoto L, Li Y, Dodson GS, Takeuchi T, Kisseleva T, Brenner DA, Dabbagh K. Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis. PLoS One 2020; 15:e0234038. [PMID: 32492075 PMCID: PMC7269334 DOI: 10.1371/journal.pone.0234038] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular adenosine triphosphate (eATP) released by damaged cells, and its purinergic receptors, comprise a crucial signaling network after injury. Purinergic receptor P2X7 (P2RX7), a major driver of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β processing, has been shown to play a role in liver injury in murine diet- and chemically-induced liver injury models. It is unclear, however, whether P2RX7 plays a role in non-alcoholic steatohepatitis (NASH) and which cell type is the main target of P2RX7 pharmacological inhibition. Here, we report that P2RX7 is expressed by infiltrating monocytes and resident Kupffer cells in livers from NASH-affected individuals. Using primary isolated human cells, we demonstrate that P2RX7 expression in CD14+ monocytes and Kupffer cells primarily mediates IL-1β release. In addition, we show that pharmacological inhibition of P2RX7 in monocytes and Kupffer cells, blocks IL-1β release, reducing hepatocyte caspase 3/7 activity, IL-1β-mediated CCL2 and CCL5 chemokine gene expression and secretion, and hepatic stellate cell (HSC) procollagen secretion. Consequently, in a chemically-induced nonhuman primate model of liver fibrosis, treatment with a P2RX7 inhibitor improved histological characteristics of NASH, protecting from liver inflammation and fibrosis. Taken together, these findings underscore the critical role of P2RX7 in the pathogenesis of NASH and implicate P2RX7 as a promising therapeutic target for the management of this disease.
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Affiliation(s)
- Bernat Baeza-Raja
- Second Genome Inc., South San Francisco, California, United States of America
| | - Andrew Goodyear
- Second Genome Inc., South San Francisco, California, United States of America
| | - Xiao Liu
- Department of Surgery, University of California San Diego, La Jolla, California, United States of America
| | - Kevin Lam
- Department of Surgery, University of California San Diego, La Jolla, California, United States of America
| | - Lynn Yamamoto
- Second Genome Inc., South San Francisco, California, United States of America
| | - Yingwu Li
- Second Genome Inc., South San Francisco, California, United States of America
| | - G. Steven Dodson
- Second Genome Inc., South San Francisco, California, United States of America
| | - Toshi Takeuchi
- Second Genome Inc., South San Francisco, California, United States of America
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, California, United States of America
| | - David A. Brenner
- Department of Medicine, University of California San Diego, La Jolla, California, United States of America
| | - Karim Dabbagh
- Second Genome Inc., South San Francisco, California, United States of America
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Wang Q, Tang Q, Zhao L, Zhang Q, Wu Y, Hu H, Liu L, Liu X, Zhu Y, Guo A, Yang X. Time serial transcriptome reveals Cyp2c29 as a key gene in hepatocellular carcinoma development. Cancer Biol Med 2020; 17:401-417. [PMID: 32587777 PMCID: PMC7309465 DOI: 10.20892/j.issn.2095-3941.2019.0335] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/26/2020] [Indexed: 12/15/2022] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is a severely lethal cancer that usually originates from chronic liver injury and inflammation. Although progress on diagnosis and treatment is obvious, the cause of HCC remains unclear. In this study, we sought to determine key genes in HCC development. Methods: To identify key regulators during HCC progression, we performed transcriptome sequencing to obtain time series gene expression data from a mouse model with diethylnitrosamine-induced liver tumors and further verified gene expression and function in vitro and in vivo. Results: Among the differentially expressed genes, Cyp2c29 was continuously downregulated during HCC progression. Overexpression of Cyp2c29 suppressed NF-κB activation and proinflammatory cytokine production by increasing the production of 14,15-epoxyeicosatrienoic acid in vitro. Furthermore, overexpression of Cyp2c29 in vivo protected against liver inflammation in mouse models of liver injury induced by both acetaminophen and CCl4. Two human homologs of mouse Cyp2c29, CYP2C8 and CYP2C9, were found to be downregulated in human HCC progression, and their expression was positively correlated with overall survival in patients with HCC (significance: P = 0.046 and 0.0097, respectively). Conclusions: Collectively, through systematic analysis and verification, we determined that Cyp2c29 is a novel gene involved in liver injury and inflammation, which may be a potential biomarker for HCC prevention and prognosis determination.
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Affiliation(s)
- Qi Wang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Qin Tang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lijun Zhao
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Qiong Zhang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yuxin Wu
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Hui Hu
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lanlan Liu
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xiang Liu
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yanhong Zhu
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Anyuan Guo
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xiangliang Yang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
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The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review. Cells 2020; 9:cells9041047. [PMID: 32331389 PMCID: PMC7226571 DOI: 10.3390/cells9041047] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome.
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35
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Al Mamun A, Wu Y, Jia C, Munir F, Sathy KJ, Sarker T, Monalisa I, Zhou K, Xiao J. Role of pyroptosis in liver diseases. Int Immunopharmacol 2020; 84:106489. [PMID: 32304992 DOI: 10.1016/j.intimp.2020.106489] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/03/2020] [Accepted: 04/05/2020] [Indexed: 12/17/2022]
Abstract
Pyroptosis is known as a novel form of pro-inflammatory cell death program, which is exceptional from other types of cell death programs. Particularly, pyroptosis is characterized by Gasdermin family-mediated pore formation and subsequently cellular lysis, also release of several pro-inflammatory intracellular cytokines. In terms of mechanism, there are two signaling pathways involved in pyroptosis, including caspase-1, and caspase-4/5/11 mediated pathways. However, pyroptosis plays important roles in immune defense mechanisms. Recent studies have demonstrated that pyroptosis plays significant roles in the development of liver diseases. In our review, we have focused on the role of pyroptosis based on the molecular and pathophysiological mechanisms in the development of liver diseases. We have also highlighted targeting of pyroptosis for the therapeutic implications in liver diseases in the near future.
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Affiliation(s)
- Abdullah Al Mamun
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Yanqing Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou 325035, Zhejiang Province, China
| | - Chang Jia
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Kasfia Jahan Sathy
- Department of Pharmacy, North South University, Bashundhara, Dhaka 1229, Bangladesh
| | - Tamanna Sarker
- Department of Pharmacy, Southeast University, Banani, Dhaka 1213, Bangladesh
| | - Ilma Monalisa
- Department of Pharmacy, Southeast University, Banani, Dhaka 1213, Bangladesh
| | - Kailiang Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
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36
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Saad KM, Shaker ME, Shaaban AA, Abdelrahman RS, Said E. The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity. Int Immunopharmacol 2020; 81:106292. [PMID: 32062076 DOI: 10.1016/j.intimp.2020.106292] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 02/08/2023]
Abstract
Acetaminophen (APAP)-induced hepatotoxicity comes among the most frequent humans' toxicities caused by drugs. So far, therapeutic interventions for such type of drug-induced toxicity are still limited. In the current study, we examined the influence of capmatinib (Cap), a novel c-Met inhibitor, on APAP-induced hepatotoxicity in mice when administered 2 h prior, 2 h post and 4 h post APAP-challenge. The results revealed that Cap administration significantly attenuated APAP-induced liver injury when administered only 2 h prior and post APAP-administration. Cap hepatoprotective effect was mediated by lowering the excessive formation of lipid peroxidation and nitrosative stress products caused by APAP. Besides, Cap attenuated APAP-induced overproduction and release of proinflammatory mediators like TNF-α, IL-1β, IL-17A, IL-6, and MCP-1. Cap treatment also led to avoidance of APAP-subsequent repair by abating APAP-induced elevation of hepatic IL-22 and PCNA expressions. In conclusion, c-Met receptor inhibition may be a potential strategy for alleviating APAP-hepatotoxicity, especially when administered in the early phase of intoxication.
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Affiliation(s)
- Kareem M Saad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed E Shaker
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology, Faculty of Pharmacy, Jouf University, Sakaka 2014, Saudi Arabia.
| | - Ahmed A Shaaban
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan
| | - Rehab S Abdelrahman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taibah University, Al Madinah Al-Munawwarah 30001, Saudi Arabia
| | - Eman Said
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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37
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Velázquez-Miranda E, Molina-Aguilar C, González-Gallardo A, Vázquez-Martínez O, Díaz-Muñoz M, Vázquez-Cuevas FG. Increased Purinergic Responses Dependent on P2Y2 Receptors in Hepatocytes from CCl 4-Treated Fibrotic Mice. Int J Mol Sci 2020; 21:ijms21072305. [PMID: 32225112 PMCID: PMC7177255 DOI: 10.3390/ijms21072305] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/17/2020] [Indexed: 01/09/2023] Open
Abstract
Inflammatory and wound healing responses take place during liver damage, primarily in the parenchymal tissue. It is known that cellular injury elicits an activation of the purinergic signaling, mainly by the P2X7 receptor; however, the role of P2Y receptors in the onset of liver pathology such as fibrosis has not been explored. Hence, we used mice treated with the hepatotoxin CCl4 to implement a reversible model of liver fibrosis to evaluate the expression and function of the P2Y2 receptor (P2Y2R). Fibrotic livers showed an enhanced expression of P2Y2R that eliminated its zonal distribution. Hepatocytes from CCl4-treated mice showed an exacerbated ERK-phosphorylated response to the P2Y2R-specific agonist, UTP. Cell proliferation was also enhanced in the fibrotic livers. Hepatic transcriptional analysis by microarrays, upon CCl4 administration, showed that P2Y2 activation regulated diverse pathways, revealing complex action mechanisms. In conclusion, our data indicate that P2Y2R activation is involved in the onset of the fibrotic damage associated with the reversible phase of the hepatic damage promoted by CCl4.
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38
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Jaeschke H, Ramachandran A. Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. Food Chem Toxicol 2020; 138:111240. [PMID: 32145352 DOI: 10.1016/j.fct.2020.111240] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/26/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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39
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Purine signaling regulating HSCs inflammatory cytokines secretion, activation, and proliferation plays a critical role in alcoholic liver disease. Mol Cell Biochem 2020; 466:91-102. [PMID: 31989367 DOI: 10.1007/s11010-020-03691-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 01/21/2020] [Indexed: 12/23/2022]
Abstract
Purine signaling pathway plays an important role in inflammation and tissue damage. To investigate the role of purine signaling pathway in acute alcoholic liver injury and chronic alcoholic liver fibrosis, we replicated two animal models and two cellular models. We found that body weights, liver indexes, serum biochemical parameters, serum fibrosis indexes, and pathological and immunohistochemical results had significant changes in two treatment groups compared with two control groups. In addition, gene expressions of purine receptors, inflammatory cytokines, fibrogenic cytokines, and inflammasomes increased obviously in two animal models and two cellular models. Furthermore, purine receptor inhibitors could significantly inhibit protein expressions of purine receptors and reduce protein expressions of inflammatory cytokines, fibrogenic cytokines, and inflammasomes. Besides, P2X7R small interfering ribonucleic acid (siRNA) had the same effects. Meanwhile, we detected protein expressions of inflammatory cytokines secreted by inflammasomes, and we found that purine receptor-mediated inflammasomes activation was a key event in the process of chronic alcoholic liver fibrosis. In summary, this study shows that inhibition of purine receptors can alleviate acute alcoholic liver injury and chronic alcoholic liver fibrosis in mice. Therefore, purine receptor is a potential new target for the treatment of acute alcoholic liver injury and chronic alcoholic fibrosis.
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40
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Horst AK, Tiegs G, Diehl L. Contribution of Macrophage Efferocytosis to Liver Homeostasis and Disease. Front Immunol 2019; 10:2670. [PMID: 31798592 PMCID: PMC6868070 DOI: 10.3389/fimmu.2019.02670] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022] Open
Abstract
The clearance of apoptotic cells is pivotal for both maintaining tissue homeostasis and returning to homeostasis after tissue injury as part of the regenerative resolution response. The liver is known for its capacity to remove aged and damaged cells from the circulation and can serve as a graveyard for effector T cells. In particular Kupffer cells are active phagocytic cells, but during hepatic inflammatory responses incoming neutrophils and monocytes may contribute to pro-inflammatory damage. To stimulate resolution of such inflammation, myeloid cell function can change, via sensing of environmental changes in the inflammatory milieu. Also, the removal of apoptotic cells via efferocytosis and the signaling pathways that are activated in macrophages/phagocytes upon their engulfment of apoptotic cells are important for a return to tissue homeostasis. Here, we will discuss, how efferocytosis mechanisms in hepatic macrophages/phagocytes may regulate tissue homeostasis and be involved in tissue regeneration in liver disease.
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Affiliation(s)
- Andrea Kristina Horst
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gisa Tiegs
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Linda Diehl
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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41
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Wu J, Lin S, Wan B, Velani B, Zhu Y. Pyroptosis in Liver Disease: New Insights into Disease Mechanisms. Aging Dis 2019; 10:1094-1108. [PMID: 31595205 PMCID: PMC6764727 DOI: 10.14336/ad.2019.0116] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 01/16/2019] [Indexed: 12/12/2022] Open
Abstract
There has been increasing interest in pyroptosis as a novel form of pro-inflammatory programmed cell death. The mechanism of pyroptosis is significantly different from other forms of cell death in its morphological and biochemical features. Pyroptosis is characterized by the activation of two different types of caspase enzymes—caspase-1 and caspase-4/5/11, and by the occurrence of a proinflammatory cytokine cascade and an immune response. Pyroptosis participates in the immune defense mechanisms against intracellular bacterial infections. On the other hand, excessive inflammasome activation can induce sterile inflammation and eventually cause some diseases, such as acute or chronic hepatitis and liver fibrosis. The mechanism and biological significance of this novel form of cell death in different liver diseases will be evaluated in this review. Specifically, we will focus on the role of pyroptosis in alcoholic and non-alcoholic fatty liver disease, as well as in liver failure. Finally, the therapeutic implications of pyroptosis in liver diseases will be discussed.
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Affiliation(s)
- Jiali Wu
- 1Liver research center of the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China
| | - Su Lin
- 1Liver research center of the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China
| | - Bo Wan
- 2Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom
| | - Bharat Velani
- 3Basildon and Thurrock University Hospitals NHS Foundation Trust, Nethermayne, Basildon, Essex SS16 5NL, United Kingdom
| | - Yueyong Zhu
- 1Liver research center of the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China
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42
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Velázquez-Miranda E, Díaz-Muñoz M, Vázquez-Cuevas FG. Purinergic signaling in hepatic disease. Purinergic Signal 2019; 15:477-489. [PMID: 31576486 DOI: 10.1007/s11302-019-09680-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 09/02/2019] [Indexed: 12/11/2022] Open
Abstract
Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs). In this context, purines announce tissue alterations to initiate a reparative response that involve the formation of the inflammasome complex and the recruitment of specialized cells of the immune system. The present review focuses on the role of the purinergic system in liver damage, mainly during the onset and development of fibrosis. After hepatocellular injury, extracellular ATP promotes a signaling cascade that ameliorates tissue alterations to restore the hepatic function. However, if cellular damage becomes chronic, ATP orchestrates an aberrant reparative process that results in severe liver diseases such as fibrosis and cirrhosis. ATP and adenosine, their receptors, and extracellular ectonucleotidases are mediators of unique processes that will be reviewed in detail.
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Affiliation(s)
- E Velázquez-Miranda
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, C.P. 76230, Juriquilla, Querétaro, México
| | - M Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, C.P. 76230, Juriquilla, Querétaro, México
| | - F G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, C.P. 76230, Juriquilla, Querétaro, México.
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Pu S, Liu Q, Li Y, Li R, Wu T, Zhang Z, Huang C, Yang X, He J. Montelukast Prevents Mice Against Acetaminophen-Induced Liver Injury. Front Pharmacol 2019; 10:1070. [PMID: 31620001 PMCID: PMC6759817 DOI: 10.3389/fphar.2019.01070] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 08/22/2019] [Indexed: 02/05/2023] Open
Abstract
Acetaminophen (APAP) is a widely used over-the-counter antipyretic and analgesic drug. Overdose of APAP is the leading cause of hospital admission for acute liver failure. Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (Cysltr1), which protects from inflammation and oxidative stress. However, the function of montelukast in APAP-induced hepatotoxicity remains unknown. In this study, we examined whether pharmacological inhibition of Cystlr1 could protect mice against APAP-induced hepatic damage. We found that APAP treatment upregulated messenger RNA and protein levels of Cysltr1 both in vitro and in vivo. Pharmacological inhibition of Cysltr1 by montelukast ameliorated APAP-induced acute liver failure. The hepatoprotective effect of montelukast was associated with upregulation of hepatic glutathione/glutathione disulfide level, reduction in c-Jun-NH2-terminal kinase activation and oxidative stress. In mouse primary hepatocytes, inhibition of Cysltr1 by montelukast ameliorated the expression of inflammatory-related genes and APAP-induced cytotoxicity. We conclude that montelukast may be used to treat APAP-induced acute hepatic injury.
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Affiliation(s)
- Shiyun Pu
- Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Rui Li
- Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Tong Wu
- Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Zijing Zhang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Cuiyuan Huang
- Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Xuping Yang
- Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Jinhan He
- Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
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Waller K, James C, de Jong A, Blackmore L, Ma Y, Stagg A, Kelsell D, O'Dwyer M, Hutchins R, Alazawi W. ADAM17-Mediated Reduction in CD14 ++CD16 + Monocytes ex vivo and Reduction in Intermediate Monocytes With Immune Paresis in Acute Pancreatitis and Acute Alcoholic Hepatitis. Front Immunol 2019; 10:1902. [PMID: 31507587 PMCID: PMC6718469 DOI: 10.3389/fimmu.2019.01902] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 07/26/2019] [Indexed: 12/16/2022] Open
Abstract
Impaired immune responses and increased susceptibility to infection characterize acute inflammatory conditions such as pancreatitis and alcoholic hepatitis and are major causes of morbidity and mortality. However, the mechanisms that drive this apparent immune paresis remain poorly understood. Monocytes mediate host responses to damage and pathogens in health and disease, and three subsets of monocytes have been defined based on CD14 and CD16 expression. We sought to determine the changes in monocyte subsets in acute pancreatitis (AP) and acute alcoholic hepatitis (AAH), together with functional consequences and mechanisms that underlie this change. Peripheral blood mononuclear cells (PBMCs) from patients with AP or AAH were compared with healthy controls. Monocyte subsets were defined by HLA-DR, CD14, and CD16 expression. Changes in surface and intracellular protein expression and phosphorylation were determined by flow cytometry. Phenotype and function were assessed following stimulation with lipopolysaccharide (LPS) or other agonists in the presence of specific inhibitors of TNFα and a disintegrin and metalloproteinase 17 (ADAM17). Patients with AP and AAH had reduced CD14++CD16+ intermediate monocytes compared to controls. Reduction of intermediate monocytes was recapitulated ex vivo by stimulating healthy control PBMCs with Toll-like receptor (TLR) agonists LPS, flagellin or polyinosilic:polycytidylic acid (poly I:C). Stimulation caused shedding of CD14 and CD16, which could be reversed using the ADAM17 inhibitor, TMI005 but not direct inhibitors of TNFα, a known ADAM17-target. Culturing PBMCs from healthy controls resulted in expansion of intermediate monocytes, which did not occur when LPS was in the culture medium. Cultured intermediate monocytes showed reduced expression of CX3CR1, CCR2, TLR4, and TLR5. We found reduced migratory responses, intracellular signaling and pro-inflammatory cytokine production, and increased expression of IL-10. Stimulation with TLR agonists results in ADAM17-mediated shedding of phenotypic markers from CD16+ monocytes, leading to apparent “loss” of intermediate monocytes. Reduction in CD14++CD16− monocytes and increased CD14++CD16+ is associated with altered responses in functional assays ex vivo. Patients with AP and AAH had reduced proportions of CD14++CD16+ monocytes and reduced phosphorylation of NFκB and IL-6 production in response to bacterial LPS. Together, these processes may contribute to the susceptibility to infection observed in AP and AAH.
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Affiliation(s)
- Kathryn Waller
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Charlotte James
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Anja de Jong
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Laura Blackmore
- Institute of Liver Studies and Transplantation, King's College London, London, United Kingdom
| | - Yun Ma
- Institute of Liver Studies and Transplantation, King's College London, London, United Kingdom
| | - Andrew Stagg
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - David Kelsell
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | | | - Robert Hutchins
- Hepatopancreaticobiliary Unit, Barts Health NHS Trust, London, United Kingdom
| | - William Alazawi
- Blizard Institute, Queen Mary University of London, London, United Kingdom
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Hudson G, Flannigan KL, Venu VKP, Alston L, Sandall CF, MacDonald JA, Muruve DA, Chang TKH, Mani S, Hirota SA. Pregnane X Receptor Activation Triggers Rapid ATP Release in Primed Macrophages That Mediates NLRP3 Inflammasome Activation. J Pharmacol Exp Ther 2019; 370:44-53. [PMID: 31004077 PMCID: PMC6542184 DOI: 10.1124/jpet.118.255679] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 04/08/2019] [Indexed: 12/15/2022] Open
Abstract
The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that acts as a xenobiotic sensor, responding to compounds of foreign origin, including pharmaceutical compounds, environmental contaminants, and natural products, to induce transcriptional events that regulate drug detoxification and efflux pathways. As such, the PXR is thought to play a key role in protecting the host from xenobiotic exposure. More recently, the PXR has been reported to regulate the expression of innate immune receptors in the intestine and modulate inflammasome activation in the vasculature. In the current study, we report that activation of the PXR in primed macrophages triggers caspase-1 activation and interleukin-1β release. Mechanistically, we show that this response is nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3-dependent and is driven by the rapid efflux of ATP and P2X purinoceptor 7 activation following PXR stimulation, an event that involves pannexin-1 gating, and is sensitive to inhibition of Src-family kinases. Our findings identify a mechanism whereby the PXR drives innate immune signaling, providing a potential link between xenobiotic exposure and the induction of innate inflammatory responses.
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Affiliation(s)
- Grace Hudson
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Kyle L Flannigan
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Vivek Krishna Pulakazhi Venu
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Laurie Alston
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Christina F Sandall
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Justin A MacDonald
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Daniel A Muruve
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Thomas K H Chang
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Sridhar Mani
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Simon A Hirota
- Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.)
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Cui BW, Bai T, Yang Y, Zhang Y, Jiang M, Yang HX, Wu M, Liu J, Qiao CY, Zhan ZY, Wu YL, Kang DZ, Lian LH, Nan JX. Thymoquinone Attenuates Acetaminophen Overdose-Induced Acute Liver Injury and Inflammation Via Regulation of JNK and AMPK Signaling Pathway. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:577-594. [PMID: 30974967 DOI: 10.1142/s0192415x19500307] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 β release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.
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Affiliation(s)
- Ben-Wen Cui
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Ting Bai
- † Medical College of Dalian University, Dalian 251122, Liaoning Province, China
| | - Yong Yang
- † Medical College of Dalian University, Dalian 251122, Liaoning Province, China
| | - Yu Zhang
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Min Jiang
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Hong-Xu Yang
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Mei Wu
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Jian Liu
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Chun-Ying Qiao
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Zi-Ying Zhan
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Yan-Ling Wu
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Dong-Zhou Kang
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Li-Hua Lian
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
| | - Ji-Xing Nan
- * Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China
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Guerra Martinez C. P2X7 receptor in cardiovascular disease: The heart side. Clin Exp Pharmacol Physiol 2019; 46:513-526. [PMID: 30834550 DOI: 10.1111/1440-1681.13079] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 02/21/2019] [Accepted: 02/28/2019] [Indexed: 01/10/2023]
Abstract
The P2X7 receptor is a ligand-gated purinergic receptor activated by extracellular ATP. The receptor is highly expressed in immune cells and in the brain, and, upon activation, the P2X7 receptor allows a cation flux, leading to the distinct activation of intracellular signalling pathways as the secretion of pro-inflammatory cytokines, and modulation of cell survival. Through these molecular mechanisms, P2X7 is known to play important roles in physiology and pathophysiology of a wide spectrum of diseases, including cancer, inflammatory diseases, neurological, respiratory and more recently cardiovascular diseases. Recent studies demonstrated that the P2X7 could modulate the assembly of the NLRP3 inflammasome, leading to the secretion of pro-inflammatory factors and worsen the cardiac disease phenotypes. This review discusses the critical molecular function of P2X7 in the modulation of the onset, progression and resolution of cardiovascular diseases and analyses the putative future use of P2X7-based therapies that modulate the IL-1β secretion arm and direct P2X7 antagonists.
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Affiliation(s)
- Camila Guerra Martinez
- Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas
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48
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Vuerich M, Robson SC, Longhi MS. Ectonucleotidases in Intestinal and Hepatic Inflammation. Front Immunol 2019; 10:507. [PMID: 30941139 PMCID: PMC6433995 DOI: 10.3389/fimmu.2019.00507] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 02/25/2019] [Indexed: 12/21/2022] Open
Abstract
Purinergic signaling modulates systemic and local inflammatory responses. Extracellular nucleotides, including eATP, promote inflammation, at least in part via the inflammasome upon engagement of P2 purinergic receptors. In contrast, adenosine generated during eATP phosphohydrolysis by ectonucleotidases, triggers immunosuppressive/anti-inflammatory pathways. Mounting evidence supports the role of ectonucleotidases, especially ENTPD1/CD39 and CD73, in the control of several inflammatory conditions, ranging from infectious disease, organ fibrosis to oncogenesis. Our experimental data generated over the years have indicated both CD39 and CD73 serve as pivotal regulators of intestinal and hepatic inflammation. In this context, immune cell responses are regulated by the balance between eATP and adenosine, potentially impacting disease outcomes as in gastrointestinal infection, inflammatory bowel disease, ischemia reperfusion injury of the bowel and liver, autoimmune or viral hepatitis and other inflammatory conditions, such as cancer. In this review, we report the most recent discoveries on the role of ENTPD1/CD39, CD73, and other ectonucleotidases in the regulation of intestinal and hepatic inflammation. We discuss the present knowledge, highlight the most intriguing and promising experimental data and comment on important aspects that still need to be addressed to develop purinergic-based therapies for these important illnesses.
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Affiliation(s)
- Marta Vuerich
- Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Simon C Robson
- Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.,Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Maria Serena Longhi
- Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.,Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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49
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Su QQ, Tian YY, Liu ZN, Ci LL, Lv XW. Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity. Int Immunopharmacol 2019; 66:52-61. [DOI: 10.1016/j.intimp.2018.11.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 12/18/2022]
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50
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Triantafyllou E, Woollard KJ, McPhail MJW, Antoniades CG, Possamai LA. The Role of Monocytes and Macrophages in Acute and Acute-on-Chronic Liver Failure. Front Immunol 2018; 9:2948. [PMID: 30619308 PMCID: PMC6302023 DOI: 10.3389/fimmu.2018.02948] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 11/30/2018] [Indexed: 12/28/2022] Open
Abstract
Acute and acute-on-chronic liver failure (ALF and ACLF), though distinct clinical entities, are considered syndromes of innate immune dysfunction. Patients with ALF and ACLF display evidence of a pro-inflammatory state with local liver inflammation, features of systemic inflammatory response syndrome (SIRS) and vascular endothelial dysfunction that drive progression to multi-organ failure. In an apparent paradox, these patients are concurrently immunosuppressed, exhibiting acquired immune defects that render them highly susceptible to infections. This paradigm of tissue injury succeeded by immunosuppression is seen in other inflammatory conditions such as sepsis, which share poor outcomes and infective complications that account for high morbidity and mortality. Monocyte and macrophage dysfunction are central to disease progression of ALF and ACLF. Activation of liver-resident macrophages (Kupffer cells) by pathogen and damage associated molecular patterns leads to the recruitment of innate effector cells to the injured liver. Early monocyte infiltration may contribute to local tissue destruction during the propagation phase and results in secretion of pro-inflammatory cytokines that drive SIRS. In the hepatic microenvironment, recruited monocytes mature into macrophages following local reprogramming so as to promote resolution responses in a drive to maintain tissue integrity. Intra-hepatic events may affect circulating monocytes through spill over of soluble mediators and exposure to apoptotic cell debris during passage through the liver. Hence, peripheral monocytes show numerous acquired defects in acute liver failure syndromes that impair their anti-microbial programmes and contribute to enhanced susceptibility to sepsis. This review will highlight the cellular and molecular mechanisms by which monocytes and macrophages contribute to the pathophysiology of ALF and ACLF, considering both hepatic inflammation and systemic immunosuppression. We identify areas for further research and potential targets for immune-based therapies to treat these devastating conditions.
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Affiliation(s)
- Evangelos Triantafyllou
- Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London, United Kingdom
- Division of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Kevin J. Woollard
- Division of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Mark J. W. McPhail
- Department of Inflammation Biology, Institute of Liver Studies, King's College London, London, United Kingdom
| | - Charalambos G. Antoniades
- Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London, United Kingdom
| | - Lucia A. Possamai
- Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London, United Kingdom
- Division of Immunology and Inflammation, Imperial College London, London, United Kingdom
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