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Deng Q, Qu Y, Luo Y, Zhang X. An immune-liver microphysiological system method for evaluation and quality control of hepatotoxicity induced by Polygonum multiflorum thunb. Extract. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119633. [PMID: 40086609 DOI: 10.1016/j.jep.2025.119633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 02/22/2025] [Accepted: 03/12/2025] [Indexed: 03/16/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Clinical applications of Polygonum multiflorum Thunb. (PMT) have occasionally reported adverse effects on liver function, linking these instances of hepatotoxicity to PMT samples. Evaluating the hepatotoxicity of PMT, given its intricate composition and mechanisms, presents a notable challenge. Notably, three toxic components display additive/synergistic effects, further complicating the establishment of a toxicological quality control method. AIM OF THE STUDY This study aims to develop a biology-based quality control method that can reflect the multi-mechanistic hepatotoxicity of PMT. MATERIALS AND METHODS We designed a microphysiological system tailored for the immune-liver interplay, termed the i-LOC, featuring three-cell channels. This i-LOC integrates hepatic cells with two distinct immune cell types to mimic inflammatory cell infiltration. As a control, a liver-on-chip devoid of immune cells was utilized to characterize hepatotoxicity induced by inflammatory stress. RESULTS The i-LOC system exhibited remarkable sensitivity in detecting both direct and inflammation-mediated hepatotoxic effects of the three PMT toxic components. This system significantly reduced the sample size requirements by thousandfold compared to animal models, presenting a cost-effective and attractive alternative for PMT toxicological assessments. Intriguingly, the system identified the present of previously unknown PMT compounds with potential hepatotoxic properties, emphasizing the need for a comprehensive biological evaluation method. CONCLUSION This study successfully developed an i-LOC method for effectively evaluating PMT's hepatotoxicity, overcoming the complexities posed by its intricate composition and mechanisms.
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Affiliation(s)
- Quanfeng Deng
- Jiangsu Key Laboratory of Neuropsychiatric Disease and College of Pharmaceutical Science, Suzhou Medical College, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, Soochow University, 215127, Suzhou, Jiangsu Province, China; Intensive Care Unit, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518031, China
| | - Yueyang Qu
- Jiangsu Key Laboratory of Neuropsychiatric Disease and College of Pharmaceutical Science, Suzhou Medical College, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, Soochow University, 215127, Suzhou, Jiangsu Province, China
| | - Yong Luo
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, 116024, Dalian, Liaoning Province, China.
| | - Xiuli Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Disease and College of Pharmaceutical Science, Suzhou Medical College, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, Soochow University, 215127, Suzhou, Jiangsu Province, China.
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Kim JH, Yeo IJ, Son DJ, Han SB, Yoon DY, Lee DH, Hong JT. Chitinase 3-like protein 1 deficiency ameliorates drug-induced acute liver injury by inhibition of neutrophil recruitment through lipocalin-2. Front Pharmacol 2025; 16:1548832. [PMID: 40196357 PMCID: PMC11973357 DOI: 10.3389/fphar.2025.1548832] [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: 12/20/2024] [Accepted: 03/06/2025] [Indexed: 04/09/2025] Open
Abstract
Chitinase-3-like protein 1 (Chi3l1) is a member of the mammalian Chitinase-like protein family, and several studies reported that Chi3l1 is associated with various inflammatory diseases as well as liver diseases. Acetaminophen (APAP) is usually used for antipyretic drug, but its overdose induces acute liver injury (ALI). Several studies reported that subsequent inflammatory responses of the immune system play a critical role in the severity and outcome of APAP-induced ALI. In the present study, we investigated the role of Chi3l1 and its mechanism during APAP-induced ALI using Chi3l1 knock-out (KO) mice. We explored the function of Chi3l1 using APAP-injected KO mice and sought proteins associated with Chi3l1 through biological research data program for investigating mechanism. Liver histological analysis revealed that APAP-induced ALI was attenuated in KO mice compared to wild-type (WT) mice. We observed that APAP-induced neutrophil infiltration was decreased in the liver of KO mice compared to WT mice. To investigate this mechanism, we sought proteins potentially associated with Chi3l1 by mRNA sequencing and protein correlation analysis data. We found lipocalin-2 (Lcn2) and examined Chi3l1, Lcn2, and their relationship in the APAP-induced ALI model using recombinant proteins and antibodies. Our results suggest that Chi3l1 deficiency ameliorates APAP-induced liver injury through abrogating Lcn2-mediated neutrophil infiltration in the liver.
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Affiliation(s)
- Ji Hye Kim
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju, Republic of Korea
| | - In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
- College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Dong Ju Son
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Sang Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Do Young Yoon
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Dong Hun Lee
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
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He W, Yan L, Hu D, Hao J, Liou Y, Luo G. Neutrophil heterogeneity and plasticity: unveiling the multifaceted roles in health and disease. MedComm (Beijing) 2025; 6:e70063. [PMID: 39845896 PMCID: PMC11751288 DOI: 10.1002/mco2.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/04/2024] [Accepted: 12/11/2024] [Indexed: 01/24/2025] Open
Abstract
Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.
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Affiliation(s)
- Weifeng He
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Lingfeng Yan
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Dongxue Hu
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Jianlei Hao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University)Jinan UniversityZhuhaiGuangdongChina
- The Biomedical Translational Research InstituteFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Yih‐Cherng Liou
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- National University of Singapore (NUS) Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore
| | - Gaoxing Luo
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
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Wang L, Dong Z, Zhang Y, Peng L. Emerging Roles of High-mobility Group Box-1 in Liver Disease. J Clin Transl Hepatol 2024; 12:1043-1056. [PMID: 39649031 PMCID: PMC11622203 DOI: 10.14218/jcth.2024.00317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 12/10/2024] Open
Abstract
High-mobility group box-1 (HMGB1) is an architectural chromosomal protein with various roles depending on its cellular localization. Extracellular HMGB1 functions as a prototypical damage-associated molecular pattern that triggers inflammation and adaptive immune responses, mediated by specific cell surface receptors, including receptors for advanced glycation end products and toll-like receptors. Post-translational modifications of HMGB1 significantly impact various cellular processes that contribute to the pathogenesis of liver diseases. Recent studies have highlighted the close relationship between HMGB1 and the pathogenesis of acute liver injuries, including acetaminophen-induced liver injury, hepatic ischemia-reperfusion injury, and acute liver failure. In chronic liver diseases, HMGB1 plays a role in nonalcoholic fatty liver disease, alcohol-associated liver disease, liver fibrosis, and hepatocellular carcinoma. Targeting HMGB1 as a therapeutic approach, either by inhibiting its release or blocking its extracellular function, is a promising strategy for treating liver diseases. This review aimed to summarize the available evidence on HMGB1's role in liver disease, focusing on its multifaceted signaling pathways, impact on disease progression, and the translation of these findings into clinical interventions.
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Affiliation(s)
- Lu Wang
- Department of Diagnostics, Second School of Clinical Medicine, Binzhou Medical University, Yantai, Shandong, China
| | - Zhiwei Dong
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yeqiong Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Pilling D, Martinez TC, Gomer RH. Inhibition of CCl4-induced liver inflammation and fibrosis by a NEU3 inhibitor. PLoS One 2024; 19:e0308060. [PMID: 39570922 PMCID: PMC11581222 DOI: 10.1371/journal.pone.0308060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 09/26/2024] [Indexed: 11/24/2024] Open
Abstract
Sialic acids are located on the ends of many glycoconjugates and are cleaved off by enzymes called sialidases (neuraminidases). Upregulation of neuraminidase 3 (NEU3) is associated with intestinal inflammation and colitis, neuroinflammation, and lung fibrosis. Genetic ablation of NEU3 or pharmacological inhibition of NEU3 reduces lung fibrosis in mice. To determine if inhibiting NEU3 can inhibit liver fibrosis in the commonly-used CCl4 model, in this report, we examined the effects of injections of the NEU3 inhibitor 2-acetyl pyridine (2AP). 2AP inhibited CCl4-induced weight loss in female but not male mice. 2AP attenuated CCl4-induced liver inflammation and fibrosis in male and female mice, but did not affect CCl4-induced steatosis. After CCl4 treatment, female but not male mice had significant increases in liver neutrophils, and 2AP attenuated this response. 2AP also reversed CCl4-induced liver desialylation and CCl4-induced increased expression of NEU3. Patients with pulmonary fibrosis have increased desialylation of some serum proteins, and elevated serum levels of NEU3. We find that sera from patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have elevated desialylation of a serum protein and patients with NAFLD have increased levels of NEU3. These data suggest that elevated levels of NEU3 may be associated with liver inflammation and fibrosis, and that in mice this is ameliorated by injections of a NEU3 inhibitor.
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Affiliation(s)
- Darrell Pilling
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| | - Trevor C. Martinez
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| | - Richard H. Gomer
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
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Fasolato S, Bonaiuto E, Rossetto M, Vanzani P, Ceccato F, Vittadello F, Zennaro L, Rigo A, Mammano E, Angeli P, Pontisso P, Di Paolo ML. Serum Vascular Adhesion Protein-1 and Endothelial Dysfunction in Hepatic Cirrhosis: Searching for New Prognostic Markers. Int J Mol Sci 2024; 25:7309. [PMID: 39000418 PMCID: PMC11242677 DOI: 10.3390/ijms25137309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/28/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Endothelial dysfunction plays a key role in the development of liver cirrhosis. Among the biomarkers of endothelial dysfunction, the soluble form of Vascular Adhesion Protein-1 (sVAP-1) is an unconventional and less known adhesion molecule endowed also with amine oxidase activity. The aim of this study was to explore and correlate the behavior of sVAP-1 with that of the soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) and with the severity of liver cirrhosis. A cross-sectional study was carried out by enrolling 28 controls, 59 cirrhotic patients without hepatocellular carcinoma, and 56 patients with hepatocellular carcinoma (HCC), mainly caused by alcohol abuse. The levels of adhesion molecules and of the pro-inflammatory cytokines (IL-6 and TNF-αα) were determined by immunoassay and the enzymatic activity of sVAP-1 by a fluorometric assay. In non-diabetic patients without HCC, a specific behavior of sVAP-1 was highlighted. Differently from sVCAM-1, sICAM-1, and cytokines, the sVAP-1 level was significantly increased only in the early stage of disease, and then, it decreased in the last stage (866 ± 390 ng/mL vs. 545 ± 316 ng/mL, in Child-Pugh class A vs. C, respectively, p < 0.05). Bivariate analysis correlates sVAP-1 to sVCAM-1, in the absence of HCC (Spearman's rho = 0.403, p < 0.01). Multiple linear regression analysis revealed that sVCAM-1 appears to be a predictor of sVAP-1 (β coefficient = 0.374, p = 0.021). In conclusion, in non-diabetic and non-HCC cirrhotic patients, sVAP-1 may be a potential prognostic biomarker that, together with sVCAM-1 and pro-inflammatory cytokines, may provide information on the progression of sinusoidal liver endothelium damage.
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Affiliation(s)
- Silvano Fasolato
- Department of Medicine, Padua University Hospital, 35128 Padua, Italy
| | - Emanuela Bonaiuto
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy
| | - Monica Rossetto
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy
| | - Paola Vanzani
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy
| | - Fabio Ceccato
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Fabio Vittadello
- Explora s.n.c.-Research and Statistical Analysis, 35010 Padua, Italy
| | - Lucio Zennaro
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy
| | - Adelio Rigo
- Nazionale di Biostrutture e Biosistemi (INBB), Consorzio Interuniversitario Istituto, Viale Medaglie d'Oro, 00136 Roma, Italy
| | - Enzo Mammano
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Paolo Angeli
- Department of Medicine, Medical Clinic 5, University Hospital of Padua, 35128 Padua, Italy
| | - Patrizia Pontisso
- Department of Medicine, Medical Clinic 5, University Hospital of Padua, 35128 Padua, Italy
| | - Maria Luisa Di Paolo
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy
- Nazionale di Biostrutture e Biosistemi (INBB), Consorzio Interuniversitario Istituto, Viale Medaglie d'Oro, 00136 Roma, Italy
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Tang G, Nierath WF, Leitner E, Xie W, Revskij D, Seume N, Zhang X, Ehlers L, Vollmar B, Zechner D. Comparing animal well-being between bile duct ligation models. PLoS One 2024; 19:e0303786. [PMID: 38950046 PMCID: PMC11216573 DOI: 10.1371/journal.pone.0303786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 05/01/2024] [Indexed: 07/03/2024] Open
Abstract
A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model.
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Affiliation(s)
- Guanglin Tang
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
- Department of General Surgery, Fushun Central Hospital, Fushun, Liaoning, China
| | - Wiebke-Felicitas Nierath
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Emily Leitner
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Wentao Xie
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Denis Revskij
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Nico Seume
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Xianbin Zhang
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
- Department of General Surgery & Institute of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen, China
| | - Luise Ehlers
- Department of General Surgery, Fushun Central Hospital, Fushun, Liaoning, China
| | - Brigitte Vollmar
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Dietmar Zechner
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
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Sayaf K, Battistella S, Russo FP. NLRP3 Inflammasome in Acute and Chronic Liver Diseases. Int J Mol Sci 2024; 25:4537. [PMID: 38674122 PMCID: PMC11049922 DOI: 10.3390/ijms25084537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the NLRP3 inflammasome. The NLRP3 inflammasome mainly mediates pyroptosis, a highly inflammatory mode of regulated cell death, as well as IL-18 and IL-1β production. Acute and chronic liver diseases are characterized by a massive influx of pro-inflammatory stimuli enriched in reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) that promote the assemblage and activation of the NLRP3 inflammasome. As the major cause of inflammatory cytokine storm, the NLRP3 inflammasome exacerbates liver diseases, even though it might exert protective effects in regards to hepatitis C and B virus infection (HCV and HBV). Here, we summarize the current knowledge concerning NLRP3 inflammasome function in both acute and chronic liver disease and in the post liver transplant setting, focusing on the molecular mechanisms involved in NLRP3 activity.
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Affiliation(s)
- Katia Sayaf
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy; (K.S.); (S.B.)
| | - Sara Battistella
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy; (K.S.); (S.B.)
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 35128 Padua, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy; (K.S.); (S.B.)
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 35128 Padua, Italy
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Zhang M, Yan W, Wang T, Pei S, Wang J, Ji B, Wang G. Deoxyribonuclease I Alleviates Septic Liver Injury in a Rat Model Supported by Venoarterial Extracorporeal Membrane Oxygenation. ASAIO J 2024; 70:241-247. [PMID: 37923309 PMCID: PMC10885865 DOI: 10.1097/mat.0000000000002084] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023] Open
Abstract
Sepsis is an unusual systemic reaction with high mortality and secondary septic liver injury is proposed to be the major cause of mortality. Extracorporeal membrane oxygenation (ECMO) can enhance terminal organ perfusion by elevating circulatory support which is used in severe sepsis patients. However, the interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response. Besides, inflammation and apoptosis are the main mediators in the pathophysiology of septic liver injury. Therefore, we investigated the protective effect of Deoxyribonuclease I (DNase I) against septic liver injury supported by ECMO in rats. Sepsis was induced by lipopolysaccharide (LPS) and 24 hours after the administration, the rats were treated with ECMO. Then blood samples and liver tissues were collected. DNase I significantly attenuated the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and significantly decreased hepatic levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, myeloperoxidase (MPO), downstream inflammatory factor interleukin-1β (IL-1β) and interleukin-18 (IL-18), and improved neutrophil infiltration. Additionally, DNase I significantly reduced the expression of apoptosis key protein and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-labeled apoptotic hepatocytes. In summary, our findings demonstrated that DNase I alleviates liver injury in ECMO-supported septic rats by reducing the inflammatory and apoptotic responses.
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Affiliation(s)
- Mingru Zhang
- From the Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Weidong Yan
- Department of Cardiopulmonary Bypass, Fuwai Hospital, National Center for Cardiovascular Disease, State Key Laboratory of Cardiovascular Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Tianlong Wang
- Department of Cardiopulmonary Bypass, Fuwai Hospital, National Center for Cardiovascular Disease, State Key Laboratory of Cardiovascular Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shengqiang Pei
- Department of Cardiopulmonary Bypass, Fuwai Hospital, National Center for Cardiovascular Disease, State Key Laboratory of Cardiovascular Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jing Wang
- Department of Cardiopulmonary Bypass, Fuwai Hospital, National Center for Cardiovascular Disease, State Key Laboratory of Cardiovascular Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Bingyang Ji
- Department of Cardiopulmonary Bypass, Fuwai Hospital, National Center for Cardiovascular Disease, State Key Laboratory of Cardiovascular Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Guyan Wang
- From the Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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10
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Zhao J, Ghallab A, Hassan R, Dooley S, Hengstler JG, Drasdo D. A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage. iScience 2024; 27:108077. [PMID: 38371522 PMCID: PMC10869925 DOI: 10.1016/j.isci.2023.108077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 02/22/2023] [Accepted: 09/25/2023] [Indexed: 02/20/2024] Open
Abstract
This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.
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Affiliation(s)
- Jieling Zhao
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Steven Dooley
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jan Georg Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
| | - Dirk Drasdo
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
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11
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Cuadra B, Silva V, Huang YL, Diaz Y, Rivas C, Molina C, Simon V, Bono MR, Morales B, Rosemblatt M, Silva S, Acuña R, Ezquer F, Ezquer M. The Immunoregulatory and Regenerative Potential of Activated Human Stem Cell Secretome Mitigates Acute-on-Chronic Liver Failure in a Rat Model. Int J Mol Sci 2024; 25:2073. [PMID: 38396750 PMCID: PMC10889754 DOI: 10.3390/ijms25042073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/31/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF.
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Affiliation(s)
- Barbara Cuadra
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Veronica Silva
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Ya-Lin Huang
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Yael Diaz
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Claudio Rivas
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Cristobal Molina
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Valeska Simon
- Departamento de Biología, Facultad de Ciencias, Universidad del Chile, Las Encinas 3370, Ñuñoa, Santiago 7800020, Chile; (V.S.); (M.R.B.)
| | - Maria Rosa Bono
- Departamento de Biología, Facultad de Ciencias, Universidad del Chile, Las Encinas 3370, Ñuñoa, Santiago 7800020, Chile; (V.S.); (M.R.B.)
| | - Bernardo Morales
- Facultad de Ciencias de la Salud, Universidad del Alba, Atrys Chile, Guardia Vieja 339, Providencia, Santiago 7510249, Chile;
| | - Mario Rosemblatt
- Centro de Ciencia & Vida, Av. Del Valle Norte 725, Huechuraba, Santiago 8580702, Chile;
| | - Sebastian Silva
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Rodrigo Acuña
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
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12
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Mei Y, Li X, He C, Zhang Y, Kong W, Xue R, Huang X, Shi Y, Tao G, Xing M, Wang X. Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury. Chem Res Toxicol 2024; 37:42-56. [PMID: 38091573 DOI: 10.1021/acs.chemrestox.3c00250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alpha-naphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT- and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17+CD4+T cells, IFN-γ/IL-4/IL-17+iNKT cells and IFN-γ/IL-4+NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT- and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ+NK cells and IL-4+NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4+iNKT cells and IL-17+iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT- and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.
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Affiliation(s)
- Yuan Mei
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Xinyu Li
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Chao He
- Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Yiying Zhang
- Division of Biosciences, University College London, London WC1E 6BT, U.K
| | - Weichao Kong
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Rufeng Xue
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Xin Huang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yaxiang Shi
- Department of Gastroenterology, Zhenjiang Hospital Affiliated to Nanjing University of Chinese Medicine, Zhenjiang Hospital of Traditional Chinese Medicine, Zhenjiang 212003, China
| | - Gang Tao
- Department of Gastroenterology, Zhenjiang Hospital Affiliated to Nanjing University of Chinese Medicine, Zhenjiang Hospital of Traditional Chinese Medicine, Zhenjiang 212003, China
| | - Mengtao Xing
- Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China
| | - Xinzhi Wang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
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13
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Li LX, Wang L, Wang S, Zhang XN, Liu H, Zhang YJ, Wu CT, Zhang CL, Zeng T. Allyl methyl disulfide (AMDS) prevents N,N-dimethyl formamide-induced liver damage by suppressing oxidative stress and NLRP3 inflammasome activation. Food Chem Toxicol 2023; 182:114198. [PMID: 37995826 DOI: 10.1016/j.fct.2023.114198] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 10/30/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023]
Abstract
N,N-dimethylformamide (DMF), a widely consumed industrial solvent with persistent characteristics, can induce occupational liver damage and pose threats to the general population due to the enormous DMF-containing industrial efflux and emission from indoor facilities. This study was performed to explore the roles of allyl methyl disulfide (AMDS) in liver damage induced by DMF and the underlying mechanisms. AMDS was found to effectively suppress the elevation in the liver weight/body weight ratio and serum aminotransferase activities, and reduce the mortality of mice induced by DMF. In addition, AMDS abrogated DMF-elicited increases in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels and decreases in glutathione (GSH) levels in mouse livers. The increase in macrophage number, mRNA expression of M1 macrophage biomarkers, and protein expression of key components in the NF-κB pathway and NLRP3 inflammasome induced by DMF exposure were all suppressed by AMDS in mouse livers. Furthermore, AMDS inhibited DMF-induced cell damage and NF-κB activation in cocultured AML12 hepatocytes and J774A.1 macrophages. However, AMDS per se did not significantly affect the protein level and activity of CYP2E1. Collectively, these results demonstrate that AMDS effectively ameliorates DMF-induced acute liver damage possibly by suppressing oxidative stress and inactivating the NF-κB pathway and NLRP3 inflammasome.
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Affiliation(s)
- Long-Xia Li
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Lin Wang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shuo Wang
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252059, China
| | - Xiu-Ning Zhang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Hong Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yan-Jing Zhang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Chuan-Tao Wu
- The Animal Research Center, Shandong University, Jinan, Shandong, 250012, China
| | - Cui-Li Zhang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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14
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Gao J, Bao M, Xing Y, Ding Y, Han T, Wen E, Liu J, Yue S, Wang R, Wang L, Liu J, Zhao S, Huang J, Liu E, Bai L. Mediator subunit MED1 deficiency prevents carbon tetrachloride-induced hepatic fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 2023; 325:G418-G428. [PMID: 37668531 DOI: 10.1152/ajpgi.00076.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/06/2023]
Abstract
Mediator subunit mediator 1 (MED1) mediates ligand-dependent binding of the mediator coactivator complex to various nuclear receptors and plays a critical role in embryonic development, lipid and glucose metabolism, liver regeneration, and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice and positively correlated with transforming growth factor β (TGF-β) signaling and profibrotic factors. Upon treatment with carbon tetrachloride (CCl4), hepatic fibrosis was much less in liver-specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-β/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 α 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-administered MED1ΔLiv mice were enriched in the pathway of oxidoreductase activity, followed by robustly reduced oxidoreductase activity-related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that the reduction of reactive oxygen species (ROS) in MED1 knockdown hepatocytes blocked the activation of TGF-β/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.NEW & NOTEWORTHY In this study, we present the first evidence that liver mediator 1 (MED1) deficiency attenuated carbon tetrachloride-induced hepatic fibrosis in mouse. The underlying mechanism is that MED1 deficiency reduces reactive oxygen species (ROS) production in hepatocytes, thus restricts the activation of TGF-β/Smad2/3 signaling pathway and fibrogenic genes expression in hepatic stellate cells (HSCs). These data suggest that MED1 is an essential regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Jie Gao
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
- School of Biological Science Technology and Engineering, Shaanxi University of Technology, Hanzhong, People's Republic of China
| | - Miaoye Bao
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Yuanming Xing
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Yiming Ding
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Tuo Han
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Ergang Wen
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Jun Liu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Shaoyun Yue
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Rong Wang
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Ling Wang
- School of Biological Science Technology and Engineering, Shaanxi University of Technology, Hanzhong, People's Republic of China
| | - Junhui Liu
- Department of Clinical Laboratory, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Sihai Zhao
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Jiansheng Huang
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Enqi Liu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Liang Bai
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
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15
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Hassan GS, Flores Molina M, Shoukry NH. The multifaceted role of macrophages during acute liver injury. Front Immunol 2023; 14:1237042. [PMID: 37736102 PMCID: PMC10510203 DOI: 10.3389/fimmu.2023.1237042] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/15/2023] [Indexed: 09/23/2023] Open
Abstract
The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.
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Affiliation(s)
- Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Manuel Flores Molina
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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16
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Wang H, Shen H, Seo W, Hwang S. Experimental models of fatty liver diseases: Status and appraisal. Hepatol Commun 2023; 7:e00200. [PMID: 37378635 DOI: 10.1097/hc9.0000000000000200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 05/16/2023] [Indexed: 06/29/2023] Open
Abstract
Fatty liver diseases, including alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease nonalcoholic fatty liver disease (NAFLD), affect a large number of people worldwide and become one of the major causes of end-stage liver disease, such as liver cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, there are currently no approved pharmacological treatments for ALD or NAFLD. This situation highlights the urgent need to explore new intervention targets and discover effective therapeutics for ALD and NAFLD. The lack of properly validated preclinical disease models is a major obstacle to the development of clinical therapies. ALD and NAFLD models have been in the development for decades, but there are still no models that recapitulate the full spectrum of ALD and NAFLD. Throughout this review, we summarize the current in vitro and in vivo models used for research on fatty liver diseases and discuss the advantages and limitations of these models.
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Affiliation(s)
- Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Haiyuan Shen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Wonhyo Seo
- Laboratory of Hepatotoxicity, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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17
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Lim CS, Veltri B, Kashon M, Porter DW, Ma Q. Multi-walled carbon nanotubes induce arachidonate 5-lipoxygenase expression and enhance the polarization and function of M1 macrophages in vitro. Nanotoxicology 2023; 17:249-269. [PMID: 37115655 DOI: 10.1080/17435390.2023.2204161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
Fibrogenic carbon nanotubes (CNTs) induce the polarization of M1 and M2 macrophages in mouse lungs. Polarization of the macrophages regulates the production of proinflammatory and pro-resolving lipid mediators (LMs) to mediate acute inflammation and its resolution in a time-dependent manner. Here we examined the molecular mechanism by which multi-walled CNTs (MWCNTs, Mitsui-7) induce M1 polarization in vitro. Treatment of murine macrophages (J774A.1) with Mitsui-7 MWCNTs increased the expression of Alox5 mRNA and protein in a concentration- and time-dependent manner. The MWCNTs induced the expression of CD68 and that induction persisted for up to 3 days post-exposure. The expression and activity of inducible nitric oxide synthase, an intracellular marker of M1, were increased by MWCNTs. Consistent with M1 polarization, the MWCNTs induced the production and secretion of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β, and proinflammatory LMs leukotriene B4 (LTB4) and prostaglandin E2 (PGE2). The cell-free media from MWCNT-polarized macrophages induced the migration of neutrophilic cells (differentiated from HL-60), which was blocked by Acebilustat, a specific leukotriene A4 hydrolase inhibitor, or LY239111, an LTB4 receptor antagonist, but not NS-398, a cyclooxygenase 2 inhibitor, revealing LTB4 as a major mediator of neutrophil chemotaxis from MWCNT-polarized macrophages. Knockdown of Alox5 using specific small hairpin-RNA suppressed MWCNT-induced M1 polarization, LTB4 secretion, and migration of neutrophils. Taken together, these findings demonstrate the polarization of M1 macrophages by Mitsui-7 MWCNTs in vitro and that induction of Alox5 is an important mechanism by which the MWCNTs promote proinflammatory responses by boosting M1 polarization and production of proinflammatory LMs.
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Affiliation(s)
- Chol Seung Lim
- Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, USA
| | - Brandon Veltri
- Department of Microbiology, Immunology, and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Michael Kashon
- Bioanalytics Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, USA
| | - Dale W Porter
- Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, USA
| | - Qiang Ma
- Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, USA
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18
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Ishida Y, Zhang S, Kuninaka Y, Ishigami A, Nosaka M, Harie I, Kimura A, Mukaida N, Kondo T. Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice. Int J Mol Sci 2023; 24:ijms24097845. [PMID: 37175553 PMCID: PMC10177873 DOI: 10.3390/ijms24097845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Intense neutrophil infiltration into the liver is a characteristic of acetaminophen-induced acute liver injury. Neutrophil elastase is released by neutrophils during inflammation. To elucidate the involvement of neutrophil elastase in acetaminophen-induced liver injury, we investigated the efficacy of a potent and specific neutrophil elastase inhibitor, sivelestat, in mice with acetaminophen-induced acute liver injury. Intraperitoneal administration of 750 mg/kg of acetaminophen caused severe liver damage, such as elevated serum transaminase levels, centrilobular hepatic necrosis, and neutrophil infiltration, with approximately 50% mortality in BALB/c mice within 48 h of administration. However, in mice treated with sivelestat 30 min after the acetaminophen challenge, all mice survived, with reduced serum transaminase elevation and diminished hepatic necrosis. In addition, mice treated with sivelestat had reduced NOS-II expression and hepatic neutrophil infiltration after the acetaminophen challenge. Furthermore, treatment with sivelestat at 3 h after the acetaminophen challenge significantly improved survival. These findings indicate a new clinical application for sivelestat in the treatment of acetaminophen-induced liver failure through mechanisms involving the regulation of neutrophil migration and NO production.
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Affiliation(s)
- Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Siying Zhang
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Yumi Kuninaka
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Akiko Ishigami
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Mizuho Nosaka
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Isui Harie
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Akihiko Kimura
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Naofumi Mukaida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | - Toshikazu Kondo
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
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Li N, Liu H, Xue Y, Xu Z, Miao X, Guo Y, Li Z, Fan Z, Xu Y. Targetable Brg1-CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking. EMBO Mol Med 2023; 15:e16592. [PMID: 36722664 PMCID: PMC9994483 DOI: 10.15252/emmm.202216592] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 02/02/2023] Open
Abstract
Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma-related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression was elevated in mouse models of ALD, in hepatocyte exposed to alcohol, and in human ALD specimens. Manipulation of Brg1 expression in hepatocytes influenced the development of ALD in mice. Flow cytometry showed that Brg1 deficiency specifically attenuated hepatic infiltration of Ly6G+ neutrophils in the ALD mice. RNA-seq identified C-X-C motif chemokine ligand 14 (CXCL14) as a potential target for Brg1. CXCL14 knockdown alleviated whereas CXCL14 over-expression enhanced ALD pathogenesis in mice. Importantly, pharmaceutical inhibition of Brg1 with a small-molecule compound PFI-3 or administration of an antagonist to the CXCL14 receptor ameliorated ALD pathogenesis in mice. Finally, a positive correlation between Brg1 expression, CXCL14 expression, and neutrophil infiltration was detected in ALD patients. In conclusion, our data provide proof-of-concept for targeting the Brg1-CXCL14 axis in ALD intervention.
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Affiliation(s)
- Nan Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Hong Liu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Yujia Xue
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Zheng Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Xiulian Miao
- Collage of Life Sciences and Institute of Biomedical Research, Liaocheng UniversityLiaochengChina
| | - Yan Guo
- Collage of Life Sciences and Institute of Biomedical Research, Liaocheng UniversityLiaochengChina
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of PharmacologyChina Pharmaceutical UniversityNanjingChina
| | - Zhiwen Fan
- Department of PathologyNanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolNanjingChina
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
- Collage of Life Sciences and Institute of Biomedical Research, Liaocheng UniversityLiaochengChina
- State Key Laboratory of Natural Medicines, Department of PharmacologyChina Pharmaceutical UniversityNanjingChina
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20
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Raval NR, Wetherill RR, Wiers CE, Dubroff JG, Hillmer AT. Positron Emission Tomography of Neuroimmune Responses in Humans: Insights and Intricacies. Semin Nucl Med 2023; 53:213-229. [PMID: 36270830 PMCID: PMC11261531 DOI: 10.1053/j.semnuclmed.2022.08.008] [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: 08/15/2022] [Accepted: 08/30/2022] [Indexed: 11/06/2022]
Abstract
The brain's immune system plays a critical role in responding to immune challenges and maintaining homeostasis. However, dysregulated neuroimmune function contributes to neurodegenerative disease and neuropsychiatric conditions. In vivo positron emission tomography (PET) imaging of the neuroimmune system has facilitated a greater understanding of its physiology and the pathology of some neuropsychiatric conditions. This review presents an in-depth look at PET findings from human neuroimmune function studies, highlighting their importance in current neuropsychiatric research. Although the majority of human PET studies feature radiotracers targeting the translocator protein 18 kDa (TSPO), this review also considers studies with other neuroimmune targets, including monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, nitric oxide synthase, and the purinergic P2X7 receptor. Promising new targets, such as colony-stimulating factor 1, Sphingosine-1-phosphate receptor 1, and the purinergic P2Y12 receptor, are also discussed. The significance of validating neuroimmune targets and understanding their function and expression is emphasized in this review to better identify and interpret PET results.
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Affiliation(s)
- Nakul R Raval
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT; Yale PET Center, Yale University, New Haven, CT
| | - Reagan R Wetherill
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Corinde E Wiers
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jacob G Dubroff
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Ansel T Hillmer
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT; Yale PET Center, Yale University, New Haven, CT; Department of Psychiatry, Yale University, New Haven, CT.
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Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice. Pharmaceutics 2023; 15:pharmaceutics15020710. [PMID: 36840032 PMCID: PMC9959252 DOI: 10.3390/pharmaceutics15020710] [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: 01/09/2023] [Revised: 02/02/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. To understand the importance of IKKβ activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKβ activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKβ inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKβ, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses.
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22
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Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury-A Repeated Dose Study in Minipigs for 28 Days. Int J Mol Sci 2023; 24:ijms24021445. [PMID: 36674967 PMCID: PMC9863319 DOI: 10.3390/ijms24021445] [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: 11/22/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/14/2023] Open
Abstract
Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment. Notwithstanding, histopathology revealed drug-induced hepatitis, marked glycogen depletion, necrosis and steatosis. Strikingly, the genomic study revealed diclofenac to desynchronize the liver clock with manifest inductions of its components CLOCK, NPAS2 and BMAL1. The > 4-fold induced CRY1 expression underscored an activated core-loop, and the dose dependent > 60% reduction in PER2mRNA repressed the negative feedback loop; however, it exacerbated hepatotoxicity. Bioinformatics enabled the construction of gene-regulatory networks, and we linked the disruption of the liver-clock to impaired glycogenesis, lipid metabolism and the control of immune responses, as shown by the 3-, 6- and 8-fold induced expression of pro-inflammatory CXCL2, lysozyme and ß-defensin. Additionally, diclofenac treatment caused adrenocortical hypertrophy and thymic atrophy, and we evidenced induced glucocorticoid receptor (GR) activity by immunohistochemistry. Given that REV-ERB connects the circadian clock with hepatic GR, its > 80% repression alleviated immune responses as manifested by repressed expressions of CXCL9(90%), CCL8(60%) and RSAD2(70%). Together, we propose a circuitry, whereby diclofenac desynchronizes the liver clock in the control of the hepatic metabolism and immune response.
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23
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Sun L, He D, Liu Y, Wei Y, Wang L. Corynoline protects against zearalenone-induced liver injury by activating the SIRT1/Nrf2 signaling pathway. J Biochem Mol Toxicol 2023; 37:e23224. [PMID: 36161741 DOI: 10.1002/jbt.23224] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/22/2022] [Accepted: 09/16/2022] [Indexed: 01/18/2023]
Abstract
Corynoline has been reported to have anti-inflammatory and antioxidative effects. In the present study, the potential protective effects of corynoline against zearalenone (ZEA)-induced liver injury were investigated. ZEA was administered daily for 5 days. Then, liver tissues were used for subsequent experiments. Corynoline attenuated liver histopathological changes induced by ZEA. The production of tumor necrosis factor-α and interleukin-1β in liver tissues, as well as aspartate aminotransferase and alanine aminotransferase in serum, was also inhibited by corynoline. Meanwhile, ZEA-induced MPO activity and MDA content were both attenuated by corynoline. ZEA-induced NF-κB p65 and IκBα phosphorylation were inhibited by corynoline. Furthermore, SIRT1, Nrf2, and HO-1 expression were increased by corynoline. In addition, the protective effects of corynoline against liver injury were reversed by the SIRT1 inhibitor EX-527. Taken together, corynoline protected against ZEA-induced liver injury by activating the SIRT1/Nrf2 signaling pathway.
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Affiliation(s)
- Liqun Sun
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Dan He
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Yuhuan Liu
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Yunyun Wei
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Li Wang
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
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24
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Lee W, Kim SJ. Protective effects of isoflavones on alcoholic liver diseases: Computational approaches to investigate the inhibition of ALDH2 with isoflavone analogues. Front Mol Biosci 2023; 10:1147301. [PMID: 36923641 PMCID: PMC10009234 DOI: 10.3389/fmolb.2023.1147301] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/07/2023] [Indexed: 03/02/2023] Open
Abstract
Excessive and chronic alcohol intake can lead to the progression of alcoholic liver disease (ALD), which is a major cause of morbidity and mortality worldwide. ALD encompasses a pathophysiological spectrum such as simple steatosis, alcoholic steatohepatitis (ASH), fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma (HCC). Aldehyde dehydrogenase (ALDH2) is the most vital enzyme that produces acetate from acetaldehyde and is expressed at high levels in the liver, kidneys, muscles, and heart. The ALDH2*2 allele is found in up to 40% of East Asian populations, and has a significant impact on alcohol metabolism. Interestingly, several studies have shown that individuals with ALDH2 deficiency are more susceptible to liver inflammation after drinking alcohol. Furthermore, there is growing evidence of an association between ALDH2 deficiency and the development of cancers in the liver, stomach, colon, and lung. Isoflavone analogues are low molecular-weight compounds derived from plants, similar in structure and activity to estrogen in mammals, known as phytoestrogens. Recent studies have reported that isoflavone analogues have beneficial effects on the progression of ALD. This mini-review summarizes the current knowledge about the roles of isoflavone analogues in ALD and discusses the therapeutic potential of isoflavone analogues in liver pathophysiology. In particular, we highlight the significance of computational approaches in this field.
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Affiliation(s)
- Wook Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea
| | - Seung-Jin Kim
- Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, Republic of Korea.,Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon, Republic of Korea
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25
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Hou Y, Wei D, Bossila EA, Zhang Z, Li S, Bao J, Xu H, Zhang L, Zhao Y. FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:2181-2191. [PMID: 36426981 DOI: 10.4049/jimmunol.2200182] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 09/07/2022] [Indexed: 12/24/2022]
Abstract
Fatty acid binding protein 5 (FABP5) is mainly involved in the uptake, transport, and metabolism of fatty acid in the cytoplasm, and its role in immune cells has been recognized in recent years. However, the role of FABP5 in macrophage inflammation and its underlying mechanisms were not fully addressed. In our study, the acute liver injury and sepsis mouse models were induced by i.p. injection of LPS and cecal contents, respectively. Oleic acid (0.6 g/kg) was injected four times by intragastric administration every week, and this lasted for 1 wk before the LPS or cecal content challenge. We found that myeloid-specific deletion of FABP5 mitigated LPS-induced acute liver injury with reduced mortality of mice, histological liver damage, alanine aminotransferase, and proinflammatory factor levels. Metabolic analysis showed that FABP5 deletion increased the intracellular unsaturated fatty acids, especially oleic acid, in LPS-induced macrophages. The addition of oleic acid also decreased LPS-stimulated macrophage inflammation in vitro and reduced acute liver injury in LPS-induced or cecal content-induced sepsis mice. RNA-sequencing and molecular mechanism studies showed that FABP5 deletion or oleic acid supplementation increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) activation and inhibited the NF-κB pathway during the inflammatory response to LPS stimulation of macrophages. Inhibiting AMPK activation or expression by chemical or genetic approaches significantly rescued the decreased NF-κB signaling pathway and inflammatory response in LPS-treated FABP5-knockout macrophages. Our present study indicated that inhibiting FABP5 or supplementation of oleic acid might be used for the treatment of sepsis-caused acute liver injury.
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Affiliation(s)
- Yangxiao Hou
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Dong Wei
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Elhusseny A Bossila
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Biotechnology Department, Faculty of Agriculture Al-Azhar University, Cairo, Egypt
| | - Zhaoqi Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Sihong Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jiaming Bao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Huawen Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Lianfeng Zhang
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regeneration, Beijing, China
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Zhou X, Li X, Yi K, Liang C, Geng S, Zhu J, Xie C, Zhong C. Magnesium isoglycyrrhizinate ameliorates lipopolysaccharide-induced liver injury by upregulating autophagy and inhibiting inflammation via IL-22 expression. Bioorg Chem 2022; 128:106034. [DOI: 10.1016/j.bioorg.2022.106034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/01/2022] [Accepted: 07/14/2022] [Indexed: 12/15/2022]
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27
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Alimba CG, Sivanesan S, Krishnamurthi K. Mitochondrial dysfunctions elicited by solid waste leachates provide insights into mechanisms of leachates induced cell death and pathophysiological disorders. CHEMOSPHERE 2022; 307:136085. [PMID: 36007733 DOI: 10.1016/j.chemosphere.2022.136085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 06/15/2023]
Abstract
Emissions (mainly leachates and landfill gases) from solid waste facilities are laden with mixtures of dangerous xenobiotics implicated with significant increase in various pathophysiological disorders including cancer, and eventual mortality of exposed wildlife and humans. However, the molecular mechanisms of solid waste leachates induce pathophysiological disorders and cell death are still largely unknown. Although, evolving evidence implicated generation of reactive oxygen species and oxidative stress as the possible mechanism. Recent scientific reports are linking reactive oxygen species and mitochondrial dysfunctions as the player mechanism in pathophysiological disorder and apoptosis induced by xenobiotics in solid waste leachates. This systematic review presents an explicit discussion of recent scientific findings on the structural and functional alterations in mitochondria induced by solid waste leachates as the molecular mechanisms plausibly responsible for the pathophysiological disorders, cancer and cell death reported in landfill toxicology and epidemiological studies. This review aims to increase scientific understanding on solid waste leachate induced mitochondria dysfunctions as the key player in molecular mechanisms of solid waste induced toxicity. The findings in this review were mainly from using primary cells, cell lines, Drosophila and fish. Whether the findings will similarly be observed in mammalian test systems in vivo and particularly in exposed humans, remained to be investigated. Improvement in technological advancements, enforcement of legislation and regulations, and creation of sophisticated health surveillance against exposure to solid waste leachates, will expectedly mitigate human exposure to solid waste emissions and contamination of the environment.
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Affiliation(s)
- Chibuisi Gideon Alimba
- Cell Biology and Genetics Unit, Department of Zoology, University of Ibadan, Ibadan, Nigeria; Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, 44139, Dortmund, Germany.
| | - Saravanadevi Sivanesan
- Health and Toxicity Cell (HTC), CSIR-National Environmental Engineering Research Institute (NEERI), Nagpur, 440020, India; Academy of Scientific, Innovative Research (AcSIR), Ghaziabad, U.P, India
| | - Kannan Krishnamurthi
- Health and Toxicity Cell (HTC), CSIR-National Environmental Engineering Research Institute (NEERI), Nagpur, 440020, India; Academy of Scientific, Innovative Research (AcSIR), Ghaziabad, U.P, India.
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28
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Morris SM, Chauhan A. The role of platelet mediated thromboinflammation in acute liver injury. Front Immunol 2022; 13:1037645. [PMID: 36389830 PMCID: PMC9647048 DOI: 10.3389/fimmu.2022.1037645] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/14/2022] [Indexed: 12/03/2022] Open
Abstract
Acute liver injuries have wide and varied etiologies and they occur both in patients with and without pre-existent chronic liver disease. Whilst the pathophysiological mechanisms remain distinct, both acute and acute-on-chronic liver injury is typified by deranged serum transaminase levels and if severe or persistent can result in liver failure manifest by a combination of jaundice, coagulopathy and encephalopathy. It is well established that platelets exhibit diverse functions as immune cells and are active participants in inflammation through processes including immunothrombosis or thromboinflammation. Growing evidence suggests platelets play a dualistic role in liver inflammation, shaping the immune response through direct interactions and release of soluble mediators modulating function of liver sinusoidal endothelial cells, stromal cells as well as migrating and tissue-resident leucocytes. Elucidating the pathways involved in initiation, propagation and resolution of the immune response are of interest to identify therapeutic targets. In this review the provocative role of platelets is outlined, highlighting beneficial and detrimental effects in a spatial, temporal and disease-specific manner.
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Affiliation(s)
- Sean M. Morris
- The Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - Abhishek Chauhan
- The Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- *Correspondence: Abhishek Chauhan,
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29
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Zhang H, Yuan Z, Zhu Y, Yuan Z, Wang J, Nong C, Zhou S, Tang Q, Zhang L, Jiang Z, Yu Q. Th17/Treg imbalance mediates hepatic intolerance to exogenous lipopolysaccharide and exacerbates liver injury in triptolide induced excessive immune response. JOURNAL OF ETHNOPHARMACOLOGY 2022; 295:115422. [PMID: 35654348 DOI: 10.1016/j.jep.2022.115422] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/22/2022] [Accepted: 05/27/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Triptolide (TP) is a major active ingredient and toxic component of Tripterygium wilfordii Hook F (TWHF), which exhibits multiple activities and remarkable hepatotoxicity, the latter of which limits its clinical application due to the risk of liver injury. Previous research has revealed the hepatotoxicity of TP resulting in liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, existing research has not elucidated the potential immune mechanism such as Th17/Treg imbalance in TP-induced hepatic excessive immune response to exogenous LPS. AIM OF THE STUDY To investigate the role of Th17/Treg imbalance in TP-induced hepatic excessive immune response to exogenous LPS. MATERIALS AND METHODS Mice were administered with TP, LPS, neutralization antibody and small molecule inhibitor respectively. Serum transaminase level was measured to determine the severity of liver injury. Frequencies of liver Th17 and Treg cells were analyzed by flow cytometry. Serum cytokine levels were performed by ELSIA, and mRNA levels of liver cytokine were performed by qPCR. The status of neutrophil infiltration was performed by myeloperoxidase (MPO) IHC measurement. Morphological observation of liver was performed by hematoxylin and eosin (H&E) staining. RESULTS Mice given a single intragastric dose of TP (500 μg/kg) developed lethal fulminant hepatitis following intraperitoneal injection of LPS (0.1 mg/kg), characterized by low survival rate, severe liver injury, high levels of inflammation and neutrophil infiltration. Hepatic Th17/Treg imbalance emerged together with liver injury in these mice. Neutralization of IL-17A attenuated the liver injury and ameliorated the neutrophil infiltration. The TP-induced alteration of hepatic Th17/Treg balance was closely related to the outcome of immune-mediated acute liver injury triggered by LPS. Pretreatment with the STAT3 inhibitor AG490 effectively restored Th17/Treg balance, significantly reducing the production of IL-17A and finally attenuating the degree of liver injury. CONCLUSION Hepatic Th17/Treg imbalance not only exacerbates TP- and LPS-induced liver injury, but also serves as an indispensable part in the mechanisms of TP-induced hepatic intolerance to exogenous endotoxin.
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Affiliation(s)
- Haoran Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Ziqiao Yuan
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Ying Zhu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Zihang Yuan
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Jie Wang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Cheng Nong
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Shaoyun Zhou
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Qianhui Tang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
| | - Qinwei Yu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
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30
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El-Tantawy WH, Temraz A. Anti-fibrotic activity of natural products, herbal extracts and nutritional components for prevention of liver fibrosis: review. Arch Physiol Biochem 2022; 128:382-393. [PMID: 31711319 DOI: 10.1080/13813455.2019.1684952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is a grave problem worldwide, and the development of this condition is the first step towards cirrhosis. In fact, when lesions of different aetiologies chronically affect the liver, it triggers fibrogenesis, the resulting damage and the progression of fibrosis cause serious clinical influences including severe complications, expensive treatments, and death in end-stage liver disease. Although impressive progress has been reported in understanding the pathogenesis of liver fibrosis, no effective agent has been developed to prevent or reverse the fibrotic process directly. This article reviews natural products, herbal medicines and nutritional components that exhibited an anti-fibrotic activity through different mechanisms of action, including suppressing of cytokine production, inhibition of hepatic stellate cells "HSCs" propagation, modulation of the molecular mechanisms leading to hepatic fibrosis, free radical scavenging and anti-inflammatory properties.
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Affiliation(s)
| | - Abeer Temraz
- Pharmacognosy Department, Faculty of Pharmacy For Girls, Al-Azhar University, Cairo, Egypt
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Nava-Santana C, Rodríguez-Armida M, Jiménez JV, Vargas-Parra N, León DEA, Campos-Murguia A, Macías-Rodriguez R, Arteaga-Garrido A, Hernández-Villegas AC, Dominguez-Cherit G, Rivero-Sigarroa E, Gamboa-Dominguez A, Gullias-Herrero A, Sifuentes-Osornio J, Uribe-Uribe NO, Morales-Buenrostro LE. Clinicopathologic characteristics of severe COVID-19 patients in Mexico City: A post-mortem analysis using a minimally invasive autopsy approach. PLoS One 2022; 17:e0262783. [PMID: 35239660 PMCID: PMC8893646 DOI: 10.1371/journal.pone.0262783] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 01/04/2022] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Describe the histological findings of minimally ultrasound-guided invasive autopsies in deceased patients with severe SARS-CoV-2 and compare the diagnostic yield with open autopsies. DESIGN Observational post-mortem cohort study. Minimally invasive ultrasound-guided autopsies were performed in fourteen deceased patients with a confirmed diagnosis of SARS-CoV-2 pneumonia. Histological and clinical findings of lung, kidney, and liver tissue are described and contrasted with those previously reported in the literature. SETTING Single-center COVID-19 reference center in Mexico City. RESULTS Fourteen minimally invasive autopsies revealed a gross correlation with open autopsies reports: 1) Lung histology was characterized mainly by early diffuse alveolar damage (12/13). Despite low lung compliances and prolonged mechanical ventilation, the fibrotic phase was rarely observed (2/13). 2) Kidney histopathology demonstrated acute tubular injury (12/13), interstitial nephritis (11/13), and glomerulitis (11/13) as the predominant features 3) Liver histology was characterized by neutrophilic inflammation in all of the cases, as well as hepatic necrosis (8/14) despite minimal alterations in liver function testing. Hepatic steatosis was observed in most cases (12/14). SARS-CoV-2 positivity was widely observed throughout the immunohistochemical analysis. However, endothelitis and micro thrombosis, two of the hallmark features of the disease, were not observed. CONCLUSION Our data represents the largest minimally invasive, ultrasound-guided autopsy report. We demonstrate a gross histological correlation with large open autopsy cohorts. However, this approach might overlook major histologic features of the disease, such as endothelitis and micro-thrombosis. Whether this represents sampling bias is unclear.
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Affiliation(s)
- Carlos Nava-Santana
- Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - María Rodríguez-Armida
- Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - José Víctor Jiménez
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Nancy Vargas-Parra
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Diana E. Aguilar León
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Alejandro Campos-Murguia
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Ricardo Macías-Rodriguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Andrés Arteaga-Garrido
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | | | - Guillermo Dominguez-Cherit
- Department of Critical Care Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Eduardo Rivero-Sigarroa
- Department of Critical Care Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Armando Gamboa-Dominguez
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Alfonso Gullias-Herrero
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - José Sifuentes-Osornio
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Norma Ofelia Uribe-Uribe
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Luis E. Morales-Buenrostro
- Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
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Owojuyigbe OS, Larbie C, Firempong CK, Komlaga G, Emikpe BO, Oyagbemi AA. Hura crepitans stem bark extract: A potential remedy to sub-acute liver damage. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114768. [PMID: 34688802 DOI: 10.1016/j.jep.2021.114768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/13/2021] [Accepted: 10/19/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL SIGNIFICANCE AND AIM Hura crepitans is commonly used to treat liver diseases in Nigeria and Ghana. Previous studies have supported its ethnomedicinal use in protecting the liver. The present study aimed at assessing the effect of H. crepitans stem bark on the subacute carbon tetrachloride (CCl4)-induced liver damage in rats. MATERIALS AND METHODS The protective activities of ethanolic extract of H. crepitans stem bark was evaluated in CCl4-induced subacute liver damage in rats (1:1 v/v in olive oil, intraperitoneally (i.p.), twice weekly for 8 weeks). Blood samples were obtained from the rats and used for some biochemical analysis such as liver function test (Aspartate transaminase, AST; Alanine aminotransferase, ALT; and Alkaline phosphatase, ALP), liver fibrotic indices (Aspartate platelet ratio index, APRI; AST/ALT and AST/PLT ratios) and oxidative stress markers (Malondialdehyde, MDA; Reduced glutathione, GSH; Glutathione S-transferase, GST; Glutathione peroxidase, GPx; and superoxide dismutase, SOD). Histopathological analyses were carried out to determine the expression of pro-inflammatory (NF-κB, COX-2, IL-17 and IL-23) using immunohistochemical techniques. RESULTS Oral administration of H. crepitans to CCl4-induced hepatic injured rats significantly decreased oxidative stress, increased the levels of SOD, GSH, GST and GPx with reduced MDA levels. The plant also mitigated liver injury as evidenced in the significantly reduced levels of AST, ALT and ALP, while it inhibited the inflammatory process via the inhibition of NF-κB, and consequently down-regulateed the pro-inflammatory cytokines COX-2, IL-17 and IL-23, respectively. Biochemical observations were supported by improvement in liver microarchitecture. CONCLUSION The Hura crepitans demonstrated antioxidant, antiinflammatory and antifibrotic effect in hepatic injured rats. The study in a way justifies the traditional use of the plant for the treatment of subacute liver diseases in Nigerian Traditional medicine.
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Affiliation(s)
- Oluwole S Owojuyigbe
- Department of Biochemistry and Biotechnology, KNUST, Kumasi, Ghana; Department of Science Laboratory Technology, Federal Polytechnic Ede, Nigeria
| | | | | | | | | | - Ademola A Oyagbemi
- Department of Veterinary Physiology and Biochemistry, University of Ibadan, Nigeria
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Yaghoubi A, Azarpira N, Karbalay-Doust S, Daneshi S, Vojdani Z, Talaei-Khozani T. Prednisolone and mesenchymal stem cell preloading protect liver cell migration and mitigate extracellular matrix modification in transplanted decellularized rat liver. Stem Cell Res Ther 2022; 13:36. [PMID: 35090559 PMCID: PMC8800282 DOI: 10.1186/s13287-022-02711-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/10/2022] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Regenerative medicine provides promising approaches for treating chronic liver diseases. Previous studies indicate that decellularized liver architecture is damaged by invading non-hepatic inflammatory cells. This study aimed to use anti-inflammatory and regenerative potency of bone marrow-derived mesenchymal stem cells (BM-MSC) and prednisolone for reducing fibrosis and balancing inflammatory cell migration into the decellularized liver scaffold. MATERIAL AND METHOD The liver was decellularized by perfusing Sodium Lauryl Ether Sulfate (SLES), and nuclei depletion and extracellular matrix (ECM) retention were confirmed by DNA quantification, histochemical, and immunohistochemical assessments. Scaffolds were loaded with BM-MSCs, prednisolone, or a combination of both, implanted at the anatomical place in the rat partial hepatectomized and followed up for 2 and 4 weeks. RESULTS Labeled-MSCs were traced in the transplanted scaffolds; however, they did not migrate into the intact liver. Immunohistochemistry showed that the hepatoblasts, cholangiocytes, stellate, and oval cells invaded into all the scaffolds. Bile ducts were more abundant in the border of the scaffolds and intact liver. Stereological assessments showed a significant reduction in the number of lymphocytes and neutrophils in prednisolone-loaded scaffolds. The regeneration process and angiogenesis were significantly higher in the group treated with cell/prednisolone-loaded bioscaffolds. Collagen fibers were significantly reduced in the scaffolds pre-treated with cell/prednisolone, prednisolone, or BM-MSCs, compared to the control group. CONCLUSION Loading prednisolone into the scaffolds can be a worthy approach to restrict inflammation after transplantation. Although pre-loading of the scaffolds with a combination of cells/prednisolone could not alleviate inflammation, it played an important role in regeneration and angiogenesis.
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Affiliation(s)
- Atefeh Yaghoubi
- Tissue Engineering Lab, Anatomy Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplantation Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saied Karbalay-Doust
- Stereology and Morphometry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Anatomy Department, Shiraz medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sajad Daneshi
- Stereology and Morphometry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Vojdani
- Tissue Engineering Lab, Anatomy Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Tissue Engineering Lab, Anatomy Department, Shiraz University of Medical Sciences, Shiraz, Iran.
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Protective mechanisms of telmisartan against hepatic ischemia/reperfusion injury in rats may involve PPARγ-induced TLR4/NF-κB suppression. Biomed Pharmacother 2021; 145:112374. [PMID: 34915671 DOI: 10.1016/j.biopha.2021.112374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/20/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic ischemia-reperfusion (I/R) is an important cause of liver damage in many clinical situations. Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) is an inflammatory pathway activated in hepatic I/R injury. Telmisartan, a selective angiotensin II type 1 receptor antagonist and peroxisome proliferator-activated receptor-gamma (PPARγ) partial agonist, can inhibit the expression of pro-inflammatory cytokines. The present work investigated the possible protective effect of telmisartan against hepatic I/R injury and explored its possible mechanisms in rats. Rats were divided into four equal groups: sham-operated control, telmisartan-treated sham-operated control, I/R untreated, and I/R telmisartan-treated groups. Hepatic injury was evaluated biochemically by serum activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and histopathological examination. Hepatic oxidative stress biomarkers, myeloperoxidase level, PPARγ and TLR4 mRNA expression, and NF-κB and active caspase 3 immunoexpression were determined. The study showed that telmisartan attenuated hepatic I/R, as evidenced by decreased serum ALT and AST activities and confirmed by improvement of the histopathological changes. The protective effect of telmisartan was associated with modulation of oxidative stress parameters, myeloperoxidase level, PPARγ and TLR4 mRNA expression, and NF-κB and caspase 3 immunoexpression. Taken together, the current study showed that telmisartan could protect the rat liver from I/R injury. This hepatoprotective effect was attributed to, at least in part, increase in PPARγ expression and suppression of TLR4/NF-κB pathway.
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Torre P, Motta BM, Sciorio R, Masarone M, Persico M. Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System. Front Med (Lausanne) 2021; 8:781567. [PMID: 34957156 PMCID: PMC8695879 DOI: 10.3389/fmed.2021.781567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a "chronic wound healing reaction," is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.
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Affiliation(s)
- Pietro Torre
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Benedetta Maria Motta
- Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Baronissi, Italy
| | - Roberta Sciorio
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
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36
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Methneni N, Ezdini K, Ben Abdeljelil N, Van Loco J, Van den Houwe K, Jabeur R, Fekih Sallem O, Jaziri A, Fernandez-Serrano M, Khdary NH, Ben Mansour H. Occurrence of Textile Dyes and Metals in Tunisian Textile Dyeing Effluent: Effects on Oxidative Stress Status and Histological Changes in Balb/c Mice. Int J Mol Sci 2021; 22:ijms222212568. [PMID: 34830450 PMCID: PMC8619562 DOI: 10.3390/ijms222212568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 11/23/2022] Open
Abstract
Although it is known that textile wastewater contains highly toxic contaminants whose effects in humans represent public health problems in several countries, studies involving mammal species are scarce. This study was aimed to evaluate the toxicity profile of 90-days oral administration of textile dyeing effluent (TDE) on oxidative stress status and histological changes of male mice. The TDE was collected from the textile plant of Monastir, Tunisia and evaluated for the metals, aromatic amines, and textile dyes using analytical approaches. Metal analysis by ICP-MS showed that the tested TDE exhibited very high levels of Cr, As, and Sr, which exceeded the wastewater emission limits prescribed by WHO and Tunisian authority. The screening of TDE through UPLC-MS/MS confirmed the presence of two textile dyes: a triphenylmethane dye (Crystal violet) and a disperse azo dye (Disperse yellow 3). Exposure to TDE significantly altered the malondialdehyde (MDA), Conjugated dienes (CDs), Sulfhydryl proteins (SHP) and catalase levels in the hepatic and renal tissues. Furthermore, histopathology observation showed that hepatocellular and renal lesions were induced by TDE exposure. The present study concluded that TDE may involve induction of oxidative stress which ensues in pathological lesions in several vital organs suggesting its high toxicity. Metals and textile dyes may be associated with the observed toxicological effects of the TDE. These pollutants, which may have seeped into surrounding rivers in Monastir city, can cause severe health malaise in wildlife and humans.
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Affiliation(s)
- Nosra Methneni
- Research Unit of Analysis, Process Applied to the Environment–APAE (UR17ES32) Higher Institute of Applied Sciences and Technology Mahdia, University of Monastir, Monastir 5000, Tunisia; (N.M.); (O.F.S.); (A.J.)
- Laboratory of Chemical Residues and Contaminants, Direction of Food Medicines and Consumer Safety, 1050 Brussels, Belgium; (J.V.L.); (K.V.d.H.)
- Department of Chemical Engineering, Faculty of Sciences, University of Granada, 18002 Granada, Spain;
| | - Khawla Ezdini
- Laboratory of Genetic, Biodiversity and Bio-Resources Valorisation, University of Monastir, Monastir 5000, Tunisia;
| | - Nouha Ben Abdeljelil
- Department of Pathology, Fattouma Bourguiba University Hospital, Monastir 5000, Tunisia;
| | - Joris Van Loco
- Laboratory of Chemical Residues and Contaminants, Direction of Food Medicines and Consumer Safety, 1050 Brussels, Belgium; (J.V.L.); (K.V.d.H.)
| | - Kathy Van den Houwe
- Laboratory of Chemical Residues and Contaminants, Direction of Food Medicines and Consumer Safety, 1050 Brussels, Belgium; (J.V.L.); (K.V.d.H.)
| | - Riheb Jabeur
- Department of Matter and Life Sciences, Bretagne Sud University, IRDL, FRE CNRS 3744, CER Yves Coppens, BP573, 56000 Vannes, France;
| | - Ons Fekih Sallem
- Research Unit of Analysis, Process Applied to the Environment–APAE (UR17ES32) Higher Institute of Applied Sciences and Technology Mahdia, University of Monastir, Monastir 5000, Tunisia; (N.M.); (O.F.S.); (A.J.)
| | - Ahlem Jaziri
- Research Unit of Analysis, Process Applied to the Environment–APAE (UR17ES32) Higher Institute of Applied Sciences and Technology Mahdia, University of Monastir, Monastir 5000, Tunisia; (N.M.); (O.F.S.); (A.J.)
| | | | - Nezar H. Khdary
- King Abdulaziz City for Science and Technology (KACST), 11442 Riyadh, Saudi Arabia
- Correspondence: (N.H.K.); (H.B.M.)
| | - Hedi Ben Mansour
- Research Unit of Analysis, Process Applied to the Environment–APAE (UR17ES32) Higher Institute of Applied Sciences and Technology Mahdia, University of Monastir, Monastir 5000, Tunisia; (N.M.); (O.F.S.); (A.J.)
- Correspondence: (N.H.K.); (H.B.M.)
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Liu W, Zeng X, Liu Y, Liu J, Li C, Chen L, Chen H, Ouyang D. The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury. Front Pharmacol 2021; 12:723940. [PMID: 34721020 PMCID: PMC8554067 DOI: 10.3389/fphar.2021.723940] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.
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Affiliation(s)
- Wenhui Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Xiangchang Zeng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Yating Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Jinfeng Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Chaopeng Li
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Lulu Chen
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Hongying Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Dongsheng Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
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Zhang Y, de Boer M, van der Wel EJ, Van Eck M, Hoekstra M. PRMT4 inhibitor TP-064 inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo and induces peritonitis-associated neutrophilia in vivo. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166212. [PMID: 34311083 DOI: 10.1016/j.bbadis.2021.166212] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 01/19/2023]
Abstract
Previous in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses. Here we investigated the effect of PRMT4 inhibitor TP-064 treatment on macrophage inflammation in vitro and in vivo. Exposure of RAW 264.7 monocyte/macrophages to TP-064 was associated with a significant decrease in the production of pro-inflammatory cytokines upon a lipopolysaccharide challenge. Similarly, thioglycollate-elicited peritoneal cells isolated from wildtype mice treated with TP-064 showed lowered mRNA expression levels and cytokine production of pro-inflammatory mediators interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor-α in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing pro-inflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6ClowCD206hi to a pro-inflammatory LY6ChiCD206low phenotype. In addition, TP-064-treated mice accumulated (activated) neutrophils within the peritoneum as well as in the blood (7-fold higher; P < 0.001) and major organs such as kidney and liver, without apparent tissue toxicity. TP-064 treatment downregulated hepatic mRNA expression levels of the PRMT4 target genes glucose-6-phosphatase catalytic subunit (-50%, P < 0.05) and the cyclin-dependent kinases 2 (-50%, P < 0.05) and 4 (-30%, P < 0.05), suggesting a direct transcriptional effect of PRMT4 also in hepatocytes. In conclusion, we have shown that the PRMT4 inhibitor TP-064 induces peritonitis-associated neutrophilia in vivo and inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo. Our findings suggest that TP-064 can possibly be applied as therapy in NF-κB-based inflammatory diseases.
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Affiliation(s)
- Yiheng Zhang
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands.
| | - Miriam de Boer
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
| | - Ezra J van der Wel
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
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Zhang Z, Guo C, Jiang H, Han B, Wang X, Li S, Lv Y, Lv Z, Zhu Y. Inflammation response after the cessation of chronic arsenic exposure and post-treatment of natural astaxanthin in liver: potential role of cytokine-mediated cell-cell interactions. Food Funct 2021; 11:9252-9262. [PMID: 33047770 DOI: 10.1039/d0fo01223h] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ongoing groundwater arsenic contamination throughout China was first recognized in the 1960s. Groundwater arsenic contamination is a high risk for human and animal health worldwide. Apart from drinking water, diet is the second pathway for arsenic to enter the human body and eventually cause liver injury. Natural astaxanthin extracted from the green algae Haematococcus pluvialis has dominated the nutraceutical market for potential health benefits. Nevertheless, the molecular mechanism underlying the protective effect post astaxanthin against arsenic-induced hepatotoxicity remains largely obscure. In this study, we investigate the effect of natural astaxanthin (derived from Haemotococcus pluvialis) on oxidative stress and liver inflammatory response in rats after the cessation of chronic arsenic exposure. Wistar rats were given astaxanthin (250 mg kg-1) daily for 2 weeks after the cessation of exposure to sodium arsenite (300 μg L-1, drinking water, 24 weeks) by intragastric administration. The results showed that post treatment with astaxanthin attenuated liver injury induced by long-term exposure to arsenic in rats. Most importantly, post treatment with astaxanthin decreased the increasing of inflammatory cytokine NF-κB, tumor necrosis factor-α, interleukin-1β, oxidative stress level, and total arsenic content in livers of rats exposed to arsenic. In addition, post treatment with astaxanthin reversed the increasing of protein levels of alpha-smooth muscle actin and collagen Iα1, which are the activation markers of hepatic stellate cells (HSCs). Collectively, these data demonstrate that post astaxanthin treatment attenuates inflammation response in the liver after the cessation of chronic arsenic exposure via inhibition of cytokine-mediated cell-cell interactions. Daily ingestion of natural astaxanthin might be a potential and beneficial candidate for the treatment of liver damage after the cessation of chronic exposure to sodium arsenite.
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Affiliation(s)
- Zhigang Zhang
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China. and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin 150030, China
| | - Changming Guo
- College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, China
| | - Huijie Jiang
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China. and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin 150030, China
| | - Bing Han
- College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, China
| | - Xiaoqiao Wang
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China. and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin 150030, China
| | - Siyu Li
- College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, China
| | - Yueying Lv
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China.
| | - Zhanjun Lv
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China.
| | - Yan Zhu
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China. and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin 150030, China
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40
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Warner DR, Warner JB, Hardesty JE, Song YL, Chen CY, Chen Z, Kang JX, McClain CJ, Kirpich IA. Beneficial effects of an endogenous enrichment in n3-PUFAs on Wnt signaling are associated with attenuation of alcohol-mediated liver disease in mice. FASEB J 2021; 35:e21377. [PMID: 33481293 DOI: 10.1096/fj.202001202r] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/13/2022]
Abstract
Alcohol-associated liver disease (ALD) is a major human health issue for which there are limited treatment options. Experimental evidence suggests that nutrition plays an important role in ALD pathogenesis, and specific dietary fatty acids, for example, n6 or n3-PUFAs, may exacerbate or attenuate ALD, respectively. The purpose of the current study was to determine whether the beneficial effects of n3-PUFA enrichment in ALD were mediated, in part, by improvement in Wnt signaling. Wild-type (WT) and fat-1 transgenic mice (that endogenously convert n6-PUFAs to n3) were fed ethanol (EtOH) for 6 weeks followed by a single LPS challenge. fat-1 mice had less severe liver damage than WT littermates as evidenced by reduced plasma alanine aminotransferase, hepatic steatosis, liver tissue neutrophil infiltration, and pro-inflammatory cytokine expression. WT mice had a greater downregulation of Axin2, a key gene in the Wnt pathway, than fat-1 mice in response to EtOH and LPS. Further, there were significant differences between WT and fat-1 EtOH+LPS-challenged mice in the expression of five additional genes linked to the Wnt signaling pathway, including Apc, Fosl1/Fra-1, Mapk8/Jnk-1, Porcn, and Nkd1. Compared to WT, primary hepatocytes isolated from fat-1 mice exhibited more effective Wnt signaling and were more resistant to EtOH-, palmitic acid-, or TNFα-induced cell death. Further, we demonstrated that the n3-PUFA-derived lipid mediators, resolvins D1 and E1, can regulate hepatocyte expression of several Wnt-related genes that were differentially expressed between WT and fat-1 mice. These data demonstrate a novel mechanism by which n3-PUFAs can ameliorate ALD.
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Affiliation(s)
- Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Jeffrey B Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Josiah E Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Ying L Song
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Chi-Yu Chen
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zoe Chen
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.,University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA.,Robley Rex Veterans Medical Center, Louisville, KY, USA
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.,University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA
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Li D, Xie P, Zhao S, Zhao J, Yao Y, Zhao Y, Ren G, Liu X. Hepatocytes derived increased SAA1 promotes intrahepatic platelet aggregation and aggravates liver inflammation in NAFLD. Biochem Biophys Res Commun 2021; 555:54-60. [PMID: 33813276 DOI: 10.1016/j.bbrc.2021.02.124] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/24/2021] [Indexed: 12/18/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the pathological manifestation of metabolic syndrome in liver. Its pathological changes may evolve from the initial simple steatosis to non-alcoholic steatohepatitis, liver fibrosis and even liver cancer. Numerous studies have proved that platelets play a vital role in liver disease and homeostasis. Particularly, anti-platelet therapy can reduce intrahepatic platelet aggregation and improve the inflammation of fatty liver. Previous study has also confirmed that SAA is a gene closely related to high-fat diet (HFD) induced obesity, and SAA1 can promote liver insulin resistance induced by Palmitate or HFD. Here, we found that SAA1 treated platelets presented increased sensitivity of platelet aggregation, enhanced activation and increased adhesion ability, and such function was partly dependent on Toll-Like Receptor (TLR) 2 signaling. In addition, blocking SAA1 expression in vivo not only inhibited platelet aggregation in the liver tissues of NAFLD mice, but also alleviated the inflammation of fatty liver. In conclusion, our findings identify that HFD-induced hepatic overexpressed SAA1 aggravates fatty liver inflammation by promoting intrahepatic platelet aggregation, these results also imply that SAA1 may serve as a potential target for ameliorating NAFLD.
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Affiliation(s)
- Daoyuan Li
- Department of Pathology and Pathophysiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou province, PR China; Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou province, PR China
| | - Ping Xie
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou province, PR China
| | - Su Zhao
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou province, PR China
| | - Jing Zhao
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou province, PR China
| | - Yucheng Yao
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou province, PR China
| | - Yan Zhao
- Department of Ophthalmology, Guizhou Provincial People's Hospital, Guiyang, Guizhou province, PR China
| | - Guangbing Ren
- Department of Ophthalmology, Panzhou People's Hospital, Panzhou, Guizhou province, PR China
| | - Xingde Liu
- Department of Pathology and Pathophysiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou province, PR China; Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou province, PR China.
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Hyun J, Han J, Lee C, Yoon M, Jung Y. Pathophysiological Aspects of Alcohol Metabolism in the Liver. Int J Mol Sci 2021; 22:5717. [PMID: 34071962 PMCID: PMC8197869 DOI: 10.3390/ijms22115717] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The liver is the major organ that metabolizes alcohol; therefore, it is particularly sensitive to alcohol intake. Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. Despite the severity of ALD, the development of novel treatments has been hampered by the lack of animal models that fully mimic human ALD. To overcome the current limitations of ALD studies and therapy development, it is necessary to understand the molecular mechanisms underlying alcohol-induced liver injury. Hence, to provide insights into the progression of ALD, this review examines previous studies conducted on alcohol metabolism in the liver. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism.
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Affiliation(s)
- Jeongeun Hyun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea;
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea
- Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan 31116, Korea
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
| | - Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
| | - Myunghee Yoon
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea
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Liu SX, Du YC, Zeng T. A mini-review of the rodent models for alcoholic liver disease: shortcomings, application, and future prospects. Toxicol Res (Camb) 2021; 10:523-530. [PMID: 34141166 DOI: 10.1093/toxres/tfab042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 12/19/2022] Open
Abstract
Rodents are the most common models in studies of alcoholic liver disease (ALD). Although several rodents ALD models have been established and multiple mechanisms have been elucidated based on them, these models have some non-negligible shortcomings, specifically only inducing early stage (mainly steatosis, slight to moderate steatohepatitis) but not the whole spectrum of human ALD. The resistance of rodents to advanced ALD has been suggested to be due to the physiological differences between rodents and human beings. Previous studies have reported significant interstrain differences in the susceptibility to ethanol-induced liver injury and in the manifestation of ALD (such as different alteration of lipid profiles). Therefore, it would be interesting to characterize the manifestation of ethanol-induced liver damage in various rodents, which may provide a recommendation to investigators of ALD. Furthermore, more severe ALD models need to be established for the study of serious ALD forms, which may be achieved by using genetic modified rodents.
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Affiliation(s)
- Shi-Xuan Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China
| | - Yan-Chao Du
- Jinan Institute for Product Quality Inspection, 1311 Longao Bei Road, Jinan, Shandong, 250102, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China
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Gerussi A, Natalini A, Antonangeli F, Mancuso C, Agostinetto E, Barisani D, Di Rosa F, Andrade R, Invernizzi P. Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models. Int J Mol Sci 2021; 22:4557. [PMID: 33925355 PMCID: PMC8123708 DOI: 10.3390/ijms22094557] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.
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Affiliation(s)
- Alessio Gerussi
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Ambra Natalini
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Fabrizio Antonangeli
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Clara Mancuso
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet, L’Universite’ Libre de Bruxelles (ULB), 1050 Brussels, Belgium;
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center—IRCCS, Humanitas Cancer Center, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
| | - Donatella Barisani
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Raul Andrade
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), UGC Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29016 Málaga, Spain;
| | - Pietro Invernizzi
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
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Chen S, Guo H, Xie M, Zhou C, Zheng M. Neutrophil: An emerging player in the occurrence and progression of metabolic associated fatty liver disease. Int Immunopharmacol 2021; 97:107609. [PMID: 33887577 DOI: 10.1016/j.intimp.2021.107609] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/01/2021] [Accepted: 03/20/2021] [Indexed: 12/12/2022]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a common type of chronic liver disease characterized by excessive lipid accumulation in hepatocytes, but the pathogenesis is still unclear. Neutrophils, the most abundant immune cells in the human body, defend against pathogens and regulate the inflammatory response. Recent studies have indicated that excessive liver infiltration of neutrophils is a significant histological hallmark of MAFLD, and neutrophils and their derived granule proteins participate in different stages of MAFLD, including hepatic steatosis, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. Hence, in this review, we summarize the role of neutrophils in the occurrence and progression of MAFLD and provide a perspective for the clinical application of neutrophils in MAFLD diagnosis and treatment.
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Affiliation(s)
- Shiwei Chen
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Huiting Guo
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Mingjie Xie
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Cheng Zhou
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China.
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China.
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Tran M, Wu J, Wang L, Shin DJ. A Potential Role for SerpinA3N in Acetaminophen-Induced Hepatotoxicity. Mol Pharmacol 2021; 99:277-285. [PMID: 33436521 PMCID: PMC7985612 DOI: 10.1124/molpharm.120.000117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/31/2020] [Indexed: 10/25/2022] Open
Abstract
Acetaminophen (APAP) is a commonly used pain and fever reliever but is also the most frequent cause of drug-induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, whereas mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the role of SerpinA3N in relation to APAP-induced liver injury is not known. Wild-type and hepatocyte-specific SerpinA3N knockout (HKO) mice were injected intraperitoneally with a single dose of PBS or APAP (400 mg/kg) for 12 hours, and markers of liver injury, cell death, and inflammation were assessed. SerpinA3N expression was highly induced in mice with APAP overdose. SerpinA3N HKO mice had diminished liver injury and necrosis as shown by lower alanine aminotransferase and interleukin-6 levels, accompanied by suppressed inflammatory cytokines and reduced neutrophil infiltration. The reduced oxidative stress was associated with enhanced antioxidant enzyme capabilities. Taken together, hepatocyte SerpinA3N deficiency reduced APAP-induced liver injury by ameliorating inflammation and modulating the 5' AMP-activated protein kinase-unc-51-like autophagy activating kinase 1 signaling pathway. Our study provides novel insights into a potential role for SerpinA3N in APAP-induced liver injury. SIGNIFICANCE STATEMENT: Our studies indicate that serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) may have a pathophysiological role in modulating acetaminophen (APAP)-induced liver injury. More specifically, mice with hepatic deletion of SerpinA3N suppressed inflammation and liver injury to reduce APAP-induced hepatotoxicity. Controlling the inflammatory response offers possible approaches for novel therapeutics; therefore, understanding the pathophysiological role of SerpinA3N in inducing liver injury may add to the development of more efficacious treatments.
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Affiliation(s)
- Melanie Tran
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| | - Jianguo Wu
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| | - Li Wang
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| | - Dong-Ju Shin
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
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Umeshappa CS, Solé P, Surewaard BGJ, Yamanouchi J, Mohapatra S, Uddin MM, Clarke R, Ortega M, Singha S, Mondal D, Yang Y, Vignali DAA, Serra P, Kubes P, Santamaria P. Liver-specific T regulatory type-1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP. Cell Rep 2021; 34:108919. [PMID: 33789099 DOI: 10.1016/j.celrep.2021.108919] [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: 08/24/2020] [Revised: 12/17/2020] [Accepted: 03/08/2021] [Indexed: 12/17/2022] Open
Abstract
Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (Breg) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.
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Affiliation(s)
- Channakeshava Sokke Umeshappa
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Patricia Solé
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain
| | - Bas G J Surewaard
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Jun Yamanouchi
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Saswat Mohapatra
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Muhammad Myn Uddin
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Robert Clarke
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Mireia Ortega
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain
| | - Santiswarup Singha
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Debajyoti Mondal
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Yang Yang
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Pau Serra
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain
| | - Paul Kubes
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Pere Santamaria
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada; Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain.
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Tang J, Yan Z, Feng Q, Yu L, Wang H. The Roles of Neutrophils in the Pathogenesis of Liver Diseases. Front Immunol 2021; 12:625472. [PMID: 33763069 PMCID: PMC7982672 DOI: 10.3389/fimmu.2021.625472] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/25/2021] [Indexed: 01/30/2023] Open
Abstract
Neutrophils are the largest population of circulating leukocytes and the first responder against invading pathogens or other danger signals. Sophisticated machineries help them play critical roles in immunity and inflammation, including phagocytosis, superoxide production, cytokine and chemokine production, degranulation, and formation of neutrophil extracellular traps (NETs). After maturation and release from the bone marrow, neutrophils migrate to inflamed tissues in response to many stimuli. Increasing evidences indicate that neutrophils are critically involved in the pathogenesis of liver diseases, including liver cancer, thus making them promising target for the treatment of liver diseases. Here, we would like to provide the latest finding about the role of neutrophils in liver diseases and discuss the potentiality of neutrophils as target for liver diseases.
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Affiliation(s)
- Jiaojiao Tang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zijun Yan
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- Graduate Management Unit, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiyu Feng
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lexing Yu
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
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Lai Y, Tan Q, Xv S, Huang S, Wang Y, Li Y, Zeng T, Mo C, Chen Y, Huang S, Zhou C, Gao L, Lv Z. Ginsenoside Rb1 Alleviates Alcohol-Induced Liver Injury by Inhibiting Steatosis, Oxidative Stress, and Inflammation. Front Pharmacol 2021; 12:616409. [PMID: 33716743 PMCID: PMC7952325 DOI: 10.3389/fphar.2021.616409] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from Panax quinquefolium L., has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 μM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 μM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes in vivo, and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 μM in vivo. GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.
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Affiliation(s)
- Yuqi Lai
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Qinxiang Tan
- Renal Division, Beijing University of Chinese Medicine Shenzhen Hospital (Longgang), Shenzhen, China
| | - Shu Xv
- Oncology Department of Shenzhen Hospital of University of Chinese Academy of Sciences, Shenzhen, China
| | - Sha Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuhua Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yunjia Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Ting Zeng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Chan Mo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuyao Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shaohui Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Chuying Zhou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Zhiping Lv
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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50
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Li Y, Sheng Q, Zhang C, Han C, Bai H, Lai P, Fan Y, Ding Y, Dou X. STAT6 up-regulation amplifies M2 macrophage anti-inflammatory capacity through mesenchymal stem cells. Int Immunopharmacol 2021; 91:107266. [PMID: 33321466 DOI: 10.1016/j.intimp.2020.107266] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/21/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022]
Abstract
Extensive infiltration of M2 macrophages plays a crucial role in repairing acute liver failure (ALF), however, the molecular pathways whereby mesenchymal stem cells (MSCs) induce M2 macrophage polarization remains unknown. We investigated the molecular pathways involved in MSC-induced M2 polarization and describe the potential therapeutic effects of M2 macrophages on ALF. The expression of M2 macrophage markers was significantly increased after M0 macrophages were co-cultured with MSCs in vitro. MSCs induced M2 macrophage polarization by activating STAT6, whereas a STAT6 inhibitor significantly inhibited the expression of M2 macrophage polarization markers (IL-4, CD163, TGF-β, IL-10 and Arg-1). Finally, M2 macrophages significantly reduced the secretion of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from injured hepatocytes. These results demonstrated that MSCs induced M2 macrophage polarization by activating STAT6, and that M2 macrophages increased the expression of anti-inflammatory factors to alleviate ALF.
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Affiliation(s)
- Yanwei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Qiuju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Hai Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Pingping Lai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yaoxin Fan
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
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