|
1
|
Rabiu L, Zhang P, Liu Z, Tang Y, Gidado KI, Ibrahim A, Saliu MA, Tariq HK, Wan X, Xu S, Xu Z, Zhang G. TIPE2 deficiency amplifies inflammation and immune dysregulation in MASH through modulating hepatic lipid metabolism and immune cell function. Inflamm Res 2025; 74:65. [PMID: 40244311 DOI: 10.1007/s00011-025-02031-6] [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: 12/24/2024] [Revised: 03/20/2025] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Metabolic Dysfunction-Associated Steatohepatitis (MASH) affects nearly 25% of the global population, yet there are no effective pharmacological treatments. Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) is expressed in various immune cells and is crucial for regulating both innate and adaptive immune responses. However, its role in MASH development and the underlying mechanisms remain unclear. METHOD In this study, the role of TIPE2 in MASH was investigated using TIPE2 knockout (KO) mice and human hepatic LO2 cells. Immune cell infiltration, cytokine levels, and gene expression were analyzed. Techniques included flow cytometry for immune cell profiling, cytokine analysis, RNA sequencing, and quantitative PCR (qPCR) for validating gene expression changes. RESULTS TIPE2 was identified as a key regulator in MASH, influencing immune modulation and metabolic processes. TIPE2 KO mice exhibited increased infiltration and activation of natural killer (NK) cells, M1 macrophages, and myeloid-derived suppressor cells (MDSCs), along with elevated pro-inflammatory cytokines such as IFN-gamma, TNF-alpha, IL- 1 beta, and IL- 6. MDSCs from TIPE2 KO mice demonstrated enhanced PD-L1 expression, contributing to chronic liver inflammation through T cell suppression. RNA sequencing revealed that TIPE2 overexpression in human hepatic LO2 cells upregulated genes associated with amino acid biosynthesis, carbon metabolism, lipid regulation, glycolysis, and gluconeogenesis. These findings were supported by qPCR analyses of liver samples from mice, confirming TIPE2's role in maintaining lipid homeostasis and modulating immune responses. CONCLUSION The study highlights the pivotal role of TIPE2 in immune regulation and its influence on immune cell activation and inflammatory responses, which are critical in MASH progression. By exploring TIPE2-mediated immune regulation and its impact on the interplay between immune cell dynamics and liver metabolism, this research underscores TIPE2's central role in linking immune dysfunction to metabolic disturbances in MASH.
Collapse
Affiliation(s)
- Lawan Rabiu
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Pengchao Zhang
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Zhongming Liu
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
| | - Yexiao Tang
- Cancer Center, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, PR China
| | - Khalid I Gidado
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Abdulrahman Ibrahim
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Muhammad A Saliu
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Hafiza Kashaf Tariq
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Xiaochun Wan
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Shu Xu
- Cancer Center, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, PR China.
| | - Zhiming Xu
- Cancer Center, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, PR China.
| | - Guizhong Zhang
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China.
- University of Chinese Academy of Sciences, Beijing, 100049, PR China.
| |
Collapse
|
|
2
|
Noor S, Ali S, Summer M, Riaz A, Nazakat L, Aqsa. Therapeutic Role of Probiotics Against Environmental-Induced Hepatotoxicity: Mechanisms, Clinical Perspectives, Limitations, and Future. Probiotics Antimicrob Proteins 2025; 17:516-540. [PMID: 39316257 DOI: 10.1007/s12602-024-10365-6] [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] [Accepted: 09/10/2024] [Indexed: 09/25/2024]
Abstract
Hepatotoxicity is one of the biggest health challenges, particularly in the context of liver diseases, often aggravated by gut microbiota dysbiosis. The gut-liver axis has been regarded as a key idea in liver health. It indicates that changes in gut flora caused by various hepatotoxicants, including alcoholism, acetaminophen, carbon tetrachloride, and thioacetamide, can affect the balance of the gut's microflora, which may lead to increased dysbiosis and intestinal permeability. As a result, bacterial endotoxins would eventually enter the bloodstream and liver, causing hepatotoxicity and inducing inflammatory reactions. Many treatments, including liver transplantation and modern drugs, can be used to address these issues. However, because of the many side effects of these approaches, scientists and medical experts are still hoping for a therapeutic approach with fewer side effects and more positive results. Thus, probiotics have become well-known as an adjunctive strategy for managing, preventing, or reducing hepatotoxicity in treating liver injury. By altering the gut microbiota, probiotics offer a secure, non-invasive, and economical way to improve liver health in the treatment of hepatotoxicity. Through various mechanisms such as regulation of gut microbiota, reduction of pathogenic overgrowth, suppression of inflammatory mediators, modification of hepatic lipid metabolism, improvement in the performance of the epithelial barrier of the gut, antioxidative effects, and modulation of mucosal immunity, probiotics play their role in the treatment and prevention of hepatotoxicity. This review highlights the mechanistic effects of probiotics in environmental toxicants-induced hepatotoxicity and current findings on this therapeutic approach's experimental and clinical trials.
Collapse
Affiliation(s)
- Shehzeen Noor
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Shaukat Ali
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan.
| | - Muhammad Summer
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Anfah Riaz
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Laiba Nazakat
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Aqsa
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| |
Collapse
|
|
3
|
Humphries JE, Hicks A, Lanctôt C, McCallum H, Newell D, Grogan LF. Amphibian cellular immune response to chytridiomycosis at metamorphic climax. Immunol Res 2025; 73:44. [PMID: 39885107 PMCID: PMC11782352 DOI: 10.1007/s12026-025-09599-5] [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: 10/15/2024] [Accepted: 01/19/2025] [Indexed: 02/01/2025]
Abstract
The fungal disease chytridiomycosis (caused by Batrachochytrium dendrobatidis [Bd]) is a primary contributor to amphibian declines. The frog metamorphic stages, characterised by extensive physiological reorganisation and energy expenditure, have heightened susceptibility to Bd. However, little is known about how these metamorphic stages respond immunologically to Bd infection. In this study, we examined Bd infection and the cellular immune response of Mixophyes fleayi at Gosner stages 40, 42 and 45, using blood smears and skin and liver histology. Although proportional differences were observed, the impact of Bd exposure appeared negligible prior to Gosner stage 45 (onset of morbidity), with no significant differences observed in absolute leukocyte counts for blood or liver samples between control and Bd-exposed groups at Gosner stages 40 and 42. Animals exhibiting clinical signs at Gosner stage 45 demonstrated significant elevation in liver leukocyte counts, blood neutrophil and monocyte counts and neutrophil-to-lymphocyte ratios. These findings are reminiscent of the amplified inflammatory response characteristic of immunopathology in clinically infected amphibians. Interestingly, a subset of exposed animals that had apparently cleared infections at Gosner stage 45 had similar blood leukocyte counts but reduced liver leukocyte counts compared to naïve controls. This could be a consequence of prior cellular consumption during pathogen removal or effective immune regulation via anti-inflammatory protective feedback mechanisms. We recommend targeted gene expression analyses (e.g. immunomodulatory cytokines) to establish the mechanisms responsible for the varied immune expression and infection outcomes across metamorphosis.
Collapse
Affiliation(s)
- Josephine E Humphries
- School of Environment and Science, Griffith University, Southport, QLD, 4222, Australia.
- Centre for Planetary Health and Food Security, Griffith University, Southport, QLD, 4222, Australia.
| | - Allan Hicks
- School of Pharmacy and Medical Sciences, Griffith University, Southport, QLD, 4222, Australia
| | - Chantal Lanctôt
- School of Environment and Science, Griffith University, Southport, QLD, 4222, Australia
- Australian Rivers Institute, Griffith University, Southport, QLD, 4222, Australia
| | - Hamish McCallum
- Centre for Planetary Health and Food Security, Griffith University, Southport, QLD, 4222, Australia
| | - David Newell
- Faculty of Science and Engineering, Southern Cross University, Lismore, NSW, 2480, Australia
| | - Laura F Grogan
- School of Environment and Science, Griffith University, Southport, QLD, 4222, Australia
- Centre for Planetary Health and Food Security, Griffith University, Southport, QLD, 4222, Australia
- School of the Environment, University of Queensland, St Lucia, QLD, 4067, Australia
| |
Collapse
|
|
4
|
Gulzar F, Chhikara N, Kumar P, Ahmad S, Yadav S, Gayen JR, Tamrakar AK. ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells. Biochem Biophys Res Commun 2024; 735:150827. [PMID: 39423570 DOI: 10.1016/j.bbrc.2024.150827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/23/2024] [Accepted: 10/11/2024] [Indexed: 10/21/2024]
Abstract
Nucleotide-binding Oligomerization Domain 1 (NOD1) is a cytosolic pattern recognition receptor that senses specific bacterial peptidoglycan moieties, leading to the induction of inflammatory response. Besides, sensing peptidoglycan, NOD1 has been reported to sense metabolic disturbances including the ER stress-induced unfolded protein response (UPR). However, the underpinning crosstalk between the NOD1 activating microbial ligands and the metabolic cues to alter metabolic response is not yet comprehensively defined. Here, we show that underlying ER stress aggravated peptidoglycan-induced NOD1-mediated inflammatory response in hepatoma cells. The HepG2 cells, undergoing ER stress induced by thapsigargin exhibited an amplified inflammatory response induced by peptidoglycan ligand of NOD1 (i.e. iE-DAP). This aggravated inflammatory response disrupted lipid and glucose metabolism, characterized by de novo lipogenic response, and increased gluconeogenesis in HepG2 cells. Further, we characterized that the aggravation of NOD1-induced inflammatory response was dependent on inositol-requiring enzyme 1-α (IRE1-α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation, in conjunction with calcium flux. Altogether, our findings suggest that differential UPR activation makes liver cells more sensitive towards bacterial-derived ligands to pronounce inflammatory response in a NOD1-dependent manner that impairs hepatic nutrient metabolism.
Collapse
Affiliation(s)
- Farah Gulzar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Nikita Chhikara
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Pawan Kumar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Shadab Ahmad
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Shubhi Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Jiaur R Gayen
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Akhilesh K Tamrakar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India.
| |
Collapse
|
|
5
|
Zhang Y, Wu R, Zhan X, Wang XY, Xiang LW, Duan YQ, You Y, Zhang JB, Wu R, Zhang YY, Duan L. Neutrophil extracellular traps facilitate liver inflammation/fibrosis progression by entering macrophages and triggering AIM2 inflammasome-dependent pyroptosis. Cell Commun Signal 2024; 22:556. [PMID: 39568027 PMCID: PMC11577833 DOI: 10.1186/s12964-024-01944-9] [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: 08/21/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Absent in melanoma 2 (AIM2) inflammasome-dependent pyroptosis and neutrophil extracellular traps (NETs) have been implicated in chronic liver disease (CLD). However, the specific intrahepatic cell type that undergoes AIM2 inflammasome-dependent pyroptosis and how their interaction augments hepatic inflammation/fibrosis remains unclear. METHODS The expression and correlation of AIM2 inflammasome-dependent pyroptosis-related indicators and NETs were analyzed in biopsy tissue and blood specimens from chronic hepatitis patients (CHs). Cell-based experiments were conducted to investigate their interaction. In vitro and in vivo experiments were used to analyze their effects on the progression of hepatic inflammation/fibrosis as well as their clinical importance. RESULTS Elevated levels of AIM2 inflammasome-dependent pyroptosis indicators and NETs were detected in biopsy tissue and blood specimens. Circulating NETs were positively correlated with pyroptosis-related indicators, and both were related with disease severity. Confocal imaging revealed that AIM2 was mainly localized to hepatic macrophages, indicating that hepatic macrophages were the major cell type that underwent pyroptosis. NETs were directly engulfed by macrophages and then stimulated AIM2 inflammasome-dependent macrophage pyroptosis in vitro, which amplified the activation of hepatic stellate cells (HSCs) and increased collagen deposition. Administration of the NETs degradation agent DNase I or the AIM2 inflammasome activation inhibitor ODN A151 effectively alleviated chronic liver inflammation/fibrosis progression in vivo. CONCLUSIONS NETs-induced AIM2 inflammasome-dependent pyroptosis in macrophages facilitates liver inflammation/fibrosis progression. The identified NET-AIM2 inflammasome cascade could serve as a novel therapeutic target for hepatic inflammation/fibrosis progression.
Collapse
Affiliation(s)
- Yu Zhang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Lin Jiang Road, Chongqing, 400010, China
| | - Rong Wu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Lin Jiang Road, Chongqing, 400010, China
| | - Xi Zhan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Lin Jiang Road, Chongqing, 400010, China
| | - Xuan-Yi Wang
- Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin-Wei Xiang
- Department of Laboratory Medicine, Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ya-Qian Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Lin Jiang Road, Chongqing, 400010, China
| | - Yan You
- Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian-Bo Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, No.1 You Yi Road, Chongqing, 400016, China.
| | - Yun-Yuan Zhang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, No.16 Jiang Su Road, Qingdao, 266003, China.
| | - Liang Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Lin Jiang Road, Chongqing, 400010, China.
| |
Collapse
|
|
6
|
Jin YX, Hu HQ, Zhang JC, Xin XY, Zhu YT, Ye Y, Li D. Mechanism of mesenchymal stem cells in liver regeneration: Insights and future directions. World J Stem Cells 2024; 16:842-845. [PMID: 39351263 PMCID: PMC11438733 DOI: 10.4252/wjsc.v16.i9.842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/24/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are a prevalent source for stem cell therapy and play a crucial role in modulating both innate and adaptive immune responses. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in liver cells and involves immune system activation, leading to histological changes, tissue damage, and clinical symptoms. A recent publication by Jiang et al, highlighted the potential of MSCs to mitigate in NAFLD progression by targeting various molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In this editorial, we comment on their research and discuss the efficacy of MSC therapy in treating NAFLD.
Collapse
Affiliation(s)
- Yu-Xin Jin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Hang-Qi Hu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Jia-Cheng Zhang
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Xi-Yan Xin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yu-Tian Zhu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yang Ye
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China.
| | - Dong Li
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| |
Collapse
|
|
7
|
Lu JF, Xing SP, Wei X, Yang CX, Zhao GS, Ma XL, Sun XM, Guo HW, Su ZH, Fang B, Lin J, Liu YY, Zhu D. Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics. Front Pharmacol 2024; 15:1447560. [PMID: 39323644 PMCID: PMC11422225 DOI: 10.3389/fphar.2024.1447560] [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: 06/11/2024] [Accepted: 08/21/2024] [Indexed: 09/27/2024] Open
Abstract
Background Chronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD. Methods Rats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated. Results HBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1β, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD. Conclusion HBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.
Collapse
Affiliation(s)
- Jun-Fei Lu
- Pharmaceutical College, Guangxi Medical University, Nanning, China
- Department of Pharmacy, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China
| | - Shang-Ping Xing
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Xia Wei
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Chun-Xia Yang
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Gen-Shi Zhao
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Xiao-Lin Ma
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Xue-Mei Sun
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Hong-Wei Guo
- Pharmaceutical College, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Geriatric Diseases, Ministry of Education, Guangxi Medical University, Nanning, China
| | - Zhi-Heng Su
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Bin Fang
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Jun Lin
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Yan-Ying Liu
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Dan Zhu
- Pharmaceutical College, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory for Bioactive Molecules Research and Evaluation, Nanning, China
- Guangxi Beibu Gulf Marine Biomedicine Precision Development and High-value Utilization Engineering Research Center, Nanning, China
- Guangxi Health Commission Key Laboratory of Basic Research on Antigeriatric Drugs, Nanning, China
| |
Collapse
|
|
8
|
Ding C, Wang Z, Dou X, Yang Q, Ning Y, Kao S, Sang X, Hao M, Wang K, Peng M, Zhang S, Han X, Cao G. Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis. Aging Dis 2024; 15:1508-1536. [PMID: 37815898 PMCID: PMC11272191 DOI: 10.14336/ad.2023.0830] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/30/2023] [Indexed: 10/12/2023] Open
Abstract
The farnesoid X receptor (FXR), a ligand-activated transcription factor, plays a crucial role in regulating bile acid metabolism within the enterohepatic circulation. Beyond its involvement in metabolic disorders and immune imbalances affecting various tissues, FXR is implicated in microbiota modulation, gut-to-brain communication, and liver disease. The liver, as a pivotal metabolic and detoxification organ, is susceptible to damage from factors such as alcohol, viruses, drugs, and high-fat diets. Chronic or recurrent liver injury can culminate in liver fibrosis, which, if left untreated, may progress to cirrhosis and even liver cancer, posing significant health risks. However, therapeutic options for liver fibrosis remain limited in terms of FDA-approved drugs. Recent insights into the structure of FXR, coupled with animal and clinical investigations, have shed light on its potential pharmacological role in hepatic fibrosis. Progress has been achieved in both fundamental research and clinical applications. This review critically examines recent advancements in FXR research, highlighting challenges and potential mechanisms underlying its role in liver fibrosis treatment.
Collapse
Affiliation(s)
- Chuan Ding
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
- Jinhua Institute, Zhejiang Chinese Medical University, Jinhua, China.
| | - Zeping Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Xinyue Dou
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Qiao Yang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Yan Ning
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Shi Kao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Min Hao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Kuilong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Mengyun Peng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Shuosheng Zhang
- College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, China.
| | - Xin Han
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
- Jinhua Institute, Zhejiang Chinese Medical University, Jinhua, China.
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
- Jinhua Institute, Zhejiang Chinese Medical University, Jinhua, China.
| |
Collapse
|
|
9
|
Yao Y, Zuo X, Shao F, Yu K, Liang Q. Jaceosidin attenuates the progression of hepatic fibrosis by inhibiting the VGLL3/HMGB1/TLR4 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155502. [PMID: 38489889 DOI: 10.1016/j.phymed.2024.155502] [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: 06/01/2023] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND Jaceosidin (JA) is a natural flavone extracted from Artemisia that is used as a food and traditional medicinal herb. It has been reported to possess numerous biological activities. However, the regulatory mechanisms underlying amelioration of hepatic fibrosis remain unclear. HYPOTHESIS/PURPOSE We hypothesized that jaceosidin acid (JA) modulates hepatic fibrosis and inflammation. METHODS Thioacetamide (TAA) was used to establish an HF mouse model. In vitro, mouse primary hepatocytes and HSC-T6 cells were induced by TGF-β, whereas mouse peritoneal macrophages received a treatment lipopolysaccharide (LPS)/ATP. RESULTS JA decreased serum transaminase levels and improved hepatic histological pathology in TAA-treated mice stimulated by TAA. Moreover, the expression of pro-fibrogenic biomarkers associated with the activation of liver stellate cells was downregulated by JA. Likewise, JA down-regulated the expression of vestigial-like family member 3 (VGLL3), high mobility group protein B1 (HMGB1), toll-like receptors 4 (TLR4), and nucleotide-binding domain-(NOD-) like receptor protein 3 (NLRP3), thereby inhibiting the inflammatory response and inhibiting the release of mature-IL-1β in TAA-stimulated mice. Additionally, JA suppressed HMGB1 release and NLRP3/ASC inflammasome activation in LPS/ATP-stimulated murine peritoneal macrophages. JA decreases the expression of pro-fibrogenic biomarkers related to liver stellate cell activation and inhibits inflammasome activation in mouse primary hepatocytes. It also down-regulated α-SMA and VGLL3 expressions and also suppressed inflammasome activation in HSC-T6 cells. VGLL3 and α-SMA expression levels were decreased in TGF-β-stimulated HSC-T6 cells following Vgll3 knockdown. In addition, the expression levels of NLRP3 and cleaved-caspase-1 were decreased in Vgll3-silenced HSC-T6 cells. JA enhanced the inhibitory effects on Vgll3-silenced HSC-T6 cells. Finally, Vgll3 overexpression in HSC-T6 cells affected the expression levels of α-SMA, NLRP3, and cleaved-caspase-1. CONCLUSION JA effectively modulates hepatic fibrosis by suppressing fibrogenesis and inflammation via the VGLL3/HMGB1/TLR4 axis. Therefore, JA may be a candidate therapeutic agent for the management of hepatic fibrosis. Understanding the mechanism of action of JA is a novel approach to hepatic fibrosis therapy.
Collapse
Affiliation(s)
- Youli Yao
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Xiaoling Zuo
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Feng Shao
- Qingdao Jinmotang Biotechnology Co., Ltd, Qingdao, Shandong Province 266000, China
| | - Kexin Yu
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Quanquan Liang
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China.
| |
Collapse
|
|
10
|
Zhang X, Zhou C, Hu J, Hu J, Ding Y, Chen S, Wang X, Xu L, Gou Z, Zhang S, Shi W. Six-gene prognostic signature for non-alcoholic fatty liver disease susceptibility using machine learning. Medicine (Baltimore) 2024; 103:e38076. [PMID: 38728481 PMCID: PMC11081587 DOI: 10.1097/md.0000000000038076] [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: 12/28/2023] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND nonalcoholic fatty liver disease (NAFLD) is a common liver disease affecting the global population and its impact on human health will continue to increase. Genetic susceptibility is an important factor influencing its onset and progression, and there is a lack of reliable methods to predict the susceptibility of normal populations to NAFLD using appropriate genes. METHODS RNA sequencing data relating to nonalcoholic fatty liver disease was analyzed using the "limma" package within the R software. Differentially expressed genes were obtained through preliminary intersection screening. Core genes were analyzed and obtained by establishing and comparing 4 machine learning models, then a prediction model for NAFLD was constructed. The effectiveness of the model was then evaluated, and its applicability and reliability verified. Finally, we conducted further gene correlation analysis, analysis of biological function and analysis of immune infiltration. RESULTS By comparing 4 machine learning algorithms, we identified SVM as the optimal model, with the first 6 genes (CD247, S100A9, CSF3R, DIP2C, OXCT 2 and PRAMEF16) as predictive genes. The nomogram was found to have good reliability and effectiveness. Six genes' receiver operating characteristic curves (ROC) suggest an essential role in NAFLD pathogenesis, and they exhibit a high predictive value. Further analysis of immunology demonstrated that these 6 genes were closely connected to various immune cells and pathways. CONCLUSION This study has successfully constructed an advanced and reliable prediction model based on 6 diagnostic gene markers to predict the susceptibility of normal populations to NAFLD, while also providing insights for potential targeted therapies.
Collapse
Affiliation(s)
- Xiang Zhang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Chunzi Zhou
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingwen Hu
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingwen Hu
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Yueping Ding
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Shiqi Chen
- Lishui Hospital of Traditional Chinese Medicine, Lishui, China
| | - Xu Wang
- Shanghai Jinshan TCM-Integrated Hospital, Shanghai, China
| | - Lei Xu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhijun Gou
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuqiao Zhang
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weiqun Shi
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
11
|
Sotoudeheian M. Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Protein Pept Lett 2024; 31:290-304. [PMID: 38715329 DOI: 10.2174/0109298665301698240404061300] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/02/2024] [Accepted: 03/21/2024] [Indexed: 08/13/2024]
Abstract
Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver and hepatic steatosis, which can progress to critical conditions, including Metabolic dysfunction-associated Steatohepatitis (MASH), liver fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Galectin-3, a member of the galectin family of proteins, has been involved in cascades that are responsible for the pathogenesis and progression of liver fibrosis in MAFLD. This review summarizes the present understanding of the role of galectin-3 in the severity of MAFLD and its associated liver fibrosis. The article assesses the underlying role of galectin-3-mediated fibrogenesis, including the triggering of hepatic stellate cells, the regulation of extracellular degradation, and the modulation of immune reactions and responses. It also highlights the assessments of the potential diagnostic and therapeutic implications of galectin-3 in liver fibrosis during MAFLD. Overall, this review provides insights into the multifaceted interaction between galectin-3 and liver fibrosis in MAFLD, which could lead to the development of novel strategies for diagnosis and treatment of this prevalent liver disease.
Collapse
|
|
12
|
Tian WS, Zhao J, Kim MK, Tae HJ, Kim IS, Ahn D, Hwang HP, Mao MX, Park BY. Veronica persica ameliorates acetaminophen-induced murine hepatotoxicity via attenuating oxidative stress and inflammation. Biomed Pharmacother 2023; 169:115898. [PMID: 37989029 DOI: 10.1016/j.biopha.2023.115898] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/23/2023] Open
Abstract
Excess acetaminophen (APAP) commonly causes severe acute liver injury (ALI), characterized by oxidative stress, pro-inflammatory responses, and hepatocyte damage. Veronica persica (VP) is a traditional medicine with antioxidant and anti-inflammatory properties. There is a paucity of information on its medicinal value, especially its potential mechanisms for alleviating ALI. This study aimed to clarify the ameliorative effects and intracellular mechanisms of VP on APAP-induced ALI via attenuating oxidative stress and inflammation. Mice were given VP for 7 days before exposure to APAP (300 mg/kg). The HPLC and radical scavenging assay found that VP contains 12 phenolic acids and 6 flavonoids, as well as show robust antioxidant capacity. In the APAP-induced ALI model, pre-treatment with VP significantly reduces APAP-induced hepatotoxicity by observing improved hepatocyte pathological injury and further confirmed by serum biochemical indicator. Also, the reduction of TUNEL-positive regions and the regulation of Bcl-2-associated X protein indicated that VP attenuates hepatocytotoxicity. Moreover, VP pre-intervention inhibits the formation of liver pro-inflammatory cytokines, the expression of inflammatory response genes, and increases in myeloperoxidase (MPO) in APAP-exposed mice. The elevated reduced glutathione (GSH) levels and decreased oxidative stress markers indicate that VP reduces APAP-promoted oxidative stress. Further study revealed that VP inhibited the phosphorylation of NF-κB/STAT3 cascade, blocked ERK and JNK phosphorylation, and activated AMP-activated protein kinase (AMPK). To sum up, this study demonstrated that VP exists hepatoprotective abilities on APAP-induced ALI, primarily by suppressing the phosphorylation of NF-κB/STAT3 cascade and ERK-JNK and inducing AMPK activation to alleviate oxidative stress and inflammation.
Collapse
Affiliation(s)
- Wei-Shun Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - Jing Zhao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Myung-Kon Kim
- Department of Food Science and Technology, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Hyun-Jin Tae
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - In-Shik Kim
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - Dongchoon Ahn
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - Hong Pil Hwang
- Department of Surgery of Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea
| | - Ming-Xian Mao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Byung-Yong Park
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea.
| |
Collapse
|
|
13
|
Chami P, Diab Y, Khalil DN, Azhari H, Jarnagin WR, Abou-Alfa GK, Harding JJ, Hajj J, Ma J, El Homsi M, Reyngold M, Crane C, Hajj C. Radiation and Immune Checkpoint Inhibitors: Combination Therapy for Treatment of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:16773. [PMID: 38069095 PMCID: PMC10706661 DOI: 10.3390/ijms242316773] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/24/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.
Collapse
Affiliation(s)
- Perla Chami
- Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon;
| | - Youssef Diab
- Faculty of Medicine, University of Balamand, Beirut 1100, Lebanon; (Y.D.)
| | - Danny N. Khalil
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Hassan Azhari
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - William R. Jarnagin
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- Department of Surgery, Weill Medical College, Cornell University, New York, NY 10021, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- Department of Medicine, Weill Medical College, Cornell University, New York, NY 10021, USA
| | - James J. Harding
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- Department of Medicine, Weill Medical College, Cornell University, New York, NY 10021, USA
| | - Joseph Hajj
- Faculty of Medicine, University of Balamand, Beirut 1100, Lebanon; (Y.D.)
| | - Jennifer Ma
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Maria El Homsi
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Marsha Reyngold
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | | | - Carla Hajj
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- New York Proton Center, New York, NY 10035, USA
| |
Collapse
|
|
14
|
Sawada K, Chung H, Softic S, Moreno-Fernandez ME, Divanovic S. The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease. Cell Metab 2023; 35:1852-1871. [PMID: 37939656 PMCID: PMC10680147 DOI: 10.1016/j.cmet.2023.10.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/10/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
Collapse
Affiliation(s)
- Keisuke Sawada
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Hak Chung
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Samir Softic
- Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
| |
Collapse
|
|
15
|
Seo HY, Lee SH, Park JY, Han E, Han S, Hwang JS, Kim MK, Jang BK. Lobeglitazone inhibits LPS-induced NLRP3 inflammasome activation and inflammation in the liver. PLoS One 2023; 18:e0290532. [PMID: 37616215 PMCID: PMC10449201 DOI: 10.1371/journal.pone.0290532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
Liver inflammation is a common feature of chronic liver disease and is often associated with increased exposure of the liver to lipopolysaccharide (LPS). Kupffer cells (KCs) are macrophages in the liver and produce various cytokines. Activation of KCs through the NLRP3 inflammasome pathway leads to release of proinflammatory cytokines and induces hepatocyte injury and hepatic stellate cell (HSC) activation. Lobeglitazone is a peroxisome proliferator-activated receptor gamma ligand and a type of thiazolidinedione that elicits anti-inflammatory effects. However, there is no clear evidence that it has direct anti-inflammatory effects in the liver. This study showed that lobeglitazone reduces LPS-induced NLPR3 inflammasome activation and production of proinflammatory cytokines in primary KCs and hepatocytes. Cytokines secreted by activated KCs increased hepatocyte inflammation and HSC activation, and lobeglitazone inhibited these responses. In addition, lobeglitazone suppressed liver fibrosis by inhibiting LPS-induced transforming growth factor (TGF)-β secretion and TGF-β-induced CTGF expression. The inhibitory effect of lobeglitazone on inflammasome activation was associated with suppression of liver fibrosis. These results suggest that lobeglitazone may be a treatment option for inflammation and fibrosis in the liver.
Collapse
Affiliation(s)
- Hye-Young Seo
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - So-Hee Lee
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Ji Yeon Park
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Eugene Han
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Sol Han
- Department of Physiology, University of Washington, Seattle, WA, United States of America
| | - Jae Seok Hwang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu, Korea
| |
Collapse
|
|
16
|
Park HJ, Choi J, Kim H, Yang DY, An TH, Lee EW, Han BS, Lee SC, Kim WK, Bae KH, Oh KJ. Cellular heterogeneity and plasticity during NAFLD progression. Front Mol Biosci 2023; 10:1221669. [PMID: 37635938 PMCID: PMC10450943 DOI: 10.3389/fmolb.2023.1221669] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.
Collapse
Affiliation(s)
- Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Juyong Choi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Da-Yeon Yang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Baek-Soo Han
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
- Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| |
Collapse
|
|
17
|
Guo C, Liu W, Liu Z, Cai J, Yu X, Wang H, Li X, Zuo D, Jiang X, Zhang B, Liu J, Sanyal AJ, Puri P, Zhou H, Wang XY. Scavenger receptor a is a major homeostatic regulator that restrains drug-induced liver injury. Hepatology 2023; 78:45-57. [PMID: 36632993 PMCID: PMC10410742 DOI: 10.1097/hep.0000000000000044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 11/11/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIM Drug-induced liver injury occurs frequently and can be life threatening. Although drug-induced liver injury is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. Here, we interrogate the role of the pattern recognition scavenger receptor A (SRA) for regulating hepatic inflammation and drug-induced liver injury. APPROACH AND RESULTS Using acetaminophen (APAP) or halothane-induced liver injury models, we showed that SRA loss renders mice highly susceptible to drug hepatotoxicity, indicated by the increased mortality and liver pathology. Mechanistic studies revealed that APAP-induced liver injury exaggerated in the absence of SRA was associated with the decreased anti-inflammatory and prosurvival cytokine IL-10 concomitant with excessive hepatic inflammation. The similar correlation between SRA and IL-10 expression was also seen in human following APAP uptake. Bone marrow reconstitution and liposomal clodronate depletion studies established that the hepatoprotective activity of SRA mostly resized in the immune sentinel KCs. Furthermore, SRA-facilitated IL-10 production by KCs in response to injured hepatocytes mitigated activation of the Jun N-terminal kinase-mediated signaling pathway in hepatocytes. In addition, supplemental use of IL-10 with N -acetylcysteine, only approved treatment of APAP overdose, conferred mice improved protection from APAP-induced liver injury. CONCLUSION We identify a novel hepatocyte-extrinsic pathway governed by the immune receptor SRA that maintains liver homeostasis upon drug insult. Giving that drug (ie, APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective SRA-IL-10 axis may provide new opportunities to optimize the current management of drug-induced liver injury.
Collapse
Affiliation(s)
- Chunqing Guo
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Wenjie Liu
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Zheng Liu
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Jinyang Cai
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Xiaofei Yu
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Hongxia Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Xia Li
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Daming Zuo
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Xixian Jiang
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Bei Zhang
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jinze Liu
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Arun J. Sanyal
- Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Puneet Puri
- Hunter Holmes McGuire VA Medical Center, Richmond, Virginia, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Hunter Holmes McGuire VA Medical Center, Richmond, Virginia, USA
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Hunter Holmes McGuire VA Medical Center, Richmond, Virginia, USA
| |
Collapse
|
|
18
|
Kaufmann B, Seyfried N, Hartmann D, Hartmann P. Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease. Am J Physiol Gastrointest Liver Physiol 2023; 325:G42-G61. [PMID: 37129252 PMCID: PMC10312326 DOI: 10.1152/ajpgi.00017.2023] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/26/2023] [Accepted: 04/26/2023] [Indexed: 05/03/2023]
Abstract
The use of probiotics, prebiotics, and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation, and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre-, and synbiotics modulate these targets, they were identified as possible new treatment options for liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.
Collapse
Affiliation(s)
- Benedikt Kaufmann
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Nick Seyfried
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Phillipp Hartmann
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Department of Pediatrics, University of California San Diego, La Jolla, California, United States
| |
Collapse
|
|
19
|
Rizzo M, Colletti A, Penson PE, Katsiki N, Mikhailidis DP, Toth PP, Gouni-Berthold I, Mancini J, Marais D, Moriarty P, Ruscica M, Sahebkar A, Vinereanu D, Cicero AFG, Banach M, Al-Khnifsawi M, Alnouri F, Amar F, Atanasov AG, Bajraktari G, Banach M, Gouni-Berthold I, Bhaskar S, Bielecka-Dąbrowa A, Bjelakovic B, Bruckert E, Bytyçi I, Cafferata A, Ceska R, Cicero AF, Chlebus K, Collet X, Daccord M, Descamps O, Djuric D, Durst R, Ezhov MV, Fras Z, Gaita D, Gouni-Berthold I, Hernandez AV, Jones SR, Jozwiak J, Kakauridze N, Kallel A, Katsiki N, Khera A, Kostner K, Kubilius R, Latkovskis G, John Mancini G, David Marais A, Martin SS, Martinez JA, Mazidi M, Mikhailidis DP, Mirrakhimov E, Miserez AR, Mitchenko O, Mitkovskaya NP, Moriarty PM, Mohammad Nabavi S, Nair D, Panagiotakos DB, Paragh G, Pella D, Penson PE, Petrulioniene Z, Pirro M, Postadzhiyan A, Puri R, Reda A, Reiner Ž, Radenkovic D, Rakowski M, Riadh J, Richter D, Rizzo M, Ruscica M, Sahebkar A, Serban MC, Shehab AM, Shek AB, Sirtori CR, Stefanutti C, Tomasik T, Toth PP, Viigimaa M, Valdivielso P, Vinereanu D, Vohnout B, von Haehling S, Vrablik M, Wong ND, Yeh HI, Zhisheng J, Zirlik A. Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP). Pharmacol Res 2023; 189:106679. [PMID: 36764041 DOI: 10.1016/j.phrs.2023.106679] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.
Collapse
Affiliation(s)
- Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Via del Vespro 141, 90127 Palermo, Italy.
| | - Alessandro Colletti
- Department of Science and Drug Technology, University of Turin, Turin, Italy
| | - Peter E Penson
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK; Liverpool Centre for Cardiovascular Science, Liverpool, UK
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, Medical School, University College London (UCL), London, UK
| | - Peter P Toth
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA; Preventive Cardiology, CGH Medical Center, Sterling, IL, USA
| | - Ioanna Gouni-Berthold
- Department of Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Germany
| | - John Mancini
- Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - David Marais
- Chemical Pathology Division of the Department of Pathology, University of Cape Town Health Science Faculty, Cape Town, South Africa
| | - Patrick Moriarty
- Division of Clinical Pharmacology, Division of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dragos Vinereanu
- Cardiology Department, University and Emergency Hospital, Bucharest, Romania, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Arrigo Francesco Giuseppe Cicero
- Hypertension and Cardiovascular disease risk research center, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy; IRCCS Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Hukkamlı B, Dağdelen B, Sönmez Aydın F, Budak H. Comparison of the efficacy of the mouse hepatic and renal antioxidant systems against inflammation-induced oxidative stress. Cell Biochem Biophys 2023:10.1007/s12013-023-01126-3. [PMID: 36773183 DOI: 10.1007/s12013-023-01126-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2023] [Indexed: 02/12/2023]
Abstract
This study was conducted to compare the efficacy of the mouse hepatic and renal antioxidant systems against inflammation-induced oxidative stress. Increased Il-1 and Il-6 expressions, markers of inflammation, were represented by inflammation models in mouse liver and kidney tissues injected intraperitoneally with LPS. After establishing the model, the GSH level and the GSH/GSSG ratio, which are oxidative stress markers, were investigated in both tissues treated with LPS and the control group. The expression of Trx1, TrxR, and Txnip genes increased in the liver tissues of LPS-treated mice. In the kidney tissue, while Trx1 expression decreased, no change was observed in TrxR1 expression, and Txnip expression increased. In the kidneys, TRXR1 and GR activities decreased, whereas GPx activity increased. In both tissues, the TRXR1 protein expression decreased significantly, while TXNIP expression increased. In conclusion, different behaviors of antioxidant system members were observed during acute inflammation in both tissues. Additionally, it can be said that the kidney tissue is more sensitive and takes earlier measures than the liver tissue against cellular damage caused by inflammation and inflammation-induced oxidative stress.
Collapse
Affiliation(s)
- Berna Hukkamlı
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, Erzurum, 25240, Türkiye
- Department of Chemical and Chemical Processing Technologies, Boyabat Vocational School, Sinop University, Sinop, 57200, Türkiye
| | - Burak Dağdelen
- Department of Medical Biology, Faculty of Medicine, Selçuk University, Konya, 42250, Türkiye
| | - Feyza Sönmez Aydın
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, Erzurum, 25240, Türkiye
- Department of Pathology Laboratory Techniques, Vocational School, Doğuş University, Istanbul, 34775, Türkiye
| | - Harun Budak
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, Erzurum, 25240, Türkiye.
| |
Collapse
|
|
21
|
Qian H, Qian Y, Liu Y, Cao J, Wang Y, Yang A, Zhao W, Lu Y, Liu H, Zhu W. Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics. Front Cardiovasc Med 2023; 9:996809. [PMID: 36712272 PMCID: PMC9874088 DOI: 10.3389/fcvm.2022.996809] [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: 07/18/2022] [Accepted: 12/19/2022] [Indexed: 01/13/2023] Open
Abstract
Background The mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma. Methods Mice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset. Results The survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000). Conclusion Alas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.
Collapse
Affiliation(s)
- Hongyan Qian
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China,Cancer Research Center Nantong, Nantong Tumor Hospital and Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Yi Qian
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China
| | - Yi Liu
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China
| | - Jiaxin Cao
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China
| | - Yuhang Wang
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China
| | - Aihua Yang
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China
| | - Wenjing Zhao
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China
| | - Yingnan Lu
- School of Overseas Education, Changzhou University, Changzhou, China
| | - Huanxin Liu
- Shanghai Labway Medical Laboratory, Shanghai, China
| | - Weizhong Zhu
- Department of Pharmacology, School of Medicine and School of Pharmacy Nantong University, Nantong, China,*Correspondence: Weizhong Zhu, ; orcid.org/0000-0002-8740-3210
| |
Collapse
|
|
22
|
Tsukahara T, Makioka-Itaya Y, Takimoto H, Ijichi T. Oral supplementation of a cell preparation of Enterococcus faecalis strain EC-12 stimulates superoxide dismutase production in the livers of healthy and arthritis-induced mice. J Clin Biochem Nutr 2023; 72:39-45. [PMID: 36777079 PMCID: PMC9899913 DOI: 10.3164/jcbn.22-77] [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: 07/18/2022] [Accepted: 09/03/2022] [Indexed: 11/07/2022] Open
Abstract
Hepatitis, a major human chronic inflammation disease, has been linked to oxidative stress, which can be initiated by radicals produced during the oxidative metabolism. Oxidative damage has been also observed in arthritis-induced mice. Here we evaluated whether supplementation of a cell preparation of Enterococcus faecalis EC-12 could induce superoxide dismutase activity and/or damage in the livers of healthy mice or mice with arthritis. In Experiment 1, both healthy and arthritis-induced mice were orally given a saline solution, or a solution with a low (0.2 mg/mouse/day) or a high (2.0 mg/mouse/day) concentration of E. faecalis EC-12 for 49 consecutive days. Manganese superoxide dismutase activity increased in E. faecalis EC-12-supplemented mice but with no arthritis. In Experiment 2, mice received orally either a saline or an E. faecalis EC-12 suspension (10 mg/kg of body weight/day) for 28 consecutive days. No changes in tissues and levels of function markers and 8-hydroxy-2'-deoxyguanosine were observed in mouse livers, inferring that E. faecalis EC-12 supplementation caused no damage. While mRNA expression of copper/zinc superoxide dismutase remained unaltered, that of manganese superoxide dismutase increased in E. faecalis EC-12 administration mice. In conclusion, at least in healthy mice, E. faecalis EC-12 supplementation stimulated manganese superoxide dismutase activity in liver tissues with no side effects.
Collapse
Affiliation(s)
- Takamitsu Tsukahara
- Kyoto Institute of Nutrition & Pathology, 7-2 Furuikedani Tachikawa, Ujitawara, Kyoto 610-0231, Japan,To whom correspondence should be addressed. E-mail:
| | - Yuko Makioka-Itaya
- Life Science Division, Combi Corporation, Nishibori, Sakura-ku, Saitama 338-0832, Japan
| | - Hiroaki Takimoto
- Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Tetsuo Ijichi
- Life Science Division, Combi Corporation, Nishibori, Sakura-ku, Saitama 338-0832, Japan
| |
Collapse
|
|
23
|
Dibo N, Liu X, Chang Y, Huang S, Wu X. Pattern recognition receptor signaling and innate immune responses to schistosome infection. Front Cell Infect Microbiol 2022; 12:1040270. [PMID: 36339337 PMCID: PMC9633954 DOI: 10.3389/fcimb.2022.1040270] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/03/2022] [Indexed: 08/22/2023] Open
Abstract
Schistosomiasis remains to be a significant public health problem in tropical and subtropical regions. Despite remarkable progress that has been made in the control of the disease over the past decades, its elimination remains a daunting challenge in many countries. This disease is an inflammatory response-driven, and the positive outcome after infection depends on the regulation of immune responses that efficiently clear worms and allow protective immunity to develop. The innate immune responses play a critical role in host defense against schistosome infection and pathogenesis. Initial pro-inflammatory responses are essential for clearing invading parasites by promoting appropriate cell-mediated and humoral immunity. However, elevated and prolonged inflammatory responses against the eggs trapped in the host tissues contribute to disease progression. A better understanding of the molecular mechanisms of innate immune responses is important for developing effective therapies and vaccines. Here, we update the recent advances in the definitive host innate immune response to schistosome infection, especially highlighting the critical roles of pattern recognition receptors and cytokines. The considerations for further research are also provided.
Collapse
Affiliation(s)
- Nouhoum Dibo
- Department of medical parasitology, Xiangya School of Basic Medicine, Central South University, Changsha, China
| | - Xianshu Liu
- Department of medical parasitology, Xiangya School of Basic Medicine, Central South University, Changsha, China
| | - Yunfeng Chang
- Department of Forensic Medicine Science, Xiangya School of Basic Medicine, Central South University, Yueyang, China
| | - Shuaiqin Huang
- Department of medical parasitology, Xiangya School of Basic Medicine, Central South University, Changsha, China
- Hunan Provincial Key Lab of Immunology and Transmission Control on Schistosomiasis, Hunan Provincial Institute of Schistosomiasis Control, Yueyang, China
| | - Xiang Wu
- Department of medical parasitology, Xiangya School of Basic Medicine, Central South University, Changsha, China
- Hunan Provincial Key Lab of Immunology and Transmission Control on Schistosomiasis, Hunan Provincial Institute of Schistosomiasis Control, Yueyang, China
| |
Collapse
|
|
24
|
Targeting the lung epithelium after intravenous delivery by directed evolution of underexplored sites on the AAV capsid. Mol Ther Methods Clin Dev 2022; 26:331-342. [PMID: 35990749 PMCID: PMC9372736 DOI: 10.1016/j.omtm.2022.07.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/15/2022] [Indexed: 11/20/2022]
Abstract
Advances in adeno-associated virus (AAV) engineering have provided exciting new tools for research and potential solutions for gene therapy. However, the lung has not received the same tailored engineering as other major targets of debilitating genetic disorders. To address this, here we engineered the surface-exposed residues AA452-458 of AAV9 capsid proteins at the three-fold axis of symmetry and employed a Cre-transgenic-based screening platform to identify AAV capsids targeted to the lung after intravenous delivery in mice. Using a custom image processing pipeline to quantify transgene expression across whole tissue images, we found that one engineered variant, AAV9.452sub.LUNG1, displays dramatically improved transgene expression in lung tissue after systemic delivery in mice. This improved transduction extends to alveolar epithelial type II cells, expanding the toolbox for gene therapy research for diseases specific to the lung.
Collapse
|
|
25
|
Yu S, Wang J, Zheng H, Wang R, Johnson N, Li T, Li P, Lin J, Li Y, Yan J, Zhang Y, Zhu Z, Ding X. Pathogenesis from Inflammation to Cancer in NASH-Derived HCC. J Hepatocell Carcinoma 2022; 9:855-867. [PMID: 36051860 PMCID: PMC9426868 DOI: 10.2147/jhc.s377768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/17/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. As opposed to the majority of patients with HCC, approximately 20–30% of cases of non-alcoholic steatohepatitis (NASH)-derived HCC develop malignant tumours in the absence of liver cirrhosis. NASH is characterized by metabolic dysregulation, chronic inflammation and cell death in the liver, which provide a favorable setting for the transformation of inflammation into cancer. This review aims to describe the pathogenesis and the underlying mechanism of the transition from inflammation to cancer in NASH.
Collapse
Affiliation(s)
- Simiao Yu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People's Republic of China
| | - Jingxiao Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Haocheng Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Ruilin Wang
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, People's Republic of China
| | - Nadia Johnson
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People's Republic of China
| | - Tao Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Ping Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People's Republic of China
| | - Jie Lin
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Yuan Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Jin Yan
- Department of Hepatobiliary Surgery, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, People's Republic of China
| | - Ying Zhang
- Department of Hepatobiliary Surgery, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, People's Republic of China
| | - Zhenyu Zhu
- Department of Hepatobiliary Surgery, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, People's Republic of China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.,Centre of Research for Traditional Chinese Medicine Digestive, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| |
Collapse
|
|
26
|
The unique role of innate lymphoid cells in cancer and the hepatic microenvironment. Cell Mol Immunol 2022; 19:1012-1029. [PMID: 35962192 PMCID: PMC9424527 DOI: 10.1038/s41423-022-00901-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/22/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer is a complex disease, and despite incredible progress over the last decade, it remains the leading cause of death worldwide. Liver cancers, including hepatocellular carcinoma (HCC), and liver metastases are distinct from other cancers in that they typically emerge as a consequence of long-term low-grade inflammation. Understanding the mechanisms that underpin inflammation-driven tissue remodeling of the hepatic immune environment is likely to provide new insights into much needed treatments for this devastating disease. Group 1 innate lymphoid cells (ILCs), which include natural killer (NK) cells and ILC1s, are particularly enriched in the liver and thought to contribute to the pathogenesis of a number of liver diseases, including cancer. NK cells are an attractive, but underexplored, therapeutic target in hepatic disease due to their role in immunosurveillance and their ability to recognize and eliminate malignant cells. ILC1s are closely related to and share many phenotypic features with NK cells but are less well studied. Thus, their utility in immunotherapeutic approaches is not yet well understood. Here, we review our current understanding of ILCs in cancer with a particular focus on liver and liver-related diseases.
Collapse
|
|
27
|
Feng JY, Xie YQ, Zhang P, Zhou Q, Khan A, Zhou ZH, Xia XS, Liu L. Hepatoprotective Polysaccharides from Geranium wilfordii: Purification, Structural Characterization, and Their Mechanism. Molecules 2022; 27:molecules27113602. [PMID: 35684541 PMCID: PMC9182495 DOI: 10.3390/molecules27113602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/25/2022] [Accepted: 06/01/2022] [Indexed: 12/10/2022] Open
Abstract
Traditional Chinese Medicine is generally used as a decoction to guard health. Many active ingredients in the decoction are chemical ingredients that are not usually paid attention to in phytochemical research, such as polysaccharides, etc. Based on research interest in Chinese herbal decoction, crude polysaccharides from G. wilfordii (GCP) were purified to obtain two relatively homogeneous polysaccharides, a neutral polysaccharide (GNP), and an acid polysaccharide (GAP) by various chromatographic separation methods, which were initially characterized by GC-MS, NMR, IR, and methylation analysis. Studies on the hepatoprotective activity of GCP in vivo showed that GCP might be a potential agent for the prevention and treatment of acute liver injury by inhibiting the secretion levels of ALT, AST, IL-6, IL-1β, TNF-α, and MDA expression levels, increasing SOD, and the GSH-Px activity value. Further, in vitro assays, GNP and GAP, decrease the inflammatory response by inhibiting the secretion of IL-6 and TNF-α, involved in the STAT1/T-bet signaling pathway.
Collapse
Affiliation(s)
- Jia-Yi Feng
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
| | - Yan-Qing Xie
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
| | - Peng Zhang
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
| | - Qian Zhou
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
| | - Afsar Khan
- Department of Chemistry, Abbottabad Campus, COMSATS University Islamabad, Abbottabad 22060, Pakistan;
| | - Zhi-Hong Zhou
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
| | - Xian-Song Xia
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
- Correspondence: (L.L.); (X.-S.X.)
| | - Lu Liu
- Yunnan Yunzhong Research Institute of Nutrition and Health, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.-Y.F.); (Y.-Q.X.); (P.Z.); (Q.Z.); (Z.-H.Z.)
- Correspondence: (L.L.); (X.-S.X.)
| |
Collapse
|
|
28
|
Yamaguchi T, Yoshida K, Murata M, Suwa K, Tsuneyama K, Matsuzaki K, Naganuma M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23116270. [PMID: 35682957 PMCID: PMC9181097 DOI: 10.3390/ijms23116270] [Citation(s) in RCA: 4] [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: 04/18/2022] [Revised: 05/28/2022] [Accepted: 05/29/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.
Collapse
Affiliation(s)
- Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
- Correspondence: ; Tel.: +81-72-804-0101; Fax: +81-72-804-2524
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Miki Murata
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Kanehiko Suwa
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Koichi Tsuneyama
- Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan;
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| |
Collapse
|
|
29
|
The transmembrane adapter SCIMP recruits tyrosine kinase Syk to phosphorylate Toll-like receptors to mediate selective inflammatory outputs. J Biol Chem 2022; 298:101857. [PMID: 35337798 PMCID: PMC9052152 DOI: 10.1016/j.jbc.2022.101857] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 11/23/2022] Open
Abstract
Innate immune signaling by Toll-like receptors (TLRs) involves receptor phosphorylation, which helps to shape and drive key inflammatory outputs, yet our understanding of the kinases and mechanisms that mediate TLR phosphorylation is incomplete. Spleen tyrosine kinase (Syk) is a nonreceptor protein tyrosine kinase, which is known to relay adaptive and innate immune signaling, including from TLRs. However, TLRs do not contain the conserved dual immunoreceptor tyrosine-based activation motifs that typically recruit Syk to many other receptors. One possibility is that the Syk-TLR association is indirect, relying on an intermediary scaffolding protein. We previously identified a role for the palmitoylated transmembrane adapter protein SCIMP in scaffolding the Src tyrosine kinase Lyn, for TLR phosphorylation, but the role of SCIMP in mediating the interaction between Syk and TLRs has not yet been investigated. Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. We also show that Syk contributes to the phosphorylation of SCIMP and TLR4 to enhance their binding. Further evidence pinpoints two specific phosphorylation sites in SCIMP critical for its interaction with Syk-SH2 domains in the absence of immunoreceptor tyrosine-based activation motifs. Finally, using inhibitors and primary macrophages from SCIMP-/- mice, we confirm a functional role for SCIMP-mediated Syk interaction in modulating TLR4 phosphorylation, signaling, and cytokine outputs. In conclusion, we identify SCIMP as a novel, immune-specific Syk scaffold, which can contribute to inflammation through selective TLR-driven inflammatory responses.
Collapse
|
|
30
|
Chen S, Huang Y, Su H, Zhu W, Wei Y, Long Y, Shi Y, Wei J. The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats. Inflammation 2022; 45:1780-1799. [DOI: 10.1007/s10753-022-01660-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 03/10/2022] [Accepted: 03/10/2022] [Indexed: 11/24/2022]
|
|
31
|
Anti-aging effect of phlorizin on D-galactose-induced aging in mice through antioxidant and anti-inflammatory activity, prevention of apoptosis, and regulation of the gut microbiota. Exp Gerontol 2022; 163:111769. [PMID: 35337894 DOI: 10.1016/j.exger.2022.111769] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 02/28/2022] [Accepted: 03/14/2022] [Indexed: 12/29/2022]
Abstract
Aging is an inevitable and complicated process involving many physiological changes. Screening of natural biologically active anti-aging substances is a current research hotspot. Phlorizin (PZ), an important dihydrochalcone phytoconstituent, has been demonstrated to have antioxidant and anti-tumor effects. In this paper, different doses of PZ (20 and 40 mg/kg) were used to research the protective effect on D-galactose (D-gal)-induced aging mice. Following hematoxylin and eosin staining and by observing the hippocampus, we found that PZ alleviated the damage caused by D-gal in neuronal cells, while PZ enhanced the learning and memory abilities of aging mice in a radical eight-arm maze. In order to explain the reasons for these anti-aging effects, we tested the antioxidant enzyme activity and malonic dialdehyde concentration in mouse serum, liver, and brain tissue. The contents of proteins related to anti-inflammation and apoptosis in brain tissue were analyzed, and the gut microbiota was also analyzed. The results indicated that PZ improved antioxidant enzyme activity while significantly reducing the malonic dialdehyde content. Western blotting analysis suggested that PZ effectively alleviated neuro-apoptosis via regulating the expressions of Bax, Bcl-2, and caspase-3. PZ also exerted anti-inflammation effects by regulating the interleukin-1β/inhibitor of nuclear factor kappa B alpha/nuclear factor kappa-light-chain-enhancer of activated B-cells signaling pathways in brain tissues. Importantly, PZ improved the structure and diversity of the gut microbiota, and the microbiota-gut-brain axis may hold a key role in PZ-induced anti-aging effects. In conclusion, PZ can be used as a potential drug candidate to combat aging.
Collapse
|
|
32
|
An Q, Yue G, Yang X, Lou J, Shan W, Ding J, Jin Z, Hu Y, Du Q, Liao Q, Xie R, Xu J. Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases. Front Physiol 2022; 12:781069. [PMID: 35002763 PMCID: PMC8740087 DOI: 10.3389/fphys.2021.781069] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/01/2021] [Indexed: 11/16/2022] Open
Abstract
P2X receptors (P2XRs) are trimeric, non-selective cation channels activated by extracellular ATP and widely distributed in the digestive system. P2XRs have an important role in the physiological function of the digestive system, such as neurotransmission, ion transports, proliferation and apoptosis, muscle contraction, and relaxation. P2XRs can be involved in pain mechanisms both centrally and in the periphery and confirmed the association of P2XRs with visceral pain. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X(3)R or heteromeric P2X(2/3)R. Thus, peripheral P2XRs, and homomeric P2X(3) and/or heteromeric P2X(2/3)R in particular, constitute attractive targets for analgesic drugs. Recently studies have shown that P2XRs have made significant advances in inflammation and cancer. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. It is believed that with the further study of P2XRs and its subtypes, P2XRs and its specific antagonists will be expected to be widely used in the treatment of human digestive diseases in the future.
Collapse
Affiliation(s)
- Qimin An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Gengyu Yue
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xiaoxu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Weixi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jianhong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yanxia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qiushi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| |
Collapse
|
|
33
|
Wang Y, Wang P, Xu Q, Dong L, Liu Y, Chen Y, Zhou J, Lu X, Zuo D, Chen Q. Inflammatory arthritis increases the susceptibility to acute immune-mediated hepatitis in mice through enhancing leptin expression in T cells. Mol Immunol 2021; 140:97-105. [PMID: 34673376 DOI: 10.1016/j.molimm.2021.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/22/2021] [Accepted: 09/29/2021] [Indexed: 10/20/2022]
Abstract
Liver function abnormalities are common in patients with inflammatory arthritis. However, the precise mechanism is still unclear. In this study, inflammatory arthritis was established in mice by subcutaneous injection of complete Freund's adjuvant, and the intravenous injection of concanavalin A (Con A) was employed to induce acute immune-mediated hepatitis in mice. The result showed that the arthritis mice were more susceptible to ConA-induced hepatitis than the control mice, as evidenced by increased hepatic necrosis, elevated serum alanine aminotransferase activity, and raised inflammatory cytokines. Besides, the in vitro assay demonstrated that the T cells from arthritis mice were more sensitive to the Con A stimulation than those from control mice. Moreover, we determined that the level of leptin, a kind of adipokine, was significantly increased in the serum and hepatic T cells of arthritis mice. Interestingly, the data indicated that the enhanced expression of leptin in hepatic T cells is responsible for the hypersensitivity of arthritis mice-derived T cells to Con A challenge. Collectively, our findings demonstrate an unexpected role of leptin in the connection between inflammatory arthritis and acute immune-mediated hepatitis, thus providing new insight into the clinical therapy of arthritis-related liver dysfunction.
Collapse
Affiliation(s)
- Youyi Wang
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Ping Wang
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Qishan Xu
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Lijun Dong
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yunzhi Liu
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yu Chen
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jia Zhou
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xiao Lu
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Daming Zuo
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China; Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China.
| | - Qingyun Chen
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
| |
Collapse
|
|
34
|
Chen R, Du J, Zhu H, Ling Q. The role of cGAS-STING signalling in liver diseases. JHEP Rep 2021; 3:100324. [PMID: 34381984 PMCID: PMC8340306 DOI: 10.1016/j.jhepr.2021.100324] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/20/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
The recently identified novel cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) activates the downstream adaptor protein stimulator of interferon genes (STING) by catalysing the synthesis of cyclic GMP-AMP. This in turn initiates an innate immune response through the release of various cytokines, including type I interferon. Foreign DNA (microbial infection) or endogenous DNA (nuclear or mitochondrial leakage) can serve as cGAS ligands and lead to the activation of cGAS-STING signalling. Therefore, the cGAS-STING pathway plays essential roles in infectious diseases, sterile inflammation, tumours, and autoimmune diseases. In addition, cGAS-STING signalling affects the progression of liver inflammation through other mechanisms, such as autophagy and metabolism. In this review, we summarise recent advances in our understanding of the role of cGAS-STING signalling in the innate immune modulation of different liver diseases. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING pathway in the treatment of liver diseases.
Collapse
Key Words
- AIM2, absent in melanoma 2
- ALD, alcohol-related liver disease
- APCs, antigen-presenting cells
- CDNs, cyclic dinucleotides
- DAMPs, damage-associated molecular patterns
- DCs, dendritic cells
- ER, endoplasmic reticulum
- GVHD, graft-versus-host disease
- HCC, hepatocellular carcinoma
- HSCs, hepatic stellate cells
- IFN-I, type I interferon
- IL, interleukin
- IRF3, interferon regulatory factor 3
- IRI, ischaemia refusion injury
- KCs, Kupffer cells
- LSECs, liver sinusoidal endothelial cells
- MHC, major histocompatibility complex
- NAFLD, non-alcoholic fatty liver disease
- NK cells, natural killer cells
- NPCs, non-parenchymal cells
- PAMPs, pathogen-associated molecular patterns
- PD-1, programmed cell death protein-1
- PD-L1, programmed cell death protein ligand-1
- PPRs, pattern recognition receptors
- SAVI, STING-associated vasculopathy with onset in infancy
- STING, stimulator of interferon genes
- TBK1, TANK-binding kinase 1
- TGF-β1, transforming growth factor-β1
- TLR, Toll-like receptor
- TNF, tumour necrosis factor
- XRCC, X-ray repair cross complementing
- aHSCT, allogeneic haematopoietic stem cell transplantation
- cGAMP, cyclic guanosine monophosphate-adenosine monophosphate
- cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase
- cGAS-STING signalling
- dsDNA, double-strand DNA
- hepatocellular carcinoma
- innate immune response
- liver injury
- mTOR, mammalian target of rapamycin
- mtDNA, mitochondrial DNA
- nonalcoholic fatty liver disease
- siRNA, small interfering RNA
- ssRNA, single-stranded RNA
- viral hepatitis
Collapse
Affiliation(s)
- Ruihan Chen
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiamin Du
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qi Ling
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
35
|
Yang F, Feng B, Niu YJ, Hu CY, Meng YH. Fu instant tea ameliorates fatty liver by improving microbiota dysbiosis and elevating short-chain fatty acids in the intestine of mice fed a high-fat diet. FOOD BIOSCI 2021. [DOI: 10.1016/j.fbio.2021.101207] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
36
|
Tahmasebi S, Neishaboori H, Jafari D, Faghihzadeh E, Esmaeilzadeh A, Mirshafiey A. The effects of guluronic acid (G2013), a new emerging treatment, on inflammatory factors in nonalcoholic steatohepatitis patients under in vitro conditions. Immunopharmacol Immunotoxicol 2021; 43:562-570. [PMID: 34314306 DOI: 10.1080/08923973.2021.1954946] [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: 10/20/2022]
Abstract
BACKGROUND Nonalcoholic Steatohepatitis (NASH) results from the accumulation of fatty acids in the liver. The elevated production of pro-inflammatory factors is the reason for the hyper inflammation in NASH. The α-L-Guluronic acid (G2013), a new member of NSAID family, is a plant-originated agent with immunomodulatory properties. The current study investigated the effects of G2013 on inflammatory factors in PBMCs of NASH patients. METHODS PBMCs of 14 NASH patients and 14 healthy controls were isolated and cultured. The patient's cells were treated with low (5 µg/mL) and moderate (25 µg/mL) doses of G2013 alongside the diclofenac optimum dose (3 µg/mL). The expression and secretion levels of variables were assessed by real-time PCR and ELISA, respectively. RESULTS Findings indicated that the expression levels of TLR4 and NF-κB, as well as the secretion levels of TNF-α and IL-6 cytokines, were significantly elevated in NASH patients compared to healthy individuals. The expression levels of TLR4 and NF-κB were strikingly downregulated in treated cells of patients in both low and moderate doses of G2013. A considerable reduction was obtained in the secretion level of IL-6 using both low and moderate doses of G2013 and in the secretion level of TNF-α using the moderate dose of G2013. CONCLUSION The results indicated that G2013 could meaningfully decrease the expression and secretion levels of evaluated factors (TLR4, NF-κB, TNF-α, and IL-6) in PMBCs of NASH cases. Since there is no effective treatment for NASH patients, we hope that G2013 would be a promising immunomodulatory agent in reducing inflammation and improvement of patients.
Collapse
Affiliation(s)
- Safa Tahmasebi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Neishaboori
- Department of Internal Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Davood Jafari
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.,Immunotherapy Research and Technology Group, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Elham Faghihzadeh
- Department of Epidemiology and Biostatics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Abdolreza Esmaeilzadeh
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.,Immunotherapy Research and Technology Group, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
37
|
Fianchi F, Liguori A, Gasbarrini A, Grieco A, Miele L. Nonalcoholic Fatty Liver Disease (NAFLD) as Model of Gut-Liver Axis Interaction: From Pathophysiology to Potential Target of Treatment for Personalized Therapy. Int J Mol Sci 2021; 22:6485. [PMID: 34204274 PMCID: PMC8233936 DOI: 10.3390/ijms22126485] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut-liver axis-the complex network of cross-talking between the gut, microbiome and liver through the portal circulation-have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.
Collapse
Affiliation(s)
- Francesca Fianchi
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Liguori
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Grieco
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Luca Miele
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| |
Collapse
|
|
38
|
Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
Collapse
Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
| |
Collapse
|
|
39
|
Frissen M, Liao L, Schneider KM, Djudjaj S, Haybaeck J, Wree A, Rolle-Kampczyk U, von Bergen M, Latz E, Boor P, Trautwein C. Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury. Hepatology 2021; 73:1836-1854. [PMID: 32748971 DOI: 10.1002/hep.31494] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 05/29/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Cholestatic liver injury leads to cell death and subsequent inflammation and fibrosis. As shown for primary biliary cholangitis (PBC), the mechanisms and circuits between different cell death pathways leading to disease progression are incompletely defined. Common bile duct ligation (BDL) is a well-established murine model to mimic cholestatic liver injury. Here, we hypothesized that pyroptotic cell death by the Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3 (Nlrp3) inflammasome plays an essential role during human and murine cholestasis. APPROACH AND RESULTS NLRP3 activation was analyzed in humans with cholestatic liver injury. Wild-type (WT) and Nlrp3-/- mice were subjected to BDL for 2 or 28 days. Chronic cholestasis in humans and mice is associated with NLRP3 activation and correlates with disease activity. Acute BDL in Nlrp3-deficient mice triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death. In contrast, NLRP3 deletion led to decreased liver injury and inflammation in chronic cholestasis. Moreover, bridging fibrosis was observed in WT, but not in NLRP3 knockout, mice 28 days after BDL. In contrast, lack of NLRP3 expression attenuated kidney injury and fibrosis after acute and chronic BDL. Importantly, administration of MCC950, an NLRP3 small molecule inhibitor, reduced BDL-induced disease progression in WT mice. CONCLUSIONS NLRP3 activation correlates with disease activity in patients with PBC. NLRP3 has a differential role during acute and chronic cholestatic liver injury in contrast to kidney injury. Disease progression during chronic cholestasis can be targeted through small molecules and thus suggests a potential clinical benefit for humans, attenuating liver and kidney injury.
Collapse
Affiliation(s)
- Mick Frissen
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lijun Liao
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Kai Markus Schneider
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sonja Djudjaj
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Johannes Haybaeck
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.,Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Wree
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Eicke Latz
- Institute for Innate Immunity, University Clinic Bonn, Bonn, Germany
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University, Aachen, Germany.,Department of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| |
Collapse
|
|
40
|
Fathi F, Sanei B, Ganjalikhani Hakemi M, Saidi RF, Rezaei A. Liver Resection Promotes (Regulates) Proinflammatory Cytokines in Patients with Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2021; 2021:5593655. [PMID: 33987145 PMCID: PMC8093046 DOI: 10.1155/2021/5593655] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Several animal studies have shown the roles of cytokines in regulating liver regeneration following liver resection (LR), which is a type of surgery designed to remove cancerous tumors from the liver. This study investigated how the expressions and serum levels of some pro- and anti-inflammatory cytokines in patients with hepatocellular carcinoma (HCC) were changed during LR. METHODS Liver tissues from 15 patients with HCC were collected and the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1 β, IL-10, and transforming growth factor-beta1 (TGF-β1) were assessed using real-time PCR assay at different times before and after LR. The serum values of TNF-α and IL-6 were also measured by ELISA. RESULTS After 60 and 90 minutes of LR, IL-6 gene expression was significantly increased (P < 0.001 - 0.05). The same trend was also observed in TNF-α expression after 90 minutes of LR (P < 0.01). No significant changes were observed in the expressions of IL-1α, IL-1β, IL-10, and TGF-β1 before and after LR. In addition, LR had significant effects on TNF-α and IL-6 serum levels (P < 0.05 - 0.0001). CONCLUSION Our data provided further evidence to reveal that IL-6 and TNF-α cytokines are critical to improve liver regeneration.
Collapse
Affiliation(s)
- Farshid Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Behnam Sanei
- Department of Hepatobiliary & Pancreatic Surgery and Liver Transplantation, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Reza F. Saidi
- Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University Syracuse, Syracuse, NY 13210, USA
| | - Abbas Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
41
|
Zhang CH, Sheng JQ, Xie WH, Luo XQ, Xue YN, Xu GL, Chen C. Mechanism and Basis of Traditional Chinese Medicine Against Obesity: Prevention and Treatment Strategies. Front Pharmacol 2021; 12:615895. [PMID: 33762940 PMCID: PMC7982543 DOI: 10.3389/fphar.2021.615895] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
In the last few decades, the incidences of obesity and related metabolic disorders worldwide have increased dramatically. Major pathophysiology of obesity is termed "lipotoxicity" in modern western medicine (MWM) or "dampness-heat" in traditional Chinese medicine (TCM). "Dampness-heat" is a very common and critically important syndrome to guild clinical treatment in TCM. However, the pathogenesis of obesity in TCM is not fully clarified, especially by MWM theories compared to TCM. In this review, the mechanism underlying the action of TCM in the treatment of obesity and related metabolic disorders was thoroughly discussed, and prevention and treatment strategies were proposed accordingly. Hypoxia and inflammation caused by lipotoxicity exist in obesity and are key pathophysiological characteristics of "dampness-heat" syndrome in TCM. "Dampness-heat" is prevalent in chronic low-grade systemic inflammation, prone to insulin resistance (IR), and causes variant metabolic disorders. In particular, the MWM theories of hypoxia and inflammation were applied to explain the "dampness-heat" syndrome of TCM, and we summarized and proposed the pathological path of obesity: lipotoxicity, hypoxia or chronic low-grade inflammation, IR, and metabolic disorders. This provides significant enrichment to the scientific connotation of TCM theories and promotes the modernization of TCM.
Collapse
Affiliation(s)
- Chang-Hua Zhang
- College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Jun-Qing Sheng
- College of Life Science, Nanchang University, Nanchang, China
| | - Wei-Hua Xie
- College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Xiao-Quan Luo
- Experimental Animal Science and Technology Center of TCM, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Ya-Nan Xue
- College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Guo-Liang Xu
- Research Center for Differentiation and Development of Basic Theory of TCM, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
|
42
|
Ogunmoyole T, Dada I, Adebamigbe OA. Ameliorative potentials of Persea americana leaf extract on toxicants - induced oxidative assault in multiple organs of wistar albino rat. CLINICAL PHYTOSCIENCE 2021. [DOI: 10.1186/s40816-020-00237-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Abstract
Background
Persea americana (PA) is a popular medicinal plant in folkloric medicines. The present study therefore investigates the ameliorative potentials of its leaves extract on carbon tetrachloride and rifampicin-induced toxicity in the liver, kidney and heart of albino rat. This was aimed at assessing the potentials of the plant in the management of liver, kidney and heart diseases.
Methodology
Forty (40) rats were randomly divided into eight (8) groups of five animals each. Groups I and II were administered with only distilled water and carbon tetrachloride (CCl4) respectively. Groups III and IV animals received 3.0 ml/kg bw of CCl4 and were treated with the extract at 50 mg/kg bw and 100 mg/kg respectively, while group V received 100 mg/kg bw. of silymarin orally for 14 days. Groups VI animals were administered with rifampicin (250 mg/kg bw.) only, while groups VII and VIII animals received rifampicin and were treated with 50 mg and 100 mg/kg bw of the extract respectively. Activities of creatine kinase, aspartate amino transferase, alanine amino transferase, alkaline phosphatase, superoxide dismutase, catalase as well as levels of urea, uric acid, bilirubin and malonidialdehyde (MDA) were assayed. Lipid profiles and histopathological examination of liver and kidney slices were also performed.
Result
Treatment with P. americana significantly (p < 0.05) restored all deranged biochemical parameters (creatine kinase, aspartate amino transferase, alanine amino transferase, alkaline phosphatase, urea, uric acid, bilirubin, MDA, lipid profile as well as superoxide dismutase and catalase) in a dose-dependent manner. Normal hepatic and renal histoarchitecture were also restored following treatment with P. americana.
Conclusion
Amelioration of distorted cardiac, hepatic and renal histoarchitecture as well as restoration of lipid profile, biomarkers of liver and kidney injury and antioxidant enzymes (catalase and superoxide dismutase) affirm the potential usefulness of P. americana in the management of liver, kidney and heart diseases.
Collapse
|
|
43
|
Coelho I, Duarte N, Barros A, Macedo MP, Penha-Gonçalves C. Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage. Front Immunol 2021; 11:616044. [PMID: 33628208 PMCID: PMC7897679 DOI: 10.3389/fimmu.2020.616044] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery. Trem-2 gene ablation led to a delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. During tissue recovery, we found that macrophages transitioning to Kupffer cells expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with a unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2. During tissue recovery, lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs), whose transcriptional program was compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and by striking in vitro morphological changes towards typical endothelial cells. In conclusion, we found that the dynamics of liver macrophages in response to liver injury are critically controlled by Trem-2 and this regulation is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from pro-inflammatory to tissue repair phase by driving the acquisition of restorative properties in phagocytic macrophages.
Collapse
Affiliation(s)
- Inês Coelho
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Nádia Duarte
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - André Barros
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Maria Paula Macedo
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
- APDP Diabetes Portugal, Education and Research Center (APDP-ERC), Lisbon, Portugal
- Department of Medical Sciences, Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal
| | - Carlos Penha-Gonçalves
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
- APDP Diabetes Portugal, Education and Research Center (APDP-ERC), Lisbon, Portugal
| |
Collapse
|
|
44
|
Maroni L, Fianchi F, Miele L, Svegliati Baroni G. The pathophysiology of gut–liver connection. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:97-122. [DOI: 10.1016/b978-0-12-821927-0.00002-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
45
|
Sweet DR, Vasudevan NT, Fan L, Booth CE, Keerthy KS, Liao X, Vinayachandran V, Takami Y, Tugal D, Sharma N, Chan ER, Zhang L, Qing Y, Gerson SL, Fu C, Wynshaw-Boris A, Sangwung P, Nayak L, Holvoet P, Matoba K, Lu Y, Zhou G, Jain MK. Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation. Nat Commun 2020; 11:5872. [PMID: 33208733 PMCID: PMC7674440 DOI: 10.1038/s41467-020-19760-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 10/23/2020] [Indexed: 12/20/2022] Open
Abstract
Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease. Inflammation contributes to the development of metabolic disease through incompletely understood mechanisms. Here the authors report that deletion of the transcription factor KLF2 in myeloid cells leads to increased feeding and weight gain in mice with concomitant peripheral and central tissue inflammation, while overexpression protects against diet-induced metabolic disease.
Collapse
Affiliation(s)
- David R Sweet
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.,Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Neelakantan T Vasudevan
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Liyan Fan
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.,Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Chloe E Booth
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Komal S Keerthy
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Xudong Liao
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Vinesh Vinayachandran
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Yoichi Takami
- Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Derin Tugal
- Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Nikunj Sharma
- DBPAP/OVRR/CBER, Food and Drug Administration, Silver Spring, MD, USA
| | - E Ricky Chan
- Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Lilei Zhang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Yulan Qing
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.,National Center for Regenerative Medicine, Seidman Cancer Center, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA
| | - Stanton L Gerson
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.,National Center for Regenerative Medicine, Seidman Cancer Center, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA
| | - Chen Fu
- Department of Genetics and Genome Sciences, Case Western Reserve University, and University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Anthony Wynshaw-Boris
- Department of Genetics and Genome Sciences, Case Western Reserve University, and University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Panjamaporn Sangwung
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.,Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
| | - Lalitha Nayak
- Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, USA
| | - Paul Holvoet
- Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Keiichiro Matoba
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Yuan Lu
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.,Charles River Laboratories, Ashland, OH, USA
| | - Guangjin Zhou
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Mukesh K Jain
- Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
| |
Collapse
|
|
46
|
Wu T, Shen M, Guo X, Huang L, Yang J, Yu Q, Chen Y, Xie J. Cyclocarya paliurus polysaccharide alleviates liver inflammation in mice via beneficial regulation of gut microbiota and TLR4/MAPK signaling pathways. Int J Biol Macromol 2020; 160:164-174. [DOI: 10.1016/j.ijbiomac.2020.05.187] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 02/08/2023]
|
|
47
|
Wang Z, Xu G, Wang H, Zhan X, Gao Y, Chen N, Li R, Song X, Guo Y, Yang R, Niu M, Wang J, Liu Y, Xiao X, Bai Z. Icariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation. Acta Pharm Sin B 2020; 10:1619-1633. [PMID: 33088683 PMCID: PMC7564030 DOI: 10.1016/j.apsb.2020.03.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/20/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022] Open
Abstract
Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside Ⅱ (ICS Ⅱ), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS Ⅱ exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO2), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS Ⅱ. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS Ⅱ on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS Ⅱ causes the increase of aminotransferase activity, hepatic inflammation and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inflammasome inhibitor). In conclusion, these findings demonstrate that ICS Ⅱ causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS Ⅱ may be a risk factor and responsible for EF-induced liver injury.
Collapse
Affiliation(s)
- Zhilei Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Guang Xu
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Hongbo Wang
- Department of Hepatobiliary Surgery Center, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Xiaoyan Zhan
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Yuan Gao
- School of Chinese Materia Medica, Capital Medical University, Beijing 100029, China
| | - Nian Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ruisheng Li
- Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Xueai Song
- Integrative Medical Center, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Yuming Guo
- Integrative Medical Center, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Ruichuang Yang
- Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Ming Niu
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Jiabo Wang
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Youping Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- Corresponding authors.
| | - Xiaohe Xiao
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
- Integrative Medical Center, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
- Corresponding authors.
| | - Zhaofang Bai
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
- Corresponding authors.
| |
Collapse
|
|
48
|
Osei-Bordom D, Bozward AG, Oo YH. The hepatic microenvironment and regulatory T cells. Cell Immunol 2020; 357:104195. [PMID: 32861844 DOI: 10.1016/j.cellimm.2020.104195] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/11/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022]
Abstract
The human liver is regarded as a lymphoid organ that contributes to both local and systemic immune response. Intrahepatic immune cells including regulatory T cells (Tregs) reside in the hepatic microenvironment which is enriched with proinflammatory cytokines, chemokines and metabolites. In addition, the hepatic microenvironment has the unique ability to establish and maintain immune tolerance despite the continuous influx of the gut derived microbial products via the portal vein. Regulatory T cells play a crucial role in maintaining the hepatic tolerogenic state; however, the phenotypic stability, function and survival of Tregs in the inflamed liver microenvironment is still poorly understood. Despite this, Tregs immunotherapy remains as an appealing therapeutic option in autoimmune and immune mediated liver diseases. In order to advance cell therapy, it is important for us to further our understanding of the hepatic microenvironment, with the aim of developing ways to modify the hostile, inflamed environment to one which is more favourable. By doing so, T cell stability and function would be enhanced, resulting in improved clinical outcomes.
Collapse
Affiliation(s)
- Daniel Osei-Bordom
- Centre for Liver Research and NIHR BRC, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; European Reference Network Centre: Rare Liver, United Kingdom; Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, United Kingdom
| | - Amber G Bozward
- Centre for Liver Research and NIHR BRC, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; European Reference Network Centre: Rare Liver, United Kingdom
| | - Ye Htun Oo
- Centre for Liver Research and NIHR BRC, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; European Reference Network Centre: Rare Liver, United Kingdom; Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, United Kingdom.
| |
Collapse
|
|
49
|
Immunological distinctions between nonalcoholic steatohepatitis and hepatocellular carcinoma. Exp Mol Med 2020; 52:1209-1219. [PMID: 32770081 PMCID: PMC8080649 DOI: 10.1038/s12276-020-0480-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/09/2020] [Accepted: 06/16/2020] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, ranges from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is a more aggressive form characterized by hepatocyte injury, inflammation, and fibrosis. Increasing evidence suggests that NASH is a risk factor for hepatocellular carcinoma (HCC), which is the fifth most common cancer worldwide and the second most common cause of cancer-related death. Recent studies support a strong mechanistic link between the NASH microenvironment and HCC development. The liver has a large capacity to remove circulating pathogens and gut-derived microbial compounds. Thus, the liver is a central player in immunoregulation. Altered immune responses are tightly associated with the development of NASH and HCC. The objective of this study was to differentiate the roles of specific immune cell subsets in NASH and HCC pathogenesis. Clarifying the role of specific cells in the immune system in the transition from non-alcoholic fatty liver disease (NAFLD) to liver cancer will help to understand disease progression and may open avenues towards new preventive and therapeutic strategies. NAFLD is the most common chronic liver disease. Growing evidence suggests that its most aggressive form, non-alcoholic steatohepatitis (NASH), can promote the development of liver cancer, the second most common cause of cancer deaths worldwide. Chang-Woo Lee and colleagues at Sungkyunkwan University, Suwon, South Korea review the immunological distinction between NASH and liver cancer, focusing on the levels and activities of six key types of immune system cells. Chronic inflammation mediated by the immune system can create conditions for NAFLD, NASH and liver cancer to develop and worsen.
Collapse
|
|
50
|
Ortiz M, Soto-Alarcón SA, Orellana P, Espinosa A, Campos C, López-Arana S, Rincón MA, Illesca P, Valenzuela R, Videla LA. Suppression of high-fat diet-induced obesity-associated liver mitochondrial dysfunction by docosahexaenoic acid and hydroxytyrosol co-administration. Dig Liver Dis 2020; 52:895-904. [PMID: 32620521 DOI: 10.1016/j.dld.2020.04.019] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Obesity-induced by high-fat diet (HFD) is associated with liver steatosis, oxidative stress and mitochondrial dysfunction, which can be eluded by the co-administration of the lipid metabolism modulator docosahexaenoic acid (DHA) and the antioxidant hydroxytyrosol (HT). METHODS C57BL/6J mice fed a HFD were orally administered either with vehicle, DHA, HT or DHA+HT for 12 weeks. We measured parameters related to insulin resistance, serum lipid levels, liver fatty acid (FA) content and steatosis score, concomitantly with those associated with mitochondrial energy functions modulated by the transcriptional coactivator PGC-1a. RESULTS HFD induced insulin resistance, liver steatosis with n-3 FA depletion, and loss of mitochondrial respiratory functions with diminished NAD+/NADH ratio and ATP levels compared with CD, with the parallel decrease in the expression of the components of the PGC-1α cascade, namely, PPAR-α, FGF21 and AMPK, effects that were not observed in mice subjected to DHA and HT co-administration. CONCLUSIONS Data presented indicate that the combination of DHA and HT prevents the development of liver steatosis and the associated mitochondrial dysfunction induced by HFD, thus strengthening the significance of this protocol as a therapeutic strategy avoiding disease evolution into more irreversible forms characterised by the absence of adequate pharmacological therapy in human obesity.
Collapse
Affiliation(s)
- Macarena Ortiz
- Nutrition and Dietetics School, Faculty of Health Sciences, Catholic University of Maule, Curico, Chile
| | - Sandra A Soto-Alarcón
- Nutrition Department, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70000, Santiago, Chile
| | - Paula Orellana
- Nutrition Department, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70000, Santiago, Chile
| | - Alejandra Espinosa
- Department of Medical Technology, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Cristian Campos
- Department of Medical Technology, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Sandra López-Arana
- Nutrition Department, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70000, Santiago, Chile
| | - Miguel A Rincón
- Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile
| | - Paola Illesca
- Biochemistry Department, Faculty of Biochemistry, University of Litoral, Santa Fe, Argentina
| | - Rodrigo Valenzuela
- Nutrition Department, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70000, Santiago, Chile.
| | - Luis A Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Science, Faculty of Medicine, University of Chile, Santiago, Chile
| |
Collapse
|