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Wang X, Fang X, Zhou J, Pu H, Shang Q, Li J, Qin X, Zhao Q, Gu W. Hepatoprotective effects of wine-steamed Schisandra sphenanthera fruit in alleviating APAP-induced liver injury via the gut-liver axis. Food Funct 2025; 16:3643-3657. [PMID: 40243619 DOI: 10.1039/d5fo00656b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Drug-induced liver injury (DILI) is a common adverse drug reaction that can result in liver injury, particularly in cases of paracetamol (APAP) abuse. Schisandra sphenanthera Rehd. et Wils. has attracted attention due to its hepatoprotective properties, and the underlying mechanism is unclear. In this study, a mouse model of APAP-induced liver injury was employed to evaluate network pharmacology analysis, histopathological analysis, the gut microbiota, and fecal metabolome to investigate the mechanism by which S. sphenanthera fruit extract (SFE) alleviates DILI. Network pharmacology indicated that the SFE can attenuate APAP-induced liver injury via key targets, including MAPK3 and CASP3. Furthermore, SFE effectively alleviated APAP-induced oxidative stress (MDA, SOD, and GSH) and inflammation (IL-6, TNF-α, and IL-1β). Further analysis of gut microbiota and fecal metabolites revealed that SFE promoted the growth of Bacteroidales and Erysipelotrichales, and decreased the growth of Lactobacillales, leading to increased production of tryptophan metabolites. Correlation analysis showed that the increase in gut microbiota by SFE was positively correlated with improved antioxidant ability and improved liver and gut function. In conclusion, SFE pretreatment can alleviate APAP-induced liver injury by targeting the gut-liver axis, and provides a valuable reference for the clinical use of SFE in the prevention or treatment of DILI.
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Affiliation(s)
- Xiaorui Wang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Xilin Fang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Jia Zhou
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Han Pu
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Qianqian Shang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Jianhua Li
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Xiaolu Qin
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Qiaozhu Zhao
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
| | - Wei Gu
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China.
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Lin X, Xia L, Zhou Y, Xie J, Tuo Q, Lin L, Liao D. Crosstalk Between Bile Acids and Intestinal Epithelium: Multidimensional Roles of Farnesoid X Receptor and Takeda G Protein Receptor 5. Int J Mol Sci 2025; 26:4240. [PMID: 40362481 PMCID: PMC12072030 DOI: 10.3390/ijms26094240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders.
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Affiliation(s)
| | | | | | | | | | | | - Duanfang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; (X.L.); (L.X.); (Y.Z.); (J.X.); (Q.T.); (L.L.)
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Bayoude A, Zhang J, Shen Y, Tilyek A, Chai C. Ribes diacanthum Pall modulates bile acid homeostasis and oxidative stress in cholestatic mice by activating the SIRT1/FXR and Keap1/Nrf2 signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 342:119400. [PMID: 39864603 DOI: 10.1016/j.jep.2025.119400] [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: 12/22/2024] [Revised: 01/20/2025] [Accepted: 01/23/2025] [Indexed: 01/28/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cholestatic liver injury (CLI) is a pathophysiological syndrome characterized by the accumulation of bile acids (BAs), which leads to significant hepatic dysfunction. This condition is frequently associated with disturbances in BAs homeostasis and the induction of oxidative stress. Ribes diacanthum Pall (RDP), a conventional folk medicinal plant, has been employed in Mongolia, the Inner Mongolia region of China, and other areas for the remediation of hepatic disorders. However, the specific mechanism and chemical composition by which RDP exerts its effects remain unknown. AIM OF THE STUDY The aim of this research was to assess the protective impact of RDP on CLI and probe into the underlying mechanism and pinpoint the active constituents of RDP. MATERIALS AND METHODS For this study, a CLI mouse model induced via bile duct ligation (BDL) was used to investigate the hepatoprotective effect of RDP. Mice were administered low, medium, or high doses of RDP for 6 consecutive days, beginning 3 days prior to BDL induction. Subsequently, serum biochemical parameters, hepatic histopathology, and cholestatic markers were analyzed. An HPLC-QTOF-MS/MS analysis was also conducted to identify the prototype constituents in RDP. Furthermore, component-directed network pharmacology was utilized to identify the active constituents, central targets, and signaling cascades of RDP. Eventually, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were adopted to confirm the associated antioxidant enzymes, BAs transporters, and metabolic enzymes. Molecular docking was applied to forecast the binding affinity between the components and core targets. RESULTS RDP effectively ameliorated the pathological liver damage and cholestasis in BDL-induced CLI mice. Moreover, 43 components within RDP were identified through HPLC-QTOF-MS/MS analysis. Altogether 106 potential targets were detected, and the high-affinity targets, namely Keap1 and SIRT1, were located through the PPI network. The results of GO and KEGG analysis indicated that the reaction to oxidative stress and BAs homeostasis are significantly associated with the RDP treatment of CLI. In the in vivo experimental study, the findings revealed that RDP alleviated the BDL-induced oxidative damage. Simultaneously, RDP augmented the expressions of BAs efflux transporters and the metabolic enzymes in liver tissues, thus promoting BAs excretion and metabolism in cholestatic rodents. Mechanically, RDP attenuated hepatic oxidative stress and the accumulation of BAs, protecting the liver from BDL-induced cholestasis via the Keap1/Nrf2 and SIRT1/FXR signaling axis. The molecular docking result indicated that bolusanthol C and 3,6,3',4'-tetrahydroxyflavone possess a superior binding affinity to the two core targets (Keap1, SIRT1). CONCLUSION These results suggest that RDP ameliorate CLI by regulating BAs homeostasis and alleviating oxidative stress through the SIRT1/FXR and Keap1/Nrf2 signaling pathways, presenting a novel therapeutic strategy for cholestasis. Additionally, bolusanthol C and 3,6,3',4'-tetrahydroxyflavone may function as key pharmacological agents in RDP, responsible for its protective effects against CLI.
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Affiliation(s)
- Alamusi Bayoude
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
| | - Jiaxin Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
| | - Yuanjiang Shen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
| | - Akhtolkhyn Tilyek
- Department of Pharmaceutical Chemistry and Pharmacognosy, Mongolian University of Pharmaceutical Sciences, Ulaanbaatar, 18130, Mongolia
| | - Chengzhi Chai
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China.
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Li F, Han Q, Cai Y, Li Y, Yang Y, Li J, Wu R, Chen R, Liu R. Si-Ni-San ameliorates cholestatic liver injury by favoring P. goldsteinii colonization. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118804. [PMID: 39270883 DOI: 10.1016/j.jep.2024.118804] [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: 07/15/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Current treatment options for cholestatic liver diseases are limited, and addressing impaired intestinal barrier has emerged as a promising therapeutic approach. Si-Ni-San (SNS) is a Traditional Chinese Medicine (TCM) formula commonly utilized in the management of chronic liver diseases. Our previous studies have indicated that SNS effectively enhanced intestinal barrier function through the modulation of gut microbiota. AIM OF THE STUDY This study aims to verify the therapeutic effects of SNS on cholestatic liver injury, focusing on elucidating the underlying mechanism involving the gut-liver axis. MATERIALS AND METHODS The 16s RNA gene sequencing, non-targeted metabolomics were used to investigate the effects of SNS on the gut microbiota dysbiosis. Fecal microbiota transplantation (FMT) was conducted to identify potential beneficial probiotics underlying the therapeutic effects of SNS. RESULTS Our results demonstrated that SNS significantly ameliorated cholestatic liver injury induced by partial bile duct ligation (pBDL). Additionally, SNS effectively suppressed cholestasis-induced inflammation and barrier dysfunction in both the small intestine and colon. While SNS did not impact the intestinal FXR-FGF15-hepatic CYP7A1 axis, it notably improved gut microbiota dysbiosis and modulated the profile of microbial metabolites, including beneficial secondary bile acids and tryptophan derivatives. Furthermore, gut microbiota depletion experiments and FMT confirmed that the therapeutic benefits of SNS in cholestatic liver disease are dependent on gut microbiota modulation, particularly through the promotion of the growth of potential probiotic P. goldsteinii. Moreover, a synergistic improvement in cholestatic liver injury was observed with the co-administration of P. goldsteinii and SNS. CONCLUSION Our study underscores that SNS effectively alleviates cholestatic liver injury by addressing gut microbiota dysbiosis and enhancing intestinal barrier function, supporting its rational clinical utilization. Furthermore, we highlight P. goldsteinii as a promising probiotic candidate for the management of cholestatic liver diseases.
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Affiliation(s)
- Fanghong Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qi Han
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yajie Cai
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yufei Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yang Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jianan Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ruiyu Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ranyun Chen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Zhang W, Yin L, Wang H, Long C, Liu J, Deng P, Yue Y, Li J, He M, Lu Y, Luo Y, Chen S, Tao J, Tian L, Xie J, Chen M, Yu Z, Zhou Z, Gao P, Pi H. Multiomics analysis elucidated the role of inflammatory response and bile acid metabolism disturbance in electric shock-induced liver injury in mice. Chin J Traumatol 2025:S1008-1275(24)00182-2. [PMID: 39827045 DOI: 10.1016/j.cjtee.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 01/22/2025] Open
Abstract
PURPOSE Organ damage caused by electric shock has attracted great attention. Some animal investigations and clinical cases have suggested that electric shock can induce liver injury. This study aimed to investigate the potential mechanism of liver injury induced by electric shock. METHODS Healthy male C57BL/6J mice aged 6-8 weeks were romandly divided into two groups: control group and electric shock group. Mice in the electric shock group were shocked on the top of the skull with an electric baton (20 kV) for 5 sec, while mice in the control group were exposed to only the acoustic and light stimulation produced by the electric baton. The effect of electric shock on liver function was evaluated by histological and biochemical analysis, and a metabolomics and transcriptomics study was performed to investigate how electric shock might induce liver damage. All data of this study were analyzed using a two-tailed unpaired Student's t-test in SPSS 22.0 Statistical Package. RESULTS The electric shock group had significantly higher serum aspartate aminotransferase and alanine aminotransferase levels than the control group (p < 0.001), and the shock notably caused cytoplasmic swelling and vacuolization, mild inflammatory cell (mainly macrophages and monocytes) infiltration and acute focal necrosis in hepatocytes (p < 0.001). A total of 47 differential metabolites and 249 differentially expressed genes (DEGs) were detected using metabolomic and transcriptomic analyses. These differential metabolites were significantly enriched in primary bile acid biosynthesis (p < 0.05). Gene ontology functional analysis of the DEGs revealed that electric shock disturbed a key biological process involved in the inflammatory response in the mouse liver, and a significant number of DEGs were enriched in Kyoto Encyclopedia of Genes and Genomes-identified pathways related to inflammation, such as the interleukin-17, tumor necrosis factor and mitogen-activated protein kinase signalling pathway. Transcriptomic and metabolomic analyses revealed that bile acid metabolism disturbance including up-regulation of the taurochenodesoxycholic acid, chenodeoxycholic acid and taurocholic acid, and down-regulation of chenodeoxycholic acid clycine conjugate may contribute to the electric shock-induced inflammatory response. CONCLUSION Electric shock can induce liver inflammatory injury through the interleukin-17, tumor necrosis factor, and mitogen-activated protein kinase signaling pathway, and the bile acid metabolism disturbance including up-regulation of the taurochenodesoxycholic acid, chenodeoxycholic acid and taurocholic acid, and down-regulation of chenodeoxycholic acid clycine conjugate may contribute to inflammatory liver injury following electric shock.
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Affiliation(s)
- Wenjuan Zhang
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Luncai Yin
- Department of Oncology, Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, 402360, China
| | - Hui Wang
- Nuclear Medicine Department, General Hospital of Tibet Military Area Command, Lhasa, 850007, Xizang, China
| | - Ce Long
- General Hospital of Xizang Military Area Command, Lhasa, 850007, Xizang, China
| | - Jin Liu
- Cardiovascular Department, General Hospital of Xizang Military Area Command, Lhasa, 850007, Xizang, China
| | - Ping Deng
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Yang Yue
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Jingdian Li
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Mindi He
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Yonghui Lu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Yan Luo
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Siyu Chen
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Jiawen Tao
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Li Tian
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Jia Xie
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Mengyan Chen
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Zhengping Yu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Zhou Zhou
- Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Peng Gao
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China
| | - Huifeng Pi
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University, Chongqing, 400038, China; State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400038, China.
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Shen X, Zhang X, Li K, Huang G, Li X, Hou Y, Ge X. Combined bacterial translocation and cholestasis aggravates liver injury by activation pyroptosis in obstructive jaundice. Heliyon 2024; 10:e35793. [PMID: 39220957 PMCID: PMC11363856 DOI: 10.1016/j.heliyon.2024.e35793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 08/02/2024] [Accepted: 08/02/2024] [Indexed: 09/04/2024] Open
Abstract
This study explores the mechanism by which obstructive jaundice (OJ) induces liver damage through pyroptosis. We induced OJ in rats via bile duct ligation and assessed liver damage using serum biochemical markers and histological analysis of liver tissue. Pyroptosis was investigated through immunofluorescence, ELISA, Western blot, and quantitative RT-PCR techniques. Additionally, we examined intestinal function and fecal microbiota alterations in the rats using 16S rDNA sequencing. In vitro experiments involved co-culturing Kupffer cells and hepatocytes, which were then exposed to bile and lipopolysaccharide (LPS). Our findings indicated that OJ modified the gut microbiota, increasing LPS levels, which, in conjunction with bile, initiated a cycle of inflammation, fibrosis, and cell death in the liver. Mechanistically, OJ elevated necrotic markers such as ATP, which in turn activated pyroptotic pathways. Increased levels of pyroptosis-related molecules, including NLRP3, caspase-1, gasdermin D, and IL-18, were confirmed. In our co-cultured cell model, bile exposure resulted in cell death and ATP release, leading to the activation of the NLRP3 inflammasome and its downstream effectors, caspase-1 and IL-18. The combination of bile and LPS significantly intensified pyroptotic responses. This study is the first to demonstrate that LPS and bile synergistically exacerbate liver injury by promoting necrosis and pyroptosis, unveiling a novel mechanism of OJ-associated hepatic damage and suggesting avenues for potential preventive or therapeutic interventions.
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Affiliation(s)
- Xin Shen
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xin Zhang
- Luoyang Orthopedic-Traumatological Hospital of Henan Province (Henan Provincial Orthopedic Hospital), Luoyang, 471002, Henan, China
| | - Kaiyu Li
- Department of General Surgery, Heilongjiang Provincial Hospital, 82 Zhongshan Road, Harbin, 150036, Heilongjiang, China
| | - Guangming Huang
- Department of General Surgery, Heilongjiang Provincial Hospital, 82 Zhongshan Road, Harbin, 150036, Heilongjiang, China
| | - Xinyu Li
- Department of General Surgery, Heilongjiang Provincial Hospital, 82 Zhongshan Road, Harbin, 150036, Heilongjiang, China
| | - Yunlong Hou
- National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Shijiazhuang, 050000, Hebei, China
| | - Xin Ge
- Department of General Surgery, Heilongjiang Provincial Hospital, 82 Zhongshan Road, Harbin, 150036, Heilongjiang, China
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Zhu Y, Yu M, Aisikaer M, Zhang C, He Y, Chen Z, Yang Y, Han R, Li Z, Zhang F, Ding J, Lu X. Contriving a novel of CHB therapeutic vaccine based on IgV_CTLA-4 and L protein via immunoinformatics approach. J Biomol Struct Dyn 2024; 42:6323-6341. [PMID: 37424209 DOI: 10.1080/07391102.2023.2234043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 07/01/2023] [Indexed: 07/11/2023]
Abstract
Chronic infection induced by immune tolerance to hepatitis B virus (HBV) is one of the most common causes of hepatic cirrhosis and hepatoma. Fortunately, the application of therapeutic vaccine can not only reverse HBV-tolerance, but also serve a potentially effective therapeutic strategy for treating chronic hepatitis B (CHB). However, the clinical effect of the currently developed CHB therapeutic vaccine is not optimistic due to the weak immunogenicity. Given that the human leukocyte antigen CTLA-4 owns strong binding ability to the surface B7 molecules (CD80 and CD86) of antigen presenting cell (APCs), the immunoglobulin variable region of CTLA-4 (IgV_CTLA-4) was fused with the L protein of HBV to contrive a novel therapeutic vaccine (V_C4HBL) for CHB in this study. We found that the addition of IgV_CTLA-4 did not interfere with the formation of L protein T cell and B cell epitopes after analysis by means of immunoinformatics approaches. Meanwhile, we also found that the IgV_CTLA-4 had strong binding force to B7 molecules through molecular docking and molecular dynamics (MD) simulation. Notably, our vaccine V_C4HBL showed good immunogenicity and antigenicity by in vitro and in vivo experiments. Therefore, the V_C4HBL is promising to again effectively activate the cellular and humoral immunity of CHB patients, and provides a potentially effective therapeutic strategy for the treatment of CHB in the future.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Yuejie Zhu
- Reproductive Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Infectious Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Mingkai Yu
- Department of Immunology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
- Xinjiang Key Molecular Biology Laboratory of Endemic Disease, Xinjiang Medical University, Urumqi, China
| | - Maierhaba Aisikaer
- Department of Immunology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
- Xinjiang Key Molecular Biology Laboratory of Endemic Disease, Xinjiang Medical University, Urumqi, China
| | - Chuntao Zhang
- Department of Microbiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - Yueyue He
- Department of Immunology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
- Xinjiang Key Molecular Biology Laboratory of Endemic Disease, Xinjiang Medical University, Urumqi, China
| | - Zhiqiang Chen
- Department of Immunology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
- Xinjiang Key Molecular Biology Laboratory of Endemic Disease, Xinjiang Medical University, Urumqi, China
| | - Yinyin Yang
- Xinjiang Key Molecular Biology Laboratory of Endemic Disease, Xinjiang Medical University, Urumqi, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - Rui Han
- Reproductive Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Zhiwei Li
- Clinical Laboratory Center, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, China
| | - Fengbo Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jianbing Ding
- Department of Immunology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
- Xinjiang Key Molecular Biology Laboratory of Endemic Disease, Xinjiang Medical University, Urumqi, China
| | - Xiaobo Lu
- Infectious Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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de Boer RJ, van Lidth de Jeude JF, Heijmans J. ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis. Cancer Lett 2024; 587:216678. [PMID: 38360143 DOI: 10.1016/j.canlet.2024.216678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/17/2024]
Abstract
Endoplasmic reticulum (ER) stress and the adaptive response that follows, termed the unfolded protein response (UPR), are crucial molecular mechanisms to maintain cellular integrity by safeguarding proper protein synthesis. Next to being important in protein homeostasis, the UPR is intricate in cell fate decisions such as proliferation, differentiation, and stemness. In the intestine, stem cells are critical in governing epithelial homeostasis and they are the cell of origin of gastrointestinal malignancies. In this review, we will discuss the role of ER stress and the UPR in the gastrointestinal tract, focusing on stem cells and carcinogenesis. Insights in mechanisms that connect ER stress and UPR with stemness and carcinogenesis may broaden our understanding in the development of cancer throughout the gastrointestinal tract and how we can exploit these mechanisms to target these malignancies.
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Affiliation(s)
- Ruben J de Boer
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 69-71, Amsterdam, The Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Jooske F van Lidth de Jeude
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 69-71, Amsterdam, The Netherlands
| | - Jarom Heijmans
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 69-71, Amsterdam, The Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands; Amsterdam UMC, University of Amsterdam, Department of General Internal Medicine and Department of Hematology, Meibergdreef 9, Amsterdam, The Netherlands.
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Chen W, Lin F, Feng X, Yao Q, Yu Y, Gao F, Zhou J, Pan Q, Wu J, Yang J, Yu J, Cao H, Li L. MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation. Asian J Pharm Sci 2024; 19:100889. [PMID: 38419761 PMCID: PMC10900800 DOI: 10.1016/j.ajps.2024.100889] [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: 07/13/2023] [Revised: 12/13/2023] [Accepted: 01/14/2024] [Indexed: 03/02/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis, with no curative treatment available, and liver transplantation is inevitable for end-stage patients. Human placental mesenchymal stem cell (hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis, inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease. Here, we prepared hpMSC-derived exosomes (ExoMSC) and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2-/- mice and multicellular organoids established from PSC patients. The results showed that ExoMSC ameliorated liver fibrosis in Mdr2-/- mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis, and the percentage of CD4+IL-17A+T cells was reduced both in ExoMSC-treated Mdr2-/- mice (Mdr2-/--Exo) in vivo and ExoMSC-treated Th17 differentiation progressed in vitro. Furthermore, ExoMSC improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids. Thus, our data demonstrate the anti-fibrosis effect of ExoMSC in PSC disease by inhibiting Th17 differentiation, and ameliorating the Th17-induced microenvironment, indicating the promising potential therapeutic role of ExoMSC in liver fibrosis of PSC or Th17-related diseases.
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Affiliation(s)
- Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feiyan Lin
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xudong Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yingduo Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiahang Zhou
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiaoling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jinfeng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
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10
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Wang Y, Zhao D, Su L, Tai YL, Way GW, Zeng J, Yan Q, Xu Y, Wang X, Gurley EC, Zhou XQ, Liu J, Liu J, Chen W, Hylemon PB, Zhou H. Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model. Cell Biosci 2024; 14:14. [PMID: 38273376 PMCID: PMC10809567 DOI: 10.1186/s13578-024-01195-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/09/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2-/- mice) and elucidate the underlying mechanisms. METHODS Mdr2-/-mice (12-14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC-MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing. RESULTS BBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota. CONCLUSION BBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.
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Affiliation(s)
- Yanyan Wang
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Derrick Zhao
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Lianyong Su
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Yun-Ling Tai
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Grayson W Way
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Jing Zeng
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Qianhua Yan
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Xu
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Xuan Wang
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Emily C Gurley
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Xi-Qiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinze Liu
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA
| | - Jinpeng Liu
- Department of Computer Science, University of Kentucky, Lexington, KY, USA
| | - Weidong Chen
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA.
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Wu L, Zhou J, Zhou A, Lei Y, Tang L, Hu S, Wang S, Xiao X, Chen Q, Tu D, Lu C, Lai Y, Li Y, Zhang X, Tang B, Yang S. Lactobacillus acidophilus ameliorates cholestatic liver injury through inhibiting bile acid synthesis and promoting bile acid excretion. Gut Microbes 2024; 16:2390176. [PMID: 39205654 PMCID: PMC11364073 DOI: 10.1080/19490976.2024.2390176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 06/13/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Gut microbiota dysbiosis is involved in cholestatic liver diseases. However, the mechanisms remain to be elucidated. The purpose of this study was to examine the effects and mechanisms of Lactobacillus acidophilus (L. acidophilus) on cholestatic liver injury in both animals and humans. Bile duct ligation (BDL) was performed to mimic cholestatic liver injury in mice and serum liver function was tested. Gut microbiota were analyzed by 16S rRNA sequencing. Fecal bacteria transplantation (FMT) was used to evaluate the role of gut microbiota in cholestasis. Bile acids (BAs) profiles were analyzed by targeted metabolomics. Effects of L. acidophilus in cholestatic patients were evaluated by a randomized controlled clinical trial (NO: ChiCTR2200063330). BDL induced different severity of liver injury, which was associated with gut microbiota. 16S rRNA sequencing of feces confirmed the gut flora differences between groups, of which L. acidophilus was the most distinguished genus. Administration of L. acidophilus after BDL significantly attenuated hepatic injury in mice, decreased liver total BAs and increased fecal total BAs. Furthermore, after L. acidophilus treatment, inhibition of hepatic Cholesterol 7α-hydroxylase (CYP7α1), restored ileum Fibroblast growth factor 15 (FGF15) and Small heterodimer partner (SHP) accounted for BAs synthesis decrease, whereas enhanced BAs excretion was attributed to the increase of unconjugated BAs by enriched bile salt hydrolase (BSH) enzymes in feces. Similarly, in cholestasis patients, supplementation of L. acidophilus promoted the recovery of liver function and negatively correlated with liver function indicators, possibly in relationship with the changes in BAs profiles and gut microbiota composition. L. acidophilus treatment ameliorates cholestatic liver injury through inhibited hepatic BAs synthesis and enhances fecal BAs excretion.
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Affiliation(s)
- Lingyi Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jianchun Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - An Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yuanyuan Lei
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Li Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiping Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Xu Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiao Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Dianji Tu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Cheng Lu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yi Lai
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yiding Li
- Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Tibet, China
| | - Xiao Zhang
- Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Tibet, China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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12
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Zhang L, Zheng Z, Huang H, Fu Y, Chen T, Liu C, Yi Q, Lin C, Zeng Y, Ou Q, Zeng Y. Multi-omics reveals deoxycholic acid modulates bile acid metabolism via the gut microbiota to antagonize carbon tetrachloride-induced chronic liver injury. Gut Microbes 2024; 16:2323236. [PMID: 38416424 PMCID: PMC10903553 DOI: 10.1080/19490976.2024.2323236] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/21/2024] [Indexed: 02/29/2024] Open
Abstract
Deoxycholic acid (DCA) serves essential functions in both physiological and pathological liver processes; nevertheless, the relationship among DCA, gut microbiota, and metabolism in chronic liver injury remain insufficiently understood. The primary objective of this study is to elucidate the potential of DCA in ameliorating chronic liver injury and evaluate its regulatory effect on gut microbiota and metabolism via a comprehensive multi-omics approach. Our study found that DCA supplementation caused significant changes in the composition of gut microbiota, which were essential for its antagonistic effect against CCl4-induced chronic liver injury. When gut microbiota was depleted with antibiotics, the observed protective efficacy of DCA against chronic liver injury became noticeably attenuated. Mechanistically, we discovered that DCA regulates the metabolism of bile acids (BAs), including 3-epi DCA, Apo-CA, and its isomers 12-KLCA and 7-KLCA, IHDCA, and DCA, by promoting the growth of A.muciniphila in gut microbiota. This might lead to the inhibition of the IL-17 and TNF inflammatory signaling pathway, thereby effectively countering CCl4-induced chronic liver injury. This study illustrates that the enrichment of A. muciniphila in the gut microbiota, mediated by DCA, enhances the production of secondary bile acids, thereby mitigating chronic liver injury induced by CCl4. The underlying mechanism may involve the inhibition of hepatic IL-17 and TNF signaling pathways. These findings propose a promising approach to alleviate chronic liver injury by modulating both the gut microbiota and bile acids metabolism.
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Affiliation(s)
- Li Zhang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zhiyi Zheng
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Huanhuan Huang
- Department of Pediatrics, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ya Fu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Tianbin Chen
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Can Liu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qiang Yi
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Caorui Lin
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yongjun Zeng
- Department of Cardiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qishui Ou
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yongbin Zeng
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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13
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Li XJY, Zhou F, Li YJ, Xue XY, Qu JR, Fan GF, Liu J, Sun R, Wu JZ, Zheng Q, Liu RP. LncRNA H19-EZH2 interaction promotes liver fibrosis via reprogramming H3K27me3 profiles. Acta Pharmacol Sin 2023; 44:2479-2491. [PMID: 37580495 PMCID: PMC10692088 DOI: 10.1038/s41401-023-01145-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/25/2023] [Indexed: 08/16/2023]
Abstract
Liver fibrosis is a wound-healing process characterized by excess formation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). Previous studies show that both EZH2, an epigenetic regulator that catalyzes lysine 27 trimethylation on histone 3 (H3K27me3), and long non-coding RNA H19 are highly correlated with fibrogenesis. In the current study, we investigated the underlying mechanisms. Various models of liver fibrosis including Mdr2-/-, bile duct ligation (BDL) and CCl4 mice were adapted. We found that EZH2 was markedly upregulated and correlated with H19 and fibrotic markers expression in these models. Administration of EZH2 inhibitor 3-DZNeP caused significant protective effects in these models. Furthermore, treatment with 3-DZNeP or GSK126 significantly inhibited primary HSC activation and proliferation in TGF-β-treated HSCs and H19-overexpreesing LX2 cells in vivo. Using RNA-pull down assay combined with RNA immunoprecipitation, we demonstrated that H19 could directly bind to EZH2. Integrated analysis of RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) further revealed that H19 regulated the reprogramming of EZH2-mediated H3K27me3 profiles, which epigenetically promoted several pathways favoring HSCs activation and proliferation, including epithelial-mesenchymal transition and Wnt/β-catenin signaling. In conclusion, highly expressed H19 in chronic liver diseases promotes fibrogenesis by reprogramming EZH2-mediated epigenetic regulation of HSCs activation. Targeting the H19-EZH2 interaction may serve as a novel therapeutic approach for liver fibrosis.
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Affiliation(s)
- Xiao-Jiao-Yang Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Fei Zhou
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ya-Jing Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiao-Yong Xue
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jiao-Rong Qu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Gui-Fang Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jia Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Rong Sun
- The Second Hospital of Shandong University, Ji-nan, 250033, China
| | - Jian-Zhi Wu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qi Zheng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Run-Ping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
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14
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Li Z, Dong H, Bian S, Wu H, Song W, Jia X, Chen J, Zhu X, Zhao L, Xuan Z, Jin C, Zhou M, Zheng S, Song P. FXR Maintains the Intestinal Barrier and Stemness by Regulating CYP11A1-Mediated Corticosterone Synthesis in Biliary Obstruction Diseases. Int J Mol Sci 2023; 24:13494. [PMID: 37686300 PMCID: PMC10487515 DOI: 10.3390/ijms241713494] [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: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
Biliary obstruction diseases are often complicated by an impaired intestinal barrier, which aggravates liver injury. Treatment of the intestinal barrier is often neglected. To investigate the mechanism by which intestinal bile acid deficiency mediates intestinal barrier dysfunction after biliary obstruction and identify a potential therapeutic modality, we mainly used a bile duct ligation (BDL) mouse model to simulate biliary obstruction and determine the important role of the bile acid receptor FXR in maintaining intestinal barrier function and stemness. Through RNA-seq analysis of BDL and sham mouse crypts and qRT-PCR performed on intestinal epithelial-specific Fxr knockout (FxrΔIEC) and wild-type mouse crypts, we found that FXR might maintain intestinal stemness by regulating CYP11A1 expression. Given the key role of CYP11A1 during glucocorticoid production, we also found that FXR activation could promote intestinal corticosterone (CORT) synthesis by ELISA. Intestinal organoid culture showed that an FXR agonist or corticosterone increased crypt formation and organoid growth. Further animal experiments showed that corticosterone gavage treatment could maintain intestinal barrier function and stemness, decrease LPS translocation, and attenuate liver injury in BDL mice. Our study hopefully provides a new theoretical basis for the prevention of intestinal complications and alleviation of liver injury after biliary obstruction.
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Affiliation(s)
- Zequn Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Haijiang Dong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Suchen Bian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Hao Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Wenfeng Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Xing Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Jian Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Xingxin Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Long Zhao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Zefeng Xuan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Cheng Jin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Mengqiao Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Penghong Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (Z.L.)
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
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Chen X, Yu Z, Nong C, Xue R, Zhang M, Zhang Y, Sun L, Zhang L, Wang X. Activation of cDCs and iNKT cells contributes to triptolide-induced hepatotoxicity via STING signaling pathway and endoplasmic reticulum stress. Cell Biol Toxicol 2023; 39:1753-1772. [PMID: 36520315 DOI: 10.1007/s10565-022-09782-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 11/11/2022] [Indexed: 12/23/2022]
Abstract
Triptolide (TP) exhibits therapeutic potential against multiple diseases. However, its application in clinics is limited by TP-induced hepatoxicity. TP can activate invariant natural killer T (iNKT) cells in the liver, shifting Th1 cytokine bias to Th2 cytokine bias. The damaging role of iNKT cells in TP-induced hepatoxicity has been established, and iNKT cell deficiency can mitigate hepatotoxicity. However, the activation of iNKT cells in vitro by TP requires the presence of antigen-presenting cells. Therefore, we hypothesized that TP could induce dendritic cells (DCs) to activate iNKT cells, thereby leading to hepatotoxicity. The hepatic conventional DCs (cDCs) exhibited immunogenic activities after TP administration, upregulating the expression of CD1d, co-stimulatory molecules, and IL-12. Neutralization with IL-12p40 antibody extenuated TP-induced hepatotoxicity and reduced iNKT cell activation, suggesting that IL-12 could cause liver injury by activating iNKT cells. TP triggered the activation and upregulation of STING signaling pathway and increased endoplasmic reticulum (ER) stress. Downregulation of STING reduced cDC immunogenicity, inhibiting the activation of iNKT cells and hepatic damage. These indicated the regulatory effects of STING pathway on cDCs and iNKT cells, and the important roles it plays in hepatoxicity. ER stress inhibitor, 4-phenylbutyrate (4-PBA), also suppressed iNKT cell activation and liver injury, which might be regulated by the STING signaling pathway. Our results demonstrated the possible mechanisms underlying TP-induced hepatoxicity, where the activation of cDCs and iNKT cells was stimulated by upregulated STING signaling and increased ER stress as a result of TP administration.
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Affiliation(s)
- Xin Chen
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Zixun Yu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Cheng Nong
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Rufeng Xue
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Mingxuan Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Yiying Zhang
- Division of Biosciences, University College London, London, WC1E 6BT, UK
| | - Lixin Sun
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Xinzhi Wang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
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16
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Xiang D, Liu Y, Zu Y, Yang J, He W, Zhang C, Liu D. Calculus Bovis Sativus alleviates estrogen cholestasis-induced gut and liver injury in rats by regulating inflammation, oxidative stress, apoptosis, and bile acid profiles. JOURNAL OF ETHNOPHARMACOLOGY 2023; 302:115854. [PMID: 36273746 DOI: 10.1016/j.jep.2022.115854] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 10/08/2022] [Accepted: 10/18/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Natural Calculus Bovis (NCB) is a traditional Chinese medicine used for anti-inflammation, treating fever, pain, sedation, and recovering hepatobiliary function. Calculus Bovis Sativus (CBS), produced from in vitro artificial cultivation by bioengineering techniques, acts as an ideal substitute for NCB when treating various diseases. AIM OF THE STUDY Gut-liver injury is an important pathological feature of several cholestatic liver diseases, including estrogen-induced cholestasis (EIC). The strong link between cholestatic liver injury and intestinal damage emphasizes the need of considering gut-liver integrity during treatment. The purpose of this study is to look into the pharmacological activities of CBS on EIC-induced gut and liver damage. MATERIALS AND METHODS EIC-induced cholestatic rats were given oral gavage daily for five days with or without CBS (150 mg/kg). The liver/body weight, serum biochemistry, and tissue histopathology were then evaluated. Quantitative real-time PCR, Western blot analyses, and immunofluorescence were used to determine the gene expression associated with pathological alterations of the liver and intestine in EIC-induced cholestatic rats. Bile acid profiles within enterohepatic circulation were detected by liquid chromatography-mass spectrometry. RESULTS CBS significantly reduced relative liver weight, restored serum biochemistry levels, and improved the hepatic and intestinal pathological damage in EIC model rats. CBS reduced EIC-induced hepatic inflammation by inactivation of the NF-κB signaling and inhibition of TNFα, IL-1β, and IL-6 expression. CBS alleviated EIC-induced hepatic and intestinal oxidative stress by regulating Nrf2-GCLM/GCLC and Nrf2-HO-1 pathways, respectively. CBS treatment upregulated Bcl-2 and downregulated Bax and cleaved caspase3 to improve EIC-induced hepatic and intestinal cell apoptosis. Additionally, CBS reversed the disorders of bile acid profiles in the enterohepatic circulation by reducing bile acid accumulation in the liver and plasma and increasing bile excretion and intestinal reabsorption of bile acids. CONCLUSION CBS alleviates EIC-induced hepatic and intestinal injury through regulating inflammation, oxidative stress, apoptosis, and bile acid profiles. These results suggest that CBS or drugs targeting the gut-liver axis may be effective therapeutic agents for cholestasis.
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Affiliation(s)
- Dong Xiang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanan Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430030, China
| | - Yue Zu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jinyu Yang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wenxi He
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chengliang Zhang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Lv M, Zhang Y, Yang L, Cao X. Depletion of chop suppresses procedural apoptosis and enhances innate immunity in loach Misgurnus anguillicaudatus under ammonia nitrogen stress. J Anim Sci 2023; 101:skad114. [PMID: 37102217 PMCID: PMC10184690 DOI: 10.1093/jas/skad114] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/26/2023] [Indexed: 04/28/2023] Open
Abstract
Ammonia nitrogen is highly toxic to fish, and it can easily cause fish poisoning or even high mortality. So far, many studies have been conducted on the damages to fish under ammonia nitrogen stress. However, there are few studies of ammonia tolerance improvement in fish. In this study, the effects of ammonia nitrogen exposure on apoptosis, endoplasmic reticulum (ER) stress, and immune cells in loach Misgurnus anguillicaudatus were investigated. Loaches (60 d post fertilization) were exposed to different concentrations of NH4Cl, and their survival rates were examined every 6 h. The results showed that high-concentration and long-time NH4Cl exposure (20 mM + 18 h; 15 mM + 36 h) induced apoptosis and gill tissue damages, finally causing a decline in survival. chop plays an important role in ER stress-induced apoptosis, and thus we constructed a model of chop-depleted loach by using CRISPR/Cas9 technology to investigate its response to ammonia nitrogen stress. The results showed that ammonia nitrogen stress down-regulated the expressions of apoptosis-related genes in chop+/- loach gills, while wildtype (WT) exhibited an opposite gene expression regulation pattern, suggesting that the depletion of chop suppressed apoptosis level. In addition, chop+/- loach showed a larger number of immunity-related cells and higher survival rate than WT under the NH4Cl exposure, indicating that the inhibition of chop function strengthened the innate immune barrier in general, thus increasing survival. Our findings provide the theoretical basis for developing high ammonia nitrogen-tolerant germplasm with aquaculture potential.
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Affiliation(s)
- Meiqi Lv
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
| | - Yunbang Zhang
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
| | - Lijuan Yang
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiaojuan Cao
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- College of Fisheries, Engineering Research Center of Green development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education/Hubei Provincial Engineering Laboratory for Pond Aquaculture, Huazhong Agricultural University, Wuhan 430070, China
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Zhou S, Rao Z, Xia Y, Wang Q, Liu Z, Wang P, Cheng F, Zhou H. CCAAT/Enhancer-binding Protein Homologous Protein Promotes ROS-mediated Liver Ischemia and Reperfusion Injury by Inhibiting Mitophagy in Hepatocytes. Transplantation 2023; 107:129-139. [PMID: 35821597 PMCID: PMC9746334 DOI: 10.1097/tp.0000000000004244] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/28/2022] [Accepted: 05/19/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver ischemia and reperfusion (IR) injury represent a major risk factor in both partial hepatectomy and liver transplantation. CCAAT/enhancer-binding protein homologous protein (CHOP) is a key regulator of cell death, its precise molecular basis in regulating hepatocyte death during liver IR has not been delineated. METHODS Hepatocellular CHOP deficient mice were generated by bone marrow chimera models using global CHOP knockout mice. Liver partial warm ischemia model and hypoxia/reoxygenation model of primary hepatocytes were applied. Liver injury and mitophagy-related signaling pathways were investigated. IR-stressed patient liver tissues and serum samples were analyzed as well. RESULTS Mice with hepatocellular CHOP deficiency exhibited alleviated cell death, decreased reactive oxygen species (ROS) expression, and enhanced mitophagy in hepatocytes after IR, confirmed by in vitro studies of hepatocytes after hypoxia/reoxygenation. Mitochondria ROS scavenge by Mito TEMPO effectively attenuated hepatocyte death and liver IR injury of wild-type mice, whereas no significant effects were observed in hepatocellular CHOP -deficient mice. CHOP depletion upregulated dynamin-related protein 1 and Beclin-1 activation in the mitochondria of hepatocytes leading to enhanced mitophagy. Following IR, increased CHOP expression and impaired mitophagy activation were observed in the livers of patients undergoing hepatectomy. N-acetyl cysteine pretreatment significantly improved the liver function of patients after surgery. CONCLUSIONS IR-induced CHOP activation exacerbates ROS-mediated hepatocyte death by inhibiting dynamin-related protein 1-Beclin-1-dependent mitophagy.
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Affiliation(s)
- Shun Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Zhuqing Rao
- Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yongxiang Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- School of Medical, Southeast University, Nanjing, China
| | - Zheng Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Ping Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Feng Cheng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
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19
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Barmoudeh Z, Sadeghi H, Gheitasi I, Khalvati B, Omidifar N, Azizi M, Moslemi Z, Nikbakht J, Doustimotlagh AH. Fluvoxamine ameliorates oxidative stress and inflammation induced by bile-duct ligation in male rats. Heliyon 2022; 8:e12344. [PMID: 36590477 PMCID: PMC9800296 DOI: 10.1016/j.heliyon.2022.e12344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 06/14/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Cholestasis is a disorder that the bile ducts were narrowed and bile acids are not released simply. Bile acids-induced liver damage is exacerbated by inflammation and oxidative stress. The goal of the current study was to investigate the protective impacts of fluvoxamine (Flu) on oxidant-antioxidant balance and inflammatory cytokines in the bile duct ligated (BDL) rats. Methods Thirty-two male rats were arbitrarily allocated in 4 groups; sham-control (SC), SC+ 150 mg/kg Flu (SCF), bile duct ligation (BDL), and BDL+ 150 mg/kg Flu (BDLF). The rats received distilled water and Flu orally for one week. Biochemical analysis, hematoxylin and eosin staining, as well as oxidant/antioxidant status were evaluated. Also, the mRNA expression of TGF-β1, IL-1, TNF-α, and α-SMA were determined. Results The findings indicated serum values of ALT, total bilirubin, and ALP slightly declined in the BDL + Flu group in contrast to BDL rats. The plasma protein carbonyl and inflammatory markers were markedly increased in the BDL group in contrast with SC group (P ≤ 0.05). Treatment with Flu in BDL rats markedly reduced the values of hepatic nitric oxide metabolite and malondialdehyde, plasma protein carbonyl, as well as TNF-α mRNA level (P ≤ 0.05). Histological parameters were improved in the BDL + Flu group in comparison to BDL merely rats. Conclusion It seems that Flu declined oxidative stress probably by inhibiting lipid peroxidation, protein oxidation, and nitric oxide formation. Also, it reduced inflammation by decreasing TNF-α mRNA expression.
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Affiliation(s)
- Zahra Barmoudeh
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hossein Sadeghi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Izadpanah Gheitasi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Bahman Khalvati
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Navid Omidifar
- Biotechnology Research Center, Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdokht Azizi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Zahra Moslemi
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Jafar Nikbakht
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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Wang L, Feng J, Deng Y, Yang Q, Wei Q, Ye D, Rong X, Guo J. CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding. RESEARCH (WASHINGTON, D.C.) 2022; 2022:9891689. [PMID: 36299447 PMCID: PMC9575473 DOI: 10.34133/2022/9891689] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/18/2022] [Indexed: 07/29/2023]
Abstract
CCAAT/enhancer-binding proteins (C/EBPs) are a family of at least six identified transcription factors that contain a highly conserved basic leucine zipper domain and interact selectively with duplex DNA to regulate target gene expression. C/EBPs play important roles in various physiological processes, and their abnormal function can lead to various diseases. Recently, accumulating evidence has demonstrated that aberrant C/EBP expression or activity is closely associated with the onset and progression of fibrosis in several organs and tissues. During fibrosis, various C/EBPs can exert distinct functions in the same organ, while the same C/EBP can exert distinct functions in different organs. Modulating C/EBP expression or activity could regulate various molecular processes to alleviate fibrosis in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention. In this review, we will explore the features of C/EBPs and their critical functions in fibrosis in order to highlight new avenues for the development of novel therapies targeting C/EBPs.
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Affiliation(s)
- Lexun Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiaojiao Feng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanyue Deng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qianqian Yang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Quxing Wei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dewei Ye
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xianglu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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21
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Zhou J, Lu Y, Jia Y, Lu J, Jiang Z, Chen K. Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1. Mol Med 2022; 28:1. [PMID: 34979900 PMCID: PMC8722053 DOI: 10.1186/s10020-021-00429-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
Abstract
Background Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulating T2DM related lipid metabolism and the effect of ketogenic diet (KD) on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of KD on diabetic mice and its mediated mechanism. Methods Male C57BL/6J and KKAy mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo was applied. Results Hepatic PES1 expression in diabetic mice was markedly increased, which was suppressed by KD feeding with an accompanying reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, Caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar outcomes were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which were, however reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and Caspase1 promoters. The inhibition of p300 and Caspase1 expression elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of Caspase1 also alleviated the TG levels in cultured hepatocytes. Conclusion KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00429-6.
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Affiliation(s)
- Jielin Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yao Lu
- Department of Anesthesiology, The First Affiliated Hospital, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yajing Jia
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jing Lu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Zhengxuan Jiang
- Department of Ophthalmology, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230021, Anhui, China.
| | - Keyang Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China. .,Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China.
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22
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Zhou Y, Jin Y, Wang Y, Wu R. Hypoxia activates the unfolded protein response signaling network: An adaptive mechanism for endometriosis. Front Endocrinol (Lausanne) 2022; 13:945578. [PMID: 36339404 PMCID: PMC9630844 DOI: 10.3389/fendo.2022.945578] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 10/05/2022] [Indexed: 11/22/2022] Open
Abstract
Endometriosis (EMS) is a chronic gynecological disease that affects women of childbearing age. However, the exact cause remains unclear. The uterus is a highly vascularized organ that continuously exposes endometrial cells to high oxygen concentrations. According to the "planting theory" of EMS pathogenesis, when endometrial cells fall from the uterine cavity and retrograde to the peritoneal cavity, they will face severe hypoxic stress. Hypoxic stress remains a key issue even if successfully implanted into the ovaries or peritoneum. In recent years, increasing evidence has confirmed that hypoxia is closely related to the occurrence and development of EMS. Hypoxia-inducible factor-1α (HIF-1α) can play an essential role in the pathological process of EMS by regulating carbohydrate metabolism, angiogenesis, and energy conversion of ectopic endometrial cells. However, HIF-1α alone is insufficient to achieve the complete program of adaptive changes required for cell survival under hypoxic stress, while the unfolded protein response (UPR) responding to endoplasmic reticulum stress plays an essential supplementary role in promoting cell survival. The formation of a complex signal regulation network by hypoxia-driven UPR may be the cytoprotective adaptation mechanism of ectopic endometrial cells in unfavorable microenvironments.
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Ding K, Li X, Ren X, Ding N, Tao L, Dong X, Chen Z. GBP5 promotes liver injury and inflammation by inducing hepatocyte apoptosis. FASEB J 2021; 36:e22119. [PMID: 34958688 DOI: 10.1096/fj.202101448r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/02/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022]
Abstract
Liver injury is the first step in causing fibrosis, cirrhosis, and liver cancer, leading to mortality. However, the drivers of progressive liver injury are still incompletely defined. Here, we identify GBP5 as a major factor causing liver injury and inflammation. We show that the expression of GBP5 is abnormally elevated in the damaged liver, and its expression depends at least partially on the NF-κB-inducing kinase (NIK)/NF-κB2 signaling pathway. Knockout of Gbp5 ameliorates D-galactosamine/lipopolysaccharide (GalN/LPS)-induced liver injury and inflammation. Conversely, liver-specific overexpression of GBP5 induces liver injury and inflammation. Mechanistically, GBP5 induces hepatocyte apoptosis through the activation of both calpain/caspase 12/caspase 3 and TNFα/caspase 8/caspase 3 signaling pathways. Inhibition of either calpain activity or caspase 3 prevents GBP5-induced cell death. Our data demonstrate that GBP5 expression is induced by toxins or the NIK signaling pathway, which promotes both extrinsic and intrinsic apoptosis signaling pathways and further induces liver injury, providing a novel drug target for the treatment of liver injury and inflammation.
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Affiliation(s)
- Kaixin Ding
- HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xinzhi Li
- HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xiaomeng Ren
- Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, China.,Shenyang University of Chemical Technology, Shenyang, China
| | - Na Ding
- HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Li Tao
- 305 Hospital of People's Liberation Army, Beijing, China
| | - Xue Dong
- Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, China
| | - Zheng Chen
- HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
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24
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Cao Y, Fan M, Pei Y, Su L, Xiao W, Chen F, Huang J, Liu X, Gu Z, Zhang Z, Yuan F, Jiang Y, Han X. CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Deficiency Attenuates Heatstroke-Induced Intestinal Injury. Inflammation 2021; 45:695-711. [PMID: 34841454 PMCID: PMC8956533 DOI: 10.1007/s10753-021-01577-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 10/04/2021] [Indexed: 11/30/2022]
Abstract
The intestine is one of the main target organs involved in the pathological process of heatstroke. CCAAT/enhancer-binding protein homologous protein (CHOP) is involved in endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to explore the role of CHOP in heatstroke-induced intestinal injury and potential therapy. An in vitro heat stress (HS) model using Caco-2 cells was employed. We observed the role of CHOP in apoptosis-mediated intestinal epithelial cell injury secondary to HS by evaluating cell viability, lactate dehydrogenase release, apoptosis levels, and GRP78, PERK, ATF4, CHOP, Bcl-2, and BAX mRNA and protein expression. To further study the role of CHOP in HS-induced intestinal barrier dysfunction, we assessed transepithelial electrical resistance, paracellular tracer flux, ultrastructure of tight junctions, and protein expression of ZO-1 and occludin. Male wild-type mice and CHOP knockout mice were used for in vivo experiments. We evaluated serum d-lactate and diamine oxidase levels, histopathological changes, intestinal ultrastructure, and ZO-1 and occludin protein expression. HS activated the PERK-CHOP pathway and promoted apoptosis by upregulating BAX and downregulating Bcl-2; these effects were prevented by CHOP silencing. Intestinal epithelial barrier function was disrupted by HS in vitro and in vivo. CHOP silencing prevented intestinal barrier dysfunction in Caco-2 cells, whereas CHOP knockout mice exhibited decreased intestinal mucosal injury. The ER stress inhibitor 4-phenylbutyrate (4-PBA) prevented HS-induced intestinal injury in vitro and in vivo. This study indicated that CHOP deficiency attenuates heatstroke-induced intestinal injury and may contribute to the identification of a novel therapy against heatstroke associated with the ER stress pathway.
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Affiliation(s)
- Yan Cao
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Maiying Fan
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Yanfang Pei
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Lei Su
- Department of Intensive Care Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, China
| | - Weiwei Xiao
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Fang Chen
- Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Jie Huang
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Xiehong Liu
- Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Zhengtao Gu
- Department of Treatment Center For Traumatic Injuries, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Zhongwei Zhang
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China
| | - Fangfang Yuan
- Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yu Jiang
- Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China.
| | - Xiaotong Han
- Department of Emergency, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Province, No.61 Western Jiefang Road, Changsha, 410005, China.
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25
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Zhang HY, Lu ZQ, Wang GX, Xie MR, Li CS. Presepsin as a biomarker for risk stratification for acute cholangitis in emergency department: A single-center study. World J Clin Cases 2021; 9:9857-9868. [PMID: 34877324 PMCID: PMC8610894 DOI: 10.12998/wjcc.v9.i32.9857] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/28/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute cholangitis is caused by bacterial infection and has high morbidity and mortality risk. The grade of cholangitis can guide clinical treatment from single antibiotic treatment to biliary drainage. With the introduction of white blood cell (WBC) count, C-reactive protein (CRP), and total bilirubin (T-Bil) into the diagnostic criteria and severity grading for acute cholangitis, the diagnosis rate and grading have significantly improved. However, early risk stratification assessments are challenging in the emergency department. Therefore, we hope to find an ideal predictive biomarker for cholangitis grade. Presepsin is a promising biomarker for the early diagnosis, severity, and prognosis of acute bacterial infections.
AIM To assess the grading value of presepsin in patients with acute cholangitis.
METHODS This clinical study was conducted at the Beijing Friendship Hospital, a 2000-bed teaching hospital with approximately 200000 emergency admissions per year. In this prospective observational study, 336 patients with acute cholangitis meeting the Tokyo Guidelines 2018 diagnostic criteria in the emergency department from May 2019 to December 2020 were analyzed. WBC count, CRP, procalcitonin (PCT), presepsin, T-Bil, and blood culture results were collected. The values were compared using the Pearson χ2 test, Fisher’s exact test, or Mann-Whitney U test. The area under the receiver operating characteristic curve (AUC) of the value was examined using the Delong test. The correlations among the key research indicators were determined using Pearson correlation.
RESULTS In total, 336 patients were examined, which included 107, 106, and 123 patients classified as having mild, moderate, and severe cholangitis, respectively. WBC count, CRP, PCT, presepsin, T-Bil, direct bilirubin, and sequential organ failure assessment scores of moderate and severe cholangitis patients were higher than those of mild cholangitis patients (P = 0.000). The AUC of presepsin in predicting moderate acute cholangitis was 0.728, which was higher than that of CRP (0.631, P = 0.043) and PCT (0.585, P = 0.002), and same as that of WBC count (0.746, P = 0.713) and T-Bil (0.686, P = 0.361). The AUC of presepsin in predicting severe acute cholangitis was 0.715, which was higher than that of WBC count (0.571, P = 0.008), CRP (0.590, P = 0.009), PCT (0.618, P = 0.024), and T-Bil (0.559, P = 0.006). The presepsin levels in the positive blood culture group were higher (2830.8pg/mLvs1987.8pg/mL, P = 0.000), and the AUC of presepsin (0.688) proved that it was a good biomarker for predicting positive bacterial culture.
CONCLUSION Presepsin can predict positive blood culture in patients with acute cholangitis. It is superior to WBC count, CRP, PCT, and T-Bil for the risk stratification of acute cholangitis.
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Affiliation(s)
- Han-Yu Zhang
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhao-Qing Lu
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Guo-Xing Wang
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Miao-Rong Xie
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Chun-Sheng Li
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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Xue X, Wu J, Ding M, Gao F, Zhou F, Xu B, Lu M, Li J, Li X. Si-Wu-Tang ameliorates fibrotic liver injury via modulating intestinal microbiota and bile acid homeostasis. Chin Med 2021; 16:112. [PMID: 34736501 PMCID: PMC8570021 DOI: 10.1186/s13020-021-00524-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Background Fibrotic liver injury is a progressive scarring event, which may permanently affect liver function and progress into devastating end-stage liver diseases due to the absence of effective therapies. Si-Wu-Tang (SWT), a traditional Chinese medicine formula used in clinic to treat gynecological disorders for centuries, has been investigated in recent preliminary findings for its role in alleviating chronic liver diseases. Here we aim to elucidate the therapeutic effects and possible mechanisms of SWT against fibrotic liver injury. Methods UHPLC-MS/MS was performed to investigate the chemical characterization of SWT. After intragastrically administered with carbon tetrachloride (CCl4) every 3 days for 1-week, C57BL/6 mice were orally administered with SWT (5.2, 10.4 and 20.8 g/kg) once daily for 3 weeks along with CCl4 challenge. Liver function was determined by the measurement of serum biomarkers, hematoxylin and eosin (H&E) and Masson’s trichrome staining. Intestinal inflammatory infiltration and the disruption of intestinal barrier were examined by H&E and E-cadherin immunohistochemical staining. The microbial composition of intestinal content was determined by 16S rRNA sequencing. Serum bile acids (BAs) profiling was analyzed by LC–MS/MS. Simultaneously, the expression of genes of interest was determined by qPCR and western blot. Results SWT exhibited remarkable therapeutic effects on CCl4-induced liver fibrosis, as indicated by improved collagen accumulation in livers, intestinal barrier injury and hepatic and intestinal inflammatory response. Results of 16S rRNA sequencing revealed that SWT treatment strikingly restructured intestinal microbiota in fibrotic mice by increasing the relative abundances of Bacteroides and Lachnoclostridium and decreasing the relative abundances of Alistipes and Rikenellaceae. UHPLC-MS/MS data suggested that SWT altered the composition of BAs in circulation as evidenced by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4 mice. Notably, SWT efficiently improved the imbalance of BA homeostasis in livers caused by CCl4 via activating farnesoid X receptor (FXR)-fibroblast growth factor 15 enterohepatic and FXR-small heterodimer partner hepatic pathways. Conclusion SWT decreased inflammatory response, reconstructed gut microbiota-mediated BA homeostasis as well as activated FXR pathways, which eventually protected against CCl4-induced fibrotic liver injury. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00524-0.
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Affiliation(s)
- Xiaoyong Xue
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Jianzhi Wu
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Mingning Ding
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Feng Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Fei Zhou
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Bing Xu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Mingjun Lu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Jun Li
- Gynecology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China.
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Hsu CF, Lin MW, Huang CC, Li TH, Liu CW, Huang SF, Yang YY, Huang YH, Hou MC, Lin HC. Roles and mechanisms of circulating CEACAM1 in the cirrhosis-related intestinal hyperpermeability: in vitro approach. J Chin Med Assoc 2021; 84:851-859. [PMID: 34261981 DOI: 10.1097/jcma.0000000000000582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Cirrhosis-related intestinal hyperpermeability and endotoxemia are characterized by intestinal epithelial cell apoptosis, impaired restitution (proliferation and migration), decreased tight junction protein levels, and subsequent barrier dysfunction. In addition to endotoxin and tumor necrosis factor-α (TNFα), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) plays crucial roles in the regulation of apoptosis, restitution, tight junction protein-maintained barrier function of intestinal epithelial cells. METHODS This study aims to explore the roles and underlying mechanisms of CEACAM1 in cirrhosis-related intestinal hyperpermeability through in vitro approach. RESULTS In cirrhotic patients, high serum levels of intestinal hyperpermeability (zonulin and endotoxin) markers were accompanied by elevated serum levels of TNFα and soluble CEACAM1. In in vitro experiments, we evaluated the individual and interacted roles of TNFα and human recombinant CEACAM1 (hrCEACAM1) in LC-sera (sera of cirrhotic patients)-induced intestinal hyperpermeability-related pathogenic signals. In the cell Line human from human colon (Caucasian colon adenocarcinoma) (Caco-2) cell culture, LC-sera, TNFα, and hrCEACAM1 increased apoptosis (measured by Terminal deoxynucleotidyl transferase [TdT] dUTP nick end labeling+/annexin-5+propidium iodide+ cells and caspase-3 activity), decreased restitution capacity (proliferation and migration), and disrupted tight junction protein-maintained barrier function in Caco-2 cells. The pathogenic changes mentioned above were accompanied by an increase in intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase release, and endoplasmic reticulum stress-related signals in the LC-sera or TNFα-pretreated Caco-2 cells. Concomitant incubation of Caco-2 cells with anti-CEACAM1 suppressed these LC-sera or TNFα-induced negative effects on restitution, barrier function, and cell viability. CONCLUSION This study demonstrated that sera from cirrhotic patients contain soluble CEACAM1, which is involved in the pathogenesis of intestinal hyperpermeability. Accordingly, it is noteworthy to explore the potential use of anti-CEACAM1 treatment for cirrhosis-related intestinal hyperpermeability and endotoxemia.
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Affiliation(s)
- Chien-Fu Hsu
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
| | - Ming-Wei Lin
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Preventive Medicine, Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chia-Chang Huang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tzu-Hao Li
- Division of Preventive Medicine, Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Chih-Wei Liu
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Allergy, Immunology and Rheumatology Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shiang-Fen Huang
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ying-Ying Yang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Han-Chieh Lin
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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Qin XY, Gailhouste L. Non-Genomic Control of Dynamic MYCN Gene Expression in Liver Cancer. Front Oncol 2021; 10:618515. [PMID: 33937011 PMCID: PMC8085327 DOI: 10.3389/fonc.2020.618515] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/23/2020] [Indexed: 11/13/2022] Open
Abstract
Upregulated MYCN gene expression is restricted to specialized cell populations such as EpCAM+ cancer stem cells in liver cancer, regardless of DNA amplification and mutation. Here, we reviewed the role of MYCN gene expression in liver homeostasis, regeneration, and tumorigenesis, and discussed the potential non-genomic mechanisms involved in controlling MYCN gene expression in liver cancer, with a focus on inflammation-mediated signal transduction and microRNA-associated post-transcriptional regulation. We concluded that dynamic MYCN gene expression is an integrated consequence of multiple signals in the tumor microenvironment, including tumor growth-promoting signals, lipid desaturation-mediated endoplasmic reticulum stress adaptation signals, and tumor suppressive miRNAs, making it a potential predictive biomarker of tumor stemness and plasticity. Therefore, understanding and tracing the dynamic changes and functions of MYCN gene expression will shed light on the origin of liver tumorigenesis at the cellular level and the development of novel therapeutic and diagnostic strategies for liver cancer treatment.
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Affiliation(s)
- Xian-Yang Qin
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Japan
| | - Luc Gailhouste
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Japan
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Xiang D, Yang J, Xu Y, Lan L, Li G, Zhang C, Liu D. Estrogen cholestasis induces gut and liver injury in rats involving in activating PI3K/Akt and MAPK signaling pathways. Life Sci 2021; 276:119367. [PMID: 33775691 DOI: 10.1016/j.lfs.2021.119367] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/28/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUNDS Estrogen and its metabolites often lead to intrahepatic cholestasis in susceptible women with pregnancy, administration of oral contraceptives and postmenopausal hormone replacement therapy. Recently, dysfunction of the gut-liver axis has been suggested to play a pivotal role in the progression of cholestasis, but details about estrogen cholestasis (EC)-induced gut and liver injury are still largely unknown. This study aims to gain insight into EC-induced gut and liver injury and cell signaling implicated. METHODS Male rats were exposed to 5 and 10 mg/kg of 17α-ethinylestradiol via subcutaneous injection for 5 successive days to simulate human EC. RESULTS By detection of these estrogen cholestatic rats, we found that EC induced inflammation in the liver but not in the intestine through activating NF-κB signaling pathway. EC strongly induced oxidative stress in both the liver and intestine, and activated the hepatic Nrf2/Gclm/Gclc pathway and the intestinal Nrf2/Ho-1 pathway, respectively, for adaptively regulating oxidative stress. EC increased cell apoptosis in both the liver and intestine. Additionally, EC elevated phosphorylation of Akt, ERK1/2, and p38 in the liver and increased phosphorylation of p38 in the intestine. CONCLUSIONS EC induces liver inflammation, both gut and liver oxidative stress and apoptosis, involving in activating PI3K/Akt and MAPK signaling pathways. Investigation of EC-induced gut and liver injury contributes to the development of new potential therapeutic strategies.
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Affiliation(s)
- Dong Xiang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jinyu Yang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yanjiao Xu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lulu Lan
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guodong Li
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chengliang Zhang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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30
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Zou M, Wang A, Wei J, Cai H, Yu Z, Zhang L, Wang X. An insight into the mechanism and molecular basis of dysfunctional immune response involved in cholestasis. Int Immunopharmacol 2021; 92:107328. [PMID: 33412394 DOI: 10.1016/j.intimp.2020.107328] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/12/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023]
Abstract
Cholestasis is one of the most common clinical symptom of liver diseases. If patients do not receive effective treatment, cholestasis can evolve into liver fibrosis, cirrhosis and ultimately liver failure requiring liver transplantation. Currently, only ursodeoxycholic acid, obeticholic acid and bezafibrate are FDA-approved drugs, thereby requiring a breakthrough in new mechanisms and therapeutic development. Inflammation is one of the common complications of cholestasis. Hepatic accumulation of toxic hydrophobic bile acids is a highly immunogenic process involving both resident and immigrating immune cells. And the resulting inflammation may further aggravate hepatocyte injury. Though, great investigations have been made in the immune responses during cholestasis, the relationship between immune responses and cholestasis remains unclear. Moreover, scarce reviews summarize the immune responses during cholestasis and the efficacy of therapies on immune response. The main purpose of this paper is to review the existing literature on dysfunctional immune response during cholestasis and the effect of treatment on immune response which may provide an insight for researchers and drug development.
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Affiliation(s)
- Mengzhi Zou
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China
| | - Aizhen Wang
- The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huaian 223002, PR China
| | - Jiajie Wei
- Department of Nursing, School of Medicine, Jiangsu University, Zhenjiang 212013, PR China
| | - Heng Cai
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China
| | - Zixun Yu
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China
| | - Luyong Zhang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
| | - Xinzhi Wang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China.
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Li Y, Sheng Q, Zhang C, Han C, Bai H, Lai P, Fan Y, Ding Y, Dou X. STAT6 up-regulation amplifies M2 macrophage anti-inflammatory capacity through mesenchymal stem cells. Int Immunopharmacol 2021; 91:107266. [PMID: 33321466 DOI: 10.1016/j.intimp.2020.107266] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/21/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022]
Abstract
Extensive infiltration of M2 macrophages plays a crucial role in repairing acute liver failure (ALF), however, the molecular pathways whereby mesenchymal stem cells (MSCs) induce M2 macrophage polarization remains unknown. We investigated the molecular pathways involved in MSC-induced M2 polarization and describe the potential therapeutic effects of M2 macrophages on ALF. The expression of M2 macrophage markers was significantly increased after M0 macrophages were co-cultured with MSCs in vitro. MSCs induced M2 macrophage polarization by activating STAT6, whereas a STAT6 inhibitor significantly inhibited the expression of M2 macrophage polarization markers (IL-4, CD163, TGF-β, IL-10 and Arg-1). Finally, M2 macrophages significantly reduced the secretion of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from injured hepatocytes. These results demonstrated that MSCs induced M2 macrophage polarization by activating STAT6, and that M2 macrophages increased the expression of anti-inflammatory factors to alleviate ALF.
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Affiliation(s)
- Yanwei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Qiuju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Hai Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Pingping Lai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yaoxin Fan
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
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Wang Q, Li Z, Liu K, Liu J, Chai S, Chen G, Wen S, Ming T, Wang J, Ma Y, Zeng H, Liu C, Xue B. Activation of the G Protein-Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell. J Pharmacol Exp Ther 2021; 376:281-293. [PMID: 33318078 DOI: 10.1124/jpet.120.000216] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.
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Affiliation(s)
- Qian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Zhao Li
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Kaixuan Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jianbo Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shiquan Chai
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Guanyu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shuyu Wen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Tian Ming
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jiayi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Yuntao Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Honghui Zeng
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
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Zhang Y, Jiang W, Xu J, Wu N, Wang Y, Lin T, Liu Y, Liu Y. E. coli NF73-1 Isolated From NASH Patients Aggravates NAFLD in Mice by Translocating Into the Liver and Stimulating M1 Polarization. Front Cell Infect Microbiol 2020; 10:535940. [PMID: 33363046 PMCID: PMC7759485 DOI: 10.3389/fcimb.2020.535940] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Objective The gut microbiota is associated with nonalcoholic fatty liver disease (NAFLD). We isolated the Escherichia coli strain NF73-1 from the intestines of a NASH patient and then investigated its effect and underlying mechanism. Methods 16S ribosomal RNA (16S rRNA) amplicon sequencing was used to detect bacterial profiles in healthy controls, NAFLD patients and NASH patients. Highly enriched E. coli strains were cultured and isolated from NASH patients. Whole-genome sequencing and comparative genomics were performed to investigate gene expression. Depending on the diet, male C57BL/6J mice were further grouped in normal diet (ND) and high-fat diet (HFD) groups. To avoid disturbing the bacterial microbiota, some of the ND and HFD mice were grouped as “bacteria-depleted” mice and treated with a cocktail of broad-spectrum antibiotic complex (ABX) from the 8th to 10th week. Then, E. coli NF73-1, the bacterial strain isolated from NASH patients, was administered transgastrically for 6 weeks to investigate its effect and mechanism in the pathogenic progression of NAFLD. Results The relative abundance of Escherichia increased significantly in the mucosa of NAFLD patients, especially NASH patients. The results from whole-genome sequencing and comparative genomics showed a specific gene expression profile in E. coli strain NF73-1, which was isolated from the intestinal mucosa of NASH patients. E. coli NF73-1 accelerates NAFLD independently. Only in the HFD-NF73-1 and HFD-ABX-NF73-1 groups were EGFP-labeled E. coli NF73-1 detected in the liver and intestine. Subsequently, translocation of E. coli NF73-1 into the liver led to an increase in hepatic M1 macrophages via the TLR2/NLRP3 pathway. Hepatic M1 macrophages induced by E. coli NF73-1 activated mTOR-S6K1-SREBP-1/PPAR-α signaling, causing a metabolic switch from triglyceride oxidation toward triglyceride synthesis in NAFLD mice. Conclusions E. coli NF73-1 is a critical trigger in the progression of NAFLD. E. coli NF73-1 might be a specific strain for NAFLD patients.
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Affiliation(s)
- Yifan Zhang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Weiwei Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Jun Xu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China.,Institute of Clinical Molecular Biology & Central Laboratory, Peking University People's Hospital, Beijing, China
| | - Na Wu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China.,Institute of Clinical Molecular Biology & Central Laboratory, Peking University People's Hospital, Beijing, China
| | - Yang Wang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Tianyu Lin
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yun Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
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Wang S, Shuai C, Gao S, Jiang J, Luan J, Lv X. Chemokine CXCL14 acts as a potential genetic target for liver fibrosis. Int Immunopharmacol 2020; 89:107067. [PMID: 33039963 DOI: 10.1016/j.intimp.2020.107067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022]
Abstract
There are multiple causes of liver fibrosis, common ones include ethanol, toxins, and cholestasis. However, whether these different etiologies lead to the same pathological outcomes contain common genetic targets or signaling pathways, the current research has not attracted widespread attention. GSE40041 and GSE55747 were downloaded from the Gene Expression Omnibus (GEO) database. GSE40041 and GSE55747 represent the differential expression profiles in the liver of mice with bile duct ligation (BDL) and carbon tetrachloride (CCl4) induced liver fibrosis models, respectively. By using GEO2R, 701 differential expression genes (DEGs) in GSE40041 and 6540 DEGs in GSE55747 were identified. 260 co-DEGs were shared and extracted for gene ontology (GO) analysis. Through GO analysis, it was found that the regulation of cell migration in biological processes (BPs) was closely related to the pathogenesis of liver fibrosis, and the genes involved in this process include a key gene, chemokine (C-X-C motif) ligand 14 (CXCL14). Subsequently, further bioinformatic analysis showed that CXCL14 may be regulated by miR-122 to participate in the progression of liver fibrosis. Then real-time PCR and western blotting were performed to validate the expression of CXCL14 in liver tissue after liver fibrosis caused by different etiologies (ethanol, CCl4). The expression of CXCL4 in liver fibrosis induced by BDL was verified in another GEO dataset. Basically consistent with our bioinformatics results, our experimental results showed that the expression of CXCL14 was most significantly increased in alcoholic liver fibrosis model, followed by CCl4-induced liver fibrosis, which was also significantly increased in the BDL-induced model. Thus, CXCL14 can act as a common potential genetic target for different liver fibrosis diseases.
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Affiliation(s)
- Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Chen Shuai
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Jia Jiang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China.
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China.
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Chopyk DM, Grakoui A. Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. Gastroenterology 2020; 159:849-863. [PMID: 32569766 PMCID: PMC7502510 DOI: 10.1053/j.gastro.2020.04.077] [Citation(s) in RCA: 274] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/16/2020] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Intestinal barrier dysfunction and dysbiosis contribute to development of diseases in liver and other organs. Physical, immunologic, and microbiologic (bacterial, fungal, archaeal, viral, and protozoal) features of the intestine separate its nearly 100 trillion microbes from the rest of the human body. Failure of any aspect of this barrier can result in translocation of microbes into the blood and sustained inflammatory response that promote liver injury, fibrosis, cirrhosis, and oncogenic transformation. Alterations in intestinal microbial populations or their functions can also affect health. We review the mechanisms that regulate intestinal permeability and how changes in the intestinal microbiome contribute to development of acute and chronic liver diseases. We discuss individual components of the intestinal barrier and how these are disrupted during development of different liver diseases. Learning more about these processes will increase our understanding of the interactions among the liver, intestine, and its flora.
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Affiliation(s)
- Daniel M. Chopyk
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA
| | - Arash Grakoui
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
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36
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Li X, Liu R. Long non-coding RNA H19 in the liver-gut axis: A diagnostic marker and therapeutic target for liver diseases. Exp Mol Pathol 2020; 115:104472. [DOI: 10.1016/j.yexmp.2020.104472] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/21/2020] [Accepted: 05/21/2020] [Indexed: 12/12/2022]
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Exogenous Therapeutics of Microrna-29a Attenuates Development of Hepatic Fibrosis in Cholestatic Animal Model through Regulation of Phosphoinositide 3-Kinase p85 Alpha. Int J Mol Sci 2020; 21:ijms21103636. [PMID: 32455716 PMCID: PMC7279217 DOI: 10.3390/ijms21103636] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/14/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022] Open
Abstract
Recent studies have found that microRNA-29a (miR-29a) levels are significantly lower in fibrotic livers, as shown with human liver cirrhosis. Such downregulation influences the activation of hepatic stellate cells (HSC). Phosphoinositide 3-kinase p85 alpha (PI3KP85α) is implicated in the regulation of proteostasis mitochondrial integrity and unfolded protein response (UPR) and apoptosis in hepatocytes. This study aimed to investigate the potential therapeutic role of miR-29a in a murine bile duct ligation (BDL)-cholestatic injury and liver fibrosis model. Mice were assigned to four groups: sham, BDL, BDL + scramble miRs, and BDL + miR-29a-mimic. Liver fibrosis and inflammation were assessed by histological staining and mRNA/protein expression of representative markers. Exogenous therapeutics of miR-29a in BDL-stressed mice significantly attenuated glutamic oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) and liver fibrosis, and caused a significant downregulation in markers related to inflammation (IL-1β), fibrogenesis (TGF-β1, α-SMA, and COL1α1), autophagy (p62 and LC3B II), mitochondrial unfolded protein response (UPRmt; C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and Lon protease-1 (LONP1, a mitochondrial protease), and PI3KP85α within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic directly targets mRNA 3′ untranslated region (UTR) of PI3KP85α to suppress its expression in HepG2 cell line. Our data provide new insights that therapeutic miR-29a improves cholestasis-induced hepatic inflammation and fibrosis and proteotstasis via blocking PI3KP85α, highlighting the potential of miR-29a targeted therapy for liver injury.
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Gijbels E, Vilas-Boas V, Annaert P, Vanhaecke T, Devisscher L, Vinken M. Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol 2020; 94:1151-1172. [PMID: 32152650 DOI: 10.1007/s00204-020-02691-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/25/2020] [Indexed: 02/07/2023]
Abstract
Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
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Affiliation(s)
- Eva Gijbels
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Vânia Vilas-Boas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Pieter Annaert
- Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O&N2, Herestraat 49-box 921, 3000, Leuven, Belgium
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Lindsey Devisscher
- Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Faculty of Medicine and Health Sciences, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
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Duan M, Yang Y, Peng S, Liu X, Zhong J, Guo Y, Lu M, Nie H, Ren B, Zhang X, Liu L. C/EBP Homologous Protein (CHOP) Activates Macrophages and Promotes Liver Fibrosis in Schistosoma japonicum-Infected Mice. J Immunol Res 2019; 2019:5148575. [PMID: 31886304 PMCID: PMC6914929 DOI: 10.1155/2019/5148575] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/29/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022] Open
Abstract
CCAAT/enhancer-binding homologous protein (CHOP), a transcriptional regulator induced by endoplasmic reticulum stress (ER stress) is a pivotal factor in the ER stress-mediated apoptosis pathway. Previous studies have shown that CHOP is involved in the formation of fibrosis in a variety of tissues and is associated with alternative macrophage activation. The role of CHOP in the pathologic effects of liver fibrosis in schistosomiasis has not been reported, and underlying mechanisms remain unclear. This study is aimed at understanding the effect of CHOP on liver fibrosis induced by Schistosoma japonicum (S. japonicum) in vivo and clarifying its mechanism. C57BL/6 mice were infected with cercariae of S. japonicum through the abdominal skin. The liver fibrosis was examined. The level of IL-13 was observed. The expressions of CHOP, Krüppel-like factor 4 (KLF4), signal transducer and activator of transcription 6 (STAT6), phosphorylation STAT6, interleukin-13 receptor alpha 1 (IL-13Rα1), and interleukin-4 receptor alpha (IL-4Rα) were analysed. The eosinophilic granuloma and collagen deposition were found around the eggs in mice infected for 6 and 10 weeks. IL-13 in plasma and IL-13Rα1 and IL-4Rα in liver tissue were significantly increased. The phosphorylated STAT6 was enhanced while Krüppel-like factor 4 (KLF4) was decreased in liver tissue. The expression of CHOP and colocalization of CHOP and CD206 were increased. Overall, these results suggest that CHOP plays a critical role in hepatic fibrosis induced by S. japonicum, likely through promoting alternative activation of macrophages.
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Affiliation(s)
- Mengyun Duan
- Department of Medical Imaging, Medical School of Yangtze University, Jingzhou 434023, China
| | - Yuan Yang
- Department of Radiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Shuang Peng
- Department of Medical Imaging, Medical School of Yangtze University, Jingzhou 434023, China
| | - Xiaoqin Liu
- Department of Medical Imaging, Medical School of Yangtze University, Jingzhou 434023, China
| | - Jixin Zhong
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Yurong Guo
- Department of Medical Imaging, Medical School of Yangtze University, Jingzhou 434023, China
| | - Min Lu
- Department of Medical Imaging, Medical School of Yangtze University, Jingzhou 434023, China
| | - Hao Nie
- Department of Pathogenic Biology, Medical School of Yangtze University, Jingzhou 434023, China
- Clinical Molecular Immunology Center, Medical School of Yangtze University, Jingzhou 434023, China
| | - Boxu Ren
- Department of Medical Imaging, Medical School of Yangtze University, Jingzhou 434023, China
| | - Xiangzhi Zhang
- Department of Pharmacology, Medical School of Yangtze University, Jingzhou 434023, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Jingzhou 434023, China
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Wei Z, Zhao D, Zhang Y, Chen Y, Zhang S, Li Q, Zeng P, Li X, Zhang W, Duan Y, Han J, Yang X. Rosiglitazone ameliorates bile duct ligation-induced liver fibrosis by down-regulating NF-κB-TNF-α signaling pathway in a PPARγ-dependent manner. Biochem Biophys Res Commun 2019; 519:854-860. [PMID: 31561855 DOI: 10.1016/j.bbrc.2019.09.084] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 09/19/2019] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a major cause of morbidity and mortality worldwide. One of its therapeutic targets is peroxisome proliferator-activated receptor γ (PPARγ), with its ligands including rosiglitazone being tested in pre-clinical and clinical studies. However, the effects of rosiglitazone on bile duct ligation (BDL)-induced liver fibrosis and the involved mechanisms remain unknown. Herein, we used floxed control (PPARγfl/fl) and hepatocyte-specific PPARγ deficient (HepPPARγ KO) mice to conduct BDL to induce liver fibrosis and treated the animals with rosiglitazone. After one week of BDL, mice in BDL group displayed liver injury evidenced by increased collagen content, fibrosis area, necrosis area and apoptotic cells, and elevated alkaline phosphatase and alanine transaminase activities in serum. Interestingly, rosiglitazone ameliorated BDL-induced liver injury in PPARγfl/fl mice but not in HepPPARγ KO mice. Mechanistically, rosiglitazone reduced BDL-induced collagen content by downregulating fibrotic related genes including transforming growth factor β1, α-smooth muscle actin and collagen type I α1, and decreased inflammation cytokine tumor necrosis factor α level by inhibiting phosphorylation of nuclear factor-κB in a PPARγ-dependent manner. Based on findings above, we demonstrated that rosiglitazone can ameliorate BDL-induced liver fibrosis in mice and confirmed its critical functions on fibrosis by regulating NF-κB-TNF-α pathway in a PPARγ-dependent manner.
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Affiliation(s)
- Zhuo Wei
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Dan Zhao
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Ye Zhang
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Shuang Zhang
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Qi Li
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Peng Zeng
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoju Li
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Wenwen Zhang
- Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Jihong Han
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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41
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Bile Duct Obstruction Leads to Increased Intestinal Expression of Breast Cancer Resistance Protein With Reduced Gastrointestinal Absorption of Imatinib. J Pharm Sci 2019; 108:3130-3137. [DOI: 10.1016/j.xphs.2019.05.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/04/2019] [Accepted: 05/14/2019] [Indexed: 12/12/2022]
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42
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Kwong EK, Liu R, Zhao D, Li X, Zhu W, Wang X, Gurley EC, Lai G, Liu J, Hylemon PB, Zhou H. The role of sphingosine kinase 2 in alcoholic liver disease. Dig Liver Dis 2019; 51:1154-1163. [PMID: 31003959 PMCID: PMC6682426 DOI: 10.1016/j.dld.2019.03.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 02/08/2023]
Abstract
Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide. However, the exact mechanisms underlying ALD remain unclear. Previous studies reported that sphingosine kinase 2 (SphK2) plays an essential role in regulating hepatic lipid metabolism. In the current study, we demonstrate that compared to wild-type (WT) mice, SphK2 deficient (SphK2-/-) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 days. This is accompanied by a down-regulation of steroid 7-alpha-hydroxylase (Cyp7b1) and an up-regulation of pro-inflammatory mediators (Tnfα, F4/80, Il-1β). In vitro experiments showed that alcohol induced SphK2 expression in mouse primary hepatocytes and cultured mouse macrophages. Furthermore, alcohol feeding induced a more severe intestinal barrier dysfunction in SphK2-/- mice than WT mice. Deficiency of SphK2 impaired the growth of intestinal organoids. Finally, SphK2 expression levels were down-regulated in the livers of human patients with alcoholic cirrhosis and hepatocellular carcinoma compared to healthy controls. In summary, these findings suggest that SphK2 is a crucial regulator of hepatic lipid metabolism and that modulating the SphK2-mediated signaling pathway may represent a novel therapeutic strategy for the treatment of ALD and other metabolic liver diseases.
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Affiliation(s)
- Eric K. Kwong
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Runping Liu
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Derrick Zhao
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xiaojiaoyang Li
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Weiwei Zhu
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xuan Wang
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Emily C. Gurley
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Guanhua Lai
- Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
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Liu F, Sun Z, Hu P, Tian Q, Xu Z, Li Z, Tian X, Chen M, Huang C. Determining the protective effects of Yin-Chen-Hao Tang against acute liver injury induced by carbon tetrachloride using 16S rRNA gene sequencing and LC/MS-based metabolomics. J Pharm Biomed Anal 2019; 174:567-577. [PMID: 31261038 DOI: 10.1016/j.jpba.2019.06.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/20/2019] [Accepted: 06/21/2019] [Indexed: 12/12/2022]
Abstract
Yin-Chen-Hao Tang (YCHT), consisting of Artemisia annua L., Gardenia jasminoides Ellis, and Rheum Palmatum L., has been used to relieve liver diseases in China for thousands of years. Several protective mechanisms of YCHT on liver injury have been investigated based on metabolomics, but the effects of YCHT on the alterations in the gut microbiota are still unclear. In this study, an integrated approach based on 16S rRNA gene sequencing combined with high-performance liquid chromatography-mass spectrometry (HPLC-MS) metabolic profiling was performed to assess the effects of YCHT on liver injury induced by carbon tetrachloride (CCl4) through the regulation of the relative abundances of gut microbiota and their relationships with biomarker candidates. A total of twelve significantly altered bacterial genera and nine metabolites were identified, which returned to normal levels after YCHT treatment. The relative abundances of the identified microbiota, including significantly elevated amounts of p_Firmicutes, c_Clostridia, o_Clostridiales, f_Ruminococcaceae, g_[Eubacterium]_coprostanoligenes_group, s_uncultured_bacterium_f_Lachnospiraceae and remarkedly increased amounts of p_Bacteroidetes, c_Bacteroidia, o_Bacteroidales, f_Bacteroidaceae, g_Bacteroides and s_uncultured_bacterium_g_Bacteroides, were found in model rats compared with controls. Potential biomarkers, including lower levels of LysoPC (16:1(9Z)/0:0), LysoPC (20:3(5Z,8Z,11Z)), LysoPC (17:0), LysoPC (20:1(11Z)) and 3-hydroxybutyric acid and higher amounts of ornithine, L-kynurenine, hippuric acid and taurocholic acid are involved in several custom metabolic pathways, such as arginine and proline metabolism, tryptophan metabolism, glycerophospholipid metabolism and primary bile acid biosynthesis. Interestingly, there was a strong correlation between the perturbed gut microbiota in genera c_Clostridia and o_Clostridiales and the altered plasma metabolite 3-hydroxybutyric acid. This finding means that the hepatoprotective effects of YCHT may be due to the regulation of the production of the functional metabolite 3-hydroxybutyric acid through changes in the proportions of c_Clostridia and o_Clostridiales. These results showed that the hepatoprotective effects of YCHT not only focused on custom metabolic pathways but also depended on the changes in the gut microbiota in liver injury. These findings suggest that the 16S rRNA gene sequencing and LC-MS based metabolomics approach can be applied to comprehensively evaluate the effects of traditional Chinese medicines (TCMs).
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Affiliation(s)
- Fang Liu
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China
| | - Zhaolin Sun
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China
| | - Pei Hu
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China
| | - Qiang Tian
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, Sichuan, 621010, PR China
| | - Zhou Xu
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China
| | - Zhixiong Li
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China
| | - Xiaoting Tian
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China
| | - Mingcang Chen
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China.
| | - Chenggang Huang
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China.
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44
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Fang J, Luo L, Ke Z, Liu C, Yin L, Yao Y, Feng Q, Huang C, Zheng P, Fan S. Polydatin protects against acute cholestatic liver injury in mice via the inhibition of oxidative stress and endoplasmic reticulum stress. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.02.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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45
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Abstract
Endoplasmic reticulum (ER) stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion. The unfolded protein response (UPR), comprising of inositol-requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6) signaling pathways, is a protective cellular response activated by ER stress. However, UPR activation can also induce cell death upon persistent ER stress. The liver is susceptible to ER stress given its synthetic and other biological functions. Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and UPR signaling pathways in the pathogenesis of liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, alpha-1 antitrypsin deficiency, cholestatic liver disease, drug-induced liver injury, ischemia/reperfusion injury, viral hepatitis and hepatocellular carcinoma. Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of UPR pathways during the development of the diseases. Moreover ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
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Affiliation(s)
- Xiaoying Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tarry Building 15-709, 303 East Superior Street, Chicago, IL 60611, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Corresponding author: Xiaoying-liu@northwestern
| | - Richard M. Green
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tarry Building 15-709, 303 East Superior Street, Chicago, IL 60611, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Loeuillard E, El Mourabit H, Lei L, Lemoinne S, Housset C, Cadoret A. Endoplasmic reticulum stress induces inverse regulations of major functions in portal myofibroblasts during liver fibrosis progression. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3688-3696. [DOI: 10.1016/j.bbadis.2018.10.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/27/2018] [Accepted: 10/02/2018] [Indexed: 12/12/2022]
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47
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Wang J, Dong R, Zheng S. Roles of the inflammasome in the gut‑liver axis (Review). Mol Med Rep 2018; 19:3-14. [PMID: 30483776 PMCID: PMC6297761 DOI: 10.3892/mmr.2018.9679] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
The gut-liver axis connects the liver with the intestine via bile acid metabolism. Bile acid dysregulation leads to intestinal dysbiosis, that allows enterogenous pathogenic bacteria, including Gram-negative bacteria and their products lipopolysaccharide (LPS), into the liver via the portal vein, triggering inflammation in the liver. The inflammasome serves as an intracellular pattern recognition receptor that detects pathogens or danger signals and mediates innate immunity in the liver or gut. Specifically, the NACHT, LRR and PYD domains-containing protein (NLRP)6 inflammasome maintains intestinal microbial balance, by promoting interleukin (IL)-18-dependent antimicrobial peptide synthesis and mucus secretion from goblet cells. The NLRP3 inflammasome, in contrast, primarily induces IL-1β and aggravates inflammatory liver injury. Furthermore, the NLRP3 inflammasome affects the epithelial integrity of cholangiocytes by inducing the production of pro-inflammatory cytokines. In addition, bile acids, including deoxycholic acid and chenodeoxycholic acid, are able to activate the NLRP3 inflammasome in macrophages; however, bile acids have the potential to exert the opposite role by interacting with the membrane-bound Takeda G-protein receptor 5 or by activating nuclear farnesoid-X receptor. Therefore, further investigation of the molecular mechanisms underlying the inflammasome, involved in the gut-liver axis, may provide important insights into the identification of a potential therapeutic target for the treatment of liver and gut diseases. The present review discusses the roles of the inflammasome in the gut-liver axis, and the emerging associations between the inflammasome and the intestinal microbiota or the bile acids in the gut-liver axis.
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Affiliation(s)
- Junfeng Wang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai 201102, P.R. China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai 201102, P.R. China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai 201102, P.R. China
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48
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Xiang T, Ge S, Wen J, Xie J, Yang L, Wu X, Cheng N. The possible association between AQP9 in the intestinal epithelium and acute liver injury‑induced intestinal epithelium damage. Mol Med Rep 2018; 18:4987-4993. [PMID: 30320400 PMCID: PMC6236304 DOI: 10.3892/mmr.2018.9542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 08/31/2018] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to investigate the expression and function of aquaporin (AQP)9 in the intestinal tract of acute liver injury rat models. A total of 20 Sprague Dawley rats were randomly divided into four groups: Normal control (NC) group and acute liver injury groups (24, 48 and 72 h). Acute liver injury rat models were established using D-amino galactose, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbil) and albumin were determined using an automatic biochemical analyzer. Proteins levels of myosin light chain kinase (MLCK) in rat intestinal mucosa were investigated via immunohistochemistry. Pathological features were observed using hematoxylin and eosin (H&E) staining. MLCK, AQP9 and claudin-1 protein expression levels were detected via western blotting. Levels of ALT and AST in acute liver injury rats were revealed to steadily increase between 24 and 48 h time intervals, reaching a peak level at 48 h. Furthermore, TBil levels increased significantly until 72 h. Levels of ALT were revealed to significantly increase until the 48 h time interval, and then steadily decreased until the 72 h time interval. The acute liver injury 72 h group exhibited the greatest levels of MLCK expression among the three acute liver injury groups; however, all three acute liver injury groups exhibited enhanced levels of MLCK expression compared with the NC group. Protein levels of AQP9 and claudin-1 were enhanced in the NC group compared with the three acute liver injury groups. H&E staining demonstrated that terminal ileum mucosal layer tissues obtained from the acute liver injury rats exhibited visible neutrophil infiltration. Furthermore, the results revealed that levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-10 serum cytokines were significantly increased in the acute liver injury groups. In addition, AQP9 protein expression was suppressed in acute liver injury rats, which induced pathological alterations in terminal ileum tissues may be associated with changes of claudin-1 and MLCK protein levels.
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Affiliation(s)
- Tianxin Xiang
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shanfei Ge
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jiangxiong Wen
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Junfeng Xie
- Department of Gastroenterology, the People's Hospital of Ganzhou City, Ganzhou, Jiangxi 341000, P.R. China
| | - Lixia Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaoping Wu
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Na Cheng
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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49
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Liu R, Li X, Hylemon PB, Zhou H. Conjugated Bile Acids Promote Invasive Growth of Esophageal Adenocarcinoma Cells and Cancer Stem Cell Expansion via Sphingosine 1-Phosphate Receptor 2-Mediated Yes-Associated Protein Activation. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2042-2058. [PMID: 29963993 PMCID: PMC6105923 DOI: 10.1016/j.ajpath.2018.05.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/05/2018] [Accepted: 05/15/2018] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma (EAC) is the sixth leading cause of cancer deaths worldwide and has been dramatically increasing in incidence over the past decade. Gastroesophageal reflux and Barrett esophagus are well-established risk factors for disease progression. Conjugated bile acids (CBAs), including taurocholate (TCA), represent the major bile acids in the gastroesophageal refluxate of advanced Barrett esophagus and EAC patients. Our previous studies suggested that CBA-induced activation of sphingosine 1-phosphate receptor 2 (S1PR2) plays a critical role in promoting cholangiocarcinoma cell invasive growth. However, the role of CBAs in EAC development and underlying mechanisms remains elusive. In the current study, we identified that the expression level of S1PR2 is correlated to invasiveness of EAC cells. TCA significantly promoted cell proliferation, migration, invasion, transformation, and cancer stem cell expansion in highly invasive EAC cells (OE-33 cells), but had less effect on the lower invasive EAC cells (OE-19 cells). Pharmacologic inhibition of S1PR2 with specific antagonist JTE-013 or knockdown of S1PR2 expression significantly reduced TCA-induced invasive growth of OE-33 cells, whereas overexpression of S1PR2 sensitized OE-19 cells to TCA-induced invasive growth. Furthermore, TCA-induced activation of S1PR2 was closely associated with YAP and β-catenin signaling pathways. In conclusion, CBA-induced activation of the S1PR2 signaling pathway is critically involved in invasive growth of EAC cells and represents a novel therapeutic target for EAC.
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Affiliation(s)
- Runping Liu
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia
| | - Xiaojiaoyang Li
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia
| | - Huiping Zhou
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia.
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50
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Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease. Gastroenterol Res Pract 2018; 2018:7192646. [PMID: 30026758 PMCID: PMC6031203 DOI: 10.1155/2018/7192646] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/08/2018] [Indexed: 12/11/2022] Open
Abstract
Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies.
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