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1
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Karsten REH, Gier K, de Meijer VE, Huibers WHC, Permentier HP, Verpoorte E, Olinga P. Studying the intracellular bile acid concentration and toxicity in drug-induced cholestasis: Comprehensive LC-MS/MS analysis with human liver slices. Toxicol In Vitro 2025; 104:106011. [PMID: 39855581 DOI: 10.1016/j.tiv.2025.106011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 01/27/2025]
Abstract
Drug-induced cholestasis (DIC) is a leading cause of drug-induced liver injury post-drug marketing, characterized by bile flow obstruction and toxic bile constituent accumulation within hepatocytes. This study investigates the toxicity associated with intracellular bile acid (BA) accumulation during DIC development. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, we examined intracellular BA concentrations in human precision-cut liver slices (PCLS) following the administration of cyclosporin A and chlorpromazine, both with and without an established BA mixture. Our findings indicate toxicity of cyclosporin A upon BA addition, while chlorpromazine's toxicity remained unaffected. Although neither drug led to the accumulation of all BAs intracellularly, BA mixture addition resulted in the accumulation of unconjugated BAs associated with DIC, such as deoxycholic acid (DCA) and cholic acid (CA). Additionally, cyclosporin A increased taurolithocholic acid (TLCA) concentrations. In the absence of the BA mixture, a decrease in conjugated BAs was observed, suggesting inhibition of BA metabolism by cholestatic drugs and warranting further investigation. The evident increase in CA and DCA for both drugs (and TLCA for cyclosporin A), despite not exacerbating toxicity with chlorpromazine, suggests these increases may be related to DIC development and possible toxicity. In conclusion, the current human PCLS model is appropriate for investigating and detecting essential contributors to DIC and can be used in future studies elucidating DIC ex vivo.
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Affiliation(s)
- R E H Karsten
- University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Analysis, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
| | - K Gier
- University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Analysis, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
| | - V E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands
| | - W H C Huibers
- University of Groningen, Groningen Research Institute of Pharmacy, Department of Analytical Biochemistry and Interfaculty Mass Spectrometry Center, A. Deusinglaan 16, 9713 AV Groningen, the Netherlands
| | - H P Permentier
- University of Groningen, Groningen Research Institute of Pharmacy, Department of Analytical Biochemistry and Interfaculty Mass Spectrometry Center, A. Deusinglaan 16, 9713 AV Groningen, the Netherlands
| | - E Verpoorte
- University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Analysis, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
| | - P Olinga
- University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
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Zhang P, Li X, Liang J, Zheng Y, Tong Y, Shen J, Chen Y, Han P, Chu S, Liu R, Zheng M, Zhai Y, Tang X, Zhang C, Qu H, Mi P, Chai J, Yuan D, Li S. Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells. Nat Commun 2025; 16:2093. [PMID: 40025016 PMCID: PMC11873286 DOI: 10.1038/s41467-025-57351-2] [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: 01/29/2024] [Accepted: 02/18/2025] [Indexed: 03/04/2025] Open
Abstract
Cholestatic liver diseases are characterized by excessive bile acid accumulation in the liver. Endothelial cells (ECs) shape the local microenvironment in both normal conditions and liver injury, yet their role in cholestasis is unclear. Through a comparative analysis of single-cell RNA sequencing data from various murine models of liver injury, we identify distinctive Myc activation within ECs during obstructive cholestasis resulting from bile duct ligation (BDL). Myc overexpression in ECs significantly upregulates P-selectin, increasing neutrophil infiltration and worsening cholestatic liver injury. This process occurs through the FXR, activated by chenodeoxycholic acid (CDCA) and its conjugate TCDCA. Inhibiting P-selectin with PSI-697 reduces neutrophil recruitment and alleviates injury. Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils. The findings identify ECs as key drivers of cholestatic liver injury through a Myc-driven program and suggest that targeting the CDCA/FXR/Myc/P-selectin axis may offer a therapeutic approach.
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Affiliation(s)
- Peng Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinying Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jinyuan Liang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuanwen Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yao Tong
- School of Medicine, Chongqing University, Chongqing, China
| | - Jing Shen
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Yatai Chen
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Penghu Han
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Shuzheng Chu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ruirui Liu
- Institute of Pathology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mengqi Zheng
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Yunjiao Zhai
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Xiaolong Tang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cuijuan Zhang
- Institute of Pathology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hui Qu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China.
| | - Ping Mi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Jin Chai
- Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center and Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China.
| | - Detian Yuan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Shiyang Li
- Advanced Medical Research Institute, Shandong University, Jinan, China.
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Ishihara N, Koma YI, Omori M, Komatsu S, Torigoe R, Yokoo H, Nakanishi T, Yamanaka K, Azumi Y, Tsukamoto S, Kodama T, Nishio M, Shigeoka M, Yokozaki H, Fukumoto T. Chemokine (C-C Motif) Ligand 2/CCR2/Extracellular Signal-Regulated Kinase Signal Induced through Cancer Cell-Macrophage Interaction Contributes to Hepatocellular Carcinoma Progression. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:589-608. [PMID: 39756577 DOI: 10.1016/j.ajpath.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/07/2025]
Abstract
Tumor-infiltrating macrophages, known as tumor-associated macrophages, play a crucial role in the tumor microenvironment. Herein, immunohistochemistry revealed that intratumoral CD68-positive macrophages are associated with poor prognosis and clinicopathologic factors in patients with hepatocellular carcinoma (HCC). Subsequently, an indirect co-culture system involving HCC cells and peripheral blood-derived macrophages was developed. cDNA microarray analysis revealed that chemokine (C-C motif) ligand 2 (CCL2) was highly expressed in HCC cells co-cultured with macrophages. CCL2 neutralization suppressed proliferation, migration, and phosphorylation of extracellular signal-regulated kinase (Erk) in HCC cells and macrophages enhanced through co-culture. In contrast, recombinant human CCL2 (rhCCL2) addition facilitated these malignant phenotypes and increased Erk phosphorylation levels in HCC cells and macrophages. The primary CCL2 receptor, CCR2, was expressed in HCC cells and macrophages and was up-regulated in co-cultured HCC cells. CCR2 inhibition suppressed malignant phenotypes and reduced phosphorylated levels of Erk enhanced by rhCCL2. Additionally, the inhibition of Erk signal suppressed rhCCL2-enhanced malignant phenotypes. Moreover, serum CCL2 levels were higher in patients with HCC than those in healthy donors. On the basis of immunohistochemistry, CCL2-positive cases with high CCR2 expression and phosphorylated Erk-positive cases exhibited poor survival outcomes. Therefore, CCL2 up-regulation through interactions between HCC cells and macrophages contributed to HCC progression, making the CCL2/CCR2/Erk signal a potential target for HCC treatment.
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Affiliation(s)
- Nobuaki Ishihara
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu-Ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Masaki Omori
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shohei Komatsu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Rikuya Torigoe
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroki Yokoo
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takashi Nakanishi
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Keitaro Yamanaka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Obstetrics and Gynecology, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuki Azumi
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shuichi Tsukamoto
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takayuki Kodama
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mari Nishio
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Manabu Shigeoka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takumi Fukumoto
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
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Yousefi Z, Nourbakhsh M, Sahebghadam Lotfi A. Pirfenidone Downregulates eIF6, P311, and TGF-β Expression and Improves Liver Fibrosis Induced by Bile Duct Ligation in Wistar Rats: Evidence for Liver Regeneration. DNA Cell Biol 2025; 44:109-124. [PMID: 39681345 DOI: 10.1089/dna.2024.0194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024] Open
Abstract
Liver fibrosis (LF) is a clinical disorder characterized by inflammation and excessive accumulation of extracellular matrix (ECM). This study investigates the effects of the antifibrotic compound pirfenidone (PFD) on improving LF through histological changes and modulation of eukaryotic translation initiation factor 6 (eIF6), P311, and transforming growth factor beta (TGF-β) in rats with bile duct ligation (BDL)-induced LF. Rats received daily doses of PFD (200 and 500 mg/kg) for 4 weeks. The study encompassed biochemical, pathological, and immunohistochemical (IHC) analyses. mRNA levels of eIF6, P311, TGF-β, ECM deposition, hepatic stellate cell (HSC) activation, and inflammatory mediator genes were measured by RT-qPCR. Protein levels of eIF6, P311, and TGF-β were detected by western blotting. Compared with the BDL group, PFD dose-dependently reduced hydroxyproline content, liver index, biochemical parameters, fibrosis score, and fibrosis area. PFD also modulated BDL-induced hepatic inflammation, ECM accumulation, and HSC activation. IHC staining of Ki-67 and hepatocyte paraffin-1 revealed that PFD enhanced liver regeneration. The research confirmed that PFD gradually downregulated elevated eIF6, P311, and TGF-β levels in BDL-induced LF. These findings suggest that PFD could be a potential treatment for LF, as it may help attenuate fibrosis and enhance liver regeneration, possibly through the modulation of these specific markers.
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Affiliation(s)
- Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mitra Nourbakhsh
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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5
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Fuchs CD, Simbrunner B, Baumgartner M, Campbell C, Reiberger T, Trauner M. Bile acid metabolism and signalling in liver disease. J Hepatol 2025; 82:134-153. [PMID: 39349254 DOI: 10.1016/j.jhep.2024.09.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.
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Affiliation(s)
- Claudia D Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximillian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Clarissa Campbell
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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6
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Li L, Peng H, Li Z, Zhou F, Yu Q. FTO-mediated regulation of Kupffer cell polarization and interleukin-6 secretion promotes biliary epithelial cell proliferation in intrahepatic bile duct stones. Cytojournal 2024; 21:83. [PMID: 39917013 PMCID: PMC11801660 DOI: 10.25259/cytojournal_193_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/26/2024] [Indexed: 02/09/2025] Open
Abstract
Objective Intrahepatic cholangiolithiasis (Intrahepatic bile duct stones, IBDSs) is a common hepatobiliary disease characterized by bile duct obstruction and inflammation, often leading to severe complications such as cholangitis, cirrhosis, and cholangiocarcinoma. This study investigates the role of fat mass and obesity-associated (FTO) protein, an RNA demethylase, in regulating Kupffer cell (KC) polarization, interleukin (IL)-6 secretion, and subsequent human intrahepatic biliary epithelial cell (HiBEC) proliferation in IBDS. Material and Methods Liver tissues from patients with IBDS were analyzed for FTO expression, KC M2 polarization, and IL-6 levels. In vitro experiments with FTO silencing in KCs were conducted to examine the effects on M2 polarization, IL-6 production, and HiBEC proliferation. Mechanistic analysis focused on the c-Jun N-terminal kinase (JNK)/p38 and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways. Results The patients with IBDS showed significantly higher KC M2 polarization, elevated FTO expression, and increased IL-6 levels relative to the controls. Without FTO silencing, IL-6 secretion and HiBEC proliferation remained at high baseline levels. However, FTO silencing reduced M2 polarization, IL-6 secretion, and HiBEC proliferation through the JNK/p38 pathway. Activating the PI3K/AKT pathway partially reversed these inhibitory effects. Conclusion FTO plays a critical role in IBDS by promoting the M2 polarization of KCs, which leads to increased IL-6 secretion and induced pathological HiBEC proliferation. Targeting FTO may represent a novel therapeutic strategy for managing IBDS and preventing disease progression.
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Affiliation(s)
- Lixiang Li
- Department of Hepatobiliary Surgery, Lujiang County People’s Hospital, Hefei, China
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
- The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei, China
| | - Hui Peng
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
- The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei, China
| | - Ziyi Li
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
- The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei, China
| | - Fuhai Zhou
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
- The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei, China
| | - Qingsheng Yu
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
- The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei, China
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Wu J, Wen L, Liu X, Li Q, Sun Z, Liang C, Xie F, Li X. Silybin: A Review of Its Targeted and Novel Agents for Treating Liver Diseases Based on Pathogenesis. Phytother Res 2024; 38:5713-5740. [PMID: 39310970 DOI: 10.1002/ptr.8347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/02/2024] [Accepted: 09/09/2024] [Indexed: 12/13/2024]
Abstract
Liver disease represents a significant global public health concern. Silybin, derived from Silybum marianum, has been demonstrated to exhibit a range of beneficial properties, including anti-inflammatory, antioxidative, antifibrotic, antiviral, and cytoprotective effects. These attributes render it a promising candidate for the treatment of liver fibrosis, cirrhosis, liver cancer, viral hepatitis, non-alcoholic fatty liver disease, and other liver conditions. Nevertheless, its low solubility and low bioavailability have emerged as significant limitations in its clinical application. To address these limitations, researchers have developed a number of silybin formulations. This study presents a comprehensive review of the results of research on silybin for the treatment of liver diseases in recent decades, with a particular focus on novel formulations based on the pathogenesis of the disease. These include approaches targeting the liver via the CD44 receptor, folic acid, vitamin A, and others. Furthermore, the study presents the findings of studies that have employed nanotechnology to enhance the low bioavailability and low solubility of silybin. This includes the use of nanoparticles, liposomes, and nanosuspensions. This study reviews the application of silybin preparations in the treatment of global liver diseases. However, further high-quality and more complete experimental studies are still required to gain a more comprehensive understanding of the efficacy and safety of these preparations. Finally, the study considers the issues that arise during the research of silybin formulations.
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Affiliation(s)
- Jijiao Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lin Wen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolian Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zihao Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuipeng Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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8
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Sun Z, Chen G. Impact of heterogeneity in liver matrix and intrahepatic cells on the progression of hepatic fibrosis. Tissue Cell 2024; 91:102559. [PMID: 39293139 DOI: 10.1016/j.tice.2024.102559] [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: 04/23/2024] [Revised: 08/05/2024] [Accepted: 09/09/2024] [Indexed: 09/20/2024]
Abstract
Liver fibrosis is a disease with a high prevalence worldwide. The development of hepatic fibrosis results from a combination of factors within the liver, such as extracellular matrix (ECM) deposition, hepatic stellate cells (HSCs) activation, collagen cross-linking, and inflammatory response. Heterogeneity in fibrotic liver is the result of a combination of heterogeneity in the intrahepatic microenvironment as well as heterogeneous expression of fibrosis-associated enzymes and cells, complicating the study of the mechanisms underlying the progression of liver fibrosis. The role of this heterogeneity on the crosstalk between cells and matrix and on the fibrotic process is worth exploring. In this paper, we will describe the phenomenon and mechanism of heterogeneity of liver matrix and intrahepatic cells in the process of hepatic fibrosis and discuss the crosstalk between heterogeneous factors on the development of fibrosis. The elucidation of heterogeneity is important for a deeper understanding of the pathological mechanisms of liver fibrosis as well as for clinical diagnosis and targeted therapies.
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Affiliation(s)
- Zhongtao Sun
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
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9
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Lozzi I, Arnold A, Barone M, Johnson JC, Sinn BV, Eschrich J, Gebert P, Wang R, Hu M, Feldbrügge L, Schirmeier A, Reutzel-Selke A, Malinka T, Krenzien F, Schöning W, Modest DP, Pratschke J, Sauer IM, Felsenstein M. Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma. Oncoimmunology 2024; 13:2406052. [PMID: 39359389 PMCID: PMC11445892 DOI: 10.1080/2162402x.2024.2406052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 08/06/2024] [Accepted: 09/14/2024] [Indexed: 10/04/2024] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation. Methods Liver tissue samples were collected during 2008-2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53). Results CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression. Conclusions These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC.
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Affiliation(s)
- Isis Lozzi
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alexander Arnold
- Department of Pathology, CCM, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Matthias Barone
- Translational Immunology, Berlin Institute of Health & Charité University Medicine, Berlin, Germany
| | - Juliette Claire Johnson
- Translational Immunology, Berlin Institute of Health & Charité University Medicine, Berlin, Germany
| | - Bruno V Sinn
- Department of Pathology, CCM, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Johannes Eschrich
- Department of Hepatology and Gastroenterology, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
| | - Pimrapat Gebert
- Institute of Biometry and Clinical Epidemiology, CCM, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ruonan Wang
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mengwen Hu
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Linda Feldbrügge
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
| | - Anja Schirmeier
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anja Reutzel-Selke
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thomas Malinka
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
| | - Wenzel Schöning
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Dominik P Modest
- Department of Hematology, Oncology, and Cancer Immunology, CCM, CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
- DKFZ, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Johann Pratschke
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Matthäus Felsenstein
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
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10
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Khaksari M, Pourali M, Rezaei Talabon S, Gholizadeh Navashenaq J, Bashiri H, Amiresmaili S. Protective effects of 17-β-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response. Cytokine 2024; 181:156686. [PMID: 38991382 DOI: 10.1016/j.cyto.2024.156686] [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: 04/20/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/13/2024]
Abstract
Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERβ) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1β, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.
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Affiliation(s)
- Mohammad Khaksari
- Neuroscince and Endocrinology and Metabolism Research Centers, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | | | | | | | - Hamideh Bashiri
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Ira
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11
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Yang Z, Xia H, Lai J, Qiu L, Lin J. Artesunate alleviates sepsis-induced liver injury by regulating macrophage polarization via the lncRNA MALAT1/PTBP1/IFIH1 axis. Diagn Microbiol Infect Dis 2024; 110:116383. [PMID: 38889486 DOI: 10.1016/j.diagmicrobio.2024.116383] [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: 01/31/2024] [Revised: 05/13/2024] [Accepted: 05/24/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND The present study aimed to explore the regulatory effects of artesunate on macrophage polarization in sepsis. METHODS Cell models and mice models were established using lipopolysaccharide (LPS), followed by treatment with various concentrations of artesunate. The phenotype of the macrophages was determined by flow cytometry. RNA immunoprecipitation was used to confirm the binding between MALAT1 and polypyrimidine tract-binding protein 1 (PTBP1), as well as between PTBP1 and interferon-induced helicase C domain-containing protein 1 (IFIH1). RESULTS Treatment with artesunate inhibited M1 macrophage polarization in Kupffer cells subjected to LPS stimulation by downregulating MALAT1. Furthermore, MALAT1 abolished the inhibitory effect of artesunate on M1 macrophage polarization by recruiting PTBP1 to promote IFIH. In vivo experiments confirmed that artesunate alleviated septic liver injury by affecting macrophage polarization via MALAT1. CONCLUSION The present study showed that artesunate alleviates LPS-induced sepsis in Kupffer cells by regulating macrophage polarization via the lncRNA MALAT1/PTBP1/IFIH1 axis.
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Affiliation(s)
- Zhaobin Yang
- Department of Medical Intensive Care Unit, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, Fujian Province, China
| | - Hao Xia
- Department of Medical Intensive Care Unit, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, Fujian Province, China
| | - Jiawei Lai
- Department of Medical Intensive Care Unit, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, Fujian Province, China
| | - Luzhen Qiu
- Department of Medical Intensive Care Unit, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, Fujian Province, China.
| | - Jiandong Lin
- Department of Intensive Care Unit, The First Affiliated Hospital of Fujian Medical University, Fuzhou City, Fujian Province, China.
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12
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Zhuang L, Jia N, Zhang L, Zhang Q, Antwi SO, Sartorius K, Wu K, Sun D, Xi D, Lu Y. Gpbar-1/cAMP/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167266. [PMID: 38806072 DOI: 10.1016/j.bbadis.2024.167266] [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: 10/30/2023] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
Acute cholestatic liver injury (ACLI) is a disease associated with bile duct obstruction that causes liver inflammation and apoptosis. Although G protein-coupled bile acid receptor1 (Gpbar-1) has diverse metabolic roles, its involvement in ACLI-associated immune activation remains unclear. Liver tissues and blood samples from 20 patients with ACLI and 20 healthy individuals were analyzed using biochemical tests, H&E staining, western blotting, and immunohistochemistry to verify liver damage and expression of Gpbar-1. The expression of Gpbar-1, cAMP/PKA signaling, and the NLRP3 inflammasome was tested in wild-type (WT) and Gpbar-1 knockdown (si-Gpbar-1) mice with ACLI induced by bile duct ligation (BDL) and in primary Kupffer cells (KCs) with or without Gpbar-1-siRNA. The results showed that total bile acids and Gpbar-1 expressions were elevated in patients with ACLI. Gpbar-1 knockdown significantly worsened BDL-induced acute hepatic damage, inflammation, and liver apoptosis in vivo. Knockdown of Gpbar-1 heightened KC sensitivity to lipopolysaccharide (LPS) stimulation. Gpbar-1 activation inhibited LPS-induced pro-inflammatory responses in normal KCs but not in Gpbar-1-knockdown KCs. Notably, NLRP3-ASC inflammasome expression was effectively enhanced by Gpbar-1 deficiency. Additionally, Gpbar-1 directly increased intracellular cAMP levels and PKA phosphorylation, thus disrupting the NLRP3-ASC inflammasome. The pro-inflammatory characteristic of Gpbar-1 deficiency was almost neutralized by the NLRP3 inhibitor CY-09. In vitro, M1 polarization was accelerated in LPS-stimulated Gpbar-1-knockdown KCs. Therapeutically, Gpbar-1 deficiency exacerbated BDL-induced ACLI, which could be rescued by inhibition of the NLRP3-ASC inflammasome. Our study reveal that Gpbar-1 may act as a novel immune-mediated regulator of ACLI by inhibiting the NLRP3-ASC inflammasome.
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Affiliation(s)
- Lin Zhuang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China; Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China
| | - Naixin Jia
- Department of Hepatobiliary Surgery, Kunshan First People's Hospital affiliated to Jiangsu University, Kunshan, Jiangsu 215300, China
| | - Li Zhang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China
| | - Qi Zhang
- Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China
| | - Samuel O Antwi
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Kurt Sartorius
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; School of Laboratory Medicine and Molecular Sciences, College of Health Sciences, University of Kwazulu-Natal, Durban 4041, South Africa; UKZN Gastrointestinal Cancer Research Unit, University of Kwazulu-Natal, Durban 4041, South Africa
| | - Kejia Wu
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China
| | - Donglin Sun
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China.
| | - Dong Xi
- Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China.
| | - Yunjie Lu
- Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; Department of Hepatopancreatobiliary surgery, The First Affiliated Hospital of Soochow University, Suzhou 215100, China.
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14
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Wang J, Lu H, Li Q. Hepatic macrophage niche: a bridge between HBV-mediated metabolic changes with intrahepatic inflammation. Front Immunol 2024; 15:1414594. [PMID: 39091506 PMCID: PMC11291371 DOI: 10.3389/fimmu.2024.1414594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/02/2024] [Indexed: 08/04/2024] Open
Abstract
Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV's exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression.
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Affiliation(s)
- Jun Wang
- The Third People’s Hospital of Shenzhen (National Clinical Research Center for Infectious Diseases) and The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
- Clinical Research Center, The Fifth People’s Hospital of Wuxi, Jiangnan University, Wuxi, Jiangsu, China
| | - Hongzhou Lu
- The Third People’s Hospital of Shenzhen (National Clinical Research Center for Infectious Diseases) and The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Qian Li
- The Third People’s Hospital of Shenzhen (National Clinical Research Center for Infectious Diseases) and The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
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15
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Ding X, Pang Y, Liu Q, Zhang H, Wu J, Lei J, Zhang T. GO-PEG Represses the Progression of Liver Inflammation via Regulating the M1/M2 Polarization of Kupffer Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306483. [PMID: 38229561 DOI: 10.1002/smll.202306483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 01/03/2024] [Indexed: 01/18/2024]
Abstract
As a highly promising nanomaterial, exploring the impact of the liver, a vital organ, stands out as a crucial focus in the examination of its biological effects. Kupffer cells (KCs) are one of the first immune cells to contact with exotic-substances in liver. Therefore, this study investigates the immunomodulatory effects and mechanisms of polyethylene glycol-modified graphene oxide (GO-PEG) on KCs. Initial RNA-seq and KEGG pathway analyses reveal the inhibition of the TOLL-like receptor, TNF-α and NOD-like receptor pathways in continually stimulated KCs exposed to GO-PEG. Subsequent biological experiments validate that a 48-hour exposure to GO-PEG alleviates LPS-induced KCs immune activation, characterized by a shift in polarization from M1 to M2. The underlying mechanism involves the absorption of double-stranded RNA/single-stranded RNA, inhibiting the activation of TLR3 and TLR7 in KCs. Employing a Kupffer/AML12 cell co-culture model and animal studies, it is observed that GO-PEG indirectly inhibit oxidative stress, mitochondrial dysfunction, and apoptosis in AML12 cells, partially mitigating systemic inflammation and preserving liver tissue/function. This effect is attributed to the paracrine interaction between KCs and hepatocytes. These findings suggest a meaningful and effective strategy for treating liver inflammation, particularly when combined with anti-inflammatory drugs.
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Affiliation(s)
- Xiaomeng Ding
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Yanting Pang
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Qing Liu
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Haopeng Zhang
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Jiawei Wu
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Jialin Lei
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Ting Zhang
- Ministry of Education Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China
- Jiangsu key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210009, China
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16
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Pham HN, Pham L, Sato K. Deconvolution analysis identified altered hepatic cell landscape in primary sclerosing cholangitis and primary biliary cholangitis. Front Med (Lausanne) 2024; 11:1327973. [PMID: 38818402 PMCID: PMC11138208 DOI: 10.3389/fmed.2024.1327973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Introduction Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are characterized by ductular reaction, hepatic inflammation, and liver fibrosis. Hepatic cells are heterogeneous, and functional roles of different hepatic cell phenotypes are still not defined in the pathophysiology of cholangiopathies. Cell deconvolution analysis estimates cell fractions of different cell phenotypes in bulk transcriptome data, and CIBERSORTx is a powerful deconvolution method to estimate cell composition in microarray data. CIBERSORTx performs estimation based on the reference file, which is referred to as signature matrix, and allows users to create custom signature matrix to identify specific phenotypes. In the current study, we created two custom signature matrices using two single cell RNA sequencing data of hepatic cells and performed deconvolution for bulk microarray data of liver tissues including PSC and PBC patients. Methods Custom signature matrix files were created using single-cell RNA sequencing data downloaded from GSE185477 and GSE115469. Custom signature matrices were validated for their deconvolution performance using validation data sets. Cell composition of each hepatic cell phenotype in the liver, which was identified in custom signature matrices, was calculated by CIBERSORTx and bulk RNA sequencing data of GSE159676. Deconvolution results were validated by analyzing marker expression for the cell phenotype in GSE159676 data. Results CIBERSORTx and custom signature matrices showed comprehensive performance in estimation of population of various hepatic cell phenotypes. We identified increased population of large cholangiocytes in PSC and PBC livers, which is in agreement with previous studies referred to as ductular reaction, supporting the effectiveness and reliability of deconvolution analysis in this study. Interestingly, we identified decreased population of small cholangiocytes, periportal hepatocytes, and interzonal hepatocytes in PSC and PBC liver tissues compared to healthy livers. Discussion Although further studies are required to elucidate the roles of these hepatic cell phenotypes in cholestatic liver injury, our approach provides important implications that cell functions may differ depending on phenotypes, even in the same cell type during liver injury. Deconvolution analysis using CIBERSORTx could provide a novel approach for studies of specific hepatic cell phenotypes in liver diseases.
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Affiliation(s)
- Hoang Nam Pham
- Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University—Central Texas, Killeen, TX, United States
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
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Mao J, Tan L, Tian C, Wang W, Zhang H, Zhu Z, Li Y. Research progress on rodent models and its mechanisms of liver injury. Life Sci 2024; 337:122343. [PMID: 38104860 DOI: 10.1016/j.lfs.2023.122343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.
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Affiliation(s)
- Jingxin Mao
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Cheng Tian
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Hao Zhang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Zhaojing Zhu
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Yan Li
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China.
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18
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Zhou L, Lu G, Nie Y, Ren Y, Shi JS, Xue Y, Xu ZH, Geng Y. Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut-liver axis. Gut Microbes 2024; 16:2370634. [PMID: 38935546 PMCID: PMC11212577 DOI: 10.1080/19490976.2024.2370634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 06/17/2024] [Indexed: 06/29/2024] Open
Abstract
Diet is a key player in gut-liver axis. However, the effect of different dietary patterns on gut microbiota and liver functions remains unclear. Here, we used rodent standard chow and purified diet to mimic two common human dietary patterns: grain and plant-based diet and refined-food-based diet, respectively and explored their impacts on gut microbiota and liver. Gut microbiota experienced a great shift with notable increase in Desulfovibrio, gut bile acid (BA) levels elevated significantly, and liver inflammation was observed in mice fed with the purified diet. Liver inflammation and elevated gut BA levels also occurred in mice fed with the chow diet after receiving Desulfovibrio desulfuricans ATCC 29,577 (DSV). Restriction of sulfur-containing amino acids (SAAs) prevented liver injury mainly through higher hepatic antioxidant and detoxifying ability and reversed the elevated BA levels due to excess Desulfovibrio. Ex vivo fermentation of human fecal microbiota with primary BAs demonstrated that DSV enhanced production of secondary BAs. Higher concentration of both primary and secondary BAs were found in the gut of germ-free mice after receiving DSV. In conclusion, Restriction of SAAs in diet may become an effective dietary intervention to prevent liver injury associated with excess Desulfovibrio in the gut.
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Affiliation(s)
- Lingxi Zhou
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China
| | - Gexue Lu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Yawen Nie
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Yilin Ren
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jin-Song Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Yuzheng Xue
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Zheng-Hong Xu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China
- College of Biomass Science and Engineering, Sichuan University, Chengdu, China
| | - Yan Geng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
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19
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Wang MQ, Zhang KH, Liu FL, Zhou R, Zeng Y, Chen AL, Yu Y, Xia Q, Zhu CC, Lin CZ. Wedelolactone alleviates cholestatic liver injury by regulating FXR-bile acid-NF-κB/NRF2 axis to reduce bile acid accumulation and its subsequent inflammation and oxidative stress. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155124. [PMID: 38014837 DOI: 10.1016/j.phymed.2023.155124] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/09/2023] [Accepted: 09/27/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Cholestatic liver diseases (CLD) comprise a variety of disorders of bile formation, which causes chronic exposure to bile acid (BA) in the liver generally and results in hepatotoxicity and progressive hepatobiliary injury. Wedelolactone (7-methoxy-5, 11, 12-trihydroxy-coumestan, WED), the natural active compound derived from Ecliptae Herba, has been reported with valuable bioactivity for liver protection. Nevertheless, the effect of WED on cholestatic liver injury (CLI) remains unexplored. PURPOSE The present study aims to elucidate the protective effect of WED on Alpha-naphthylisothiocyanate (ANIT)-induced CLI mice, and to investigate its potential pharmacological mechanism. METHODS The anit-cholestatic and hepatoprotective effects of WED were evaluated in ANIT-induced CLI mice. Non-targeted metabolomics study combined with ingenuity pathway analysis (IPA) was used to explore the key mechanism of WED. The BA metabolic profile in enterohepatic circulation was analyzed to evaluate the effect of WED in regulating BA metabolism. Furthermore, molecular dynamics (MD) simulation and cellular thermal shift assay (CETSA) were used to simulate and verify the targeting activation of WED on the Farnesoid X receptor (FXR). The core role of FXR in WED promoting BA transportation, and alleviating BA accumulation-induced hepatotoxicity was further evaluated in WT and FXR knockout mice or hepatocytes. RESULTS WED dose-dependently alleviated ANIT-induced cholestasis and liver injury in mice, and simultaneously suppressed the signaling pathway of nuclear factor-kappa B/nuclear factor-erythroid 2-related factor 2 (NF-κB/NRF2) to relieve inflammation and oxidative stress. At the metabolite level, WED improved the metabolic disorder in CLI mice focusing on the metabolism of BA, arachidonic acid, and glycerophospholipid, that closely related to the process of BA regulation, inflammation, and oxidative damage. WED targeting activated FXR, which then transcribed its target genes, including the bile salt export pump (BSEP) and the BA transporter, and subsequently increased BA transportation to restore the damaged enterohepatic circulation of BA. Meanwhile, WED alleviated hepatic BA accumulation and protected the liver from BA-induced damage via NF-κB/NRF2 signaling pathway. Furthermore, FXR deficiency suppressed the protective effect of WED in vitro and in vivo. CONCLUSION WED regulated BA metabolism and alleviated hepatic damage in cholestasis. It protected the liver according to adjusted BA transportation and relieved BA accumulation-related hepatotoxicity via FXR-bile acid-NF-κB/NRF2 axis. Our study provides novel insights that WED might be a promising strategy for cholestatic liver disease.
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Affiliation(s)
- Mei-Qi Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kai-Hui Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fang-Le Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yun Zeng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - A-Li Chen
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yang Yu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Quan Xia
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Chen-Chen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Chao-Zhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
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20
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Xu GX, Wei S, Yu C, Zhao SQ, Yang WJ, Feng YH, Pan C, Yang KX, Ma Y. Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions. Front Cell Dev Biol 2023; 11:1199519. [PMID: 37261074 PMCID: PMC10228659 DOI: 10.3389/fcell.2023.1199519] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/05/2023] [Indexed: 06/02/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging as the leading causes of liver disease worldwide. These conditions can lead to cirrhosis, liver cancer, liver failure, and other related ailments. At present, liver transplantation remains the sole treatment option for end-stage NASH, leading to a rapidly growing socioeconomic burden. Kupffer cells (KCs) are a dominant population of macrophages that reside in the liver, playing a crucial role in innate immunity. Their primary function includes phagocytosing exogenous substances, presenting antigens, and triggering immune responses. Moreover, they interact with other liver cells during the pathogenesis of NAFLD, and this crosstalk may either delay or exacerbate disease progression. Stimulation by endogenous signals triggers the activation of KCs, resulting in the expression of various inflammatory factors and chemokines, such as NLRP3, TNF-α, IL-1B, and IL-6, and contributing to the inflammatory cascade. In the past 5 years, significant advances have been made in understanding the biological properties and immune functions of KCs in NAFLD, including their interactions with tissue molecules, underlying molecular mechanisms, signaling pathways, and relevant therapeutic interventions. Having a comprehensive understanding of these mechanisms and characteristics can have enormous potential in guiding future strategies for the prevention and treatment of NAFLD.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yong Ma
- *Correspondence: Kun-Xing Yang, ; Yong Ma,
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21
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Engin AB, Engin A, Engin ED, Memis L. Does lithium attenuate the liver damage due to oxidative stress and liver glycogen depletion in experimental common bile duct obstruction? Toxicol Appl Pharmacol 2023; 466:116489. [PMID: 36963521 DOI: 10.1016/j.taap.2023.116489] [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: 12/08/2022] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/26/2023]
Abstract
In extrahepatic cholestasis, the molecular mechanisms of liver damage due to bile acid accumulation remain elusive. In this study, the activation of glutamatergic receptors was hypothesized to be responsible for bile acid-induced oxidative stress and liver damage. Recent evidence showed that lithium, as an N-methyl-d-aspartate receptor (NMDAR) GluN2B subunit inhibitor, may act on the glutamate/NMDAR signaling axis. Guinea pigs were assigned to four groups, as sham laparotomy (SL), bile duct ligated (BDL), lithium-treated SL (SL + Li) and lithium-treated BDL (BDL + Li) groups. Cholestasis-induced liver injury was evaluated by aspartate aminotransferase (AST), alanine transaminase (ALT), interleukin-6 (IL-6), tissue malondialdehyde (MDA), copper‑zinc superoxide dismutase and reduced glutathione levels. The liability of glutamate/NMDAR signaling axis was clarified by glutamate levels in both plasma and liver samples, with the production of nitric oxide (NO), as well as with the serum calcium concentrations. Blood glucose, glucagon, insulin levels and glucose consumption rates, in addition to tissue glycogen were measured to evaluate the liver glucose-glycogen metabolism. A high liver damage index (AST/ALT) was calculated in BDL animals in comparison to SL group. In the BDL animals, lithium reduced plasma NO and glutamate in addition to tissue glutamate concentrations, while serum calcium increased. The antioxidant capacities and liver glycogen contents significantly increased, whereas blood glucose levels unchanged and tissue MDA levels decreased 3-fold in lithium-treated cholestatic animals. It was concluded that lithium largely protects the cholestatic hepatocyte from bile acid-mediated damage by blocking the NMDAR-GluN2B subunit.
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Affiliation(s)
- Ayse Basak Engin
- Gazi University, Faculty of Pharmacy, Department of Toxicology, Ankara, Turkey.
| | - Atilla Engin
- Gazi University, Faculty of Medicine, Department of General Surgery, Ankara, Turkey
| | - Evren Doruk Engin
- Ankara University, Biotechnology Institute, Gumusdere Campus, Kecioren, Ankara, Turkey
| | - Leyla Memis
- Gazi University, Faculty of Medicine, Department of Pathology, Ankara, Turkey
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22
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Nimphy J, Ibrahim S, Dayoub R, Kubitza M, Melter M, Weiss TS. Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun. Int J Mol Sci 2023; 24:ijms24098107. [PMID: 37175814 PMCID: PMC10179097 DOI: 10.3390/ijms24098107] [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: 04/11/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.
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Affiliation(s)
- Jonas Nimphy
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Sara Ibrahim
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Rania Dayoub
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Marion Kubitza
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Michael Melter
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Thomas S Weiss
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
- Center for Liver Cell Research, University Hospital Regensburg, 93053 Regensburg, Germany
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23
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Dunster JL, Gibbins JM, Nelson MR. Exploring the constituent mechanisms of hepatitis: a dynamical systems approach. MATHEMATICAL MEDICINE AND BIOLOGY : A JOURNAL OF THE IMA 2023; 40:24-48. [PMID: 36197900 PMCID: PMC10009886 DOI: 10.1093/imammb/dqac013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/07/2022]
Abstract
Hepatitis is the term used to describe inflammation in the liver. It is associated with a high rate of mortality, but the underlying disease mechanisms are not completely understood and treatment options are limited. We present a mathematical model of hepatitis that captures the complex interactions between hepatocytes (liver cells), hepatic stellate cells (cells in the liver that produce hepatitis-associated fibrosis) and the immune components that mediate inflammation. The model is in the form of a system of ordinary differential equations. We use numerical techniques and bifurcation analysis to characterize and elucidate the physiological mechanisms that dominate liver injury and its outcome to a healthy or unhealthy, chronic state. This study reveals the complex interactions between the multiple cell types and mediators involved in this complex disease and highlights potential problems in targeting inflammation in the liver therapeutically.
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Affiliation(s)
| | - Jonathan M Gibbins
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, RG6 6AS, UK
| | - Martin R Nelson
- School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
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24
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Wu X, Jiang D, Yang Y, Li S, Ding Q. Modeling drug-induced liver injury and screening for anti-hepatofibrotic compounds using human PSC-derived organoids. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:6. [PMID: 36864321 PMCID: PMC9981852 DOI: 10.1186/s13619-022-00148-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 11/01/2022] [Indexed: 03/04/2023]
Abstract
Preclinical models that can accurately predict the toxicity and efficacy of candidate drugs to human liver tissue are in urgent need. Human liver organoid (HLO) derived from human pluripotent stem cells offers a possible solution. Herein, we generated HLOs, and demonstrated the utility of these HLOs in modeling a diversity of phenotypes associated with drug-induced liver injury (DILI), including steatosis, fibrosis, and immune responses. Phenotypic changes in HLOs after treatment with tool compounds such as acetaminophen, fialuridine, methotrexate, or TAK-875 showed high concordance with human clinical data in drug safety testings. Moreover, HLOs were able to model liver fibrogenesis induced by TGFβ or LPS treatment. We further devised a high-content analysis system, and established a high-throughput anti-fibrosis drug screening system using HLOs. SD208 and Imatinib were identified that can significantly suppress fibrogenesis induced by TGFβ, LPS, or methotrexate. Taken together, our studies demonstrated the potential applications of HLOs in drug safety testing and anti-fibrotic drug screening.
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Affiliation(s)
- Xiaoshan Wu
- grid.28056.390000 0001 2163 4895School of Biotechnology, East China University of Science and Technology, Shanghai, 200237 P. R. China ,grid.410726.60000 0004 1797 8419CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 P. R. China ,School of Pharmacy, Fujian Health College, Fujian, 350101 P. R. China
| | - Dacheng Jiang
- grid.410726.60000 0004 1797 8419CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 P. R. China
| | - Yi Yang
- grid.28056.390000 0001 2163 4895School of Biotechnology, East China University of Science and Technology, Shanghai, 200237 P. R. China
| | - Shuang Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
| | - Qiurong Ding
- School of Biotechnology, East China University of Science and Technology, Shanghai, 200237, P. R. China. .,CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China. .,Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, P. R. China.
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25
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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26
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Luo Y, Kang J, Luo J, Yan Z, Li S, Lu Z, Song Y, Zhang X, Yang J, Liu A. Hepatocytic AP-1 and STAT3 contribute to chemotaxis in alphanaphthylisothiocyanate-induced cholestatic liver injury. Toxicol Lett 2023; 373:184-193. [PMID: 36460194 DOI: 10.1016/j.toxlet.2022.11.020] [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: 08/07/2022] [Revised: 11/24/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188-9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid. The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis. The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl3, there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI.
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Affiliation(s)
- Yishuang Luo
- School of Medicine, Ningbo University, 315211 Ningbo, China; Ningbo Haishu District Center for Disease Control and Prevention, 315000 Ningbo, China
| | - Jinyu Kang
- School of Medicine, Ningbo University, 315211 Ningbo, China; The Affiliated Lihuili Hospital, Ningbo University, 315000 Ningbo, China
| | - Jia Luo
- School of Medicine, Ningbo University, 315211 Ningbo, China
| | - Zheng Yan
- School of Medicine, Ningbo University, 315211 Ningbo, China
| | - Shengtao Li
- School of Medicine, Ningbo University, 315211 Ningbo, China
| | - Zhuoheng Lu
- School of Medicine, Ningbo University, 315211 Ningbo, China
| | - Yufei Song
- The Affiliated Lihuili Hospital, Ningbo University, 315000 Ningbo, China
| | - Xie Zhang
- The Affiliated Lihuili Hospital, Ningbo University, 315000 Ningbo, China
| | - Julin Yang
- Ningbo College of Health Sciences, 315100 Ningbo, China
| | - Aiming Liu
- School of Medicine, Ningbo University, 315211 Ningbo, China.
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27
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De Muynck K, Vanderborght B, De Ponti FF, Gijbels E, Van Welden S, Guilliams M, Scott CL, Beschin A, Vinken M, Lefere S, Geerts A, Verhelst X, Van Vlierberghe H, Devisscher L. Kupffer Cells Contested as Early Drivers in the Pathogenesis of Primary Sclerosing Cholangitis. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:366-379. [PMID: 36642171 DOI: 10.1016/j.ajpath.2022.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 01/15/2023]
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic chronic immune-mediated cholestatic liver disease characterized by fibro-inflammatory bile duct strictures, progressive hepatobiliary fibrosis, and gut-liver axis disruption. The pathophysiology of PSC remains insufficiently characterized, which hampers the development of effective therapies. Hepatic macrophages (MFs) are implicated in PSC pathogenesis, but the exact role of Kupffer cells (KCs) is unclear. Using the latest markers to discriminate resident KCs (ResKCs) from their monocyte-derived counterparts (MoKCs), and two models for intrahepatic and extrahepatic cholestasis, respectively, this study shows that CLEC4F+TIM4+ ResKCs are depleted after chronic cholestatic liver injury, whereas infiltrating CLEC4F+TIM4- MoKCs are already enriched during the acute phase. Transcriptional profiling of hepatic MF subsets during early cholestatic injury indicates that ResKCs are indeed activated and that MoKCs express even higher levels of pro-inflammatory and proliferative markers compared with ResKCs. Conditional depletion of KCs, by using Clec4fDTR transgenic mice, before and during early cholestasis induction had no effect, however, on the composition of the hepatic myeloid cell pool following injury progression and did not affect disease outcomes. Taken together, these results provide new insights on the heterogeneity of the MF pool during experimental PSC and evidence that depletion of resident and activated KCs during sclerosing cholangitis does not affect disease outcome in mice.
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Affiliation(s)
- Kevin De Muynck
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium; Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium; Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Federico F De Ponti
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, Vlaams Instituut voor Biotechnologie-UGent Center for Inflammation Research, Ghent, Belgium
| | - Eva Gijbels
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium; Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sophie Van Welden
- Inflammatory Bowel Disease Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Intestinal Barrier Signaling in Disease and Therapy, Vlaams Instituut voor Biotechnologie-UGent Center for Inflammation Research, Ghent, Belgium
| | - Martin Guilliams
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium; Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, Vlaams Instituut voor Biotechnologie-UGent Center for Inflammation Research, Ghent, Belgium
| | - Charlotte L Scott
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, Vlaams Instituut voor Biotechnologie-UGent Center for Inflammation Research, Ghent, Belgium
| | - Alain Beschin
- Cellular & Molecular Immunology Research Group, Vrije Universiteit Brussel, Brussels, Belgium; Myeloid Cell Immunology Lab, Vlaams Instituut voor Biotechnologie-Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Anja Geerts
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Xavier Verhelst
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, Ghent, Belgium.
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Shearn CT, Anderson AL, Miller CG, Noyd RC, Devereaux MW, Balasubramaniyan N, Orlicky DJ, Schmidt EE, Sokol RJ. Thioredoxin reductase 1 regulates hepatic inflammation and macrophage activation during acute cholestatic liver injury. Hepatol Commun 2023; 7:e0020. [PMID: 36633484 PMCID: PMC9833450 DOI: 10.1097/hc9.0000000000000020] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/27/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND AND AIMS Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by periportal inflammation with progression to hepatic fibrosis and ultimately cirrhosis. We recently reported that the thioredoxin antioxidant response is dysregulated during primary sclerosing cholangitis. The objective of this study was to examine the impact of genetic and pharmacological targeting of thioredoxin reductase 1 (TrxR1) on hepatic inflammation and liver injury during acute cholestatic injury. APPROACH AND RESULTS Primary mouse hepatocytes and intrahepatic macrophages were isolated from 3-day bile duct ligated (BDL) mice and controls. Using wildtype and mice with a liver-specific deletion of TrxR1 (TrxR1LKO), we analyzed the effect of inhibition or ablation of TrxR1 signaling on liver injury and inflammation. Immunohistochemical analysis of livers from BDL mice and human cholestatic patients revealed increased TrxR1 staining in periportal macrophages and hepatocytes surrounding fibrosis. qPCR analysis of primary hepatocytes and intrahepatic macrophages revealed increased TrxR1 mRNA expression following BDL. Compared with sham controls, BDL mice exhibited increased inflammation, necrosis, and increased mRNA expression of pro-inflammatory cytokines, fibrogenesis, the NLRP3 inflammatory complex, and increased activation of NFkB, all of which were ameliorated in TrxR1LKO mice. Importantly, following BDL, TrxR1LKO induced periportal hepatocyte expression of Nrf2-dependent antioxidant proteins and increased mRNA expression of basolateral bile acid transporters with reduced expression of bile acid synthesis genes. In the acute BDL model, the TrxR1 inhibitor auranofin (10 mg/kg/1 d preincubation, 3 d BDL) ameliorated BDL-dependent increases in Nlrp3, GsdmD, Il1β, and TNFα mRNA expression despite increasing serum alanine aminotransferase, aspartate aminotransferase, bile acids, and bilirubin. CONCLUSIONS These data implicate TrxR1-signaling as an important regulator of inflammation and bile acid homeostasis in cholestatic liver injury.
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Affiliation(s)
- Colin T. Shearn
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Aimee L. Anderson
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Colin G. Miller
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Reed C. Noyd
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Michael W. Devereaux
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Nata Balasubramaniyan
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Edward E. Schmidt
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, Montana, USA
- Laboratory of Redox Biology, Departments of Pharmacology and Physiology, University of Veterinary Medicine Budapest, Hungary
| | - Ronald J. Sokol
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado, USA
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29
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Tsomidis I, Notas G, Xidakis C, Voumvouraki A, Samonakis DN, Koulentaki M, Kouroumalis E. Enzymes of Fibrosis in Chronic Liver Disease. Biomedicines 2022; 10:biomedicines10123179. [PMID: 36551935 PMCID: PMC9776355 DOI: 10.3390/biomedicines10123179] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction: Liver fibrosis has been extensively studied at the cellular and molecular level, but very few data exist on the final enzymatic stages of collagen synthesis (prolyl hydroxylase, PH) and degradation (matrix metalloproteinases, MMPs), particularly in primary biliary cholangitis (PBC). Aim: We studied enzyme activities in liver tissue from patients with chronic liver diseases and compared them to normal livers. Patients: Eighteen patients with PBC of early and late stages (Ludwig’s classification) and seven on treatment with ursodeoxycholate (UDCA) were studied and compared to 34 patients with alcoholic liver disease (ALD), 25 patients with chronic viral liver disease and five normal biopsies. Sera were available from a total of 140 patients. Methods: The tritiated water released from the tritiated proline was measured in PH assessment. 14C intact and heat-denatured collagen substrates were used to measure collagenase and gelatinases, respectively. 3H Elastin was the substrate for elastase. In serum, ELISAs were used for MMP-1, TIMP-1, and TIMP-2 measurements while MMP-2 and MMP-9 were estimated by zymography. Results: PH was significantly increased in early and late PBC. Collagenase was reduced only in the late stages (p < 0.01), where the ratio PH/collagenase was increased. UDCA treatment restored values to almost normal. Gelatinases were reduced in late stages (p < 0.05). In contrast to PBC and ALD fibrosis, collagen synthesis is not increased in viral fibrosis. The balance shifted towards collagen deposition due to reduced degradation. Interestingly, gelatinolytic activity is not impaired in ALD. Elastase was similar to controls in all diseases studied. TIMP-1 was reduced in early PBC and viral and alcoholic hepatitis and cirrhosis (p < 0.001). Conclusions: (1) There is evidence that collagen synthesis increases in the early stages of PBC, but the collagenolytic mechanism may compensate for the increased synthesis. (2) In viral disease, fibrosis may be due to decreased degradation rather than increased synthesis. (3) The final biochemical stages of liver fibrosis may be quantitatively different according to underlying etiology.
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Affiliation(s)
- Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Chalkidiki, Greece
- Laboratory of Gastroenterology and Hepatology, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
| | - George Notas
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
| | - Costas Xidakis
- Laboratory of Gastroenterology and Hepatology, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Chalkidiki, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology, PAGNI University Hospital, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
| | - Mairi Koulentaki
- Department of Gastroenterology, PAGNI University Hospital, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
- Department of Gastroenterology, PAGNI University Hospital, School of Medicine, University of Crete, 71500 Heraklion, Crete, Greece
- Correspondence:
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The Clostridium Metabolite P-Cresol Sulfate Relieves Inflammation of Primary Biliary Cholangitis by Regulating Kupffer Cells. Cells 2022; 11:cells11233782. [PMID: 36497042 PMCID: PMC9736483 DOI: 10.3390/cells11233782] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/12/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE To study the effect and mechanism of the Clostridium metabolite p-Cresol sulfate (PCS) in primary biliary cholangitis (PBC). METHODS Gas chromatography-mass spectrometry (GC-MS) was used to detect differences in tyrosine, phenylalanine, tryptophan, PCS, and p-Cresyl glucuronide (PCG) between the serum of PBC patients and healthy controls. In vivo experiments, mice were divided into the normal control, PBC group, and PBC tyrosine group. GC-MS was used to detect PCS and PCG. Serum and liver inflammatory factors were compared between groups along with the polarization of liver Kupffer cells. Additionally, PCS was cultured with normal bile duct epithelial cells and Kupffer cells, respectively. PCS-stimulated Kupffer cells were co-cultured with lipopolysaccharide-injured bile duct epithelial cells to detect changes in inflammatory factors. RESULTS Levels of tyrosine and phenylalanine were increased, but PCS level was reduced in PBC patients, with PCG showing a lower concentration distribution in both groups. PCS in PBC mice was also lower than those in normal control mice. After oral administration of tyrosine feed to PBC mice, PCS increased, liver inflammatory factors were decreased, and anti-inflammatory factors were increased. Furthermore, Kupffer cells in the liver polarized form M1 transitioned to M2. PCS can damage normal bile duct epithelial cells and suppress the immune response of Kupffer cells. But PCS protects bile duct epithelial cells damaged by LPS through Kupffer cells. CONCLUSIONS PCS produced by Clostridium-metabolized tyrosine reduced PBC inflammation, suggesting that intervention by food, or supplementation with PCS might represent an effective clinical strategy for treating PBC.
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31
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Wang Y, Zhang R, Li J, Han X, Lu H, Su J, Liu Y, Tian X, Wang M, Xiong Y, Lan T, Zhang G, Liu Z. MiR-22-3p and miR-29a-3p synergistically inhibit hepatic stellate cell activation by targeting AKT3. Exp Biol Med (Maywood) 2022; 247:1712-1731. [PMID: 35833537 PMCID: PMC9638961 DOI: 10.1177/15353702221108379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Hepatic fibrosis (HF) is a worldwide health problem for which there is no medically effective drug treatment at present, and which is characterized by activation of hepatic stellate cells (HSCs) and excessive extracellular matrix (ECM) deposition. The HF model in cholestatic rats by ligating the common bile duct was induced and the differentially expressed miRNAs in the liver tissues were analyzed by microarray, which showed that miR-22-3p and miR-29a-3p were significantly downregulated in bile-duct ligation (BDL) rat liver compared with the sham control. The synergistic anti-HF activity and molecular mechanism of miR-22-3p and miR-29a-3p by targeting AKT serine/threonine kinase 3 (AKT3) in HSCs were explored. The expression levels of miR-22-3p and miR-29a-3p were downregulated in activated LX-2 and human primary normal hepatic fibroblasts (NFs), whereas AKT3 was found to be upregulated in BDL rat liver and activated LX-2 cells. The proliferation, colony-forming, and migration ability of LX-2 were inhibited synergistically by miR-22-3p and miR-29a-3p. In addition, cellular senescence was induced and the expressions of the LX-2 fibrosis markers COL1A1 and α-SMA were inhibited by miR-22-3p and miR-29a-3p synergistically. Subsequently, these two miRNAs binding to the 3'UTR of AKT3 mRNA was predicted and evidenced by the luciferase reporter assay. Furthermore, the proliferation, migration, colony-forming ability, and the expression levels of COL1A1 and α-SMA were promoted and cellular senescence was inhibited by AKT3 in LX-2 cells. Thus, miR-22-3p/miR-29a-3p/AKT3 regulates the activation of HSCs, providing a new avenue in the study and treatment of HF.
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Affiliation(s)
- Yitong Wang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Ronghua Zhang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Jingwu Li
- The Cancer Institute, Hebei Key Laboratory of Molecular Oncology, Tangshan People’s Hospital, Tangshan 063001, China
| | - Xiangyang Han
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Hongjian Lu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Jinghui Su
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Yutan Liu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Xiaoli Tian
- Paraplegia Sanatorium of Tangshan, Tangshan 063000, China
| | - Meimei Wang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Yanan Xiong
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
| | - Tao Lan
- Hepatobiliary Pancreatic Surgery Department, Cangzhou People’s Hospital, Cangzhou 061000, China
| | - Guangling Zhang
- Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, School of Clinical Medicine, North China University of Science and Technology, Tangshan 063210, China,Guangling Zhang.
| | - Zhiyong Liu
- Health Science Center, North China University of Science and Technology, Tangshan 063210, China
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Song M, Chen Z, Qiu R, Zhi T, Xie W, Zhou Y, Luo N, Fuqian Chen, Liu F, Shen C, Lin S, Zhang F, Gao Y, Liu C. Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury. Redox Biol 2022; 55:102404. [PMID: 35868156 PMCID: PMC9304672 DOI: 10.1016/j.redox.2022.102404] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/01/2022] [Accepted: 07/10/2022] [Indexed: 11/28/2022] Open
Abstract
The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner. NLRP3-inhibition by geniposidic acid (GPA), a novel NLRP3-specific covalent inhibitor that directly interacts with NLRP3, in hepatocytes and macrophages abated BA-induced inflammation. Moreover, NLRP3-deletion or its inhibition mitigated ANIT-induced cholestatic inflammation, whereas disrupting the crosstalk between hepatic macrophages and hepatocytes attenuated the hepatoprotective effect of GPA against ANIT-induced cholestatic inflammation. Therefore, blocking this crosstalk by suppressing NLRP3 inflammasome activation may represent a novel therapeutic strategy for cholestasis.
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Key Words
- alanine aminotransferase, alt
- α-naphthalene isothiocyanate, anit
- apoptosis-associated speck-like protein, asc
- aspartate transaminase, ast
- β-mercaptoethanol, β-me
- bile acids, ba
- bile duct ligation, bdl
- biotinylated gpa, bio-gpa
- bone-marrow-derived macrophage, bmdm
- geniposidic acid, gpa
- kupffer cells, kcs
- nod-like receptor protein 3, nlrp3
- primary mouse hepatocytes, pmhs
- primary sclerosing cholangitis, psc
- taurocholic acid, tca
- total bile acid, tba
- total bilirubin, tbil
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Affiliation(s)
- Meng Song
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Zijun Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Ruian Qiu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Tingwei Zhi
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Wenmin Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Yingya Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Nachuan Luo
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, 510632, China
| | - Fuqian Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Fang Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Chuangpeng Shen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Sheng Lin
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Fengxue Zhang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Yong Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
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Wang T, Li XJ, Qin LH, Liang X, Xue HH, Guo J, Li SF, Zhang LW. Better detoxifying effect of ripe forsythiae fructus over green forsythiae fructus and the potential mechanisms involving bile acids metabolism and gut microbiota. Front Pharmacol 2022; 13:987695. [PMID: 36034807 PMCID: PMC9417252 DOI: 10.3389/fphar.2022.987695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Forsythiae Fructus (FF), the fruit of Forsythia suspensa (Thunb.) Vahl. (Lianqiao), is one of the most fundamental herbs in Traditional Chinese Medicines (TCM), mainly due to its heat-clearing and detoxifying effects. There are two types of FF, the greenish fruits that start to ripen (GF) and the yellow fruits that are fully ripe (RF), called “Qingqiao” and “Laoqiao” referred to the Chinese Pharmacopoeia, respectively. It undergoes a complex series of changes during the maturation of FF. However, the clinical uses and preparation of phytopharmaceuticals of FF have not been distinguished to date. Moreover, there is limited information on the study of the difference in pharmacological activity between RF and GF. In this study, a rat model of bile duct ligation (BDL)-induced cholestasis was used to compare the differences in their effects. RF was found to have better results than GF in addressing toxic bile acids (BAs) accumulation and related pathological conditions caused by BDL. The underlying mechanism may be related to the interventions of gut microbiota. The results of the present study suggest that the better detoxifying effect of RF than GF may be indirectly exerted through the regulation of gut microbiota and thus the improvement of BAs metabolism.
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Affiliation(s)
- Tao Wang
- Institute of Molecule Science, Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China
- Department of Pharmacy, Changzhi Medical College, Changzhi, China
| | - Xu-Jiong Li
- Department of Physiology, Changzhi Medical College, Changzhi, China
- *Correspondence: Xu-Jiong Li, ; Li-Wei Zhang,
| | - Ling-Hao Qin
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xue Liang
- Institute of Molecule Science, Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China
| | - Huan-Huan Xue
- Institute of Molecule Science, Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China
| | - Jing Guo
- Institute of Molecule Science, Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China
| | - Shi-Fei Li
- Institute of Molecule Science, Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China
| | - Li-Wei Zhang
- Institute of Molecule Science, Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China
- *Correspondence: Xu-Jiong Li, ; Li-Wei Zhang,
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34
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Beyer D, Hoff J, Sommerfeld O, Zipprich A, Gaßler N, Press AT. The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation. Mol Med 2022; 28:84. [PMID: 35907792 PMCID: PMC9338540 DOI: 10.1186/s10020-022-00510-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/13/2022] [Indexed: 12/25/2022] Open
Abstract
Liver failure is a life-threatening complication of infections restricting the host's response to infection. The pivotal role of the liver in metabolic, synthetic, and immunological pathways enforces limits the host's ability to control the immune response appropriately, making it vulnerable to ineffective pathogen resistance and tissue damage. Deregulated networks of liver diseases are gradually uncovered by high-throughput, single-cell resolved OMICS technologies visualizing an astonishing diversity of cell types and regulatory interaction driving tolerogenic signaling in health and inflammation in disease. Therefore, this review elucidates the effects of the dysregulated host response on the liver, consequences for the immune response, and possible avenues for personalized therapeutics.
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Affiliation(s)
- Dustin Beyer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany
| | - Jessica Hoff
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.,Center for Sepsis Control and Care, Jena University Hospital, Bachstr. 18, 07743, Jena, Germany
| | - Oliver Sommerfeld
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.,Center for Sepsis Control and Care, Jena University Hospital, Bachstr. 18, 07743, Jena, Germany
| | - Alexander Zipprich
- Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany
| | - Nikolaus Gaßler
- Pathology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany. .,Center for Sepsis Control and Care, Jena University Hospital, Bachstr. 18, 07743, Jena, Germany. .,Medical Faculty, Friedrich-Schiller-University Jena, Kastanienstr. 1, 07747, Jena, Germany.
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35
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Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022; 19:432-450. [PMID: 35165436 DOI: 10.1038/s41575-021-00566-7] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
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36
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Li W, Chang N, Li L. Heterogeneity and Function of Kupffer Cells in Liver Injury. Front Immunol 2022; 13:940867. [PMID: 35833135 PMCID: PMC9271789 DOI: 10.3389/fimmu.2022.940867] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022] Open
Abstract
Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.
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Vasina EA, Kulezneva JV, Melekhina OV, Tsvirku VV, Efanov MG, Patrushev IV, Kurmanseitova LI, Bondar LV. Hepatobiliary scintigraphy in the assessment of bile outflow in patients with biliodigestive anastomosis. ANNALY KHIRURGICHESKOY GEPATOLOGII = ANNALS OF HPB SURGERY 2022; 27:82-93. [DOI: 10.16931/1995-5464.2022-2-82-93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim. To determine the character of bile outflow in patients who underwent biliary tract reconstructive surgery without any clinical and instrumental evidence of the stricture of biliodigestive anastomosis.Materials and methods. The authors analyzed the findings of radionuclide biliary tract studies conducted in 102 patients with biliodigestive anastomosis from 2016 to 2020. The significant relationship between clinical data and hepatobiliary scintigraphy results was confirmed using Fisher’s exact test.Results. In 75 patients (73.5%), bile outflow disturbance was attributed to the efferent loop motility. Of these cases, 3 (4%) involved paresis of the efferent loop, while 70 (93.3%) exhibited multiple episodes of reflux from the efferent loop into the biliodigestive anastomosis and the intrahepatic bile ducts. In 2 patients (2.6%) showing no clinical signs of chronic cholangitis, a rare reflux from the efferent loop into the biliodigestive anastomosis and the intrahepatic bile ducts was noted.Conclusions. Efferent loop dysfunction can greatly disturb bile outflow following the formation of a biliodigestive anastomosis, thus creating conditions for the development of complications.
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Affiliation(s)
- E. A. Vasina
- Moscow Clinical Scientific Center named after A.S. Loginov
| | | | | | - V. V. Tsvirku
- Moscow Clinical Scientific Center named after A.S. Loginov
| | - M. G. Efanov
- Moscow Clinical Scientific Center named after A.S. Loginov
| | | | - L. I. Kurmanseitova
- Clinic of Endoscopic and Minimally Invasive Surgery, Stavropol State Medical University
| | - L. V. Bondar
- Moscow Clinical Scientific Center named after A.S. Loginov
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Pham L, Kyritsi K, Zhou T, Ceci L, Baiocchi L, Kennedy L, Chakraborty S, Glaser S, Francis H, Alpini G, Sato K. The Functional Roles of Immune Cells in Primary Liver Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:826-836. [PMID: 35337836 PMCID: PMC9194651 DOI: 10.1016/j.ajpath.2022.02.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/05/2022] [Accepted: 02/18/2022] [Indexed: 12/12/2022]
Abstract
Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Incidence of liver cancer has been increasing in recent years, and the 5-year survival is <20%. HCC and CCA are often accompanied with a dense stroma coupled with infiltrated immune cells, which is referred to as the tumor microenvironment. Populations of specific immune cells, such as high density of CD163+ macrophages and low density of CD8+ T cells, are associated with prognosis and survival rates in both HCC and CCA. Immune cells in the tumor microenvironment can be a therapeutic target for liver cancer treatments. Previous studies have introduced immunotherapy using immune checkpoint inhibitors, pulsed dendritic cells, or transduced T cells, to enhance cytotoxicity of immune cells and inhibit tumor growth. This review summarizes current understanding of the roles of immune cells in primary liver cancer covering HCC and CCA.
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Affiliation(s)
- Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, Texas
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Leonardo Baiocchi
- Hepatology Unit, Department of Medicine, University of Tor Vergata, Rome, Italy
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
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Chung T, Park YN. Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front Med (Lausanne) 2022; 9:857140. [PMID: 35433771 PMCID: PMC9008308 DOI: 10.3389/fmed.2022.857140] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with an increasing incidence worldwide. Recently, histopathologic classification of small duct type and large duct type iCCA has been introduced. Both these types of tumors exhibit differences in clinicopathological features, mutational profiles, and prognosis. Small duct type iCCA is composed of non-mucin-producing cuboidal cells, whereas large duct type iCCA is composed of mucin-producing columnar cells, reflecting different cells of origin. Large duct type iCCA shows more invasive growth and poorer prognosis than small duct type iCCA. The background liver of small duct type iCCA often shows chronic liver disease related to hepatitis B or C viral infection, or alcoholic or non-alcoholic fatty liver disease/steatohepatitis, in contrast to large duct type iCCA that is often related to hepatolithiasis and liver fluke infection. Cholangiolocarcinoma is a variant of small duct type iCCA composed of naïve-looking cuboidal cells forming cords or ductule-like structures, and shows better prognosis than the conventional small duct type. Fibrous tumor stroma, one of the characteristic features of iCCA, contains activated fibroblasts intermixed with innate and adaptive immune cells. The types of stroma (mature versus immature) are related to tumor behavior and prognosis. Low tumor-infiltrating lymphocyte density, KRAS alteration, and chromosomal instability are related to immune-suppressive tumor microenvironments with resistance to programmed death 1/ programmed death ligand 1 blockade. Data from recent large-scale exome analyses have revealed the heterogeneity in the molecular profiles of iCCA, showing that small duct type iCCA exhibit frequent BAP1, IDH1/2 hotspot mutations and FGFR2 fusion, in contrast to frequent mutations in KRAS, TP53, and SMAD4 observed in large duct type iCCA. Multi-omics analyses have proposed several molecular classifications of iCCA, including inflammation class and proliferation class. The inflammation class is enriched in inflammatory signaling pathways and expression of cytokines, while the proliferation class has activated oncogenic growth signaling pathways. Diverse pathologic features of iCCA and its associated multi-omics characteristics are currently under active investigation, thereby providing insights into precision therapeutics for patients with iCCA. This review provides the latest knowledge on the histopathologic classification of iCCA and its associated molecular features, ranging from tumor microenvironment to genomic and transcriptomic research.
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Affiliation(s)
- Taek Chung
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Young Nyun Park
- Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Young Nyun Park,
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Kinaneh S, Hijaze W, Mansour-Wattad L, Hammoud R, Zaidani H, Kabala A, Hamoud S. Heparanase Inhibition Prevents Liver Steatosis in E 0 Mice. J Clin Med 2022; 11:jcm11061672. [PMID: 35329997 PMCID: PMC8954723 DOI: 10.3390/jcm11061672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 12/22/2022] Open
Abstract
Background: Non-alcoholic fatty liver disease affects up to 30% of adults in the USA, and is associated with a higher incidence of chronic liver morbidity and mortality. Several molecular pathways are involved in the pathology of liver steatosis, including lipid uptake, lipogenesis, lipolysis, and beta-oxidation. The enzyme heparanase has been implicated in liver steatosis. Herein, we investigated the effect of heparanase inhibition on liver steatosis in E0 mice. Methods: In vivo experiments: Male wild-type mice fed with either chow diet (n = 4) or high-fat diet (n = 6), and male E0 mice fed with chow diet (n = 8) or high-fat diet (n = 33) were included. Mice on a high-fat diet were treated for 12 weeks with PG545 at low dose (6.4 mg/kg/week, ip, n = 6) or high dose (13.3 mg/kg/week, ip, n = 7), SST0001 (1.2 mg/mouse/day, ip, n = 6), or normal saline (control, n = 14). Animals were sacrificed two days after inducing peritonitis. Serum was analyzed for biochemical parameters. Mouse peritoneal macrophages (MPMs) were harvested and analyzed for lipid content. Livers were harvested for histopathological analysis of steatosis, lipid content, and the expression of steatosis-related factors at the mRNA level. In vitro experiments: MPMs were isolated from untreated E0 mice aged 8–10 weeks and were cultured and treated with either PG545 or SST0001, both at 50 µg/mL for 24 h, followed by assessment of mRNA expression of steatosis related factors. Results: Heparanase inhibition significantly attenuated the development of liver steatosis, as was evident by liver histology and lipid content. Serum analysis indicated lowering of cholesterol and triglycerides levels in mice treated with heparanase inhibitors. In liver tissue, assessment of mRNA expression of key factors in lipid uptake, lipolysis, lipogenesis, and beta-oxidation exhibited significant downregulation following PG545 treatment and to a lesser extent when SST0001 was applied. However, in vitro treatment of MPMs with PG545, but not SST0001, resulted in increased lipid content in these cells, which is opposed to their effect on MPMs of treated mice. This may indicate distinct regulatory pathways in the system or isolated macrophages following heparanase inhibition. Conclusion: Heparanase inhibition significantly attenuates the development of liver steatosis by decreasing tissue lipid content and by affecting the mRNA expression of key lipid metabolism regulators.
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Affiliation(s)
- Safa Kinaneh
- Department of Physiology, Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (S.K.); (A.K.)
| | - Walaa Hijaze
- Department of Emergency Medicine, Rambam Health Care Campus, Haifa 3109601, Israel; (W.H.); (H.Z.)
| | - Lana Mansour-Wattad
- Department of Internal Medicine E, Rambam Health Care Campus, Haifa 3109601, Israel;
| | - Rawan Hammoud
- Faculty of Biotechnology, Hadassah Academic College, Jerusalem 9101001, Israel;
| | - Hisam Zaidani
- Department of Emergency Medicine, Rambam Health Care Campus, Haifa 3109601, Israel; (W.H.); (H.Z.)
| | - Aviva Kabala
- Department of Physiology, Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (S.K.); (A.K.)
| | - Shadi Hamoud
- Department of Internal Medicine E, Rambam Health Care Campus, Haifa 3109601, Israel;
- Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel
- Correspondence: ; Tel.: +972-4-7772300; Fax: +972-4-7771691
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Li Q, Che F, Wei Y, Jiang HY, Zhang Y, Song B. Role of noninvasive imaging in the evaluation of intrahepatic cholangiocarcinoma: from diagnosis and prognosis to treatment response. Expert Rev Gastroenterol Hepatol 2021; 15:1267-1279. [PMID: 34452581 DOI: 10.1080/17474124.2021.1974294] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Intrahepatic cholangiocarcinoma is the second most common liver cancer. Desmoplastic stroma may be revealed as distinctive histopathologic findings favoring intrahepatic cholangiocarcinoma. Meanwhile, a range of imaging manifestations is often accompanied with rich desmoplastic stroma in intrahepatic cholangiocarcinoma, which can indicate large bile duct ICC, and a higher level of cancer-associated fibroblasts with poor prognosis and weak treatment response. AREAS COVERED We provide a comprehensive review of current state-of-the-art and recent advances in the imaging evaluation for diagnosis, staging, prognosis and treatment response of intrahepatic cholangiocarcinoma. In addition, we discuss precursor lesions, cells of origin, molecular mutation, which would cause the different histological classification. Moreover, histological classification and tumor microenvironment, which are related to the proportion of desmoplastic stroma with many imaging manifestations, would be also discussed. EXPERT OPINION The diagnosis, prognosis, treatment response of intrahepatic cholangiocarcinoma may be revealed as the presence and the proportion of desmoplastic stroma with a range of imaging manifestations. With the utility of radiomics and artificial intelligence, imaging is helpful for ICC evaluation. Multicentre, large-scale, prospective studies with external validation are in need to develop comprehensive prediction models based on clinical data, imaging findings, genetic parameters, molecular, metabolic, and immune biomarkers.
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Affiliation(s)
- Qian Li
- Department of Radiology, Sichuan University West China Hospital, Chengdu, China
| | - Feng Che
- Department of Radiology, Sichuan University West China Hospital, Chengdu, China
| | - Yi Wei
- Department of Radiology, Sichuan University West China Hospital, Chengdu, China
| | - Han-Yu Jiang
- Department of Radiology, Sichuan University West China Hospital, Chengdu, China
| | - Yun Zhang
- Department of Radiology, Sichuan University West China Hospital, Chengdu, China
| | - Bin Song
- Department of Radiology, Sichuan University West China Hospital, Chengdu, China
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De Muynck K, Vanderborght B, Van Vlierberghe H, Devisscher L. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective. Cells 2021; 10:2959. [PMID: 34831182 PMCID: PMC8616442 DOI: 10.3390/cells10112959] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
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Affiliation(s)
- Kevin De Muynck
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
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McClave SA. Can feeding strategies alter immune signaling and gut sepsis in critical illness? JPEN J Parenter Enteral Nutr 2021; 45:66-73. [PMID: 34477220 DOI: 10.1002/jpen.2260] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/19/2021] [Accepted: 08/31/2021] [Indexed: 11/06/2022]
Abstract
The insult necessitating admission to the intensive care unit propels the patient along a course involving increasing oxidative stress, immune dysregulation, and adverse outcomes. As the largest immune organ with the greatest microbial burden, the gastrointestinal tract may change the speed and direction the patient follows along this pathway. The gut's influence is mediated by a complex process of cross-talk immune signaling between the intestinal epithelium, the liver, and the microbiome. Agents which invoke this response vary from mitochondrial DNA, inflammatory cytokines, and bacterial organisms to short chain fatty acids and bile salts. The site of action of these agents again varies widely from Pattern Recognition Receptors, G protein receptors, and Farnesoid X receptors in the gut and liver to transcriptional factors in epithelial cells, hepatocytes, macrophages, and neutrophils. While the initial focus of response may be local within the gastrointestinal tract and liver, the process extends in a systemic manner to affect immune tissue and various organs at distant sites. The gut can modulate this cross-talk signaling through numerous strategies in design of nutritional therapy. The physiologic response to luminal nutrients and short chain fatty acids, and more novel approaches like use phosphorylated polyethylene glycol, bovine serum-derived immunoglobulin, and specialized pro-resolving molecules may help slow disease progression and even reverse the patient's course toward one of health and recovery. The optimal benefit to be derived from nutritional therapy may have more to do with the degree to which immune cross-talk signaling can be modified by such innovative strategies. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Stephen A McClave
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine
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Yang Y, Zhao Y, Zhang L, Zhang F, Li L. The Application of Mesenchymal Stem Cells in the Treatment of Liver Diseases: Mechanism, Efficacy, and Safety Issues. Front Med (Lausanne) 2021; 8:655268. [PMID: 34136500 PMCID: PMC8200416 DOI: 10.3389/fmed.2021.655268] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.
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Affiliation(s)
- Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel) 2021; 9:vaccines9050422. [PMID: 33922362 PMCID: PMC8146949 DOI: 10.3390/vaccines9050422] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
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Abstract
Clinical disorders that impair bile flow result in retention of bile acids and cholestatic liver injury, characterized by parenchymal cell death, bile duct proliferation, liver inflammation and fibrosis. However, the pathogenic role of bile acids in the development of cholestatic liver injury remains incompletely understood. In this review, we summarize the current understanding of this process focusing on the experimental and clinical evidence for direct effects of bile acids on each major cellular component of the liver: hepatocytes, cholangiocytes, stellate cells and immune cells. During cholestasis bile acids accumulated in the liver, causing oxidative stress and mitochondrial injury in hepatocytes. The stressed hepatocytes respond by releasing inflammatory cytokines through activation of specific signaling pathways and transcription factors. The recruited neutrophils and other immune cells then cause parenchymal cell death. In addition, bile acids also stimulate the proliferation of cholangiocytes and stellate cells that are responsible for bile duct proliferation and liver fibrosis. This review explores the evidence for bile acid involvement in these phenomena. The role of bile acid receptors, TGR5, FXR and the sphingosine-1-phosphate receptor 2 and the inflammasome are also examined. We hope that better understanding of these pathologic effects will facilitate new strategies for treating cholestatic liver injury.
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Affiliation(s)
- Shi-Ying Cai
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
| | - James L Boyer
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
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Taylor SA, Chen SY, Gadhvi G, Feng L, Gromer KD, Abdala-Valencia H, Nam K, Dominguez ST, Montgomery AB, Reyfman PA, Ostilla L, Wechsler JB, Cuda CM, Green RM, Perlman H, Winter DR. Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. PLoS One 2021; 16:e0244743. [PMID: 33411796 PMCID: PMC7790256 DOI: 10.1371/journal.pone.0244743] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Background & aims Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. Methods We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. Results We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. Conclusions We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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Affiliation(s)
- Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America
- * E-mail:
| | - Shang-Yang Chen
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Gaurav Gadhvi
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Liang Feng
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America
| | - Kyle D. Gromer
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America
| | - Hiam Abdala-Valencia
- Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Kiwon Nam
- Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Salina T. Dominguez
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Anna B. Montgomery
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Paul A. Reyfman
- Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Lorena Ostilla
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America
| | - Joshua B. Wechsler
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America
| | - Carla M. Cuda
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Richard M. Green
- Division of Gastroenterology and Hepatology, Northwestern University, Chicago, Illinois, United States of America
| | - Harris Perlman
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Deborah R. Winter
- Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
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Fabris L, Sato K, Alpini G, Strazzabosco M. The Tumor Microenvironment in Cholangiocarcinoma Progression. Hepatology 2021; 73 Suppl 1:75-85. [PMID: 32500550 PMCID: PMC7714713 DOI: 10.1002/hep.31410] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 05/07/2020] [Accepted: 05/16/2020] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of immune cells. Functional roles of the reactive tumor stroma are not fully elucidated; however, recent studies suggest that the tumor microenvironment plays a key role in the progression and invasiveness of CCA. CCA cells exchange autocrine/paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment. This crosstalk is under the control of signals mediated by various cytokines, chemokines, and growth factors. In addition, extracellular vesicles (EVs), exosomes and microvesicles, containing cargo mediators, such as proteins and RNAs, play a key role in cell-to-cell communication, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communications between CCA cells and other liver cells provide a potential novel target for the management of CCA. This review summarizes current understandings of the tumor microenvironment and intercellular communications in CCA and their role in tumor progression.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padua, Italy,Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Keisaku Sato
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT,Correspondence: Mario Strazzabosco MD, PhD, Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA,
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Damiris K, Tafesh ZH, Pyrsopoulos N. Efficacy and safety of anti-hepatic fibrosis drugs. World J Gastroenterol 2020; 26:6304-6321. [PMID: 33244194 PMCID: PMC7656211 DOI: 10.3748/wjg.v26.i41.6304] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/30/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Recent progress in our understanding of the pathways linked to progression from hepatic insult to cirrhosis has led to numerous novel therapies being investigated as potential cures and inhibitors of hepatic fibrogenesis. Liver cirrhosis is the final result of prolonged fibrosis, which is an intimate balance between fibrogenesis and fibrinolysis. A number of these complex mechanisms are shared across the various etiologies of liver disease. Thankfully, investigation has yielded some promising results in regard to reversal of fibrosis, particularly the indirect benefits associated with antiviral therapy for the treatment of hepatitis B and C and the farnesoid receptor agonist for the treatment of primary biliary cholangitis and metabolic associated fatty liver disease. A majority of current clinical research is focused on targeting metabolic associated fatty liver disease and its progression to metabolic steatohepatitis and ultimately cirrhosis, with some hope of potential standardized therapeutics in the near future. With our ever-evolving understanding of the underlying pathophysiology, these therapeutics focus on either controlling the primary disease (the initial trigger of fibrogenesis), interrupting receptor ligand interactions and other intracellular communications, inhibiting fibrogenesis, or even promoting resolution of fibrosis. It is imperative to thoroughly test these potential therapies with the rigorous standards of clinical therapeutic trials in order to ensure the highest standards of patient safety. In this article we will briefly review the key pathophysiological pathways that lead to liver fibrosis and present current clinical and experimental evidence that has shown reversibility of liver fibrosis and cirrhosis, while commenting on therapeutic safety.
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Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Zaid H Tafesh
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
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Sun X, Ye C, Deng Q, Chen J, Guo C. Contribution of glutaredoxin-1 to Fas s-glutathionylation and inflammation in ethanol-induced liver injury. Life Sci 2020; 264:118678. [PMID: 33127518 DOI: 10.1016/j.lfs.2020.118678] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/19/2020] [Accepted: 10/26/2020] [Indexed: 11/17/2022]
Abstract
AIMS The reversible protein S-glutathionylation (PSSG) modification of Fas augments apoptosis, which can be reversed by the cytosolic deglutathionylation enzyme glutaredoxin-1 (Grx1), but its roles in alcoholic liver injury remain unknown. Therefore, the objective of this study was to investigate the impact of genetic ablation of Grx1 on Fas S-glutathionylation (Fas-SSG) in regulating ethanol-induced injury. MATERIALS AND METHODS We evaluated the Grx1 activity and oxidative damage, hepatic injury related indicators, Fas-SSG, we also assess the nuclear factor-κB (NF-κB) signaling, its downstream signal, and Akt signaling cascades, Furthermore, the number of Kupffer cells and related proinflammatory cytokines between WT and Grx1- groups after alcohol exposure. KEY FINDINGS Ethanol-fed mice had increased Grx1 activity and oxidative damage in the liver. Grx1-deficient mice had more serious liver damage when exposed to ethanol compared to that of wild-type mice, accompanied by increased alanine aminotransferase and aspartate aminotransferase levels, Fas-SSG, cleaved caspase-3 and hepatocyte apoptosis. Grx1 ablation resulted in the suppression of ethanol-induced NF-κB signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-κB prevented Fas-induced apoptosis in WT mice but not Grx1-/- mice. Furthermore, the number of Kupffer cells and related proinflammatory cytokines, including Akt, were lower in Grx1-/- livers than those of the controls. SIGNIFICANCE Grx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.
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Affiliation(s)
- Xiaomin Sun
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Ultrasound, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Cuilian Ye
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Qin Deng
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jingyu Chen
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Ultrasound, Children's Hospital of Chongqing Medical University, Chongqing, China.
| | - Chunbao Guo
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
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