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Monti F, Perazza F, Leoni L, Stefanini B, Ferri S, Tovoli F, Zavatta G, Piscaglia F, Petroni ML, Ravaioli F. RANK-RANKL-OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives. Int J Mol Sci 2024; 25:9193. [PMID: 39273141 PMCID: PMC11395242 DOI: 10.3390/ijms25179193] [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: 08/05/2024] [Revised: 08/22/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.
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Affiliation(s)
- Federico Monti
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
| | - Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
| | - Laura Leoni
- Department of Dietetics and Clinical Nutrition, Maggiore-Bellaria Hospital, Azienda Unità Sanitaria Locale (AUSL), 40138 Bologna, Italy;
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Silvia Ferri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Guido Zavatta
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
- Unit of Clinical Nutrition and Metabolism, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.M.); (F.P.); (B.S.); (F.T.); (G.Z.); (F.P.); (M.L.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
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Ayyasamy R, Fan S, Czernik P, Lecka-Czernik B, Chattopadhyay S, Chakravarti R. 14-3-3ζ suppresses RANKL signaling by destabilizing TRAF6. J Biol Chem 2024; 300:107487. [PMID: 38908751 PMCID: PMC11331427 DOI: 10.1016/j.jbc.2024.107487] [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: 05/12/2024] [Accepted: 05/31/2024] [Indexed: 06/24/2024] Open
Abstract
Macrophages are essential regulators of inflammation and bone loss. Receptor activator of nuclear factor-κβ ligand (RANKL), a pro-inflammatory cytokine, is responsible for macrophage differentiation to osteoclasts and bone loss. We recently showed that 14-3-3ζ-knockout (YwhazKO) rats exhibit increased bone loss in the inflammatory arthritis model. 14-3-3ζ is a cytosolic adaptor protein that actively participates in many signaling transductions. However, the role of 14-3-3ζ in RANKL signaling or bone remodeling is unknown. We investigated how 14-3-3ζ affects osteoclast activity by evaluating its role in RANKL signaling. We utilized 14-3-3ζ-deficient primary bone marrow-derived macrophages obtained from wildtype and YwhazKO animals and RAW264.7 cells generated using CRISPR-Cas9. Our results showed that 14-3-3ζ-deficient macrophages, upon RANKL stimulation, have bigger and stronger tartrate-resistant acid phosphatase-positive multinucleated cells and increased bone resorption activity. The presence of 14-3-3ζ suppressed RANKL-induced MAPK and AKT phosphorylation, transcription factors (NFATC1 and p65) nuclear translocation, and subsequently, gene induction (Rank, Acp5, and Ctsk). Mechanistically, 14-3-3ζ interacts with TRAF6, an essential component of the RANKL receptor complex. Upon RANKL stimulation, 14-3-3ζ-TRAF6 interaction was increased, while RANK-TRAF6 interaction was decreased. Importantly, 14-3-3ζ supported TRAF6 ubiquitination and degradation by the proteasomal pathway, thus dampening the downstream RANKL signaling. Together, we show that 14-3-3ζ regulates TRAF6 levels to suppress inflammatory RANKL signaling and osteoclast activity. To the best of our knowledge, this is the first report on 14-3-3ζ regulation of RANKL signaling and osteoclast activation.
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Affiliation(s)
- R Ayyasamy
- Department of Physiology & Pharmacology, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA
| | - S Fan
- Department of Medical Microbiology & Immunology, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA
| | - P Czernik
- Department of Orthopedics, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA
| | - B Lecka-Czernik
- Department of Orthopedics, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA
| | - S Chattopadhyay
- Department of Medical Microbiology & Immunology, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA; Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - R Chakravarti
- Department of Physiology & Pharmacology, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA.
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Pham HN, Pham L, Sato K. Bioinformatic analysis identified novel candidate genes with the potentials for diagnostic blood testing of primary biliary cholangitis. PLoS One 2023; 18:e0292998. [PMID: 37844121 PMCID: PMC10578581 DOI: 10.1371/journal.pone.0292998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 10/03/2023] [Indexed: 10/18/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by intrahepatic bile duct destruction and cholestatic liver injury. Diagnosis of PBC is generally based on the existence of anti-mitochondrial antibody (AMA) in blood samples; however, some PBC patients are negative for serum AMA tests, and invasive liver histological testing is required in rare PBC cases. The current study seeks novel candidate genes that are associated with PBC status and have potentials for blood diagnostic testing. Human transcriptomic profiling data of liver and blood samples were obtained from Gene Expression Omnibus (GEO). Three GEO data series (GSE79850, GSE159676, and GSE119600) were downloaded, and bioinformatic analyses were performed. Various differentially expressed genes were identified in three data series by comparing PBC patients and control individuals. Twelve candidate genes were identified, which were upregulated in both liver tissues and blood samples of PBC patients in all three data series. The enrichment analysis demonstrated that 8 out of 12 candidate genes were associated with biological functions, which were closely related to autoimmune diseases including PBC. Candidate genes, especially ITGAL showed good potentials to distinguish PBC with other diseases. These candidate genes could be useful for diagnostic blood testing of PBC, although further clinical studies are required to evaluate their potentials as diagnostic biomarkers.
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Affiliation(s)
- Hoang Nam Pham
- Department of Life Sciences, University of Science and Technology of Hanoi, Hanoi, Vietnam
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University–Central Texas, Killeen, Texas, United States of America
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
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Sayed SZ, Abd El-Hafez AH, Abu El-Ela MA, Mourad MAF, Mousa SO. OPG/RANK/RANKL axis relation to cardiac iron-overload in children with transfusion-dependent thalassemia. Sci Rep 2023; 13:12568. [PMID: 37532711 PMCID: PMC10397306 DOI: 10.1038/s41598-023-39596-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 07/27/2023] [Indexed: 08/04/2023] Open
Abstract
OPG/RANK/RANKL axis was reportedly involved in initiating various diseases, especially bone and cardiovascular diseases. This study aimed to assess the relationship between some OPG, RANK, and RANKL polymorphisms and alleles and iron-overload-induced cardiomyopathy in children with transfusion-dependent thalassemia (TDT). This study included 80 TDT children and 80 age and sex-matched controls. Real-time PCR was done for rs207318 polymorphism for the OPG gene and rs1805034, rs1245811, and rs75404003 polymorphisms for the RANK gene, and rs9594782 and rs2277438 polymorphisms for the RANKL gene. Cardiac T2* MRI and ejection fraction (EF) were done to assess the myocardial iron status and cardiac function. In this study, there were no significant differences in frequencies of the studied polymorphisms between cases and controls (p > 0.05 in all). In TDT children, OPG rs2073618 (G > C) had a significant relation to myocardial iron overload (p = 0.02). Its C allele had significantly more frequent normal EF than its G allele (p = 0.04). RANK rs75404403 (C > DEL) had a significant relation to cardiac dysfunction (p = 0.02). Moreover, the C allele of that gene had significantly more frequent affected EF than its DEL allele (p = 0.02). The A allele of RANKL rs2277438 (G > A) had significantly less frequent severe cardiac iron overload than the G allele (p = 0.04). In conclusion, the OPG/ RANK/RANKL genes may act as genetic markers for iron-induced cardiomyopathy in TDT children. Some of the studied genes' polymorphisms and alleles were significantly related to myocardial iron overload and cardiac dysfunction in TDT children.
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Affiliation(s)
- Samira Zein Sayed
- Department of Pediatrics, Faculty of Medicine, Minia University, El Minya, Egypt
| | | | | | | | - Suzan Omar Mousa
- Department of Pediatrics, Faculty of Medicine, Minia University, El Minya, Egypt.
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Pugliese N, Arcari I, Aghemo A, Lania AG, Lleo A, Mazziotti G. Osteosarcopenia in autoimmune cholestatic liver diseases: Causes, management, and challenges. World J Gastroenterol 2022; 28:1430-1443. [PMID: 35582674 PMCID: PMC9048470 DOI: 10.3748/wjg.v28.i14.1430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/05/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidity. Further, sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients. The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected. Although timely diagnosis, prevention, and management of osteosarcopenia are crucial to limit the consequences, there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD. International guidelines recommend screening for bone disease at the time of diagnosis of CLD. However, the optimal monitoring strategies and treatments have not been defined yet and vary among centers. We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD, and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.
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Affiliation(s)
- Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Andrea G Lania
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
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Lleo A, Gershwin ME. Targeting the RANK/RANKL pathway in autoimmune disease and malignancy: future perspectives. Expert Rev Clin Immunol 2021; 17:933-936. [PMID: 34425712 DOI: 10.1080/1744666x.2021.1971972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/20/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
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The genetic architecture of primary biliary cholangitis. Eur J Med Genet 2021; 64:104292. [PMID: 34303876 DOI: 10.1016/j.ejmg.2021.104292] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/03/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genome-wide association studies (GWAS), which identified many variants predisposing or protecting toward the development of the disease. While a progressive endeavour toward the characterization of candidate loci and downstream pathways is currently ongoing, there is still a relatively large portion of heritability of PBC to be revealed. In addition, genetic variation behind progression of the disease and therapeutic response are mostly to be investigated yet. This review outlines the state-of-the-art regarding the genetic architecture of PBC and provides some hints for future investigations, focusing on the study of gene-gene interactions, the application of whole-genome sequencing techniques, and the investigation of X chromosome that can be helpful to cover the missing heritability gap in PBC.
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Clinical Management of Primary Biliary Cholangitis-Strategies and Evolving Trends. Clin Rev Allergy Immunol 2021; 59:175-194. [PMID: 31713023 DOI: 10.1007/s12016-019-08772-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PBC is a chronic progressive autoimmune disorder involving the destruction of intrahepatic small bile ducts, cholestasis, fibrosis, and ultimately cirrhosis if left untreated. It is largely driven by the autoimmune response, but bile acids and the intestinal microbiota are implicated in disease progression as well. The only drugs licensed for PBC are UDCA and OCA. UDCA as a first-line and OCA as a second-line therapy are safe and effective, but the lack of response in a significant portion of patients and inadequate control of symptoms such as fatigue and pruritus remain as concerns. Liver transplantation is an end-stage therapy for many patients refractory to UDCA, which gives excellent survival rates but also moderate to high recurrence rates. The limited options for FDA-approved PBC therapies necessitate the development of alternative approaches. Currently, a wide variety of experimental drugs exist targeting immunological and physiological aspects of PBC to suppress inflammation. Immunological therapies include drugs targeting immune molecules in the B cell and T cell response, and specific cytokines and chemokines implicated in inflammation. Drugs targeting bile acids are also noteworthy as bile acids can perpetuate hepatic inflammation and lead to fibrosis over time. These include FXR agonists, ASBT inhibitors, and PPAR agonists such as bezafibrate and fenofibrate. Nonetheless, many of these drugs can only delay disease progression and fail to enhance patients' quality of life. Nanomedicine shows great potential for treatment of autoimmune diseases, as it provides a new approach that focuses on tolerance induction rather than immunosuppression. Tolerogenic nanoparticles carrying immune-modifying agents can be engineered to safely and effectively target the antigen-specific immune response in autoimmune diseases. These may work well with PBC especially, given the anatomical features and immunological specificity of the disease. Nanobiological therapy is thus an area of highly promising research for future treatment of PBC.
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Abstract
Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Lleo A, Ma X, Gershwin ME, Invernizzi P. Letter to the Editor: Might Denosumab Fit in Primary Biliary Cholangitis Treatment? Hepatology 2020; 72:359-360. [PMID: 31863485 DOI: 10.1002/hep.31085] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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Arase Y, Kagawa T, Tanaka A. Reply. Hepatology 2020; 72:360-361. [PMID: 31863598 PMCID: PMC7496154 DOI: 10.1002/hep.31084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Yoshitaka Arase
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
- Division of Gastroenterology and Hepatology, Tokai University Oiso Hospital, Oisomachi, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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RANKL Is Involved in Runx2-Triggered Hepatic Infiltration of Macrophages in Mice with NAFLD Induced by a High-Fat Diet. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6953421. [PMID: 32596356 PMCID: PMC7273465 DOI: 10.1155/2020/6953421] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/11/2020] [Accepted: 04/30/2020] [Indexed: 12/25/2022]
Abstract
Background Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is significant in the activation of inflammation. Runt-related transcription factor 2 (Runx2) promotes the hepatic infiltration of macrophages in nonalcoholic fatty liver disease (NAFLD). We studied how RANKL affects Runx2-triggered macrophage infiltration in NAFLD. Method 30 male C57BL/6J mice at 4 weeks of age were utilized in this study, 20 mice received a high-fat diet (HFD), and 10 mice received standard rodent chow over 8 months. The histopathologic features of the liver were identified by H&E, Oil red O, and Masson staining. Runx2, RANKL, and F4/80 were analyzed by western blot, real-time PCR, and immunohistochemistry in vivo, respectively. Lentivirus or siRNA was utilized for transwell assay to investigate the role of RANKL in Runx2-induced macrophage migration in vitro. Results Compared to controls, during NAFLD development, HFD increased Runx2 and RANKL in vivo in NASH (P < 0.01). Meanwhile, a correlation between the expression of Runx2 and RANKL (P < 0.05) was evident. In addition, the hepatic infiltration of macrophages was increased upon HFD feeding, and analysis showed that the macrophage infiltration was correlated with the expression of Runx2 or RANKL (P < 0.05). In vitro, we found that overexpression or deficiency of Runx2 increased or decreased the production of RANKL in mHSCs. Then, transwell assay revealed that RANKL was involved in Runx2-induced macrophage migration. Conclusions Overall, RANKL is involved in Runx2-triggered macrophage migration during NAFLD pathogenesis, which may provide an underlying therapeutic target for NAFLD.
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Li Y, Xi Y, Tao G, Xu G, Yang Z, Fu X, Liang Y, Qian J, Cui Y, Jiang T. Sirtuin 1 activation alleviates primary biliary cholangitis via the blocking of the NF-κB signaling pathway. Int Immunopharmacol 2020; 83:106386. [PMID: 32193100 DOI: 10.1016/j.intimp.2020.106386] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 12/12/2022]
Abstract
This report sought to establish the mechanistic role of sirtuin-1 (Sirt1), a NAD+-dependent deacetylase in the modulation of primary biliary cholangitis (PBC) pathogenesis. 64 PBC patients (diagnosed based on practice guidelines for American Association for the Study of Liver Diseases) and 60 healthy controls were included in this study. Clinically, the mRNA expression level of Sirt1 in macrophages differentiated from peripheral blood mononuclear cells (PBMCs) of PBC subjects substantially decreased when compared with the healthy controls but not in other Sirt family genes (Sirt2-7). Consistent with clinical results, a PBC murine model showed that levels of Sirt1 significantly decreased in the liver and Kupffer cells of mice treated with polyinosinic/polycytidylic acid (poly I:C) for 16 weeks. A TAK1 inhibitor (NG25) prevented the poly I:C-induced Sirt1 protein level decreasing in Kupffer cells but not MAPK inhibitor. Sirt1 activators resveratrol (RSV) and SRT1720 (SRT) ameliorated poly I:C-induced hepatic injury observed via histopathologic analysis and decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the PBC murine model. Furthermore, Sirt1 activators significantly reduced pro-inflammatory cytokines levels such as interleukin-1 beta (IL-1β), IL-6, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in serum in poly I:C-induced mice. In addition, Sirt1 activators significantly inhibited the phosphorylated and acetylated levels of the RelA/p65 subunit of the nuclear transcription factor (NF-κB) but not the interferon regulatory factor (IRF) 3 in poly I:C-injured mice livers. Significantly, RSV improved the interaction between Sirt1 and p65, which may contribute to the decreased activity of NF-κB. In summary, the Sirt1 signaling pathway plays an essential role in the development of PBC and this may represent a novel approach and target for the treatment of PBC.
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Affiliation(s)
- Yong Li
- Department of Laboratory Medicine, First People's Hospital of Taicang, Taicang Hospital Affiliated to Suzhou University, Taicang 215400, Jiangsu, China
| | - Yanhai Xi
- Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Guohua Tao
- Department of Laboratory Medicine, First People's Hospital of Nantong, 226001 Jiangsu, China
| | - Guohua Xu
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Zhejiang, China
| | - Xingli Fu
- Jiangsu University Health Science Center, Zhenjiang, Jiangsu, China
| | - Yan Liang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Jianping Qian
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China
| | - Yanhong Cui
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China
| | - Tingwang Jiang
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China.
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Hao YL, Bian ZL, Ju LL, Liu Y, Qin G. RANK/RANKL Acts as a Protective Factor by Targeting Cholangiocytes in Primary Biliary Cholangitis. Dig Dis Sci 2020; 65:470-479. [PMID: 31377883 DOI: 10.1007/s10620-019-05758-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 07/22/2019] [Indexed: 12/09/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the highly selective autoimmune injury of small intrahepatic bile ducts. Studies reported that the cholangiocytes from PBC patients expressed significantly higher levels of both receptor activator of nuclear factor-kappa B (RANK) and its ligand RANKL. However, the accurate role of RANK/RANKL axis in PBC remains unclear. METHODS Forty patients with PBC were enrolled according to the inclusion criteria. The biochemical parameters (alkaline phosphatase, ALP; gamma-glutamyltransferase, GGT; alanine aminotransferase, ALT; aspartate transaminase, AST; total bilirubin, TB) were collected at baseline and followed-up after 6 months of treatment with ursodeoxycholic acid (UDCA, 15 mg/kg d). Stages of PBC were diagnosed based on liver biopsy histopathology according to Nakanuma's criteria. RANK expression in hepatic tissues was detected by immunohistochemistry. The cellular immunofluorescence method was used to locate the distribution of RANK in the human intrahepatic biliary epithelial cells (HIBECs) cultured in vitro. HIBECs were treated with RANKL at a concentration of 100 ng/ml or transfected with RANK-overexpressing lentivirus (LV-RANK). CCK-8 assay and cell cycle assay were used to detect the cell proliferation. Real-time PCR was used to detect the expression of IL-6, E-cadherin, VCAM, ICAM-1, TNF-α, and CD80. RESULTS RANK expression in liver biopsies from early PBC patients (stage I + stage II) was significantly lower than that from advanced PBC patients (stage III + stage IV) (1.7 ± 0.63 vs. 2.3 ± 0.45 scores, P < 0.05). High-RANK patients seemed to have better response to UDCA than low-RANK patients (88.9% vs. 40.9%, P < 0.05). The baseline biochemical parameters between the two groups were comparable. The decline percentages of ALP and GGT after UDCA treatment were more obvious in high-RANK patients than those in low-RANK patients (53.90% ± 9.82% vs. 23.93% ± 6.24%, P < 0.05; 74.11% ± 7.18% vs. 48.00% ± 8.17%, P < 0.05, respectively). HIBECs proliferation was significantly inhibited after treatment of RANKL or transfection with LV-RANK. Increased expression of IL-6 and E-cadherin was observed in HIBECs treated with RANKL or LV-RANK. CONCLUSION The overall hepatic RANK expression was associated with disease severity and biochemical response in PBC patients. Activation of RANK/RANKL signaling pathway inhibited cholangiocytes proliferation in vitro. Our study suggested that RANK/RANKL pathway might be a potential target of immunotherapy of PBC based on its involvement in the occurrence and development of the disease.
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Affiliation(s)
- Yan-Li Hao
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China
| | - Zhao-Lian Bian
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China.,Division of Gastroenterology and Hepatology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China
| | - Lin-Ling Ju
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China
| | - Yuan Liu
- Department of Gastroenterology, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China
| | - Gang Qin
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China.
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Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, Kather JN, Schmitt N, Kautz N, Breuhahn K, Ismail L, Heide D, Hetzer J, García-Beccaria M, Hövelmeyer N, Waisman A, Urbanik T, Mueller S, Gdynia G, Banales JM, Roessler S, Schirmacher P, Jäger D, Schölch S, Keitel V, Heikenwalder M, Schulze-Bergkamen H, Köhler BC. Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice. Gastroenterology 2019; 156:1190-1205.e14. [PMID: 30445013 DOI: 10.1053/j.gastro.2018.11.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 10/25/2018] [Accepted: 11/01/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Cholangiocyte proliferation and ductular reaction contribute to the onset and progression of liver diseases. Little is known about the role of the transcription factor nuclear factor-κB (NF-κB) in this process. We investigated the activities of the RELB proto-oncogene NF-κB subunit in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction. METHODS We obtained liver tissue samples from patients with primary sclerosing cholangitis, primary biliary cholangitis, hepatitis B or C virus infection, autoimmune hepatitis, alcoholic liver disease, or without these diseases (controls) from a tissue bank in Germany. Tissues were analyzed by immunohistochemistry for levels of RELB and lymphotoxin β (LTB). We studied mice with liver parenchymal cell (LPC)-specific disruption of the cylindromatosis (CYLD) lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (CyldΔLPC mice and Cyld/RelbΔLPC mice) and compared them with C57BL/6 mice (controls). Mice were fed 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or standard chow diets to induce biliary injury or were given injections of CCl4 to induce non-cholestatic liver fibrosis. Liver tissues were analyzed by histology, immunohistochemistry, immunoblots, in situ hybridization, and quantitative real-time polymerase chain reaction. Cholangiocytes were isolated from normal human liver, incubated with LTB receptor agonist, and transfected with small interfering RNAs to knock down RELB. RESULTS In liver tissues from patients with primary sclerosing cholangitis, primary biliary cholangitis, chronic infection with hepatitis B or C virus, autoimmune hepatitis, or alcoholic liver disease, we detected increased nuclear translocation of RELB and increased levels of LTB in cholangiocytes that formed reactive bile ducts compared with control liver tissues. Human cholangiocytes, but not those with RELB knockdown, proliferated with exposure to LTB. The phenotype of CyldΔLPC mice, which included ductular reaction, oval cell activation, and biliary fibrosis, was completely lost from Cyld/RelbΔLPC mice. Compared with livers from control mice, livers from CyldΔLPC mice (but not Cyld/RelbΔLPC mice) had increased levels of mRNAs encoding cytokines (LTB; CD40; and tumor necrosis factor superfamily [TNFSF] members TNFSF11 [RANKL], TNFSF13B [BAFF], and TNFSF14 [LIGHT]) produced by reactive cholangiocytes. However, these strains of mice developed similar levels of liver fibrosis in response to CCl4 exposure. CyldΔLPC mice and Cyld/RelbΔLPC mice had improved liver function on the DDC diet compared with control mice fed the DDC diet. CONCLUSION Reactive bile ducts in patients with chronic liver diseases have increased levels of LTB and nuclear translocation of RELB. RELB is required for the ductular reaction and development of biliary fibrosis in CyldΔLPC mice. Deletion of RELB and CYLD from LPCs protects mice from DDC-induced cholestatic liver fibrosis.
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Affiliation(s)
- Christin Elßner
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Benjamin Goeppert
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Longerich
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Anna-Lena Scherr
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Lahiri Kanth Nanduri
- German Cancer Consortium (DKTK) and Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technical University Dresden, Dresden, Germany
| | - Christian Rupp
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Jakob Nikolas Kather
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Nathalie Schmitt
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Nicole Kautz
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Kai Breuhahn
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Lars Ismail
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jenny Hetzer
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - María García-Beccaria
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Hövelmeyer
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Toni Urbanik
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Sebastian Mueller
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg, Germany
| | - Georg Gdynia
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV-EHU) CIBERehd, IKERBASQUE, San Sebastian, Spain
| | - Stephanie Roessler
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Sebastian Schölch
- German Cancer Consortium (DKTK) and Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technical University Dresden, Dresden, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Bruno Christian Köhler
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
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Lian M, Wang Q, Jiang X, Zhang J, Wei Y, Li Y, Li B, Chen W, Zhang H, Miao Q, Peng Y, Xiao X, Sheng L, Zhang W, Fang J, Tang R, Gershwin ME, Ma X. The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4-Related Sclerosing Cholangitis. Hepatology 2018; 68:1922-1936. [PMID: 29774578 DOI: 10.1002/hep.30095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/08/2018] [Accepted: 04/22/2018] [Indexed: 12/24/2022]
Abstract
The primary function of myeloid-derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune-mediated diseases. In immunoglobulin G4 (IgG4)-related disease (IgG4-RD), it has been hypothesized that there are selective regulatory defects that lead to a T helper 2 (Th2) bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4-related sclerosing cholangitis (IgG4-SC), the most common extrapancreatic involvement of IgG4-RD, as well as controls consisting of primary sclerosing cholangitis, autoimmune hepatitis, and healthy volunteers, to study MDSCs. We report dramatically increased levels of receptor activator for nuclear factor kappa B ligand (RANKL) expression in serum and liver from patients with IgG4-SC compared to both liver-disease and healthy controls. Moreover, in IgG4-SC liver, RANKL-secreting cells specifically colocalized with cluster of differentiation 38-positive plasma cells and MDSCs, particularly monocytic MDSCs, and express the RANKL receptor in liver. Similarly, the frequency and number of peripheral blood MDSCs were significantly increased. Importantly, serum expression levels of RANKL were inversely correlated with the serum level of gamma-glutamyltransferase but significantly positively correlated with the frequency of MDSCs. Moreover, we confirmed that RANKL induced the expansion and activation of MDSCs through the RANKL/RANK/nuclear factor kappa B signal pathway. Of note, RANKL-treated MDSCs suppressed T-cell proliferation and induced Th2 differentiation. Conclusion: Our data suggest that plasma cell-derived RANKL induces the expansion and activation of MDSCs, which suppress T-cell proliferation and contribute to the Th2-type response characteristic of IgG4-SC.
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Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiang Jiang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yiran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yanmei Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Weihua Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Haiyan Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yanshen Peng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Li Sheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, CA
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, CA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
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Jiang H, Gao P, Chen H, Zhong Z, Shu M, Zhang Z, She J, Liu J. The Prognostic Value of CD8 + and CD45RO + T Cells Infiltration and Beclin1 Expression Levels for Early Postoperative Cholangitis of Biliary Atresia Patients after Kasai Operation. J Korean Med Sci 2018; 33:e198. [PMID: 30034306 PMCID: PMC6052325 DOI: 10.3346/jkms.2018.33.e198] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 04/12/2018] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Postoperative cholangitis is a common but severe complication after Kasai portoenterostomy for biliary atresia (BA). This study aimed to identify its prognostic factors. METHODS Two sets of liver paraffin-embedded tissue samples were collected from BA patients who received Kasai portoenterostomy (n = 25 and n = 31, respectively). Patients were divided into non-cholangitis and cholangitis groups. The infiltration of CD4+, CD8+, CD45RO+, CD68+ cells and expression of Beclin1 were quantitatively evaluated in immunohistochemical analysis. RESULTS Cholangitis group had a significantly lower CD8+ T cell infiltration but a higher CD45RO+ cell infiltration, and a lower Beclin1 level than non-cholangitis group (all P < 0.01). Multivariate logistic regression analysis indicated that infiltration of CD8+ cells (odds ratio [OR], 0.112; 95% confidence interval [CI], 0.022-0.577) and CD45RO+ cells (OR, 3.88; 95% CI, 1.37-11.03), and Beclin1 level (OR, 0.088; 95% CI, 0.018-0.452) were independent influence factors for early postoperative cholangitis. Receiver operating characteristic (ROC) analysis showed that area under ROC curve (AUROC) values for CD8+ cells, CD45RO+ cells and Beclin1 were 0.857, 0.738 and 0.900, respectively. CONCLUSION Our findings demonstrated the CD8+ cells, CD45RO+ cells and Beclin1 level possessed the prognostic value for early postoperative cholangitis following Kasai operation, which may be helpful to develop new prevention and treatment strategies for postoperative cholangitis.
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Affiliation(s)
- Hong Jiang
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Pengfei Gao
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Huadong Chen
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhihai Zhong
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Man Shu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhichong Zhang
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jinbiao She
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Juncheng Liu
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Tanaka A, Leung PS, Young HA, Gershwin ME. Therapeutic and immunological interventions in primary biliary cholangitis: from mouse models to humans. Arch Med Sci 2018; 14:930-940. [PMID: 30002712 PMCID: PMC6040118 DOI: 10.5114/aoms.2017.70995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/15/2017] [Indexed: 12/12/2022] Open
Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Patrick S.C. Leung
- Division of Rheumatology Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Howard A. Young
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA
| | - M. Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
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Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis. Anal Cell Pathol (Amst) 2017; 2017:7492836. [PMID: 29410945 PMCID: PMC5749170 DOI: 10.1155/2017/7492836] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 09/17/2017] [Accepted: 10/26/2017] [Indexed: 12/20/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA) for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC) transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.
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Chronic Autoimmune Epithelitis in Sjögren's Syndrome and Primary Biliary Cholangitis: A Comprehensive Review. Rheumatol Ther 2017; 4:263-279. [PMID: 28791611 PMCID: PMC5696286 DOI: 10.1007/s40744-017-0074-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Indexed: 12/12/2022] Open
Abstract
Within the spectrum of autoimmune diseases, Sjögren's syndrome and primary biliary cholangitis are exemplary and can be coined as chronic epithelitis based on their frequent coexistence in clinical practice and the highly specific immune-mediated injury of the small bile ducts and the exocrine glands. The pathogenic mechanisms underlying the diseases are similar, with apoptosis being the key element leading to organ-specific immune-mediated injury directed against the small bile ducts and salivary gland epithelia, respectively along with similar epidemiological features, such as female predominance and the age of onset in the fifth decade of life. Indeed, novel insights into the pathogenesis of the diseases have been obtained in recent years, including a better definition of the role of B and T cells, particularly Th17 cells, and the mechanisms of autoantibody-mediated tissue injury, with anti-mitochondrial antibodies and SS-A/SS-B being identified as specific for primary biliary cholangitis and Sjögren's syndrome, respectively. These findings have opened the possibility to new targeted therapies, but most clinical needs remain unmet, particularly from a therapeutic standpoint where options diverge, with bile acids being the predominant treatment strategy in primary biliary cholangitis and immunomodulators being used to treat Sjögren's syndrome. Here we provide a comprehensive review of the most recent findings on the pathogenesis, clinical manifestations and therapeutic options for Sjögren's syndrome and primary biliary cholangitis, respectively, while stressing the common traits between these conditions. Our cumulative hypothesis is that similarities outnumber differences and that this may prove advantageous towards a better management of patients.
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MicroRNA-424 inhibits cell migration, invasion, and epithelial mesenchymal transition by downregulating doublecortin-like kinase 1 in ovarian clear cell carcinoma. Int J Biochem Cell Biol 2017; 85:66-74. [DOI: 10.1016/j.biocel.2017.01.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/12/2017] [Accepted: 01/29/2017] [Indexed: 12/12/2022]
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