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Zhao Y, Wei S, Chen L, Zhou X, Ma X. Primary biliary cholangitis: molecular pathogenesis perspectives and therapeutic potential of natural products. Front Immunol 2023; 14:1164202. [PMID: 37457696 PMCID: PMC10349375 DOI: 10.3389/fimmu.2023.1164202] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic immune liver disease characterized by persistent cholestasis, interlobular bile duct damage, portal inflammation, liver fibrosis, eventual cirrhosis, and death. Existing clinical and animal studies have made a good progress in bile acid metabolism, intestinal flora disorder inflammatory response, bile duct cell damage, and autoimmune response mechanisms. However, the pathogenesis of PBC has not been clearly elucidated. We focus on the pathological mechanism and new drug research and development of PBC in clinical and laboratory in the recent 20 years, to discuss the latest understanding of the pathological mechanism, treatment options, and drug discovery of PBC. Current clinical treatment mode and symptomatic drug support obviously cannot meet the urgent demand of patients with PBC, especially for the patients who do not respond to the current treatment drugs. New treatment methods are urgently needed. Drug candidates targeting reported targets or signals of PBC are emerging, albeit with some success and some failure. Single-target drugs cannot achieve ideal clinical efficacy. Multitarget drugs are the trend of future research and development of PBC drugs.
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Affiliation(s)
- Yanling Zhao
- Department of Pharmacy, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lisheng Chen
- Department of Pharmacy, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiao Ma
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Qiao L, Deng C, Wang Q, Zhang W, Fei Y, Xu Y, Zhao Y, Li Y. Serum Clusterin and Complement Factor H May Be Biomarkers Differentiate Primary Sjögren's Syndrome With and Without Neuromyelitis Optica Spectrum Disorder. Front Immunol 2019; 10:2527. [PMID: 31708932 PMCID: PMC6823228 DOI: 10.3389/fimmu.2019.02527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/10/2019] [Indexed: 01/05/2023] Open
Abstract
Background: Neuromyelitis optica spectrum disorder (NMOSD) is a neurological complication of primary Sjögren's syndrome (pSS). Objective: We aimed to explore potential serological differences between pSS patients with and without NMOSD. Methods: There were 4 pSS patients with NMOSD and 8 pSS patients without NMOSD enrolled as the screening group for two-dimensional difference gel electrophoresis (DIGE) analysis. Then differential expressed protein spots between groups were identified by MALDI-TOF/TOF MS. The levels of the identified potential biomarkers were verified by ELISA in a second independent cohort including 22 pSS patients with NMOSD, 26 pSS without NMOSD and 30 NMOSD patients. Results: Nine proteins were identified significantly differently expressed (more than 1.5-fold, p < 0.05) between these two groups. Serum levels of clusterin and complement factor H (CFH) were further verified by ELISA. Results showed that the serum clusterin was significantly higher in NMOSD with pSS than without (298.33 ± 184.52 vs. 173.49 ± 63.03 ng/ml, p < 0.01), while the levels of CFH were lower in pSS patients with NMOSD than without (24.19 ± 1.79 vs. 25.87 ± 3.98 ng/ml, p < 0.01). Conclusion: This is the first study of serological comparative proteomics between pSS patients with and without NMOSD. Serum clusterin and CFH might be potential biomarkers for pSS patients with NMOSD and play important role in the pathogenesis of the disease but needs further verification.
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Affiliation(s)
- Lin Qiao
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Chuiwen Deng
- Key Laboratory of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Ministry of Education, Beijing, China
| | - Qian Wang
- Key Laboratory of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Ministry of Education, Beijing, China
| | - Wen Zhang
- Key Laboratory of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Ministry of Education, Beijing, China
| | - Yunyun Fei
- Key Laboratory of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Ministry of Education, Beijing, China
| | - Yan Xu
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yan Zhao
- Key Laboratory of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Ministry of Education, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Chascsa DM, Lindor KD. Antimitochondrial Antibody-Negative Primary Biliary Cholangitis: Is It Really the Same Disease? Clin Liver Dis 2018; 22:589-601. [PMID: 30259855 DOI: 10.1016/j.cld.2018.03.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antimitochondrial antibody (AMA)-negative primary biliary cholangitis (PBC) is a term reserved for patients with clinical and histopathological findings consistent with PBC but without positive AMA. There does not seem to be a natural progression from AMA negativity to positivity. Antinuclear and antismooth muscle antibodies are frequently found in the absence of histologic autoimmune hepatitis features. The disease course may be more severe than AMA-positive. Response to standard therapy for PBC and autoimmune hepatitis varies. Nevertheless, there is insufficient evidence to suggest AMA-negative PBC is different enough to warrant classification as a separate disease from AMA-positive PBC.
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Affiliation(s)
- David M Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA; Office of the Provost, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA.
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Abstract
Primary biliary cholangitis (PBC) is a chronic progressive cholestatic disease characterized by destruction of small- and medium-sized intrahepatic bile ducts. It is no longer a rare disease, since many new asymptomatic cases are incidentally identified. Liver biopsy is diagnostically critical but not always feasible or practical to be performed. Many potential, noninvasive, markers have been proposed to replace liver biopsy and further provide the assessment of disease severity and ultimate prognosis. In this review, we evaluated serum biomarkers proposed for diagnosis, extent of fibrosis, disease prognosis and attempts for early prediction of treatment response. Older biochemical and immunological markers are presented along with recent reports including the role of microRNAs and promising results based on proteomics and metabolomics.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University Hospital and Medical School, University of Crete, Heraklion, Crete, Greece
| | - Demetrius Samonakis
- Department of Gastroenterology, University Hospital of Heraklion, Crete, Greece
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Deng CW, Wang L, Fei YY, Hu CJ, Yang YJ, Peng LY, Zeng XF, Zhang FC, Li YZ. Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study. World J Gastroenterol 2017; 23:8489-8499. [PMID: 29358857 PMCID: PMC5752709 DOI: 10.3748/wjg.v23.i48.8489] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 11/21/2017] [Accepted: 11/28/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics. METHODS Nine antimitochondrial antibody (AMA)-positive PBC patients and nine age- and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells (HiBECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with MaxQuant software (version 1.5.2.8), DAVID platform, and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC. RESULTS In total, 1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them, 371 were determined to be significantly differentially expressed between AMA-positive and -negative PBC patients (P < 0.05). Fisher's exact test was performed for enrichment analysis of Gene Ontology protein annotations (biological processes, cellular components, and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and -negative PBC patients. As expected, autoantigens related to mitochondria were highly enriched in AMA-positive PBC patients. However, lower levels of AMA were also detected in AMA-negative PBC patients. In addition, autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation, recognition of phagocytosis, and complement activation. CONCLUSION AMA-negative PBC individuals may not exist, but rather, those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.
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Affiliation(s)
- Chui-Wen Deng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Yun-Yun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Chao-Jun Hu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Yun-Jiao Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Lin-Yi Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Xiao-Feng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Feng-Chun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Yong-Zhe Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
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Huang YQ. Recent advances in the diagnosis and treatment of primary biliary cholangitis. World J Hepatol 2016; 8:1419-1441. [PMID: 27957241 PMCID: PMC5124714 DOI: 10.4254/wjh.v8.i33.1419] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/26/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC), formerly referred to as primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocyte-mediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific anti-mitochondrial autoantibodies (AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches (e.g., acoustic radiation force impulse imaging, vibration controlled transient elastography, and magnetic resonance elastography), clinical features, serological characteristics covering biochemical markers, immunoglobulins, infections markers, biomarkers, predictive fibrosis marker, specific antibodies (including AMAs such as AMA-M2), anti-nuclear autoantibodies [such as anti-multiple nuclear dot autoantibodies (anti-sp100, PML, NDP52, anti-sp140), anti-rim-like/membranous anti-nuclear autoantibodies (anti-gp210, anti-p62), anti-centromere autoantibodies, and some of the novel autoantibodies], histopathological characteristics of PBC, diagnostic advances, and anti-diastole of PBC. Furthermore, this review emphasizes the recent advances in research of PBC in terms of therapies, including ursodeoxycholic acid, budesonide, methotrexate, obeticholic acid, cyclosporine A, fibrates such as bezafibrate and fenofibrate, rituximab, mesenchymal stem cells transplant, and hepatic transplant. Currently, hepatic transplant remains the only optimal choice with acknowledged treatment efficiency for end-stage PBC patients.
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Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic liver diseases (CLD) in adults and are associated with immune mechanisms. PBC is considered a model autoimmune disease, and more than 90% of patients present very specific autoantibodies against mitochondrial antigens. Whether PSC should be considered an autoimmune or merely immune-mediated disease is still under debate. This review addresses the clinical relevance of autoantibodies in CLD and their pathogenic mechanisms and illustrates the technology available for appropriate autoantibody detection.
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Affiliation(s)
- Simona Marzorati
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 113, Rozzano, Milan 20089, Italy; Department of Electronics, Information and Bioengineering, Politecnico di Milano, via Ponzio 34/5, Milan 20133, Italy
| | - Pietro Invernizzi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 113, Rozzano, Milan 20089, Italy; Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, GBSF, 451 Health Science Drive, Davis, CA 95616, USA
| | - Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 113, Rozzano, Milan 20089, Italy.
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