المؤلفون: Pu Wu, Sinan Xie, Yunshi Cai, Hu Liu, Yinghao Lv, Ying Yang, Yucheng He, Bangjie Yin, Tian Lan, Hong Wu

المصدر: Frontiers in Immunology, Vol 15 (2024)

مصطلحات موضوعية: primary sclerosing cholangitis (PSC), Mendelian randomization (MR), immune cells, genome-wide association study (GWAS), causal effect, Immunologic diseases. Allergy, RC581-607

الوصف: BackgroundObservational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood.MethodsA bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran’s Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy.ResultsIn forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032–1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086–1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630–0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823–0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28− CD127− CD25++ CD8+ T cell AC, CD28− CD25++ CD8+ T cell AC, CD28− CD8+ T cell/CD8+ T cell, CD28− CD8+ T cell AC, and CD45 RA− CD28− CD8+ T cell AC.ConclusionOur study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1395513/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/d0778ccd052a4d6599f89b079e3ea11cTest

المؤلفون: Ekser, Burcin, Mihaylov, Plamen, Mangus, Richard S.

المساهمون: Surgery, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Complications, Liver transplantation, Outcomes, Primary sclerosing cholangitis (PSC)

وصف الملف: application/pdf

العلاقة: HepatoBiliary Surgery and Nutrition; Ekser B, Mihaylov P, Mangus RS. Assessment of morbidity and mortality after liver transplantation for primary sclerosing cholangitis. Hepatobiliary Surg Nutr. 2024;13(1):154-156. doi:10.21037/hbsn-23-599; https://hdl.handle.net/1805/41444Test

الإتاحة: https://doi.org/10.21037/hbsn-23-599Test
https://hdl.handle.net/1805/41444Test

المؤلفون: Miquilena, Milagros, Morao, Cesar, Martínez, Yauribel, Guerrero, María, Rodríguez G, Magaly

المصدر: Revista GEN; Vol. 77 Núm. 4 (2023): Octubre - Diciembre; 167-173 ; 2477-975X ; 0016-3503

مصطلحات موضوعية: Hepatobiliary disorders, pediatric inflammatory bowel disease (IBD), ulcerative rectocolitis (UCR), Crohn's disease (CD), indeterminate colitis (IC), extraintestinal manifestations (MEI), Primary sclerosing cholangitis (PSC), Alteraciones hepatobiliares, enfermedad inflamatoria intestinal en pediatría (EII), Rectocolitis Ulcerosa (RCU), Enfermedad de Crohn (EC), Colitis Indeterminada (CI), manifestaciones extraintestinales (MEI), Colangitis esclerosante primaria (CEP)

الوصف: Background: Inflammatory bowel disease includes Crohn's disease, ulcerative rectocolitis and indeterminate colitis, whose evolution is chronic and fluctuating, and present various extraintestinal manifestations, mainly in the hepatobiliary tree Objective: To describe the hepatobiliary alterations of inflammatory bowel disease in patients pediatric patients of the Gastroenterology clinic of the JM De Los Ríos Hospital, during the period 2002-2023. Patients and Methods: Descriptive, observational, ambispective, cross-sectional study; patients diagnosed with inflammatory bowel disease between the ages of 2 and 18 years are included; who met inclusion criteria for IBD; Obtaining the information through medical records. The data was analyzed by descriptive statistics; mean, median and percentages Results: 33 patients diagnosed with IBD: RCU 22/33 (67%), CD 10/33 (30%) and CI 1/33 (3%). The average age of debut was 10 years. We found extra intestinal manifestations in 30/33 (91%); Hepatobiliary alterations being the most frequent 15/33 (45%), predominantly transient hypertransaminasaemia 12/15 (80%), followed by primary sclerosing cholangitis (PSC), 2/15 (13%) and gallbladder lithiasis 1/15 (7 %). The ultrasound findings were; diffuse liver parenchymal process 9/15 (60%), hepatomegaly 3/15 (20%), ascites 1/15 (7%), periportal fibrosis 1/15 (7%), and gallstones 1/15 (7%) . 47% of the patients had a severe IBD clinical activity index at the time of the hepatobiliary alterations. Conclusion: Extraintestinal complications in IBD are common; including liver and biliary tree involvement. Clinical and paraclinical evaluation is important in order to obtain a timely diagnosis and establish an early treatment that avoids other complications and manages to optimize the quality of life of patients in this age group. ; Introducción: La enfermedad inflamatoria intestinal comprende, Enfermedad de Crohn, Rectocolitis ulcerosa y Colitis Indeterminada, cuya evolución es crónica y fluctuante, y presentan diversas manifestaciones ...

وصف الملف: application/pdf

العلاقة: http://saber.ucv.ve/ojs/index.php/rev_gen/article/view/28201/144814493832Test; http://190.169.94.12/ojs/index.php/rev_gen/article/view/28201Test

الإتاحة: http://190.169.94.12/ojs/index.php/rev_gen/article/view/28201Test

المؤلفون: Jixuan Wang, Zhiwen Sun, Jingri Xie, Wanli Ji, Yang Cui, Zongxiong Ai, Guoying Liang

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: inflammasomes, pyroptosis, autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), gut microbiota, Immunologic diseases. Allergy, RC581-607

الوصف: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1150879/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/0de25fa0b85f4598899f80996b399cbdTest

المؤلفون: Beata Kasztelan-Szczerbinska, Anna Rycyk-Bojarzynska, Agnieszka Szczerbinska, Halina Cichoz-Lach

المصدر: Nutrients, Vol 15, Iss 3, p 760 (2023)

مصطلحات موضوعية: primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), bile acids (BAs), gut microbiome (GM), ursodeoxycholic acid (UDCA), obeticholic acid (OCA), Nutrition. Foods and food supply, TX341-641

الوصف: Primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are rare immune-related cholangiopathies with still poorly explained pathogenesis. Although triggers of chronic inflammation with subsequent fibrosis that affect cholangiocytes leading to obliteration of bile ducts and conversion to liver cirrhosis are unclear, both disorders are regarded to be multifactorial. Different factors can contribute to the development of hepatocellular injury in the course of progressive cholestasis, including (1) body accumulation of bile acids and their toxicity, (2) decreased food intake and nutrient absorption, (3) gut microbiota transformation, and (4) reorganized host metabolism. Growing evidence suggests that intestinal microbiome composition not only can be altered by liver dysfunction, but in turn, it actively impacts hepatic conditions. In this review, we highlight the role of key factors such as the gut–liver axis, intestinal barrier integrity, bile acid synthesis and circulation, and microbiome composition, which seem to be strongly related to PBC and PSC outcome. Emerging treatments and future therapeutic strategies are also presented.

العلاقة: https://www.mdpi.com/2072-6643/15/3/760Test; https://doaj.org/toc/2072-6643Test; https://doaj.org/article/208b45e57f60431c970e5db57784d612Test

الإتاحة: https://doi.org/10.3390/nu15030760Test
https://doaj.org/article/208b45e57f60431c970e5db57784d612Test

المؤلفون: Shouyan Wu, Yuhan Cao, Henglei Lu, Xinming Qi, Jianhua Sun, Yang Ye, Likun Gong

المصدر: Biomedicine & Pharmacotherapy, Vol 153, Iss , Pp 113512- (2022)

مصطلحات موضوعية: Primary sclerosing cholangitis (PSC), Peribiliary gland niche, Ductular reaction, Fibrosis, 18β-glycyrrhetinic acid (GA), Therapeutic strategy, Therapeutics. Pharmacology, RM1-950

الوصف: Primary sclerosing cholangitis (PSC) is a rare but progressive and fatal autoimmune disease without clear pathogenesis and effective therapies. Peribiliary macrophage recruitment and peribiliary gland (PBG) proliferation and expansion have been associated with various cholangiopathies. This study aimed to evaluate the involvement of the PBG niche and macrophages in PSC progression, potential treatment strategies, and the underlying mechanism in acute and chronic experimental PSC. First, the upregulation of chemokines and fibrosis in PSC patients was confirmed via RNA-seq analysis. In vivo data illustrated that inflammation and fibrosis are the main characteristics, and recession of these can effectively interfere with PSC. Histopathological staining and RT-PCR revealed that more significant ductular reaction (DR) and PBG proliferation in the chronic PSC model, in which fibrosis mainly accumulated in the peribiliary area. In vitro, a transwell migration experiment showed that MCP-1 secreted by cholangiocytes in PBG niche, which recruited monocyte-derived macrophages (MoMFs) to the peribiliary area and promoted inflammation and fibrosis. Then, the luciferase assay and EMSA showed that POU6F1 could activate MCP-1 transcription. Furthermore, 18β-Glycyrrhetinic acid (GA) reduced macrophages and fibrosis accumulated in the peribiliary, space and reduced PBG proliferation to benefit acute and chronic PSC models. Collectively, our results indicated that POU6F1 transcriptionally activates MCP-1, promoting the recruitment and infiltration of MoMFs and fibrosis into the PBG niche in PSC mouse models, and GA effectively suppressed the above phenotypes. These findings provide potential targets and a theoretical basis for the clinical treatment of PSC.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332222009015Test; https://doaj.org/toc/0753-3322Test

الوصول الحر: https://doaj.org/article/8255f19ec8e249068e03b2d3e53f9f29Test

المؤلفون: Hajime ISOMOTO, Jun-ichi OKANO, Kenji OYAMA, Suguru IKEDA, Takaaki SUGIHARA, Takakazu NAGAHARA, Takuya KIHARA, Yukako MATSUKI, 大山 賢治, 岡野 淳一, 木原 琢也, 杉原 誉明, 松木 由佳子, 永原 天和, 池田 傑, 磯本 一

المصدر: 日本消化器病学会雑誌 / Nippon Shokakibyo Gakkai Zasshi. 2022, 119(12):1088

المؤلفون: Katherine Arndtz, Yung-Yi Chen, Anna Rowe, Victoria Homer, Amanda Kirkham, Jessica Douglas-Pugh, Daniel Slade, Douglas Thorburn, Eleanor Barnes, Guruprasad Aithal, Philip Newsome, David Smith, David Adams, Christopher Weston, Gideon Hirschfield

المصدر: Efficacy and Mechanism Evaluation, Vol 9, Iss 1 (2022)

مصطلحات موضوعية: alkaline phosphatase (alp), buteo, btt1023, dose-limiting toxicity (dlt), primary sclerosing cholangitis (psc), vascular adhesion protein-1 (vap-1), Medicine

الوصف: Background: Primary sclerosing cholangitis is a progressive and fibrotic liver disease. Treatments remain inadequate, and patients with persistent elevations in activity of alkaline phosphatase are at greatest risk of disease progression. Studies in patient cohorts have implicated the serum amine oxidase vascular adhesion protein 1 in the pathophysiology of disease, including liver fibrogenesis. We hypothesised that blockade of serum amine oxidase by a monoclonal antibody would result in a reduction in liver fibrosis/injury, as evaluated by serum liver tests and other non-invasive markers of liver injury. Objectives: To evaluate the open-label effect on liver injury markers of treatment with the anti-vascular adhesion protein 1 monoclonal antibody BTT1023 in patients with primary sclerosing cholangitis over a 78-day treatment period. Design: A single-arm, two-stage, open-label, multicentre, Phase II clinical trial. Setting: Ambulatory liver disease practices in tertiary care hospitals. Participants: Patients with primary sclerosing cholangitis at risk of disease progression, based on elevated activity of serum alkaline phosphatase, and without evidence of infection, liver failure or advanced disease. Intervention: Seven intravenous infusions of BTT1023 (8 mg/kg of timolumab) over a 78-day treatment period. The intervention was split into a dose-confirmatory stage (to confirm pharmacokinetics), followed by a confirmed expansion cohort stage. Main outcome measures: Our primary outcome measure was patient response to treatment at day 99, measured by a reduction in activity of serum alkaline phosphatase of ≥ 25% from baseline to day 99. Secondary markers of efficacy were assessed based on evaluation of changes in markers of liver injury and liver fibrosis. Safety assessments were performed throughout. Results: Thirty-five patients were consented and screened for eligibility. Twenty-three patients were treated across the two stages of the trial. Interim assessment demonstrated a failure to meet the primary end point, leading to trial discontinuation on the grounds of futility. Multiple exploratory markers were evaluated in a final cohort of 22 patients (modified intention-to-treat analysis). No treatment-related effects were evident. No new safety concerns were seen. Conclusions: No preliminary evidence for disease modification was demonstrated. Limitations: It is clear that this study is limited in its design. Even if there were a better biomarker of fibrosis turnover that could be considered the ‘gold standard’, the design and duration would have had real-world resource limitations. With limited opportunity to test a new agent in large numbers of patients over a prolonged period, it was necessary to aim to see efficacy in a small cohort over a short period. Given the absence of any proven biochemical surrogate of disease activity in primary sclerosing cholangitis, alkaline phosphatase was chosen as an end point. This remains a difficult end point (yet one that does capture biliary injury) and, therefore, despite limitations, this study did demonstrate short-term safety. Future work: Future research will require attention to an ongoing debate regarding the optimal end points for assessing efficacy, as well as consideration of duration of treatment, even in early-phase studies. This raises the challenge of how to fund early experimental trials with ‘high risk of failure’ adequately to ensure that clearer results (negative or positive) arise by the end of the study. Trial registration: Current Controlled Trials ISRCTN11233255, EudraCT 2014-002393-37 and NCT02239211. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 1. See the NIHR Journals Library website for further project information.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2050-4365Test; https://doaj.org/toc/2050-4373Test

الوصول الحر: https://doaj.org/article/3861c15d56054a6882cf103a0170f68aTest

المؤلفون: Mohan S, Mok S, Judge T

المصدر: Clinical and Experimental Gastroenterology, Vol Volume 13, Pp 467-473 (2020)

مصطلحات موضوعية: inflammatory bowel diseases (ibd), ulcerative colitis (uc), crohn’s disease (cd), arthritis, primary sclerosing cholangitis (psc), uveitis, and pyoderma gangrenosum, Diseases of the digestive system. Gastroenterology, RC799-869

الوصف: Sachin Mohan,1– 3 Shaffer Mok,4 Thomas Judge5 1Department of Gastroenterology and Hepatology, University of Minnesota School of Medicine, St Paul, MN, USA; 2Regions Hospital, Department of Gastroenterology and Hepatology, St Paul, MN, USA; 3Health Partners Digestive Care Center, St Paul, MN, 55130, USA; 4Division of Gastroenterology and Hepatology, University Hospital Digestive Health Institute, Westlake, OH 44145, USA; 5Division of Gastroenterology and Liver Diseases, Cooper University Hospital, Mount Laurel, NJ 08054, USACorrespondence: Sachin MohanRegions Hospital, Department of Gastroenterology and Hepatology, 435 Phalen Blvd, St Paul, MN 55130, USATel +1 651-254-8680Fax +1 651-254-8656Email sachinmohan01@gmail.comPurpose: Utilization of genetic databases to identify genes involved in ulcerative colitis (UC), Crohn’s disease (CD), and their extra-intestinal manifestations.Methods: Protein coding genes involved in ulcerative colitis (3783 genes), Crohn’s disease (3980 genes), uveitis (1043 genes), arthritis (5583 genes), primary sclerosing cholangitis (PSC) (1313 genes), and pyoderma gangrenosum (119 genes) were categorized using four genetic databases. These include Genecards: The Human Gene Database (www.genecards.org), DisGeNET (https://www.disgenet.orgTest/), The Comparative Toxicogenomics Database (http://ctdbase.orgTest/) and the Universal Protein Resource (https://www.uniprot.orgTest/). NDex, Network Data Exchange (http://www.ndexbio.orgTest/), was then utilized for mapping a unique signal pathway from the identified shared genes involved in the above disease processes.Results: We have detected a unique array of 20 genes with the highest probability of overlay in UC, CD, uveitis, arthritis, pyoderma gangrenosum, and PSC. Figure 1 represents the interactome of these 20 protein coding genes. Of note, unique immune modulators in different disease processes are also noted. Interleukin-25 (IL-25) and monensin-resistant homolog 2 (MON-2) are only noted in UC, CD, pyoderma gangrenosum, and arthritis. Arachidonate 5-lipoxygenase (ALOX5) is involved in UC, CD, and arthritis. SLCO1B3 is exclusively involved with pyoderma gangrenosum, UC, and CD. As expected, TNF involvement is noted in CD, UC, PSC, and arthritis. Table 1 depicts the detailed result.Conclusion: Our work has identified a distinctive set of genes involved in IBD and its associated extra-intestinal disease processes. These genes play crucial roles in mechanisms of immune response, inflammation, and apoptosis and further our understanding of this complex disease process. We postulate that these genes play a critical role at intersecting pathways involved in inflammatory bowel disease, and these novel molecules, their upstream and downstream effectors, are potential targets for future therapeutic agents.Keywords: inflammatory bowel diseases, IBD, ulcerative colitis, UC, Crohn’s disease, CD, arthritis, primary sclerosing cholangitis, PSC, uveitis, pyoderma gangrenosum

وصف الملف: electronic resource

العلاقة: https://test.dovepress.com/identification-of-novel-therapeutic-molecular-targets-in-inflammatory--peer-reviewed-article-CEGTest; https://doaj.org/toc/1178-7023Test

الوصول الحر: https://doaj.org/article/59b1e254fbdb40bcab7036495ad39464Test

المؤلفون: Alexander Ney, Andres Garcia-Sampedro, George Goodchild, Pilar Acedo, Giuseppe Fusai, Stephen P. Pereira

المصدر: Frontiers in Oncology, Vol 11 (2021)

مصطلحات موضوعية: cholangiocarcinoma, primary sclerosing cholangitis (PSC), biliary strictures, ERCP (Endoscopic Retrograde Cholangiopancreatography), early detection, biomarkers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Cholangiocarcinoma is an uncommon and highly aggressive biliary tract malignancy with few manifestations until late disease stages. Diagnosis is currently achieved through a combination of clinical, biochemical, radiological and histological techniques. A number of reported cancer biomarkers have the potential to be incorporated into diagnostic pathways, but all lack sufficient sensitivity and specificity limiting their possible use in screening and early diagnosis. The limitations of standard serum markers such as CA19-9, CA125 and CEA have driven researchers to identify multiple novel biomarkers, yet their clinical translation has been slow with a general requirement for further validation in larger patient cohorts. We review recent advances in the diagnostic pathway for suspected CCA as well as emerging diagnostic biomarkers for early detection, with a particular focus on non-invasive approaches.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2021.699401/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/77f838fe40cf44139381510d63ccff81Test