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Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure
The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis. Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects...
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Published in: | BMC medicine 2024-03, Vol.22 (1), p.95-17, Article 95 |
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creator | Hassan, Hozeifa Mohamed Liang, Xi Xin, Jiaojiao Lu, Yingyan Cai, Qun Shi, Dongyan Ren, Keke Li, Jun Chen, Qi Li, Jiang Li, Peng Guo, Beibei Yang, Hui Luo, Jinjin Yao, Heng Zhou, Xingping Hu, Wen Jiang, Jing Li, Jun |
description | The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis.
Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.
THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value ( |
doi_str_mv | 10.1186/s12916-024-03318-x |
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Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.
THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis.
THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.</description><identifier>ISSN: 1741-7015</identifier><identifier>EISSN: 1741-7015</identifier><identifier>DOI: 10.1186/s12916-024-03318-x</identifier><identifier>PMID: 38439091</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Acute-On-Chronic Liver Failure ; Analysis ; Animals ; Apoptosis ; Biological markers ; Biomarkers ; Care and treatment ; Cirrhosis ; Development and progression ; Enzyme-linked immunosorbent assay ; Enzymes ; Genes ; Health aspects ; Hepatitis ; Hepatitis B ; Hepatitis B virus ; Hepatocellular apoptosis ; Humans ; Immune response ; Immune system ; Immune-metabolism disorder ; Inflammation ; Inflammatory response ; Leukocytes, Mononuclear ; Liver ; Liver cancer ; Liver Cirrhosis ; Liver diseases ; Liver failure ; Liver transplants ; Medical prognosis ; Metabolism ; Mice ; Molecular mechanics ; Mortality ; Pathogenesis ; Pathogens ; Peripheral blood mononuclear cells ; Phenotype ; Polymerase chain reaction ; Prospective Studies ; Rats ; Risk factors ; Severity prediction ; Survival analysis ; Thrombospondin ; Thrombospondin 1 ; Thrombospondin 1 - genetics ; Transcriptomes</subject><ispartof>BMC medicine, 2024-03, Vol.22 (1), p.95-17, Article 95</ispartof><rights>2024. The Author(s).</rights><rights>COPYRIGHT 2024 BioMed Central Ltd.</rights><rights>2024. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c546t-ddf4fdb9678b0e9e40bce1d9ed7662ddba1cf055f89de0489e61477e49bfc39c3</cites><orcidid>0000-0001-9463-6007 ; 0000-0002-7236-8088</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10913480/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2956863495?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38439091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hassan, Hozeifa Mohamed</creatorcontrib><creatorcontrib>Liang, Xi</creatorcontrib><creatorcontrib>Xin, Jiaojiao</creatorcontrib><creatorcontrib>Lu, Yingyan</creatorcontrib><creatorcontrib>Cai, Qun</creatorcontrib><creatorcontrib>Shi, Dongyan</creatorcontrib><creatorcontrib>Ren, Keke</creatorcontrib><creatorcontrib>Li, Jun</creatorcontrib><creatorcontrib>Chen, Qi</creatorcontrib><creatorcontrib>Li, Jiang</creatorcontrib><creatorcontrib>Li, Peng</creatorcontrib><creatorcontrib>Guo, Beibei</creatorcontrib><creatorcontrib>Yang, Hui</creatorcontrib><creatorcontrib>Luo, Jinjin</creatorcontrib><creatorcontrib>Yao, Heng</creatorcontrib><creatorcontrib>Zhou, Xingping</creatorcontrib><creatorcontrib>Hu, Wen</creatorcontrib><creatorcontrib>Jiang, Jing</creatorcontrib><creatorcontrib>Li, Jun</creatorcontrib><title>Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure</title><title>BMC medicine</title><addtitle>BMC Med</addtitle><description>The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis.
Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.
THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis.
THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.</description><subject>Acute-On-Chronic Liver Failure</subject><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological markers</subject><subject>Biomarkers</subject><subject>Care and treatment</subject><subject>Cirrhosis</subject><subject>Development and progression</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Enzymes</subject><subject>Genes</subject><subject>Health aspects</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B virus</subject><subject>Hepatocellular apoptosis</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immune-metabolism disorder</subject><subject>Inflammation</subject><subject>Inflammatory response</subject><subject>Leukocytes, Mononuclear</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver Cirrhosis</subject><subject>Liver diseases</subject><subject>Liver failure</subject><subject>Liver transplants</subject><subject>Medical prognosis</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Molecular mechanics</subject><subject>Mortality</subject><subject>Pathogenesis</subject><subject>Pathogens</subject><subject>Peripheral blood mononuclear cells</subject><subject>Phenotype</subject><subject>Polymerase chain reaction</subject><subject>Prospective Studies</subject><subject>Rats</subject><subject>Risk factors</subject><subject>Severity prediction</subject><subject>Survival analysis</subject><subject>Thrombospondin</subject><subject>Thrombospondin 1</subject><subject>Thrombospondin 1 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>BMC medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hassan, Hozeifa Mohamed</au><au>Liang, Xi</au><au>Xin, Jiaojiao</au><au>Lu, Yingyan</au><au>Cai, Qun</au><au>Shi, Dongyan</au><au>Ren, Keke</au><au>Li, Jun</au><au>Chen, Qi</au><au>Li, Jiang</au><au>Li, Peng</au><au>Guo, Beibei</au><au>Yang, Hui</au><au>Luo, Jinjin</au><au>Yao, Heng</au><au>Zhou, Xingping</au><au>Hu, Wen</au><au>Jiang, Jing</au><au>Li, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure</atitle><jtitle>BMC medicine</jtitle><addtitle>BMC Med</addtitle><date>2024-03-05</date><risdate>2024</risdate><volume>22</volume><issue>1</issue><spage>95</spage><epage>17</epage><pages>95-17</pages><artnum>95</artnum><issn>1741-7015</issn><eissn>1741-7015</eissn><abstract>The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis.
Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.
THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis.
THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>38439091</pmid><doi>10.1186/s12916-024-03318-x</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-9463-6007</orcidid><orcidid>https://orcid.org/0000-0002-7236-8088</orcidid><oa>free_for_read</oa></addata></record> |
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language | eng |
recordid | cdi_doaj_primary_oai_doaj_org_article_0ff396ac72ca4cccbfd97b76af1b8bc4 |
source | Publicly Available Content Database (Proquest) (PQ_SDU_P3); PubMed Central |
subjects | Acute-On-Chronic Liver Failure Analysis Animals Apoptosis Biological markers Biomarkers Care and treatment Cirrhosis Development and progression Enzyme-linked immunosorbent assay Enzymes Genes Health aspects Hepatitis Hepatitis B Hepatitis B virus Hepatocellular apoptosis Humans Immune response Immune system Immune-metabolism disorder Inflammation Inflammatory response Leukocytes, Mononuclear Liver Liver cancer Liver Cirrhosis Liver diseases Liver failure Liver transplants Medical prognosis Metabolism Mice Molecular mechanics Mortality Pathogenesis Pathogens Peripheral blood mononuclear cells Phenotype Polymerase chain reaction Prospective Studies Rats Risk factors Severity prediction Survival analysis Thrombospondin Thrombospondin 1 Thrombospondin 1 - genetics Transcriptomes |
title | Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T09%3A49%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Thrombospondin%201%20enhances%20systemic%20inflammation%20and%20disease%20severity%20in%20acute-on-chronic%20liver%20failure&rft.jtitle=BMC%20medicine&rft.au=Hassan,%20Hozeifa%20Mohamed&rft.date=2024-03-05&rft.volume=22&rft.issue=1&rft.spage=95&rft.epage=17&rft.pages=95-17&rft.artnum=95&rft.issn=1741-7015&rft.eissn=1741-7015&rft_id=info:doi/10.1186/s12916-024-03318-x&rft_dat=%3Cgale_doaj_%3EA785304104%3C/gale_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c546t-ddf4fdb9678b0e9e40bce1d9ed7662ddba1cf055f89de0489e61477e49bfc39c3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2956863495&rft_id=info:pmid/38439091&rft_galeid=A785304104&rfr_iscdi=true |