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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
Main Authors: 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
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container_start_page 95
container_title BMC medicine
container_volume 22
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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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 (&lt; 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 (&lt; 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 - genetics</subject><subject>Transcriptomes</subject><issn>1741-7015</issn><issn>1741-7015</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptkktr3DAUhU1paR7tH-iiGAolG6eSJUvWqoTQRyDQTboWelzNaLClqWSHzL-vnEnTmVK0kJDO-S6691TVO4wuMe7Zp4xbgVmDWtogQnDfPLyoTjGnuOEIdy8PzifVWc4bhNqOc_q6OiE9JQIJfFq5u3WKo455G4P1ocY1hLUKBnKdd3mC0ZvaBzeocVSTj6FWwdbWZ1AZ6gz3kPy0K4pamXmCJobGFGAorsGXx9opP8wJ3lSvnBoyvH3az6ufX7_cXX9vbn98u7m-um1MR9nUWOuos1ow3msEAijSBrAVYDljrbVaYeNQ17leWEC0F8Aw5Ryo0M4QYch5dbPn2qg2cpv8qNJORuXl40VMK6nS5M0AEjlHBFOGt0ZRY4x2VnDNmXJY99rQwvq8Z21nPYI1EKakhiPo8Uvwa7mK9xKXzhLao0K4eCKk-GuGPMnRZwPDoALEOctWEM5R19Kl2Id_pJs4p1B6VVQd6xmhovurWqnygzKXWAqbBSqveN8RRDFaWJf_UZVll3HGAM6X-yPDxwPDGtQwrXMc5mXg-VjY7oUmxZwTuOduYCSXTMp9JmXJpHzMpHwopveHfXy2_Akh-Q3mwd5Z</recordid><startdate>20240305</startdate><enddate>20240305</enddate><creator>Hassan, Hozeifa Mohamed</creator><creator>Liang, Xi</creator><creator>Xin, Jiaojiao</creator><creator>Lu, Yingyan</creator><creator>Cai, Qun</creator><creator>Shi, Dongyan</creator><creator>Ren, Keke</creator><creator>Li, Jun</creator><creator>Chen, Qi</creator><creator>Li, Jiang</creator><creator>Li, Peng</creator><creator>Guo, Beibei</creator><creator>Yang, Hui</creator><creator>Luo, Jinjin</creator><creator>Yao, Heng</creator><creator>Zhou, Xingping</creator><creator>Hu, Wen</creator><creator>Jiang, Jing</creator><creator>Li, Jun</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9463-6007</orcidid><orcidid>https://orcid.org/0000-0002-7236-8088</orcidid></search><sort><creationdate>20240305</creationdate><title>Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure</title><author>Hassan, Hozeifa Mohamed ; 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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 (&lt; 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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identifier ISSN: 1741-7015
ispartof BMC medicine, 2024-03, Vol.22 (1), p.95-17, Article 95
issn 1741-7015
1741-7015
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
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