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Grandt J, Johansen CD, Jensen ASH, Werge MP, Rashu EB, Møller A, Junker AE, Hobolth L, Mortensen C, Vyberg M, Serizawa RR, Møller S, Gluud LL, Wewer Albrechtsen NJ. The hepatic transcriptome is differentially regulated by a standardized meal in healthy individuals compared to patients with fatty liver disease. PLoS One 2025; 20:e0307345. [PMID: 40489530 DOI: 10.1371/journal.pone.0307345] [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: 07/22/2024] [Accepted: 04/24/2025] [Indexed: 06/11/2025] Open
Abstract
The human liver is dynamic organ with minute to hourly adaptions in response to feeding. Patients with non-alcoholic fatty liver disease (NAFLD) and cirrhosis have altered transcriptomic features compared to controls but how and if food intake affects such is unknown in humans. Our aim was to investigate the hepatic transcriptome at both fasting and postprandial states in patients with NAFLD, cirrhosis, and healthy controls and secondly to develop a browsable resource enabling easy and unrestricted access to such data. We hypothesized that hepatic transcriptome differed between groups, and this was also regulated by food intake. We obtained liver tissue by transjugular liver biopsies from patients with NAFLD (n = 9, mean age 49 (16 SD) y, BMI 35 (5) kg/m2), cirrhosis (n = 9, age 61 (11) y, BMI 32 (5) kg/m2) and healthy controls (n = 10, age 25 (3) y, BMI 23 (3) kg/m2). The hepatic transcriptome was sequenced using NGS and evaluated in bioinformatic analyses to assess differentially expressed genes (DEG) and gene ontology biological processes (GOBP). We identified 553 DEG between healthy controls and patients with NAFLD, 5527 DEG between healthy controls and patients with cirrhosis, and 3898 DEG in NAFLD compared with cirrhosis. A hitherto uncharacterized gene (MET proto-oncogene) was differentially expressed in human NAFLD and cirrhosis. The hepatic transcriptome changed significantly during a standardized meal and these changes were blunted in patients with NAFLD and cirrhosis. GOBP analyses revealed an increase in pro-inflammatory and pro-fibrotic genes in NAFLD and cirrhosis, as well as a decrease in genes related to metabolism. Data were made browsable using two web-based apps. The hepatic transcriptome is differentially regulated by a standardized meal in healthy individuals compared to patients with fatty liver disease.
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Affiliation(s)
- Josephine Grandt
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christian D Johansen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne-Sofie H Jensen
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel P Werge
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
| | - Elias B Rashu
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
| | - Andreas Møller
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
| | - Anders E Junker
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
| | - Lise Hobolth
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
| | | | - Mogens Vyberg
- Department of Pathology, Copenhagen University Hospital Hvidovre, Denmark
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | | | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, University Hospital Copenhagen - Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Copenhagen Center for Translational Research, University Hospital Copenhagen - Bispebjerg and Frederiksberg, Copenhagen, Denmark
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2
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Bahr J, Poschmann G, Jungmann A, Busch M, Ding Z, Vogt J, Zalfen R, Steinhausen J, Euan Martínez AA, Wachtmeister T, Rickert D, Lautwein T, Alter C, Amrute JM, Lavine KJ, Köhrer K, Levkau B, Most P, Stühler K, Hesse J, Schrader J. A secretome atlas of cardiac fibroblasts from healthy and infarcted mouse hearts. Commun Biol 2025; 8:675. [PMID: 40301568 PMCID: PMC12041564 DOI: 10.1038/s42003-025-08083-y] [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: 07/31/2024] [Accepted: 04/12/2025] [Indexed: 05/01/2025] Open
Abstract
Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI mouse hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis are identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclose protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins include SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at days 3 and 5 post-MI reveals the dynamic nature of protein secretion. Specific in-vivo labeling of miCF proteins via biotin ligase TurboID using the POSTN promotor mirrors the in-vitro data. In summary, we identify numerous paracrine factors specifically secreted from CF in mice and humans. This secretome atlas may lead to new biomarkers and/or therapeutic targets for the activated CF.
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Affiliation(s)
- Jasmin Bahr
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Gereon Poschmann
- Institute for Molecular Medicine, Proteome Research, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Andreas Jungmann
- Division of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany
| | - Martin Busch
- Division of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany
| | - Zhaoping Ding
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Jens Vogt
- Institute of Molecular Medicine III, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ria Zalfen
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Julia Steinhausen
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Arlen Aurora Euan Martínez
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Thorsten Wachtmeister
- Genomics & Transcriptomics Laboratory, Biological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Daniel Rickert
- Genomics & Transcriptomics Laboratory, Biological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tobias Lautwein
- Genomics & Transcriptomics Laboratory, Biological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Christina Alter
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Junedh M Amrute
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | - Kory J Lavine
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
| | - Karl Köhrer
- Genomics & Transcriptomics Laboratory, Biological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Bodo Levkau
- Institute of Molecular Medicine III, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Patrick Most
- Division of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany
| | - Kai Stühler
- Institute for Molecular Medicine, Proteome Research, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Molecular Proteomics Laboratory, Biological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Julia Hesse
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
- CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Jürgen Schrader
- Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
- CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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3
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Marjot T. New evidence of cross-disease communication between heart and liver. J Hepatol 2025; 82:541-543. [PMID: 39721919 DOI: 10.1016/j.jhep.2024.11.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024]
Affiliation(s)
- Thomas Marjot
- Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, UK; Translational Gastroenterology and Liver Unit (TGLU), Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, UK.
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Vachliotis ID, Anastasilakis AD, Rafailidis V, Polyzos SA. Osteokines in Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2024; 13:703-723. [PMID: 39225951 DOI: 10.1007/s13679-024-00586-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
PURPOSE OF REVIEW To critically summarize evidence on the potential role of osteokines in the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS There are emerging data supporting that certain osteokines, which are specific bone-derived proteins, may beneficially or adversely affect hepatic metabolism, and their alterations in the setting of osteoporosis or other bone metabolic diseases may possibly contribute to the development and progression of NAFLD. There is evidence showing a potential bidirectional association between NAFLD and bone metabolism, which may imply the existence of a liver-bone axis. In this regard, osteocalcin, osteoprotegerin, bone morphogenic protein 4 (BMP4) and BMP6 appear to have a positive impact on the liver, thus possibly alleviating NAFLD, whereas osteopontin, receptor activator of nuclear factor kappa Β ligand (RANKL), sclerostin, periostin, BMP8B, and fibroblast growth factor 23 (FGF23) appear to have a negative impact on the liver, thus possibly exacerbating NAFLD. The potential implication of osteokines in NAFLD warrants further animal and clinical research in the field that may possibly result in novel therapeutic targets for NAFLD in the future.
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Affiliation(s)
- Ilias D Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | | | - Vasileios Rafailidis
- Department of Clinical Radiology, AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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5
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Arteel GE. Hepatic Extracellular Matrix and Its Role in the Regulation of Liver Phenotype. Semin Liver Dis 2024; 44:343-355. [PMID: 39191427 PMCID: PMC12057067 DOI: 10.1055/a-2404-7973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
The hepatic extracellular matrix (ECM) is most accurately depicted as a dynamic compartment that comprises a diverse range of players that work bidirectionally with hepatic cells to regulate overall homeostasis. Although the classic meaning of the ECM referred to only proteins directly involved in generating the ECM structure, such as collagens, proteoglycans, and glycoproteins, the definition of the ECM is now broader and includes all components associated with this compartment. The ECM is critical in mediating phenotype at the cellular, organ, and even organismal levels. The purpose of this review is to summarize the prevailing mechanisms by which ECM mediates hepatic phenotype and discuss the potential or established role of this compartment in the response to hepatic injury in the context of steatotic liver disease.
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Affiliation(s)
- Gavin E. Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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6
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Xie W, Gan J, Zhou X, Tian H, Pan X, Liu W, Li X, Du J, Xu A, Zheng M, Wu F, Li Y, Lin Z. Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti. Cell Metab 2024; 36:1269-1286.e9. [PMID: 38838640 DOI: 10.1016/j.cmet.2024.04.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 02/20/2024] [Accepted: 04/30/2024] [Indexed: 06/07/2024]
Abstract
Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.
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Affiliation(s)
- Wei Xie
- The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan 523326, China; Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Jing Gan
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaodong Zhou
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Huiying Tian
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xingchao Pan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Wenyue Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaokun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Jie Du
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Anzhen Hospital of Capital Medical University, the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100029, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong 999077, China
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
| | - Fan Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Yuling Li
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Anzhen Hospital of Capital Medical University, the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100029, China.
| | - Zhuofeng Lin
- The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan 523326, China; Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; The Innovation Center of Cardiometabolic Disease, Guangdong Medical University, Dongguan 523808, China.
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7
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Caon E, Forlano R, Mullish BH, Manousou P, Rombouts K. Liver sinusoidal cells in the diagnosis and treatment of liver diseases: Role of hepatic stellate cells. SINUSOIDAL CELLS IN LIVER DISEASES 2024:513-532. [DOI: 10.1016/b978-0-323-95262-0.00025-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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8
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Dong Y, Wang X, Xu L, Li X, Dai H, Mao X, Chu Y, Yuan X, Liu H. Development of a Chimeric Protein BiPPB-mIFNγ-tTβRII for Improving the Anti-Fibrotic Activity in Vivo by Targeting Fibrotic Liver and Dual Inhibiting the TGF-β1/Smad Signaling Pathway. Protein J 2023; 42:753-765. [PMID: 37690089 DOI: 10.1007/s10930-023-10147-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2023] [Indexed: 09/12/2023]
Abstract
Excessive production of transforming growth factor β1 (TGF-β1) in activated hepatic stellate cells (aHSCs) promotes liver fibrosis by activating the TGF-β1/Smad signaling pathway. Thus, specifically inhibiting the pro-fibrotic activity of TGF-β1 in aHSCs is an ideal strategy for treating liver fibrosis. Overexpression of platelet-derived growth factor β receptor (PDGFβR) has been demonstrated on the surface of aHSCs relative to normal cells in liver fibrosis. Interferon-gamma peptidomimetic (mIFNγ) and truncated TGF-β receptor type II (tTβRII) inhibit the TGF-β1/Smad signaling pathway by different mechanisms. In this study, we designed a chimeric protein by the conjugation of (1) mIFNγ and tTβRII coupled via plasma protease-cleavable linker sequences (FNPKTP) to (2) PDGFβR-recognizing peptide (BiPPB), namely BiPPB-mIFNγ-tTβRII. This novel protein BiPPB-mIFNγ-tTβRII was effectively prepared using Escherichia coli expression system. The active components BiPPB-mIFNγ and tTβRII were slowly released from BiPPB-mIFNγ-tTβRII by hydrolysis using the plasma protease thrombin in vitro. Moreover, BiPPB-mIFNγ-tTβRII highly targeted to fibrotic liver tissues, markedly ameliorated liver morphology and fibrotic responses in chronic liver fibrosis mice by both inhibiting the phosphorylation of Smad2/3 and inducing the expression of Smad7. Meanwhile, BiPPB-mIFNγ-tTβRII markedly reduced the deposition of collagen fibrils and expression of fibrosis-related proteins in acute liver fibrosis mice. Furthermore, BiPPB-mIFNγ-tTβRII showed a good safety performance in both liver fibrosis mice. Taken together, BiPPB-mIFNγ-tTβRII improved the in vivo anti-liver fibrotic activity due to its high fibrotic liver-targeting potential and the dual inhibition of the TGF-β1/Smad signaling pathway, which may be a potential candidate for targeting therapy on liver fibrosis.
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Affiliation(s)
- Yixin Dong
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xiaohua Wang
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Liming Xu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xin Li
- Department of Pediatrics, Hongqi Hospital Affiliated to Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Haibing Dai
- Department of Biology, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xu Mao
- Department of Pharmacology, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Yanhui Chu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xiaohuan Yuan
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China.
| | - Haifeng Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China.
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, 157011, Mudanjiang, PR China.
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Liu X, Tuerxusssn Z, Balati Y, Gong P, Zhang Z, Bao Z, Yang Y, He P, Muhuyati. The Effect and Mechanism of POSTN and Its Alternative Splicing on the Apoptosis of Myocardial Cells in Acute Myocardial Infarction: A Study in Vitro. Cell Biochem Biophys 2023; 81:481-491. [PMID: 37572219 PMCID: PMC10465634 DOI: 10.1007/s12013-023-01157-w] [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] [Accepted: 07/31/2023] [Indexed: 08/14/2023]
Abstract
Our study aimed to investigate key molecular targets in the pathogenesis of AMI, and provide new strategy for the treatment. In this work, the myocardial ischemia and hypoxia model was constructed by using HL-1 mouse cardiomyocytes. The over-expressing POSTN wild-type, mutant and negative control lentiviruses (GV492-POSTNWT,GV492-POSTN-MUT, GV492-NC) was conducted and transfected. Cardiomyocytes were examined for cell proliferation and apoptosis to explore the effects of POSTN and its alternative splicing. The endoplasmic reticulum stess-related apoptosis proteins were selected and detected. We found that POSTN could promote the proliferation of normal and hypoxic cardiomyocytes and inhibit their apoptosis. The mechanism by which POSTN inhibited cardiomyocyte apoptosis may be through inhibiting the GRP78-eIF2α-ATF4-CHOP pathway of endoplasmic reticulum stress. Alternative splicing of POSTN could inhibit the apoptosis of ischemic and hypoxic cardiomyocytes, and its mechanism needs to be confirmed by further studies. We drawed the conclusion that POSTN might be a potential therapeutic target for AMI.
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Affiliation(s)
- Xuemei Liu
- Department of Respiratory Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Zulikaier Tuerxusssn
- The Second Department of Coronary Heart Disease, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Yumaierjiang Balati
- The Second Department of Coronary Heart Disease, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Pengfei Gong
- Department of Integrated Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Ze Zhang
- The Second Department of Coronary Heart Disease, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Zhen Bao
- Department of Integrated Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Yuchun Yang
- Department of Integrated Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Pengyi He
- The Second Department of Coronary Heart Disease, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China.
| | - Muhuyati
- Department of Integrated Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China.
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Wang Z, Li G, Li M, Hu L, Hao Z, Li Q, Sun C. Periostin contributes to the adventitial remodeling of atherosclerosis by activating adventitial fibroblasts. ATHEROSCLEROSIS PLUS 2022; 50:57-64. [PMID: 36643802 PMCID: PMC9833252 DOI: 10.1016/j.athplu.2022.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/12/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022]
Abstract
Background and aims Adventitial remodeling is an important pathological process of atherosclerosis, but cues implicated in adventitial remodeling are far from fully understood. Periostin (POSTN), a matricellular protein, has been demonstrated to have multiple roles in cardiovascular diseases. The aim of the study was to explore the function of POSTN in adventitial remodeling during atherosclerosis. Methods An atherosclerosis model was constructed based on ApoE-/- mice fed a high-fat and high-cholesterol diet. The expression of POSTN in the adventitia of mouse atherosclerotic vascular specimens was detected by immunohistochemical staining. The roles of POSTN in regulating adventitial fibroblast activation were assessed by cell contractility and activation marker α-smooth muscle actin (α-SMA) expression evaluation in adventitial fibroblasts overexpressing POSTN. In addition, we performed quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting to examine the expression of the proinflammatory chemokines transforming growth factor-β1 (TGF-β1) and monocyte chemotactic protein 1 (MCP1), as well as some extracellular matrix (ECM)-related proteins, in POSTN-overexpressing adventitial fibroblasts. Finally, the integrin-related signaling pathway was detected upon POSTN overexpression in adventitial fibroblasts. Results POSTN was highly expressed in the adventitia of atherosclerotic aortae in the mouse atherosclerosis model and promoted the activation and contraction of adventitial fibroblasts. Meanwhile, POSTN also induced adventitial fibroblasts to express TGF-β1, monocyte chemotactic protein-1 (MCP1), and ECM-related proteins and activated the phosphorylation of focal adhesion kinase (FAK) and Src. Conclusions Our results revealed that POSTN is elevated in adventitia during atherosclerosis and contributes to the adventitial remodeling of atherosclerosis by activating adventitial fibroblasts.
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Key Words
- Adventitial fibroblasts
- Adventitial remodeling
- Atherosclerosis
- COL1A1, collagen Ⅰ
- COL3A1, collagen Ⅲ
- DMEM, Dulbecco's modified Eagle's medium
- ECM, extracellular matrix
- FAK, focal adhesion kinase
- FBS, fetal bovine serum
- MCP1, monocyte chemotactic protein-1
- MMPs, matrix metalloproteinases
- POSTN
- POSTN, periostin
- TGF-β1
- TGF-β1, transforming growth factor-β1
- qRT-PCR, quantitative real-time polymerase chain reaction
- α-SMA, α-smooth muscle actin
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Affiliation(s)
- Zhonghua Wang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China,Department of Cardiovascular Medicine, Affiliated to the First People's Hospital of Chenzhou of University of South China, Chenzhou No. 1 People's Hospital, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
| | - Guoliang Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Mingpeng Li
- Department of Cardiovascular Medicine, Affiliated to the First People's Hospital of Chenzhou of University of South China, Chenzhou No. 1 People's Hospital, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
| | - Lu Hu
- Department of Cardiovascular Medicine, Affiliated to the First People's Hospital of Chenzhou of University of South China, Chenzhou No. 1 People's Hospital, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
| | - Zichen Hao
- Department of Cardiovascular Medicine, Affiliated to the First People's Hospital of Chenzhou of University of South China, Chenzhou No. 1 People's Hospital, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
| | - Qian Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Chaofeng Sun
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China,Corresponding author. Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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11
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Kołakowski A, Dziemitko S, Chmielecka A, Żywno H, Bzdęga W, Charytoniuk T, Chabowski A, Konstantynowicz-Nowicka K. Molecular Advances in MAFLD—A Link between Sphingolipids and Extracellular Matrix in Development and Progression to Fibrosis. Int J Mol Sci 2022; 23:ijms231911380. [PMID: 36232681 PMCID: PMC9569877 DOI: 10.3390/ijms231911380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/18/2022] [Accepted: 09/23/2022] [Indexed: 11/25/2022] Open
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of matrix molecules and inflammatory processes lead to progressive fibrosis, cirrhosis, and ultimately liver failure. In addition, increased accumulation of sphingolipids accompanied by increased expression of pro-inflammatory cytokines in the ECM is closely related to lipogenesis, MAFLD development, and its progression to fibrosis. In our work, we will summarize all information regarding the role of sphingolipids e.g., ceramide and S1P in MAFLD development. These sphingolipids seem to have the most significant effect on macrophages and, consequently, HSCs which trigger the entire cascade of overproduction matrix molecules, especially type I and III collagen, proteoglycans, elastin, and also tissue inhibitors of metalloproteinases, which as a result cause the development of liver fibrosis.
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Affiliation(s)
- Adrian Kołakowski
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Sylwia Dziemitko
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | | | - Hubert Żywno
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Wiktor Bzdęga
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Tomasz Charytoniuk
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
- Department of Ophthalmology, Antoni Jurasz University Hospital No. 1, 85-094 Bydgoszcz, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
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12
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Sunkar S, Namratha K, Neeharika D. Identification of hub genes associated with human osteoarthritis cartilage: An in silico approach. Meta Gene 2022. [DOI: 10.1016/j.mgene.2022.101015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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13
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Chen J, Jayachandran M, Bai W, Xu B. A critical review on the health benefits of fish consumption and its bioactive constituents. Food Chem 2022; 369:130874. [PMID: 34455321 DOI: 10.1016/j.foodchem.2021.130874] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/10/2021] [Accepted: 08/14/2021] [Indexed: 12/12/2022]
Abstract
As one of food sources, fish provides sufficient nutrition to human. Diverse nutrients in fish make fish an important nutrient source available easily across the globe. Fish is proven to possess several health benefits, such as anti-oxidation, anti-inflammation, wound healing, neuroprotection, cardioprotection, and hepatoprotection properties. Fish proteins, such as immunoglobins, act as defense agents against viral and bacterial infections and prevent protein-calorie malnutrition. Besides, fish oil constituents, such as polyunsaturated fatty acids (PUFAs), regulate various signaling pathways, such as nuclear factor kappa B pathway, Toll-like receptor pathway, transforming growth factor-β (TGF-β) pathway, and peroxisome proliferators activated receptor (PPAR) pathways. In this review, the literature about health benefits of fish consumption are accumulated from PubMed, Google Scholar, Scopus, and the mechanistic action of health benefits are summarized. Fish consumption at least twice per week as part of a healthy diet is beneficial for a healthy heart. More advances in this field could pose fish as a major nutrients source of foods.
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Affiliation(s)
- Jiali Chen
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, China
| | - Muthukumaran Jayachandran
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Weibin Bai
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, China
| | - Baojun Xu
- Programme of Food Science and Technology, BNU-HKBU United International College, Zhuhai, China.
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14
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Li G, Hu L, Hu Z, Li Y, Yuan C, Takaki K, Hu Y. Nutrition and protein function, properties (structure, rheology, thermal stability) analysis of Nepture volute based on proteomics and in vitro digestion/cells model. FOOD BIOSCI 2021. [DOI: 10.1016/j.fbio.2021.101321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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15
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Lee CH, Choe SJ, Kim DH, Kim EJ, Eom M, Hong SP, Choi EH. Skin atrophy caused by topical glucocorticoids is less common in patients with atopic dermatitis than in those with psoriasis. Exp Dermatol 2021; 31:182-190. [PMID: 34351656 DOI: 10.1111/exd.14441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 06/22/2021] [Accepted: 08/02/2021] [Indexed: 11/30/2022]
Abstract
Although the long-term use of topical glucocorticoids (TGC) may induce skin atrophy including striae distensae (SD), patients with atopic dermatitis (AD) appear to have lesser degree of skin atrophy than those with psoriasis (PSO). Periostin, encoded by POSTN, is involved in tissue remodelling processes of chronic AD lesions. This study was designed to investigate the difference in the occurrence of skin atrophy in patients with AD or PSO when treated with TGC and to elucidate the association between skin atrophy and periostin. Big data analysis using Korean Health Claims Database was performed to determine the prevalence of SD in AD and PSO patients. Blood and skin eosinophils count and dermal fibrosis between AD and PSO patients were compared, and immunohistochemistry for periostin and mRNA sequencing in the dermis were performed. Animal experiments using AD and PSO murine model were conducted. Big data analysis revealed that patients with AD have significantly lesser degree of SD than patients with PSO. The ratio of the dermal fibrous tissues and eosinophil counts were significantly higher in AD patients. In AD skin, periostin was more widely distributed in the entire dermis and POSTN mRNAs were significantly upregulated. Dermal thickness and fibrosis were significantly higher in AD mice even after TGC treatment. A significant positive correlation was observed between dermal fibrosis and tissue eosinophil counts. Lesser skin atrophy in AD patients even after long-term TGC application could be resulted from skin fibrosis caused by increased tissue eosinophils and periostin deposition.
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Affiliation(s)
- Chung Hyeok Lee
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Sung Jay Choe
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Dong Hye Kim
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Eun Jung Kim
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Minseob Eom
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Seung-Phil Hong
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Eung Ho Choi
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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16
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Milaciu MV, Ciumărnean L, Matei DM, Vesa ȘC, Sabin O, Bocșan IC, Pop RM, Negrean V, Buzoianu AD, Acalovschi M. Cytokines, paraoxonase-1, periostin and non-invasive liver fibrosis scores in patients with non-alcoholic fatty liver disease and persistently elevated aminotransferases: A pilot study. Exp Ther Med 2021; 21:533. [PMID: 33815606 PMCID: PMC8014973 DOI: 10.3892/etm.2021.9965] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. The aim of this study was to evaluate the possible association between paraoxonase-1 (PON1), periostin (POSTN), tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 serum concentration with non-invasive liver fibrosis scores, in a cohort of patients with NAFLD. We studied a cohort of 52 patients diagnosed with NAFLD. The NAFLD fibrosis score (NFS), Fibrosis-4 Index (FIB-4), AST to platelet ratio index (APRI) and BARD scores were calculated for each patient. We determined the PON1, POSTN, TNF-α, IL-6, and IL-10 serum values using ELISA kits. There was no correlation between PON1 or POSTN serum levels and non-invasive liver fibrosis. The TNF-α serum values were independently associated with the liver fibrosis scores (P=0.02 for NFS and P=0.002 for FIB-4). Age and metabolic syndrome were also independently linked to the fibrosis scores. In conclusion, serum levels of TNF-α, age and metabolic syndrome were associated with the non-invasive liver fibrosis scores.
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Affiliation(s)
- Mircea Vasile Milaciu
- Department 5-Internal Medicine, 4th Medical Clinic, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania
| | - Lorena Ciumărnean
- Department 5-Internal Medicine, 4th Medical Clinic, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania
| | - Daniela Maria Matei
- Department 5-Internal Medicine, 3rd Medical Clinic, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Ștefan Cristian Vesa
- Department 2-Functional Sciences, Discipline of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Octavia Sabin
- Department 2-Functional Sciences, Discipline of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Ioana Corina Bocșan
- Department 2-Functional Sciences, Discipline of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Raluca Maria Pop
- Department 2-Functional Sciences, Discipline of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vasile Negrean
- Department 5-Internal Medicine, 4th Medical Clinic, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania
| | - Anca Dana Buzoianu
- Department 5-Internal Medicine, 3rd Medical Clinic, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Monica Acalovschi
- Doctoral School, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
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Smirne C, Mulas V, Barbaglia MN, Mallela VR, Minisini R, Barizzone N, Burlone ME, Pirisi M, Grossini E. Periostin Circulating Levels and Genetic Variants in Patients with Non-Alcoholic Fatty Liver Disease. Diagnostics (Basel) 2020; 10:E1003. [PMID: 33255560 PMCID: PMC7760606 DOI: 10.3390/diagnostics10121003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/18/2020] [Accepted: 11/23/2020] [Indexed: 11/24/2022] Open
Abstract
Circulating periostin has been suggested as a possible biomarker in non-alcoholic fatty liver disease (NAFLD) in Asian studies. In the present study, we aimed to test its still controversial relevance in a Caucasian population. In patients with histologically-proven NAFLD (N. = 74; 10 with hepatocellular carcinoma, HCC) plasma periostin concentrations were analyzed. POSTN haplotype analysis was based on rs9603226, rs3829365, and rs1029728. Hepatitis C patients (N. = 81, 7 HCC) and healthy subjects (N. = 27) were used as controls. The median plasma periostin concentration was 11.6 ng/mL without differences amongst groups; it was not influenced by age, liver fibrosis or steatosis. However, possession of haplotype two (rs9603226 = G, rs3829365 = C, rs1028728 = A) was associated with lower circulating periostin compared to other haplotypes. Moreover, periostin was higher in HCC patients. At multivariate analysis, HCC remained the only predictor of high periostin. In conclusion, plasma periostin concentrations in Caucasians NAFLD patients are not influenced by the degree of liver disease, but are significantly higher in HCC. Genetically-determined differences may account for some of the variability. These data suggest extreme caution in predicting a possible future role of periostin antagonists as a rational therapeutic alternative for NAFLD, but show a potential periostin role in the management of NAFLD-associated HCC.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Violante Mulas
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Matteo Nazzareno Barbaglia
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Venkata Ramana Mallela
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Nadia Barizzone
- Department of Health Sciences, Università’ del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy;
| | - Michela Emma Burlone
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, via Solaroli, 17, 28100 Novara, Italy; (V.M.); (M.N.B.); (V.R.M.); (R.M.); (M.E.B.); (M.P.); (E.G.)
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18
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De Marco Verissimo C, Jewhurst HL, Tikhonova IG, Urbanus RT, Maule AG, Dalton JP, Cwiklinski K. Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. PLoS Negl Trop Dis 2020; 14:e0008510. [PMID: 32760059 PMCID: PMC7437470 DOI: 10.1371/journal.pntd.0008510] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/18/2020] [Accepted: 06/22/2020] [Indexed: 11/18/2022] Open
Abstract
Serine protease inhibitors (serpins) regulate proteolytic events within diverse biological processes, including digestion, coagulation, inflammation and immune responses. The presence of serpins in Fasciola hepatica excretory-secretory products indicates that the parasite exploits these to regulate proteases encountered during its development within vertebrate hosts. Interrogation of the F. hepatica genome identified a multi-gene serpin family of seven members that has expanded by gene duplication and divergence to create an array of inhibitors with distinct specificities. We investigated the molecular properties and functions of two representatives, FhSrp1 and FhSrp2, highly expressed in the invasive newly excysted juvenile (NEJ). Consistent with marked differences in the reactive centre loop (RCL) that executes inhibitor-protease complexing, the two recombinant F. hepatica serpins displayed distinct inhibitory profiles against an array of mammalian serine proteases. In particular, rFhSrp1 efficiently inhibited kallikrein (Ki = 40 nM) whilst rFhSrp2 was a highly potent inhibitor of chymotrypsin (Ki = 0.07 nM). FhSrp1 and FhSrp2 are both expressed on the NEJ surface, predominantly around the oral and ventral suckers, suggesting that these inhibitors protect the parasites from the harmful proteolytic effects of host proteases, such as chymotrypsin, during invasion. Furthermore, the unusual inhibition of kallikrein suggests that rFhSrp1 modulates host responses such as inflammation and vascular permeability by interfering with the kallikrein-kinin system. A vaccine combination of rFhSrp1 and rFhSrp2 formulated in the adjuvant Montanide ISA 206VG elicited modest but non-significant protection against a challenge infection in a rat model, but did induce some protection against liver pathogenesis when compared to a control group and a group vaccinated with two well-studied vaccine candidates, F. hepatica cathepsin L2 and L3. This work highlights the importance of F. hepatica serpins to regulate host responses that enables parasite survival during infection and, coupled with the vaccine data, encourages future vaccine trials in ruminants. Serpins are protease inhibitors that regulate various biological processes, including digestion, blood coagulation, inflammation and immune responses. The liver fluke, Fasciola hepatica, produces an array of inhibitors to regulate proteolytic enzymes they encounter during development within the mammalian host. In this study, we identified seven different serpins that have evolved to inhibit a range of host proteases. In particular, we characterized two representatives, FhSrp1 and FhSrp2, that we found highly expressed on the surface of the invasive newly excysted juvenile (NEJ), suggesting that they protect the parasites from harmful proteolytic effects during invasion. Contrasting inhibitory profiles were observed; while recombinant FhSrp1 inhibited kallikrein, recombinant FhSrp2 was a highly potent inhibitor of chymotrypsin. The unusual inhibition of kallikrein suggests that rFhSrp1 influences host responses such as inflammation and vascular permeability by interfering with the kallikrein-kinin system. Conversely, chymotrypsin is typically inhibited by trematode-specific serpins, implying a conserved mechanism to regulate digestive enzymes. The ability of the liver fluke serpin family to inhibit such an array of proteases highlights the importance of these inhibitors in parasite-host interactions and encourages future investigations of serpins as candidate anti-parasite vaccine targets for the control of fasciolosis in ruminants.
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Affiliation(s)
- Carolina De Marco Verissimo
- Centre for One Health and Ryan Institute, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
- * E-mail:
| | - Heather L. Jewhurst
- Centre for One Health and Ryan Institute, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
| | - Irina G. Tikhonova
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast, United Kingdom
| | - Rolf T. Urbanus
- Thrombosis and Hemostasis Laboratory, Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Aaron G. Maule
- Microbe & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - John P. Dalton
- Centre for One Health and Ryan Institute, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
| | - Krystyna Cwiklinski
- Centre for One Health and Ryan Institute, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
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19
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Zhu Y, Liu C, Chen X, Lu S, Chen J. Hepatoprotective effects and mechanisms of Ixeris denticulate water extract on liver cirrhosis in experimental rat. BMC Complement Med Ther 2020; 20:175. [PMID: 32503634 PMCID: PMC7275494 DOI: 10.1186/s12906-020-02957-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 05/19/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To explore the protective effect and mechanisms of Ixeris denticulate water extract (IDWE) in the development of liver cirrhosis in experimental rat. METHODS Sixty rats were randomly divided into five groups: control group, model group and IDWE (2, 4 and 8 g/kg) treatment groups. Alanine transferase (ALT), aspartate transaminase (AST), albumin (ALB), tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-6 and IL-8 in serum and superoxide dismutase (SOD), malondialdehyde (MDA) in liver tissue were evaluated, respectively. The liver index, liver morphology and liver histopathological analysis were detected as a supportive data. The liver protein expression of Bcl-2 and Bax were assessed by western blot, and NF-κB p65 protein expression was determined by immunohistochemistry analysis. RESULTS The result showed that a significantly decrease in the levels of serum AST, ALT and serum inflammatory factors TNF-α, IL-6 and IL-8 in IDWE-treated rats. The levels of serum ALB and SOD in liver tissue were markedly increased after IDWE treated, compared with model rats. Furthermore, IDWE-treated group also exhibited a down-regulated protein expression of NF-κB p65 and Bax, up-regulated Bcl-2 protein expression. CONCLUSIONS IDWE could effectively alleviate the course of liver cirrhosis in rat model, which may be a potent hepatoprotective agent in clinical therapy in the future.
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Affiliation(s)
- Yinhong Zhu
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou, 321012, China.
| | - Changling Liu
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou, 321012, China
| | - Xiaobei Chen
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou, 321012, China
| | - Shengjia Lu
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou, 321012, China
| | - Jie Chen
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou, 321012, China
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20
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Jia Y, Gao L, Yang X, Zhang F, Chen A, Wang S, Shao J, Tan S, Zheng S. Blockade of periostin-dependent migration and adhesion by curcumol via inhibition of nuclear factor kappa B signaling in hepatic stellate cells. Toxicology 2020; 440:152475. [PMID: 32344006 DOI: 10.1016/j.tox.2020.152475] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Curcumol, a guaiane-type sesquiterpenoid hemiketal extracted from the herb Rhizoma Curcumae, exhibits multiple-pharmacological activities. We previously reported that curcumol ameliorated hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. In this study, we aimed to investigate the effect of curcumol on HSC migration and adhesion, and reveal its regulation mechanisms. MATERIALS AND METHODS Cellular viability was determined by Cell Counting Kit-8. Cell migration was detected by boyden chamber and cell scratch experiment. Recombinant human periostin (rh POSTN) and adeno-associated viral (AAV)-GFP-periostin were used to achieve POSTN overexpression in vitro and in vivo, respectively. Nuclear factor kappa B (NF-κB)-p65 overexpression was achieved by using plasmid. ELISA was conducted to detect POSTN level. Immunohistochemistry, qRT-PCR, Western blotting, and immunofluorescence were performed to assess associated factor expression. RESULTS Curcumol suppressed HSC migration and adhesion, and reduced the secretion and expression of POSTN. By gain of function POSTN in HSCs, using rh POSTN, we found that the inhibition of HSC migration and adhesion by curcumol depended on the decrease of POSTN. Besides, curcumol protection against chronic CCl4-caused hepatic fibrosis could be impaired by POSTN overexpression. Moreover, we showed that curcumol repressed NF-κB signaling and the production of pro-inflammatory factor. Importantly, curcumol down-regulation of POSTN was rescued by knock-in of NF-κB, as well as the inhibition of HSC migration and adhesion. CONCLUSION These findings reveal the molecular mechanism of curcumol-reduced HSC migration and adhesion, by which points to the possibility of using curcumol based on NF-κB dependent POSTN for the treatment of fibrogenesis.
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Affiliation(s)
- Yan Jia
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China
| | - Liyuan Gao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China
| | - Xiang Yang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO 63104, USA
| | - Shijun Wang
- Shandong Co-Innovation Center of TCM Formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China.
| | - Shanzhong Tan
- Department of Hepatology, Integrated Traditional Chinese and Western Medicine, Nanjing Second Hospital, China.
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, China.
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Han T, Mignatti P, Abramson SB, Attur M. Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration. PLoS One 2020; 15:e0231501. [PMID: 32330138 PMCID: PMC7182230 DOI: 10.1371/journal.pone.0231501] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 03/24/2020] [Indexed: 11/18/2022] Open
Abstract
Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblast-specific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/β-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA.
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Affiliation(s)
- Tianzhen Han
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Orthopedic Hospital, New York, NY, United States of America
| | - Paolo Mignatti
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Orthopedic Hospital, New York, NY, United States of America
| | - Steven B. Abramson
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Orthopedic Hospital, New York, NY, United States of America
| | - Mukundan Attur
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Orthopedic Hospital, New York, NY, United States of America
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Wang K, Xu J, Liu Y, Cui Z, He Z, Zheng Z, Huang X, Zhang Y. Self-assembled Angelica sinensis polysaccharide nanoparticles with an instinctive liver-targeting ability as a drug carrier for acute alcoholic liver damage protection. Int J Pharm 2020; 577:118996. [DOI: 10.1016/j.ijpharm.2019.118996] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 12/07/2019] [Accepted: 12/23/2019] [Indexed: 12/11/2022]
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