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1
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Suzuki Y, Nampei M, Kawakita F, Oinaka H, Nakajima H, Suzuki H. The effect of Fibulin-5 on early brain injury after subarachnoid hemorrhage in mice. Neurochem Int 2025; 187:105989. [PMID: 40339910 DOI: 10.1016/j.neuint.2025.105989] [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: 02/26/2025] [Revised: 04/18/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Early brain injury (EBI) is an important cause that determines outcomes after aneurysmal subarachnoid hemorrhage (SAH). Our recent clinical study reported that a high concentration of plasma fibulin-5 (FBLN5), one of matricellular proteins, was associated with poor outcomes after SAH. The aim of this study was to investigate whether and how FBLN5 was associated with EBI during an acute phase of SAH in mice. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or four dosages (0.001, 0.01, 0.1, and 1 μg) of short or long recombinant FBLN5 (rFBLN5) were randomly administrated by an intracerebroventricular injection. Neurobehavioral test, measurements of brain water content, immunohistochemical staining, and Western blotting were performed to evaluate EBI 24 h after SAH. Short rFBLN5 had no significant effects on EBI, but administration of long rFBLN5 containing an arginine-glycine-aspartic acid motif improved neurobehavior functions depending on the dosages, without affecting brain edema. Administration of long rFBLN5 also reduced cleaved caspase-3-dependent neuronal apoptosis, associated with the inhibition of post-SAH upregulation of transforming growth factor-β1, but no significant changes in the expression level of Smad 2/3, mitogen-activated protein kinases, and another matricellular protein tenascin-C. Although further research is required to clarify the detailed mechanism, this study demonstrated for the first time that FBLN5 played a protective role against neuronal apoptosis in an acute phase of experimental SAH.
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Affiliation(s)
- Yume Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Mai Nampei
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Fumihiro Kawakita
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hiroki Oinaka
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hideki Nakajima
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hidenori Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
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2
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Deritei D, Inuzuka H, Castaldi PJ, Yun JH, Xu Z, Anamika WJ, Asara JM, Guo F, Zhou X, Glass K, Wei W, Silverman EK. HHIP protein interactions in lung cells provide insight into COPD pathogenesis. Hum Mol Genet 2025; 34:777-789. [PMID: 39945347 PMCID: PMC12037150 DOI: 10.1093/hmg/ddaf016] [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: 09/16/2024] [Revised: 01/16/2025] [Accepted: 02/10/2025] [Indexed: 02/19/2025] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes. However, the biological relationships between the identified COPD susceptibility genes are largely unknown. Genes associated with a complex disease are often in close network proximity, i.e. their protein products often interact directly with each other and/or similar proteins. In this study, we use affinity purification mass spectrometry (AP-MS) to identify protein interactions with HHIP, a well-established COPD GWAS gene which is part of the sonic hedgehog pathway, in two disease-relevant lung cell lines (IMR90 and 16HBE). To better understand the network neighborhood of HHIP, its proximity to the protein products of other COPD GWAS genes, and its functional role in COPD pathogenesis, we create HUBRIS, a protein-protein interaction network compiled from 8 publicly available databases. We identified both common and cell type-specific protein-protein interactors of HHIP. We find that our newly identified interactions shorten the network distance between HHIP and the protein products of several COPD GWAS genes, including DSP, MFAP2, TET2, and FBLN5. These new shorter paths include proteins that are encoded by genes involved in extracellular matrix and tissue organization. We found and validated interactions to proteins that provide new insights into COPD pathobiology, including CAVIN1 (IMR90) and TP53 (16HBE). The newly discovered HHIP interactions with CAVIN1 and TP53 implicate HHIP in response to oxidative stress.
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Affiliation(s)
- Dávid Deritei
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, United States
| | - Peter J Castaldi
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - Jeong Hyun Yun
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - Zhonghui Xu
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - Wardatul Jannat Anamika
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - John M Asara
- Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, United States
| | - Feng Guo
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Yunlong District, Xuzhou, Jiangsu 221004, China
| | - Xiaobo Zhou
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - Kimberly Glass
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, United States
| | - Edwin K Silverman
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
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3
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Okuyama T, Tsuno T, Inoue R, Fukushima S, Kyohara M, Matsumura A, Miyashita D, Nishiyama K, Takano Y, Togashi Y, Meguro-Horike M, Horike SI, Kin T, Shapiro AJ, Yanagisawa H, Terauchi Y, Shirakawa J. The matricellular protein Fibulin-5 regulates β-cell proliferation in an autocrine/paracrine manner. iScience 2025; 28:111856. [PMID: 39995864 PMCID: PMC11848788 DOI: 10.1016/j.isci.2025.111856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 11/20/2024] [Accepted: 01/17/2025] [Indexed: 02/26/2025] Open
Abstract
The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role of Fbln5 in β-cell replication. Fbln5 expression was increased upon glucose stimulation in β-cells of mouse and human islets. β-Cell-specific Fbln5-knockout (βFbln5KO) mice exhibit significantly reduced β-cell proliferation in vivo but not in vitro. Secreted extracellular Fbln5 enhances β-cell replication. Fbln5-deficient β-cells exhibit the downregulated expression of the gene encoding Polo-like kinase 1 (PLK1), which is accompanied by ERK-mediated FoxM1 nuclear export. These data suggest that Fbln5 is secreted from β-cells in response to glucose and plays important roles in the appropriate maintenance of β-cell functions in an autocrine or paracrine manner.
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Affiliation(s)
- Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takahiro Tsuno
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Ryota Inoue
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Anzu Matsumura
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kuniyuki Nishiyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Yusuke Takano
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makiko Meguro-Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Shin-ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
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4
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Krymchenko R, Coşar Kutluoğlu G, van Hout N, Manikowski D, Doberenz C, van Kuppevelt TH, Daamen WF. Elastogenesis in Focus: Navigating Elastic Fibers Synthesis for Advanced Dermal Biomaterial Formulation. Adv Healthc Mater 2024; 13:e2400484. [PMID: 38989717 DOI: 10.1002/adhm.202400484] [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: 02/07/2024] [Revised: 05/31/2024] [Indexed: 07/12/2024]
Abstract
Elastin, a fibrous extracellular matrix (ECM) protein, is the main component of elastic fibers that are involved in tissues' elasticity and resilience, enabling them to undergo reversible extensibility and to endure repetitive mechanical stress. After wounding, it is challenging to regenerate elastic fibers and biomaterials developed thus far have struggled to induce its biosynthesis. This review provides a comprehensive summary of elastic fibers synthesis at the cellular level and its implications for biomaterial formulation, with a particular focus on dermal substitutes. The review delves into the intricate process of elastogenesis by cells and investigates potential triggers for elastogenesis encompassing elastin-related compounds, ECM components, and other molecules for their potential role in inducing elastin formation. Understanding of the elastogenic processes is essential for developing biomaterials that trigger not only the synthesis of the elastin protein, but also the formation of a functional and branched elastic fiber network.
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Affiliation(s)
- Roman Krymchenko
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - Gizem Coşar Kutluoğlu
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
- MedSkin Solutions Dr. Suwelack AG, 48727, Billerbeck, Germany
| | - Noor van Hout
- Department of Dermatology, Radboud university medical center, Nijmegen, 6525 GA, The Netherlands
| | | | | | - Toin H van Kuppevelt
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - Willeke F Daamen
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
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5
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Wu ML, Wheeler K, Silasi R, Lupu F, Griffin CT. Endothelial Chromatin-Remodeling Enzymes Regulate the Production of Critical ECM Components During Murine Lung Development. Arterioscler Thromb Vasc Biol 2024; 44:1784-1798. [PMID: 38868942 PMCID: PMC11624602 DOI: 10.1161/atvbaha.124.320881] [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: 02/23/2024] [Accepted: 05/29/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND The chromatin-remodeling enzymes BRG1 (brahma-related gene 1) and CHD4 (chromodomain helicase DNA-binding protein 4) independently regulate the transcription of genes critical for vascular development, but their coordinated impact on vessels in late-stage embryos has not been explored. METHODS In this study, we genetically deleted endothelial Brg1 and Chd4 in mixed background mice (Brg1fl/fl;Chd4fl/fl;VE-Cadherin-Cre), and littermates that were negative for Cre recombinase were used as controls. Tissues were analyzed by immunostaining, immunoblot, and flow cytometry. Quantitative reverse transcription polymerase chain reaction was used to determine gene expression, and chromatin immunoprecipitation revealed gene targets of BRG1 and CHD4 in cultured endothelial cells. RESULTS We found Brg1/Chd4 double mutants grew normally but died soon after birth with small and compact lungs. Despite having normal cellular composition, distal air sacs of the mutant lungs displayed diminished ECM (extracellular matrix) components and TGFβ (transforming growth factor-β) signaling, which typically promotes ECM synthesis. Transcripts for collagen- and elastin-related genes and the TGFβ ligand Tgfb1 were decreased in mutant lung endothelial cells, but genetic deletion of endothelial Tgfb1 failed to recapitulate the small lungs and ECM defects seen in Brg1/Chd4 mutants. We instead found several ECM genes to be direct targets of BRG1 and CHD4 in cultured endothelial cells. CONCLUSIONS Collectively, our data highlight essential roles for endothelial chromatin-remodeling enzymes in promoting ECM deposition in the distal lung tissue during the saccular stage of embryonic lung development.
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Affiliation(s)
- Meng-Ling Wu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Kate Wheeler
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Robert Silasi
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Florea Lupu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Courtney T. Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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6
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Neupane S, Williamson DB, Roth RA, Halabi CM, Haltiwanger RS, Holdener BC. Poglut2/3 double knockout in mice results in neonatal lethality with reduced levels of fibrillin in lung tissues. J Biol Chem 2024; 300:107445. [PMID: 38844137 PMCID: PMC11261140 DOI: 10.1016/j.jbc.2024.107445] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/08/2024] [Accepted: 05/17/2024] [Indexed: 06/30/2024] Open
Abstract
Fibrillin microfibrils play a critical role in the formation of elastic fibers, tissue/organ development, and cardiopulmonary function. These microfibrils not only provide structural support and flexibility to tissues, but they also regulate growth factor signaling through a plethora of microfibril-binding proteins in the extracellular space. Mutations in fibrillins are associated with human diseases affecting cardiovascular, pulmonary, skeletal, and ocular systems. Fibrillins consist of up to 47 epidermal growth factor-like repeats, of which more than half are modified by protein O-glucosyltransferase 2 (POGLUT2) and/or POGLUT3. Loss of these modifications reduces secretion of N-terminal fibrillin constructs overexpressed in vitro. Here, we investigated the role of POGLUT2 and POGLUT3 in vivo using a Poglut2/3 double knockout (DKO) mouse model. Blocking O-glucosylation caused neonatal death with skeletal, pulmonary, and eye defects reminiscent of fibrillin/elastin mutations. Proteomic analyses of DKO dermal fibroblast medium and extracellular matrix provided evidence that fibrillins were more sensitive to loss of O-glucose compared to other POGLUT2/3 substrates. This conclusion was supported by immunofluorescent analyses of late gestation DKO lungs where FBN levels were reduced and microfibrils appeared fragmented in the pulmonary arteries and veins, bronchioles, and developing saccules. Defects in fibrillin microfibrils likely contributed to impaired elastic fiber formation and histological changes observed in DKO lung blood vessels, bronchioles, and saccules. Collectively, these results highlight the importance of POGLUT2/3-mediated O-glucosylation in vivo and open the possibility that O-glucose modifications on fibrillin influence microfibril assembly and or protein interactions in the ECM environment.
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Affiliation(s)
- Sanjiv Neupane
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA
| | - Daniel B Williamson
- Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA
| | - Robyn A Roth
- Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Carmen M Halabi
- Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Robert S Haltiwanger
- Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA.
| | - Bernadette C Holdener
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
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7
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Ellis MW, Riaz M, Huang Y, Anderson CW, Hoareau M, Li X, Luo H, Lee S, Park J, Luo J, Batty LD, Huang Q, Lopez CA, Reinhardt DP, Tellides G, Qyang Y. De Novo Elastin Assembly Alleviates Development of Supravalvular Aortic Stenosis-Brief Report. Arterioscler Thromb Vasc Biol 2024; 44:1674-1682. [PMID: 38752350 PMCID: PMC11209776 DOI: 10.1161/atvbaha.124.320790] [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: 02/19/2024] [Revised: 04/19/2024] [Accepted: 05/01/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of ELN, is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin. METHODS We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell-derived vascular smooth muscle cells and developmental Eln+/- mouse models to establish de novo elastin assembly as a new therapeutic intervention. RESULTS We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell-derived vascular smooth muscle cells and in utero to Eln+/- mice. CONCLUSIONS We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell-derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in Eln+/- mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.
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MESH Headings
- Elastin/metabolism
- Animals
- Humans
- Catechin/analogs & derivatives
- Catechin/pharmacology
- Disease Models, Animal
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/drug effects
- Aortic Stenosis, Supravalvular/metabolism
- Aortic Stenosis, Supravalvular/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/drug effects
- Cell Proliferation/drug effects
- Induced Pluripotent Stem Cells/metabolism
- Induced Pluripotent Stem Cells/drug effects
- Mice
- Cells, Cultured
- Mice, Inbred C57BL
- Female
- Male
- Mice, Knockout
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Affiliation(s)
- Matthew W. Ellis
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, 06519, USA
| | - Muhammad Riaz
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Yan Huang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Christopher W. Anderson
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
- Department of Pathology, Yale University, New Haven, CT, 06520, USA
| | - Marie Hoareau
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Xin Li
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Hangqi Luo
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Seoyeon Lee
- Biological and Biomedical Sciences, Yale University, New Haven, CT 06511, USA
| | - Jinkyu Park
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Jiesi Luo
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Luke D. Batty
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
- Department of Pathology, Yale University, New Haven, CT, 06520, USA
| | - Qunhua Huang
- Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Colleen A. Lopez
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Dieter P. Reinhardt
- Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
| | - George Tellides
- Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06520, USA
- Department of Surgery, Yale School of Medicine, New Haven, CT, 06519, USA
| | - Yibing Qyang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
- Department of Pathology, Yale University, New Haven, CT, 06520, USA
- Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06520, USA
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8
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Deritei D, Inuzuka H, Castaldi PJ, Yun JH, Xu Z, Anamika WJ, Asara JM, Guo F, Zhou X, Glass K, Wei W, Silverman EK. HHIP protein interactions in lung cells provide insight into COPD pathogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.01.586839. [PMID: 38617310 PMCID: PMC11014494 DOI: 10.1101/2024.04.01.586839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes. However, the biological relationships between the identified COPD susceptibility genes are largely unknown. Genes associated with a complex disease are often in close network proximity, i.e. their protein products often interact directly with each other and/or similar proteins. In this study, we use affinity purification mass spectrometry (AP-MS) to identify protein interactions with HHIP , a well-established COPD GWAS gene which is part of the sonic hedgehog pathway, in two disease-relevant lung cell lines (IMR90 and 16HBE). To better understand the network neighborhood of HHIP , its proximity to the protein products of other COPD GWAS genes, and its functional role in COPD pathogenesis, we create HUBRIS, a protein-protein interaction network compiled from 8 publicly available databases. We identified both common and cell type-specific protein-protein interactors of HHIP. We find that our newly identified interactions shorten the network distance between HHIP and the protein products of several COPD GWAS genes, including DSP, MFAP2, TET2 , and FBLN5 . These new shorter paths include proteins that are encoded by genes involved in extracellular matrix and tissue organization. We found and validated interactions to proteins that provide new insights into COPD pathobiology, including CAVIN1 (IMR90) and TP53 (16HBE). The newly discovered HHIP interactions with CAVIN1 and TP53 implicate HHIP in response to oxidative stress.
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9
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Yombo DJK, Madala SK, Vemulapalli CP, Ediga HH, Hardie WD. Pulmonary fibroelastosis - A review. Matrix Biol 2023; 124:1-7. [PMID: 37922998 PMCID: PMC10841596 DOI: 10.1016/j.matbio.2023.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/11/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
Elastin is a long-lived fibrous protein that is abundant in the extracellular matrix of the lung. Elastic fibers provide the lung the characteristic elasticity during inhalation with recoil during exhalation thereby ensuring efficient gas exchange. Excessive deposition of elastin and other extracellular matrix proteins reduces lung compliance by impairing ventilation and compromising gas exchange. Notably, the degree of elastosis is associated with the progressive decline in lung function and survival in patients with interstitial lung diseases. Currently there are no proven therapies which effectively reduce the elastin burden in the lung nor prevent dysregulated elastosis. This review describes elastin's role in the healthy lung, summarizes elastosis in pulmonary diseases, and evaluates the current understanding of elastin regulation and dysregulation with the goal of guiding future research efforts to develop novel and effective therapies.
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Affiliation(s)
- Dan J K Yombo
- Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati, OH, USA
| | - Satish K Madala
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio USA
| | - Chanukya P Vemulapalli
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio USA
| | - Harshavardhana H Ediga
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio USA
| | - William D Hardie
- Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati, OH, USA.
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10
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Saifi MA, Ho IC. Citrullination of matrisomal proteins in health and diseases. Philos Trans R Soc Lond B Biol Sci 2023; 378:20220244. [PMID: 37778384 PMCID: PMC10542447 DOI: 10.1098/rstb.2022.0244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/24/2023] [Indexed: 10/03/2023] Open
Abstract
Proteins once translated are subjected to post-translational modifications (PTMs) that can critically modify their characteristics. Citrullination is a unique type of PTM that is catalysed by peptidylarginine deiminase (PAD) enzymes, which regulate a multitude of physiological functions such as apoptosis, gene expression and immune response by altering the structure and function of cellular proteins. However, emerging data have unravelled compelling evidence to support that PAD-mediated citrullination is not exclusive to cellular proteins; rather citrullination of extracellular matrix (ECM) proteins also plays a major contributing role in various physiological/pathological conditions. Here, we discuss putative mechanisms for citrullination-induced alterations in the function of ECM proteins. Further, we put emphasis on influential roles of ECM citrullination in various pathological scenarios to underscore the clinical potential of its manipulation in human diseases. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
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Affiliation(s)
- Mohammad Aslam Saifi
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - I-Cheng Ho
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
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11
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Zhou M, Jin W, Li P, Wang R, Guo X. Traditional Chinese Medicine in the treatment of hemorrhoids-a review of preparations used and their mechanism of action. Front Pharmacol 2023; 14:1270339. [PMID: 37927595 PMCID: PMC10620711 DOI: 10.3389/fphar.2023.1270339] [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: 07/31/2023] [Accepted: 10/04/2023] [Indexed: 11/07/2023] Open
Abstract
Hemorrhoids are a proctological disease primarily characterized by bleeding, prolapse, edema, and pain, severely affecting the quality of life. Surgery is an effective treatment for hemorrhoids, but the cost is relatively high, and complications such as difficulty in defecation, persistent pain, and heavy bleeding may occur postoperatively. Traditional Chinese Medicine (TCM) has a distinctive advantage in alleviating the clinical symptoms of hemorrhoid patients, reducing pain, and improving the quality of life. However, there are few summary literature about the mechanism of TCM in the prevention and treatment of hemorrhoids. Based on the etiology of hemorrhoids in both traditional Chinese and Western medicine, this paper reviews the recent research on the mechanism of TCM in the treatment of hemorrhoids, hoping to provide a basis for the better application of TCM in clinical and experimental research.
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Affiliation(s)
- Meng’en Zhou
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | | | | | | | - Xiutian Guo
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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12
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Raja E, Clarin MTRDC, Yanagisawa H. Matricellular Proteins in the Homeostasis, Regeneration, and Aging of Skin. Int J Mol Sci 2023; 24:14274. [PMID: 37762584 PMCID: PMC10531864 DOI: 10.3390/ijms241814274] [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: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Matricellular proteins are secreted extracellular proteins that bear no primary structural functions but play crucial roles in tissue remodeling during development, homeostasis, and aging. Despite their low expression after birth, matricellular proteins within skin compartments support the structural function of many extracellular matrix proteins, such as collagens. In this review, we summarize the function of matricellular proteins in skin stem cell niches that influence stem cells' fate and self-renewal ability. In the epidermal stem cell niche, fibulin 7 promotes epidermal stem cells' heterogeneity and fitness into old age, and the transforming growth factor-β-induced protein ig-h3 (TGFBI)-enhances epidermal stem cell growth and wound healing. In the hair follicle stem cell niche, matricellular proteins such as periostin, tenascin C, SPARC, fibulin 1, CCN2, and R-Spondin 2 and 3 modulate stem cell activity during the hair cycle and may stabilize arrector pili muscle attachment to the hair follicle during piloerections (goosebumps). In skin wound healing, matricellular proteins are upregulated, and their functions have been examined in various gain-and-loss-of-function studies. However, much remains unknown concerning whether these proteins modulate skin stem cell behavior, plasticity, or cell-cell communications during wound healing and aging, leaving a new avenue for future studies.
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Affiliation(s)
- Erna Raja
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
| | - Maria Thea Rane Dela Cruz Clarin
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
- Ph.D. Program in Humanics, School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba 305-8577, Japan
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
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13
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Malta MD, Cerqueira MT, Marques AP. Extracellular matrix in skin diseases: The road to new therapies. J Adv Res 2023; 51:149-160. [PMID: 36481476 PMCID: PMC10491993 DOI: 10.1016/j.jare.2022.11.008] [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] [Received: 09/12/2022] [Revised: 11/15/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The extracellular matrix (ECM) is a vital structure with a dynamic and complex organization that plays an essential role in tissue homeostasis. In the skin, the ECM is arranged into two types of compartments: interstitial dermal matrix and basement membrane (BM). All evidence in the literature supports the notion that direct dysregulation of the composition, abundance or structure of one of these types of ECM, or indirect modifications in proteins that interact with them is linked to a wide range of human skin pathologies, including hereditary, autoimmune, and neoplastic diseases. Even though the ECM's key role in these pathologies has been widely documented, its potential as a therapeutic target has been overlooked. AIM OF REVIEW This review discusses the molecular mechanisms involved in three groups of skin ECM-related diseases - genetic, autoimmune, and neoplastic - and the recent therapeutic progress and opportunities targeting ECM. KEY SCIENTIFIC CONCEPTS OF REVIEW This article describes the implications of alterations in ECM components and in BM-associated molecules that are determinant for guaranteeing its function in different skin disorders. Also, ongoing clinical trials on ECM-targeted therapies are discussed together with future opportunities that may open new avenues for treating ECM-associated skin diseases.
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Affiliation(s)
- M D Malta
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, 4805-017 Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - M T Cerqueira
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, 4805-017 Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - A P Marques
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, 4805-017 Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4805-017 Guimarães, Portugal.
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14
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Dong H, Ferruzzi J, Liu M, Brewster LP, Leshnower BG, Gleason RL. Effect of Aging, Sex, and Gene (Fbln5) on Arterial Stiffness of Mice: 20 Weeks Adult Fbln5-knockout Mice Have Older Arteries than 100 Weeks Wild-Type Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.30.542920. [PMID: 37398425 PMCID: PMC10312538 DOI: 10.1101/2023.05.30.542920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
The arterial stiffening is a strong independent predictor of cardiovascular risk and has been used to characterize the biological age of arteries ('arterial age'). Here we revealed that the Fbln5 gene knockout (Fbln5 -/- ) significantly increases the arterial stiffening for both male and female mice. We also showed that the arterial stiffening increases with natural aging, but the stiffening effect of Fbln5 -/- is much more severe than aging. The arterial stiffening of 20 weeks old mice with Fbln5 -/- is much higher than that at 100 weeks in wild-type (Fbln5 +/+ ) mice, which indicates that 20 weeks mice (equivalent to ∼26 years old humans) with Fbln5 -/- have older arteries than 100 weeks wild-type mice (equivalent to ∼77 years humans). Histological microstructure changes of elastic fibers in the arterial tissue elucidate the underlying mechanism of the increase of arterial stiffening due to Fbln5-knockout and aging. These findings provide new insights to reverse 'arterial age' due to abnormal mutations of Fbln5 gene and natural aging. This work is based on a total of 128 biaxial testing samples of mouse arteries and our recently developed unified-fiber-distribution (UFD) model. The UFD model considers the fibers in the arterial tissue as a unified distribution, which is more physically consistent with the real fiber distribution of arterial tissues than the popular fiber-family-based models (e.g., the well-know Gasser-Ogden-Holzapfel [GOH] model) that separate the fiber distribution into several fiber families. Thus, the UFD model achieves better accuracies with less material parameters. To our best knowledge, the UFD model is the only existing accurate model that could capture the property/stiffness differences between different groups of the experimental data discussed here.
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15
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Ezure T. Subcutaneous fat infiltration into the dermal layer induces wrinkle formation. Skin Res Technol 2023; 29:e13296. [PMID: 36973974 PMCID: PMC10155789 DOI: 10.1111/srt.13296] [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] [Received: 01/22/2023] [Accepted: 02/15/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND Wrinkles appear with aging, producing an aged impression, but the mechanism of wrinkle formation has not yet been fully elucidated. We recently reported that subcutaneous fat infiltrates into the dermal layer with aging and impairs skin elasticity, but the contribution of this process to wrinkle formation is still unclear. PURPOSE We aimed to clarify the contribution of dermal fat infiltration to wrinkle formation by analyzing the relationship between them in the forehead of female volunteers. METHODS We measured the severity of fat infiltration in the forehead of 29 middle-aged female volunteers by means of ultrasonography. Fixed wrinkles present when the eyes were closed and wrinkles transiently formed when the eyes were open were evaluated using a photograph-based 6-grade evaluation system for each type of wrinkle. RESULTS Fat infiltration at the forehead area was observed similarly to that in the cheek area as we reported previously. We found that opening the eyes induced the formation of stable transient wrinkles, the grade of which was significantly related to fat infiltration severity. Furthermore, fat infiltration was also significantly related to the severity of fixed wrinkles. Moreover, the severity of transient wrinkles was significantly related to that of fixed wrinkles. CONCLUSIONS Our results suggest that fat infiltration into the dermal layer enhances transient wrinkle formation during facial expression by impairing the ability of the skin to resist deformation, thereby promoting fixed wrinkle formation. Therefore, fat infiltration is a critical cause of wrinkle formation.
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Affiliation(s)
- Tomonobu Ezure
- Shiseido Co., Ltd., MIRAI Technology InstituteYokohamaJapan
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16
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Chou E, Pirruccello JP, Ellinor PT, Lindsay ME. Genetics and mechanisms of thoracic aortic disease. Nat Rev Cardiol 2023; 20:168-180. [PMID: 36131050 DOI: 10.1038/s41569-022-00763-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2022] [Indexed: 11/09/2022]
Abstract
Aortic disease has many forms including aortic aneurysm and dissection, aortic coarctation or abnormalities in aortic function, such as loss of aortic distensibility. Genetic analysis in humans is one of the most important experimental approaches in uncovering disease mechanisms, but the relative infrequency of thoracic aortic disease compared with other cardiovascular conditions such as coronary artery disease has hindered large-scale identification of genetic associations. In the past decade, advances in machine learning technology coupled with large imaging datasets from biobank repositories have facilitated a rapid expansion in our capacity to measure and genotype aortic traits, resulting in the identification of dozens of genetic associations. In this Review, we describe the history of technological advances in genetic discovery and explain how newer technologies such as deep learning can rapidly define aortic traits at scale. Furthermore, we integrate novel genetic observations provided by these advances into our current biological understanding of thoracic aortic disease and describe how these new findings can contribute to strategies to prevent and treat aortic disease.
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Affiliation(s)
- Elizabeth Chou
- Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
| | - James P Pirruccello
- Harvard Medical School, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
- Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick T Ellinor
- Harvard Medical School, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
- Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA
- Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
| | - Mark E Lindsay
- Harvard Medical School, Boston, MA, USA.
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA.
- Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA.
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17
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Bian X, Yin S, Yin X, Fang T, Wang Y, Yang S, Jiang X, Xue Y, Ye F, Zhang L. Clinical and Biological Significances of FBLN5 in Gastric Cancer. Cancers (Basel) 2023; 15:553. [PMID: 36672502 PMCID: PMC9856449 DOI: 10.3390/cancers15020553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/07/2023] [Accepted: 01/15/2023] [Indexed: 01/18/2023] Open
Abstract
Abnormal FBLN5 expression levels are related to various cancer types. This study is the first to explore its clinical and biological significances in gastric cancer (GC). We used The Cancer Genome Atlas-GC (TCGA-GC) and Gene Expression Omnibus (GEO) databases to identify the differential expression of FBLN5, and its association with clinical pathological characteristics was analyzed. A Kaplan-Meier plotter was used to calculate the impact of FBLN5 on GC patient prognosis, and the biological functions of FBLN5 were analyzed. In addition, we constructed a GC tissue microarray, and performed an immunohistochemical staining of FBLN5 to verify our findings. Western blotting was conducted simultaneously to confirm that FBLN5 was overexpressed in GC. We found that the high level of FBLN5 mRNA in GC was associated with a poor prognosis. High FBLN5 expression levels were significantly correlated with INFc and N3 lymph node metastasis. Univariate and multivariate analyses showed that FBLN5 expression levels and lymph node metastasis rate were independent risk factors related to GC patient prognosis, which can be combined to construct a nomogram to serve patients. Therefore, we believe that FBLN5 is significantly related to the poor prognosis of GC patients. FBLN5 is a valuable prognostic indicator to evaluate the prognosis of GC.
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Affiliation(s)
- Xiulan Bian
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Shengjie Yin
- Department of Medical Oncology, Municipal Hospital of Chifeng, Chifeng 024000, China
| | - Xin Yin
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Tianyi Fang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Yufei Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Shuo Yang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Xinju Jiang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Yingwei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Fei Ye
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Lei Zhang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
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18
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Suzuki Y, Oinaka H, Nakajima H, Nampei M, Kawakita F, Miura Y, Yasuda R, Toma N, Suzuki H, pSEED Group. Plasma Fibulin-5 Levels as an Independent Predictor of a Poor Outcome after an Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci 2022; 23:ijms232315184. [PMID: 36499510 PMCID: PMC9740042 DOI: 10.3390/ijms232315184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/27/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5's roles in SAH. This study was aimed at examining the relationships between serially measured plasma FBLN5 levels and neurovascular events or outcomes in 204 consecutive aneurysmal SAH patients, including 77 patients (37.7%) with poor outcomes (90-day modified Rankin Scale 3-6). Plasma FBLN5 levels were not related to angiographic vasospasm, delayed cerebral ischemia, and delayed cerebral infarction, but elevated levels were associated with severe admission clinical grades, any neurological exacerbation and poor outcomes. Receiver-operating characteristic curves indicated that the most reasonable cut-off values of plasma FBLN5, in order to differentiate 90-day poor from good outcomes, were obtained from analyses at days 4-6 for all patients (487.2 ng/mL; specificity, 61.4%; and sensitivity, 62.3%) and from analyses at days 7-9 for only non-severe patient (476.8 ng/mL; specificity, 66.0%; and sensitivity, 77.8%). Multivariate analyses revealed that the plasma FBLN5 levels were independent determinants of the 90-day poor outcomes in both all patients' and non-severe patients' analyses. These findings suggest that the delayed elevation of plasma FBLN5 is related to poor outcomes, and that FBLN5 may be a new molecular target to reveal a post-SAH pathophysiology.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hidenori Suzuki
- Correspondence: ; Tel.: +81-59-232-1111; Fax: +81-59-231-5212
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19
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Cárdenas-León CG, Mäemets-Allas K, Klaas M, Lagus H, Kankuri E, Jaks V. Matricellular proteins in cutaneous wound healing. Front Cell Dev Biol 2022; 10:1073320. [PMID: 36506087 PMCID: PMC9730256 DOI: 10.3389/fcell.2022.1073320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022] Open
Abstract
Cutaneous wound healing is a complex process that encompasses alterations in all aspects of the skin including the extracellular matrix (ECM). ECM consist of large structural proteins such as collagens and elastin as well as smaller proteins with mainly regulative properties called matricellular proteins. Matricellular proteins bind to structural proteins and their functions include but are not limited to interaction with cell surface receptors, cytokines, or protease and evoking a cellular response. The signaling initiated by matricellular proteins modulates differentiation and proliferation of cells having an impact on the tissue regeneration. In this review we give an overview of the matricellular proteins that have been found to be involved in cutaneous wound healing and summarize the information known to date about their functions in this process.
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Affiliation(s)
| | - Kristina Mäemets-Allas
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Mariliis Klaas
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Heli Lagus
- Department of Plastic Surgery and Wound Healing Centre, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Viljar Jaks
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia,Dermatology Clinic, Tartu University Clinics, Tartu, Estonia,*Correspondence: Viljar Jaks,
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20
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Navneet S, Rohrer B. Elastin turnover in ocular diseases: A special focus on age-related macular degeneration. Exp Eye Res 2022; 222:109164. [PMID: 35798060 PMCID: PMC9795808 DOI: 10.1016/j.exer.2022.109164] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 12/30/2022]
Abstract
The extracellular matrix (ECM) and its turnover play a crucial role in the pathogenesis of several inflammatory diseases, including age-related macular degeneration (AMD). Elastin, a critical protein component of the ECM, not only provides structural and mechanical support to tissues, but also mediates several intracellular and extracellular molecular signaling pathways. Abnormal turnover of elastin has pathological implications. In the eye elastin is a major structural component of Bruch's membrane (BrM), a critical ECM structure separating the retinal pigment epithelium (RPE) from the choriocapillaris. Reduced integrity of macular BrM elastin, increased serum levels of elastin-derived peptides (EDPs), and elevated elastin antibodies have been reported in AMD. Existing reports suggest that elastases, the elastin-degrading enzymes secreted by RPE, infiltrating macrophages or neutrophils could be involved in BrM elastin degradation, thus contributing to AMD pathogenesis. EDPs derived from elastin degradation can increase inflammatory and angiogenic responses in tissues, and the elastin antibodies are shown to play roles in immune cell activity and complement activation. This review summarizes our current understanding on the elastases/elastin fragments-mediated mechanisms of AMD pathogenesis.
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Affiliation(s)
- Soumya Navneet
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, USA.
| | - Bärbel Rohrer
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, USA; Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA; Ralph H. Johnson VA Medical Center, Division of Research, Charleston, SC, USA.
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21
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Ramachandra AB, Mikush N, Sauler M, Humphrey JD, Manning EP. Compromised Cardiopulmonary Function in Fibulin-5 Deficient Mice. J Biomech Eng 2022; 144:081008. [PMID: 35171214 PMCID: PMC8990734 DOI: 10.1115/1.4053873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/08/2022] [Indexed: 11/08/2022]
Abstract
Competent elastic fibers are critical to the function of the lung and right circulation. Murine models of elastopathies can aid in understanding the functional roles of the elastin and elastin-associated glycoproteins that constitute elastic fibers. Here, we quantify together lung and pulmonary arterial structure, function, and mechanics with right heart function in a mouse model deficient in the elastin-associated glycoprotein fibulin-5. Differences emerged as a function of genotype, sex, and arterial region. Specifically, functional studies revealed increased lung compliance in fibulin-5 deficiency consistent with a histologically observed increased alveolar disruption. Biaxial mechanical tests revealed that the primary branch pulmonary arteries exhibit decreased elastic energy storage capacity and wall stress despite only modest differences in circumferential and axial material stiffness in the fibulin-5 deficient mice. Histological quantifications confirm a lower elastic fiber content in the fibulin-5 deficient pulmonary arteries, with fragmented elastic laminae in the outer part of the wall - likely the reason for reduced energy storage. Ultrasound measurements confirm sex differences in compromised right ventricular function in the fibulin-5 deficient mice. These results reveal compromised right heart function, but opposite effects of elastic fiber dysfunction on the lung parenchyma (significantly increased compliance) and pulmonary arteries (trend toward decreased distensibility), and call for further probing of ventilation-perfusion relationships in pulmonary pathologies. Amongst many other models, fibulin-5 deficient mice can contribute to our understanding of the complex roles of elastin in pulmonary health and disease.
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Affiliation(s)
| | - Nicole Mikush
- Translational Research Imaging Center, Yale School of Medicine, New Haven, CT 06520
| | - Maor Sauler
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510
| | - Jay D. Humphrey
- Department of Biomedical Engineering and Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520
| | - Edward P. Manning
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510; West Haven Connecticut VA and Pulmonary and Critical Care Medicine, VA Connecticut Healthcare System, West Haven, CT 06516
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22
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Deng L, Li Z, Tang C, Han Y, Zhang L, Liao Q. Quantitative analysis of the serum proteome during early pregnancy in mares. Anim Sci J 2022; 93:e13727. [PMID: 35476278 DOI: 10.1111/asj.13727] [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: 08/11/2021] [Revised: 02/02/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
Abstract
Equine pregnancy is currently diagnosed by rectal palpation, ultrasonographic examination, or by measuring changes in hormones in the blood. In the present study, we identified proteins that are differentially expressed in the sera of early pregnant and non-pregnant mares in order to develop a novel method for diagnosing equine pregnancy. Serum samples were obtained from 18 adult mares, pregnancy at day 32 after ovulation (n = 9) and in diestrus (n = 9). Proteomic analysis of the samples was conducted using liquid chromatography-electrospray ionization-tandem mass spectrometry. We identified 467 proteins from a total of 3514 peptides. Thirty-two proteins (15 upregulated and 17 downregulated) were significantly differentially expressed between the two groups. The Gene Ontology enrichment analysis revealed that they are related to extracellular matrix assembly, blood coagulation, and hemostasis, and the prominent molecular functions were integrin binding, cell adhesion molecule binding, and glycine C-acetyltransferase activity. The pathway analysis of Kyoto Encyclopaedia of Genes and Genomes showed that the top three pathways identified were glycine, serine, and threonine metabolism; cysteine and methionine metabolism; and ether lipid metabolism. The selected five serum proteins were newly potential candidates for pregnancy diagnosis in mares.
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Affiliation(s)
- Liang Deng
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Zheng Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Chi Tang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China.,Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Yuwei Han
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Linxi Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Qingchao Liao
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
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23
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Combined Treatment of Monopolar and Bipolar Radiofrequency Increases Skin Elasticity by Decreasing the Accumulation of Advanced Glycated End Products in Aged Animal Skin. Int J Mol Sci 2022; 23:ijms23062993. [PMID: 35328415 PMCID: PMC8950306 DOI: 10.3390/ijms23062993] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 01/27/2023] Open
Abstract
It is well known that skin aging is related to the destruction of collagen and elastin fibers by metalloproteinases (MMPs). Aged fibroblasts have a decreased ability to synthesize collagen and elastin. Nuclear factor erythroid 2-related factor 2 (NRF2) involves glyoxalase (GLO) activation, which inhibits the production of advanced glycated end products (AGE) and the expression of its receptor (RAGE). RAGE increases nuclear transcription factor-kappa B (NF-κB), which upregulates MMPs and decreases skin elasticity. NRF2 also decreases M1 macrophages, which secrete tumor necrosis factor-alpha (TNF-α), thereby decreasing AGE production. It is well known that radiofrequency (RF) decreases skin elasticity by increasing collagen synthesis. We evaluated whether RF increases skin elasticity via NRF2/GLO and whether they decrease AGE and RAGE expression in aged animal skin. We also compared the effects of RF based on the modes (monopolar or bipolar) or the combination used. In aged skin, NRF2, GLO-1, and M2 macrophage expression was decreased, and their expression increased when RF was applied. M1 and TNF-α demonstrated increased expression in the aged skin and decreased expression after RF application. AGE accumulation and RAGE, NF-κB, and MMP2/3/9 expression were increased in the aged skin, and they were decreased by RF. The papillary and reticular fibroblast markers showed decreased expression in young skin and increased expression in aged skin. The densities of collagen and elastin fiber in the aged skin were low, and they were increased by RF. In conclusion, RF leads to increased collagen and elastin fibers by increasing NRF2/GLO-1 and modulating M1/M2 polarization, which leads to decreased AGE and RAGE and, consequently, decreased NF-κB, which eventually slows collagen and elastin destruction. RF also leads to increased collagen and elastin fiber synthesis by increasing papillary and reticular fibroblast expression.
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24
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Zheng L, Yue X, Li M, Hu J, Zhang B, Zhang R, Zheng G, Chen R, Dong H. Contribution of FBLN5 to Unstable Plaques in Carotid Atherosclerosis via mir128 and mir532-3p Based on Bioinformatics Prediction and Validation. Front Genet 2022; 13:821650. [PMID: 35356421 PMCID: PMC8959633 DOI: 10.3389/fgene.2022.821650] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/28/2022] [Indexed: 11/30/2022] Open
Abstract
FBLN5, a member of the short fibulins in the fibulin family of extracellular matrix/matricellular proteins, is involved in interactions with components of the basement membrane and extracellular matrix proteins. It plays key roles in endothelial tissues in many vascular diseases. In this study, the relationship between FBLN5 and carotid atherosclerotic plaque stability as well as the regulatory roles of miRNAs were evaluated. Differential gene expression analyses and weighted gene co-expression network analysis (WGCNA) based on the GSE163154 dataset (including 16 samples without intraplaque hemorrhage and 27 samples with intraplaque hemorrhage) in GEO revealed that FBLN5 is related to plaque stability and is the most significantly differentially expressed gene. LASSO regression was used to evaluate genes obtained from the intersection of differentially expressed genes and clinically significant modules identified by WGCNA. A prediction model based on eight genes, including FBLN5, was constructed and showed an accuracy of 0.951 based on an ROC analysis. Low FBLN5 expression in plaque tissues was confirmed by immunohistochemistry and western blotting. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses showed that FBLN5 acted mainly by the maintenance of the cellular matrix and reactive oxygen species production. miRNAs upstream of these eight predictive genes, including FBLN5, were identified and used to construct a network diagram. These results revealed that hsa-mir-128 and hsa-mir-532-3p were upstream regulatory factors of FBLN5, as verified by PCR assays of human plaque tissues demonstrating that both miRNAs were significantly up-regulated. Therefore, FBLN5 may play an important role in carotid atherosclerosis via hsa-mir-128 and hsa-mir-532-3p as well as become an essential target for treatment.
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Affiliation(s)
- Lin Zheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinyang Yue
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Minhui Li
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jie Hu
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Bojin Zhang
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Ruijing Zhang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Guoping Zheng
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | | | - Honglin Dong
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
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25
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Bazmi M, Escobar AL. Autonomic Regulation of the Goldfish Intact Heart. Front Physiol 2022; 13:793305. [PMID: 35222073 PMCID: PMC8864152 DOI: 10.3389/fphys.2022.793305] [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: 10/11/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Autonomic regulation plays a central role in cardiac contractility and excitability in numerous vertebrate species. However, the role of autonomic regulation is less understood in fish physiology. Here, we used Goldfish as a model to explore the role of autonomic regulation. A transmural electrocardiogram recording showed perfusion of the Goldfish heart with isoproterenol increased the spontaneous heart rate, while perfusion with carbamylcholine decreased the spontaneous heart rate. Cardiac action potentials obtained via sharp microelectrodes exhibited the same modifications of the spontaneous heart rate in response to isoproterenol and carbamylcholine. Interestingly, the duration of the cardiac action potentials lengthened in the presence of both isoproterenol and carbamylcholine. To evaluate cardiac contractility, the Goldfish heart was perfused with the Ca2+ indicator Rhod-2 and ventricular epicardial Ca2+ transients were measured using Pulsed Local Field Fluorescence Microscopy. Following isoproterenol perfusion, the amplitude of the Ca2+ transient significantly increased, the half duration of the Ca2+ transient shortened, and there was an observable increase in the velocity of the rise time and fall time of the Ca2+ transient, all of which are compatible with the shortening of the action potential induced by isoproterenol perfusion. On the other hand, carbamylcholine perfusion significantly reduced the amplitude of the Ca2+ transient and increased the half duration of the Ca2+ transient. These results are interesting because the effect of carbamylcholine is opposite to what happens in classically used models, such as mouse hearts, and the autonomic regulation of the Goldfish heart is strikingly similar to what has been observed in larger mammalian models resembling humans.
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Affiliation(s)
- Maedeh Bazmi
- Quantitative Systems Biology Program, School of Natural Sciences, University of California, Merced, Merced, CA, United States
| | - Ariel L Escobar
- Department of Bioengineering, School of Engineering, University of California, Merced, Merced, CA, United States
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26
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Kim HM, Byun KA, Oh S, Yang JY, Park HJ, Chung MS, Son KH, Byun K. A Mixture of Topical Forms of Polydeoxyribonucleotide, Vitamin C, and Niacinamide Attenuated Skin Pigmentation and Increased Skin Elasticity by Modulating Nuclear Factor Erythroid 2-like 2. Molecules 2022; 27:1276. [PMID: 35209068 PMCID: PMC8879610 DOI: 10.3390/molecules27041276] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 12/14/2022] Open
Abstract
It is well-known that increased oxidative stress caused by ultraviolet B (UV-B) radiation induces melanogenesis and activates metalloproteinases (MMPs), which degrade collagen and elastin fibers, leading to decreased skin elasticity. Various antioxidant agents, such as vitamin C and niacinamide, have been evaluated for use as treatments for photoaging or skin pigmentation. In this study, we evaluated the ability of a topical liquid formula of polydeoxyribonucleotide (PDRN), vitamin C, and niacinamide (PVN) delivered via a microneedling therapy system (MTS) to attenuate photoaging and pigmentation by increasing nuclear factor erythroid 2-like 2 (NRF2)/heme oxygenase-1 (HO-1) and decreasing MMP expression in a UV-B-radiated animal model. The effects of the PVN were compared with those of individual PDRN and hydroquinone (HQ) compounds. The expression of NRF2/HO-1 significantly increased in response to HQ, PDRN, and PVN in UV-B-radiated animal skin. The activity of nicotinamide adenine dinucleotide phosphate hydrogen oxidase decreased in response to HQ, PDRN, and PVN, and the superoxide dismutase activity increased. The expression of tumor protein p53 and microphthalmia-associated transcription factor and tyrosinase activity decreased in response to HQ, PDRN, and PVN, and this decrease was accompanied by decreased melanin content in the skin. The expression of nuclear factor kappa-light-chain enhancer of activated B cells and MMP2/3/9 decreased in response to HQ, PDRN, and PVN in UV-B-radiated skin. However, the expression of collagen type I α1 chain and the amount of collagen fibers that were evaluated by Masson's trichrome staining increased in response to HQ, PDRN, and PVN. The contents of elastin fibers, fibrillin 1/2 and fibulin 5 increased in response to HQ, PDRN, and PVN. In conclusion, PVN delivered via MTS led to decreased melanogenesis and destruction of collagen and elastin fibers by MMPs, and, thus, PVN decreased skin pigmentation and increased skin elasticity.
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Affiliation(s)
- Hyoung Moon Kim
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Korea; (H.M.K.); (K.-A.B.)
| | - Kyung-A Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Korea; (H.M.K.); (K.-A.B.)
- Functional Cellular Networks Laboratory, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea; (S.O.); (J.Y.Y.)
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea; (S.O.); (J.Y.Y.)
| | - Jin Young Yang
- Functional Cellular Networks Laboratory, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea; (S.O.); (J.Y.Y.)
| | - Hyun Jun Park
- Maylin Anti-Aging Center Apgujeong, Seoul 06005, Korea;
| | | | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gil Medical Center, Gachon University, Incheon 21565, Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Korea; (H.M.K.); (K.-A.B.)
- Functional Cellular Networks Laboratory, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea; (S.O.); (J.Y.Y.)
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27
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Ellis MW, Riaz M, Huang Y, Anderson CW, Luo J, Park J, Lopez CA, Batty LD, Gibson KH, Qyang Y. Epigallocatechin gallate facilitates extracellular elastin fiber formation in induced pluripotent stem cell derived vascular smooth muscle cells for tissue engineering. J Mol Cell Cardiol 2022; 163:167-174. [PMID: 34979103 PMCID: PMC8920537 DOI: 10.1016/j.yjmcc.2021.12.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 02/03/2023]
Abstract
Tissue engineered vascular grafts possess several advantages over synthetic or autologous grafts, including increased availability and reduced rates of infection and thrombosis. Engineered grafts constructed from human induced pluripotent stem cell derivatives further offer enhanced reproducibility in graft production. One notable obstacle to clinical application of these grafts is the lack of elastin in the vessel wall, which would serve to endow compliance in addition to mechanical strength. This study establishes the ability of the polyphenol compound epigallocatechin gallate, a principal component of green tea, to facilitate the extracellular formation of elastin fibers in vascular smooth muscle cells derived from human induced pluripotent stem cells. Further, this study describes the creation of a doxycycline-inducible elastin expression system to uncouple elastin production from vascular smooth muscle cell proliferative capacity to permit fiber formation in conditions conducive to robust tissue engineering.
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Affiliation(s)
- Matthew W Ellis
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06519, USA
| | - Muhammad Riaz
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA
| | - Yan Huang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA
| | - Christopher W Anderson
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Department of Pathology, Yale University, New Haven, CT 06520, USA
| | - Jiesi Luo
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA
| | - Jinkyu Park
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA
| | - Colleen A Lopez
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA
| | - Luke D Batty
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Department of Pathology, Yale University, New Haven, CT 06520, USA
| | - Kimberley H Gibson
- Center for Cellular and Molecular Imaging: Electron Microscopy, Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Yibing Qyang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Department of Pathology, Yale University, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
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28
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Allen-Brady K, Bortolini MAT, Damaser MS. Mouse Knockout Models for Pelvic Organ Prolapse: a Systematic Review. Int Urogynecol J 2022; 33:1765-1788. [PMID: 35088092 DOI: 10.1007/s00192-021-05066-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/13/2021] [Indexed: 02/03/2023]
Abstract
INTRODUCTION AND HYPOTHESIS Mouse knockout (KO) models of pelvic organ prolapse (POP) have contributed mechanistic evidence for the role of connective tissue defects, specifically impaired elastic matrix remodeling. Our objective was to summarize what mouse KO models for POP are available and what have we learned from these mouse models about the pathophysiological mechanisms of POP development. METHODS We conducted a systematic review and reported narrative findings according to PRISMA guidelines. Two independent reviewers searched PubMed, Scopus and Embase for relevant manuscripts and conference abstracts for the time frame of January 1, 2000, to March 31, 2021. Conference abstracts were limited to the past 5 years. RESULTS The search strategy resulted in 294 total titles. We ultimately included 25 articles and an additional 11 conference abstracts. Five KO models have been studied: Loxl1, Fbln5, Fbln3, Hoxa11 and Upii-sv40t. Loxl1 and Fbln5 KO models have provided the most reliable and predictable POP phenotype. Loxl1 KO mice develop POP primarily from failure to heal after giving birth, whereas Fbln5 KO mice develop POP with aging. These mouse KO models have been used for a wide variety of investigations including genetic pathways involved in development of POP, biomechanical properties of the pelvic floor, elastic fiber deposition, POP therapies and the pathophysiology associated with mesh complications. CONCLUSIONS Mouse KO models have proved to be a valuable tool in the study of specific genes and their role in the development and progression of POP. They may be useful to study POP treatments and POP complications.
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Affiliation(s)
- Kristina Allen-Brady
- Department of Internal Medicine, University of Utah, Williams Building 295 Chipeta Way, Salt Lake City, UT, USA.
| | - Maria A T Bortolini
- Department of Gynecology, Sector of Urogynecology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Margot S Damaser
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
- Advanced Platform Technology Center, Louis Stokes Department of Veterans Affairs Medical Center, Cleveland, OH, USA
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29
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Increased Risk of Aortic Dissection with Perlecan Deficiency. Int J Mol Sci 2021; 23:ijms23010315. [PMID: 35008739 PMCID: PMC8745340 DOI: 10.3390/ijms23010315] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/24/2021] [Accepted: 12/25/2021] [Indexed: 12/22/2022] Open
Abstract
Perlecan (HSPG2), a basement membrane-type heparan sulfate proteoglycan, has been implicated in the development of aortic tissue. However, its role in the development and maintenance of the aortic wall remains unknown. Perlecan-deficient mice (Hspg2−/−-Tg: Perl KO) have been found to show a high frequency (15–35%) of aortic dissection (AD). Herein, an analysis of the aortic wall of Perl KO mice revealed that perlecan deficiency caused thinner and partially torn elastic lamina. Compared to the control aortic tissue, perlecan-deficient aortic tissue showed a significant decrease in desmosine content and an increase in soluble tropoelastin levels, implying the presence of immature elastic fibers in Perl KO mice. Furthermore, the reduced expression of the smooth muscle cell contractile proteins actin and myosin in perlecan-deficient aortic tissue may explain the risk of AD. This study showed that a deficiency in perlecan, which is localized along the elastic lamina and at the interface between elastin and fibrillin-1, increased the risk of AD, largely due to the immaturity of extracellular matrix in the aortic tissue. Overall, we proposed a new model of AD that considers the deficiency of extracellular molecule perlecan as a risk factor.
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The Role of the Stromal Extracellular Matrix in the Development of Pterygium Pathology: An Update. J Clin Med 2021; 10:jcm10245930. [PMID: 34945227 PMCID: PMC8707182 DOI: 10.3390/jcm10245930] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/31/2022] Open
Abstract
Pterygium is a benign fibrovascular lesion of the bulbar conjunctiva with frequent involvement of the corneal limbus. Its pathogenesis has been mainly attributed to sun exposure to ultraviolet-B radiation. Obtained evidence has shown that it is a complex and multifactorial process which involves multiple mechanisms such as oxidative stress, dysregulation of cell cycle checkpoints, induction of inflammatory mediators and growth factors, angiogenic stimulation, extracellular matrix (ECM) disorders, and, most likely, viruses and hereditary changes. In this review, we aim to collect all authors’ experiences and our own, with respect to the study of fibroelastic ECM of pterygium. Collagen and elastin are intrinsic indicators of physiological and pathological states. Here, we focus on an in-depth analysis of collagen (types I and III), as well as the main constituents of elastic fibers (tropoelastin (TE), fibrillins (FBNs), and fibulins (FBLNs)) and the enzymes (lysyl oxidases (LOXs)) that carry out their assembly or crosslinking. All the studies established that changes in the fibroelastic ECM occur in pterygium, based on the following facts: An increase in the synthesis and deposition of an immature form of collagen type III, which showed the process of tissue remodeling. An increase in protein levels in most of the constituents necessary for the development of elastic fibers, except FBLN4, whose biological roles are critical in the binding of the enzyme LOX, as well as FBN1 for the development of stable elastin. There was gene overexpression of TE, FBN1, FBLN5, and LOXL1, while the expression of LOX and FBLN2 and -4 remained stable. In conclusion, collagen and elastin, as well as several constituents involved in elastic fiber assembly are overexpressed in human pterygium, thus, supporting the hypothesis that there is dysregulation in the synthesis and crosslinking of the fibroelastic component, constituting an important pathogenetic mechanism for the development of the disease.
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Hassanein SS, Abdel-Mawgood AL, Ibrahim SA. EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer. Front Oncol 2021; 11:766659. [PMID: 34976811 PMCID: PMC8714827 DOI: 10.3389/fonc.2021.766659] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022] Open
Abstract
Lung cancer remains the leading cause of cancer-related death and is associated with a poor prognosis. Lung cancer is divided into 2 main types: the major in incidence is non-small cell lung cancer (NSCLC) and the minor is small cell lung cancer (SCLC). Although NSCLC progression depends on driver mutations, it is also affected by the extracellular matrix (ECM) interactions that activate their corresponding signaling molecules in concert with integrins and matrix metalloproteinases (MMPs). These signaling molecules include cytoplasmic kinases, small GTPases, adapter proteins, and receptor tyrosine kinases (RTKs), particularly the epidermal growth factor receptor (EGFR). In NSCLC, the interplay between ECM and EGFR regulates ECM stiffness, angiogenesis, survival, adhesion, migration, and metastasis. Furthermore, some tumor-promoting ECM components (e.g., glycoproteins and proteoglycans) enhance activation of EGFR and loss of PTEN. On the other hand, other tumor-suppressing glycoproteins and -proteoglycans can inhibit EGFR activation, suppressing cell invasion and migration. Therefore, deciphering the molecular mechanisms underlying EGFR and ECM interactions might provide a better understanding of disease pathobiology and aid in developing therapeutic strategies. This review critically discusses the crosstalk between EGFR and ECM affecting cell behavior of NSCLC, as well as the involvement of ECM components in developing resistance to EGFR inhibition.
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Affiliation(s)
- Sarah Sayed Hassanein
- Biotechnology Program, Basic and Applied Sciences (BAS) Institute, Egypt-Japan University of Science and Technology (E-JUST), Alexandria, Egypt
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Ahmed Lotfy Abdel-Mawgood
- Biotechnology Program, Basic and Applied Sciences (BAS) Institute, Egypt-Japan University of Science and Technology (E-JUST), Alexandria, Egypt
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Protective Effect of Fat-Tissue-Derived Products against Ultraviolet Irradiation-Induced Photoaging in Mouse Skin. Plast Reconstr Surg 2021; 148:1290-1299. [PMID: 34644267 DOI: 10.1097/prs.0000000000008562] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Exposure to ultraviolet radiation causes erythema, inflammation, and photoaging. Mechanical micronization of adipose tissue can concentrate functional cells and has great potential as an alternative for regenerative medicine. Stromal vascular fraction gel is produced by means of a series of mechanical processes of lipoaspirates and can be injected intradermally. This study aimed to assess the therapeutic effect of stromal vascular fraction gel on photoaging skin. METHODS A photoaging model was established in nude mice. Photoaging mice received treatments of stromal vascular fraction gel, fat, tretinoin, or phosphate-buffered saline. Photoaging skin was characterized by histologic and immunohistochemical analyses. Expression of collagen synthesis-related or photoaging-related genes was assessed. RESULTS Stromal vascular fraction gel, fat, and tretinoin reversed photoaging, whereas stromal vascular fraction gel demonstrated the greatest therapeutic effect. Treatment with stromal vascular fraction gel restored intradermal fat tissue content and increased dermal collagen density. Injection of stromal vascular fraction gel had the strongest effect on stimulating fibroblasts and increasing the expression of transforming growth factor β1 (TGF-β1), propeptide of type-I procollagen, and Smad 2, decreasing the expression of Smad 3, compared with fat and tretinoin. Expression of photoaging-related genes was significantly reduced, whereas expression of fibulin-5 was significantly increased after stromal vascular fraction gel treatment. CONCLUSIONS Stromal vascular fraction gel demonstrated remarkable therapeutic effects in reversing photoaging skin. Stromal vascular fraction gel can be injected intradermally and survive within dermal layer after grafting. This product increased TGF-β1expression and activated fibroblasts to produce propeptide of type I procollagen, thus increasing the amount of collagen I, leading to thickening of the dermis of photoaging skin.
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Beyens A, Pottie L, Sips P, Callewaert B. Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:273-309. [PMID: 34807425 DOI: 10.1007/978-3-030-80614-9_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the skin, but may show systemic elastolysis. Mendelian forms are often pleiotropic in nature and classified upon systemic manifestations and mode of inheritance. Though impaired elastogenesis is a common denominator in all Mendelian forms of CL, the underlying gene defects are diverse and affect structural components of the elastic fiber or impair metabolic pathways interfering with cellular trafficking, proline synthesis, or mitochondrial functioning. In this chapter we provide a detailed overview of the clinical and molecular characteristics of the different cutis laxa types and review the latest insights on elastic fiber assembly and homeostasis from both human and animal studies.
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Affiliation(s)
- Aude Beyens
- Center for Medical Genetics Ghent, Department of Dermatology, Department of Biomolecular Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium
| | - Lore Pottie
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Patrick Sips
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Bert Callewaert
- Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium.
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Quintana DD, Anantula Y, Garcia JA, Engler-Chiurazzi EB, Sarkar SN, Corbin DR, Brown CM, Simpkins JW. Microvascular degeneration occurs before plaque onset and progresses with age in 3xTg AD mice. Neurobiol Aging 2021; 105:115-128. [PMID: 34062487 PMCID: PMC9703920 DOI: 10.1016/j.neurobiolaging.2021.04.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 01/06/2023]
Abstract
Heart disease and vascular disease positively correlate with the incidence of Alzheimer's disease (AD). Although there is ostensible involvement of dysfunctional cerebrovasculature in AD pathophysiology, the characterization of the specific changes and development of vascular injury during AD remains unclear. In the present study, we established a time-course for the structural changes and degeneration of the angioarchitecture in AD. We used cerebrovascular corrosion cast and µCT imaging to evaluate the geometry, topology, and complexity of the angioarchitecture in the brain of wild type and 3xTg AD mice. We hypothesized that changes to the microvasculature occur early during the disease, and these early identifiable aberrations would be more prominent in the brain subregions implicated in the cognitive decline of AD. Whole-brain analysis of the angioarchitecture indicated early morphological abnormalities and degeneration of microvascular networks in 3xTg AD mice. Our analysis of the hippocampus and cortical subregions revealed microvascular degeneration with onset and progression that was subregion dependent.
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Affiliation(s)
- Dominic D Quintana
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - Yamini Anantula
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - Jorge A Garcia
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - Elizabeth B Engler-Chiurazzi
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - Saumyendra N Sarkar
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - Deborah R Corbin
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - Candice M Brown
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV
| | - James W Simpkins
- Department of Neuroscience, Center of Basic and Translational Stroke Research Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV.
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Yanagisawa H, Yokoyama U. Extracellular matrix-mediated remodeling and mechanotransduction in large vessels during development and disease. Cell Signal 2021; 86:110104. [PMID: 34339854 DOI: 10.1016/j.cellsig.2021.110104] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 01/08/2023]
Abstract
The vascular extracellular matrix (ECM) is synthesized and secreted during embryogenesis and facilitates the growth and remodeling of large vessels. Proper interactions between the ECM and vascular cells are pivotal for building the vasculature required for postnatal dynamic circulation. The ECM serves as a structural component by maintaining the integrity of the vessel wall while also regulating intercellular signaling, which involves cytokines and growth factors. The major ECM component in large vessels is elastic fibers, which include elastin and microfibrils. Elastin is predominantly synthesized by vascular smooth muscle cells (SMCs) and uses microfibrils as a scaffold to lay down and assemble cross-linked elastin. The absence of elastin causes developmental defects that result in the subendothelial proliferation of SMCs and inward remodeling of the vessel wall. Notably, elastic fiber formation is attenuated in the ductus arteriosus and umbilical arteries. These two vessels function during embryogenesis and close after birth via cellular proliferation, migration, and matrix accumulation. In dynamic postnatal mechano-environments, the elastic fibers in large vessels also serve an essential role in proper signal transduction as a component of elastin-contractile units. Disrupted mechanotransduction in SMCs leads to pathological conditions such as aortic aneurysms that exhibit outward remodeling. This review discusses the importance of the ECM-mainly the elastic fiber matrix-in large vessels during developmental remodeling and under pathological conditions. By dissecting the role of the ECM in large vessels, we aim to provide insights into the role of ECM-mediated signal transduction that can provide a basis for seeking new targets for intervention in vascular diseases.
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Affiliation(s)
- Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, The University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan.
| | - Utako Yokoyama
- Department of Physiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
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Sun B, Tomita B, Salinger A, Tilvawala RR, Li L, Hakami H, Liu T, Tsoyi K, Rosas IO, Reinhardt DP, Thompson PR, Ho IC. PAD2-mediated citrullination of Fibulin-5 promotes elastogenesis. Matrix Biol 2021; 102:70-84. [PMID: 34274450 DOI: 10.1016/j.matbio.2021.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022]
Abstract
The formation of elastic fibers is active only in the perinatal period. How elastogenesis is developmentally regulated is not fully understood. Citrullination is a unique form of post-translational modification catalyzed by peptidylarginine deiminases (PADs), including PAD1-4. Its physiological role is largely unknown. By using an unbiased proteomic approach of lung tissues, we discovered that FBLN5 and LTBP4, two key elastogenic proteins, were temporally modified in mouse and human lungs. We further demonstrated that PAD2 citrullinated FBLN5 preferentially in young lungs compared to adult lungs. Genetic ablation of PAD2 resulted in attenuated elastogenesis in vitro and age-dependent emphysema in vivo. Mechanistically, citrullination protected FBLN5 from proteolysis and subsequent inactivation of its elastogenic activity. Furthermore, citrullinated but not native FBLN5 partially rescued in vitro elastogenesis in the absence of PAD activity. Our data uncover a novel function of citrullination, namely promoting elastogenesis, and provide additional insights to how elastogenesis is regulated.
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Affiliation(s)
- Bo Sun
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Beverly Tomita
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Ari Salinger
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Ronak R Tilvawala
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Ling Li
- Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
| | - Hana Hakami
- Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
| | - Tao Liu
- Harvard Medical School, Boston, MA 02115, USA; Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Konstantin Tsoyi
- Pulmonary, Critical Care and Sleep Medicine Section, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ivan O Rosas
- Pulmonary, Critical Care and Sleep Medicine Section, Baylor College of Medicine, Houston, TX 77030, USA
| | - Dieter P Reinhardt
- Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
| | - Paul R Thompson
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - I-Cheng Ho
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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He W, Huang C, Zhang X, Wang D, Chen Y, Zhao Y, Li X. Identification of transcriptomic signatures and crucial pathways involved in non-alcoholic steatohepatitis. Endocrine 2021; 73:52-64. [PMID: 33837926 DOI: 10.1007/s12020-021-02716-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE Our study aimed to uncover the crucial genes and functional pathways involved in the development of non-alcoholic steatohepatitis (NASH). METHODS Liver transcriptome datasets were integrated with Robust rank aggregation (RRA) method, and transcriptomic signatures for NASH progression and fibrosis severity in NAFLD were developed. The functions of transcriptomic signatures were explored by multiple bioinformatic analyses, and their diagnostic role was also evaluated. RESULTS RRA analyses of 12 transcriptome datasets comparing NASH with non-alcoholic fatty liver (NAFL) identified 116 abnormally up-regulated genes in NASH patients. RRA analyses of five transcriptome datasets focusing fibrosis severity identified 78 abnormally up-regulated genes in NAFLD patients with advanced fibrosis. The functions of those transcriptomic signatures of NASH development or fibrosis progression were similar, and were both characterized by extracellular matrix (ECM)-related pathways (Adjusted P < 0.05). The transcriptomic signatures could effectively differentiate NASH from NAFL, and could help to identify NAFLD patients with advanced fibrosis. Gene set enrichment analysis and weighted gene co-expression network analysis further validated the key role of ECM-related pathways in NASH development. The top 10 up-regulated genes in NASH patients were SPP1, FBLN5, CHI3L1, CCL20, CD24, FABP4, GPNMB, VCAN, EFEMP1, and CXCL10, and their functions were mainly related to either ECM-related pathways or immunity-related pathways. Single cell RNA-sequencing analyses revealed that those crucial genes were expressed by distinct cells such as hepatocytes, macrophages, and hepatic stellate cells. CONCLUSIONS Transcriptomic signatures related to NASH development and fibrosis severity of NAFLD patients are both characterized by ECM-related pathways, and fibrosis is a main player during NASH progression. This study uncovers some novel key genes involved in NASH progression, which may be promising therapeutic targets.
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Affiliation(s)
- Weiwei He
- School of Medicine, Xiamen University, Xiamen, China
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China
| | - Caoxin Huang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China
| | - Xiaofang Zhang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China
| | - Dongmei Wang
- School of Medicine, Xiamen University, Xiamen, China
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China
| | - Yinling Chen
- School of Medicine, Xiamen University, Xiamen, China
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China
| | - Yan Zhao
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China.
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China.
| | - Xuejun Li
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China.
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, China.
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen, China.
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Oxidative Stress Mediates Vascular Tortuosity. Antioxidants (Basel) 2021; 10:antiox10060926. [PMID: 34200411 PMCID: PMC8228074 DOI: 10.3390/antiox10060926] [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: 04/15/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 11/17/2022] Open
Abstract
Vascular tortuosity is associated with various disorders and is being increasingly detected through advances in imaging techniques. The underlying mechanisms for vascular tortuosity, however, remain unclear. Here, we tested the hypothesis that oxidative stress mediates the generation of tortuous vessels. We used the bilateral common carotid artery (CCA) ligation model to induce vascular tortuosity. Both young and adult rats showed basilar artery tortuous morphological changes one month after bilateral CCA ligation. These tortuous changes were permanent but more pronounced in the adult rats. Microarray and real-time PCR analysis revealed that these tortuous changes were accompanied by the induction of oxidative stress-related genes. Moreover, the indicated model in rabbits showed that tortuous morphological changes to the basilar artery were suppressed by antioxidant treatment. These results are highly suggestive of the significance of oxidative stress in the development of vascular tortuosity. Although further studies will be needed to elucidate the possible mechanisms by which oxidative stress enhances vascular tortuosity, our study also points toward possible prophylaxis and treatment for vascular tortuosity.
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Shudo Y, MacArthur JW, Kunitomi Y, Joubert L, Kawamura M, Ono J, Thakore A, Jaatinen K, Eskandari A, Hironaka C, Shin HS, Woo YPJ. Three-Dimensional Multilayered Microstructure Using Needle Array Bioprinting System. Tissue Eng Part A 2021; 26:350-357. [PMID: 32085692 DOI: 10.1089/ten.tea.2019.0313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Tissue engineering is an essential component of developing effective regenerative therapies. In this study, we introduce a promising method to create scaffold-free three-dimensional (3D) tissue engineered multilayered microstructures from cultured cells using the "3D tissue fabrication system" (Regenova®; Cyfuse, Tokyo, Japan). This technique utilizes the adhesive nature of cells. When cells are cultured in nonadhesive wells, they tend to aggregate and form a spheroidal structure. The advantage of this approach is that cellular components can be mixed into one spheroid, thereby promoting the formation of extracellular matrices, such as collagen and elastin. This system enables one to create a predesigned 3D structure composed of cultured cells. We found that the advantages of this system to be (1) the length, size, and shape of the structure that were designable and highly reproducible because of the computer controlled robotics system, (2) the graftable structure could be created within a reasonable period (8 days), and (3) the constructed tissue did not contain any foreign material, which may avoid the potential issues of contamination, biotoxicity, and allergy. The utilization of this robotic system enabled the creation of a 3D multilayered microstructure made of cell-based spheres with a satisfactory mechanical properties and abundant extracellular matrix during a short period of time. These results suggest that this new technology will represent a promising, attractive, and practical strategy in the field of tissue engineering. Impact statement The utilization of the "three dimensional tissue fabrication system" enabled the creation of a three-dimensional (3D) multilayered microstructure made of cell-based spheres with a satisfactory mechanical properties and abundant extracellular matrix during a short period of time. These results suggest that this new technology will represent a promising, attractive, and practical strategy in the field of tissue engineering.
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Affiliation(s)
- Yasuhiro Shudo
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - John W MacArthur
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | | | - Lydia Joubert
- Cell Sciences Imaging Facility, Stanford School of Medicine, Stanford University, Stanford, California
| | - Masashi Kawamura
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - Jiro Ono
- Cyfuse Biomedical K.K., Tokyo, Japan
| | - Akshara Thakore
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - Kevin Jaatinen
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - Anahita Eskandari
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - Camille Hironaka
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - Hye Sook Shin
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
| | - Yi-Ping Joseph Woo
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
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Liu G, Philp AM, Corte T, Travis MA, Schilter H, Hansbro NG, Burns CJ, Eapen MS, Sohal SS, Burgess JK, Hansbro PM. Therapeutic targets in lung tissue remodelling and fibrosis. Pharmacol Ther 2021; 225:107839. [PMID: 33774068 DOI: 10.1016/j.pharmthera.2021.107839] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.
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Affiliation(s)
- Gang Liu
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Ashleigh M Philp
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia; St Vincent's Medical School, UNSW Medicine, UNSW, Sydney, NSW, Australia
| | - Tamera Corte
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Mark A Travis
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom
| | - Heidi Schilter
- Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, Australia
| | - Nicole G Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Chris J Burns
- Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Mathew S Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Sukhwinder S Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Janette K Burgess
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pathology and Medical Biology, Groningen, The Netherlands; Woolcock Institute of Medical Research, Discipline of Pharmacology, The University of Sydney, Sydney, NSW, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia.
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Koba T, Takeda Y, Narumi R, Shiromizu T, Nojima Y, Ito M, Kuroyama M, Futami Y, Takimoto T, Matsuki T, Edahiro R, Nojima S, Hayama Y, Fukushima K, Hirata H, Koyama S, Iwahori K, Nagatomo I, Suzuki M, Shirai Y, Murakami T, Nakanishi K, Nakatani T, Suga Y, Miyake K, Shiroyama T, Kida H, Sasaki T, Ueda K, Mizuguchi K, Adachi J, Tomonaga T, Kumanogoh A. Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres. ERJ Open Res 2021; 7:00658-2020. [PMID: 33778046 PMCID: PMC7983195 DOI: 10.1183/23120541.00658-2020] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/18/2020] [Indexed: 12/28/2022] Open
Abstract
There is an unmet need for novel biomarkers in the diagnosis of multifactorial COPD. We applied next-generation proteomics to serum extracellular vesicles (EVs) to discover novel COPD biomarkers. EVs from 10 patients with COPD and six healthy controls were analysed by tandem mass tag-based non-targeted proteomics, and those from elastase-treated mouse models of emphysema were also analysed by non-targeted proteomics. For validation, EVs from 23 patients with COPD and 20 healthy controls were validated by targeted proteomics. Using non-targeted proteomics, we identified 406 proteins, 34 of which were significantly upregulated in patients with COPD. Of note, the EV protein signature from patients with COPD reflected inflammation and remodelling. We also identified 63 upregulated candidates from 1956 proteins by analysing EVs isolated from mouse models. Combining human and mouse biomarker candidates, we validated 45 proteins by targeted proteomics, selected reaction monitoring. Notably, levels of fibulin-3, tripeptidyl-peptidase 2, fibulin-1, and soluble scavenger receptor cysteine-rich domain-containing protein were significantly higher in patients with COPD. Moreover, six proteins; fibulin-3, tripeptidyl-peptidase 2, UTP-glucose-1-phosphate uridylyl transferase, CD81, CD177, and oncoprotein-induced transcript 3, were correlated with emphysema. Upregulation of fibulin-3 was confirmed by immunoblotting of EVs and immunohistochemistry in lungs. Strikingly, fibulin-3 knockout mice spontaneously developed emphysema with age, as evidenced by alveolar enlargement and elastin destruction. We discovered potential pathogenic biomarkers for COPD using next-generation proteomics of EVs. This is a novel strategy for biomarker discovery and precision medicine. This study identified novel biomarkers for COPD using next-generation proteomics of serum extracellular vesicles. Notably, the expression of fibulin-3 is correlated with lung function and emphysema. This could be useful for personalised medicine.https://bit.ly/2JfRCgk
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Affiliation(s)
- Taro Koba
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshito Takeda
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryohei Narumi
- Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Takashi Shiromizu
- Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Yosui Nojima
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Mari Ito
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Muneyoshi Kuroyama
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yu Futami
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takayuki Takimoto
- Dept of Respiratory Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Kita-Ku, Sakai, Osaka, Japan
| | - Takanori Matsuki
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryuya Edahiro
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Satoshi Nojima
- Dept of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshitomo Hayama
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kiyoharu Fukushima
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Haruhiko Hirata
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shohei Koyama
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kota Iwahori
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Izumi Nagatomo
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Mayumi Suzuki
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuya Shirai
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Teruaki Murakami
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kaori Nakanishi
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takeshi Nakatani
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yasuhiko Suga
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kotaro Miyake
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takayuki Shiroyama
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hiroshi Kida
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takako Sasaki
- Dept of Biochemistry II, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Koji Ueda
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Koto, Tokyo, Japan
| | - Kenji Mizuguchi
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Jun Adachi
- Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Atsushi Kumanogoh
- Dept of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Yuan R, Li Y, Yang B, Jin Z, Xu J, Shao Z, Miao H, Ren T, Yang Y, Li G, Song X, Hu Y, Wang X, Huang Y, Liu Y. LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:797-810. [PMID: 33614230 PMCID: PMC7868718 DOI: 10.1016/j.omtn.2021.01.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.
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Affiliation(s)
- Ruiyan Yuan
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Bo Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Baixiang Road, Wenzhou 325000, China
| | - Zhaohui Jin
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jiacheng Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Ziyu Shao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Huijie Miao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Tai Ren
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guoqiang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiaoling Song
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yunping Hu
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu’an Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Ying Huang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
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Upregulation of PTK7 and β-catenin after vaginal mechanical dilatation: an examination of fibulin-5 knockout mice. Int Urogynecol J 2021; 32:2993-2999. [PMID: 33547906 DOI: 10.1007/s00192-021-04693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/10/2021] [Indexed: 01/13/2023]
Abstract
INTRODUCTION AND HYPOTHESIS Pelvic organ prolapse (POP) in women is associated with deficiency of elastic fibers, and fibulin-5 is known to be a critical protein in the synthesis of elastin. The purpose of this study is to investigate the related pathway for the synthesis of elastin via fibulin-5 using fibulin-5 knockout mice. METHODS Fibulin-5 knockout mice were generated using the CRISPR/Cas9 system, and vaginal dilatation was used to mimic vaginal delivery. We divided the mice into three groups: Fbln5+/+ mice immediately after dilatation (Fbln5+/+ day0), Fbln5+/+ mice 3 days after dilatation (Fbln5+/+ day3) and Fbln5-/- mice 3 days after dilatation (Fbln5-/- day3). Proteins related to elastogenesis in the vaginal wall were measured by liquid chromatography mass spectrometry (LC-MS/MS) analysis, and differences in the expression of these proteins between the Fbln5-/- mice and the Fbln5+/+ mice were analyzed using western blotting. RESULTS In the LC-MS/MS analysis, protein tyrosine kinase 7 (PTK7) was not detected in the Fbln5-/- day3 group, although the expression increased by > 1.5 times between the Fbln5+/+ day0 and day3 groups. PTK7 and β-catenin are known to act in the Wnt/β-catenin pathway, and both were upregulated after dilatation in the Fbln5+/+ mice, though not in the Fbln5-/- mice. CONCLUSION Our findings suggest that these proteins are involved in elastogenesis via fibulin-5, and the impairment of these proteins might be the underlying cause of POP manifestation.
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Gharesouran J, Hosseinzadeh H, Ghafouri-Fard S, Jabbari Moghadam Y, Ahmadian Heris J, Jafari-Rouhi AH, Taheri M, Rezazadeh M. New insight into clinical heterogeneity and inheritance diversity of FBLN5-related cutis laxa. Orphanet J Rare Dis 2021; 16:51. [PMID: 33509220 PMCID: PMC7845118 DOI: 10.1186/s13023-021-01696-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background FBLN5-related cutis laxa (CL) is a rare disorder that involves elastic fiber-enriched tissues and is characterized by lax skin and variable systemic involvement such as pulmonary emphysema, arterial involvement, inguinal hernias, hollow viscus diverticula and pyloric stenosis. This type of CL follows mostly autosomal recessive (AR) and less commonly autosomal dominant patterns of inheritance. Results In this study, we detected a novel homozygous missense variant in exon 6 of FBLN5 gene (c.G544C, p.A182P) by using whole exome sequencing in a consanguineous Iranian family with two affected members. Our twin patients showed some of the clinical manifestation of FBLN5-related CL but they did not present pulmonary complications, gastrointestinal and genitourinary abnormalities. The notable thing about this monozygotic twin sisters is that only one of them showed ventricular septal defect, suggesting that this type of CL has intrafamilial variability. Co-segregation analysis showed the patients’ parents and relatives were heterozygous for detected variation suggesting AR form of the CL. In silico prediction tools showed that this mutation is pathogenic and 3D modeling of the normal and mutant protein revealed relative structural alteration of fibulin-5 suggesting that the A182P can contribute to the CL phenotype via the combined effect of lack of protein function and partly misfolding-associated toxicity. Conclusion We underlined the probable roles and functions of the involved domain of fibulin-5 and proposed some possible mechanisms involved in AR form of FBLN5-related CL. However, further functional studies and subsequent clinical and molecular investigations are needed to confirm our findings.
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Affiliation(s)
- Jalal Gharesouran
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Hosseinzadeh
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yalda Jabbari Moghadam
- Department of Otorhinolaryngology, School of Medicine, Sina Medical Research and Training Hospital, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Pediatrics, School of Medicine, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Rezazadeh
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran.
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García-Valero J, Olloquequi J, Rodríguez E, Martín-Satué M, Texidó L, Ferrer J. Decreased Expression of EC-SOD and Fibulin-5 in Alveolar Walls of Lungs From COPD Patients. Arch Bronconeumol 2021; 58:S0300-2896(21)00016-8. [PMID: 33640211 DOI: 10.1016/j.arbres.2020.12.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 11/25/2022]
Abstract
INTRODUCTION The aim of this study is to analyze the expression of the main oxidant scavenger superoxide dismutase (EC-SOD), its main binding protein Fibulin-5 and several oxidative and nitrosative-derived products in the lung of COPD patients and controls. MATERIALS AND METHODS Lung tissue samples from 19 COPD patients and 20 control subjects were analyzed. The architecture of elastic fibres was assessed by light and electron microscope histochemical techniques, and levels of EC-SOD and fibulin-5 were analyzed by immunohistochemistry and RT-PCR. The impact of oxidative stress on the extracellular matrix was estimated by immunolocalization of 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) and 3-nitrotyrosine (3-NYT) adducts. RESULTS Alveolar walls of COPD patients exhibited abnormal accumulations of collapsing elastic fibres, showing a pierced pattern in the amorphous component. The semiquantitative analysis revealed that COPD patients have a significantly reduced expression of both EC-SOD and fibulin-5 (0.59±0.64 and 0.62±0.61, respectively) in alveolar, bronchiolar and arteriolar walls compared to control subjects (1.39±0.63 and 1.55±0.52, respectively, p<0.05). No significant changes in mRNA levels of these proteins were observed between groups. Among the oxidation markers, malondialdehyde was the best in distinguishing COPD patients. CONCLUSIONS COPD patients show a reduced expression of EC-SOD and fibulin-5 in the lung interstitium. Paralleling the reduction of EC-SOD levels, the decrease of fibulin-5 expression in COPD lungs supports the hypothesis of an impaired pulmonary antioxidant response in COPD patients.
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Affiliation(s)
- José García-Valero
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Jordi Olloquequi
- Laboratory of Cellular and Molecular Pathology, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Esther Rodríguez
- Department of Pneumology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona and CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
| | - Mireia Martín-Satué
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Laura Texidó
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Jaume Ferrer
- Department of Pneumology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona and CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.
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Creamer TJ, Bramel EE, MacFarlane EG. Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies. Genes (Basel) 2021; 12:183. [PMID: 33514025 PMCID: PMC7912671 DOI: 10.3390/genes12020183] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/15/2022] Open
Abstract
Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin-myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.
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Affiliation(s)
- Tyler J. Creamer
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (T.J.C.); (E.E.B.)
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Emily E. Bramel
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (T.J.C.); (E.E.B.)
- Predoctoral Training in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Elena Gallo MacFarlane
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (T.J.C.); (E.E.B.)
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Mészáros B, Sámano-Sánchez H, Alvarado-Valverde J, Čalyševa J, Martínez-Pérez E, Alves R, Shields DC, Kumar M, Rippmann F, Chemes LB, Gibson TJ. Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications. Sci Signal 2021; 14:eabd0334. [PMID: 33436497 PMCID: PMC7928535 DOI: 10.1126/scisignal.abd0334] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022]
Abstract
The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.
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Affiliation(s)
- Bálint Mészáros
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
| | - Hugo Sámano-Sánchez
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
| | - Jesús Alvarado-Valverde
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences
| | - Jelena Čalyševa
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences
| | - Elizabeth Martínez-Pérez
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Laboratorio de bioinformática estructural, Fundación Instituto Leloir, C1405BWE Buenos Aires, Argentina
| | - Renato Alves
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
| | - Denis C Shields
- School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Manjeet Kumar
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
| | - Friedrich Rippmann
- Computational Chemistry & Biology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany
| | - Lucía B Chemes
- Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo A. Ugalde", IIB-UNSAM, IIBIO-CONICET, Universidad Nacional de San Martín, CP1650 San Martín, Buenos Aires, Argentina.
| | - Toby J Gibson
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
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Eekhoff JD, Steenbock H, Berke IM, Brinckmann J, Yanagisawa H, Wagenseil JE, Lake SP. Dysregulated assembly of elastic fibers in fibulin-5 knockout mice results in a tendon-specific increase in elastic modulus. J Mech Behav Biomed Mater 2021; 113:104134. [PMID: 33045519 PMCID: PMC8146012 DOI: 10.1016/j.jmbbm.2020.104134] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/29/2020] [Accepted: 10/04/2020] [Indexed: 12/15/2022]
Abstract
Elastic fiber assembly is coordinated in part by fibulin-5, a matricellular protein. When fibulin-5 is not available to guide elastogenesis, elastin forms into disconnected globules instead of the dense elastic fiber core found in healthy tissues. Despite the growing evidence for a significant role of elastic fibers in tendon mechanics and the clinical relevance to cutis laxa, a human disease which can be caused by a mutation in the gene encoding fibulin-5, it is unknown how malformed elastic fibers affect tendon function. Therefore, this study investigated the effects of dysregulated elastic fiber assembly in tendons from fibulin-5 knockout mice in comparison to wild-type controls. Due to evidence for a more prominent role of elastic fibers in tendons with higher functional demands, both the energy-storing Achilles tendon and the more positional tibialis anterior tendon were evaluated. The linear modulus of knockout Achilles tendons was increased compared to controls, yet there was no discernible change in mechanical properties of the tibialis anterior tendon across genotypes. Transmission electron microscopy confirmed the presence of malformed elastic fibers in knockout tendons while no other changes to tendon composition or structure were found. The mechanism behind the increase in linear modulus in fibulin-5 knockout Achilles tendons may be greater collagen engagement due to decreased regulation of strain-induced structural reorganization. These findings support the theory of a significant, functionally distinct role of elastic fibers in tendon mechanics.
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Affiliation(s)
- Jeremy D Eekhoff
- Department of Biomedical Engineering, Washington University in St. Louis, USA
| | - Heiko Steenbock
- Institute of Virology and Cell Biology, University of Lübeck, Germany
| | - Ian M Berke
- Department of Biomedical Engineering, Washington University in St. Louis, USA
| | - Jürgen Brinckmann
- Institute of Virology and Cell Biology, University of Lübeck, Germany; Department of Dermatology, University of Lübeck, Germany
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan
| | - Jessica E Wagenseil
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, USA
| | - Spencer P Lake
- Department of Biomedical Engineering, Washington University in St. Louis, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, USA; Department of Orthopaedic Surgery, Washington University in St. Louis, USA.
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Siadat SM, Zamboulis DE, Thorpe CT, Ruberti JW, Connizzo BK. Tendon Extracellular Matrix Assembly, Maintenance and Dysregulation Throughout Life. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:45-103. [PMID: 34807415 DOI: 10.1007/978-3-030-80614-9_3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
In his Lissner Award medal lecture in 2000, Stephen Cowin asked the question: "How is a tissue built?" It is not a new question, but it remains as relevant today as it did when it was asked 20 years ago. In fact, research on the organization and development of tissue structure has been a primary focus of tendon and ligament research for over two centuries. The tendon extracellular matrix (ECM) is critical to overall tissue function; it gives the tissue its unique mechanical properties, exhibiting complex non-linear responses, viscoelasticity and flow mechanisms, excellent energy storage and fatigue resistance. This matrix also creates a unique microenvironment for resident cells, allowing cells to maintain their phenotype and translate mechanical and chemical signals into biological responses. Importantly, this architecture is constantly remodeled by local cell populations in response to changing biochemical (systemic and local disease or injury) and mechanical (exercise, disuse, and overuse) stimuli. Here, we review the current understanding of matrix remodeling throughout life, focusing on formation and assembly during the postnatal period, maintenance and homeostasis during adulthood, and changes to homeostasis in natural aging. We also discuss advances in model systems and novel tools for studying collagen and non-collagenous matrix remodeling throughout life, and finally conclude by identifying key questions that have yet to be answered.
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Affiliation(s)
| | - Danae E Zamboulis
- Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Chavaunne T Thorpe
- Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
| | - Jeffrey W Ruberti
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Brianne K Connizzo
- Department of Biomedical Engineering, Boston University, Boston, MA, USA.
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50
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Reichheld SE, Muiznieks LD, Huynh Q, Wang N, Ing C, Miao M, Sitarz EE, Pomès R, Sharpe S, Keeley FW. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Biopolymers 2020; 112:e23414. [PMID: 33351193 DOI: 10.1002/bip.23414] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 01/01/2023]
Abstract
Elastin is a major polymeric protein of the extracellular matrix, providing critical properties of extensibility and elastic recoil. The rs2071307 genomic polymorphism, resulting in the substitution of a serine for a glycine residue in a VPG motif in tropoelastin, has an unusually high minor allele frequency in humans. A consequence of such allelic heterozygosity would be the presence of a heterogeneous elastin polymer in up to 50% of the population, a situation which appears to be unique to Homo sapiens. VPG motifs are extremely common in hydrophobic domains of tropoelastins and are the sites of transient β-turns that are essential for maintaining the conformational flexibility required for its function as an entropic elastomer. Earlier data demonstrated that single amino acid substitutions in tropoelastin can have functional consequences for polymeric elastin, particularly when present in mixed polymers. Here, using NMR and molecular dynamics approaches, we show the rs2071307 polymorphism reduces local propensity for β-turn formation, with a consequent increase in polypeptide hydration and an expansion of the conformational ensemble manifested as an increased hydrodynamic radius, radius of gyration and asphericity. Furthermore, this substitution affects functional properties of polymeric elastin, particularly in heterogeneous polymers mimicking allelic heterozygosity. We discuss whether such effects, together with the unusually high minor allele frequency of the polymorphism, could imply some some evolutionary advantage for the heterozygous state.
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Affiliation(s)
- Sean E Reichheld
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA
| | - Lisa D Muiznieks
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA.,Elvesys Microfluidics Innovation Center, 172 rue de Charonne, 75011, Paris, France
| | - Quang Huynh
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA
| | - Nick Wang
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA.,135 W 52nd St. Apt 20A, 10019-7691, New York, New York, USA
| | - Christopher Ing
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA.,ProteinQure, Suite 304, 119 Spadina Avenue, M5V2L1, Toronto, Ontario, Canada
| | - Ming Miao
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA
| | - Eva E Sitarz
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA
| | - Régis Pomès
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Simon Sharpe
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Fred W Keeley
- Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, USA.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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