scholarly journals Distinct Metalloproteinase Expression and Functions in Systemic Sclerosis and Fibrosis: What We Know and the Potential for Intervention

2021 ◽  
Vol 12 ◽  
Author(s):  
Edwin Leong ◽  
Michael Bezuhly ◽  
Jean S. Marshall
Keyword(s):  
Systemic Sclerosis ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Stiffness ◽  
Therapeutic Approaches ◽  
Internal Organs ◽  
Ecm Remodeling ◽  
Tissue Microenvironment ◽  
Ecm Proteins ◽  
And Function ◽  
Endogenous Enzymes

Systemic sclerosis (SSc) is a chronic debilitating idiopathic disorder, characterized by deposition of excessive extracellular matrix (ECM) proteins such as collagen which leads to fibrosis of the skin and other internal organs. During normal tissue repair and remodeling, the accumulation and turnover of ECM proteins are tightly regulated by the interaction of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinases (TIMPs). SSc is associated with dysregulation of the activity of these proteolytic and inhibitory proteins within the tissue microenvironment, tipping the balance toward fibrosis. The resultant ECM accumulation further perpetuates tissue stiffness and decreased function, contributing to poor clinical outcomes. Understanding the expression and function of these endogenous enzymes and inhibitors within specific tissues is therefore critical to the development of therapies for SSc. This brief review describes recent advances in our understanding of the functions and mechanisms of ECM remodeling by metalloproteinases and their inhibitors in the skin and lungs affected in SSc. It highlights recent progress on potential candidates for intervention and therapeutic approaches for treating SSc fibrosis.

scholarly journals Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1151 ◽  
Author(s):  
Salvatore Napoli ◽  
Chiara Scuderi ◽  
Giuseppe Gattuso ◽  
Virginia Di Bella ◽  
Saverio Candido ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Matrix Metalloproteinases ◽  
Therapeutic Response ◽  
Therapeutic Potential ◽  
Akt Signaling ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Therapeutic Approaches ◽  
Functional Roles ◽  
Tissue Microenvironment ◽  
Melanoma Patients

The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.

Role of Matrix Metalloproteinases in Degenerative Kidney Disorders

2018 ◽  
Vol 25 (15) ◽  
pp. 1805-1816 ◽  
Author(s):  
Shifa Narula ◽  
Chanderdeep Tandon ◽  
Simran Tandon
Keyword(s):  
Matrix Metalloproteinases ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Transforming Growth Factor Β1 ◽  
Bioactive Molecules ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Ecm Remodeling ◽  
Surface Receptors ◽  
Calcium Dependent ◽  
Ecm Degradation

Matrix metalloproteinases (MMPs) are members of calcium dependent-zinc containing endopeptidases that play a pivotal role in extracellular matrix (ECM) remodeling. MMPs are also known to cleave non-matrix proteins, including cell surface receptors, TNF-α, angiotensin-II, growth factors, (especially transforming growth factor-β1, ΤGF- β1) plasminogen, endothelin and other bioactive molecules. The tissue inhibitors of metalloproteinases (TIMPs) inhibit the activity of MMPs and decrease ECM degradation. Various patho-physiological conditions have been linked with the imbalance of ECM synthesis and degradation. Numerous studies have reported the significance of MMPs and TIMPs in the progression of kidney pathologies, including glomerulonephritis, diabetic nephropathy, renal cancer, and nephrolithiasis. Although dysregulated activity of MMPs could directly or indirectly lead to pathological morbidities, their contribution in disease progression is still understated. Specifically, MMP activity in the kidneys and it's relation to kidney diseases has been the subject of a limited number of investigations. Therefore, the aim of the present review is to provide an updated insight of the involvement of MMPs and TIMPs in the pathogenesis of inflammatory and degenerative kidney disorders.

scholarly journals Dynamically remodeled hepatic extracellular matrix predicts prognosis of early-stage cirrhosis

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yuexin Wu ◽  
Yuyan Cao ◽  
Keren Xu ◽  
Yue Zhu ◽  
Yuemei Qiao ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Basement Membrane ◽  
Type Iv Collagen ◽  
Patient Survival ◽  
Early Stage ◽  
Ecm Remodeling ◽  
Type Iv ◽  
Ecm Proteins ◽  
Stage Disease ◽  
Cirrhotic Patients

AbstractLiver cirrhosis remains major health problem. Despite the progress in diagnosis of asymptomatic early-stage cirrhosis, prognostic biomarkers are needed to identify cirrhotic patients at high risk developing advanced stage disease. Liver cirrhosis is the result of deregulated wound healing and is featured by aberrant extracellular matrix (ECM) remodeling. However, it is not comprehensively understood how ECM is dynamically remodeled in the progressive development of liver cirrhosis. It is yet unknown whether ECM signature is of predictive value in determining prognosis of early-stage liver cirrhosis. In this study, we systematically analyzed proteomics of decellularized hepatic matrix and identified four unique clusters of ECM proteins at tissue damage/inflammation, transitional ECM remodeling or fibrogenesis stage in carbon tetrachloride-induced liver fibrosis. In particular, basement membrane (BM) was heavily deposited at the fibrogenesis stage. BM component minor type IV collagen α5 chain expression was increased in activated hepatic stellate cells. Knockout of minor type IV collagen α5 chain ameliorated liver fibrosis by hampering hepatic stellate cell activation and promoting hepatocyte proliferation. ECM signatures were differentially enriched in the biopsies of good and poor prognosis early-stage liver cirrhosis patients. Clusters of ECM proteins responsible for homeostatic remodeling and tissue fibrogenesis, as well as basement membrane signature were significantly associated with disease progression and patient survival. In particular, a 14-gene signature consisting of basement membrane proteins is potent in predicting disease progression and patient survival. Thus, the ECM signatures are potential prognostic biomarkers to identify cirrhotic patients at high risk developing advanced stage disease.

scholarly journals Endothelium as a Source and Target of H2S to Improve Its Trophism and Function

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 486
Author(s):  
Valerio Ciccone ◽  
Shirley Genah ◽  
Lucia Morbidelli
Keyword(s):  
Endothelial Dysfunction ◽  
Vessel Wall ◽  
Redox Reactions ◽  
Single Layer ◽  
Fine Tuning ◽  
Therapeutic Approaches ◽  
Impaired Wound Healing ◽  
Blood Fluidity ◽  
And Function ◽  
And Control

The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.

scholarly journals How Changes in the Nutritional Landscape Shape Gut Immunometabolism

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 823
Author(s):  
Jian Tan ◽  
Duan Ni ◽  
Rosilene V. Ribeiro ◽  
Gabriela V. Pinget ◽  
Laurence Macia
Keyword(s):  
Immune Cells ◽  
Metabolic Pathways ◽  
Immune Cell ◽  
Food Additives ◽  
Cell Activity ◽  
Inflammatory Cells ◽  
Therapeutic Approaches ◽  
Food Antigens ◽  
And Function ◽  
Micro Organisms

Cell survival, proliferation and function are energy-demanding processes, fuelled by different metabolic pathways. Immune cells like any other cells will adapt their energy production to their function with specific metabolic pathways characteristic of resting, inflammatory or anti-inflammatory cells. This concept of immunometabolism is revolutionising the field of immunology, opening the gates for novel therapeutic approaches aimed at altering immune responses through immune metabolic manipulations. The first part of this review will give an extensive overview on the metabolic pathways used by immune cells. Diet is a major source of energy, providing substrates to fuel these different metabolic pathways. Protein, lipid and carbohydrate composition as well as food additives can thus shape the immune response particularly in the gut, the first immune point of contact with food antigens and gastrointestinal tract pathogens. How diet composition might affect gut immunometabolism and its impact on diseases will also be discussed. Finally, the food ingested by the host is also a source of energy for the micro-organisms inhabiting the gut lumen particularly in the colon. The by-products released through the processing of specific nutrients by gut bacteria also influence immune cell activity and differentiation. How bacterial metabolites influence gut immunometabolism will be covered in the third part of this review. This notion of immunometabolism and immune function is recent and a deeper understanding of how lifestyle might influence gut immunometabolism is key to prevent or treat diseases.

Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis

2003 ◽  
Vol 285 (6) ◽  
pp. L1222-L1232 ◽  
Author(s):  
Erica L. Martin ◽  
Brent Z. Moyer ◽  
M. Cynthia Pape ◽  
Barry Starcher ◽  
Kevin J. Leco ◽  
...  
Keyword(s):  
Negative Impact ◽  
Cecal Ligation ◽  
Lung Compliance ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Wild Type ◽  
Gelatinase Activity ◽  
Lung Structure ◽  
And Function ◽  
Knockout Animals

Matrix metalloproteinases (MMPs) are degradative enzymes, which act to remodel tissue. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the degradation/inhibition activities has been associated with many diseases, including sepsis. We have previously shown that TIMP-3 knockout animals develop spontaneous, progressive air space enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either sham or CLP surgery, allowed to recover for 6 h, and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared with sham wild-type mice. Additionally, the TIMP-3 knockout mice showed a significant increase in compliance following CLP. Rapid compliance changes were accompanied by significantly decreased collagen and fibronectin levels and increased gelatinase (MMP-2 and -9) abundance and activation. Additionally, in situ zymography showed increased airway-associated gelatinase activity in the knockout animals enhanced following CLP. In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP.

scholarly journals Epigenetic Regulations of Inflammatory Cyclooxygenase-Derived Prostanoids: Molecular Basis and Pathophysiological Consequences

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Hedi Harizi
Keyword(s):  
Target Genes ◽  
Inflammatory Diseases ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Immunological Disorders ◽  
Tissue Microenvironment ◽  
Individual Variations ◽  
Fine Regulation ◽  
Additional Level ◽  
The Impact

The potential relevance of prostanoid signaling in immunity and immunological disorders, or disease susceptibility and individual variations in drug responses, is an important area for investigation. The deregulation of Cyclooxygenase- (COX-) derived prostanoids has been reported in several immunoinflammatory disorders such as asthma, rheumatoid arthritis, cancer, and autoimmune diseases. In addition to the environmental factors and the genetic background to diseases, epigenetic mechanisms involved in the fine regulation of prostanoid biosynthesis and/or receptor signaling appeared to be an additional level of complexity in the understanding of prostanoid biology and crucial in controlling the different components of the COX pathways. Epigenetic alterations targeting inflammatory components of prostanoid biosynthesis and signaling pathways may be important in the process of neoplasia, depending on the tissue microenvironment and target genes. Here, we focused on the epigenetic modifications of inflammatory prostanoids in physiological immune response and immunological disorders. We described how major prostanoids and their receptors can be functionally regulated epigenetically and consequently the impact of these processes in the pathogenesis inflammatory diseases and the development of therapeutic approaches that may have important clinical applications.

scholarly journals The Effects of Ionising and Non-Ionising Electromagnetic Radiation on Extracellular Matrix Proteins

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3041
Author(s):  
Ren Jie Tuieng ◽  
Sarah H. Cartmell ◽  
Cliona C. Kirwan ◽  
Michael J. Sherratt
Keyword(s):  
Extracellular Matrix ◽  
Electromagnetic Radiation ◽  
Cell Biology ◽  
Biological Effects ◽  
Well Being ◽  
Ecm Proteins ◽  
Clinical Consequences ◽  
Radiation Induced ◽  
And Function ◽  
Cellular Components

Exposure to sub-lethal doses of ionising and non-ionising electromagnetic radiation can impact human health and well-being as a consequence of, for example, the side effects of radiotherapy (therapeutic X-ray exposure) and accelerated skin ageing (chronic exposure to ultraviolet radiation: UVR). Whilst attention has focused primarily on the interaction of electromagnetic radiation with cells and cellular components, radiation-induced damage to long-lived extracellular matrix (ECM) proteins has the potential to profoundly affect tissue structure, composition and function. This review focuses on the current understanding of the biological effects of ionising and non-ionising radiation on the ECM of breast stroma and skin dermis, respectively. Although there is some experimental evidence for radiation-induced damage to ECM proteins, compared with the well-characterised impact of radiation exposure on cell biology, the structural, functional, and ultimately clinical consequences of ECM irradiation remain poorly defined.

scholarly journals Scleroderma and Mitral Stenosis: a New Cardiac Involvement or an Association by Chance

2016 ◽  
Vol 8 ◽  
Author(s):  
Ahmadreza Zarifian ◽  
Alireza Sepehri Shamloo ◽  
Mohammad Sobhan Sheikh Andalibi ◽  
Hamid Hoseinikhah ◽  
Fereshteh Ghaderi ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Mitral Valve ◽  
Mitral Stenosis ◽  
Autoimmune Disorder ◽  
Underlying Disease ◽  
Vascular Lesions ◽  
Successful Outcome ◽  
Unknown Etiology ◽  
Internal Organs ◽  
Adequate Management

<p><strong>Introduction:</strong> Systemic Sclerosis (SSc) is an autoimmune disorder with unknown etiology, which presents with vascular lesions and fibrosis of the skin and internal organs. Cardiac, renal, and pulmonary involvements are major causes of death in systemic sclerosis. Although a major cause of scleroderma deaths is cardiac failure, scleroderma rarely causes valvular disease. This is the eighth global report on scleroderma in company with mitral stenosis and the first one in Iran.</p><p><strong>Case report:</strong> The patient was a 48-year-old woman with severe mitral stenosis who was diagnosed with scleroderma 6 months before. Echocardiographic assessments had revealed no clinical manifestation of heart involvement in her previous visits. We used cardiac surgical treatment with successful outcome.</p><strong>Conclusion:</strong> The present case confirms the data from the currently available literature, indicating that mitral valve involvement in systemic sclerosis is a rare occurrence. Awareness of this uncommon association and adequate management to prevent complications of the underlying disease are prerequisites for successful mitral valve repair or replacement in such patients.

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