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Biomedicines
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Role of Matrix Metalloproteinase in Diseases
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Role of Matrix Metalloproteinase in Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 14180

Special Issue Editor

Prof. Dr. Shinji Takai

E-Mail Website
Guest Editor
Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, Takatsuki, Japan
Interests: aneurysm; atherosclerosis; chymase; cardiac diseases; fibrosis, hypertension; inflammation; inhibitor; renal failure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Matrix metalloproteinases are enzymes that degrade the extracellular matrix, including collagen, elastin, and fibronectin, and their enzymatic actions are deeply involved in promoting the infiltration of inflammatory cells and the progression of fibrosis. Augmentation of these enzymes has been observed in various diseases, including vascular, heart, lung, liver, and kidney diseases, and the inhibition of these enzymes is expected to prevent and treat various diseases. Matrix metalloproteinases are expressed as their proforms which are activated by enzymes such as elastase and chymase, and the enhancement or inhibition of process also plays an important role in the regulation of matrix metalloproteinases, resulting in the involvement of various diseases. In this Special Issue, we are looking for a wide range of matrix metalloproteinase-related diseases.

Prof. Dr. Shinji Takai
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiac diseases
  • digestive diseases
  • fibrosis
  • hepatic diseases
  • inhibitor
  • inflammation
  • matrix metalloproteinase
  • renal diseases, pulmonary diseases
  • vascular diseases

Published Papers (7 papers)

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Research

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13 pages, 328 KiB  
Article
The Modifying Effect of Obesity on the Association of Matrix Metalloproteinase Gene Polymorphisms with Breast Cancer Risk
by Nadezhda Pavlova, Sergey Demin, Mikhail Churnosov, Evgeny Reshetnikov, Inna Aristova, Maria Churnosova and Irina Ponomarenko
Biomedicines 2022, 10(10), 2617; https://doi.org/10.3390/biomedicines10102617 - 18 Oct 2022
Cited by 13 | Viewed by 1270
Abstract
Objective: We investigated the possible modifying effect of obesity on the association of matrix metalloproteinase (MMP) gene polymorphisms with breast cancer (BC) risk. Methods: A total of 1104 women divided into two groups according to their body mass index (BMI): BMI [...] Read more.
Objective: We investigated the possible modifying effect of obesity on the association of matrix metalloproteinase (MMP) gene polymorphisms with breast cancer (BC) risk. Methods: A total of 1104 women divided into two groups according to their body mass index (BMI): BMI ≥ 30 (119 BC, and 190 control) and BMI < 30 (239 BC, and 556 control) were genotyped for specially selected (according to their association with BC in the previous study) 10 single-nucleotide polymorphisms (SNP) of MMP1, 2, 3, 8, and 9 genes. Logistic regression association analysis was performed in each studied group of women (with/without obesity). Functional annotation of BC-correlated MMP polymorphic variants was analyzed by in silico bioinformatics. Results: We observed significant differences in the involvement of MMP SNPs in BC in obese and non-obese women. Polymorphic loci MMP9 (c.836 A > G (rs17576) and c. 1721 C > G (rs2250889)) were BC-protective factors in obese women (OR 0.71, allelic model, and OR 0.55, additive model, respectively). Genotypes TT MMP2 (c.-1306 C > T,rs243865) and AA MMP9 (c. 1331-163 G > A,rs3787268) determined BC susceptibility in non-obese women (OR 0.31, and OR 2.36, respectively). We found in silico substantial multidirectional influences on gene expression in adipose tissue BC-related polymorphic loci: BC risk allele A-rs3787268 in non-obese women is associated with low expression NEURL2, PLTP, RP3-337O18.9, SPATA25, and ZSWIM1, whereas BC risk allele A-rs17576 in obese women is associated with high expression in the same genes in visceral and/or subcutaneous adipose. Conclusions: our study indicated that obesity has a significant modifying effect on the association of MMP genes with BC risk in postmenopausal women. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
21 pages, 22352 KiB  
Article
The Effect of Citicoline on the Expression of Matrix Metalloproteinase-2 (MMP-2), Transforming Growth Factor-β1 (TGF-β1), and Ki-67, and on the Thickness of Scleral Tissue of Rat Myopia Model
by Eka Wahyuningsih, Dimas Wigid, Astrid Dewi, Hariwati Moehariadi, Hidayat Sujuti and Nanda Anandita
Biomedicines 2022, 10(10), 2600; https://doi.org/10.3390/biomedicines10102600 - 17 Oct 2022
Cited by 4 | Viewed by 1370
Abstract
Citicoline, presumed to be involved in the dopaminergic pathway, might play a role as a candidate agent in controlling myopia. However, its study with respect to myopia is limited. The aim of this study is to demonstrate the effect of citicoline on the [...] Read more.
Citicoline, presumed to be involved in the dopaminergic pathway, might play a role as a candidate agent in controlling myopia. However, its study with respect to myopia is limited. The aim of this study is to demonstrate the effect of citicoline on the expression of MMP-2, TGF-β1, and Ki-67, and on the thickness of scleral tissue of a rat myopia model. Immunohistochemistry was performed to evaluate the expression of MMP-2, TGF-β1, and Ki-67 as the markers for fibroblast proliferation. Hematoxylin and eosin staining were used to evaluate scleral thickness. An electronic digital caliper was used to evaluate the axial length. The treatment group administered with 200 mg/kg BW/day had the lowest mean MMP-2 expression, axial elongation, and fibroblast proliferation, but it had the highest mean scleral thickness. The treatment group administered with 300 mg/kg BW/day had the highest mean TGF-β1 expression. Citicoline is able to decrease MMP-2 expression and fibroblast proliferation and increase TGF-β1 expression and scleral tissue thickness significantly in the scleral tissue of rat models for myopia. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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23 pages, 4139 KiB  
Article
The Gelatinase Inhibitor ACT-03 Reduces Gliosis in the Rapid Kindling Rat Model of Epilepsy, and Attenuates Inflammation and Loss of Barrier Integrity In Vitro
by Diede W. M. Broekaart, Till S. Zimmer, Sophie T. Cohen, Rianne Tessers, Jasper J. Anink, Helga E. de Vries, Jan A. Gorter, Roger Prades, Eleonora Aronica and Erwin A. van Vliet
Biomedicines 2022, 10(9), 2117; https://doi.org/10.3390/biomedicines10092117 - 29 Aug 2022
Viewed by 1906
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases responsible for the cleavage of intra- and extracellular proteins. Several brain MMPs have been implicated in neurological disorders including epilepsy. We recently showed that the novel gelatinase inhibitor ACT-03 has disease-modifying effects in models of epilepsy. Here, we [...] Read more.
Matrix metalloproteinases (MMPs) are endopeptidases responsible for the cleavage of intra- and extracellular proteins. Several brain MMPs have been implicated in neurological disorders including epilepsy. We recently showed that the novel gelatinase inhibitor ACT-03 has disease-modifying effects in models of epilepsy. Here, we studied its effects on neuroinflammation and blood–brain barrier (BBB) integrity. Using the rapid kindling rat model of epilepsy, we examined whether ACT-03 affected astro- and microgliosis in the brain using immunohistochemistry. Cellular and molecular alterations were further studied in vitro using human fetal astrocyte and brain endothelial cell (hCMEC/D3) cultures, with a focus on neuroinflammatory markers as well as on barrier permeability using an endothelial and astrocyte co-culture model. We observed less astro- and microgliosis in the brains of kindled animals treated with ACT-03 compared to control vehicle-treated animals. In vitro, ACT-03 treatment attenuated stimulation-induced mRNA expression of several pro-inflammatory factors in human fetal astrocytes and brain endothelial cells, as well as a loss of barrier integrity in endothelial and astrocyte co-cultures. Since ACT-03 has disease-modifying effects in epilepsy models, possibly via limiting gliosis, inflammation, and barrier integrity loss, it is of interest to further evaluate its effects in a clinical trial. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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17 pages, 4183 KiB  
Article
Differential Modulation of Matrix Metalloproteinases-2 and -7 in LAM/TSC Cells
by Silvia Ancona, Emanuela Orpianesi, Clara Bernardelli, Eloisa Chiaramonte, Raffaella Chiaramonte, Silvia Terraneo, Fabiano Di Marco and Elena Lesma
Biomedicines 2021, 9(12), 1760; https://doi.org/10.3390/biomedicines9121760 - 24 Nov 2021
Cited by 4 | Viewed by 1703
Abstract
Matrix metalloproteinase (MMP) dysregulation is implicated in several diseases, given their involvement in extracellular matrix degradation and cell motility. In lymphangioleiomyomatosis (LAM), a pulmonary rare disease, MMP-2 and MMP-9 have been detected at high levels in serum and urine. LAM cells, characterized by [...] Read more.
Matrix metalloproteinase (MMP) dysregulation is implicated in several diseases, given their involvement in extracellular matrix degradation and cell motility. In lymphangioleiomyomatosis (LAM), a pulmonary rare disease, MMP-2 and MMP-9 have been detected at high levels in serum and urine. LAM cells, characterized by a mutation in the tuberous sclerosis complex (TSC)1 or TSC2, promote cystic lung destruction. The role of MMPs in invasive and destructive LAM cell capability has not yet been fully understood. We evaluated MMP-2 and MMP-7 expression, secretion, and activity in primary LAM/TSC cells that bear a TSC2 germline mutation and an epigenetic modification and depend on epidermal growth factor (EGF) for survival. 5-azacytidine restored tuberin expression with a reduction of MMP-2 and MMP-7 levels and inhibits motility, similarly to rapamycin and anti-EGFR antibody. Both drugs reduced MMP-2 and MMP-7 secretion and activity during wound healing and decreased their expression in lung nodules of a LAM mouse model. In LAM/TSC cells, MMP-2 and MMP-7 are dependent on tuberin expression, cellular adhesion, and migration. MMPs appears sensitive to rapamycin and anti-EGFR antibody only during cellular migration. Our data indicate a complex and differential modulation of MMP-2 and MMP-7 in LAM/TSC cells, likely critical for lung parenchyma remodeling during LAM progression. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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Review

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13 pages, 868 KiB  
Review
Pathophysiological Role of Chymase-Activated Matrix Metalloproteinase-9
by Shinji Takai and Denan Jin
Biomedicines 2022, 10(10), 2499; https://doi.org/10.3390/biomedicines10102499 - 07 Oct 2022
Cited by 6 | Viewed by 1740
Abstract
Chymase present in mast cells can directly form matrix metalloproteinase (MMP)-9 from proMMP-9. Chymase-activated MMP-9 has been reportedly closely related to the pathogenesis of various diseases, and inflammation-related diseases in particular. Upregulated chymase and MMP-9 have been observed in tissues from patients and [...] Read more.
Chymase present in mast cells can directly form matrix metalloproteinase (MMP)-9 from proMMP-9. Chymase-activated MMP-9 has been reportedly closely related to the pathogenesis of various diseases, and inflammation-related diseases in particular. Upregulated chymase and MMP-9 have been observed in tissues from patients and animal models of aortic aneurysm, inflammatory gastrointestinal and hepatic diseases, acute pancreatic failure, atopic dermatitis and rheumatoid arthritis. Chymase at these regions is only derived from mast cells, while MMP-9 is derived from macrophages and neutrophils in addition to mast cells. Chymase inhibitors attenuate MMP-9 formation from pro-MMP-9, and ameliorate the development and progression of these disorders, along with reduction in inflammatory cell numbers. MMP-9 activated by chymase might also be involved in angiogenesis in the tumor environment. Development of angiogenesis around several cancers is closely related to the expression of chymase and MMP-9, and postoperative survival curves have revealed that patients with a higher number of chymase positive cells have lower survival rates. In this review, we wanted to clarify the role of chymase-activated MMP-9, which might become an important therapeutic target for various inflammatory disorders. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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24 pages, 2541 KiB  
Review
Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors
by Jody M. de Jong, Diede W. M. Broekaart, Anika Bongaarts, Angelika Mühlebner, James D. Mills, Erwin A. van Vliet and Eleonora Aronica
Biomedicines 2022, 10(10), 2475; https://doi.org/10.3390/biomedicines10102475 - 03 Oct 2022
Cited by 3 | Viewed by 2266
Abstract
Seizures are one of the most common symptoms of brain tumors. The incidence of seizures differs among brain tumor type, grade, location and size, but paediatric-type diffuse low-grade gliomas/glioneuronal tumors are often highly epileptogenic. The extracellular matrix (ECM) is known to play a [...] Read more.
Seizures are one of the most common symptoms of brain tumors. The incidence of seizures differs among brain tumor type, grade, location and size, but paediatric-type diffuse low-grade gliomas/glioneuronal tumors are often highly epileptogenic. The extracellular matrix (ECM) is known to play a role in epileptogenesis and tumorigenesis because it is involved in the (re)modelling of neuronal connections and cell-cell signaling. In this review, we discuss the epileptogenicity of brain tumors with a focus on tumor type, location, genetics and the role of the extracellular matrix. In addition to functional problems, epileptogenic tumors can lead to increased morbidity and mortality, stigmatization and life-long care. The health advantages can be major if the epileptogenic properties of brain tumors are better understood. Surgical resection is the most common treatment of epilepsy-associated tumors, but post-surgery seizure-freedom is not always achieved. Therefore, we also discuss potential novel therapies aiming to restore ECM function. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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20 pages, 5221 KiB  
Review
Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides
by Sang Yeol Lee
Biomedicines 2021, 9(2), 198; https://doi.org/10.3390/biomedicines9020198 - 17 Feb 2021
Cited by 11 | Viewed by 2734
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn’s disease. Regulation of MMPs is closely associated with signaling molecules, especially [...] Read more.
Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn’s disease. Regulation of MMPs is closely associated with signaling molecules, especially mitogen-activated protein kinases (MAPKs), including three representative kinases, extracellular signal regulated kinases (ERK), p38 and c-Jun N-terminal kinases (JNK). Ginseng (Panax sp.) is a plant which has been traditionally used for medicinal applications. Ginsenosides are major metabolites which have potentials to treat various human diseases. In this review, the pharmacological effects of ginsenosides have been rigorously investigated; these include anti-metastatic and anti-inflammatory activities of ginsenosides associated with suppression of MMPs via regulation of various signaling pathways. This will highlight the importance of MMPs as therapeutic targets for anti-metastatic and anti-inflammatory drug development based on ginsenosides. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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