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Experimental Biology and Medicine... Sep 2023Preeclampsia increases the risk of pregnancy-related complications, nevertheless a successful spiral vessel remodeling, and trophoblast invasion reduces disorders of...
Preeclampsia increases the risk of pregnancy-related complications, nevertheless a successful spiral vessel remodeling, and trophoblast invasion reduces disorders of pregnancy. Matrix metalloproteinase-2 (MMP-2) clears the path for trophoblast invasion, and activation of MMP-2 largely depends on extracellular matrix metalloproteinases inducer (EMMPRIN) protein. This study aimed to investigate gene polymorphism and MMP-2 activity in preeclampsia patients. Archival whole blood and serum samples of 74 preeclampsia and 66 normotensive pregnant women age-matched were used in this case-control study. Genomic DNA was extracted from the whole blood samples and gene amplified with specific primers following fragments sequence mutation analysis. Serum MMP-2 activity was determined using enzyme-linked immunosorbent assay (ELISA) and socio-demographic data of participants retrieved from the database. Age of preeclampsia patients (32.78 ± 6.39) years and body mass index (BMI) (33.09 ± 7.27) kg/m compared with the normotensive counterparts (32.33 ± 5.56) years and (32.33 ± 5.56) kg/m,respectively, were not statistically significant ( > 0.05). Serum matrix metalloprotease-2 (MMP-2) activity was significantly reduced in preeclampsia group (16.34 ± 7.07) compared with the normotensives (25.63 ± 4.56) ( < 0.001), and rs424243T/G variant (55.6%) was overrepresented among the cases compared with the normotensives (16.7%). The single-nucleotide polymorphism T/G was found to be associated with preeclampsia (odds ratio [OR] = 7.63; 95% confidence interval [CI] = 3.95-14.75; < 0.0001). Decreased activity of MMP-2 and rs424243T/G SNP of gene was reported in preeclampsia. These preliminary data warrant a further investigation into the relationship between gene polymorphism and MMP-2 activity in preeclampsia.
Topics: Adult; Female; Humans; Pregnancy; Basigin; Case-Control Studies; Extracellular Matrix; Matrix Metalloproteinase 2; Polymorphism, Genetic; Pre-Eclampsia
PubMed: 37937473
DOI: 10.1177/15353702231199464 -
International Journal of Molecular... Dec 2023Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour.... (Review)
Review
Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Prognosis; Radiation Oncology; Head and Neck Neoplasms; Matrix Metalloproteinases; Tumor Microenvironment
PubMed: 38203696
DOI: 10.3390/ijms25010527 -
Molecules (Basel, Switzerland) Jul 2023Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be... (Review)
Review
Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.
Topics: Humans; Matrix Metalloproteinase Inhibitors; Neoplasms; Matrix Metalloproteinases; Antineoplastic Agents; Extracellular Matrix
PubMed: 37513440
DOI: 10.3390/molecules28145567 -
Medicine Jul 2023Matrix metalloproteinase 9 (MMP9), a zinc ion-dependent endopeptidase, is one of the most complex matrix metalloproteinases in the gelatinase family. During tissue...
Matrix metalloproteinase 9 (MMP9), a zinc ion-dependent endopeptidase, is one of the most complex matrix metalloproteinases in the gelatinase family. During tissue remodeling, MMP9 leads to gelatin and collagen degradation, which in turn promotes tumor invasion and metastasis. However, comprehensive pan-cancer analysis has not been performed for MMP9. In addition, the diagnostic and prognostic value of MMP9 as a cancer biomarker remain poorly understood, as well as the utility of MMP9 expression as a predictor of immunological responses. Based on a comprehensive analysis of bioinformatics information, we investigated MMP9 expression in different cancers, correlations between MMP9 expression and cancer prognosis and gene mutations, and relationships between MMP9 expression and immune cell infiltration. Our results indicated that MMP9 was highly expressed in most malignant cancers. MMP9 expression was significantly positively or negatively associated with the clinical prognoses of patients with different kinds of cancer. Furthermore, MMP9 expression significantly correlated with infiltrating cells and the expression levels of immune checkpoint genes. This pan-cancer analysis provides comprehensive information on the potential value of MMP9 as a theranostic biomarker.
Topics: Humans; Prognosis; Matrix Metalloproteinase 9; Neoplasms
PubMed: 37505149
DOI: 10.1097/MD.0000000000034499 -
Biomedicine & Pharmacotherapy =... Oct 2023Nonalcoholic steatohepatitis (NASH) is a progressive fibrotic disease associated with an increased risk of developing hepatocellular carcinoma; at present, no efficient...
Nonalcoholic steatohepatitis (NASH) is a progressive fibrotic disease associated with an increased risk of developing hepatocellular carcinoma; at present, no efficient therapeutic strategy has been established. Herein, we examined the efficacy of PRI-724, a potent inhibitor of CBP/β-catenin signaling, for treating NASH-related liver fibrosis and disorder and characterized its mechanism. Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice exhibited NASH-induced liver fibrosis that is characterized by steatosis, lobular inflammation, hepatocellular injury and collagen fibrils. To examine the therapeutic effect, CDAHFD-fed mice were administered PRI-724. Serum levels of ALT and pro-fibrotic molecule, i.e. Mac-2 bp, alpha smooth muscle actin, type I and type III collagens, decreased significantly. mRNA levels of the matrix metalloproteinases Mmp8 and Mmp9 in the liver were significantly increased, and increases in the abundance of MMP9-producing neutrophils and macrophages were observed. MarcoMmp9Cd68 Kupffer cells were only observed in the livers of mice treated with PRI-724, and Mmp9 expression in MarcoCd68 Kupffer cells increased 4.3-fold. Moreover, hepatic expression of the lipid metabolism regulator, pyruvate dehydrogenase kinase 4 and liver lipid droplets also decreased significantly. PRI-724-treated NASH mice not only recovered from NASH-related liver fibrosis through the effect of PRI-724 down-regulating the expression of pro-fibrotic genes and up-regulating the expression of anti-fibrotic genes, but they also recovered from NASH-induced liver disorder. PRI-724, a selective CBP/β-catenin inhibitor, thus shows a potent therapeutic effect for NASH-related liver fibrosis and for decreasing adipose tissue in the liver.
Topics: Animals; Mice; Non-alcoholic Fatty Liver Disease; Matrix Metalloproteinase 9; beta Catenin; Liver Cirrhosis; Antineoplastic Agents; Liver Neoplasms
PubMed: 37647690
DOI: 10.1016/j.biopha.2023.115379 -
Tissue Engineering and Regenerative... Aug 2023Extracellular matrix (ECM) components confer biomechanical properties, maintain cell phenotype and mediate tissue homeostasis. ECM remodeling is complex and plays a key... (Review)
Review
Extracellular matrix (ECM) components confer biomechanical properties, maintain cell phenotype and mediate tissue homeostasis. ECM remodeling is complex and plays a key role in both physiological and pathological processes. Matrix metalloproteinases (MMPs) are a group of enzymes responsible for ECM degradation and have been accepted as a key regulator in ECM remodeling. In this mini-review, we summarize MMPs categories, functions and the targeted substrates. We then discuss current understanding of the role of MMPs-mediated events, including inflammation reaction, angiogenesis, cellular activities, etc., in ECM remodeling in the context of regenerative medicine.
Topics: Humans; Regenerative Medicine; Matrix Metalloproteinases; Extracellular Matrix; Inflammation
PubMed: 37160567
DOI: 10.1007/s13770-023-00536-x -
BMC Complementary Medicine and Therapies Sep 2023Excessive extracellular matrix (ECM) deposition in adipose tissue is a hallmark of fibrosis, leading to disrupted adipose tissue homeostasis and metabolic dysfunction....
BACKGROUND
Excessive extracellular matrix (ECM) deposition in adipose tissue is a hallmark of fibrosis, leading to disrupted adipose tissue homeostasis and metabolic dysfunction. Hesperetin, a flavonoid compound, has shown promising anti-inflammatory, anti-obesity and anti-diabetic properties. Therefore, we investigated the anti-fibrotic effects of hesperetin, through targeting ECM components and matrix metalloproteinase enzymes.
METHODS
3T3-L1 cells were cultured in DMEM, containing 10% FBS and 1% penicillin/streptomycin. Cells were treated with a range of hesperetin concentrations, and the cell viability was determined using MTT assay. Subsequently, the expression of genes encoding collagen VI, osteopontin, matrix metalloproteinase-2 (Mmp-2) and Mmp-9 was analyzed using specific primers and real-time PCR technique. To evaluate protein levels of collagen VI and osteopontin, Western blotting was performed.
RESULTS
Hesperetin affected the viability of 3T3-L1 adipocytes with IC50 of 447.4 µM, 339.2 µM and 258.8 µM (24 h, 48 and 72 h, respectively). Hesperetin significantly reduced the gene and protein expression of both collagen VI and osteopontin in 3T3-L1 pre-adipocytes, in a time- and dose-dependent manner. Hesperetin was also able to cause a remarkable decline in gene expression of Mmp2 and Mmp9.
CONCLUSION
Hesperetin could potently reduce the production of markers of adipose tissue fibrosis and might be considered a potential anti-fibrotic compound in obesity. Thus, hesperetin has the potency to be used for the treatment of obesity-associated fibrosis.
Topics: Matrix Metalloproteinase 2; Osteopontin; Adipocytes; Adipose Tissue
PubMed: 37697354
DOI: 10.1186/s12906-023-04152-z -
Biochemical Pharmacology Sep 2023Hypertension is one of the leading risk factors for the development of heart failure. Despite being a multifactorial disease, in recent years, preclinical and clinical... (Review)
Review
Hypertension is one of the leading risk factors for the development of heart failure. Despite being a multifactorial disease, in recent years, preclinical and clinical studies suggest strong evidence of the pivotal role of inflammatory cells and cytokines in the remodeling process and cardiac dysfunction. During the heart remodeling, activation of extracellular matrix metalloproteinases (MMPs) occurs, with MMP-2 being one of the main proteases secreted by cardiomyocytes, fibroblasts, endothelial and inflammatory cells in cardiac tissue. In this review, we will address the process of cardiac remodeling and injury induced by the increase in MMP-2 and the main signaling pathways involving cytokines and inflammatory cells in the process of transcriptional, secretion and activation of MMP-2. In addition, an interaction and coordinated action between MMP-2 and inflammation are explored and significant in maintaining the cardiac cycle. These observations suggest that new therapeutic opportunities targeting MMP-2 could be used to reduce inflammatory biomarkers and reduce cardiac damage in hypertension.
Topics: Humans; Matrix Metalloproteinase 2; Heart Failure; Hypertension; Inflammation; Cytokines
PubMed: 37459959
DOI: 10.1016/j.bcp.2023.115684 -
Cellular Signalling Sep 2023The Wnt/β-catenin signaling pathway is associated with the regulation of cancer stem cells, and it can be driven by epigenetic modifications. Here, we aim to identify...
The Wnt/β-catenin signaling pathway is associated with the regulation of cancer stem cells, and it can be driven by epigenetic modifications. Here, we aim to identify epigenetic modifications involved in the control of the Wnt/β-catenin signaling and investigate the role of this pathway in the accumulation of cancer stem cells (CSC) and chemoresistance of Head and Neck Squamous Cell Carcinoma (HNSCC). Quantitative-PCR, western blot, shRNA assay, viability assay, flow cytometry assay, spheres formation, xenograft model, and chromatin immunoprecipitation were employed to evaluate the Wnt/β-catenin pathway and EZH2 in wild-type and chemoresistant oral carcinoma cell lines, and in the populations of CSC and non-stem cells. We demonstrated that β-catenin and EZH2 were accumulated in cisplatin-resistant and CSC population. The upstream genes of the Wnt/β-catenin signaling (APC and GSK3β) were decreased, and the downstream gene MMP7 was increased in the chemoresistant cell lines. The inhibition of β-catenin and EZH2 combined effectively decreased the CSC population in vitro and reduced the tumor volume and CSC population in vivo. EZH2 inhibition increased APC and GSK3β, and the Wnt/β-catenin inhibition reduced MMP7 levels. In contrast, EZH2 overexpression decreased APC and GSK3β and increased MMP7. EZH2 and β-catenin inhibitors sensitized chemoresistant cells to cisplatin. EZH2 and H3K27me3 bounded the promoter of APC, leading to its repression. These results suggest that EZH2 regulates β-catenin by inhibiting the upstream gene APC contributing to the accumulation of cancer stem cells and chemoresistance. Moreover, the pharmacological inhibition of the Wnt/β-catenin combined with EZH2 can be an effective strategy for treating HNSCC.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Cisplatin; beta Catenin; Glycogen Synthase Kinase 3 beta; Matrix Metalloproteinase 7; Cell Line, Tumor; Wnt Signaling Pathway; Head and Neck Neoplasms; Neoplastic Stem Cells; Gene Expression Regulation, Neoplastic; Enhancer of Zeste Homolog 2 Protein
PubMed: 37331417
DOI: 10.1016/j.cellsig.2023.110773 -
Chemico-biological Interactions Nov 2023Tetracaine, a long-acting amino ester-type local anesthetic, prevents the initiation and propagation of action potentials by reversibly blocking voltage-gated sodium...
Tetracaine, a long-acting amino ester-type local anesthetic, prevents the initiation and propagation of action potentials by reversibly blocking voltage-gated sodium channels (VGSCs). These channels, which are highly expressed in several carcinomas (e.g. breast, prostate, colon and lung cancers) have been implicated in promoting metastatic behaviours. Recent evidence suggests that local anesthetics can suppress cancer progression. In this paper, we aimed to explore whether tetracaine would reduce the invasive characteristics of breast cancer cells. In a comparative approach, we used two cell lines of contracting metastatic potential: MDA-MB-231 (strongly metastatic) and MCF-7 (weakly metastatic). Tetracaine (50 μM and 75 μM) did not affect the proliferation of both MDA-MB-231 and MCF-7 cells. Importantly, tetracaine suppressed the migratory, invasive, and adhesive capacities of MDA-MB-231 cells; there was no effect on the motility of MCF-7 cells. Tetracaine treatment also significantly decreased the expression and activity levels of MMP-2 and MMP-9, whilst increasing TIMP-2 expression in MDA-MB-231 cells. On the other hand, VGSC α/Nav1.5 and VGSC-β1 mRNA and protein expression levels were not affected. We conclude that tetracaine has anti-invasive effects on breast cancer cells and may be exploited clinically, for example, in surgery and/or in combination therapies.
Topics: Male; Humans; Breast Neoplasms; Tetracaine; Cell Line, Tumor; Voltage-Gated Sodium Channels; Matrix Metalloproteinases; Neoplasm Invasiveness; Cell Movement
PubMed: 37806380
DOI: 10.1016/j.cbi.2023.110730