Search Results (13)

Ovarian cancer (OC) has an extremely unfavourable prognosis. This is due to its asymptomatic course and lack of screening tests. Therefore, new methods are needed to diagnose OC. The aim of this study was to evaluate the concentrations and diagnostic utility of selected matrilysins and stromelysins in the diagnosis of OC in comparison with the classical markers CA125 and HE4. The study group included 100 patients with serous OC, 70 with serous cysts (BL), and 50 healthy women (HW). Selected MMPs were determined by ELISA, routine markers by CMIA. Ovarian cancer patients have elevated concentrations of MMP-7, MMP-26, MMP-10 as well as CA125 and HE4 in the total group and subgroups (stage I + II, and III + IV). The highest values of diagnostic parameters—SP, SE, NPV, PPV, and ACC, as compared to CA125 and HE4, were observed for MMP-7. Performing ROC analyses showed that the highest AUC values were observed for MMP-7, CA125, and HE4, in the whole group of patients and divided into stages I and II according to FIGO. Performing ROC analyses for groups III and IV according to FIGO was associated with an increase in AUC for the MMPs studied. Of the MMPs tested, MMP-7, MMP-26, and MMP-10 have the highest potential in diagnostics of serous ovarian cancer patients. Full article

Metalloproteinases (MMPs) play a significant role in cancer pathogenesis. We investigated the levels of MMP-7, MMP-26, MMP-3, and MMP-10 in comparison with the levels of a tumor marker (CA125) in the plasma of postmenopausal patients in early stages of endometrial cancer (EC) compared with control groups: patients with benign lesions (myoma uteri) and healthy controls. Plasma MMP levels were determined by ELISA and CA125 by CMIA methods. The study showed that plasma MMP-7 levels were significantly higher in EC patients compared to both control groups, whereas MMP-3 and MMP-26 levels were significantly higher in EC patients than in healthy women. MMP-7 showed the highest diagnostic sensitivity (SE), specificity (SP), positive (PPV) and negative predictive value (NPV), and diagnostic power (AUC) compared to other MMPs or CA125 in EC patients overall and patients with stage I and II EC. A combined analysis showed higher SE, NPV, and AUC levels in total EC patients and stage I and II EC patients—with the highest values for the combination MMP-7+CA125 (96%, 92%, 95%; 95%, 96%, and 98%; 0.9420, 0.9158, and 0.9693, respectively) or MMP-26 with CA125 (86%, 86%, and 86%; 59%, 73%, 73%; 0.8219, 0.8086, and 0.8353, respectively). The results suggest the usefulness of MMPs, especially MMP-7 and MMP-26, in combined panels with CA125 in diagnosing EC patients. Full article

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. Full article

Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes. Full article

Stromelysin-1 and stromelysin-2 (matrix metalloproteinase 3; MMP-3 and matrix metalloproteinase 10; MMP-10, respectively) are enzymes that activate other metalloproteinases. Apart from collagen, they also degrade elastin, fibronectin, gelatin and laminin. In carcinogenic processes, they are involved in angiogenesis and metastasis. Therefore, the aim of this study was to evaluate the DNA content, expression and activity of both stromelysines in cancers of human kidney. Renal carcinoma tissue samples were analyzed. Low- and high-grade cancer tissues were collected. Control material was collected from part of the kidney opposite to the tumor. DNA content, stromelysines content and stromelysin-1 and stromelysin-2 activity were measured using ELISA and Western blot methods. A higher content of deoxyribonucleic acid in low- and high-grade cancer tissues in comparison to the respective control tissue was observed. Both stromelysines were presented in control and cancer tissues in high-molecular-weight complexes. The content of MMP-10 was significantly higher in comparison to MMP-3 in all investigated tissues. Moreover, the content of stromelysin-2 was significantly higher in high-grade (G3) tissues compared to grade 2 (G2) kidney cancer. A significant decrease in the actual and specific activities of both stromelysines was observed with the increase in renal cancer grade. The presented results may indicate that the degradation of extracellular matrix increases with a higher grade of cancer. Moreover, the elevated content and decreased specific activity of stromelysin-2 in cancer tissue indicate that MMP-10 is mainly present in an inactive form in renal carcinoma. Detailed knowledge of the mechanism and participation of stromelysines in extracellular matrix degradation may be important in understanding the pathomechanism of renal cancer development. Therefore, the potential application of stromelysines in the monitoring or prognosis of kidney cancer should be discussed. Full article

Matrix metalloproteinase-9 (MMP9, gelatinase B) plays a key role in the degradation of extracellular-matrix (ECM) proteins in both normal physiology and multiple pathologies, including those linked with inflammation. MMP9 is excreted as an inactive proform (proMMP9) by multiple cells, and particularly neutrophils. The proenzyme undergoes subsequent processing to active forms, either enzymatically (e.g., via plasmin and stromelysin-1/MMP3), or via the oxidation of a cysteine residue in the prodomain (the “cysteine-switch”). Activated leukocytes, including neutrophils, generate O₂⁻ and H₂O₂ and release myeloperoxidase (MPO), which catalyzes hypochlorous acid (HOCl) formation. Here, we examine the reactivity of HOCl and a range of low-molecular-mass and protein chloramines with the pro- and activated forms of MMP9. HOCl and an enzymatic MPO/H₂O₂/Cl⁻ system were able to generate active MMP9, as determined by fluorescence-activity assays and gel zymography. The inactivation of active MMP9 also occurred at high HOCl concentrations. Low (nM—low μM) concentrations of chloramines formed by the reaction of HOCl with amino acids (taurine, lysine, histidine), serum albumin, ECM proteins (laminin and fibronectin) and basement membrane extracts (but not HEPES chloramines) also activate proMMP9. This activation is diminished by the competitive HOCl-reactive species, methionine. These data indicate that HOCl-mediated oxidation and MMP-mediated ECM degradation are synergistic and interdependent. As previous studies have shown that modified ECM proteins can also stimulate the cellular expression of MMP proteins, these processes may contribute to a vicious cycle of increasing ECM degradation during disease development. Full article

The atherosclerotic vascular disease is a cardiovascular continuum in which the main role is attributed to atherosclerosis, from its appearance to its associated complications. The increasing prevalence of cardiovascular risk factors, population ageing, and burden on both the economy and the healthcare system have led to the development of new diagnostic and therapeutic strategies in the field. The better understanding or discovery of new pathophysiological mechanisms and molecules modulating various signaling pathways involved in atherosclerosis have led to the development of potential new biomarkers, with key role in early, subclinical diagnosis. The evolution of technological processes in medicine has shifted the attention of researchers from the profiling of classical risk factors to the identification of new biomarkers such as midregional pro-adrenomedullin, midkine, stromelysin-2, pentraxin 3, inflammasomes, or endothelial cell-derived extracellular vesicles. These molecules are seen as future therapeutic targets associated with decreased morbidity and mortality through early diagnosis of atherosclerotic lesions and future research directions. Full article

Introduction: Periodontitis is characterized by the destruction of tooth-supporting tissues. Matrix metalloproteinases (MMPs) play a significant part in the degradation of collagen structure. The gingival crevicular fluid (GCF) levels of MMPs increase with the progression of periodontal inflammation. Polymorphisms can be responsible for high expression of MMPs and can exacerbate the breakdown of collagen structure. This study aims to investigate the effect of MMP-3 -1171 5A/6A polymorphism and the GCF levels of MMP-3 in a group of Turkish periodontitis patients. Materials and Methods: Non-smoking, stage II grade A periodontitis (S II-Gr A) (n = 68) and stage II grade B periodontitis (S II-Gr C) (n = 64) patients were recruited. Healthy individuals (H) (n = 72) without signs of gingivitis or periodontitis served as the control. Venous blood was collected from participants to obtain DNA, and the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method was used to detect polymorphism. GCF samples were taken to assess MMP-3 levels using an enzyme-linked immunosorbent assay (ELISA). Results: The MMP-3 -1179 5A/6A distribution showed no significant difference between the groups (p > 0.05). However, the MMP-3 GCF levels of the S II-Gr C group were higher than those of both the S II-Gr A and H groups (p < 0.05), and elevated MMP-3 levels were detected in S II-Gr A compared to H (p < 0.05). Conclusion: The MMP-3 GCF levels showed an association with periodontal tissue destruction, although single nucleotide polymorphism was not associated with the S II-Gr C and S II-Gr A groups in the Turkish population. Full article

Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful watch of FDA for a long time due to suspicion, that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking protocol to discern the potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >67,000 protein structures from the Protein Data Bank and examined. Several new potential protein targets with successfully docked troglitazone and rosiglitazone were identified. The focus was devoted to human proteins so that existing or new potential side effects could be explained or proposed. Certain targets of troglitazone such as 3-oxo-5-beta-steroid 4-dehydrogenase, neutrophil collagenase, stromelysin-1, and VLCAD were pinpointed, which could explain its hepatoxicity, with additional ones indicating that its application could lead to the treatment/development of cancer. Results for rosiglitazone discerned its interaction with members of the matrix metalloproteinase family, which could lead to cancer and neurodegenerative disorders. The concerning cardiovascular side effects of rosiglitazone could also be explained. We firmly believe that our results deepen the mechanistic understanding of the side effects of both drugs, and potentially with further development and research maybe even help to minimize them. On the other hand, the novel inverse molecular docking protocol on the other hand carries the potential to develop into a standard tool to predict possible cross-interactions of drug candidates potentially leading to adverse side effects. Full article

Background: Stromelysins are potential breast cancer biomarkers. The aim of the study was to evaluate if plasma levels of selected metalloproteinases (MMPs) (stromelysin-1 (MMP-3) and stromelysin-10 (MMP-10)) and cancer antigen 15-3 (CA 15-3) used separately and in combination demonstrated diagnostic usefulness in breast cancer (BC). Methods: The study group consisted of 120 patients with BC, while the control group included 40 patients with benign breast cancer and 40 healthy individuals. Concentrations of MMP-3 and MMP-10 were determined by enzyme-linked immunosorbent assay; CA 15-3 was determined by chemiluminescent microparticle immunoassay. Results: In the group of patients with BC, the area under the curve (AUC) was significantly higher for all markers (except MMP-3) and all sets of markers. At the earliest disease stage, only MMP-10 had a significantly higher AUC (AUC = 0.8692, p < 0.001). Moreover, MMP-10 had the highest AUC (0.9166) among parameters tested separately. The highest AUC was observed for the combination of MMP-10 + CA 15-3 and MMP-3 + MMP-10 + CA 15-3 in line with disease progression (stage I 0.8884 and 0.8906, stage II 0.9244 and 0.9308, stages III + IV 0.9919 and 0.9944, respectively, p < 0.001 in all cases). Conclusions: The results suggest that MMP-10 could be a potential marker in early stages of BC. Moreover, plasma concentration of MMP-10 and MMP-3 in combination with CA 15-3 may improve diagnosis of this type of cancer. Full article

The extracellular matrix (ECM) of the myotendinous junction (MTJ) undergoes dramatic physical and biochemical remodeling during the first 48 h of development in zebrafish, transforming from a rectangular fibronectin-dominated somite boundary to a chevron-shaped laminin-dominated MTJ. Matrix metalloproteinase 11 (Mmp11, a.k.a. Stromelysin-3) is both necessary and sufficient for the removal of fibronectin at the MTJ, but whether this protease acts directly on fibronectin and how its activity is regulated remain unknown. Using immunofluorescence, we show that both paralogues of Mmp11 accumulate at the MTJ during this time period, but with Mmp11a present early and later replaced by Mmp11b. Moreover, Mmp11a also accumulates intracellularly, associated with the Z-discs of sarcomeres within skeletal muscle cells. Using the epitope-mediated MMP activation (EMMA) assay, we show that despite having a weaker paired basic amino acid motif in its propeptide than Mmp11b, Mmp11a is activated by furin, but may also be activated by other mechanisms intracellularly. One or both paralogues of tissue inhibitors of metalloproteinase-4 (Timp4) are also present at the MTJ throughout this process, and yeast two-hybrid assays reveal distinct and specific interactions between various domains of these proteins. We propose a model in which Mmp11a activity is modulated (but not inhibited) by Timp4 during early MTJ remodeling, followed by a phase in which Mmp11b activity is both inhibited and spatially constrained by Timp4 in order to maintain the structural integrity of the mature MTJ. Full article

Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases with an extensive range of substrate specificities. Collectively, these enzymes are able to degrade various components of extracellular matrix (ECM) proteins. Based on their structure and substrate specificity, they can be categorized into five main subgroups, namely (1) collagenases (MMP-1, MMP-8 and MMP-13); (2) gelatinases (MMP-2 and MMP-9); (3) stromelysins (MMP-3, MMP-10 and MMP-11); (4) matrilysins (MMP-7 and MMP-26); and (5) membrane-type (MT) MMPs (MMP-14, MMP-15, and MMP-16). The alterations made to the ECM by MMPs might contribute in skin wrinkling, a characteristic of premature skin aging. In photocarcinogenesis, degradation of ECM is the initial step towards tumor cell invasion, to invade both the basement membrane and the surrounding stroma that mainly comprises fibrillar collagens. Additionally, MMPs are involved in angiogenesis, which promotes cancer cell growth and migration. In this review, we focus on the present knowledge about premature skin aging and skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, with our main focus on members of the MMP family and their functions. Full article

Cardiac disease in thalassemia is determined by the accumulation of iron in the tissue. Genetic factors could influence the severity and the rapidity of the modifications of the cardiac tissue. Mutations or polymorphisms of genes have already been described as being implicated in cardiac disease. In particular, we studied the polymorphisms C1091T in the Connexin 37 gene (CX 37), 4G -668 5G in the Plasminogen Activator Inhibitor-1 gene (PAI 1) and 5A-1171 6A in the Stromelysin-1 gene (SL) in 193 randomly selected patients affected by hemoglobinopathies and 100 normal subjects randomly selected from the general population. A retrospective analysis based on history, clinical data and imaging studies was carried out to assess the presence and type of heart disease. The results of our study do not demonstrate a close association between polymorphism in these candidate genes and cardiac disease, and in particular with myocardial infarction in a cohort of Sicilian patients affected by hemoglobinopathies.

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