Higher MMP-9 Research Articles

Mechanical Stress-Oxidative Stress Axis: Biological Basis in the Vaginal Wall and Pelvic Floor Muscles of Rats with Simulated Birth Injury.

Vaginal delivery and resulting pelvic floor muscle (PFM) dysfunction are significant risk factors for pelvic floor dysfunction (PFD). Despite this, the biological basis underlying PFD after childbirth remain unclear. This study was aimed at assessing the early response of the vaginal wall and PFM to simulated birth injury (SBI) in rats. Forty female Sprague-Dawley rats were divided into four groups: control (sham operation), and 1, 4, and 14days post-injury. In the SBI groups, a catheter was inserted into the vagina with 130g of weight attached to the end, and the balloon was inflated to 5ml for 2h. Evaluation of vaginal tissues and PFMs included histological, immunohistochemical, Western blot, and uniaxial biomechanical testing. In the vaginal wall, the SBI group showed significantly lower COL1A1 expression and higher MMP-2 and MMP-9 expression. At 4 and 14days post-injury, there was a significant decrease in PFM fiber area and increased collagen content. The SBI group also exhibited significant increases in the expression of Nrf2, NQO1, HO-1, and SOD-2, indicating involvement of oxidative stress in both the vaginal wall and PFMs. Protein expression of Pax7 and MyoG, as well as the number of fibers with centralized nuclei, continued to increase significantly after SBI. Additionally, the vaginal wall of the SBI group showed a decreasing trend in tensile strength and elastic modulus, with a greater ultimate strain. Extracellular matrix remodeling, oxidative stress, decreased biomechanical properties, and muscle dysmyogenesis may collectively contribute to increased susceptibility to PFD development.

Myristicin Inhibit Invasion and Migration of Melanoma Cells through Suppression of MMP2 and MMP9 Gene Expression

Melanoma is the deadliest type of skin cancer, having a high mortality rate. This cancer has an aggressive nature, is highly invasive, and has the tendency to metastasize. Matrix metalloproteinases (MMPs) are essential in that process, especially MMP2 and MMP9. Their expression is upregulated during metastasis progression. Myristicin is one example of a compound that can be utilized to target MMP 2 and MMP 9 in melanoma. This research concerns the activity of myristicin to inhibit melanoma cell invasion and migration by suppressing MMP2 and MMP9 gene expression. The MTT assay in this study demonstrated that myristicin exhibited strong cytotoxic activity against melanoma cells. This compound works in a dose-dependent manner by inhibiting cell migration and invasion. The invasion test was performed using the transwell assay, whereas the migration test was performed using the wound healing assay. The invasion assay results were consistent with MMP2 and MMP9 gene expression. These two genes were analyzed using the RT-qPCR technique. It has been demonstrated that low gene expression in melanoma cells inhibits cell invasion. In contrast, higher MMP2 and MMP9 gene expression was associated with an increase in the number of invasive cells on average. However, MMP2 and MMP9 in excessive expression and uncontrolled activity impair the ability of melanoma cells to form a monolayer sheet to cover wound gaps. This condition significantly reduced the migration rate and percentage of wound closure.

Inhibition of osteosarcoma metastasis in vivo by targeted downregulation of MMP1 and MMP9

Osteosarcoma (OS) mortality stems from lung metastases. Matrix metalloproteinases (MMPs) facilitate metastatic dissemination by degrading extracellular matrix components. Herein we studied the impact of targeted MMP downregulation on OS metastasis. Differential gene expression analysis of human OS cell lines revealed high MMP9 expression in the majority of OS cell lines. Furthermore, 143B, a metastatic OS cell line, exhibited increased MMP1 and MMP9 mRNA levels. Gene set enrichment analysis on metastatic and non-metastatic OS patient specimens indicated epithelial-mesenchymal transition as the most enriched gene set, with MMP9 displaying strong association to genes in this network. Using the same dataset, Kaplan-Meier analysis revealed a correlation between MMP1 expression and dismal patient survival. Hence, we undertook targeted suppression of MMP1 and MMP9 gene expression in OS cell lines. The ability of OS cells to migrate and form colonies was markedly reduced upon MMP1 and MMP9 downregulation, whereas their cell proliferation capacity remained intact. MMP9 downregulation decreased tumor growth and lung metastases area in an orthotopic mouse OS model. Consistently, human OS lung metastasis specimens displayed marked MMP9 protein expression. Our findings highlight the role of MMP1 and MMP9 in OS metastasis, warranting further exploration of simultaneous inhibition of MMPs for future OS therapeutics.

Copper metabolism–related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer

ObjectivesTo comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism. MethodsCopper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays. ResultsFour copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration. ConclusionThe identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

Expression of Hormones' Receptors in Human Corneal Endothelium from Fuchs' Dystrophy: A Possible Gender' Association.

Background: Age and sex are the most significant risk of factors for advanced Fuchs dystrophy. Nevertheless, few data are available on the hormone's receptor pattern expressed in adult and advanced fuchs endothelial corneal dystrophy (FECD). We investigated the impact of gender, growth factors and extracellular matrix (ECM) regulatory proteins expressed by the dystrophic endothelia. Methods: Ten dystrophic endothelial tissues and 10 normal endothelial sheets (corneoscleral specimens; Eye Bank) were used for this characterization study. Hormones' receptors (ERα, AR, PR, SHBG), few growth factors (VEGFA, βNGF, TGFβ1), some ECM regulators (MMP1, MMP7) and few inflammatory cytokines (IFNγ, IL10) were analyzed by real-time RT-PCR. Results: ERα transcripts were significantly increased, AR and SHBG transcripts were decreased in Fuchs endothelia from female patients, and no changes were detected for PR transcripts. VEGFA, βNGF and TGFβ1 transcripts were upregulated in Fuchs' endothelia, but not significantly linked to gender. High MMP1 and low MMP7 transcripts' expression were detected in Fuchs' specimens, mainly in males than females. An increased IFNγ (Th1) transcript expression was observed in females than males, and a trend to increase for IL10 (Th2) transcripts was detected in males than females. Conclusions: Our findings clearly indicate that hormone receptors, growth factors and matrix mediators as well as a Th1 pathway are predominant in Fuchs' dystrophy, displaying a pattern of expression specific for the female phenotype. The differential expression of hormones' receptors and the Th1/Th2 ratio might prompt to new theories to be tested in vitro and in vivo models, such as the use of hormonal substitute for counteracting this endothelial cell lost.

- Correlation between dental fluorosis risk and bone specific alkaline phosphatase, osteocalcin, matrix metalloproteinase and parathyroid hormone in children

Objective Investigating the association between dental fluorosis occurrence in children and bone metabolism-related indicators including bone-specific alkaline phosphatase (BALP), osteocalcin (OC), matrix metalloproteinase (MMP-2, MMP-9, MMP-20), and parathyroid hormone (PTH).Methods A total of 189 cases of school-age children underwent health examinations in our hospital were enrolled, according to the presence or absence of dental fluorosis, they were divided into fluorosis group (n=97) and fluoride-free group (n=92), and the serum BALP, OC, MMP-2, MMP-9, MMP-20, and PTH levels of the two groups were compared, relevant clinical data were collected.In this study, multivariate logistic regression was employed to examine the factors associated with the development of dental fluorosis in children. Results The urine fluoride levels, BALP, MMP-2, and MMP-9 of the children influorosis group were higher thanfluoride-free group, and the mother's educational level, per capita annual household income, OC, and PTH were lower thanfluoride-free group (P<0.05).Based on Spearman correlation analysis, a positive correlation was identified between the urinary fluoride level, the extent of dental fluorosis, and indicators such as BALP, MMP-2, and MMP-9. (r=0.618, 0.558, 0.567, 0.597, 0.602, 0.571, P<0.001), and negatively correlated with OC and PTH (r=-0.580, -0.603, -0.549, -0.515, P<0.001).As the urinary fluoride level and the extent of dental fluorosis increased, there was a gradual elevation in serum BALP, MMP-2, and MMP-9 levels in children, while OC and PTH levels gradually decreased (P<0.05).After adjusting for confounding factors including urinary fluoride,maternal education level, and per capita annual household income, multivariate Logistic regression analysis showed that BALP, OC, MMP-2, MMP-9, PTH were independently associated with the risk of dental fluorosis (P<0.05). Conclusion High BALP, MMP-2, MMP-9, low OC, and PTH are independent factors affecting the occurrence of dental fluorosis and are related tothe extent of dental fluorosis.

Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD

There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na+/K+-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPD in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPD in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPD overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPD-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder.

Machine learning application identifies plasma markers for proteinuria in metastatic colorectal cancer patients treated with Bevacizumab.

Proteinuria is a common complication after the application of bevacizumab therapy in patients with metastatic colorectal cancer, and severe proteinuria can lead to discontinuation of the drug. There is a lack of sophisticated means to predict bevacizumab-induced proteinuria, so the present study aims to predict bevacizumab-induced proteinuria using peripheral venous blood samples. A total of 122 subjects were enrolled and underwent pre-treatment plasma markers, and we followed them for six months with proteinuria as the endpoint event. We then analyzed the clinical features and plasma markers for grade ≥ 2 proteinuria occurrence using machine learning to construct a model with predictive utility. One hundred sixteen subjects were included in the statistical analysis. We found that high baseline systolic blood pressure, low baseline HGF, high baseline ET1, high baseline MMP2, and high baseline ACE1 were risk factors for the development of grade ≥ 2 proteinuria in patients with metastatic colorectal cancer who received bevacizumab. Then, we constructed a support vector machine model with a sensitivity of 0.889, a specificity of 0.918, a precision of 0.615, and an F1 score of 0.727. We constructed a machine learning model for predicting grade ≥ 2 bevacizumab-induced proteinuria, which may provide proteinuria risk assessment for applying bevacizumab in patients with metastatic colorectal cancer.

Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction.

Studies have shown that neutrophil-mediated formation of neutrophil extracellular traps (NETs) leads to increased inflammatory response and cellular tissue damage during myocardial infarction (MI). We aimed to identify and validate possible hub genes in the process of NETs-mediated cell damage. We performed an immune cell infiltration analysis of the MI transcriptome dataset based on CIBERSORT and ssGSEA algorithms. Gene expression profiles of NETs formation (GSE178883) were used to analyze the physiological processes of peripheral blood neutrophils after phorbol myristate acetate (PMA) stimulation. Bioinformatics and machine learning algorithms were utilized to find candidate hub genes based on NETs-related genes and transcriptome datasets (GSE66360 and GSE179828). We generated the receiver operating curve (ROC) to evaluate the diagnostic value of hub genes. Next, the correlation between hub genes and immune cells was analyzed using CIBERSORT, ssGSEA and xCell algorithms. Finally, we used quantitative real-time PCR (qRT-PCR) and immunohistochemistry to verify gene expression. Immune cell infiltration analysis revealed that inflammatory cells such as neutrophils were highly expressed in the peripheral blood of patients with MI. Functional analysis of differentially expressed genes (DEGs) in GSE178883 indicated that the potential pathogenesis lies in immune terms. Using weighted gene co-expression network analysis (WGCNA) and machine learning algorithms, we finally identified the seven hub genes (FCAR, IL1B, MMP9, NFIL3, CXCL2, ICAM1, and ZFP36). The qRT-PCR results showed that IL-1B, MMP9, and NFIL3 mRNA expression was up-regulated in the MI group compared to the control. Immunohistochemical results showed high MMP9, IL-1B, and NFIL3 expression in the infarcted area compared to the non-infarcted area and sham-operated groups. We identified seven hub genes associated with NETs-mediated cellular damage during MI. Our results may provide insights into the mechanisms of neutrophil-mediated cell injury during MI.

P126 Differential granulocyte populations as therapeutic targets in fistula

Abstract Background Despite the recent increase in therapeutic options in IBD care, treatment of perianal disease and in particular fistula remains highly challenging. Specific targeted medical therapy is not currently available, and a majority of patients fails to respond to surgical intervention. In contrast, cryptoglandular fistula show much higher response rates with closure in up to 80-90% of patients. Interestingly, the most present cell type in fistula, the granulocyte, is also the least studied due to their fragile nature. To fill this void, we evaluated granulocytes in perianal fistula and those present in the blood. Methods Curettage material of 18 fistula (Crohn n=15 and cryptoglandular n=5) was obtained and processed by mass cytometry. Two additional samples were obtained (1 Crohn, 1 cryptoglandular) together with matching blood samples and assessed by single cell RNASeq. Results As expected, granulocytes formed the majority of all cells in all fistula (mean 64%). Cryptoglandular fistula displayed significantly more granulocytes than Crohn’s related fistula. Single cell analysis showed 4 subsets: Subset 1 was the main subset in blood, and expressed high levels of LAMTOR4. Interestingly, although found both in blood and fistula, abundance was much higher in blood (80 vs 10%) and signaling cascades differed. In blood, activity was associated with degranulation, IL8 activity and migration. In fistula, a very strong IFNa/b signature was present. Subset 2 expressed high MMP9, and showed degranulating activity. Subsets 3 and 4 were almost exclusively found in the fistula tracts, and were defined by expression of PI3 and LRG1 respectively. Pathway analysis showed the PI3+ population to have strong cytokine signaling but little degranulating or migratory activity. Conversely, the LRG1+ population showed little cytokine activity, but stronger degranulating activity and integrin signaling. The two populations also expressed distinctive chemokine receptors, with PI3+ cells expressing high levels of CXCR4, while LRG1+ express CXC1 and CXCR2, suggesting differntial recruiment and potential modulation. In that light, it is interesting to note the proportion of PI3+ and LRG1+ cells differed between patients, with the majority of Crohn derived cells being PI3+ while the cryptoglandular fistula mainly contained LRG1+ cells. Conclusion Granulocytes form the main cellular component of fistula tracts in both Crohn and cryptoglandular fistula. Four different subsets of granulocytes could be identified, of which the two main subtypes in fistula tracts appear to differ significantly both in phenotype, activity and method of recruitment. This data may be a starting point for specific interventions in this highly abundant but often overlooked cell type.

MMP-9 EXPRESSION IN ORAL SQUAMOUS CELL CARCINOMA USING IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION TECHNIQUES

Research into matrix-metalloproteinases (MMP) and their inhibition in certain cancers has moved significantly, studies on MMP expression in oral squamous cell carcinoma (OSCC) remains scarce. MMP-9, a gelatinase-degrading enzyme, destroys matrix proteins in gingivitis and adult periodontitis. MMP-9 genetic (mRNA) and protein profiles were examined to determine MMP-9 expression in oral cancer in this study. Our gender findings indicate that the majority of patients were males and consumers of various tobacco forms.The buccal mucosa was involved in 52% of OSCCs, followed by the tongue (33%), and the gingivobuccal sulcus (9%).The levels of MMP-9 detected in OSCC grades were higher than controls in the order of well-, followed by moderately- and lastly poorly-differentiated grades.Immunohistochemistryseemed to be a reliable approach for measuring MMP-9 expression in OSCC samples when compared to RT-qPCR and western blotting. The association of high MMP-9 levels with well-differentiated OSCC grade implies its potential as a biomarker for early detection of OSCC which could lead to the development of early OSCC treatments. More studies with larger samples might aid in the evaluation of the techniques used.

Lung and blood perioperative metalloproteinases in patients undergoing oncologic lung surgery: Prognostic implications.

Metalloproteinases (MMPs) have been reported to be related to oncologic outcomes. The main goal of the study was to study the relationship between these proteins and the long-term prognosis of patients undergoing oncologic lung resection surgery. This was a substudy of the phase IV randomized control trial (NCT02168751). We analyzed MMP-2, -3, -7, and -9 in blood samples and bronchoalveolar lavage (LBA) and the relationship between MMPs and long postoperative outcomes (survival and disease-free time of oncologic recurrence). Survival was longer in patients who had lower MMP-2 levels than those with higher MMP-2 in blood samples taken 6 h after surgery (6.8 vs. 5.22 years; p = 0.012) and MMP-3 (6.82 vs. 5.35 years; p = 0.03). In contrast, survival was longer when MMP-3 levels were higher in LBA from oncologic lung patients than those with lower MMP-3 (7.96 vs. 6.02 years; p = 0.005). Recurrence-free time was longer in patients who had lower MMP-3 levels in blood samples versus higher (5.97 vs. 4.23 years; p = 0.034) as well as lower MMP-7 (5.96 vs. 4.5 years; p = 0.041) or lower MMP-9 in LBA samples (6.21 vs. 4.18 years; p = 0.012). MMPs were monitored during the perioperative period of oncologic lung resection surgery. These biomarkers were associated with mortality and recurrence-free time. The role of the different MMPs analyzed during the study do not have the same prognostic implications after this kind of surgery.

Matrix metalloproteinase MMP-7 as a new prognostic biomarker for gastric cancer

BACKGROUND: According to statistics, gastric cancer is in a leading position among all gastrointestinal cancers. The most effective treatment for gastric cancer is surgery. There are now heterogeneous clinical outcomes for patients in the same stage of the disease. The main reason for this is the fact that differences in types of gastric cancer occur not only at the histological level, but also at the molecular level. Finding the universal biomarkers that can provide information about patient prognosis is a subject of interest to scientists around the world. MMP-7 is the smallest molecule in the family of matrix metalloproteinases that contributes significantly to oncogenesis by affecting apoptosis and degradation of the extracellular matrix. MMP-7 hyperexpression is associated with aggressive tumor phenotype and worsens prognosis in patients with gastric cancer. Therefore, MMP-7 can be a promising biomarker in the treatment of gastric cancer.
 AIM: To identify possible correlations between the expression of MMP-7 in patients with gastric cancer and their prognosis.
 MATERIALS AND METHODS: The study included samples of 80 patients diagnosed with diffuse gastric cancer, who were selected based on our inclusion and exclusion criteria. 30 sectional stomach samples were taken as a comparison group. Of the 80 patients included in the study, gastrectomy was performed in 55% cases (44 people) and gastric resection was performed in 45% cases (36 people).
 RESULTS: In our work, the expression level of MMP-7 0.8±0.07 was indicated as high, and the expression rate of 0.40±0.067 as low. During the study, we assessed the link between the level of MMP-7 expression and the clinical characteristics of the tumor. We evaluated the following indicators: the disease stage, the presence of lesions of lymph nodes, the size of the tumor. Patients with increased MMP-7 expression in tumor tissue have a better prognosis than patients with low MMP-7 expression.
 CONCLUSION: The results of our study showed high MMP-7 expression in tumor tissue, which allowed us to establish a correlation between MMP-7 expression and adverse clinical outcomes. The data obtained may indicate the possible use of MMP-7 as a biomarker for gastric cancer.

Resistin Induces Migration and Invasion in PC3 Prostate Cancer Cells: Role of Extracellular Vesicles.

Resistin is an adipokine with metabolic and inflammatory functions. Epidemiological and translational studies report that an increase in plasma levels and tissue expression of resistin increases the aggressiveness of prostate tumor cells. Extracellular vesicles (EVs) are secreted constitutively and induced by cytokines, growth factors, and calcium and are found in multiple biological fluids such as saliva, serum, semen, and urine. In particular, EVs have been shown to promote tumor progression through the induction of proliferation, growth, angiogenesis, resistance to chemotherapy, and metastasis. However, the role of resistin in the migration, invasion, and secretion of EVs in invasive prostate tumor cells remains to be studied. In the present study, we demonstrate that resistin induces increased migration and invasion in PC3 cells. In addition, these phenomena are accompanied by increased p-FAK levels and increased secretion of MMP-2 and MMP-9 in resistin-treated PC3 cells. Interestingly, EVs isolated from supernatants of PC3 cells treated with resistin induce an increase in migration and invasion accompanied by high MMP-2 and MMP-9 secretion in an autocrine stimulation model. In summary, our data for the first time demonstrate that resistin induces migration and invasion, partly through the secretion of EVs with pro-invasive characteristics in PC3 cells.

Effect of SARS-CoV-2 Infection and BNT162b2 Vaccination on the mRNA Expression of Genes Associated with Angiogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovered in December 2019 in Wuhan, China, caused the coronavirus disease 2019 (COVID-19). Due to the rate of spread of this virus, the World Health Organization, in March 2020, recognised COVID-19 as a worldwide pandemic. The disease is multisystemic with varying degrees of severity. Unfortunately, despite intensive research, the molecular changes caused by SARS-CoV-2 remain unclear. Mechanisms affected by the virus infection include endothelial dysfunction and angiogenesis. Similarly, the vaccines developed so far affect the process of angiogenesis, contributing to the development of undesirable effects on part of the cardiovascular system. The presented research aimed to investigate the impact of the SARS-CoV-2 infection and the Pfizer Comirnaty vaccine (BNT162b2) on the molecular aspect of angiogenesis. We found that convalescents vaccinated with one dose of BNT162b2 were characterised by higher MMP-7 (metalloproteinases 7) expression than non-vaccinated convalescents and healthy volunteers vaccinated with one dose of BNT162b2. Moreover, non-vaccinated convalescents showed increased mRNA expression of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1) compared to healthy volunteers vaccinated with one dose of BNT162b2. In addition, we showed significant sex differences in the expression of MMP-7. In conclusion, the results of our study suggest a significant impact of SARS-CoV-2 infection and vaccination on the course of angiogenesis at the molecular level.

The Role of Matrix Metalloproteinase 13 and Vitamin D in Osteoarthritis: A Hospital-Based Observational Study.

Introduction Osteoarthritis (OA) is the most common form of degenerative joint disease characterized by the progressive degeneration of articular cartilage, osteophyte formation, and joint space narrowing. Matrix metalloproteinases (MMPs) are potential biomarkers for osteoarthritis. Aims and objective The study's aim is the estimation of serum and synovial fluid matrix metalloproteinase (MMP) 13 and serum vitamin D levels in the grade 3 and grade 4 stages of osteoarthritis according to the Kellgren and Lawrence (KL) system of classification. Materials and methods A total of 100 subjects were included; of them, 25 patients with grade 3 and 25 patients with grade 4 knee osteoarthritis diagnosed clinically and radiologically according to the Kellgren and Lawrence criteria have been enrolled in the study, and 50 patients with knee pain having a diagnosis other than degenerative OA of the knee were taken as controls. Venous blood and synovial fluid have been collected from all of them for the estimation of MMP-13 and vitamin D. The enzyme-linked immunosorbent assay (ELISA) and chemiluminescent microparticle immunoassay (CMIA) methods were used for the estimation of MMP-13 and vitamin D, respectively. Results The mean value of synovial fluid MMP-13 was found to be elevated in grade 4 as compared to grade 3 and the control group, whereas the mean value of serum MMP-13 was found to be elevated in grade 3 as compared to grade 4 and control. The level of serum vitamin D was found deficient in OA patients as compared to control. The Kruskal-Wallis test was performed to compare these groups, and there was a significant difference between these groups(p-value of <0.05). Summary and conclusion High synovial and serum MMP-13 is associated with knee structural abnormalities in patients with knee OA as compared to the control groupsuggesting that MMP-13 can be a biomarker in knee OA, whereas the decreased level of vitamin D may be associated with an increased risk for the progression of OA; hence, serum vitamin D may be a good indicator for the prediction of the initiation of OA.

Galectin-3 and matrix metalloproteinases 2 and 9 in peripheral blood of gastric cancer patients

Background: High incidence of gastric cancer (GC), its aggressive clinical course, rapid tumor dissemination, low sensitivity to chemotherapy and lack of reliable laboratory diagnostic criteria urgently require a search for the most informative markers associated with key biologic properties of the tumors.&#x0D; Aim: Comparative analysis of galectin-3, matrix metalloproteinase (MMP)-2, and MMP-9 levels in peripheral blood of GC patients and healthy donors, assessment of association of these markers with clinical morphological characteristics of the disease, and prognosis of overall and relapse-free survival.&#x0D; Materials and methods: Sixty (60) primary treatment-nave GC patients (38 men, 22 women) aged 29 to 81 years and 90 healthy donors compatible with their age and sex were included into the study. Galectin-3 was measured in EDTA plasma, MMP-2 and MMP-9 in serum with standard direct enzyme immunoassay kits "Human MMP-2 (total)", "Human MMP-9 (total)", "Human Galectin-3" (RD Systems, USA).&#x0D; Results: Plasma galectin-3 concentration in the GC patients was significantly higher than in the healthy controls (median 12.9 and 10.6 ng/ml, respectively; p 0.0001). No difference in serum MMP-9 levels between GC patients and control subjects were found, while MMP-2 level in the control group was significantly higher, than in the GC patients (p = 0.039). No association between galectin-3, MMP-2, and MMP-9 blood levels in the GC patients could be identified. In contrast to GC patients, there was a positive correlation of plasma galectin-3 with age in the control group (rs = 0.51, p 0.005). No associations between the biomarkers levels in blood and clinical and morphological characteristics of GC were established, except MMP-9 being higher at Т4а invasion depth as compared to the earlier Т2 level. Marked differences in the overall survival depending on plasma galectin-3 levels were found, with the cut-off level of 12.9 ng/ml: the 5-year overall survival in the patients with low galectin-3 was better, than in those with its higher level (50 and 43%, respectively; however, the difference was non-significant, р 0.1). Both overall and relapse-free survival of the GC patients was higher in those with low ( 212 ng/ml) serum MMP-2: the 5-year overall survival in this group comprised 60% versus 23% in the patients with higher MMP-2 (p = 0.018). The difference in relapse-free survival was non-significant. Serum MMP-9 levels had no significant impact on the survival of GC patients.&#x0D; Conclusion: The ambiguous data on the clinical role of galectin-3, MMP-2, MMP-9 in GC obtained in this study indicate the necessity of further investigation of their possible utility for the diagnostics and prognosis of treatment results.

MMP2 is a immunotherapy related biomarker and correlated with cancer-associated fibroblasts infiltrate in melanoma

BackgroundMounting evidence supports that matrix metalloproteinase (MMPs) are highly associated with tumor progression and that targeting MMPs may overcome the barrier of immune suppression. Among these, whether MMP2 functions as an immunosuppressive role in melanoma, remains unclear.MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the prognosis of MMP2 in melanoma, after which Tumor immune estimation resource (TIMER) was used to explore the relationship between MMP2 expression and cancer associated fibroblasts (CAFs) infiltration. Finally, we evaluated the efficacy of MMP2 inhibitor on CAFs infiltration and immunotherapy using a mouse melanoma model.ResultsIn general, the expression of MMP2, MMP13, MMP16, MMP17 and MMP25 were significantly associated with skin cutaneous melanoma (SKCM) patients prognosis, among which MMP2 low expression benefited patients the most. Especially, the overall survival (OS) of BRAF mutation patients with high MMP2 expression was significantly lower than the MMP2 low expression group, but there was no significant difference in BRAF wild-type patients. KEGG and GO enrichment analysis indicated that MMP2 related genes were mostly associated with extracellular structure organization, collagen-containing extracellular matrix and extracellular matrix structural constituent. Furthermore, in almost all cancers, MMP2 expression was positively correlated with CAFs infiltration. MMP2 inhibitor works synergistically with PD-1 antibody and induces tumor regression in a mouse melanoma model, which is dependent on decreased CAFs infiltration.ConclusionsThis suggests that MMP2 plays a vital role in the regulation of CAFs infiltration, potentially participating in immunotherapy response, and thus representing a valuable target of immunotherapy in melanoma.

Comparison of circulating matrix metalloproteinase-2 levels in untreated acute myeloid leukemia patients with remission status

BACKGROUND: Matrix metalloproteinases (MMPs) are proteases responsible for cleaving and rebuilding connective tissue components and also affect early carcinogenesis events, tumor development, growth, and neovascularization. The study aimed to evaluate the level of MMP-2 in acute myeloid leukemia (AML) patients in comparison with that in remission status, and healthy subjects, and to find its correlation with hematologic parameters.PATIENTS, MATERIALS, AND METHODS: This study included sixty newly diagnosed AML patients. Remission status was assessed after induction chemotherapy. The overall survival (OS) was determined after 6 months. The plasma MMP-2 level was measured at diagnosis by enzyme immunoassay. Twenty-eight healthy individuals were recruited as a control group.RESULTS: Plasma MMP-2 was higher in AML patients than in healthy individuals (P = 0.005). The level of MMP-2 was much higher in the M5 subtype than in the other subtypes (P = 0.0001). There was no statistically significant difference in the level of MMP-2 between patients who achieved complete remission and those who did not (P = 0.113). After 6 months, no significant difference in the initial MMP-2 levels was found between deceased and alive patients (P = 0.174). A positive correlation of MMP-2 level was found with white blood cell (WBC) count and hemoglobin (P = 0.0001 and 0.033, respectively) while insignificant with age, platelet count, and blast counts.CONCLUSIONS: The high MMP-2 level in AML patients suggests a possible role in the pathogenesis. However, it does not show any association with remission status or OS. The elevation was significantly associated with marrow monocytosis (M5) and correlated with a higher WBC count.

TNF-induced metalloproteinase-9 production is associated with neurological manifestations in HTLV-1-infected individuals.

HTLV-1-infected individuals may develop a neurologic inflammatory condition known as HTLV-1-associated myelopathy (HAM/TSP), in which the high production of TNF is observed. These patients exhibit higher proviral loads, enhanced production of proinflammatory cytokines and lymphocyte proliferation in comparison to asymptomatic HTLV-1 carriers and those presenting overactive bladder (OAB-HTLV-infected). Metalloproteinases (MMPs) are known to degrade the components of the blood-brain barrier, favoring the migration of infected cells into the central nervous system. Moreover, the unbalanced production of MMPs and their inhibitors (TIMPs) has also been associated with tissue damage. The present work studied the production of MMP-9 and TIMPs in HTLV-1-infected individuals with and without neurological manifestations. HAM/TSP patients presented higher concentrations of MMP-9 in peripheral blood mononuclear cell (PBMC) culture supernatants, as well as a higher MMP-9/TIMP-3 ratio when compared to the other groups studied. MMP-9 levels positively correlated with proviral load and TNF in OAB-HTLV-infected individuals, and the in vitro neutralization of TNF significantly decreased MMP-9 levels in PBMC culture supernatants. Our findings indicate an association between MMP-9 production and the proinflammatory state associated with HTLV-1 infection, as well as HAM/TSP.