Prognostic value of matrix metalloproteinase-2 protein and matrix metalloproteinase-9 protein in colorectal cancer: a meta-analysis.

INTRODUCTION: Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are critical components of the extracellular matrix (ECM) in colorectal cancer (CRC). We aimed to evaluate the prognostic value of MMP-2 and MMP-9 in patients with CRC. METHODS: We performed a meta-analysis of cohort studies with available data on the effect of MMP-2 and MMP-9 expression on both disease-free survival (DFS) and overall survival (OS) by the risk ratios (RRs) with their 95% confidence intervals (CIs). Studies were subgrouped based on the different tissue types, including cancer tissue and normal tissue, and the subgroup effect of MMP expression in different tissues was analyzed through meta-regression. To ensure the quality and reduce the risk of bias, the Newcastle‒Ottawa Scale (NOS) was used to assess the included studies. A sensitivity analysis was randomly performed to assess the potential impact of each study on our results. RESULTS: Eighteen trials were selected (Table 1) and included a total of 3944 patients. According to our primary meta-analysis, the expression of MMP-2 was significantly associated with a decrease in OS (RR = 1.75, 95% CI = 1.34 to 2.29, P < 0.001) and DFS (RR = 2.62, 95% CI = 1.25 to 5.49, P < 0.001), and the expression of MMP-9 was not significantly associated with a decrease in OS (RR = 1.48, 95% CI = 0.97 to 2.24, P = 0.069) or DFS (RR = 1.60, 95% CI = 0.87 to 2.94, P = 0.133). According to the subgroup analysis of MMPs in different tissues, high MMP-2 expression in cancer tissue (RR = 1.90, 95% CI = 1.29 to 2.79) and normal tissue (RR = 1.59, 95% CI = 1.17 to 2.17) were significant indicators of poor OS. High MMP-2 expression in cancer tissue was significant indicator of poor DFS (RR = 2.12, 95% CI = 1.09 to 4.11). MMP-9 expression was also associated with poor OS (RR = 1.40, 95% CI = 0.85 to 2.29), but the difference in OS between the high and low expression groups was not statistically significant. CONCLUSIONS: High MMP-2 expression, especially in cancer tissue, is significantly associated with both poor DFS and poor OS in patients with CRC. High MMP-9 expression tended to indicate a poor prognosis of CRC but the correlation was not significant.

Significance of Fibrillin-1, Filamin A, MMP2 and SOX9 in Mitral Valve Pathology.

Genetic factors play a significant role in the pathogenesis of mitral valve diseases, including mitral valve prolapse (MVP) and mitral valve regurgitation. Genes like Fibrillin-1 (FBN1), Filamin A (FLNA), matrix metalloproteinase 2 (MMP2), and SRY-box transcription factor 9 (SOX9) are known to influence mitral valve pathology but knowledge of the exact mechanism is far from clear. Data regarding serum parameters, transesophageal echocardiography, and genetic and histopathologic parameters were investigated in 54 patients who underwent cardiovascular surgery for mitral valve regurgitation. The possible association between Fibrillin-1, Filamin A, MMP2, and SOX9 gene expressions was checked in relationship with the parameters of systemic inflammatory response. The mRNA expression levels (RQ-relative quantification) were categorized into three distinct groups: low (RQ < 1), medium/normal (RQ = 1-2), and high (RQ > 2). Severe fibrosis of the mitral valve was reflected by high expression of FBN1 and low expression of MMP2 (p < 0.05). The myxoid degeneration level was associated with the mRNA expression level for FBN1 and a low lymphocyte-monocyte ratio was associated with an increased mRNA expression of FBN1 (p < 0.05). A high number of monocytes was associated with high values of FBN1 whereas the increase in the number of lymphocytes was associated with high levels of MMP2. In addition, we observed that the risk of severe hyalinization was enhanced by a low mRNA expression of FLNA and/or SOX9. In conclusion, a lower FLNA mRNA expression can reflect the aging process that is highlighted in mitral valve pathology as a higher risk for hyalinization, especially in males, that might be prevented by upregulation of the SOX9 gene. FBN1 and MMP2 influence the inflammation-related fibrotic degeneration of the mitral valve. Understanding the genetic base of mitral valve pathology can provide insights into disease mechanisms, risk stratification, and potential therapeutic targets.

Pro-Inflammatory Adipokine and Cytokine Profiles in the Saliva of Obese Patients with Non-Alcoholic Fatty Liver Disease (NAFLD)-A Pilot Study.

Undiagnosed and untreated non-alcoholic fatty liver disease (NAFLD) can lead to the development of many complications, such as cirrhosis, hepatocellular carcinoma, or cardiovascular diseases. Obese people are at increased risk of developing NAFLD. Due to the current lack of routine diagnostics, it is extremely important to look for new diagnostic methods and markers for this disease. The aim of this study was to assess the concentration of selected pro-inflammatory adipokines and cytokines in the unstimulated saliva of obese people with fatty liver disease in various stages (with or without slight fibrosis) and to analyze them for possible use as early markers of NAFLD diagnosis. The study involved 96 people who were divided into 5 groups based on the criterion of body mass index (BMI) and the degree of fatty liver (liver elastography). There were statistically significant differences between the groups in the concentrations of MMP-9 (matrix metalloproteinase 9), resistin, and IL-1ß (interleukin 1ß) in saliva. Statistically significant, positive correlations between hepatic steatosis and the concentration of MMP-2 (matrix metalloproteinase 2), resistin, and IL-1ß in saliva were also found. Statistically significant positive correlations were also found between the concentration of resistin in saliva and the concentration of ALT (alanine aminotransferase) and GGTP (gamma-glutamyl transpeptidase) in serum. MMP-2, IL-1ß, and resistin may be potential markers of NAFLD development, assessed in saliva. However, further research is needed because this is the first study to evaluate the concentrations of the selected pro-inflammatory parameters in the saliva of patients with NAFLD.

The Influence of New Silicate Cement Mineral Trioxide Aggregate (MTA Repair HP) on Metalloproteinase MMP-2 and MMP-9 Expression in Cultured THP-1 Macrophages.

The aim of the present study was to investigate the new silicate cement mineral trioxide aggregate (MTA Repair HP) with respect to its effect on the inflammation process involving the tooth and periodontal tissues. The composition of MTA Repair HP was supplemented with plasticizer agents which can have a negative effect on the modulation of tooth inflammation. The silicate-based material in question is widely used in regeneration of the pulp-dentin complex, treatment of perforations of various locations in the tooth, as well as in surgical treatment of the complications of periapical tissue. The improved bioceramic restorative cement can affect the expression of metalloproteinases MMP-2 and MMP-9 in monocytes/macrophages involved in modulation of inflammation and regenerative processes of the tooth and periodontal tissues. The novel aspect of the present study lies in the application of the model of THP-1 monocyte/macrophage and applying the biomaterial in direct contact with the cells. Hence, it provides a representation of clinical conditions with respect to regenerative pulp and periodontal treatment with the use of MTA Repair HP. A lack of macrophage activation (as measured with flow cytometry) was found. Moreover, the study identified a lack of expression stimulation of the studied metalloproteinases (with the use of Western blotting and fluorescent microscopy). Similarly, no increase in MMP-2 and MMP-9 concentration was found (measured by ELISA method) in vitro when incubated with MTA Repair HP. Based on the results it can be concluded that new MTA Repair HP does not increase the inflammatory response in monocytes/macrophages associated with the activity of the described enzymes. It can also be speculated that they do not affect the process of dentin regeneration in which MMP-2 and MMP-9 play significant roles.

MED28 and forkhead box M1 (FOXM1) mediate matrix metalloproteinase 2 (MMP2)-dependent cellular migration in human nonsmall cell lung cancer (NSCLC) cells.

Non-small-cell lung cancer (NSCLC) accounts for the majority of the lung cancer cases that have become a leading cause of cancer deaths worldwide. Overexpression of transcription factor forkhead box M1 (FOXM1) is involved in the inauspicious development of several types of cancer, including lung tumor aggressiveness. Our laboratory has previously found that MED28, a Mediator subunit for transcriptional activation, modulates cell growth, epithelial-mesenchymal transition, migration, and invasion in human breast cancer cells. The objective of the current study is to investigate the potential role of MED28 and FOXM1 in NSCLC. In addition to A549 and PC9 cells, we also used a doxycycline-inducible system to generate FOXM1-overexpressed A549-DN cells, and we explored the connection of MED28 with FOXM1 and their effect on migration. Herein, we report that the increased expression levels of both MED28 and FOXM1 elevated the expression of matrix metalloproteinase 2 (MMP2), a metastasis marker, which enhanced cell migration and matrigel invasion of NSCLC cells. Furthermore, MED28 interacted with FOXM1, and both exhibited a mutual effect on the expression and subcellular localization. Moreover, MED28 small interfering RNA-mediated MMP2 gene suppression could be attenuated by inducible expression of a constitutively active form of FOXM1, which consequently restored the migration and invasion ability of NSCLC cells. Our data indicate that MED28 interacts with FOXM1, and each affects the expression and localization of the other, and, more importantly, both regulate MMP2-dependent migration and invasion in human lung cancer cells.

Epidermal growth factor receptor-mediated regulation of matrix metalloproteinase-2 and matrix metalloproteinase-9 in MCF-7 breast cancer cells.

In breast cancer, increased epidermal growth factor receptor (EGFR) expression and phosphorylation have been correlated with increased invasive potential and poor prognosis. Interaction of EGFR with its ligand epidermal growth factor (EGF) activates cellular signalling cascades promoting tumour invasion. Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are upregulated in most cancers and play crucial roles in modulating invasion and metastasis. EGFR-mediated regulation of MMP-2 and MMP-9 in breast cancer was investigated using metastatic human breast ductal carcinoma cell line MCF-7. Culture of MCF-7 cells on 1 µg/ml EGF-coated culture dishes for 24 h led to appreciable increase in MMP-2 and MMP-9 expression and activity. Expression of membrane type-1 matrix metalloproteinase (MT1-MMP) and focal adhesion kinase (FAK), phosphorylation of EGFR and phosphatidylinositol 3' kinase (PI3K), and nuclear translocation of EGFR and cellular migration were also appreciably increased. Targeting EGFR-EGF interactions by treatment of MCF-7 cells with anti-EGFR monoclonal antibodies prior to culture on EGF prevented appreciable upregulation of MMP-2 and MMP-9 expression and activity. Increased expression of MT1-MMP and FAK, phosphorylation of EGFR and PI3K and enhanced cell migration were also inhibited. Treatment of cells with PI3K inhibitor LY294002 prevented upregulation of MMP-2 and MMP-9 indicating that EGFR-mediated signalling for MMP regulation occurs through PI3K. As increased EGFR activity has been observed in highly invasive breast cancers, targeting EGFR-EGF interactions might render such cancers less invasive by inhibiting EGFR-mediated upregulation of MMP-2 and MMP-9 and therefore could be of importance in their clinical management.

Protease Nexin-1 affects the migration and invasion of C6 glioma cells through the regulation of urokinase Plasminogen Activator and Matrix Metalloproteinase-9/2.

Protease Nexin-1 (PN-1) or Serpine2 is a physiological regulator of extracellular proteases as thrombin and urokinase (uPA) in the brain. Besides, PN-1 is also implicated in some human cancers and further identified as a substrate for Matrix Metalloproteinase (MMP)-9, a key enzyme in tumor invasiveness. Our aim was to study the role of PN-1 in the migration and invasive potential of glioma cells, using the rat C6 glioma cell line as stable clones transfected with pAVU6+27 vector expressing PN-1 short-hairpin RNA. We find that PN-1 knockdown enhanced the in vitro migration and invasiveness of C6 cells which also showed a strong gelatinolytic activity by in situ zymography. PN-1 silencing did not alter prothrombin whereas increased uPA, MMP-9 and MMP-2 expression levels and gelatinolytic activity in a conditioned medium from stable C6 cells. Selective inhibitors for MMP-9 (Inhibitor I), MMP-2 (Inhibitor III) or exogenous recombinant PN-1 added to the culture medium of C6 silenced cells restored either the migration and invasive ability or gelatinolytic activity thus validating the specificity of PN-1 silencing strategy. Phosphorylation levels of extracellular signal-related kinases (Erk1/2 and p38 MAPK) involved in MMP-9 and MMP-2 signaling were increased in PN-1 silenced cells. This study shows that PN-1 affects glioma cell migration and invasiveness through the regulation of uPA and MMP-9/2 expression levels which contribute to the degradation of extracellular matrix during tumor invasion.

Peritoneal effluent MMP-2 and PAI-1 in encapsulating peritoneal sclerosis.

BACKGROUND: Recently, the use of effluent matrix metalloproteinase 2 (MMP-2) and plasminogen activator inhibitor 1 (PAI-1) as potential biomarkers of peritoneal fibrosis has been demonstrated during longitudinal follow-up of incident peritoneal dialysis (PD) patients. This study focuses on effluent MMP-2 and PAI-1 as early diagnostic markers in the preceding years of patients who develop encapsulating peritoneal sclerosis (EPS). STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: PD patients who developed EPS were compared with controls using a 1:3 case-control design with a minimum PD duration of 57 months. INDEX TESTS: Dialysate appearance rates of MMP-2 and PAI-1. REFERENCE TEST: EPS cases identified by 2 experienced nephrologists and a radiologist based on predefined criteria. RESULTS: 11 patients developed EPS within our center. The time course of MMP-2 appearance rates, studied by means of a linear repeated-measures model 4 years prior to the diagnosis of EPS, showed no difference between long-term controls and patients with EPS. In contrast, higher PAI-1 appearance rates were found in patients with EPS compared with controls (P=0.01). At a lag time of 1 year prior to EPS diagnosis, time-specific receiver operating characteristic curve analyses indicated a discriminative ability for PAI-1 appearance rate of 0.77 (95% CI, 0.63-0.91). A discriminative capacity was absent for those of MMP-2. LIMITATIONS: Low event rate of EPS prevented independent validation in this single-center study. CONCLUSIONS: Elevated levels of PAI-1 appearance rates are present in patients who develop EPS, pointing to progressive peritoneal fibrosis and sclerosis. The PAI-1 appearance rate has fair discriminative capacity from 3 years prior to EPS diagnosis. Therefore, effluent PAI-1 may aid in monitoring peritoneal fibrosis and serve as a biomarker for EPS.

A review of matrix metalloproteinase-2-sensitive nanoparticles as a novel drug delivery for tumor therapy.

Matrix metalloproteinase-2 (MMP-2)-responsive nanodrug vehicles have garnered significant attention as antitumor drug delivery systems due to the extensive research on matrix metalloproteinases (MMPs) within the tumor extracellular matrix (ECM). These nanodrug vehicles exhibit stable circulation in the bloodstream and accumulate specifically in tumors through various mechanisms. Upon reaching tumor tissues, their structures are degraded in response to MMP-2 within the ECM, resulting in drug release. This controlled drug release significantly increases drug concentration within tumors, thereby enhancing its antitumor efficacy while minimizing side effects on normal organs. This review provides an overview of MMP-2 characteristics, enzyme-sensitive materials, and current research progress regarding their application as MMP-2-responsive nanodrug delivery system for anti-tumor drugs, as well as considering their future research prospects. In conclusion, MMP-2-sensitive drug delivery carriers have a broad application in all kinds of nanodrug delivery systems and are expected to become one of the main means for the clinical development and application of nanodrug delivery systems in the future.

The hydrogen sulfide donor 4-carboxyphenyl-isothiocyanate decreases blood pressure and promotes cardioprotective effect through reduction of oxidative stress and nuclear factor kappa B/matrix metalloproteinase (MMP)-2 axis in hypertension.

AIMS: Our aim was to evaluate whether the hydrogen sulfide (H2S) donor, 4-carboxyphenyl-isothiocyanate (4-CPI), exerts cardioprotective effect in the two kidney- one clip (2K-1C) rats through oxidative stress and MMP-2 activity attenuation and compare it with the classical H2S donor, Sodium Hydrosulfide (NaHS). MATERIALS AND METHODS: Renovascular hypertension (two kidneys-one clip; 2K-1C) was surgically induced in male Wistar rats. After two weeks, normotensive (2K) and hypertensive rats were intraperitoneally treated with vehicle (0.6 % dimethyl sulfoxide), NaHS (0.24 mg/Kg/day) or with 4-CPI (0.24 mg/Kg/day), for more 4 weeks. Systolic blood pressure (SBP) was evaluated weekly by tail-cuff plethysmography. Heart function was assessed by using the Millar catheter. Cardiac hypertrophy and fibrosis were evaluated by hematoxylin and eosin, and Picrosirius Red staining, respectively. The H2S was analyzed using WSP-1 fluorimetry and the cardiac oxidative stress was measured by lucigenin chemiluminescence and Amplex Red. MMP-2 activity was measured by in-gel gelatin or in situ zymography assays. Nox1, gp91phox, MMP-2 and the phospho-p65 subunit (Serine 279) nuclear factor kappa B (NF-κB) levels were evaluated by Western blotting. KEY FINDINGS: 4-CPI reduced blood pressure in hypertensive rats, decreased cardiac remodeling and promoted cardioprotection through the enhancement of cardiac H2S levels. An attenuation of oxidative stress, with inactivation of the p65-NF-κB/MMP-2 axis was similarly observed after NaHS or 4-CPI treatment in 2K-1C hypertension. SIGNIFICANCE: H2S is a mediator that promotes cardioprotective effects and decreases blood pressure, and 4-CPI seems to be a good candidate to reverse the maladaptive remodeling and cardiac dysfunction in renovascular hypertension.

The Possible Effect of ß-Blocker Use on the Circulating MMP-2/TIMP-2 System in Patients with Chronic Kidney Disease on Conservative Treatment.

Background: The purpose of the study was to determine whether the use of ß-adrenoceptor antagonists (ß-blockers) can affect metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in patients with chronic kidney disease (CKD) on conservative treatment. Methods: The circulating MMP-2/TIMP-2 system, proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the marker of oxidative stress-Cu/Zn superoxide dismutase (Cu/Zn SOD)-were measured in 23 CKD patients treated with ß-blockers [ß-blockers (+)] and in 27 CKD patients not receiving the above medication [ß-blockers (-)]. Results: The levels of MMP-2, TIMP-2, and IL-6 were significantly lower in the ß-blockers (+) than in the ß-blockers (-) group, whereas Cu/Zn SOD concentrations were not affected by ß-blocker use. There was a strong, independent association between MMP-2 and TIMP-2 in both analyzed patient groups. In the ß-blockers (+) group, MMP-2 levels were indirectly related to the signs of inflammation, whereas in the ß-blockers (-) group, the alterations in the MMP-2/TIMP-2 system were associated with the oxidative stress marker and CKD etiology. Conclusions: This study is the first to suggest that the use of ß-blockers was associated with the reduction in IL-6 and the MMP-2/TIMP-2 system in CKD, providing a pharmacological rationale for the use of ß-blockers to reduce inflammation and abnormal vascular remodeling in CKD.

Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence.

Objective: This study aimed to explore the association of single nucleotide polymorphisms (SNP) in the matrix metalloproteinase 2 (MMP-2) signaling pathway and the risk of vascular senescence (VS). Methods: In this cross-sectional study, between May and November 2022, peripheral venous blood of 151 VS patients (case group) and 233 volunteers (control group) were collected. Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway, assessed through carotid-femoral pulse wave velocity (cfPWV), and analyzed using multivariate logistic regression. The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality regression (GMDR) modeling. Results: Within the multivariate logistic regression models, four SNPs were screened to have significant associations with VS: chemokine (C-C motif) ligand 2 (CCL2) rs4586, MMP2 rs14070, MMP2 rs7201, and MMP2 rs1053605. Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype, and those of the T/T genotype had a 19.375-fold increased risk. CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions. Conclusion: CCL2 rs4586, MMP-2 rs14070, MMP-2 rs7201, and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

High molecular weight heparin-induced angiogenesis mainly mediated via basic fibroblast growth factor-2- an in-vivo (CAM) and in-silico analysis.

Background: High-molecular weight heparin (HMWH), a molecule extensively used as an anticoagulant, shows concentration-dependent angiogenic and anti-angiogenic potential. So far, no studies have reported the interactive potential of HMWH with various pro-angiogenic growth factors under physiological conditions. Haence, we aimed to find the impact of major pro-angiogenic growth factors under HMWH induced angiogenesis. Methods: Chicken Chorioallantoic Membranes (CAMs) are incubated with various concentrations of HMWH. Semiquantitative PCR method was implemented to measure the changes in the transcription level of pro-angiogenic growth factors. The scanning electron microscopic technique is applied to find the morphological changes in CAM. Molecular docking and molecular dynamics simulation studies using NAMD and CHARMM force field discerned the heparin-binding mode with the pro-angiogenic growth factors. Results: HMWH can enhance the transcription level of major pro-angiogenic growth factors, significantly impacting FGF2 under 100 µM concentration. The in-silico analysis reveals that HMWH shows the highest binding affinity with FGF2. Further, molecular dynamics and interaction studies using 1 kDa Heparin against FGF2 showed that the former binds stably with the latter due to a strong salt bridge formation between the sulfate groups and arginine residues (ARG 119 and ARG109). Conclusion: The combined experimental and in-silico analysis results reveal that HMWH can interact with pro-angiogenic growth factors under micromolar concentration while inducing angiogenesis. This observation further supports the therapeutic benefits of HMWH as an angiogenic factor under such low concentration. This technique is used to replenish the blood supply to chronic wounds to speed healing and prevent unnecessary amputations.

Matrix Metalloproteinase-2 and CKD Progression: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort. Study Design: In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N = 3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N = 1,439). Setting & Participants: CRIC is a multicenter prospective cohort of adults with CKD. Exposure: MMP-2 measured in plasma at baseline and at year 2. Outcomes: A composite kidney endpoint (KRT/eGFR halving). Analytical Approach: Weighted Cox proportional hazards models for case-cohort participants. Results: Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300 ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P = 0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein < 2.5 g/dL at study entry. Heterogeneity of effect was found with proteinuria, with a baseline MMP-2 level of ≥300 ng/mL associated with an increased risk of the composite kidney endpoint (HR, 1.30; 95% CI, 1.09-1.54) only with proteinuria ≥ 442 mg/g. Limitations: The observational study design limits causal interpretation. Conclusions: Elevated MMP-2 is associated with CKD progression, particularly among those with low inflammation and those with proteinuria. Future investigations are warranted to confirm the reduction in risk of CKD progression among these subgroups of patients with CKD.

Matrix metalloproteinase 2 (MMP-2) is a matrix-degrading protease involved in fibrosis and elevated in chronic kidney disease (CKD). Longitudinal patterns of MMP-2 have not previously been assessed as a predictor of CKD progression in a large prospective cohort. Here, we found that a higher baseline level and an increasing or persistently elevated 2-year pattern of MMP-2 were associated with CKD progression, independent of all covariates except proteinuria. The association of baseline MMP-2 with CKD progression differed by level of proteinuria, whereas levels of inflammation modified the associations of 2-year MMP-2 patterns with CKD progression.

TEM1 up-regulates MMP-2 and promotes ECM remodeling for facilitating invasion and migration of uterine sarcoma.

OBJECTIVES: To explore the correlation between tumor endothelial marker 1 (TEM1) and matrix metalloproteinase 2 (MMP-2) in uterine sarcoma and their roles in the progression of uterine sarcoma. METHODS: Uterine leiomyosarcoma (uLMS, n = 25) and uterine leiomyoma (n = 25) specimens were collected from a total of 50 patients. Immunohistochemistry assay was conducted to determine the expression of TEM1, MMP-2 and MMP-9. TEM1 over expression (hTEM1) and low expression (shRNA-TEM1) MES-SA cell lines were established as in vitro uterine sarcoma models. MMP-2 mRNA, protein expression and enzymatic activity were verified using qPCR, Western blot and gelatin zymography respectively. MMP-2 expression was downregulated using MMP-2 siRNA in hTEM1 MES-SA cells to better study the role of MMP-2. The invasive and migratory capacities of hTEM1, shRNA-TEM1, and hTEM1 treated with MMP-2 siRNA MES-SA cells were determined using transwell assays. Extracellular matrix (ECM) remodeling mediated by TEM1 was examined using cell-ECM adhesion and fluorescent gelatin-ECM degradation assays. The immunofluorescence of F-actin was examined to analyze the formation of invadopodia. Subcutaneous and intraperitoneal xenografts were established to validate the role of TEM1 in promoting uterine sarcoma metastasis. RESULTS: TEM1 and MMP-2 were expressed in 92% (n = 23) and 88% (n = 22) of uterine leiomyosarcoma specimens, respectively. Both TEM1 and MMP-2 were highly expressed in 100% (n = 17) of high stage (III-IV) uterine leiomyosarcoma specimens. In addition, TEM1 expression was positively correlated with MMP-2 expression in uterine leiomyosarcoma. The successful establishment of in vitro uterine sarcoma models was confirmed with qPCR and Western blotting tests. TEM1 promoted the invasion and metastasis of uterine sarcoma in vivo and in vitro. MMP-2 expression and activity were up-regulated in hTEM1 cells but down-regulated in shRNA-TEM1 cells. Importantly, MMP-2 knockdown impaired the invasive and migratory capacity of hTEM1 cells. TEM1 promoted ECM remodeling by increasing cell-ECM adhesion and ECM degradation. TEM1 overexpression also induced the formation of invadopodia. CONCLUSION: TEM1 was co-expressed and positively correlated with MMP-2 in uterine leiomyosarcoma specimens. In addition, both TEM1 and MMP-2 were associated with tumor development. TEM1 promoted uterine sarcoma progression by regulating MMP-2 activity and ECM remodeling.

Enzyme-trigger ratiometric fluorescent nanoplatform for diagnosis and imaging of oral diseases.

Oral health is an essential part of overall health. Matrix metalloproteinase-2 (MMP-2) is a potential biomarker for diseases. The ability to accurately detect MMP-2 in vivo and in vitro is of great importance for the early diagnosis and prognosis, as well as the treatment evaluation, of oral diseases. In this study, cyanine 3 (Cy3) polypeptide containing the specific peptide substrate (PLGVR) of MMP-2 was modified onto SiO2-coated upconversion nanoparticles to fabricate a fluorescence resonance energy transfer (FRET)-based ratiometric fluorescent nanoplatform (UCNPs@SiO2@Cy3-pep). The green upconversion luminescence of UCNPs@SiO2 is quenched by Cy3, while its red upconversion luminescence is undisturbed. After Cy3 is cleaved at the PLGVR peptide by MMP-2, it is detached from the surface of UCNPs@SiO2, resulting in the recovery of green luminescence. Based on this principle, we applied UCNPs@SiO2@Cy3-pep to detect MMP-2 activity in different oral disease samples and models. We found that the level of MMP-2 in saliva of patients with oral cancer was 10 times higher than that of healthy individuals. In addition, the MMP-2 level in patients with periodontitis and severe dental caries also increased to varying degrees compared with that in healthy patients. Finally, in vitro and in vivo imaging experiments revealed that the nanoplatform was effective in monitoring MMP-2 level. Together, the developed nanoplatform can be an ideal tool for medical diagnosis of MMP-2-related diseases.

Short term effect of tetrahydrocurcumin on adipose angiogenesis in very high-fat diet-induced obesity mouse model.

Tetrahydrocurcumin (THC) has been shown to possess anti-angiogenic activities. This study aims to investigate the effects of THC on adipose angiogenesis and expression of angiogenic factors that occurs in 60% high-fat diet-induced obese mice. Male ICR mice were randomly divided into 3 groups: mice fed with a low-fat diet (LFD group); mice fed with very high fat diet (VHFD group), and mice fed with VHFD supplemented with THC (300 mg/kg/day orally) (VHFD+THC treated group) for 6 weeks. Body weight (BW), food intake, fasting blood sugar (FBS), lipid profiles and visceral fats weight (VF) were measured. The microvascular density (MVD), TNF-α, VEGF, MMP-2, and MMP-9 expressions were evaluated. The VHFD group had significantly increased total cholesterol, triglyceride, food intake, BW, VF, VF/BW ratio, adipocyte size and the number of crown-liked structures as compared to LFD group. THC supplementation markedly reduced these parameters and adipocyte hypertrophy and inflammation in white adipose tissues. MVD, TNF-α, VEGF, MMP-2, and MMP-9 were over-expressed in the VHFD group. However, THC supplementation decreased MVD and reduced expression of TNF-α, VEGF, MMP-2, and MMP-9. In conclusion, THC suppressed angiogenesis in adipose tissue by the downregulation of TNF-α, VEGF, MMP-2, and MMP-9. With its effects on lipid metabolism as well as on food consumption, THC could contribute to lower visceral fat and body weight. Overall, our study demonstrated the potential benefit of THC in mitigating obesity and associated metabolic disorders along with elucidated the suppression of adipose angiogenesis as one of its underlying mechanisms.

Diagnostic and Therapeutic Approaches for Glioblastoma and Neuroblastoma Cancers Using Chlorotoxin Nanoparticles.

Glioblastoma multiforme (GB) and high-risk neuroblastoma (NB) are known to have poor therapeutic outcomes. As for most cancers, chemotherapy and radiotherapy are the current mainstay treatments for GB and NB. However, the known limitations of systemic toxicity, drug resistance, poor targeted delivery, and inability to access the blood-brain barrier (BBB), make these treatments less satisfactory. Other treatment options have been investigated in many studies in the literature, especially nutraceutical and naturopathic products, most of which have also been reported to be poorly effective against these cancer types. This necessitates the development of treatment strategies with the potential to cross the BBB and specifically target cancer cells. Compounds that target the endopeptidase, matrix metalloproteinase 2 (MMP-2), have been reported to offer therapeutic insights for GB and NB since MMP-2 is known to be over-expressed in these cancers and plays significant roles in such physiological processes as angiogenesis, metastasis, and cellular invasion. Chlorotoxin (CTX) is a promising 36-amino acid peptide isolated from the venom of the deathstalker scorpion, Leiurus quinquestriatus, demonstrating high selectivity and binding affinity to a broad-spectrum of cancers, especially GB and NB through specific molecular targets, including MMP-2. The favorable characteristics of nanoparticles (NPs) such as their small sizes, large surface area for active targeting, BBB permeability, etc. make CTX-functionalized NPs (CTX-NPs) promising diagnostic and therapeutic applications for addressing the many challenges associated with these cancers. CTX-NPs may function by improving diffusion through the BBB, enabling increased localization of chemotherapeutic and genotherapeutic drugs to diseased cells specifically, enhancing imaging modalities such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), optical imaging techniques, image-guided surgery, as well as improving the sensitization of radio-resistant cells to radiotherapy treatment. This review discusses the characteristics of GB and NB cancers, related treatment challenges as well as the potential of CTX and its functionalized NP formulations as targeting systems for diagnostic, therapeutic, and theranostic purposes. It also provides insights into the potential mechanisms through which CTX crosses the BBB to bind cancer cells and provides suggestions for the development and application of novel CTX-based formulations for the diagnosis and treatment of GB and NB in the future.

MMP-2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma.

BACKGROUND: Doxorubicin, a first-line anticancer drug for osteosarcoma treatment, has been the subject of recent research exploring the mechanisms behind its chemoresistance and its ability to enhance cell migration at sublethal concentrations. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase and zinc-dependent endopeptidase, is well-known for degrading the extracellular matrix and promoting cancer metastasis. Our previous work demonstrated that nuclear MMP-2 regulates ribosomal RNA transcription via histone clipping, thereby controlling gene expression. Additionally, MMP-2 activity is regulated by the non-receptor tyrosine kinase and oncogene, Src, which plays a crucial role in cell adhesion, invasion, and metastasis. Src kinase is primarily regulated by two endogenous inhibitors: C-terminal Src kinase (Csk) and Csk homologous kinase (CHK/MATK). AIM: In this study, we reveal that the MMP-2 gene acts as an upstream regulator of Src kinase activity by suppressing its endogenous inhibitor, CHK/MATK, in osteosarcoma cells. METHODS AND RESULTS: We show that enhanced osteosarcoma cell migration which is induced by sublethal concentrations of doxorubicin can be overcome by inactivating the MMP-2 gene or overexpressing CHK/MATK. Our findings highlight the MMP-2 gene as a promising additional target for combating cancer cell migration and metastasis. This is due to its role in suppressing on the gene and protein expression of the tumor suppressor CHK/MATK in osteosarcoma. CONCLUSION: By targeting the MMP-2 gene, we can potentially enhance the effectiveness of doxorubicin treatment and reduce chemoresistance in osteosarcoma.

Effect of Commonly Used Cosmetic Preservatives on Healthy Human Skin Cells.

Cosmetic products contain preservatives to prevent microbial growth. The various types of preservatives present in skincare products applied on the skin induce many side effects. We tested several types of preservatives such as phenoxyethanol, methyl paraben, propyl paraben, imidazolidinyl urea (IU), the composition of gluconolactone and sodium benzoate (GSB), diazolidinyl urea (DU), and two grapefruit essential oils, one of which was industrially produced and a second which was freshly distilled from fresh grapefruit peels. This study aimed to find the relationship between preservative concentration, cell growth, collagen secretion, and cell viability. We hypothesized that these products induced a decrease in collagen secretion from human dermal fibroblasts. Our research, for the first time, addressed the overall effect of other preservatives on skin extracellular matrix (ECM) by studying their effect on metalloproteinase-2 (MMP-2) activity. Except for cytotoxicity and contact sensitivity tests, there are no studies of their effect on skin ECM in the available literature. These studies show potential antimicrobial activity, especially from the compounds IU and DU towards reference bacteria and the compounds methyl paraben and propyl paraben against reference fungi. The MTS test showed that fibroblasts are more sensitive to the tested group of preservatives than keratinocytes, which could be caused by the differences between the cells' structures. The grapefruit oils exhibited the most cytotoxicity to both tested cell lines compared to all considered preservatives. The most destructive influence of preservatives on collagen synthesis was observed in the case of IU and DU. In this case, the homemade grapefruit oil turned out to be the mildest one. The results from a diverse group of preservatives show that whether they are natural or synthesized compounds, they require controlled use. Appropriate dosages and evaluation of preservative efficacy should not be the only aspects considered. The complex effect of preservatives on skin processes and cytotoxicity is an important topic for modern people.