Matrix Metalloproteinase-9 Concentrations Research Articles

Serum Concentrations of Matrix Metalloproteinase-1 and Procollagen Type I Carboxy Terminal Propeptide Discriminate Infarct-Like Myocarditis and Non-ST-Segment-Elevation Myocardial Infarction.

Biomarkers simplifying the diagnostic workup by discriminating between non-ST-segment-elevation myocardial infarction (NSTEMI) and infarct-like myocarditis are an unmet clinical need. A total of 105 subjects were categorized into groups as follows: ST-segment-elevation myocardial infarction (n=36), NSTEMI (n=22), infarct-like myocarditis (n=19), cardiomyopathy-like myocarditis (n=18), and healthy control (n=10). All subjects underwent cardiac magnetic resonance imaging, and serum concentrations of matrix metalloproteinase-1 (MMP-1) and procollagen type I carboxy terminal propeptide (PICP) were measured. Biomarker concentrations in subjects presenting with acute coronary syndrome and non-ST-segment-elevation, for example NSTEMI or infarct-like myocarditis, categorized as the non-ST-segment-elevation acute coronary syndrome-like cohort, were of particular interest for this study. Compared with healthy controls, subjects with myocarditis had higher serum concentrations of MMP-1 and PICP, while no difference was observed in individuals with myocardial infarction. In the non-ST-segment-elevation acute coronary syndrome-like cohort, MMP-1 concentrations discriminated infarct-like myocarditis and NSTEMI with an area under the receiver operating characteristiccurve (AUC) of 0.95 (95% CI, 0.89-1.00), whereas high-sensitivity cardiac troponin Tperformed inferiorly (AUC, 0.74 [95% CI, 0.58-0.90]; P=0.012). Application of an optimal MMP-1 cutoff had 94.4% sensitivity (95% CI, 72.7%-99.9%) and 90.9% specificity (95% CI, 70.8%-98.9%) for the diagnosis of infarct-like myocarditis in this cohort. The AUC of PICP in this context was 0.82 (95% CI, 0.68-0.97). As assessed by likelihood ratio tests, incorporating MMP-1 or PICP with age and C-reactive protein into composite prediction models enhanced their diagnostic performance. MMP-1 and PICP could potentially be useful biomarkers for differentiating between NSTEMI and infarct-like myocarditis in individuals with non-ST-segment-elevation acute coronary syndrome-like presentation, though further research is needed to validate their clinical applicability.

Growth Differentiation Factor 15 and Matrix Metalloproteinase 3 in Plasma as Biomarkers for Neuropathy and Nephropathy in Type 1 Diabetes.

Diabetic neuropathy and nephropathy are common complications of type 1 diabetes (T1D). The symptoms are often elusive in the early stages, and available diagnostic methods can be improved using biomarkers. Matrix metalloproteinase 3 (MMP-3) has been identified in the kidneys and is thought to be involved in diabetic nephropathy. Growth differentiation factor 15 (GDF-15) has been suggested to have positive effects in diabetes, but is otherwise associated with adverse effects such as cardiovascular risk, declined kidney function, and neurodegeneration. This study aims to investigate plasma MMP-3 and GDF-15 as systemic biomarkers for diabetic neuropathy and nephropathy in T1D. The study involves patients with childhood-onset T1D (n = 48, age 38 ± 4 years) and a healthy control group (n = 30, age 38 ± 5 years). Neurophysiology tests, evaluations of albuminuria, and measurements of routine biochemical markers were conducted. The neuropathy impairment assessment (NIA) scoring system, where factors such as loss of sensation and weakened reflexes are evaluated, was used to screen for symptoms of neuropathy. MMP-3 and GDF-15 concentrations were determined in heparinized plasma using ELISA kits. In total, 9 patients (19%) had albuminuria, and 25 (52%) had diabetic neuropathy. No significant differences were found in MMP-3 concentrations between the groups. GDF-15 levels were higher in T1D, with median and interquartile range (IQR) of 358 (242) pg/mL in T1D and 295 (59) in controls (p < 0.001). In the merged patient group, a positive correlation was found between MMP-3 and plasma creatinine, a negative correlation was found between MMP-3 and estimated glomerular filtration rate (eGFR; rho = -0.358, p = 0.012), and there was a positive correlation between GDF-15 and NIA (rho = 0.723, p < 0.001) and high-sensitive C-reactive protein (rho = 0.395, p = 0.005). MMP-3 was increased in macroalbuminuria and correlated positively with NIA only in the nine T1D patients with albuminuria (rho = 0.836, p = 0.005). The present study indicates that high MMP-3 is associated with low eGFR, high plasma creatinine, and macroalbuminuria, and that GDF-15 can be a biomarker for diabetic neuropathy in T1D. MMP-3 may be useful as biomarker for neuropathy in T1D with albuminuria.

Local proteolytic system indicators as suspective factors of keratolysis development after urgent keratoplasty

Purpose: to determine the concentration of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in the tear of patients with cornea melting and to assess whether these factors can be used as prognostically significant biomarkers of keratolysis. Material and methods. 20 patients who underwent urgent penetrating keratoplasty were tested for cornea perforation (melting) before and after the procedure. For control, 12 healthy adults (24 eyes) were tested. The tear fluid was collected before the surgery and on the 7th day after it with the help of filtering paper. MMP-9 and TIMP-1 concentrations were determined by ELISA. The course of the early postoperative period was assessed according to the area of keratotransplant epithelization on the 7th day after surgery. Results. MMP-9 and TIMP-1 concentrations in the tears of all patients before the surgery were significantly higher than the ones of healthy controls. The patients who were supposed to have re-keratoplasty had a significantly higher MMP-9 concentration than the ones who expected the first keratoplasty. An uncomplicated early postoperative period showed a statistically significant decrease of MMP-9 and TIMP-1 concentrations, whilst the complicated one demonstrated a significant increase of both markers. The highest increase of both markers was shown by the patients who underwent re-keratoplasty. Conclusion. MMP-9 concentration in the tears is a valid marker of the clinical course of the early post-keratoplasty period. To ensure a successful donor cornea engraftment, the levels of MMP-9 and TIMP-1 in the tear must be high enough before the surgery and the concentration of the ferment should decrease timely after its main functions have been completed. A 2-fold (or greater) decrease of MMP-9 concentration in the tear on the 7th day after keratoplasty can be considered a marker of the favorable prognosis for engraftment.

Adaptive enzyme-responsive self-assembling multivalent apelin ligands for targeted myocardial infarction therapy

Microvascular dysfunction following myocardial infarction exacerbates coronary flow obstruction and impairs the preservation of ventricular function. The apelinergic system, known for its pleiotropic effects on improving vascular function and repairing ischemic myocardium, has emerged as a promising therapeutic target for myocardial infarction. Despite its potential, the natural apelin peptide has an extremely short circulating half-life. Current apelin analogs have limited receptor binding efficacy and poor targeting, which restricts their clinical applications. In this study, we utilized an enzyme-responsive peptide self-assembly technique to develop an enzyme-responsive small molecule peptide that adapts to the expression levels of matrix metalloproteinases in myocardial infarction lesions. This peptide is engineered to respond to the high concentration of matrix metalloproteinases in the lesion area, allowing for precise and abundant presentation of the apelin motif. The changes in hydrophobicity allow the apelin motif to self-assemble into a supramolecular multivalent peptide ligand-SAMP. This self-assembly behavior not only prolongs the residence time of apelin in the myocardial infarction lesion but also enhances the receptor-ligand interaction through increased receptor binding affinity due to multivalency. Studies have demonstrated that SAMP significantly promotes angiogenesis after ischemia, reduces cardiomyocyte apoptosis, and improves cardiac function. This novel therapeutic strategy offers a new approach to restoring coronary microvascular function and improving damaged myocardium after myocardial infarction.

System proteinase/inhibitors in the pathogenesis of experimental kidney tuberculosis

BACKGROUND: Damage to the kidney parenchyma of various origins is associated with the accumulation of extracellular matrix proteins, the regulation of which involves the matrix metalloproteinase/inhibitor system. AIM: To evaluate the pathogenetic role of the proteinase/blood inhibitor system in experimental renal tuberculosis. MATERIAL AND METHODS: When modeling the process, a clinical strain 5582 of the Beijing genotype with multidrug resistance of mycobacteria was used. The study was conducted on 20 rabbits, divided into three groups: the first (n=6) included infected untreated animals; in the second (n=7) and third (n=7) anti-tuberculosis therapy was administered orally for 18.5 weeks; in the third, treatment was carried out in combination with a single injection of autologous mesenchymal stem cells into the ear vein. Blood levels of matrix metalloproteinases-1 and -9, tissue inhibitor of metalloproteinases-1, cystatin C and neutrophil elastase were determined. Morphological changes in the kidney parenchyma at the end of the experiment were assessed using 26 indicators, including tubulointerstitial and vascular changes. The median and interquartile ranges were calculated, the Kruskal–Wallis test, analysis of covariance, and the projective classification method were used. RESULTS: The progression of kidney tuberculosis was accompanied by a significant increase in the level of neutrophil elastase by 1.9 times, matrix metalloproteinase-9 by 2.2 times, and cystatin C by 1.5 times compared to the initial level. The treatment carried out in the second and third groups contributed to the normalization of these indicators. The concentrations of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in all three groups did not change relative to the baseline level. Covariance analysis showed that in the pathogenesis of renal tuberculosis changes in matrix metalloproteinase-1 (p=0.003), matrix metalloproteinase-9 (p=0.002), tissue inhibitor of metalloproteinases-1 (p=0.01) and cystatin C (p=0.0001) were primarily associated with vascular changes, found in all study groups. A linear combination containing three morphological characteristics allowed us to identify differences between the three groups with 90% accuracy. CONCLUSION: Renal tuberculosis, caused by a multidrug-resistant pathogen, is characterized by an imbalance in the proteinase/inhibitor system and impaired renal function, the degree of which is associated with the morphological characteristics of vascular and tubulointerstitial changes.

#2307 Serum NGAL, MMP-9 and suPAR in the assessment of kidney impairment and cardiovascular risk in children and adolescents with type 1 diabetes or obesity

Abstract Background and Aims Type 1 diabetes mellitus (DM1) and obesity represent two chronic paediatric diseases with worryingly rising incidence, characterized by chronic inflammation, endothelial dysfunction and increased risk for kidney impairment and cardiovascular disease. The aim of this cross-sectional study was to explore the potential usefulness of serum Neutrophil Gelatinase-Associated Lipocalin (NGAL), Matrix Metalloproteinase-9 (MMP-9) and Soluble Urokinase Plasminogen Activator Receptor (suPAR) for predicting early kidney injury or increased cardiovascular risk in children and adolescents with DM1 or obesity. Method Serum samples were obtained from children and adolescents aged &amp;lt;18 years old with DM1 (n=35) or obesity (n=38) and normal renal function with no history of albuminuria, as well as from healthy controls (n=23). Serum NGAL, MMP-9 and suPAR concentrations were measured using commercially available sandwich ELISA kits (NGAL: (DY1757-05), MMP-9: (DMP900); suPAR: (DUP00); R&amp;D systems). All patients were evaluated for anthropometric indices (weight, height, BMI) while for different degrees of weight status we used the body mass index (BMI) z-score adjusted for age and sex. Estimated glomerular filtration rate (eGFR) was calculated according to the revised bedside Schwartz formula. Results Serum NGAL values were found significantly higher in patients with obesity but not in those with DM1. A positive correlation was found in patients with T1DM with diabetes duration (Spearman rho 0.364, p=0.044), and in all study participants with BMI z-score (Spearman rho 0.401, p=0.004). Furthermore, serum MMP-9 levels were significantly increased in patients with T1DM and in patients with obesity compared to controls. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls (Table 1). Finally, serum suPAR levels showed a negative correlation with age (Spearman rho −0.359, p&amp;lt;0.001) and creatinine levels (Spearman rho −0.334, p=0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p=0.009). Conclusion Circulating NGAL, MMP-9 levels may prove useful as surrogate biomarkers to creatinine, GFR and albumin excretion rate for early detection of kidney injury, inflammation or endothelial dysfunction and cardiovascular complications in children and adolescents with T1DM or obesity. Children with obesity may have impaired inflammation status, kidney and endothelial function to a higher degree compared to children with T1DM, which may suggest that obesity may impose a greater health burden than T1DM, at least during childhood or the first years after T1DM diagnosis.

220 Litter performance, serum collagen, and hormone concentrations in prolapsed and non-prolapsed sows

Abstract Pelvic organ prolapse is one of the top leading causes of sow mortality today and widely considered a multifactorial issue. Previous reports observed prolapsed sows having decreased serum concentrations of various trace minerals and increased tumor necrosis factor-alpha compared with non-prolapsed sows. Additionally, collagen, hormones, and previous litter performance are other factors proposed to be associated with POP. A study was completed to determine differences in serum collagen type 1 (COL1), matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metalloproteinase 1 (TIMP-1), as well as relaxin and estradiol differences in the serum concentration between prolapsed and non-prolapsed sows. Furthermore, previous litter performance, lactation days, pigs born, stillborns, mummified, and pigs weaned on prolapse rate were evaluated. The study utilized 44 prolapsed sows and 44 non-prolapsed sows of similar parity, location, management, and stage of production. Blood was collected from the prolapsed and non-prolapsed sows upon discovery. Serum samples were analyzed using radioimmunoassay for estradiol content. Additionally, COL1, MMP-1, TIMP-1, and relaxin concentrations were determined from the serum using ELISA testing. Data were analyzed using the PROC GLIMMIX procedure in SAS. Prolapsed sows had decreased (P &amp;lt; 0.05) COL1 and TIMP-1 concentrations in the serum compared with the non-prolapsed sows. Prolapsed sows had marginally greater (P &amp;lt; 0.10) MMP-1 concentration compared with non-prolapsed sows. There were no differences (P &amp;gt; 0.10) between prolapsed and non-prolapsed serum concentraions of sows for estradiol and relaxin. Prolapsed sows had longer lactation days (P &amp;lt; 0.05) in the litter before prolapsing compared with non-prolapsed sows. Additionally, stillborns in the previous litter were marginally greater (P = 0.06) in prolapsed sows when compared with the non-prolapsed sows. There were no differences (P &amp;gt; 0.10) in pigs born, mummified, or pigs weaned between prolapsed and non-prolapsed sows. This study suggests that there is a reduced concentration of serum COL1 and TIMP-1 found in prolapsed sows compared with non-prolapsed sows and a marginally increased MMP-1 concentration in prolapsed sows. This could influence the structural integrity of the connective tissue that supports the pelvic organs. We found no differences in serum estradiol or relaxin levels. Additionally, lactation days and stillborn pigs in the litter prior to prolapsing could be contributing factors to prolapse. This work further supports the idea that prolapse is a multifactorial issue.

A study of inflammatory biomarkers in crystalline silica exposed rock drillers

BackgroundCrystalline silica (CS) exposure can cause serious lung disease in humans, but mechanisms of pulmonary toxicity have not been completely elucidated.AimsTo assess pro-inflammatory and anti-inflammatory biomarkers and biomarkers related to the development of chronic obstructive pulmonary disease and fibrosis in serum of rock drillers exposed to CS.MethodsRock drillers (N = 123) exposed to CS and non-specified particulate matter (PM) were compared to 48 referents without current or past exposure to PM in a cross-sectional study.ResultsThe rock drillers had been exposed to CS for 10.7 years on average. Geometric mean (GM) current exposure was estimated to 36 µg/m3. Their GM concentration of matrix metalloproteinase 12 (MMP-12) was significantly higher (16 vs. 13 ng/L; p = 0.04), while interleukin (IL) 6 and IL-8 were significantly lower compared to the referents. Also pentraxin 3 was significantly lower (3558 vs. 4592 ng/L; p = 0.01) in the rock drillers. A dose-response relationship was observed between cumulative exposure to CS and MMP-12, the highest exposed subgroup having significantly higher MMP-12 concentrations than the referents.ConclusionExposure to CS may increase circulating MMP-12 concentrations in a dose-response related fashion. The results may also suggest a down-regulation of pro-inflammatory pathways.

Features of The Dynamics of Profibrotic Markers and Regression of Left Ventricular Hypertrophy After Renal Denervation in Patients With Resistant Hypertension and Stenosing Atherosclerosis of the Coronary Arteries.

To compare the changes in serum concentrations of matrix metalloproteinases (MMPs) and their tissue inhibitor (TIMP) to the dynamics of blood pressure (BP) and parameters of left ventricular hypertrophy (LVH) 6 months after renal denervation (RD) in patients with resistant arterial hypertension (RAH) and complicated coronary atherosclerosis. In 22 RAH patients with complicated coronary atherosclerosis (revascularization and/or history of myocardial infarction (MI)), 24-hour BP monitoring, echocardiography, and measurement of blood MMPs and TIMP were performed at baseline and six months after RD. The comparison group consisted of 48 RAH patients without a history of coronary revascularization or MI. In 6 months after RD, BP was decreased comparably in both groups. In the group of complicated atherosclerosis, there were no significant changes in profibrotic markers or LVH parameters. Thus, at baseline and after 6 months, the values of the studied indicators were the following: left ventricular myocardial mass (LVMM) 233.1±48.1 and 243.0±52.0 g, LVMM index 60.6±14.5 and 62.8±10 .9 g/m2.7, proMMP-1 4.9 [2.1; 7.7] and 3.6 [2.0; 9.4] ng/ml, MMP-2 290.4 [233.1; 352.5] and 352.2 [277.4; 402.9] ng/ml, MMP-9 220.6 [126.9; 476.7] and 263.5 [82.9; 726.2] ng/ml, TIMP-1 395.7 [124.7; 591.4] and 424.2 [118.2; 572.0] ng/ml, respectively. In the comparison group, on the contrary, there was a significant decrease in LVMM from 273.6±83.3 g to 254.1±70.4 g, LVMM index from 67.1±12.3 to 64.0±14.4 g/m2.7, proMMP-1 from 7.2 [3.6; 11.7] to 5.9 [3.5; 10.9] ng/ml, MMP-2 from 328.9 [257.1; 378.1] to 272.8 [230.2; 343.2] ng/ml, MMP-9 from 277.9 [137.0; 524.0] to 85.5 [34.2; 225.9] ng/ml, and the MMP-9/TIMP-1 ratio from 0.80 [0.31; 1.30] to 0.24 [0.07; 0.76]. The BP dynamics in this group was inversely correlated with MMP-2 at 6 months (r=-0.38), and the MMP-9/TIMP-1 ratio was correlated with LVMM and the LVMM index at baseline (r=0.39 and r=0.39) and at 6 months (r=0.37 and r=0.32). The change in TIMP-1 from 543.9 [277.5; 674.1] to 469.8 [289.7; 643.6] ng/ml was not significant (p=0.060). In RAH patients with complicated coronary atherosclerosis, the dynamics of profibrotic biomarkers and LVH parameters after RD was absent despite the pronounced antihypertensive effect, probably due to the low reversibility of cardiovascular remodeling processes or more complex regulatory mechanisms of the MMP system.

Proteolytic system parameters in the brain of rats with hyperhomocysteinemia

Hyperhomocysteinemia (HHcy) is now being actively studied as a potential risk factor and/or biomarker for numerous pathological conditions, including brain diseases. This study aimed to analyze the proteolytic processes in the brains of rats with HHcy. Total proteolytic activity, metal-dependent, and serine proteases activities, the content of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases-1, cytokines, serine proteases, total protein and medium and low molecular-weight substances (MLMWS), were evaluated. HHcy was induced by DL-homocysteine thiolactone (HTL) daily intragastric administration (200 mg·kg–1 of body weight) to young and adult albino non-linear male rats for 8 weeks following rat sacrifice and brain harvesting. It was established that HHcy causes an increase in total proteolytic activity and a rise in MLMWS levels in rat brains. Serine protease activity increased to a greater extent compared to metal-dependent one, and bigger changes were observed in young rats. Rise in MMP-9 and -10 levels (in young animals), a decline in MMP-3 and -8 levels, and a decrease in the content of interleukin-1β, interferon-γ, interleukin-4 and tumor necrosis factor-α (the last two in young animals) was also detected. No significant changes were found in serine protease content. Therefore, proteolysis intensification in the brain of rats with HHcy is more likely caused by protease up-regulation through mechanisms stimulated by homocysteine, HTL, and oxidative stress, without involving pro-inflammatory signaling pathways.

Relationship between gingival and peri-implant sulcular fluid active matrix metalloproteinase-8 concentration and clinical indices in healthy and diseased conditions

Aim: The study was to evaluate the active matrix metalloproteinase-8 (aMMP-8) concentration in gingival crevicular fluid (GCF) and in peri-implant sulcular fluid (PISF) in healthy and diseased conditions, before and after non-surgical treatment, and to compare it with the various clinical parameters used to estimate the gingival and peri-implant inflammation. Methods: Plaque index/modified PI (PI/mPI), gingival index/simplified GI (GI/sGI), probing depth (PD), bleeding on probing index/modified BOPI (BOPI/mBOPI), radiographic bone loss/radiographic marginal bone loss (rBL/rMBL), and GCF/PISF samples were evaluated, before and 3 months after non-surgical treatment, GCF/PISF samples were analyzed by a chair-side mouth-rinse test (ImplantSafe®) in combination with a digital reader (ORALyzer®). Results: In all groups, aMMP-8 median levels were statistically higher in the PISF than in GCF and they did not change after treatment. Moreover, it was statistically higher in Group 3 (periodontitis/peri-implantitis) compared to the other groups. A positive correlation of the GCF/PISF and aMMP-8 median concentration was seen with increasing PD and BOPI/mBOPI values. A higher covariation of aMMP-8 mean levels in GCF with PD was found when compared to PISF levels. aMMP-8 mean levels in PISF expressed a higher covariation with increasing grades of sGI, rMBL, and BOPI while aMMP-8 GCF concentration established a better covariation with PD and PI. Conclusions: PISF of sites with peri-implant mucositis and peri-implantitis showed higher levels of aMMP-8 compared to sites with gingivitis and periodontitis. Compared to clinical indices, aMMP-8 concentration in GCF/PISF can be a beneficial adjunctive diagnostic tool for early identification and screening of the risk of peri-implant diseases. After non-surgical therapy, PISF aMMP-8 concentration remained mostly unchanged, while the GCF concentration of aMMP-8 significantly decreased.

Parameters of the mmp / timp system in assessing the clinical course of pulmonary tuberculoma

Aim. To study the parameters of the matrix metalloproteinase (MMP) / tissue inhibitors of metalloproteinase (TIMP) system in assessing the clinical course of pulmonary tuberculoma.Materials and methods. We examined 87 patients (55 men and 32 women), average age 33 [28; 43] years, with a morphologically and bacteriologically confirmed diagnosis of tuberculoma, who received treatment at St. Petersburg Research Institute of Phthisiopulmonology. In all patients, computed tomography of the chest, fiberoptic bronchoscopy, and lung function tests were performed. In the blood serum, concentrations of MMP-1, -8, -9, and their tissue inhibitor TIMP-1 were determined using ELISA (R&amp;D Systems, USA), and the activity of α2-macroglobulin (MG) was determined by the enzyme assays. For statistical data processing, Statistica 10.0 and R were used.Results. In the study group, single and multiple tuberculomas were revealed in 37 and 63% of cases, respectively, necrotic areas – in 50% of patients, external respiration disorders – in 48% of cases, and catarrhal bronchitis (CB) – in 77% of cases. Tobacco smokers (TS) were identified in 69% of cases. Significant differences between MMP concentrations allowed us to distinguish four patterns from the characteristics adopted for the clinical and radiological assessment of disease intensity. It was shown that an increase in the levels of MMP-1 and MMP-9 can be a predictor of tuberculoma progression caused by a diffuse process with necrotic areas and bronchogenic dissemination (pattern 1, 2). Changes in the levels of MMP-8, TIMP-1 or MG (pattern 3, 4) were associated with permanent exposure to a non-specific component of inflammation (TS or CB).Conclusion. Changes in the MMP / TIMP system parameters can be used as objective laboratory protein biomarkers to assess the clinical course of pulmonary tuberculoma.

The role of Matrix Metalloproteinase-2 and Galectin-3 as predictive biomarkers for all-cause mortality in patients undergoing transfemoral transcatheter aortic valve implantation

Background Currently available risk scores fail to accurately predict morbidity and mortality in patients with severe symptomatic aortic stenosis who undergo transcatheter aortic valve implantation (TAVI). In this context, biomarkers like matrix metalloproteinase-2 (MMP-2) and Galectin-3 (Gal-3) may provide additional prognostic information. Methods Patients with severe aortic stenosis undergoing consecutive, elective, transfemoral TAVI were included. Baseline demographic data, functional status, echocardiographic findings, clinical outcomes and biomarker levels were collected and analysed. Results The study cohort consisted of 89 patients (age 80.4 ± 5.1 years, EuroScore II 7.1 ± 5.8%). During a median follow-up period of 526 d, 28 patients (31.4%) died. Among those who died, median baseline MMP-2 (alive: 221.6 [170.4; 263] pg/mL vs. deceased: 272.1 [225; 308.8] pg/mL, p < 0.001) and Gal-3 levels (alive: 19.1 [13.5; 24.6] pg/mL vs. deceased: 25 [17.6; 29.5] pg/mL, p = 0.006) were higher than in survivors. In ROC analysis, MMP-2 reached an acceptable level of discrimination to predict mortality (AUC 0.733, 95% CI [0.62; 0.83], p < 0.001), but the predictive value of Gal-3 was poor (AUC 0.677, 95% CI [0.56; 0.79], p = 0.002). Kaplan–Meier and Cox regression analyses showed that patients with MMP-2 and Gal-3 concentrations above the median at baseline had significantly impaired long-term survival (p = 0.004 and p = 0.02, respectively). Conclusions In patients with severe aortic stenosis undergoing transfemoral TAVI, MMP-2 and to a lesser extent Gal-3, seem to have additive value in optimizing risk prediction and streamlining decision-making.

Serum MMP-8 and TIMP-1 concentrations in a population-based cohort: effects of age, gender, and health status

BackgroundMatrix-degrading proteinases and their regulators, such as matrix metalloproteinase 8 (MMP-8) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), may contribute to various pathological events. Elevated MMP-8 concentrations have been associated with e.g., cardiovascular diseases and periodontitis. However, there is little knowledge on physiological concentrations of these molecules in serum, or the effect of demographic or lifestyle factors on their levels.Design and methodsWe investigated the effect of various demographic characteristics and behavioral habits, such as aging, sex, smoking, and BMI, on serum concentrations of MMP-8 and TIMP-1. We used the FINRISK97 cohort (n = 8,446), which has comprehensive information on demographic and lifestyle factors, clinical data, laboratory measurements, and register data available. Further, we investigated the concentrations of MMP-8, TIMP-1, and the MMP-8/TIMP-1 ratio in different age groups of healthy and diseased participants. T-test was used to compare log-transformed mean levels in different groups and linear regression was used to evaluate the association between MMP-8 and TIMP-1 and selected diseases and background variables.ResultsMMP-8 levels decreased with increasing age in the whole population and for women, while TIMP-1 concentration increased slightly with age for the whole population and both genders separately (p for linear trend &amp;lt;0.001). The concentrations of MMP-8 were lower and TIMP-1 higher in men compared to women (p &amp;lt; 0.001). Additionally, significant positive association was found for MMP-8 and smoking, CRP, and inverse association with obesity and fasting time. For TIMP-1, significant positive associations were found with smoking, CRP and obesity, and an inverse association with prevalent diabetes.ConclusionThe association of serum MMP-8 and TIMP-1 concentrations with cardiometabolic risk is frequently investigated. MMP-8 levels decrease significantly with age and fasting time. In addition, sex, smoking, and obesity are associated with both MMP-8 and TIMP-1 concentrations. These factors should be carefully considered in epidemiological studies on serum MMP-8 and TIMP-1.

MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study

Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p<0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p=0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5at hospital discharge) by 2.33 times per 1000ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

Association of Serum Macrophage Migration Inhibitory Factor with 3-Month Poor Outcome and Malignant Cerebral Edema in Patients with Large Hemispheric Infarction.

We aimed to investigate the associations of macrophage migration inhibitory factor (MIF), toll-like receptors 2 and 4 (TLR2/4), and matrix metalloproteinase 9 (MMP9) with 3-month poor outcome, death, and malignant cerebral edema (MCE) in patients with large hemispheric infarction (LHI). Patients with LHI within 24h of onset were enrolled consecutively. Serum MIF, TLR2/4, and MMP9 concentrations on admission were measured. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3months. MCE was defined as a decreased level of consciousness, anisocoria and midline shift > 5mm or basal cistern effacement, or indications for decompressive craniectomy during hospitalization. The cutoff values for MIF/MMP9 were obtained from the receiver operating characteristic curve. Of the 130 patients with LHI enrolled, 90 patients (69.2%) had 3-month poor outcome, and MCE occurred in 55 patients (42.3%). Patients with serum MIF concentrations ≤ 7.82ng/mL for predicting 3-month poor outcome [adjusted odds ratio (OR) 2.827, 95% confidence interval (CI) 1.144-6.990, p = 0.024] also distinguished death (adjusted OR 4.329, 95% CI 1.841-10.178, p = 0.001). Similarly, MMP9 concentrations ≤ 46.56ng/mL for predicting 3-month poor outcome (adjusted OR 2.814, 95% CI 1.236-6.406, p = 0.014) also distinguished 3-month death (adjusted OR 3.845, 95% CI 1.534-9.637, p = 0.004). Lower serum MIF and MMP9 concentrations at an early stage were independently associated with 3-month poor outcomes and death in patients with LHI. These findings need further confirmation in larger sample studies.

Correlation Between HIF1-A Expression and Airway Remodeling in COPD.

Airway remodeling is a significant pathological characteristic of chronic obstructive pulmonary disease (COPD). In recent years, hypoxia-inducible factor 1-α (HIF-1α), a member of the hypoxia-inducible factor protein family, has gained attention. However, the potential correlation between HIF-1α and COPD airway remodeling remains unclear. This study explored the expression patterns of HIF-1α in patients with COPD and its association with airway remodelling. This investigation aims to furnish novel insights for the clinical identification of prospective therapeutic targets for ameliorating COPD-related airway remodelling. A total of 88 subjects were included, consisting of 28 controls and 60 COPD patients. Various staining methods were employed to observe the pathological changes in airway tissues. Immunohistochemistry was utilized to detect the expression of HIF-1α and MMP9 (matrix metalloproteinase 9) in airway tissues. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration in serum of HIF-1α and MMP9. Computed tomography (CT) airway parameters were measured in all participants to assess airway remodeling. The relationship between serum HIF-1α and MMP9 concentrations and airway parameters was analyzed. Staining of airway structures in COPD patients revealed significant pathological changes associated with airway remodelling, including mixed cilia and subepithelial fibrosis. The expression of HIF-1α and MMP9 was significantly higher in both human airway tissue and serum compared to controls. Chest CT scans exhibited typical imaging features of airway remodeling and increased airway parameters. The findings suggest a correlation between increased HIF-1α expression and COPD airway remodelling. This study provides novel evidence that HIF-1α may be a potential biomarker for airway remodelling in COPD patients.

The role of matrix metalloproteinase-9 and the tissue inhibitor of metalloproteinase — 1 in endogenous uveitis in children

Purpose: to determine the content of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases — 1 (TIMP-1) in the tear and blood serum (BS) and to analyze how these parameters correlate with the clinical course of endogenous uveitis in children.Materials and methods. 131 eyes with uveitis of 74 patients aged 3 to 17 (mean age 10.57 ± 3.29 years) were examined. The content of MMP-9 was found in 281 samples of the tear and 48 samples of BS. The dynamics of MMP-9 in the tear was studied in 55 patients (100 eyes), in BS — in 9 children. The content of TIMP-1 was studied in 173 tear samples and 25 BS samples. The dynamics of TIMP-1 was studied in the tear of 31 patients (56 eyes). The concentration of MMP-9 and TIMP-1 was determined by enzyme immunoassay (ELISA) using the kits ELISA for MMP-9/ELISA for tissue metalloproteinase inhibitor 1 (Cloud clone corporation, USA).Results. The content of MMP-9 in the tear dropped compared to the control group (p = 0.09). The highest content of MMP-9 in panuveitis was found in the tear as compared to the anterior and intermediate uveitis (p = 0.01). The highest MMP-9 concentration was found in cases of 3rd degree of proliferation, in contrast to the 1st and 2nd degrees (p = 0.16). An increased content of TIMP-1 was found in the tear in subactive/intermediate uveitis in contrast to inactive uveitis (p=0.08). An imbalance of MMP-9 was revealed in relation to TIMP-1 in the tears. In the early postoperative period, an increase in the content of MMP-9 and a decrease in TIMP-1 in the tear returning to the initial level was noted, which corresponds to normal wound healing.Conclusion. An increase in the content of TIMP-1 in the tear is associated with subactive/intermediate uveitis. The content of MMP-9 in the tear correlates with the proliferative process stage. A higher MMP-9 content in the tear in panuveitis, in contrast to the anterior and intermediate uveitis is associated with the involvement of all sections of the choroid of the eye into the inflammatory process. The decrease in the content of MMP-9 in the tears is probably explained by the inhibitory effect of glucocorticosteroid (GCS) therapy.

Tolperisone hydrochloride improves motor functions in Parkinson’s disease via MMP-9 inhibition and by downregulating p38 MAPK and ERK1/2 signaling cascade

The mitogen-activated protein kinase (MAPK) signaling pathway, particularly the p38 MAPK and ERK1/2, has been implicated in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that MAPK signaling pathway can influence the expression of matrix metalloproteinase 9 (MMP-9), known for its involvement in various physiological and pathological processes, including neurodegenerative diseases. This study explores the modulation of MMP-9 expression via the MAPK/ERK signaling cascade and its potential therapeutic implications in the context of PD-associated motor dysfunction. Here, tolperisone hydrochloride (TL), a muscle relaxant that blocks voltage-gated sodium and calcium channels, was used as a treatment to observe its effect on MAPK signaling and MMP-9 expression. Rotenone (RT) exposure in mice resulted in a significant reduction in substantia nigra and primary motor cortex neurons, which were further evidenced by impairments in motor function. When TL was administered, neuron count was restored (89.0 ± 4.78 vs 117.0 ± 4.46/mm2), and most of the motor dysfunction was alleviated. Mechanistically, TL reduced the protein expression of phospho-p38MAPK (1.06 fold vs 1.00 fold) and phospho-ERK1/2 (1.16 fold vs 1.02 fold), leading to the inhibition of MAPK signaling, as well as reduced MMP-9 concentrations (2.76 ± 0.10 vs 1.94 ± 0.10 ng/mL) in the process of rescuing RT-induced neuronal cell death and motor dysfunction. Computational analysis further revealed TL’s potential inhibitory properties against MMP-9 along with N and L-type calcium channels. These findings shed light on TL's neuroprotective effects via MMP-9 inhibition and MAPK signaling downregulation, offering potential therapeutic avenues for PD-associated motor dysfunction.

The role of matrix metalloproteinase-2 and miR-196a2 in bronchial asthma pathogenesis and diagnosis

BackgroundBronchial asthma is a persistent inflammatory respiratory condition that restricts the passage of air and causes hyperresponsiveness. Chronic asthma can be classified into three categories: mild, moderate, and severe. Remodeling took place as the extracellular matrix accumulated in the walls of the airways. Inflammation occurs as a result of the damage caused by matrix metalloproteinase-2 (MMP-2) to basement membrane type IV collagen. The severity of asthma may be associated with miR-196a2. The objective of our study was to investigate the underlying mechanisms and clinical relevance of miR-196a2 and MMP-2 serum levels in relation to the severity of asthma. MethodsThis study recruited 85 controls and 95 asthmatics classified as mild, moderate, or severe. Expression of miR-196a2 was measured by quantitative reverse transcriptase PCR. Using the enzyme-linked immunosorbent assay (ELISA), MMP-2, IL-6, and total immunoglobulin E (IgE) levels in the serum of asthmatics of various grades were compared to a control group. MMP-2's diagnostic and prognostic potential was determined using ROC curve analysis. This study also measured blood Eosinophils and PFTs. We examined MMP-2's connections with IgE, blood Eosinophils, and PFTs. ResultsThe current investigation found that miR-196a2 expression was significantly higher in the control group than in asthmatic patients as a whole. The study found that severe asthmatics had higher MMP-2, IL-6, and IgE serum levels than healthy controls. We identified the MMP-2 serum concentration cutoff with great sensitivity and specificity. Significant relationships between MMP-2 serum level and miR-196a2 expression in the patient group with severe asthmatics were found. The MMP-2, IL-6, and IgE serum levels were considerably higher in mild, moderate, and severe asthmatics than controls. The miR-196a2 expression and MMP-2 serum concentration correlated positively with IgE and blood eosinophils % and negatively with all lung function tests in the asthmatic patient group.Conclusion: the study revealed that the elevated miR-196a2 expression and serum concentration of MMP-2, IL-6, and IgE associated with elevated blood eosinophils % is associated with pathophysiology and degree of asthma severity. The miR-196a2 expression and MMP-2 serum concentration have a promising diagnostic and prognostic ability in bronchial asthma.