TIMP-1 In Patients Research Articles

Markers of Collagen Degradation in Remodeling and Diastolic Dysfunction of Left Ventricle in Patients with Arterial Hypertension

Introduction. Myocardial remodeling is a consequence or predictor of several cardiovascular diseases. The key process in myocardial remodeling is the degradation of collagen fibers, mediated by the activity of matrix metalloproteinases and their tissue inhibitor.The aim of this study was to evaluate serum levels of matrix metalloproteinase type 9 and tissue inhibitor of matrix metalloproteinase type 1 in female patients with arterial hypertension, myocardial remodeling, and diastolic dysfunction.Materials and methods. A cross-sectional study that included 84 postmenopausal women. All patients underwent echocardiography. Left ventricular remodeling was assessed according to Ganau classification, and diastolic function was evaluated using transmittal flow parameters. Serum analysis included the determination of MMP-9 and TIMP-1 levels using an enzyme-linked immunosorbent assay.Results. The median concentration of MMP-9 in the sample was 2 295.00 (923.60–4 114.00) ng/ml, TIMP — 1–17 010.00 (16 780.00–17 170.00) ng/ml. When evaluating the echocardiographic parameters of the patients included in the study, changes were revealed that indicate structural and functional remodeling of the LV and DD. 29 patients (35 %) had normal geometry, 6 patients (7 %) had concentric myocardial remodeling, 21 patients (25 %) had concentric myocardial hypertrophy, 28 cases (33 %) had eccentric myocardial hypertrophy. Statistically significant changes in the activity of MMP-9 and TIMP-1 were revealed in patients with various structural and geometric variants of remodeling. DD was detected in all patients included in the study: I degree was detected in 25 patients (30 %), II degree was determined in 59 cases (70 %). Using one-way analysis of variance, statistically significant differences in the level of MMP-9 in patients with grades I and II DD were determined. MMP-9 and MMP-9/TIMP-1 in patients with grade II DD are significantly higher than in patients with grade I.Discussion. Under pathophysiological conditions, the proteolytic properties of MMP-9 contribute to the stimulation of the immune response, initiating pathogenesis and aggravating the progression of the disease. Evaluation of the activity of MMP-9 and TIMP-1 in patients with arterial hypertension may be a marker of myocardial remodeling.Conclusion. An increase in the activity of matrix metalloproteinase type 9 and a decrease in the activity of a tissue inhibitor of matrix metalloproteinases type 1 were revealed in patients with arterial hypertension, myocardial remodeling and LV diastolic dysfunction. The level of MMP-9 is associated with the degree of diastolic dysfunction and the structural-geometric type of LV remodeling.

TIMP-1 in the prognosis of patients who underwent coronary artery bypass surgery: a 12-year follow-up study.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been linked to clinical outcomes in patients with coronary artery disease (CAD). However, the prognostic value of TIMP-1 in patients with CAD who underwent coronary artery bypass grafting (CABG) has not been elucidated. We aimed to investigate the correlations of TIMP-1 with high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the long-term prognosis of consecutive patients who underwent CABG. A total of 234 patients (age: 70.4 ± 10.5 years, 84.6% men) with CAD who underwent CABG were prospectively enrolled. Preoperative levels of MMPs, TIMP-1, hs-CRP, and NT-proBNP were recorded. Major adverse cardiovascular events (MACE) were defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. During a median follow-up of 12.1 years, 120 deaths were recorded. The deceased were older, had more manifest acute coronary syndrome (ACS), a lower left ventricular ejection fraction (LVEF), and an estimated glomerular filtration rate (eGFR), but significantly higher MMP13, TIMP-1, hs-CRP, and NT-proBNP compared with the survivors. After adjusting for age, sex, manifest ACS, eGFR, LVEF, total cholesterol, and triglycerides, TIMP-1 (hazard ratio and 95% confidence intervals per SD: 1.506, 1.183-1.917), hs-CRP (1.349, 1.183-1.561), and NT-ProBNP (1.707, 1.326-2.199) were all independently associated with all-cause mortality. The mediation analysis revealed that the mortality risks of TIMP-1 were partially mediated by NT-proBNP (62.2%) and hs-CRP (25.3%). The associations of TIMP-1 with MACE were partially mediated by NT-proBNP (54.4%) but not hs-CRP. TIMP-1 was an independent predictor of long-term outcomes after CABG, with possible roles in subclinical inflammation and postoperative cardiac remodeling.

Plasma Levels of MMPs and TIMP-1 in Patients with Osteoarthritis After Recovery from COVID-19.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPS) play a key role in the pathogenesis of osteoarthritis (OA). Recent research showed the involvement of some MMPs in COVID-19, but the results are limited and contradictory. In this study, we investigated the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10) and TIMP-1 in the plasma of patients with OA after recovery from COVID- 19. The experiment involved patients aged 39 to 80 diagnosed with knee OA. All study participants were divided into three research groups: the control group included healthy individuals, the group OA included patients with enrolled cases of OA, and the third group of OA and COVID-19 included patients with OA who recovered from COVID-19 6-9 months ago. The levels of MMPs and TIMP-1 were measured in plasma by enzyme-linked immunosorbent assay. The study showed a change in the levels of MMPs in patients with OA who had COVID- 19 and those who did not have a history of SARS-CoV-2 infection. Particularly, patients with OA who were infected with coronavirus established an increase in MMP-2, MMP-3, MMP-8, and MMP-9, compared to healthy controls. Compared to normal subjects, a significant decrease in MMP-10 and TIMP-1 was established in both groups of patients with OA and convalescent COVID-19. Thus, the results suggest that COVID-19 can affect the proteolysis-antiproteolysis system even after a long postinfectious state and may cause complications of existing musculoskeletal pathologies.

Changes in Serum Levels of Matrix Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinases-1 in Patients with Essential Hypertension.

Hypertension (HTN) is a leading risk factor for cardiovascular (CV) disease. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are thought to be actively involved in the remodeling of the CV extracellular matrix (ECM) during hypertensive damage. Therefore, in this study, we aimed to investigate serum levels of MMP-1 and TIMP-1 in patients with essential HTN and compare them with those of normotensive individuals. We measured serum concentrations of MMP-1 and TIMP-1 in 60 patients with HTN and 20 healthy controls using an ELISA. The obtained results showed that in patients with HTN, the mean levels of MMP-1 (1.82 ± 0.9 ng/mL) were significantly higher (p = 0.03) than the mean levels in the control group (1.19 ± 0.7 ng/mL). The levels of TIMP-1 in patients with essential HTN (0.44 ± 0.1 ng/mL) were also significantly higher (p = 0.005) than those in the control group (0.33 ± 0.1 ng/mL). In HTN, elevated serum MMP-1 levels may be associated with increased collagen degradation in the CV ECM, whereas elevated TIMP-1 levels may favor its accumulation and the development of pathological remodeling and fibrosis of the heart and arterial vessels.

The effect of surgery on the levels of matrix metalloproteinases in patients with inguinal hernia.

Matrix metalloproteinases (MMPs) are associated with the alteration of extracellular matrix. The purpose of this study was to investigate how the levels of matrix metalloproteinases and their inhibitors - TIMPs are influenced by the presence of inguinal hernia as well as by its surgical treatment. The studied group consisted of 25 patients with inguinal hernia and 21 healthy controls for comparison. Two blood samples - before and after the treatment were collected from patients. Serum concentrations of MMPs and TIMPs were analysed by multiplex immunoassays. There was a difference in circulating levels of MMPs in patients before the surgery compared to healthy controls - the concentrations of MMP-2 and MMP-9 were significantly lower (p=0.026, p=0.018, respectively). After the surgery, the levels of MMPs, especially MMP-2 (p<0.0001), were significantly decreased in patients compared to the preoperative values, apart from MMP-9. On the contrary, MMP-9 showed significant increase after the surgery (p<0.0001). Circulation levels of TIMP-2 in patients were significantly decreased in comparison with controls (p=0.004), whereas levels of TIMP-1 were similar to controls. Both tested metalloproteinase inhibitors showed a significant decrease in detected levels (TIMP-1 p=0.0004; TIMP-2 p<0.0001) after the procedure compared to the preoperative values. The levels of MMPs, especially MMP-2 and MMP-9, and their inhibitors TIMP-1 and TIMP-2 are involved by the presence of inguinal hernia as well as are influenced by the surgery.

New aspects in the pathogenesis of miscarriage in women with extragenital pathology

Study objective: to determine the dynamics of type 9 metalloproteinase (MMP-9) and its tissue inhibitor-1 (TIMP-1) in the pathogenesis of early miscarriage in women with chronic diseases of the hepatobiliary system.Materials and methods. The study included 39 women with a history of early pregnancy miscarriage, who were diagnosed with chronic liver diseases as a result of clinical, instrumental and laboratory studies (17 persons with steatosis and 22 persons with non-alcoholic steatohepatitis). The control group consisted of 8 women without somatic pathology and 8 pregnant women at the first trimester of gestation. MMP-9 and TIMP-1 value in the blood serum was determined by the enzyme immunoassay.Results. MMP-9 and TIMP-1 growth in the blood serum of women with a history of miscarriage was established in the pre-gravidar period. The most significant increase in the parameters of the intercellular matrix was found in patients with non-alcoholic steatohepatitis. MMP-9 and TIMP-1 increased in in blood serum in the first trimester in women with liver diseases. MMP-9 increased against the background of a decrease in the TIMP-1 activity in patients with the threat of premature pregnancy termination. Miscarriage was diagnosed in patients with a minimum value of a tissue inhibitor. Conclusions. There is an imbalance between MMP-9 and TIMP-1 in the blood serum in women with early miscarriage and chronic diseases of the hepatobiliary system. MMP-9 and TIMP-1 level in patients with hepatic steatosis is lower than in patients with non-alcoholic steatohepatitis. MMP-9 increased during physiological pregnancy, and the TIMP-1 activity practically did not change, which indicates the role of MMP-9 in the initial stages of placentation. MMP-9 value in women with a burdened premorbid background with a physiological course of pregnancy and threatening early spontaneous miscarriage was significantly different. The highest activity of MMP-9 was in women with the threat of spontaneous miscarriage in the early stages. TIMP-1 in the first trimester in women with chronic liver disease increased in those with a favorable course of pregnancy and decreased in the threat of spontaneous miscarriage. Such changes in MMP-9 and TIMP-1 in patients with miscarriage indicate the accumulation of intercellular matrix and sclerotic changes in the vessels that provide blood to the uterus.

Ocular TGF-β, Matrix Metalloproteinases, and TIMP-1 Increase with the Development and Progression of Diabetic Retinopathy in Type 2 Diabetes Mellitus

Diabetic retinopathy (DR) is a sight-threatening late complication of diabetes mellitus (DM). Even though its pathophysiology has not been fully elucidated, several studies suggested a role for transforming growth factor- (TGF-) β, matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinase (TIMP) in the onset and progression of the disease. Consequently, the aim of this study was to analyze the concentrations of TGF-β1, TGF-β2, TGF-β3, MMP-3, MMP-9, and TIMP-1 in patients with different stages of DR in order to identify stage-specific changes in their concentrations during the progression of the disease. Serum and aqueous humor (AH) samples were collected during intraocular surgery, and eyes were classified into the following groups: healthy controls (n = 17), diabetic patients with non-apparent DR (n = 23), mild/moderate nonproliferative DR (NPDR) (n = 13), and advanced NPDR/proliferative DR (PDR) without vitreal hemorrhage (n = 14). None of the patients had been under anti-VEGF or laser treatment within six months prior to surgery. In the AH, TGF-β1 levels increased in advanced NPDR/PDR by a factor of 5.5 compared to the control group. Similarly, an increase in MMP-3 and TIMP-1 levels in the AH was evident in the later stages of DR, corresponding to a 7.7- and 2.4-fold increase compared to the control group, respectively, whereas serum levels of the studied proteins remained similar. In conclusion, increased concentrations of TGF-β1, MMP-3, and TIMP-1 in the AH, but not in the serum, in advanced NPDR/PDR indicate that the intraocular regulation for these cytokines is independent of the systemic one and suggest their involvement in the progression of DR.

Matrix Metalloproteinases (MMP-2) and Tissue Inhibitors of Metalloproteinases (TIMP-2) in Male Inguinal Hernia Patients at Different Ages.

Collagen metabolism, controlled by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), might be related to inguinal hernia formation. It was reported that the incidence of inguinal hernia and the recurrence rate after inguinal hernia repair were higher in the elderly. The objective of the research was to assess the amounts of MMP-2 and TIMP-2 in patients at different ages in order to examine the relationship between age and inguinal hernia occurrence. The research included 40 primary inguinal hernia male patients, and four groups were created: 50-59years old (A group); 60-69years old (B group); 70-79years old (C group); 80-89years old (D group). We got the samples from anterior rectus sheath fascia. Real-time fluorescence quantitative polymerase chain reaction (RT-PCR) and immunohistochemistry were applied to estimate the levels of MMP-2 and TIMP-2. The MMP-2 amounts in C and D group were statistically higher than control group (P < 0.05), and the TIMP-2 levels in C and D group were statistically lower than control group (P < 0.05). We found a positive correlation between age and expression levels of MMP-2 (r = 0.537, P < 0.001; r = 0.569, P < 0.001) and a negative correlation between age and TIMP-2 in inguinal hernia patients (r = - 0.759, P < 0.001; r = - 0.759, P < 0.001). Increased MMP-2 and reduced TIMP-2 may have some relationships with higher inguinal hernia incidence of the elderly.

Relationships between Circulating Matrix Metalloproteinases, Tissue Inhibitor TIMP-2, and Renal Function in Patients with Myocarditis

Introduction: Under physiological conditions, the myocardial extracellular matrix (ECM) is maintained by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). However, changes in the balance between MMPs and TIMPs can lead to pathological remodeling of the ECM, which contributes to cardiovascular and kidney diseases. The aim of our study was to assess levels of MMPs and TIMP-2 in patients with myocarditis and their relationship to renal function. Materials and Methods: Forty five patients with myocarditis who underwent CMR were included, comprising 11 with concurrent chronic kidney disease (CKD). Blood samples were obtained to assess serum levels of MMP-2, MMP-3, MMP-9, and TIMP-2. Results: Serum MMP-2, MMP-3, and TIMP-2 levels negatively correlated with the ejection fraction in patients with myocarditis, while MMP-3 levels correlated with longitudinal deformation (p < 0.05). Serum MMP-2, MMP-3, and TIMP-2 levels also negatively correlated with renal function, as assessed by the estimated glomerular filtration rate (eGFR) (p < 0.05). Patients with myocarditis and concurrent CKD had higher levels of MMP-2 and TIMP-2 than those without kidney damage. Conclusions: (1) We demonstrated that MMP-2, MMP-3, and TIMP-2 concentrations were related to left-ventricular ejection fraction, and MMP-3 levels correlated with longitudinal deformation, indicating MMPs play an important role in the post-inflammatory remodeling of the myocardium. (2) A negative correlation between the eGFR and MMP-2, MMP-3, and TIMP-2 and a positive correlation between creatinine and MMP-3 levels indicate the role of MMPs and TIMP-2 in renal dysfunction.

A Randomized, Triple-blind Placebo-controlled Trial to Determine the Effect of Saffron on the Serum Levels of MMP-9 and TIMP-1 in Patients with Multiple Sclerosis.

Matrix metalloproteinases (MMP)-9 facilitates the migration of T-cells to central nervous system (CNS), while tissue inhibitor of metalloproteinases-1(TIMP-1) inhibits the function of MMP-9. This study aimed to determine the appropriate treatment option for multiple sclerosis (MS). Forty-three relapsing-remitting MS (RRMS) patients were randomly divided into two groups of 22 (group A, placebo) and 21 (group B, Saffron pill) individuals. Serum samples were collected from patients' blood before using the Saffron pills/placebo pills and then after 12 months. The serum level of MMP-9 and its inhibitor, as well as TIMP-1, were measured by ELISA kits. MMP-9 serum levels noticeably decreased in patients with MS following 12 months of treatment with Saffron pills (p=0.006) while the changes were not significant before and after 12 months of treatment with placebo pills. Although the levels of TIMP-1 increased significantly after one year treating with Saffron pills (p=0.0002), a considerable difference was not observed before and after taking the placebo pills. The study finding revealed that 12-months treatment with Saffron could have a significant role in reducing the serum level of MMP-9 and increasing the serum level of TIMP-1 in RRMS patients. Therefore, modulating the serum levels of MMP-9 as an important regulator of T cell trafficking to the CNS might be a promising strategy in the treatment of MS patients.

Selected Metal Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases as Potential Biomarkers for Tubulointerstitial Fibrosis in Children with Unilateral Hydronephrosis.

Renal tubulointerstitial fibrosis caused by congenital ureteropelvic junction obstruction (UPJO) may lead to the development of obstructive nephropathy (ON) and the impairment of kidney function. Hence, the identification of early biomarkers of this condition might be of assistance in therapeutic decisions. This study evaluates serum and urinary metalloproteinases MMP-1, MMP-2, and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 as potential biomarkers of ON in children with congenital unilateral hydronephrosis (HN) caused by UPJO. Forty-five (45) children with congenital HN of different grades of severity and twenty-one (21) healthy controls were enrolled in the study. Urinary and serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured using specific ELISA kits. The urinary excretions were expressed as biomarker/creatinine (Cr) ratios. To evaluate the extracellular matrix remodelling process activity, the serum and urinary MMP-1, -2, -9/TIMP-1, -2 ratios were also calculated. In comparison with the controls, patients with HN, independent of the grade, showed significantly increased median serum MMP-9, TIMP-1, and TIMP-2, median urinary MMP-9/Cr, and TIMP-2/Cr ratios. Lower median values of serum MMP-2/TIMP-1, MMP-9/TIMP-1 in patients with HN were also revealed. Additionally, higher urinary MMP-2/Cr, lower urinary MMP-2/TIMP-2, and lower serum MMP-9/TIMP-2 ratios were observed in patients with HN grades 3 and 4. Patients with ON diagnosed by renal scintigraphy had a significantly higher median serum MMP-9 concentration and lower median serum MMP-9/TIMP-1, -2 ratios in comparison with those without this condition. Patients with nonglomerular proteinuria had a significantly higher median serum TIMP-1 concentration, a higher median urinary TIMP-2/Cr ratio, and a lower serum MMP-9/TIMP-1 ratio compared to those without this symptom. The relationship between the measured biomarkers and the relative function of the obstructed kidney showed no correlations. The ROC curve analysis showed a promising diagnostic profile for the detection of ON for serum MMP-9 and the serum MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios. In conclusion, the results of this study suggest that patients with HN, particularly with grades 3 and 4, are at higher risk of renal tubulointerstitial fibrosis. The noninvasive markers of this condition considered are urinary MMP-2/Cr and MMP-9/Cr, serum MMP-9, serum and urinary MMP-2, MMP-9/TIMP-1, -2. Additionally, serum MMP-9 and MMP-9/TIMP-1, -2 may become promising markers of ON.

Prognostic meaning of tissue inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2 in patients with colorectal cancer

The aim of this study was to analyze TIMP-1 and TIMP-2 serum levels in patients with colorectal cancer (CRC) and to correlate the results with the pathological stage of the disease and outcome in order to evaluate the role of TIMP-1 and TIMP-2 serum levels as prognostic markers. The investigation has been made on 82 patients with operable CRC without distant metastases, who had undergone blood tests in order to determine the TIMP-1 and TIMP-2 serum levels in the following points of time: preoperatively, as well as 3, 6, 9 and 12 months postoperatively. Significant differences were found between serum levels of TIMP-1 and TIMP-2 obtained preoperatively and postoperatively, as well as significant association of serum TIMP-1 levels obtained preoperatively in CRC patients in stage I and III, in the 3th and in the 6th month (p&lt;0.001) postoperatively as defined points of time with the outcome of CRC patients. Serum TIMP-2 levels obtained preoperatively was significantly associated with the outcome of the CRC patients. Analysis of the obtained TIMP-1 and TIMP-2 serum levels in CRC patients showed statistically significant differences with: disease progression, occurrence of liver metastasis, prior to and post chemotherapy treatment. The results derived a conclusion that the serum levels of TIMP-1 and TIMP-2 could be indicators for occurrence and progression of CRC, as well as valuable and useful markers for following the effects of chemotherapy treatment. Keywords: colorectal cancer, TIMP-1, TIMP-2, prognosis

EVALUATION OF BONE RESORPTIVE POTENTIAL IN THE TREATMENT OF GENERALIZED PERIODONTITIS

The aim: Is to study dynamics of resorptive potential of bone tissue by indicators of protease and antiprotease systems in the process of treatment generalized periodontitis in patients with age-related osteoporosis and without osteoporotic changes in the skeleton. Materials and methods: In 102 patients, before the start of treatment of generalized periodontitis and in 2, 4 and 12 weeks, the concentration of pro-resorbing matrix metalloproteinases: stromelysin (MMP-3), collagenase (MMP-8) and gelatinase (MMP-9) were determined in blood plasma and mixed oral fluid. The antiresorbtive potential of bone tissue was evaluated by the concentration of a tissue inhibitor of metalloproteinases (TIMP-1) in plasma. The general antiprotease activity was determined by the activity of α1-antitrypsin (α1-AT) and α2-macroglobulin (α2-MG). Results: The most significant changes are recorded for the content of MMP-9 in blood and oral fluid, regardless of the presence of systemic disorders of bone metabolism (P < 0.05). Concentration of MMP-8 is significantly increased in blood plasma and oral fluid in accordance with the severity of the disease and in the course of treatment (P <0.05). The observed increase in the ratio of MMP-8 to TIMP-1 and MMP-9 to TIMP-1 in patients with generalized periodontitis, complicated by systemic osteoporosis (P < 0.05), indicates an imbalance of the protease-antiprotease system. Conclusions: The resorptive potential of bone tissue in patients with generalized periodontitis allows us to correctly choose treatment tactics and to prevent the development of complications.

Plasma Levels and Tissue Expression of Selected Cytokines, Metalloproteinases and Tissue Inhibitors in Patients With Cervical Cancer

Cytokines, metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) take part in many processes involved in tumor progression and invasion such as degradation of the extracellular matrix, influence on immune cells associated with tumor tissue, and angiogenesis. Thus, the aim of this study was to compare the concentration of plasma levels and tissue expression of macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2 and MMP9, and their tissue inhibitors TIMP1 and TIMP2 in patients with cervical cancer, patients with high-grade cervical intraepithelial dysplasia (CIN3) and patients with ectropion. Concentration and expression of all tested parameters was measured in serum with enzyme-linked immunosorbent assay (ELISA) and in tissue with immunohistochemistry method. The epithelial expression of M-CSF and TIMP1 in cancer tissue was much stronger as compared to that in ectropion and CIN3. In the case of MMP2, lack of or weak expression in epithelial cells was observed in all tested groups. Our studies showed statistical differences of tested parameters in tissue expression and in plasma concentrations in patients with cervical cancer, patients with CIN3 and patients with ectropion. Moreover, data revealed positive correlation between plasma level and cervical cancer cell expression of VEGF. Our findings indicate a potential role of all the proteins tested here in cervical cancer diagnosis, especially VEGF. However, further studies will show whether they play a role in the progression of cancerous changes in epithelial tissue of the cervix.

Matrix metalloproteinases (MMPs) and inhibitor of metalloproteinases (TIMP) mRNA and protein expression in laryngeal squamous cell carcinoma.

IntroductionThe aim of the study was to investigate the mRNA expression and protein levels of matrix metalloproteinases (MMP) 2 (MMP-2), 9 (MMP-9), 7 (MMP-7) and their tissue inhibitor TIMP-2 in patients with laryngeal squamous cell carcinoma and control subjects and additionally to evaluate a possible correlation with clinicopathological features.Material and methodsThe expression levels of MMP-2, MMP-9, MMP-7, and TIMP-2 mRNA were detected by the real-time quantitative real time polymerase chain reaction method in 96 cases of laryngeal carcinoma vs. non-tumor tissue. The blood serum levels of MMP-2, MMP-9, MMP-7, and TIMP-2 in patients with laryngeal cancer and 100 healthy subjects were measured using the enzyme-linked immunosorbent assay (ELISA) method.ResultsThe present study demonstrated that MMP-2, MMP-7, MMP-9 and TIMP-2 mRNA expression levels in carcinoma tissue vs. non-tumor tissue and protein levels in the preoperative serum vs. those obtained in healthy controls were statistically significantly higher than in the healthy controls (p = 0.001). The only significant correlation between mRNA or concentration of measured MMPs and TIMP and the clinicopathological features was found for TIMP-2 protein and for patients with lymph node metastasis. Serum levels of TIMP-2 were higher in cases with lymph node metastasis than in those without lymph node metastasis (p < 0.05).ConclusionsThe results may suggest that MMPs and TIMP-2 are associated with laryngeal tumorigenesis, but we did not find any distinct correlation between the clinicopathological features of laryngeal squamous cell carcinoma patients and expression levels of MMPs and TIMP. The results suggest that the measurement of serum MMP-2, MMP-7, MMP-9 and TIMP-2 concentration might be helpful to diagnose laryngeal squamous cell carcinoma.

Clinical Significance of Matrix Metalloproteinases in Blood Plasma of Patients with Gastric Cancer.

Plasma levels of MMP-2, MMP-7, and MMP-9 and their tissue inhibitor TIMP-2 were measured in 89 patients with gastric cancer and the relationship between these parameters and the main clinical morphological characteristics of the disease was analyzed. Plasma levels of the proteins were measured using standard direct ELISA kits. The level of MMP-7 in patients with gastric cancer was significantly higher than in the control group (medians 2.7 and 1.2 ng/ml, respectively; p<0.01), but only in 51% patients this parameter surpassed the upper threshold normal value (2.35 ng/ml; 95% percentile of control). The level of MMP-9 in gastric cancer patients was lower than in control group by 1.6 times (medians 167 and 267 ng/ml, respectively; p<0.01). Plasma levels of MMP-2 and TIMP-2 in patients with gastric cancer and healthy subjects were similar. No appreciable associations of plasma matrixins and TIMP-2 with the main clinical morphological characteristics of the disease were detected. The patients were followed up for 8 to 85 months (median 70.8 months). Low level of MMP-2 and high level of MMP-7 in the plasma proved to be unfavorable prognostic factors for overall survival. At MMP-2<268 ng/ml, the 5-year overall survival was 32% vs. 60% for patients with the marker level higher than this threshold value (p=0.016). The differences in overall survival in relation to their MMP-7 levels for 5-year observation did not surpass 16% (39% at marker level >2.7 ng/ml and 55% at lower level; p=0.048). Plasma levels of MMP-2 and TIMP-2 were not significantly associated with overall survival. Multivariate analysis showed that only T index (p=0.034) and plasma MMP-7 level (p=0.007) were essential for overall survival. The increase in plasma or serum MMP-7 levels is a universal phenomenon in tumors of different histogenesis, which precluded the use of this parameter as a specific diagnostic marker of gastric cancer. At the same time, it could be useful for monitoring the treatment efficiency and detection of relapses. In addition, high plasma level of MMP-7 remained an independent factor of unfavorable prognosis for overall survival of patients with gastric cancer.

Diagnostic power of VEGF, MMP-9 and TIMP-1 in patients with breast cancer. A multivariate statistical analysis with ROC curve

PurposeVascular endothelial growth factor is an important factor in promoting angiogenesis in malignant processes, matrix metalloproteinase-9 in the degradation of extracellular matrix, which enhances metastasis, and tissue inhibitor of metalloproteinase-1 is its inhibitor. The aim of this study was to investigate the diagnostic power of these parameters in comparison to CA15-3 in breast cancer patients and in relation to the control group. Materials/methodsThe study included 120 breast cancer patients, 60 patients with benign breast tumors and 60 healthy women. Plasma levels of tested parameters were determined by enzyme-linked immunosorbent assay, CA15-3 by chemiluminescent microparticle immuno assay. ResultsTissue inhibitor of metalloproteinase-1 showed the highest value of sensitivity in breast cancer group (86.25%) and, more importantly, highest value in breast cancer stage I (85%). Vascular endothelial growth factor also showed high sensitivity (stage I and II–75%, III–85%, IV–70% and 76.25% in total breast cancer group) and the highest specificity (85%) from all tested parameters. It was also the only parameter which had statistically significant area under curve in all stages. In the total breast cancer group all tested parameters showed statistically significant area under curve, but the maximum range was obtained for combination: ‘vascular endothelial growth factor + CA15-3′. Vascular endothelial growth factor seems to be the best candidate for diagnosing breast cancer stage I and for differentiating between breast cancer and non-carcinoma cases. ConclusionsThe combined analysis of tested parameters and CA15-3 resulted in an increase in sensitivity and area under curve values, which provides hope for developing new panel of biomarkers that may be used in diagnosing breast cancer in the future.

Comparative analysis of mettaloproteinase system and their tissue inhibitors at periodontitis in patients with diabetes mellitus type II

The article presents the results of a comparative study of the systemic and local levels of matrix metalloproteinases MMP-2, MMP-8, MMP-9 and their tissue inhibitors TIMP-1, TIMP-2 in patients with periodontitis and type II diabetes (group I) and periodontitis without diabetes mellitus (group II). 65 patients were examined, including: 30 patients. – I group and 35 people. – II group. The control group consisted of healthy volunteers (30 people). In both patients, a signifi cant increase in MMP-9, TIMP-1, -2 in the serum, an increase in MMP-2, -8, -9, TIMP-1, -2 in saliva, as well as MMP-8 and MMP-9 in the blood obtained from the microcirculatory bed of the gingival patients. A decrease in MMP-2 and MMP-8 levels in the blood serum, as well as a decrease in the levels of MMP-2 and TIMP-2 in the blood, obtained from the ICR of the gingiva in patients of groups 1 and 2, was determined. In patients with periodontitis against diabetes mellitus II, hyperproduction of MMP-9 was established, as well as an increase in the levels of TIMP-1 in blood obtained from the ICR of the gum. In the group of patients without concomitant pathology, on the contrary, there was a more pronounced increase in MMP-8 levels, as well as an increase in TIMP-1 in saliva and TIMP-2 in serum.

Serum TIMP1 and TIMP2 concentration in patients with different grades of meningioma

ObjectiveMeningiomas are common primary brain tumors that constitute about 13% of all intracranial tumors. Matrix metalloproteinase-9 (MMP-9) is able to degrade the extracellular matrix and basement membrane leading to cancer cell invasion and metastasis. MMPs are specifically inhibited by a family of small extracellular proteins known as the tissue inhibitors of metalloproteinases (TIMPs). The objective of this project was to evaluate serum concentration of TIMP-1 and TIMP-2 in patients with different grades of meningioma. Patients and MethodsNinety samples from different stages of patients with meningitis (42 cases of grade I, 28 grade II, 20 grade III) and 51 samples from normal healthy were included in this study. Total protein concentration (TPC) and the level TIMP-1 and TIMP-2 serum were determined by Bio-Rad protein assay based on the Bradford dye procedure and enzyme-linked immunosorbent assay (ELISA), respectively. ResultsNo significant change in the TPC was seen in the serum of patients with meningioma when compared with normal controls. Results obtained demonstrated that all serum samples presented TIMP-1 and TIMP-2 expression, whereas, starting from grade I to III meningiomas, a significant decrease of TIMP-1 and TIMP-2 expression was observed as compared to controls. ConclusionThe results of this study show that a low expression of TIMP1 and TIMP2 is correlated with advanced stages of meningioma. It is also concluded that the detection of serum TIMP1 and TIMP2 may be useful in classifying different grades of meningioma.

Elevated serum concentrations of metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2) in patients with Graves' orbitopathy.

Graves' orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is characterized by dramatic tissue reactivity. Both inflammation and tissue remodeling characterize the clinical course of GO. Some data has been found regarding the association of MMPs and TIMPs in GO. Serum concentrations of MMP-9, MMP-2, TIMP-1, and TIMP-2 were determined by ELISA method. Forty-eight patients (34 females, 14 males, with median age 51.5 years) with GD and hyperthyroidism were enrolled in the study. In 28 patients, active, moderate-to-severe grade orbitopathy was diagnosed. The aim of this study was to assess the serum concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 in patients with Graves' disease (GD), with and without GO, and their relationship with disease severity, as well as to evaluate how these concentrations change after successful treatment. Median serum concentrations of MMP-2 and MMP-9 were significantly higher in all patients with GD as well as in the subgroup with GO than in the control group. Median serum concentrations of TIMP-1 and TIMP-2 were significantly higher in all patients with GD than in controls. The same significant differences were observed in the subgroups with and without GO in comparison with controls. The GO subgroup showed a significant positive correlation between the MMP-9 concentration and the serum level of TSHRAb antibodies, and a clinical activity score ≥4 according to EUGOGO. In our study we found that only MMP-9 differentiates the patients with and without GO, and may be used as a marker of the disease severity in patients with this manifestation of GD.