Serum Concentrations Of MMP-9 Research Articles

Serum and Urinary Matrix Metalloproteinase-9 Concentrations in Dehydrated Horses.

Matrix metalloproteinase-9 is increased in renal tissue in human kidney disease, but its role as a biomarker for kidney disease has not been fully evaluated yet. The aim of this study was to evaluate serum MMP-9 (sMMP-9) and urinary MMP-9 (uMMP-9) concentrations in dehydrated horses. Dehydrated horses were prospectively included. Blood and urinary samples were taken at admission, and after 12, 24, and 48 h (t0, t12, t24, t48), an anti-equine MMP-9 sandwich ELISA was used. Four healthy horses served as the controls. Serum creatinine, urea, symmetric dimethylarginine (SDMA), urine-specific gravity, urinary protein concentration, fractional sodium excretion, and urinary gamma-glutamyl transferase/creatinine ratio (uGGT/Cr) were measured. Statistical analysis included a repeated measures ANOVA and mixed linear regression model. Overall, 40 dehydrated horses were included (mild dehydration 13/40, moderate 16/40, severe 11/40). Acute kidney injury was found in 1/40 horses; 7/40 horses showed elevated serum creatinine, 11/40 horses elevated serum SDMA, and 5/28 elevated uGGT/Cr at presentation. In dehydrated horses, sMMP-9 concentrations were significantly higher on t0 (median: 589 ng/mL, range: 172-3597 ng/mL) compared to t12 (340 ng/mL, 132-1213 ng/mL), t24 (308 ng/mL, 162-1048 ng/mL), and t48 (258 ng/mL, 130-744 ng/mL). In healthy horses, sMMP-9 (239 ng/mL, 142-508 ng/mL) showed no differences over time or compared to patients. uMMP-9 and uMMP-9/creatinine did not differ over time or to the controls. No differences were found between dehydration groups. Urinary casts (p = 0.001; estimate = 135) and uGGT/Cr (p = 0.03; estimate = 6.5) correlated with sMMP-9. Serum urea was associated with uMMP-9/Cr (p = 0.01, estimate 0.9). In conclusion, sMMP-9 was elevated at arrival in dehydrated patients compared to later measurements. Correlations to uGGT/Cr and urinary casts need further evaluation.

Metalloproteinase-2 in failed back surgery syndrome caused by epidural fibrosis: can it play a role in persistent pain?

Failed Back Surgery Syndrome (FBSS) occurs in 10-40% of patients treated surgically due to disk herniation (DH). There are several factors that can cause a predisposition to FBSS, but the exact pathomechanism has not been elucidated. The aim of this study was to investigate Metalloproteinase-2 (MMP-2) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) activities in a homogeneous group of FBSS patients with epidural fibrosis in comparison to its activity in patients with surgically treated DH. DH, FBSS, and control (CG) groups consisted of 30 subjects. The patients were assessed clinically by the Numerical Rating Scale (NRS), McGill Pain Questionnaire (SF -MPQ), Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). Serum concentrations of MMP-2 and TIMP-2 were measured by using the immunoenzymatic method. There was a significantly higher MMP-2 expression (medians: 4797.49 vs. 2656.65; p < 0.0001) and TIMP-2 concentration (medians: 166.40 vs. 109.60; p < 0.0001) in the DH compared to the CG. Significantly higher MMP-2 expression (4219.95 vs. 2656.65; p < 0.0001) and TIMP-2 concentration (medians: 150.17 vs. 109.60; p = 0.0003) were also found in the FBSS compared to the CG. The activity of MMP-2, measured as MMP-2/TIMP-2, did not significantly change between the DH, FBSS, and CG. MMP2 expression (p < 0.0001) and TIMP-2 concentration (p < 0.0001) were significantly higher in the DH than FBSS. Results indicate the presence of a contribution of MMP-2 and TIMP-2 in DH and FBSS. Unchanged activity of MMP-2 can indicate an insufficiency in the MMP-2 repair system in both diseases. Lower MMP-2 expression and TIMP-2 concentration in the FBSS group can reflect the chronicity of the process.

Low-Grade Inflammatory Mediators and Metalloproteinases Yield Synchronous and Delayed Responses to Mechanical Joint Loading.

Mechanical loading is an essential factor for the maintenance of joint inflammatory homeostasis and the sensitive catabolic-anabolic signaling cascade involved in maintaining cartilage tissue health. However, abnormal mechanical loading of the joint structural tissues can propagate joint metabolic dysfunction in the form of low-grade inflammation. To date, few studies have attempted to delineate the early cascade responsible for the initiation and perpetuation of stress-mediated inflammation and cartilage breakdown in human joints. Fifteen healthy human male participants performed a walking paradigm on a cross-tilting treadmill platform. Blood samples were collected before exercise, after 30 minutes of flat walking, after 30 minutes of tilted walking, and after an hour of rest. Serum concentrations of the following biomarkers were measured: interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor alpha (TNF)-α, matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, MMP-13, transforming growth factor beta (TGF)-β, tissue inhibitor of matrix metalloproteinase 1 (TIMP)-1, and cartilage oligomeric protein (COMP). Luminex Multiplex analysis of serum showed increased concentrations of COMP, IL-1β, TNF-α, IL-10, and TGF-β from samples collected after flat and cross-tilted treadmill walking compared to baseline. Serum concentrations of MMP-1 and MMP-13 also increased, but primarily in samples collected after tilted walking. Pearson's correlation analysis showed positive correlations between the expression of COMP, TNF-α, IL-10, and MMP-13 at each study timepoint. Stress-mediated increases in serum COMP during exercise are associated with acute changes in pro and anti-inflammatory molecular activity and subsequent changes in molecules linked to joint tissue remodeling and repair.

Analysis of MMP-2-735C/T (rs2285053) and MMP-9-1562C/T (rs3918242) Polymorphisms in the Risk Assessment of Developing Lung Cancer

Matrix metalloproteinase (MMP)-2 and -9 are gelatinases which are capable of degrading type IV collagen and have been linked to cancer invasion and metastatic development. MMP-2 and MMP-9 gene polymorphisms may affect their biological function, and thus their role in cancer development and progression. We analyzed the association of the polymorphism frequencies of MMP-2-735C/T and MMP-9-1562C/T with MMP-2 and MMP-9 serum concentrations, as well as their potential effects in lung cancer patients. We conducted a retrospective, case-control study consisting of 112 lung cancer patients and 100 healthy individuals from a Caucasian population in Poland. Polymerase chain reaction with restriction fragment length polymorphism (PCR/RFLP) and electrophoresis was used to genotype genomic DNA from whole blood samples. MMP-2 and MMP-9 serum concentrations were then determined using ELISA. For statistical analysis, Statistica version 13 from TIBCO Software Inc. was utilized with a significance level &lt;0.05. Logistic regression analysis revealed that MMP-2-735CC (OR = 5.39; 95% CI = 0.62–47.17; p = 0.238504) and -735CT genotype (OR = 7.22; 95% CI = 0.78–67.14; p = 0.072836), as well as MMP-9-1562CC (OR = 1.45; 95% CI = 0.31–6.70; p = 0.757914) and -1562CT genotype (OR = 1.60; 95% CI = 0.33–7.83; p = 0.548801) were associated with a higher risk of lung cancer. There were statistically significant differences observed in the MMP-2 concentration between individuals with the -735CC genotype and the -735CT genotype (non-smoking control: 204.04 ng/mL vs. 237.00 ng/mL, respectively, p = 0.041479; adenocarcinoma patients: 157.69 ng/mL vs. 126.37 ng/mL, respectively, p = 0.013222), as well as differences in the MMP-9 concentration between individuals with the -1562CC genotype and the -1562CT genotype (smoking control: 385.67 ng/mL vs. 562.80 ng/mL, respectively, p = 0.000936; patients with other lung neoplasms: 821.64 ng/mL vs. 928.88 ng/mL, respectively p = 0.023315). The role of MMP-2-735C/T and MMP-9 -1562C/T polymorphisms in an increased risk of lung cancer cannot be dismissed. Specific genotypes affect MMP-2 and MMP-9 concentrations in both lung cancer patients and healthy controls, which may thereby increase lung cancer risk, disease aggressiveness, and patient survival outcomes.

Extracellular matrix collagen biomarker levels in patients who underwent pulmonary endarterectomy.

The role of extracellular matrix collagen biomarkers in chronic thromboembolic pulmonary hypertension (CTEPH) is not well known. Our goal was to investigate the matrix metalloproteinase (MMP)-2 and -9 protein levels in patients with CTETH. This is a prospective, cross-sectional study. Patients with CTETH who underwent pulmonary endarterectomy comprise group 1, and the control group included patients who underwent lung surgery without pulmonary hypertension (group 2) between March 2020 and March 2021. In addition to serum levels of MMP-9, the pulmonary endarterectomy and control pulmonary artery tissue samples were measured by the enzyme-linked immunosorbent assay 4pl, cubic, quadratic and Western blot techniques. Levels of MMP-2, which consist of pro MMP-2/ß-actin and active MMP-2/ß-actin and MMP-9/ß-actin, were measured only in the tissue samples. Forty-eight patients were enrolled consecutively in group 1 (n: 24) and group 2 (n: 24). The serum concentrations of MMP-9 were similar in both groups. Similarly, a comparison of tissue sample levels of pro MMP-2/ß-actin (P = 0.496) and active MMP-2/ß-actin (P = 0.216) showed no significant difference between the groups. The tissue samples from patients with CTETH had significantly lower amounts of MMP-9/ß-actin compared to the control group (P = 0.001). This study indicates that serum levels of extracellular matrix collagen biomarkers were similar in patients with CTETH who were candidates for surgery and in patients who had non-pulmonary hypertension who underwent lung surgery. Differences in levels of MMP-9/ß-actin in tissue samples may play a role in pulmonary vascular remodelling in operable patients.

The association of vitamin D status with oxidative stress biomarkers and matrix metalloproteinases in patients with knee osteoarthritis.

The association of vitamin D status with osteoarthritis (OA) has been demonstrated previously. The current study was performed to examine the association of vitamin D status with oxidative stress markers and matrix metalloproteinases (MMPs) in patients with knee OA. This case-control study was conducted on 124 subjects with mild to moderate knee OA and 65 healthy controls. Demographic data was collected from all participants at baseline. Serum levels of vitamin D as well as markers of oxidative stress including malondialdehyde (MDA), total oxidant status (TOS), superoxide dismutase (SOD), oxidative stress index (OSI), paraoxonase-1 (PON-1), glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC) were evaluated for each participant. Furthermore, serum concentrations of MMP-1, MMP-3, MMP-13, and cartilage oligomeric matrix protein (COMP) were measured. The results of the present study indicated that individuals with vitamin D insufficiency had higher levels of MDA, TOS, SOD, and OSI as well as lower levels of PON-1 and TAC. Based on the linear regression analysis, serum vitamin D levels were inversely correlated with MDA, TOS, SOD, OSI, MMP-1, and MMP-13 and positively associated with TAC levels (p < 0.0001). Patients with sufficient vitamin D levels had lower MMP-1 and MMP-13 levels compared to patients with vitamin D insufficiency (p < 0.001 and p < 0.001, respectively). Findings from this study showed a strong association between vitamin D deficiency and increased oxidative stress and MMPs activity in patients with knee OA.

Matrix Metalloproteinases in Pathogenesis of Ventilation Disorders of the Respiratory System in Patients with Chronic Pulmonary Tuberculosis

The imbalance in matrix metalloproteinase (MMP)/inhibitors system leads to degradation of extracellular matrix of connective tissue and pathological remodeling forming the morphological basis for respiratory dysfunction.The objective: to study the relationship between parameters of MMP/inhibitors system in blood and parameters of ventilation and gas exchange disorders in patients with chronic pulmonary tuberculosis (PTB).Subjects and Methods. Patients with the verified diagnosis of tuberculoma (n = 45) and fibrous-cavernous pulmonary tuberculosis (n = 85) were examined. All patients underwent computed tomography of the chest and assessment of respiratory function. Serum concentrations of MMP-1, -3, -8, -9 and their inhibitors TIMP-1 and α2-macroglobulin (MG) were tested by ELISA (R&amp;D Systems, Minneapolis, MN, USA). Statistica 7.0 and an ANCOVA model were used for statistical analysis which considered the diagnosis and smoking status as factors, and the respiratory function parameters were considered as covariates.Results. In pulmonary tuberculosis patients, the concentrations of MMP-9 and MMP-8 in the blood correlated with extension of lung parenchyma lesions when compared to tuberculomas and fibro-cavernous tuberculosis, MMP-9 and TIMP-1 with changes in lung volumes (R2 = 0.60 and 0.80; p = 0.001), and MMP-8 correlated with functional disorders of gas exchange (R2 = 0.60 and 0.80; p = 0.001). Changes in MMP-1, MMP-3, and α2-MG (R2 = 0.60 and 0.80; p = 0.45) did not correlate with extension of lung parenchymal lesions and decreased lung function.

Predictive value of longitudinal changes of serum matrix metalloproteinase-9 and brain-derived neurotrophic factor in acute ischemic stroke.

BackgroundMatrix metalloproteinase-9 (MMP-9) and brain-derived neurotrophic factor (BDNF) have documented roles in the inflammatory injury cascade of neurovascular units following ischemic brain injury. However, their dynamic changes and predictive values after acute ischemic stroke (AIS) have not been well elucidated.ObjectiveTo investigate the temporal profiles of serum MMP-9 and BDNF concentrations and their relationship with the prognosis in patients with AIS.MethodsMMP-9 and BDNF levels were measured in 42 AIS patients in prospectively collected blood samples, which were taken on the first day (Day 1), the second day (Day 2), and the fifth day (Day 5) after admission. Healthy subjects (n = 40) were used as controls. The AIS patients were divided into groups of good functional prognosis (n = 24) and poor prognosis (n = 18) according to their modified Rankin Scale score at 3 months. Longitudinal analysis of MMP-9 and BDNF and their association with neurological prognosis was performed using repeated measurement ANOVA.ResultsAt baseline (Day 1), the levels of serum MMP-9 and BDNF were significantly higher in the AIS group than in the normal control group (P < 0.01). Repeated measurement ANOVA showed a significant main effect and interaction of MMP-9 between good prognosis and the poor group (P < 0.05). Further simple-effect analysis showed that the MMP-9 level was significantly increased in the poor prognosis group compared with the good prognosis group at T5 (P < 0.05). There were no significant time-dependent or the interaction effect (all P > 0.05), but a main effect (P < 0.05) for BDNF. Compared with the poor prognosis group, the simple-effect results indicated that the BDNF level of the good prognosis group was lower at Day 1, while the same was reversed for expression at Day 5 (P < 0.05).ConclusionMMP-9 and BDNF are closely related to the prognosis of patients with AIS in a time-dependent manner. The dynamic changes of the two biomarkers are superior to baseline levels in predicting the prognosis of AIS patients. A sustained decrease in MMP-9 and an increase in BDNF levels in AIS patients after several days of treatment implied a favourable prognosis.

Serum tissue inhibitor of MMP-1 levels at any moment of the first week of spontaneous intracerebral hemorrhage may predict early mortality.

Aim: To determine whether serum levels of MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 during the firstweek after spontaneous intracerebral hemorrhage (SIH) could be used for mortality prediction. Materials & methods: We included 117 patients with severe supratentorial SIH (defined as Glasgow Coma Scale <9). We determined serum concentrations of MMP-9 and TIMP-1 at days 1, 4 and 8 of severe SIH diagnosis. Results: The area under curve of serum TIMP-1 concentrations at days 1, 4and 8 to predict 30-day mortality of 75% (p<0.001), 82% (p<0.001) and 73% (p<0.001). Conclusion: Thus, the novel findings of our study were that serum levels of TIMP-1 during the first week of SIH may be used for mortality prediction.

MMP-9 as a Biomarker for Predicting Hemorrhagic Strokes in Moyamoya Disease.

Objective: This study was conducted in order to investigate the association of matrix metalloproteinase (MMP)-9 levels with phenotypes of moyamoya disease (MMD).Methods: This study included plasma samples from 84 MMD patients. The clinical variables of these patients were reviewed from the medical record. The serum concentration of tight junction, adherens junction proteins, and MMPs (MMP-2 and MMP-9) was determined using the ELISA method. Patients with hemorrhagic-onset MMD were compared with those with ischemic-onset MMD.Results: Compared with pediatric patients, the expression of MMP-9 was significantly higher, while the MMP-2 and vascular endothelial-cadherin were lower in adult patients. In adult subgroup analysis, hemorrhagic MMD patients exhibited significantly higher serum concentrations of MMP-9 compared with ischemic MMD patients. The ROC curve identified that a baseline serum MMP-9 level >1,011 ng/ml may be associated with spontaneous hemorrhage in adult MMD patients with 70.37% sensitivity and 71.88% specificity [area under curve (AUC), 0.73; 95% CI 0.597–0.864; P = 0.003]. A late Suzuki stage (>4) (OR 4.565, 95% CI 1.028–20.280, P = 0.046) and serum concentrations of MMP-9 >1,011 ng/ml (OR 7.218, 95% CI 1.826–28.533, P = 0.005) are risk predictors of hemorrhages in MMD patients. Hemorrhagic-type MMD patients had higher serum levels of MMP-9 and BBB permeability compared with ischemic-type MMD patients. Adult MMD patients had higher serum levels of MMP-9 and BBB permeability compared with pediatric patients.Conclusions: MMP-9 might serve as a biomarker for hemorrhage prediction in MMD. Serum MMP-9 level >1,011 ng/ml is an independent risk factor of MMD hemorrhagic strokes.

The effects of memantine on the serum concentrations of matrix metalloproteinases and neurologic function of patients with ischemic stroke

Memantine was suggested as a promising treatment for stroke due to its neuroprotective property and efficacy in reducing ischemic brain injury and improving post-ischemic neurological recovery. This pilot, open-label, randomized clinical trial was conducted to investigate the impact of memantine on serum concentrations of matrix metalloproteinases (MMP)-2 and MMP-9, as neuronal damage biomarkers, and neurologic function evaluated by the National Institute of Health Stroke Scale(NIHSS) and Barthelindex(BI) in patients with ischemic stroke. Admitted patients with mild to moderate ischemic stroke were assessed for eligibility, and eligible patients were randomized to the intervention or control group. Enrolled patients in the intervention group received 20 mg memantine every 8 h for five days and then 20 mg daily for three months. Both groups managed with the standard treatments. From 77 randomized patients, 29 participants in the control group and 24 patients in the intervention group completed the study. Data showed that the increase in the serum concentrations of MMP-9 within the first 5 days of the study was significantly lower in the intervention group (P = 0.005). This effect of memantine on the MMP-2 was not significant (P = 0.448). memantine also could significantly improve the neurologic function of the patients according to NIHSS (P < 0.0001) and BI (P = 0.002) during hospitalization and after that. In conclusion, memantine could be considered as a neuroprotective agent in patients with mild to moderate ischemic stroke, based on its significant effects on reducing brain damage and improving neurologic function of the patients.

Polymorphism of IL-1β rs16944(T/C) Associated with Serum Levels of IL-1β and Subsequent Stimulation of Extracellular Matrix Degradation Affects Intervertebral Disk Degeneration Susceptibility.

PurposeTo investigate the association of polymorphism of IL-1β rs16944(T/C) with intervertebral disk degeneration (IDD), explore the possible mechanism and evaluate the predictive value of IL-1β for IDD.Patients and MethodsA total of 196 consecutive patients with IDD were recruited, and 196 healthy controls were matched to these patients based on sex and age (±3 years). The polymorphisms of IL-1β rs16944(T/C), rs1143623(G/C), rs10490571(T/C) and rs2853550(A/G) were determined, and serum IL-1β, MMP-1, MMP-3, MMP-9 and a disintegrin-like and metalloproteinase with thrombospondin motif-4 (ADAMTS-4) levels were measured. Univariate analysis was performed with Student t-test or one-way ANOVA followed by post hoc and Chi-square test. Variables with two-sided P<0.10 were included in multivariate analysis, which employed a backward stepwise logistic regression model. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value.ResultsMultivariate analysis showed that the polymorphism of IL-1β rs16944(T/C) was independently associated with IDD. The risk for IDD was significantly increased in TT and TC genotype compared with CC genotype, and the OR of TT genotype was higher than that of TC genotype. ANOVA analysis showed that serum concentration of IL-1β was highest in IL-1β rs16944 TT genotype, intermediate in TC genotype, and lowest in CC genotype. Similarly, serum concentrations of MMP-3 and ADAMTS-4 demonstrated the same tendency of TT > TC > CC genotype. Serum concentrations of MMP-1 and MMP-9 were higher in TT genotype than in TC and CC genotype. The area under curve (AUC) of IL-1β levels in predicting IDD was 0.788 (SE: 0.023, P=0.001, 95% CI: 0.742–0.834), and the predictive value was modest with a sensitivity of 77.0% and a specificity of 75%.ConclusionPolymorphism of IL-1β rs16944(T/C) affected IDD susceptibility through upregulation of serum levels of IL-1β and subsequent stimulation of ECM degradation. IL-1β levels could be applied in predicting IDD.

Serum matrix metalloproteinases MMP-9 and MMP-2 and tissue inhibitors TIMP-2 in necrotizing enterocolitis

The analysis of the balance of elastase (MMP-2, MMP-9) and TIMP-4 was performed in order to determine their involvement in the pathogenesis of NEC. A progressive duration of NEC with sepsis is accompanied by increased serum concentrations of MMP-9, MMP-2 and TIMP-4. Increases in concentrations of MMP-2&gt;503 ng/ml, MMP-9&gt;812 ng/ml TIMP-4&gt;1404 ng/ml can be regarded as statistically significant predictors of fatal outcome of NEC. The proposed method for determination of the outcomes of NEC in newborns is characterized by high sensitivity (94%) and specificity (87%).

PLASMA LEVELS OFSERUM METALLOPROTEINASES MMP-9, MMP-2 AND TISSUEINHIBITORSTIMP-2 IN NEWBORNS WITH NECROTIZING ENTEROCOLITIS

The analysis of the balance of elastase (MMP-2, MMP-9) and TIMP-4 was performed in order to determine its involvement in the pathogenesis of NEC. A progressive duration of NEC with sepsis is accompanied by increased serum concentrations of MMP-9, MMP-2 and TIMP-4. Increases in concentrations of MMP-2&gt;503 ng/ml, MMP-9&gt;812 ng/ml TIMP-4&gt;1404 ng/ml can be regarded as statistically significant predictors of fatal outcome of NEC. The proposed method for determination of the outcomes of NEC in newborns is characterized by high sensitivity (94%) and specificity (87%).

Assessment of serum concentrations of matrix metalloproteinase 1, matrix metalloproteinase 2 and tissue inhibitors of metalloproteinases 1 in atopic dermatitis in correlation with disease severity and epidermal barrier parameters.

IntroductionMatrix metalloproteinases (MMPs) are a group of proteolytic enzymes, conditioning the integrity of skin cells, however, their role in the inflammatory process of atopic dermatitis (AD) and the direct effect on the epidermal barrier parameters remain unexplained.AimTo assess MMP-1, MMP-2, tissue inhibitors of metalloproteinases (TIMP)-1 concentrations in blood serum in the context of transepidermal water loss (TEWL) and stratum corneum hydration in AD. Moreover, serum levels of MMPs and TIMP-1 were analysed in relation to the Eczema Area and Severity Index (EASI).Material and methodsForty-three AD patients and 22 control group subjects have been investigated. Serum concentrations of MMP-1, MMP-2, and TIMP-1 have been evaluated with ELISA. TEWL and stratum corneum hydration have been assessed with a TM300 Tewameter and a CM825 Corneometer. Skin lesions in patients with AD have been evaluated with the Eczema Area and Severity Index.ResultsMMP-1 and MMP-2 serum concentrations were significantly higher in the AD group. The results of TIMP-1 serum concentration were similar for both groups. The correlation between the serum concentration and the EASI was demonstrated only for MMP-2 for patients with severe and moderate AD. Patients with AD and TIMP-1 serum concentration greater than MMP-1 presented lower TEWL and higher epidermal hydration.ConclusionsThe results of this study warrant further investigation. The predominance of TIMP-1 over MMP-1 in blood serum can potentially limit TEWL and maintain the proper water content of the epidermis. Future work is necessary to establish how reliable the role of MMP-2 concentration is as an indicator of the severity of AD.

Matrix metalloproteinase-9 in pediatric rheumatic heart disease with and without heart failure.

In cardiovascular disorders, the myocardium may be subjected to the breakdown and remodeling of collagen by metalloproteinase-9 (MMP-9). We hypothesized that the serum MMP-9 concentration may be elevated in pediatric patients with rheumatic heart disease (RHD) and heart failure (HF), and its level can be correlated with the HF severity. Thus, in the present study, we aimed to evaluate the sensitivity and accuracy of MMP-9 to predict HF in children with RHD and to determine its effectiveness as an indicator of the degree of HF. This study included 98 consecutive children admitted to the Department of Pediatrics, Zagazig University Hospital, Al Sharqia Governorate, Egypt with newly diagnosed RHD. Their ages ranged from 8.5 to 16 years. Fifty-eight children had RHD without HF while 40 children were complicated with HF which was diagnosed clinically and by echocardiography. A total of 44 healthy children were enrolled as a control group. MMP-9 serum levels were estimated by enzyme-linked immunosorbent assay. The serum MMP-9 concentration was higher in the RHD without HF and RHD with HF groups than this level noted in the control (P<0.001). MMP-9 was a significant predictor of HF; area under the curve (AUC)=0.85 [95% confidence interval (CI), 0.76-0.94]. At the level of 386.9 ng/ml, MMP-9 detected HF with a sensitivity 95% (95% CI, 83.08-99.39), specificity 74.14% (95% CI, 60.96-84.74), positive predictive value 71.70% (95% CI, 61.96-79.75), negative predictive value 95.56% (95% CI, 84.67-98.82) and accuracy 82.65% (95% CI, 73.69-89.56). In addition, MMP-9 showed a significant negative correlation with ejection fraction and fractional shortening (P=0.01 and P=0.02, respectively). In conclusion; MMP-9 may be an independent sensitive marker with which to detect HF in children with RHD and it can predict the prognoses of these patients as it correlates with the severity of HF. Further studies considering MMP-9 in the detection of 'silent' RHD in school aged children and asymptomatic HF in children with known RHD especially in rural areas, are highly recommended.

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.

High serum levels of tissue inhibitor of matrix metalloproteinase-1 during the first week of a malignant middle cerebral artery infarction in non-surviving patients

BackgroundHigher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 early after ischemic stroke have been associated with lower survival. The objectives of this study were to determine serum TIMP-1 levels during the first week of a severe cerebral infarction in surviving and non-surviving patients, and whether those levels during the first week could be used as a mortality biomarker for these patients.MethodsWe included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as computer tomography showing ischaemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale (GCS) ≤ 8. We measured serum levels of matrix metalloproteinases (MMP)-9 and TIMP-1. End-point study was 30-day mortality.ResultsWe found higher TIMP-1 concentrations at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.03) of MMCAI in non- urviving (n = 34) than in surviving (n = 34) patients. We found lower serum MMP-9 concentrations at day 1 (p = 0.03) of MMCAI and no significant differences at days 4 and 8. ROC curve analysis of TIMP-1 concentrations performed at days 1, 4, and 8 of MMCAI showed an area under curve to predict 30-day mortality of 81% (p < 0.001), 80% (p < 0.001) and 72% (p = 0.07) respectively.ConclusionsThe new findings of our study were that non-surviving MMCAI patients showed higher serum TIMP-1 levels during the first week of MMCAI that surviving patients, and those levels during the first week of MMCAI could be used as mortality biomarkers.

Expression and Concentration of Matrix Metalloproteinase 9 and Tissue Inhibitor of Matrix Metalloproteinases 1 in Laryngeal Squamous Cell Carcinoma.

The aim of this study was to assess the expression of MMP-9 and TIMP-1 in cancerous tissue as well as in the serum and plasma concentrations of these proteins in patients with laryngeal cancer and compare the results to the inflammatory reaction in healthy subjects. Twenty-seven patients who were diagnosed with laryngeal carcinoma and selected for total laryngectomy were included in the study group. MMP-9 and TIMP-1 expression in tissues was assessed using immunohistochemical assays. Immunoenzymatic ELISA methods were used to measure MMP-9 and TIMP-1 concentrations in serum and plasma. MMP-9 and TIMP-1 were identified in tumor cells and in the tumor stroma compartment, as well as in macroscopically healthy mucous membrane. MMP-9 expression was more significant in tumor stroma than in the perimatrix of the mucous membrane (p = 0.047). TIMP-1 expression was significantly higher in the matrix and perimatrix of the mucous membrane than in cancer tissue (p = 0.0093) and the tumor stroma compartment (p < 0.0001). Expression of TIMP-1 was observed more frequently in tumors without infiltrated lymph nodes (p = 0.009). Serum concentrations of MMP-9 and TIMP-1 as well as plasma TIMP-1 concentration were significantly higher in the study group than in the control group (p = 0.0004, p = 0.002, and p = 0.0001, respectively). A significantly higher TIMP-1 level in plasma was found in patients with poorly differentiated tumors compared to G1 and G2 (p = 0.046). MMP-9/TIMP-1 rate in serum was significantly higher in the study group than in the control group. The balance between the level of MMP-9 and TIMP-1 is disrupted in laryngeal cancer. The significant correlation between TIMP-1 expression and the presence of lymph node metastases, as well as that between TIMP-1 plasma concentration and stage of cancer histological differentiation, might indicate the importance of this molecule as a prognostic factor during carcinogenesis.

Liver X receptor agonist T0901317 inhibits the migration and invasion of non-small-cell lung cancer cells in vivo and in vitro.

Liver X receptors are recognized as important regulators of cholesterol, fatty acid metabolism, inflammatory responses, and glucose homeostasis. The antineoplastic properties of synthetic liver X receptor (LXR) agonists (T0901317 and GW3965) have been reported in human carcinomas. Epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) is a first-line treatment for non-small-cell lung cancer patients with EGFR mutations. We used scratch and transwell assays to analyze cell migration and invasion. We evaluated tumor migration and invasion in vitro using a fluorescent orthotopic lung cancer model. An MMP9 (mouse) enzyme-linked immunosorbent assay kit was used to measure serum MMP9 concentrations. Protein expression was identified by western blot assays. In this study, we determined the effects of T0901317 and/or an EGFR-TKI on the lung cancer cell lines A549 and HCC827-8-1 in vitro and in vivo. We confirmed that the combination of the LXR agonist T0901317 and gefitinib can inhibit the migration and invasion of lung cancer both in vivo and in vitro, and this effect was possibly achieved by the inhibition of the ERK/MAPK signaling pathway. Our study showed that the combination of the LXR agonist T0901317 and gefitinib can inhibit the migration and invasion of lung cancer both in vivo and in vitro.