Tissue Inhibitor Of Metalloproteinase-1 Levels Research Articles

Melatonin Prevents UVB-Induced Skin Photoaging by Inhibiting Oxidative Damage and MMP Expression through JNK/AP-1 Signaling Pathway in Human Dermal Fibroblasts.

Exposure to ultraviolet (UV) irradiation causes damage to the skin and induces photoaging. UV irradiation stimulates production of reactive oxygen/nitrogen species, which results in activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPK) in fibroblasts. MAPKs are responsible for activation of activator protein-1 (AP-1), which subsequently upregulates expression of matrix metalloproteinases (MMPs). Melatonin is a potent free radical scavenger which is known to have photoprotective effects. The aim of this study is to investigate the underlying molecular mechanisms for the photoprotective effects of melatonin in UVB-irradiated primary human dermal fibroblasts (HDFs) in terms of EGFR activation, oxidative/nitrosative damage, JNK/AP-1 activation, MMP activities, and the levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) and type I procollagen (PIP-C). In this study, HDFs were pretreated with 1 μM of melatonin and then irradiated with 0.1 J/cm2 of UVB. Changes in the molecules were analyzed at different time points. Melatonin inhibited UVB-induced oxidative/nitrosative stress damage by reducing malondialdehyde, the ratio of oxidized/reduced glutathione, and nitrotyrosine. Melatonin downregulated UV-induced activation of EGFR and the JNK/AP-1 signaling pathway. UVB-induced activities of MMP-1 and MMP-3 were decreased and levels of TIMP-1 and PIP-C were increased by melatonin. These findings suggest that melatonin can protect against the adverse effects of UVB radiation by inhibiting MMP-1 and MMP-3 activity and increasing TIMP-1 and PIP-C levels, probably through the suppression of oxidative/nitrosative damage, EGFR, and JNK/AP-1 activation in HDFs.

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the hippocampus of lithium-pilocarpine-induced acute epileptic rats.

Epilepsy is characterised by abnormal neuronal discharges, including aberrant expression of extracellular matrix (ECM) components and synaptic plasticity stabilisation. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) interact to remodel the ECM in the central nervous system (CNS), to modulate synaptic plasticity in epileptogenesis. In the present study, the expression of MMP activators (tPA and uPA), 10 MMPs, and 3 TIMPs was detected by western blot analysis and quantitative polymerase chain reaction (RT-qPCR) to assess their potential pathogenetic role in the epileptogenesis in the hippocampus of lithium-pilocarpine hydrochloride-induced epileptic rats. Our results showed that The expression of MMP7 and MMP14 was impeded in the hippocampus of lithium-pilocarpine-induced acute epileptic rats compared with that in controls. The transcriptional level of tPA was enhanced on day 1 post-seizure in the hippocampus, while the levels of several MMPs and TIMPs did not change on days 1 and 3 post-seizure compared with that in controls. The expression of MMPs and TIMPs reflects a novel feature of epileptogenesis and may offer new perspectives for future therapeutic interventions.

Regulation of endothelial nitric oxide synthase in cardiac remodeling

ObjectivesOur previous study demonstrated that endothelial nitric oxide synthase (eNOS) gene serves as a candidate for modifiers of hypertrophic cardiomyopathy (HCM), which alters severity of HCM phenotypes. Herein, we sought to further elucidate the role of eNOS on cardiac myocyte hypertrophy and fibrosis, the major phenotypes of HCM. MethodsMale eNOS-deficient mice (eNOS−/−) and wild type control mice (eNOS+/+, C57B1/6 J) were used in this study. Myocyte size was analyzed in hematoxylin/eosin stained sections using an image analyzing system. Cardiac β-myosin heavy chain (β-MHC) and α-skeletal actin (α-SKA) levels, markers of myocyte hypertrophy were evaluated by Western blot. Cardiac collagen volume fraction (CVF) was examined in picrosirius red stained section using an image analyzing system. Cardiac expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and transforming growth factor beta 1 (TGF-β1), markers of fibrosis, were determined by Western blot. ResultsCompared to eNOS+/+ mice, we found that; 1) myocyte size was significantly increased in eNOS−/− mice; 2) cardiac expression of β-MHC was markedly elevated, while α-SKA levels remained unchanged in eNOS−/− mice; 3) cardiac total and interstitial CVF levels were significantly higher in eNOS−/− mice; and 4) cardiac TIMP-1 levels were significantly greater in eNOS−/− mice, however, cardiac TGF-β1 was not differently expressed between the two groups. ConclusionThe current study revealed that eNOS plays a beneficial role in cardiac remodeling, preventing the heart from development of myocyte hypertrophy and cardiac fibrosis. These findings support our previous report that eNOS may modify the severity of HCM phenotypes.

Altered TIMP-3 Levels in the Cerebrospinal Fluid and Plasma of Patients with Alzheimer's Disease.

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment and is suggested to play an indirect role in regulating Aβ production and the pathophysiology of Aβ deposition in brains. However, studies on the amount of TIMP-3 in bodily fluids of Alzheimer’s disease (AD) patients have not been conducted. Here, we investigated the relationship between fluid TIMP-3 levels and AD pathology. We first showed that the fluid levels of TIMP-3 were lower in AD dementia patients compared with in non-AD patients. ELISA results revealed that plasma levels of TIMP-3 in 65 patients with AD were significantly lower than those in 115 healthy control subjects and 71 mild cognitive impairment (MCI) subjects. Furthermore, we found that cerebrospinal fluid (CSF) level of TIMP-3 was decreased in AD compared with that in healthy control. These data suggest that fluid TIMP-3 levels negatively correlated with progress of cognitive decline. Collectively, our study suggests that alterations of fluid TIMP-3 levels might be associated with AD pathology.

Increase in Serum MMP-9 and TIMP-1 Concentrations during Alcohol Intoxication in Adolescents-A Preliminary Study.

Background: Alcohol consumption by adolescents is responsible for a number of adverse health and social outcomes. Despite the well-established effect of alcohol use on the development of alcoholic liver disease, the relationship between the pattern of alcohol consumption and liver fibrosis is still unclear. This study is a follow-up to work on liver damage from alcohol intoxication. The aim of our study was to explore the early effects of alcohol intoxication on liver fibrosis in adolescents. Methods: The prospective study included 57 adolescents aged 14–17 years admitted to the emergency department (ED) from February 2017 to June 2018 due to acute alcohol intoxication. Serum levels of amino terminal propeptide of type III procollagen (PIIINP), type IV collagen, matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were determined by enzyme-linked immunosorbent assays. Results: There were significant differences in MMP-9 (p = 0.02) and TIMP-1 (p = 0.007) levels between the study and control groups. Liver parameters and selected markers of fibrosis were similar in groups in terms of blood alcohol concentrations (BAC). MMP-9 was positively correlated with alanine aminotransferase (ALT) (r = 0.38; p = 0.004) and total bilirubin (r = 0.39; p = 0.004). Positive significant correlations were also found between TIMP-1 and ALT (r = 0.47; p < 0.001), AST (r = 0.29; p = 0.03) and total bilirubin (r = 0.32; p = 0.02). In receiver operating characteristic (ROC) analysis, MMP-9 (AUC = 0.67, p = 0.02) and TIMP-1 (AUC = 0.69, p = 0.003) allowed for the differentiation of patients with and without alcohol intoxication. Conclusion: Our results show that even a single episode of alcohol intoxication in adolescents can lead to imbalance in markers of fibrosis.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) serum level and genetic polymorphisms associated with cutaneous leishmania infections

IntroductionCutaneous leishmaniasis is considered a parasitic contagion resulting from the flagellated parasite belonging to the genus of Leishmania. Also, cutaneous leishmaniasis is a zoonotic ailment transmitted through the bloodsucking sand-flies bite (belonging to the Phlebotomus genus). The disease's reservoirs included wild or semi-domesticated animals, in general rodents and dogs. Tissue inhibitor metalloproteinase-1 (TIMP-1) is one of the extracellular matrix proteins that have a role in vessel wall degeneration and aneurysm development. In addition, it belongs to the zinc-dependent endopeptidases family that are involved in the degradation of connective tissues proteins which are included in vascular integrity maintenance. The Genetic deviations in the TIMP-1 genes might impact their expression at the transcription level or the enzyme activity. Therefore, the present study aimed to detect the impact of TIMP-1 serum level and single nucleotide polymorphisms (SNPs) rs41454248 and rs1043428 among the cutaneous leishmaniasis patients’ group compared to the control group. SubjectsSeventy-five cutaneous leishmaniasis patients (39 males and 36 females) with the age mean 23.91 ± 13.14 years participated in this study, compared to the matched number, age, and gender of a healthy control group (75: 38 males and 37 females) with the age mean 22.84 ± 4.35 years. In the current study, the serum level of TIM-1 and rs41454248 and rs1043428 SNPs were studied among the cutaneous leishmaniasis patients’ group compared to the control group. ResultsThe findings of the TIMP-1 level referred to a significant decrease among the cutaneous leishmaniasis patients’ group compared to the healthy control group (26339.67 ± 900.79 vs. 33480.25 ± 1098.63). Such, the rs41454248 SNPs findings referred that the GG genotype and G allele were non-significantly increased frequency percentage in cutaneous leishmaniasis patients group compared to the healthy control group (29.33 vs. 18.67%, OR: 1.81, p = 0.180; 55.0 vs. 47.0%, OR: 1.38, p = 0.204 respectively). Also, the high OR value of GG genotype and G allele referred to this genotype and allele might be a risk factor for cutaneous leishmaniasis. Likewise, the findings of rs1043428 SNPs appeared that the CC genotype and C allele were significantly increased frequency percentage in cutaneous leishmaniasis patients' group compared to the control group (37.33 vs. 4.0%, OR: 14.30, p = 3.6 × 10−7; 57.0 vs. 21.33, OR: 4.82, p = 4.5 × 10−10). Also, the high OR value of CC genotype and C allele referred to this genotype and allele might be risk factors for cutaneous leishmaniasis. In addition, the CG genotype appeared a non-significant increased frequency percentage in the patients' group compared to the control group and the value of OR referred to might be a risk factor for cutaneous leishmaniasis (33.33 vs. 25.33, OR: 1.47, p = 0.370). In addition, the serum level of TIMP-1 with the rs41454248 was significantly decreased in GA and AA genotypes of the patients’ group compared to the control. While the level was non-significantly decreased in the GG genotype of the patients' group compared to the control group. Likewise, the level of TIMP-1 with the rs1043428 was non-significantly decreased in all genotypes (except TT genotype) of the patients' group compared to the control. Whereas, a significant decrease level was appeared in the TT genotype of the patients' group compared to the healthy control group. ConclusionThe current findings demonstrated a significant association between TIMP-1 serum level and genetic polymorphisms (rs1043428 and rs41454248) among cutaneous leishmaniasis patients.

Overwork Affects Extracellular Matrix of Arterial Vessel Wall in Rats

Objective To explore the effect of overwork (OW) on extracellular matrix of arterial vessel wall in rats. Methods Random number grouping method was employed to assign 18 Sprague-Dawley rats into three groups(n=6):the control group(no special treatment),group OW(forced swimming twice a day for 15 days),and sleep deficiency(SD)+OW group(in addition to forced swimming twice a day,the rats were put on the platforms in water to limit sleep for 15 days).On the 16th day,the abdominal aorta and common carotid artery were collected after blood sampling from heart under deep anesthesia.A part of the abdominal aorta sample was taken for Masson staining of collagen fiber,and Verhoeff-Van Gieson staining was carried out for the elastic fiber of common carotid artery.Image J was employed for the quantitative analysis of collagen fiber and elastic fiber content.The expression of collagen 1(Col-1) protein was quantified by immunohistochemistry and the ultrastructure of vascular matrix was examined by transmission electron microscopy.The other part of the abdominal aorta sample was used to determine the mRNA levels of matrix metalloproteinase(MMP)-1,MMP-2,MMP-9,tissue inhibitor of metalloproteinases-1(TIMP-1),and Col-1 by quantitative real-time polymerase chain reaction. Results Compared with that in control group,the content of collagen fiber in groups OW and SD+OW had no significant change(all P>0.05);the content of elastic fiber in groups OW and SD+OW decreased(all P<0.001) and had no significant difference between each other(P>0.05).The vascular vessel wall of group OW showed slight fiber breakage,while that of group SD+OW presented wormhole-like or spongy fiber fragmentation.The mRNA levels of MMP-1 and MMP-2 in groups OW and SD+OW had no significant difference between each other(P>0.05) but were higher than that in control group(all P<0.001).The mRNA levels of MMP-9 and TIMP-1 had no significant difference among the three groups(all P>0.05).Groups OW and SD+OW had lower mRNA level(all P<0.001) and protein level(all P<0.001) of Col-1 than control group,while the mRNA and protein levels of Col-1 had no significant difference between groups OW and SD+OW(P>0.05). Conclusion OW can reduce the content of Col-1 and elastic fibers in the extracellular matrix of arterial vessels,destroy the elastic lamina of vascular wall,up-regulate the expression of MMP-1 and MMP-2,thereby injuring arterial vessels.

Elevated Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury

Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure. Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted AKI with a sensitivity of 79% and specificity of 60%. Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.

TIMP-1: A Circulating Biomarker for Pulmonary Hypertension Diagnosis Among Chronic Obstructive Pulmonary Disease Patients.

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and induces increased mortality among COPD patients. However, there are no blood biomarkers to identify PH in COPD. Here, we investigated whether circulating angiogenic factors and cytokines could serve as (a) biomarker (s) for COPD-PH patients. Using Angiogenesis and Cytokine proteome profile array assay, we measured the level of 36 cytokines and 55 angiogenesis-associated proteins in plasma from four COPD patients with PH (COPD-PH) and four COPD patients without PH (COPD), respectively, tissue inhibitor of metalloproteinase 1 (TIMP-1) and thrombospondin 1(TSP-1) were significantly different between the two groups. Enzyme-linked immunosorbent assay (ELISA) was applied to measured TIMP-1 and TSP-1 in a validation cohort (COPD-PH, n = 28; COPD, n = 18), and TIMP-1 was the only factor that was significantly different between COPD-PH and COPD patients (P < 0.01). Logistic regression analysis demonstrated that elevated TIMP-1 was an independent risk factor for COPD-PH [odds ratio (OR) = 1.258, 95% CI: 1.005–1.574, P < 0.05). Next, we explored the expression level and function of TIMP-1 in human pulmonary arterial smooth muscle cells (hPASMCs) exposed to cigarette smoking extract (CSE, a major etiological factor of COPD). In cultured hPASMCs, CSE treatment increased both TIMP-1 protein level and cell proliferation, and exogenous TIMP-1 (25 ng/mL) treatment inhibited CSE-induced hPASMCs proliferation. Overall, our results indicated that TIMP-1 elevation could serve as a circulating biomarker to diagnose PH among COPD patients, and TIMP-1 elevation in COPD-PH could be adaptive.

Changes of heparin-binding protein in severe burn patients during shock stage and its effects on human umbilical vein endothelial cells and neutrophils

Changes of heparin-binding protein in severe burn patients during shock stage and its effects on human umbilical vein endothelial cells and neutrophils

Left ventricle structure and function relations with the levels of plasma markers of fibrosis in hypertensive patients with NonSTEMI

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. The myocardial fibrosis lies in the basis of left ventricle remodelling in patients with hypertension. Cardiomyocites hypertrophy, fibroblasts proliferation, enlargement of interstitial collagen volume and their ratio disorders may increase severity of stroke and myocardial infarction. Purpose. The purpose of the study is to evaluate relations between the plasma levels of myocardium fibrosis markers and left ventricle remodelling, systolic and diastolic function in hypertensive patients with NonSTEMI. Methods. Were examined 138 hypertensive patients (both men and women) with NonSTEMI. The mean age of patients was 51.2 (11.2) years. Patients with arrhythmias and conduction abnormalities, diabetes mellitus and autoimmune diseases were excluded form the study. In all patients was performed ECG in 12 standard leads; EchoCG (according to ASE/EACVI 2015 recommendations); evaluation plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and insulin-like growth factor 1 (IGF-1). HF NYHA functional class was determined by performing 6MWT. Statistical significance was defined at the level of methods for p &amp;lt; 0,05. Results. The averaged levels for plasma markers of myocardium fibrosis were: TIMP-1 - 322.0 (250.0; 483.5) ng/mL; IGF-1 - 160.0 (141.0; 175.0) ng/mL. Results of correlative analysis revealed relations between IGF-1 and ILV mass (R=-0.59; p &amp;lt; 0.001), and weak correlation between IGF-1 and E/e" averaged (R=-0.19; p = 0.027) (Picture 1). These negative correlations may be explained by the growth in both fibroblasts and collagen production in myocardium. Also there were positive correlations between TIMP-1 and ILV mass (R = 0.63; p &amp;lt; 0.001) and TIMP-1 and E/e" average (R = 0.37; p &amp;lt; 0.001) (Picture 1) which may be due to an increase of myocardial stiffness as the result of fibrosis activity. The results of the comparison of TIMP-1 and ICF-1 plasma levels, structural and functional parameters of the LV in groups of patients with different types of LV geometry can be seen in Table 1. Conclusion. Thus, the results of the study show that plasma markers of fibrosis was significantly higher in patients with concentric and eccentric LV hypertrophy which may reflects the higher levels of myocardium stiffness. Abstract Table 1. Abstract Figure. Picture 1.

Circulating Collagen Metabolites and the Enhanced Liver Fibrosis (ELF) Score as Fibrosis Markers in Systemic Sclerosis.

Background: Serum fibrosis markers for systemic sclerosis (SSc) remain limited. The Enhanced Liver Fibrosis (ELF) score is a collagen marker set consisting of procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1), and hyaluronic acid (HA). This longitudinal study aimed to examine the performance of the ELF score and its single analytes as surrogate outcome measures of fibrosis in SSc. Methods: Eighty-five SSc patients fulfilling the 2013 ACR/EULAR criteria with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, HA, and the ELF score were measured and correlated with clinical variables including the modified Rodnan skin score (mRSS) and interstitial lung disease (ILD). Twenty SSc patients underwent a follow-up serological testing and mRSS evaluation during treatment with immunosuppressants and/or anti-fibrotic drugs. Results: Serum PIIINP, TIMP-1, and ELF score were significantly higher in patients with SSc than in healthy controls [PIIINP: 10.31 (7.83–14.10) vs. 5.61 (4.69–6.30), p < .001; TIMP-1: 110.73 (66.21–192.45) vs. 61.81 (48.86–85.24), p < .001; ELF: 10.34 (9.91–10.86) vs. 9.68 (9.38–9.99), p < .001]. Even higher levels of PIIINP, TIMP-1, and ELF score were found in patients with diffuse cutaneous SSc than those with limited cutaneous SSc. At baseline, both PIIINP and ELF score showed good correlation with mRSS (PIIINP: r = .586, p < .001; ELF: r = .482, p < .001). Longitudinal analysis showed that change in PIIINP positively correlated with change in mRSS (r = 0.701, p = .001), while change in ELF score were not related, in a statistical context, to the change in mRSS (ELF: r = .140, p = .555). Serum TIMP-1 was significantly higher in SSc patients with ILD, compared to the matched group of patients without ILD [109.45 (93.05–200.09) vs. 65.50 (40.57–110.73), p = 0.007]. Conclusion: In patients with SSc, the ELF score well correlates with the extent of skin fibrosis, while serum PIIINP is a sensitive marker for longitudinal changes of skin fibrosis. In the future, circulating collagen metabolites may potentially be used to evaluate therapeutic effects of anti-fibrotic treatments in the disease.

To study the dynamics of serum levels of vascular remodeling in patients with hypertension, including in combination with type 2 diabetes mellitus during 12‑month therapy with perindopril A.

Aim To study the dynamics of serum markers for vascular remodeling in patients with arterial hypertension (AH), including AH associated with type 2 diabetes mellitus (DM2) during the 12-month treatment with the angiotensin-converting enzyme (ACE) inhibitor, perindopril A.Material and methods The study included patients with grade 1-2 AH with or without type 2 DM (30 and 32, respectively). Perindopril A 10 mg/day was administered for the outpatient correction of previous, ineffective antihypertensive therapy. The following biomarkers were measured for all patients at baseline and at 12 months: matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), E-selectin, endothelin 1, transforming growth factor β-1 (TGF-β1), and von Willebrand factor (WF). Laboratory tests were performed with enzyme immunoassay.Results After 12 months of the perindopril A (perindopril arginine) 10 mg/day treatment, both groups achieved the goal blood pressure. Evaluation of biomarker dynamics during the perindopril A treatment showed significant decreases in MMP-9, TIMP-1, and endothelin 1 in the AH group; then the level of TIMP-1 returned to normal values (р&lt;0.05). In the AH+DM2 group, the MMP-9 concentration was significantly decreased (р&lt;0.05); the other values did not show any significant differences. In both groups, MMP-9 was significantly decreased (28.6 % (р=0.01) in group 1 and 33.2 % (р=0.00) in group 2. Notably, in none of these groups, did this index reach normal values. Also, there were no significant differences in this index between the groups (р=0.66). It should be noted that the decreases in TIMP-1 were significantly different between the groups (р=0.001). Thus, this biomarker did not significantly decrease in patients with AH and DM2 (р=0.26) whereas in group 1 (AH without DM2), the level of TIMP-1 decreased by 39.3 % and reached the normal range (р=0.005).Conclusion Concentrations of biomarkers were decreased in both groups. However, in the AH group, there were statistically significant decreases in the markers that reflect processes of fibrosis and vasoconstriction. At the same time in the AH+DM2 group, there was no significant dynamics of the biomarkers, which was most likely due to more pronounced damage of blood vessels. However, the decrease in MMP-9 may indicate an alleviation of fibrotic processes in arterial walls. These results allow a conclusion that the long-term treatment with the ACE inhibitor, perindopril A, may reverse remodeling of the vascular changes that are called "early vascular ageing".r aging".

Correlation between markers of fibrosis and myocardial remodeling in patients with various course of hypertrophic cardiomyopathy

Aim. To assess the relationship between fibrosis markers and structural and functional parameters in patients with various types of hypertrophic cardiomyopathy (HCM).Material and methods. This prospective comparative non-randomized study included 49 patients with HCM. Patients were divided into 3 groups according to the disease course: group 1 — stable course (n=12; men, 8 (67%), mean age ‒ 41±12 years); group 2 — progressive course (n=26; men, men, 16 (61%). mean age — 57±11 years); group 3 — patients with atrial fibrillation (AF) (n=11; men, 4 (36%), mean age — 63±6 years). Patients underwent standard clinical and paraclinical investigations. The levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined in all patients using enzyme-linked immunosorbent assay in blood serum.Results. In all patients with HCM, elevated levels of MMP-9 and TIMP-1 are noted compared to the reference values. In group 1, the MMP-9 level [Me (Q1; Q3)] was 226 (201;271) ng/ml; TIMP-1 — 410 (267;488) ng/ml; in group 2, the MMP-9 level was 236 (187;285) ng/ml; TIMP-1 — 421 (321;499) ng/ml. In the course with AF, the MMP-9 level was 260 (228;296) ng/ml, while TIMP-1 — 381,5 (305;466) ng/ml; no significant difference was revealed (p=0,59; p=0,90, respectively). A correlation was found between age and MMP-9 levels, as well as between MMP-9 levels and left atrial volume (p=0,034; p=0,035, respectively).Conclusion. The high activity of matrix metalloproteinases and their tissue inhibitors reflects enhanced fibrosis and myocardial remodeling in HCM, which is especially characteristic of patients with AF.

Extracellular Vesicles from miR-148a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Relieve Hepatic Fibrosis by Targeting Smad4.

Liver fibrosis is a hallmark feature of many chronic liver diseases, which is the leading cause of morbidity and mortality worldwide. Bone marrow mesenchymal stem cells (BMSCs)-derived extracellular vesicles have been applied in many diseases. In this study, we aimed to explore the specific mechanism of extracellular vesicles from BMSCs in liver fibrosis. Bioinformatics analysis was employed to screen miRNA and its target mRNA. Sirius Red staining was carried out to examine fibrosis in liver tissues. Extracellular vesicle morphology was assessed using Transmission Electron Microscopy. Quantitative real-time PCR (qRT-PCR) and western blotting analysis were performed to detect the expressions of miR-148a-5p, Smad4, transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinase 1 (TIMP-1), Collagen I, α-smooth muscle actin (α-SMA), and extracellular vesicle markers CD9, TSG101, CD63, and calnexin. Dual-luciferase report gene assay was used for the luciferase activity analysis. Bioinformatics analysis revealed miR-148a-5p as a regulator in liver fibrosis. QRT-PCR results indicated that miR-148a-5p was lowly expressed in both thioacetamide (TAA)-induced mice and TGF-β1-activated hepatic stellate cells. Extracellular vesicles from miR-148a-5p enriched BMSCs downregulated the mRNA and protein levels of TGF-β1, TIMP-1, Collagen I,and α-SMA. Further bioinformatics analysis indicated that Smad4 was related to liver fibrosis. Furthermore, the dual-luciferase report gene assay confirmed the binding relationship between miR-148a-5p and Smad4. Extracellular vesicles from miR-148a-5p enriched BMSCs attenuated hepatic fibrosis in liver fibrosis by targeting Smad4.

Urinary TIMP-2 and IGFBP-7 protein levels as early predictors of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a frequent complication associated with on-pump cardiac surgery. Early recognition may alter their prognosis. Therefore, the urinary concentrations of TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein) as predictors for AKI were studied. Repetitive blood and urine samples were collected consecutively from 50 patients. Demographic, intra-, and postoperative data were recorded prospectively. To calculate the production of the TIMP-2 and IGFBP-7 protein concentrations, urinary samples were taken preoperatively, intraoperatively at 30 and 60 min after aortic clamping and at 0, 6, 12, and 24 h after admission to the intensive care unit (ICU). AKI occurred in 14 patients (28%), all of them at Kidney Disease: Improving Global Outcomes stage 1. Predictive value for [TIMP-2] × [IGFBP7] was shown at 0 and 24 h after admission to ICU. At 0 h, the sensitivity was 84.6% and the specificity 55.6% for an ideal calculated cutoff at 0.07. After 24 h, the ideal cutoff amounted to 0.35 with a sensitivity of 53.8% and a specificity of 88.2%. The receiver operating characteristic curves demonstrated areas under the curve of 0.725 and 0.718. The suggested cutoffs of 0.3 and 2.0 could not be confirmed. The serum creatinine was reached to the peak median within 48 h after admission to ICU. Postoperative risk assessment for the development of AKI can be established by . Previously suggested cutoff values could not be confirmed. A correlation with urinary dilution parameters may enable the identification of more universal cutoffs.

Comparison of ADAMTS Levels in Pulp Tissue Samples of Healthy and Symptomatic Irreversible Pulpitis Teeth

IntroductionThe aim of this study was to compare the levels of different A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS; ie, ADAMTS-1, -4, and -9]) related to the breakdown of the proteoglycans and tissue inhibitor of metalloproteinase 3 (TIMP-3) levels that inhibit ADAMTS in the extracellular matrix of healthy pulp and symptomatic irreversible pulpitis. MethodsPulp tissue samples diagnosed with healthy and symptomatic irreversible pulpitis were collected from 48 participants. Healthy and inflamed pulps were directly transferred to Eppendorf tubes (Labosel, Istanbul, Turkey) and stored at −80°C (Nüve-DF490; Nüve, Ankara, Turkey) until further use. Routine root canal treatment procedures for the teeth were performed, after which the treatment process was completed. The levels of ADAMTS-1, -4, and -9 and TIMP-3 were measured in supernatants of human dental pulp tissue extracts using enzyme-linked immunosorbent assay kits (USCN, Wuhan, China). The independent sample t test and 1-way analysis of variance were used for parametric data, and the Kruskal-Wallis and Mann-Whitney U tests were used for nonparametric data. ResultsThere was a statistically significant difference between ADAMTS-1 and -9 and TIMP-3 levels of the healthy pulp and pulpitis groups (P < .05), but there was no significant difference for ADAMTS-4 levels (P > .05). It was found that the levels of ADAMTS-1 and -9 were higher in the pulpitis group compared with the healthy pulp group, whereas the TIMP-3 level decreased (P < .05). ConclusionsAs a result of this study, it was concluded that ADAMTS-1 and -9 and TIMP-3 might have a role in pulpal inflammation, whereas ADAMTS-4 was not related to pulpal inflammation.

Some indicators of left ventricular dysfunction in hypertensive patients, depending on the level of matrix metalloproteinases and tissue inhibitors of metalloproteinase-1

Aim. To study the level of matrix metalloproteinases-1 and -2, and tissue inhibitor of metalloproteinases-1, the indicator of left ventricular myocardial deformation in patients with stage 12 hypertension. Methods. 114 patients (40 women and 74 men) with hypertension of 12 stages observed in the cardiology Department of the Road clinical hospital Chita II were examined. The median age was 428.3 years. Left ventriclular diastolic function was studied by using tissue Doppler imaging in apical four-chamber views. Serum matrix metalloproteinase-1, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinases-1 levels were measured in all patients on automated immunoassay analyzers using ready-to-use ELISA kits. Results. An increase in serum levels of matrix metalloproteinases-1 and -2 in the group of patients with hypertension and diastolic dysfunction by 46 and 47%, respectively, was found against increased levels of serum tissue inhibitor of metalloproteinase-1 (р=0.049). In patients with diastole dysfunction, myocardial global longitudinal strain was decreased in was observed by 22.8% compared with patients without diastole dysfunction (p 0.05). The analysis revealed a moderate negative relationship between left ventricular global longitudinal strain and the serum levels of metalloproteinases-2 (r=0.64, p 0.05). Conclusion. In patients with hypertension and left ventricular diastolic dysfunction, a decrease in left ventricular global longitudinal strain is associated with the serum level of matrix metalloproteinase-2; a tissue inhibitor of metalloproteinases-1 is unrelated to left ventricular global myocardial strain.

Elevated Levels of Urinary Biomarkers TIMP-2 and IGFBP-7 Predict Acute Kidney Injury in Neonates after Congenital Heart Surgery.

Objectives This article investigated the utility of urine biomarkers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) in identifying acute kidney injury (AKI) in neonates after congenital heart surgery (CHS). TIMP-2 and IGFBP-7 are cell cycle arrest proteins detected in urine during periods of kidney stress/injury. Methods We conducted a single-center, prospective study between September 2017 and May 2019 with neonates undergoing CHS requiring cardiopulmonary bypass (CPB). Urine samples were analyzed using NephroCheck prior to surgery and 6, 12, 24, and 96 hours post-CPB. All patients were evaluated using the Acute Kidney Injury Network (AKIN) criteria. Wilcoxon rank sum tests were used to compare the medians of the [TIMP-2*IGFBP-7] values in the AKIN negative and positive groups at each time point. Receiver operating characteristic curves were used to measure how well the [TIMP-2*IGFBP-7] values predict AKIN status. Results Thirty-six patients were included. No patients met the AKIN criteria for AKI preoperatively. Postoperatively, 19 patients (53%) met the AKIN criteria for AKI diagnosis: 13 (36%) stage 1, 5 (14%) stage 2, and 1 (3%) stage 3. None required renal replacement therapy. At the 24-hour time points, patients who met the AKIN criteria for AKI had a statistically significantly higher [TIMP-2*IGFBP7] values than the patients without AKI (1.1 vs. 0.27 [ng/mL] 2 /1,000) at 24 hours (adj- p = 0.0019). Conclusion AKI is a serious complication associated with adverse outcomes in patients undergoing cardiac surgery. [TIMP-2*IGFBP-7] urinary level 24 hours after CPB is a good predictor of AKI in this population.

Comprehensive analysis of matrix metalloproteinases and their inhibitors in head and neck squamous cell carcinoma

Objective: This study aimed to explore the association of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) with cancer progression and prognosis in head and neck squamous cell carcinoma (HNSCC). Methods: Differentially expressed genes (DEGs) were identified by LIMMA package using R software. The correlation between the expression levels of MMPs and TIMPs in HNSCC cancer samples and adjacent normal tissue samples was performed using Pearson correlation analysis. The Kruskal-Wallis test (H-test) was used to determine the association between the expression level of MMPs/TIMPs and HNSCC clinical stage. The survival result was expressed as a KM curve, and the log-rank test was used for statistical analysis. Lasso regression and multivariate Cox regression analyses were used to examine whether the gene signature based on MMPs and TIMPs was an independent prognostic factor in patients with HNSCC. Results: Among the top 10 most up-regulated genes in HNSCC cancer tissues when compared with normal tissues, six genes belonged to the MMPs. Spearman correlation analysis revealed that only MMP11 and MMP23B were positively correlated with tumor stage. Survival analysis showed that patients with a high expression of MMP14, MMP20, TIMP1, and TIMP4 had a worse prognosis than low expression patients. Additionally, a novel five-gene (MMP3, MMP17, MMP19, MMP24, and TIMP1) signature was constructed and significantly associated with prognosis as an independent prognostic signature. Conclusions: Our data show that the accuracy of a single gene of MMP or TIMP as predictors of progression and prognosis of HNSCC is limited, although some studies have proposed that MMPs act as driving factors for cancer progression. The prediction performance of the five-gene signature prediction model was much better than that of the gene signatures based on every single gene in prognosis prediction.