Tissue Inhibitor Of Matrix Metalloproteinase-1 Levels Research Articles

Magnesium Orotate Influence on Thoracic Aorta in Laboratory Rabbits Receiving Levofloxacin

Scientific relevance. Fluoroquinolones are antibacterial agents associated with adverse drug reactions (ARDs), including aortic lesions; this ARD risk limits the use of fluoroquinolones. Moreover, fluoroquinolones have been reported to induce lesions in other connective tissues (cartilage, tendons), associated with magnesium deficiency.Aim. The study aimed to analyse the effects of magnesium orotate on the thoracic aorta in laboratory rabbits treated with levofloxacin.Materials and methods. The study randomised laboratory rabbits into 3 groups of 10 animals each to receive oral doses of either the carrier solution (control group), or 150 mg/kg/day levofloxacin (levofloxacin group), or 150 mg/ kg/day levofloxacin and 140 mg/kg/day magnesium orotate (levofloxacin/magnesium group). After 14 days of treatment, venous blood samples were taken to determine the serum levels of magnesium, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), as well as MMP-9 to TIMP-1 ratios. The authors conducted morphological and mechanical characterisation of thoracic aorta samples; the mechanical characterisation involved uniaxial tensile testing. Data are presented as the mean and standard deviation values.Results. The study did not detect any changes in the serum MMP-9, TIMP-1, and magnesium levels or in the MMP-9/TIMP-1 ratios. The authors identified foci of moderate elastic fibre fragmentation in the aortic media in 5 of 10 aortic samples from the levofloxacin group, in 1 of 10 samples from the levofloxacin/magnesium group, and in none from the control group (p=0.013). Rabbits from the levofloxacin group had significantly fewer medial elastic membranes than the others (p=0.015; vs the control group: p=0.022), and their elastic membranes were thinner by an average of 1.4 μm (16%) (p=0.010, vs the control group: p=0.022, vs the levofloxacin/ magnesium group: p=0.019). The analysis of covariance confirmed the dissimilarity of the relationships between the strength of the aortic wall and the quantity of medial elastic membranes in the three study groups.Conclusions. After 14 days of treatment, levofloxacin at a dose of 150 mg/kg/day reduced the elastin content in the tunica media as well as the thickness and strength of the membrane and promoted membrane fragmentation. These changes were accompanied by a decrease in vessel strength. The addition of magnesium orotate at a dose of 140 mg/kg/day preserved the structure of the medial elastic elements and prevented the loss of the aortic wall tensile strength. The results confirm the role of magnesium deficiency in the development of fluoroquinolone-induced aortic injury.

The Effect of Thiamine, Ascorbic Acid, and the Combination of Them on the Levels of Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) in Sepsis Patients.

BackgroundSepsis is a global health problem. Therapeutic agents continue to develop for the management of sepsis. Ascorbic acid and thiamine are currently potential agents intensively studied for their benefits in sepsis.MethodsThis study was a randomized controlled trial (RCT) with a pretest-posttest control group design. Randomization was using a computer. The research was conducted at Haji Adam Malik General Hospital Medan and Grand Medistra Hospital. Blood tests were at the Integrated Laboratory of the Faculty of Medicine, University of North Sumatra. The research was for 14 months. The number of patients in this study was 86 septic patients divided into four groups (NaCl, thiamine, ascorbic acid, and combination). The parameters measured were the enzyme MMP-9 and the enzyme TIMP-1.ResultsThe number of subjects who met the inclusion criteria was 147 patients. Fifty-three patients passed away during the monitoring period, and eight blood samples were damaged. The final data analyzed consisted of 86 subjects. Of the 86 septic patients obtained Based on initial MMP-9 values, MMP-9 levels increased in the 0.9% NaCl group (25.6%), while MMP-9 levels decreased after intervention in the thiamine, ascorbic acid, and combination groups but a significant decrease in MMP-9 was found in the ascorbic acid group (17.2%; p = 0.04) and the combination group (17.9%; p = 0.026). For TIMP-1 levels, a decreasing trend was only in the ascorbic acid (5.1%) and combination (5.9%) but not significant (p > 0.05). The highest MMP-9/TIMP-1 ratio was in septic patients receiving thiamine with a significant linear correlation (p < 0.05) between levels of MMP-9 and the MMP-9/TIMP-1 ratio with a moderate correlation level and significant negative correlation (p < 0.05) between TIMP-1 and the MMP-9/TIMP-1 with a moderate level of correlation.ConclusionAdministration of thiamine alone gives better advantages than ascorbic acid alone and their combination.

Epicardial adipose tissue and nonvalvular atrial fibrillation

Abstract Background Several studies revealed the relationship between epicardial fat tissue (EF) and development of atrial fibrillation (AF). Though pathophysiological mechanisms are not clear enough, the anatomy and location EF as a part of visceral adiposity tissue could lead to proinflammatory and fibrotic changes in atrial myocardium. Purpose To evaluate the paracrine effects of EF and detect the association of tissue Doppler imaging (TDI) parameters, EF thickness by cardiac magnetic resonance tomography (CMR) and biochemical markers of fibrosis and inflammation in patients with nonvalvular AF without concomitant coronary artery disease. Methods Thirty-nine patients with idiopathic paroxysmal AF, normal or slightly enlarged left atria (LA) (mean LA diameter 4,5±0,6cm) were included. The mean age was 50,8±13,9 y.o., 19 (49%) were men. The absence of coronary lesions was confirmed by angiography in all cases. Besides standard ECG and ECHO, all patients underwent TDI and CMR with late gadolinium enhancement. EP thickness at anterior left ventricular (LV) wall was estimated by CMR. The myocardial fibrotic and proinflammatory biomarkers levels - matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were estimated. Kendall rank correlation coefficient was used. If the |τ| &amp;gt;Tcr, the correlation ranked as statistically significant. Results The epicardial fat thickness was associated with TIMP-1 plasma level (τ=0,71; Tcr=0,18) and MMP-9 (τ=0,65; Tcr=0,16). Among clinical factors weight was slightly associated with fat thickness (τ=0,33; Tcr=0,26). Besides, we found correlation of MMP-9, TIMP-1 with E/e' by TDI (τ=0,65; Tcr=0,16 and τ=0,56; Tcr=0,21, relatively); and with maximal systolic strain of lateral LV wall (τ=−0,37; Tcr=0,18 and τ=−0,44; Tcr=0,16, relatively) and interventricular septum (τ=−0,36; Tcr=0,18 and τ=−0,44; Tcr=0,16, relatively). Conclusion The epicardial fat thickness by CMR is significantly associated with myocardial fibrosis markers (MMP-9, TIMP-1) in patients with AF without structural heart disease. The increasing levels of MMP-9 and TIMP-1 are associated with LV local contractility disturbances by TDI in patients with AF. This association demonstrates the paracrine effect of EF, which could lead to atrial remodeling and formation AF substrate even in patients without valvular and ischemic heart disease and with normal or slightly enlarged LA Funding Acknowledgement Type of funding sources: None.

Association of Circulating Extracellular Matrix Components with Central Hemodynamics and Arterial Distensibility of Peripheral Arteries

Background: In addition to neuronal and endothelial regulators of vascular tone, the passive mechanical properties of arteries, determined by the molecular structure of extracellular matrices, are the principle modulators of vascular distensibility. Specifically, the association between collagen type IV (Col IV), a constituent of basement membrane, and arterial compliance remains unclear. Methods: In 31 healthy adult men, radial applanation tonometry and pulse wave analysis were used to assess aortic augmentation index (AIx), aortic-to-radial pulse pressure amplification (PPAmpl), and time to reflection wave. Results: Plasma Col IV and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) concentrations were correlated with AIx (r = 0.51, p = 0.021 and r = −0.45, p = 0.042, respectively) after adjustment for age and heart rate (HR). Greater matrix metalloproteinase-9 (MMP-9) and TIMP-1 levels were associated with high PPAmpl (r = 0.45 and r = 0.64, respectively) and hence with compliant arteries. Multiple regression analyses revealed that 99% of the variation in PPAmpl was attributable to age, HR, Col IV, TIMP-1, and Col × TIMP-1 interaction (p < 0.001). No relations between tonometric variables and levels of MMP-1, -2, and -3; TIMP-2 and -4; fibronectin; glycosaminoglycans; and hydroxyproline were found. Conclusion: High circulating Col IV level indexes were associated with stiffer peripheral arteries whereas increased MMP-9 and TIMP-1 concentrations were associated with more compliant ones.

Mechanisms of Arrhythmogenesis and Risk Factors for Thromboembolic Events in Patients with Atrial Fibrillation without Concomitant Coronary and Valvular Heart Disease

Aimsidentification the correlates between parameters of tissue Doppler imaging, EF thickness by MRI and biochemical markers of fibrosis and inflammation in patients with nonvalvular AF. Retrospectively to evaluate clinical and instrumental parameters influencing the development of thromboembolic events.Methods.Data analysis was performed on 151 patients with different type of AF. A retrospective analysis included 112patients. 15 (13%) had a history of LAA thrombosis and/or thromboembolic events (stroke, TIA). The prospective analysis included 39patients. We identified groups with idiopathic AF (N = 21), AF with arterial hypertension (N = 18). And also a group with normal or slightly enlarged (4.5 sm) LA s (N = 29), and with LA 4.5 sm (N = 10). Echocardiography with tissue Doppler imaginе and cardiac MRI were performed. The level of: matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), transforming growth factor beta-1 (TGF beta-1), soluble intercellular adhesion molecule (sICAM) was assessed.Results.The following parameters were significantly associated with LA thrombosis and thromboembolic events: age over 50 years (p = 0.001), obesity (p = 0.036), persistent AF (p = 0.003), the phenomenon of spontaneous ECHO contrast in LA (p = 0.03), the blood flow velocity in the LAA less than 30 sm / s (p = 0.005), morphological type III of LAA (p = 0.012). The greatest correlation between the thickness of the EFT and biomarkers was observed relative to: MMP-9 ( =0.65; Tcr= 0.16), TIMP-1 ( = 0.71; Tcr= 0.18) in the group of idiopathic AF; and TGF-beta1 ( = 0.22; Tcr= 0.19) in the general group. The percentage of left atrial myocardial fibrosis was correlated with TIMP-1 levels. There was a correlation between E/e and MMP-9, TIMP-1 in patients with idiopathic AF ( = 0.65; Tcr= 0.16 and = 0.56; Tcr= 0.21 respectively).Conclusion.The increasing levels of MMP-9 and TIMP-1 are associated with epicardial fat thickness by MRI. In addition to CHA2DS2VASc scale, we identified novel predictors of LA thrombosis and/or thromboembolic events, which are: chronic type AF, low LAA blood flow velocity, the phenomenon of spontaneous ECHO contrast in LA and the morphological LAA type III by CT.

Galectin-3: role in the formation of various hemodynamic phenotypes of heart failure and interaction with some neurohumoral factors

Aim. To study the interaction of serum galectin-3 (Gal-3) with fibrogenic factors, cardiac remodeling, as well as parameters of central hemodynamics in various hemodynamic phenotypes of heart failure (HF). Material and methods . A total of 210 male and female patients with HF were examined (mean age 64,1±1,4 years). HF was established on the basis of patient complaints, medical history, physical examination and laboratory tests using the 2016 ESC Chronic Heart Failure Guidelines. In addition to standard diagnostic tests, enzyme immunoassays were performed: serum Gal-3, aldosterone, matrix metalloproteinase 1 (MMP1), tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Results. Patients were divided into two groups: group I (n=59) — patients with HF with reduced ejection fraction (LVEF &lt;40%), group II (n=56) — patients with HF with midrange EF (LVEF 41-49%), group III (n=95) — patients with HF with preserved EF (LVEF &gt;50%). Reference values of studied substances were as follows: Gal-3 — 8,6 [3,7; 11,7] ng/ml; aldosterone — 86,8 [47,8; 199,1] pg/ml; MMP1 — 14,5 [8,5; 18,7] ng/ml; TIMP1 — 87,4 [68,6; 115,2] ng/ml. In patients with HF, the levels of Gal-3, aldosterone and TIMP1 increased with the disease functional class (FC). In patients of group I, it significantly increased by 1,7-2,5 (p&lt;0,01), 4,1-5,9 (p&lt;0,05) and 4,1-5,7 (p&lt;0,05); in group II, 1,8-2,8 (p&lt;0,01), 5,6-6,8 (p&lt;0,01) and 6,1-8,3 (p&lt;0,01); in group III, by 2,1-3,1 (p&lt;0,01), 6,1-6,9 (p&lt;0,01) and 6,8-9,3 times (p&lt;0,01), respectively. A positive correlation was established with FC: in groups I and II, Gal-3 had a significant negative relationship with LVEF (p&lt;0,001; p&lt;0,01, respectively); in group III, Gal-3 had a moderate positive relationship with LV posterior wall thickness (p&lt;0,05), interventricular septum thickness (p&lt;0,05), the left ventricle mass index (p&lt;0,01) and LV relative wall thickness (p&lt;0,01). Conclusion. Levels of Gal-3 and aldosterone increased with HF FC and had a relevant relationship with the activation of some other neurohumoral factors. Gal-3 can be used as an early biomarker of myocardial fibrosis and cardiac remodeling, in predicting and evaluating risk factors, clinical course and outcome of the disease, as well as to assess the effectiveness of treatment in patients with these HF phenotypes.

METRONIDAZOLE GEL EFFECT ON RATS WITH BACTERIA-INDUCED PERIODONTITIS

Background: Periodontitis is an inflammatory disease in the periodontal tissue and causes progressive tissue damage. Tissue Inhibitor of Matrix Metalloproteinases-1 (TIMP-1) is directly responsible for the pathogenesis of periodontal diseases. Topical application of the metronidazole gel as a therapy for periodontal diseases can be used for additional therapy. This study aimed to analyze the effect of Metronidazole gel on periodontitis based on TIMP-1 levels in bacteria-induced periodontitis in rats. Methods: Twenty Sprague Dawley rats weighing 170-200 gram aged two months. Rats were divided into two groups: the control group and Metronidazole gel (Ti-es Metronidazole gel, 0.45 mg). Metronidazole gel was topically applied to the gingival sulcus. The gingival crevicular fluid sample was taken on day 3 with periopaper subjected to the Tissue Inhibitor of Matrix Metalloproteinase-1 level evaluation using the ELISA Method. Results: Normal reference Tissue Inhibitor of Matrix Metalloproteinase 1 levels gingival crevicular fluid 0.156-10 ng/ml. Tissue Inhibitor of Matrix Metalloproteinase 1 gingiva crevicular fluid in control and metronidazole gel was 1.34 ng/ ml and 3.57 ng /ml. There was a significant difference between control and metronidazole gel group (p&lt;0.005) Conclusion: The Application of Metronidazole gel affects TIMP-1 levels in periodontitis.

Tissue inhibitor matrix metalloproteinase 1 and risk of type 2 diabetes in a Chinese population

IntroductionThe non-invasive enhanced liver fibrosis (ELF) score—comprising tissue inhibitor of matrix metalloproteinases-1 (TIMP1), hyaluronic acid (HA) and amino-terminal propeptide of type III procollagen (PIIINP)—has been shown to accurately predict fibrosis...

ВЛИЯНИЕ СИНДРОМА ОБСТРУКТИВНОГО АПНОЭ/ГИПОПНОЭ СНА НА УРОВНИ ТКАНЕВОГО ИНГИБИТОРА МАТРИКСНЫХ МЕТАЛЛОПРОТЕИНАЗ-1 И ИНДУЦИРУЕМОГО ГИПОКСИЕЙ ФАКТОРА-1Α У ПАЦИЕНТОВ С ФИБРИЛЛЯЦИЕЙ ПРЕДСЕРДИЙ

Bacground. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with increased incidence and progression of atrial fibrillation (AF). Experimental studies indicate that OSAHS can modify the cardiac extracellular matrix (ECM). However, significant mechanisms of cardiac remodeling in AF patients with OSAHS have not been uncovered.The aim: to evaluate the impact of OSAHS on serum levels of tissue inhibitor of matrix metalloproteinase 1(TIMP-1) and hypoxia-inducible factor-1α (HIF-1α) in AF patients with ischemic heart disease (IHD) and/or arterial hypertension (AH), suffering from OSAHS.Material and methods. We examined 140 non-valvular AF patients with IHD and/or AH. Cardiorespiratory monitoring was conducted in the studied subjects and they were divided into 2 groups according to the presence of OSAHS: group 1 – non-OSAHS patients; group 2 – patients with OSAHS. Serum levels of TIMP-1 and HIF-1α were assayed using commercially available ELISA kit.Results. The patients with OSAHS had higher levels of TIMP-1 and HIF-1α than non-OSAHS patients (p&lt;0.05). The levels of TIMP-1 and HIF-1α positively correlated with the severity of OSAHS, as well as with the degree of atrial dilatation and left ventricular hypertrophy (p&lt;0.05). Multiple regression showed a link between the levels of TIMP-1, HIF-1α and the respiratory disturbance index (β=0.418; p&lt;0.001 and β=0.697; p&lt;0.001 respectively).Conclusion. Presence of OSAHS in AF patients with IHD and/or AH is associated with increased serum levels of TIMP-1 and HIF-1α, and thus modifies the ECM of cardiovascular tissues.

MMP-2, MMP-9, TIMP-1, and TIMP-2 in the Peripheral Blood of Patients with Differentiated Thyroid Carcinoma.

IntroductionThe objective of this study was to assess the clinical significance of determining the levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and TIMP-2 in the peripheral blood of patients with differentiated thyroid carcinoma (DTC).MethodsForty-nine patients with benign thyroid lesions and 57 patients with DTC were examined using the enzyme-linked immunosorbent assay method preoperatively and 1 month after operation.ResultsThe levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 in the peripheral blood of patients with DTC were significantly higher than those measured in patients with benign thyroid disease (P<0.05). After surgery, these levels in the peripheral blood of patients with benign thyroid lesions were not significantly changed (P>0.05). However, after operation, these levels in the peripheral blood of patients with DTC were significantly lower (P<0.05). These levels in the serum of patients with DTC which were tumor-node-metastasis stage, tumor diameter ≥l cm, infiltrating capsula outside or existing lymph metastasis were significantly higher than those reported in patients with early tumor-node-metastasis stage, tumor diameter <l cm or absence of lymph metastasis (P<0.05).DiscussionDetecting the levels of these factors in peripheral blood is helpful in the diagnosis of benign and malignant thyroid lesions, and can be used as a basis for the prognosis of DTC.

Predictive Markers for Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C Virus Genotype4a

Background: Egypt has the highest prevalence of hepatitis C virus worldwide. Monitoring hepatitis C-infected patients for hepatocellular carcinoma development is an important clinical issue to diagnose these patients during the potentially curable early-stage of disease. This study aims to evaluate the role of N-terminal procollagen III, matrix metalloproteinase- 2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests as predictors of hepatocellular carcinoma development upon long-term followup of non-responding hepatitis C virus patients.Methods: The study included 850 treatment-naive hepatitis C virus genotype 4a adult patients; after treatment, 360 achieved sustained viral response while 490 did not. Nonresponding patients had a 5-year rate for hepatocarcinogenesis of 8.4% and a 10-year rate of 27.5%. N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests were evaluated in all patients before and after treatment, and after hepatocellular carcinoma development. The study also included a group of 50 hepatocellular carcinoma patients who were negative for hepatitis C and hepatitis B viruses, and a group of 50 healthy subjects as controls.Results: The non-responders had significantly higher age, stage, grade, viral load, alanine aminotransferase, and aspartate aminotransferase than responders. Also N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, and alphafetoprotein were significantly higher in non-responders; after treatment they decreased in responders. In non-responders they remained higher than the control. The most significant risk factors for hepatocellular carcinoma development in non-responding hepatitis C virus patients were male gender and increased age, stage, grade, aspartate aminotransferase, Nterminal procollagen III, and tissue inhibitor of matrix metalloproteinase-1. Patients with viral-hepatocellular carcinoma were of significantly lower age, higher grade, stage, γ-glutamyltransferase, N-terminal procollagen III, and matrix metalloproteinase-2 than non-viral hepatocellular carcinoma patients. Percent positive N-terminal procollagen III, tissue inhibitor of matrix metalloproteinase-1, and alpha-fetoprotein were significantly higher in viral hepatocellular carcinoma patients.Conclusion: Data suggest that high N-terminal procollagen III and tissue inhibitor of matrix metalloproteinase-1levels after treatment might be particularly important as markers of hepatitis C virus-non-responding patients who are at higher risk of developing hepatocellular carcinoma, especially in older males with high stage and grade liver disease. However, studies of larger scale are needed to verify this suggestion.

European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis.

To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort. Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software. Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score. Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.

Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis after Major Abdominal Surgery.

Background The role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in sepsis after major abdominal surgery and sepsis-associated organ dysfunction is unexplored. Materials and Methods Fifty-three patients with sepsis after major abdominal surgery were compared to 50 operated and 50 nonoperated controls. MMP-9, TIMP-1, biomarkers of inflammation, kidney and liver injury, coagulation, and metabolic disorders were measured daily during 96 h following diagnosis of sepsis and once in controls. MMP-9/TIMP-1 ratios and disease severity scores were calculated. Use of vasopressors/inotropes, mechanical ventilation, and survival were recorded. Results Septic patients had lower MMP-9 and MMP-9/TIMP-1 ratios but higher TIMP-1 levels compared to controls. AUC-ROC for diagnosis of sepsis was 0.940 and 0.854 for TIMP-1 and 0.924 and 0.788 for MMP-9/TIMP-1 ratio (sepsis versus nonoperated and sepsis versus operated controls, resp.). Lower MMP-9 and MMP-9/TIMP-1 ratio and higher TIMP-1 levels were associated with shorter survival. MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio correlated with biomarkers of inflammation, kidney and liver injury, coagulation, metabolic disorders, and disease severity scores. Use of vasopressors/inotropes was associated with higher TIMP-1 levels. Conclusions MMP-9, TIMP-1, and MMP-9/TIMP ratio were good diagnostic or prognostic biomarkers of sepsis after major abdominal surgery and were linked to sepsis-associated organ dysfunction.

The Development of Translational Biomarkers as a Tool for Improving the Understanding, Diagnosis and Treatment of Chronic Neuropathic Pain

Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague–Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 (TIMP1) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) (p = 0.0049) which positively correlated (R = 0.68, p = ≤0.05) with increased plasma TIMP1 levels in this group (p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain (p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed (p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor (p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker.

Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome.

BackgroundMatrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity.Methods and resultsIn 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0–186.3) (median (interquartile range)), TTC 115.7 (94.3–137.7) and controls 80.9 (73.2–90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13–0.51) from decreased EF<50% at 0.08 (0.05–0.20), (p = 0.04) in TTC, but not in ACS.ConclusionsEven with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment.

Matrix metalloproteinase-9 and vascular endothelial growth factor expression change in experimental retinal neovascularization.

To investigate the signal transduction mechanism of matrix metalloproteinase-9 (MMP-9) mediated- vascular endothelial growth factor (VEGF) expression and retinal neovascularization (RNV) in oxygen-induced retinopathy (OIR) model. C57BL/6J mice were divided into four groups: control group, OIR group, OIR control group (phosphate-buffered saline by intravitreal injection) and treated group [tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) by intravitreal injection]. OIR model was established in C57BL/6J mice exposed to 75%±2% oxygen for 5d. mRNA level and protein expression of MMP-9, TIMP-1 and VEGF were measured by real-time polymerase chain reaction and Western blotting, and located by immunohistochemistry. Levels of MMP-9 and VEGF in retina were significantly increased in animals with OIR and OIR control group. Levels of TIMP-1 in retina was significantly reduced in animals with OIR and OIR control group. Furthermore, a significant correlation was found between MMP-9 and VEGF. Intravitreal injection of TIMP-1 significantly reduced MMP-9 and VEGF expression of the OIR mouse model (all P<0.05). These results demonstrate that MMP-9-mediated up-regulation of VEGF promotes RNV in retinopathy of prematurity (ROP). TIMP-1 may be a potential target for the prevention and treatment of ROP.

Paraoxonase-1 arylesterase activity is an independent predictor of myeloperoxidase levels in overweight patients with or without cardiovascular complications

ObjectivesMyeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were shown to contribute to atherogenesis, while human paraoxonase-1 (PON1) protects against oxidative stress. Although several studies investigated these biomarkers, their associations have not been completely clarified yet. We aimed to investigate these parameters in overweight hyperlipidemic, lipid-lowering therapy-naive patients (n=167) with and without vascular complications. Design and methodsMPO, MMP-9 and TIMP-1 levels were measured by ELISA. PON1 activities were detected spectrophotometrically. PON1 phenotype was calculated by using a dual substrate method. ResultsPatients with vascular complications (VC) had significantly higher MPO and TIMP-1 levels compared to those without (patients with no vascular complications; NVC) (728 (367.25–1177.90) mg/ml vs. 315.9 (176.05–687.40) mg/ml; p<0.001; and 172.7 (157.7–197.7) ng/ml vs. 152.6 (129.3–172.3) ng/ml; p<0.0001; respectively). MPO levels showed a significant negative correlation with PON1 arylesterase activity (whole patient group (W): r=0.42, p<0.0001; VC: r=0.44, p=0.01; NVC: r=0.39, p<0.0001) and positive correlations with MMP-9 (W: r=0.37, p<0.0001; VC: r=0.29, p=0.07; NVC: r=0.42, p<0.0001) and TIMP-1 (W: r=0.42, p<0.0001; VC: r=0.33, p<0.05; NVC: r=0.41, p<0.0001), respectively. PON1 arylesterase activity was found to be an independent predictor of MPO levels in the whole patient group (β=−0.350, p<0.0001) or when studied separately in the subgroups with or without cardiovascular complications (VC: β=−0.57, p<0.05; NVC: β=−0.33, p<0.0001). ConclusionsOur results suggest that parallel investigation of MPO, MMP-9 and TIMP-1 levels and PON1 arylesterase activity may be a more accurate indicator of atherosclerosis, which may allow earlier treatment and therefore, improvement of treatment efficacy.

Circulating tissue inhibitor of matrix metalloproteinase-1 is associated with aldosterone-induced diastolic dysfunction.

To test if collagen markers are associated with aldosterone-induced diastolic dysfunction. Although primary aldosteronism is associated with more prominent cardiac remodeling and diastolic dysfunction, the reversibility of diastolic function is unclear. In addition, there is no known biomarker associated with aldosterone-induced diastolic dysfunction. We enrolled 27 patients with aldosterone-producing adenoma (APA) preparing for adrenalectomy, and 27 patients with essential hypertension prospectively from October 2006 to March 2010 at a tertiary referral center. Plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured, and echocardiography including tissue Doppler images was performed in both groups and 1 year after receiving adrenalectomy in the APA group. The baseline plasma TIMP-1 level (88.4 ± 38.7 vs. 63.6 ± 32.5 ng/ml; P = 0.014), left ventricular mass index (LVMI), and E/E' ratio (11.5 ± 2.9 vs. 9.0 ± 2.1; P < 0.001) were significantly higher in the APA group. The baseline plasma TIMP-1 level significantly correlated with the E/E' ratio, LVMI, interventricular septum, and left atrial diameter. The plasma MMP-2 level did not correlate with the left ventricular structure parameters, except for interventricular septum thickness. After adrenalectomy, LVMI and E/E' ratio improved significantly. The postadrenalectomy plasma TIMP-1 levels, but not MMP-2 levels, also decreased. The change of plasma TIMP-1 levels was negatively associated with the postadrenalectomy E/E' ratio after adjustment for age, sex, BMI, and mean blood pressure (β-coefficient = - 3.6, P = 0.004). Excess of aldosterone induces cardiac diastolic dysfunction, which is reversible by adrenalectomy. TIMP-1 is associated with the aldosterone-induced diastolic dysfunction.

Association of Matrix Metalloproteinases and Their Tissue Inhibitor With Disease Activity and Development in Spondyloarthropathy and Inflammatory Bowel Disease

Objectives: This study aims to investigate whether clinical measures of disease activity and function in ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are associated with matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase -1 (TIMP-1), and if MMPs can be more useful than C-reactive protein and erythrocyte sedimentation rate in predicting disease activity in AS. Patients and methods: MMP-3, MMP-9 and TIMP-1 levels were measured by ELISA in 20 patients with AS, 20 patients with IBD, 20 patients with IBD and AS (35 males, 25 females; mean age 38.1 years; range 19 to 62 years), and 20 healthy volunteers (10 males, 10 females; median age 38.5 years; range 24 to 63 years) as a control group. Bath Ankylosing Spondylitis Disease Activity Index, Truelove-Witts activity criteria for ulcerative colitis, and Crohn's Disease of Activity Index scoring systems were used. Results: Highest MMP-3 level was in IBD group (33.51±59.56 ng/mL, p<0.045). MMP-3 levels were significantly higher in patients with IBD and IBD+AS than in patients with AS (p<0.007 and p<0.035, respectively). Highest MMP-9 levels were in the control group (10.35±2.61 ng/mL, p<0.48). MMP-9 levels were higher in AS group patients than those in IBD and IBD+AS groups, but the difference was not statistically significant (p<0.494 and p<0.260, respectively). Highest TIMP-1 levels were in the IBD group (8.11 ng/mL, p<0.006). TIMP-1 levels of IBD group were significantly higher than both AS and IBD+AS groups (p<0.033 and p<0.008, respectively). A statistically significant correlation was detected between serum MMP-3 levels and disease activity and Bath Ankylosing Spondylitis Disease Activity Index score in patients with AS (r=0.841, p<0.05). Conclusion: We concluded that serum MMP-3 levels may be a better biomarker than C-reactive protein and erythrocyte sedimentation rate in showing disease activity in AS.

The Long-Term Influence of Tissue Inhibitor of Matrix Metalloproteinase-1 in Patients with Mild to Moderate Coronary Artery Lesions in a Chinese Population: A 7-Year Follow-Up Study

Objectives: Matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and their ratio (MMP-9/TIMP-1) are involved in multiple processes that are associated with coronary heart disease and are especially associated with cardiovascular events. However, few long-term population-based clinical studies have evaluated the role of these factors in cardiovascular events in a Chinese population. Methods: A prospective study was performed on 560 patients with mild to moderate coronary artery lesions. MMP-9, TIMP-1 and their ratio were determined. Results: A total of 522 of patients completed the follow-up. The median follow-up time was 64 months. Kaplan-Meier analysis demonstrated a clear increase of the incidence of major adverse cardiac events (MACEs) during the follow-up period in subjects with above-median levels of TIMP-1 (p = 0.033), whereas there was no association with either MMP-9 (p = 0.199) or MMP-9/TIMP-1 (p = 0.631). Multivariate Cox proportional hazards analysis showed the same results after further adjustment for covariates. Patients with above-median levels of TIMP-1 were more likely to suffer from adverse outcomes than patients with below-median levels of TIMP-1. However, the lack of relationship of MACEs with MMP-9 and MMP-9/TIMP-1 remained. Conclusions: Higher circulating TIMP-1 concentrations were associated with cardiovascular events during long-term follow-up of Chinese patients with mild to moderate coronary artery lesions.