RESUMEN

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in the blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. When offspring were 3 months of age, ischemic stroke was induced. One and a half months later, blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and reported reduced levels of MMP-2 in ChDD male offspring in both tissue types. No changes were observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.

Asunto(s)

Encéfalo , Colina , Metaloproteinasa 2 de la Matriz , Animales , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/sangre , Femenino , Encéfalo/metabolismo , Masculino , Ratones , Embarazo , Colina/metabolismo , Ratones Endogámicos C57BL , Dieta , Ácido Fólico/metabolismo , Ácido Fólico/sangre , Metaloproteinasa 9 de la Matriz/metabolismo , Deficiencia de Colina , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/sangre

RESUMEN

BACKGROUND: Despite a rigorous screening process, including cardiac catheterization, a subset of patients with a single right ventricle (SRV) demonstrates suboptimal short-term outcomes after the Fontan operation. The goal of this study was to perform a comprehensive assessment of diastolic function in pre-Fontan patients with an SRV using invasive reference-standard measures and determine their associations with post-Fontan outcomes. METHODS AND RESULTS: Children aged 2 to 6 years with SRV physiology undergoing pre-Fontan heart catheterization were recruited prospectively. Patients were divided into those who had an optimal or suboptimal outcome. A suboptimal outcome was defined as length of stay ≥14 days or heart transplant/cardiac death in first year after Fontan. Patients underwent pressure-volume loop analysis using reference-standard methods. The measure of ventricular stiffness, ß, was obtained via preload reduction. Cardiac magnetic resonance imaging for extracellular volume and serum draws for matrix metalloproteinase activity were performed. Of 19 patients with an SRV, 9 (47%) had a suboptimal outcome. Mean age was 4.2±0.7 years. Patients with suboptimal outcomes had lower ventricular stiffness (0.021 [0.009-0.049] versus 0.090 [0.031-0.118] mL-1; P=0.02), lower extracellular volume (25% [28%-32%] versus 31% [28%-33%]; P=0.02), and lower matrix metalloproteinase-2 (90 [79-104] versus 108 [79-128] ng/mL; P=0.01) compared with patients with optimal outcomes. The only invasive measure that had an association with suboptimal outcome was ß (P=0.038). CONCLUSIONS: Patients with an SRV with suboptimal outcome after the Fontan operation had lower ventricular stiffness and evidence of maladaptive extracellular matrix metabolism compared with patients with optimal outcome. This appears to be a novel phenotype that may have important clinical implications and requires further study.

Asunto(s)

Procedimiento de Fontan , Ventrículos Cardíacos , Fenotipo , Humanos , Procedimiento de Fontan/efectos adversos , Preescolar , Masculino , Femenino , Niño , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/anomalías , Estudios Prospectivos , Resultado del Tratamiento , Cateterismo Cardíaco , Función Ventricular Derecha/fisiología , Trasplante de Corazón , Metaloproteinasa 2 de la Matriz/sangre , Corazón Univentricular/cirugía , Corazón Univentricular/fisiopatología , Corazón Univentricular/diagnóstico por imagen , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/fisiopatología , Factores de Tiempo

RESUMEN

OBJECTIVE: The objective of this study was to investigate the correlation between serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels and their ratios with the severity of white matter hyperintensities (WMHs) in patients with cerebral small vessel disease (CSVD). METHODS: This cross-sectional study was done on a prospective cohort of patients with CSVD. Qualitative and quantitative analyses of WMHs were performed using Fazekas grading and lesion prediction algorithm (LPA) methods. Biomarkers MMP-2, MMP-9, and TIMP-1 were measured to explore their correlation with the severity of WMHs. RESULTS: The sample consisted of 144 patients with CSVD. There were 63 male and 81 female patients, with an average age of 67.604 ± 8.727 years. Among these, 58.33% presented with white matter hyperintensities at Fazekas grading level 1, with an average total template volume of WMHs of 4.305 mL. MMP-2 (P = 0.025), MMP-9 (P = 0.008), TIMP-1 (P = 0.026), and age (P = 0.007) were identified as independent correlates of WMHs based on Fazekas grading. Independent correlates of the total template volume of WMHs included MMP-2 (P = 0.023), TIMP-1 (P = 0.046), age (P = 0.047), systolic blood pressure (P = 0.047), and homocysteine (Hcy) (P = 0.014). In addition, age (P = 0.003; P < 0.001), interleukin-6 (IL-6) (P < 0.001; P = 0.044), Hcy (P < 0.001; P < 0.001), glycated hemoglobin (HbA1c) (P = 0.016; P = 0.043), and chronic kidney disease (P < 0.001; P < 0.001) were associated with both WMHs Fazekas grading and the total template volume of WMHs. CONCLUSION: Serum levels of MMP-9, MMP-2, and TIMP-1 were independently associated with the Fazekas grading, while serum TIMP-1 and MMP-2 levels were independently related to the total template volume of WMHs. The association of TIMP-1 and MMP-2 with the severity of CSVD-related WMHs suggests their potential role as disease-related biomarkers. However, further research is required to uncover the specific mechanisms underlying these interactions.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Imagenología Tridimensional , Imagen por Resonancia Magnética , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Inhibidor Tisular de Metaloproteinasa-1 , Sustancia Blanca , Humanos , Masculino , Femenino , Metaloproteinasa 9 de la Matriz/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/sangre , Anciano , Metaloproteinasa 2 de la Matriz/sangre , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen por Resonancia Magnética/métodos , Estudios Transversales , Persona de Mediana Edad , Estudios Prospectivos , Imagenología Tridimensional/métodos , Biomarcadores/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/patología

RESUMEN

OBJECTIVE: This study investigated the intervention effect of slow-velocity eccentric-only resistance training on type 2 diabetic mellitus (T2DM) patients based on the role of matrix metalloproteinase-2 and -9 (MMP-2 and -9) in regulating extracellular matrix homeostasis. METHODS: 50 T2DM patients were randomly divided into the slow-velocity eccentric-only resistance training group (E) and control group (C). The E group performed eccentric-only resistance training 3 times a week, every other day for 10 weeks, while the C group did not. Blood samples were collected before and after training, and subjects were tested for changes in clinical parameters, insulin resistance indices [fasting insulin, homeostatic model assessment insulin resistance (HOMA-IR)], MMP-2 and -9, and hydroxyproline, and muscle strength (12-RM), respectively. RESULTS: After 10 weeks of training, the E group showed significant decreases in fasting glucose (P < .05), insulin (P < .05), insulin resistance indices (P < .05), hemoglobin A1c (HbA1c) (P < .01), triglycerides (P = .06) and MMP-2 (P < .05), while total cholesterol (P < .05), MMP-9 (P < .05), hydroxyproline (P < .01), Creatine Kinase (CK) (P < .05), and muscle strength (P < .001) significantly increased. There were no significant changes in the count of neutrophil, lymphocyte and platelet, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c). Compared with the C group, the E group showed a trend of a significant decrease in triglyceride (P < .05), lymphocyte count (P < .05), fasting glucose (P = .07), and plasma MMP-2 (P < .05), while MMP-9 (P < .05), hydroxyproline (P < .001), and muscle strength (P < .01) significantly increased. However, no significant changes were observed in insulin and insulin resistance indices, HbA1c, total cholesterol, HDL-c, LDL-c, CK, and other inflammatory indicators. CONCLUSIONS: Slow-velocity eccentric-only resistance training was beneficial for T2DM, but the potential role of MMP-2 and -9 in regulating extracellular matrix homeostasis is very different in T2DM patients.

Asunto(s)

Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Fuerza Muscular , Entrenamiento de Fuerza , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/terapia , Entrenamiento de Fuerza/métodos , Metaloproteinasa 9 de la Matriz/sangre , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Persona de Mediana Edad , Femenino , Resistencia a la Insulina/fisiología , Fuerza Muscular/fisiología , Glucemia/análisis , Hemoglobina Glucada/análisis , Adulto , Insulina/sangre

RESUMEN

Ovarian cancer (OC) has an unfavorable prognosis. Due to the lack of effective screening tests, new diagnostic methods are being sought to detect OC earlier. The aim of this study was to evaluate the concentration and diagnostic utility of selected matrix metalloproteinases (MMPs) as OC markers in comparison with HE4, CA125 and the ROMA algorithm. The study group consisted of 120 patients with OC; the comparison group consisted of 70 patients with benign lesions and 50 healthy women. MMPs were determined via the ELISA method, HE4 and CA125 by CMIA. Patients with OC had elevated levels of MMP-3 and MMP-11, similar to HE4, CA125 and ROMA values. The highest SE, SP, NPV and PPV values were found for MMP-26, CA125 and ROMA in OC patients. Performing combined analyses of ROMA with selected MMPs increased the values of diagnostic parameters. The topmost diagnostic power of the test was obtained for MMP-26, CA125, HE4 and ROMA and performing combined analyses of MMPs and ROMA enhanced the diagnostic power of the test. The obtained results indicate that the tested MMPs do not show potential as stand-alone OC biomarkers, but can be considered as additional tests to raise the diagnostic utility of the ROMA algorithm.

Asunto(s)

Algoritmos , Biomarcadores de Tumor , Antígeno Ca-125 , Metaloproteinasa 2 de la Matriz , Neoplasias Ováricas , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP , Humanos , Femenino , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Antígeno Ca-125/sangre , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Adulto , Anciano , Metaloproteinasa 2 de la Matriz/sangre , Proteínas/metabolismo , Proteínas/análisis , Metaloproteinasas de la Matriz/sangre , Metaloproteinasas de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/sangre , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Estudios de Casos y Controles , Curva ROC , Metaloproteinasa 11 de la Matriz/sangre , Metaloproteinasa 11 de la Matriz/metabolismo

RESUMEN

The levels of the MMPs in the biological samples of confirmed patients with gastric cancer are significantly elevated compared to those found in healthy people. Therefore, a novel 3D stochastic microsensor based on graphene oxide, modified with gold nanoparticles and (Z)-N-(pyridin-4-yl-methyl) octadec-9-enamide (namely N2-AuNP/GO), was designed for the determination of MMP-2 in biological samples, and validated for the screening tests of biological samples in order to be used for the early diagnosis of gastric cancer. The proposed sensor presents a low limit of quantification (1.00 × 10-22 g mL-1), high sensitivity (1.84 × 107 s-1 g-1 mL), and a wide working concentration range (1.00 × 10-22-1.00 × 10-7 g mL-1). Recovery values higher than 99.15% were recorded for the assay of MMP-2 in whole blood, gastric tissue tumors, saliva, and urine samples.

Asunto(s)

Oro , Grafito , Metaloproteinasa 2 de la Matriz , Nanopartículas del Metal , Grafito/química , Humanos , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/orina , Metaloproteinasa 2 de la Matriz/metabolismo , Nanopartículas del Metal/química , Oro/química , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/sangre , Técnicas Biosensibles/métodos

RESUMEN

OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. METHODS: The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. RESULTS: The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. DISCUSSION: Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.

Asunto(s)

Biomarcadores , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Humanos , Femenino , Masculino , Adulto , Esclerosis Múltiple Recurrente-Remitente/sangre , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Biomarcadores/sangre , Osteopontina/sangre , Factor Activador de Células B/sangre , Metaloproteinasa 2 de la Matriz/sangre , Receptor gp130 de Citocinas/sangre , Adulto Joven

RESUMEN

Background: Matrix metalloproteinase (MMP) enzyme gene polymorphisms MMP-2-1575G/A and MMP-9-1562C/T promoter polymorphism, their serum levels, and activity are associated with aortic valve calcification (AVC). Materials and Methods: The synergistic link between the risk of AVC and the alleles T and A of MMP-9 and MMP-2 was investigated, respectively. Ninety-two cases with AVC and 92 healthy individuals from the west of Iran were included, and MMP- 2-1575G/A and MMP-9-1562C/T promoter polymorphisms were detected using PCR-RFLP. The serum levels and activity of MMP-2 and -9 were assessed using ELISA and gelatin zymography methods, respectively. In addition, serum biochemical markers, including FBS, urea and creatinine, cholesterol, triglyceride, HDL, LDL, calcium, phosphorus, and blood pressure: systolic blood pressure and diastolic blood pressure were measured. Results: Heart valve calcification disease was associated with a comparatively higher frequency of the A allele of the MMP2-1575 variation (p = 0.002). In addition, the frequency of T allele of the MMP9-1562 variant was higher than the control group (p = 0.007). Conclusion: MMP-2 and MMP-9 serum levels and activities were observed to be considerably higher in the experimental group than in the control group (p < 0.001). Patients are more susceptible to cardiovascular disease than the control group due to elevated serum levels and activity of MMP-2 and MMP-9.

Asunto(s)

Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Predisposición Genética a la Enfermedad , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Regiones Promotoras Genéticas , Humanos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/sangre , Calcinosis/genética , Calcinosis/sangre , Femenino , Masculino , Irán , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/sangre , Válvula Aórtica/patología , Regiones Promotoras Genéticas/genética , Persona de Mediana Edad , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/sangre , Polimorfismo de Nucleótido Simple/genética , Anciano , Adulto , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes/genética , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/sangre , Genotipo

RESUMEN

We attempted to clarify clinical value of KiSS-1 and MMP-2 levels in breast cancer (BC) tissue in evaluating prognosis of elderly BC patients after modified radical mastectomy (MCM). The data of 192 elderly female BC patients receiving MCM in our hospital from January 2018 to December 2022 were collected. According to prognosis, patients received division into poor prognosis group (n = 43) and good prognosis group (n = 149). The serum CEA level and KiSS-1 and MMP-2 levels in BC tissue received measurement in both groups. The predictive value of KiSS-1 and MMP-2 alone and jointly in adverse prognosis of elderly BC patients after MCM received assessment. Results showed that No statistical significance was exhibited between both groups in general data (P > 0.05). The serum CEA level and MMP-2 expression in BC tissue in poor prognosis group exhibited elevation relative to those in good prognosis group, and KiSS-1 expression in BC tissue in poor prognosis group exhibited depletion relative to that in good prognosis group, indicating statistical significance (P < 0.05). The high-level KiSS-1 might be a protective element for adverse prognosis of elderly BC patients after MCM, and high-level CEA and MMP-2 might be an independent risk element for adverse prognosis of elderly BC patients after MCM (P < 0.05). KiSS-1 and MMP-2 alone and jointly predicted AUC of adverse prognosis in elderly BC patients after MCM were 0.93, 0.802 and 0.958, with certain predictive values; when cutoff values of KiSS-1 and MMP-2 were 6.15 and 2.26, the predictive value was the best. In conclusion, KiSS-1 and MMP-2 levels in BC tissue possess relation to adverse prognosis of MCM. KiSS-1 and MMP-2 levels in elderly BC patients before surgery may be detected in the future to assist in prognosis evaluation of elderly BC patients after MCM.

Asunto(s)

Neoplasias de la Mama , Kisspeptinas , Mastectomía Radical Modificada , Metaloproteinasa 2 de la Matriz , Humanos , Femenino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/sangre , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Anciano , Pronóstico , Kisspeptinas/metabolismo , Curva ROC , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/sangre , Anciano de 80 o más Años

RESUMEN

Simple and low-cost biosensing solutions are suitable for point-of-care applications aiming to overcome the gap between scientific concepts and technological production. To compete with sensitivity and selectivity of golden standards, such as liquid chromatography, the functionalization of biosensors is continuously optimized to enhance the signal and improve their performance, often leading to complex chemical assay development. In this research, the efforts are made on optimizing the methodology for electrochemical reduction of graphene oxide to produce thin film-modified gold electrodes. Under the employed specific conditions, 20 cycles of cyclic voltammetry (CV) are shown to be optimal for superior electrical activation of graphene oxide into electrochemically reduced graphene oxide (ERGO). This platform is further used to develop a matrix metalloproteinase 2 (MMP-2) biosensor, where specific anti-MMP2 aptamers are utilized as a biorecognition element. MMP-2 is a protein which is typically overexpressed in tumor tissues, with important roles in tumor invasion, metastasis as well as in tumor angiogenesis. Based on impedimetric measurements, we were able to detect as low as 3.32 pg mL-1 of MMP-2 in PBS with a dynamic range of 10 pg mL-1 - 10 ng mL-1. Further experiments with real blood samples revealed a promising potential of the developed sensor for direct measurement of MMP-2 in complex media. High specificity of detection is demonstrated - even to the closely related enzyme MMP-9. Finally, the potential of reuse was demonstrated by signal restoration after experimental detection of MMP-2.

Asunto(s)

Aptámeros de Nucleótidos , Técnicas Biosensibles , Técnicas Electroquímicas , Grafito , Metaloproteinasa 2 de la Matriz , Grafito/química , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/análisis , Aptámeros de Nucleótidos/química , Humanos , Técnicas Electroquímicas/métodos , Técnicas Biosensibles/métodos , Oxidación-Reducción , Límite de Detección , Electrodos , Oro/química

RESUMEN

Cancer stands as a prominent global cause of mortality, necessitating early detection to augment survival rates and alleviate economic burdens on healthcare systems. In particular, prostate cancer (PCa), impacting 1.41 million men globally in 2020, accentuates the demand for sensitive and cost-effective detection methods beyond traditional prostate-specific antigen (PSA) testing. While clinical techniques exhibit limitations, biosensors emerge as compact, user-friendly alternatives to traditional laboratory approaches. However, existing biosensors predominantly concentrate on PSA detection, prompting the necessity for advancing toward multiplex sensing platforms. This study introduces a compact opto-microfluidic sensor featuring a substrate of gold nanospikes, fabricated via electrodeposition, for enhanced sensitivity. Embedded within a microfluidic chip, this nanomaterial enables the precise and concurrent measurement of PSA, alongside two complementary PCa biomarkers, matrix metalloproteinase-2 (MMP-2) and anti-α-methylacyl-CoA racemase (anti-AMACR) in diluted human plasma, offering a comprehensive approach to PSA analysis. Taking advantage of the localized surface plasmon resonance principle, this biosensor offers robustness and sensitivity in real sample analysis without the need for labeling agents. With the limit of detection at 0.22, 0.37, and 0.18 ng/mL for PSA, MMP-2, and anti-AMACR, respectively, this biosensing platform holds promise for point-of-care analysis, underscoring its potential impact on medical diagnostics.

Asunto(s)

Técnicas Biosensibles , Oro , Metaloproteinasa 2 de la Matriz , Antígeno Prostático Específico , Neoplasias de la Próstata , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/sangre , Masculino , Técnicas Biosensibles/métodos , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/análisis , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/análisis , Oro/química , Racemasas y Epimerasas , Dispositivos Laboratorio en un Chip , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/análisis , Técnicas Analíticas Microfluídicas/instrumentación

RESUMEN

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

Asunto(s)

Hemorragia Cerebral , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Metaloproteinasa 9 de la Matriz , Trombectomía , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/sangre , Masculino , Femenino , Trombectomía/métodos , Anciano , Hemorragia Cerebral/etiología , Hemorragia Cerebral/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/terapia , Persona de Mediana Edad , Procedimientos Endovasculares/métodos , Pronóstico , Anciano de 80 o más Años , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/sangre , Biomarcadores , Resultado del Tratamiento , Estudios Transversales , Curva ROC , Circulación Colateral

RESUMEN

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

Asunto(s)

Estenosis de la Válvula Aórtica , Biomarcadores , Galectina 3 , Metaloproteinasa 2 de la Matriz , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Metaloproteinasa 2 de la Matriz/sangre , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Biomarcadores/sangre , Masculino , Femenino , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/sangre , Galectina 3/sangre , Anciano de 80 o más Años , Anciano , Pronóstico , Galectinas , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo

RESUMEN

AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Asunto(s)

Atrios Cardíacos , Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Proteómica , Espironolactona , Humanos , Espironolactona/uso terapéutico , Femenino , Masculino , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Anciano , Proteómica/métodos , Persona de Mediana Edad , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Biomarcadores/sangre , Péptido Natriurético Encefálico/sangre , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/metabolismo , Fragmentos de Péptidos/sangre , Volumen Sistólico/fisiología

RESUMEN

BACKGROUND: Inflammation has an important role in the pathogenesis of schizophrenia. The aim of this study was to investigate the levels of tumor necrosis factor (TNF) and matrix metalloproteinase-2 (MMP-2) in male patients with treatment-resistant schizophrenia (TRS) and chronic medicated schizophrenia (CMS), and the relationship with psychopathology. METHODS: The study enrolled 31 TRS and 49 cm male patients, and 53 healthy controls. Serum MMP-2 and TNF-α levels were measured by the Luminex liquid suspension chip detection method. Positive and Negative Syndrome Scale (PANSS) scores were used to evaluate symptom severity and Repeatable Battery for the Assessment of Neuropsychological Status was used to assess cognitive function. RESULTS: Serum TNF-α and MMP-2 levels differed significantly between TRS, CMS and healthy control patients (F = 4.289, P = 0.016; F = 4.682, P = 0.011, respectively). Bonferroni correction demonstrated that serum TNF-α levels were significantly elevated in CMS patients (P = 0.022) and MMP-2 levels were significantly higher in TRS patients (P = 0.014) compared to healthy controls. In TRS patients, TNF-α was negatively correlated with age (r=-0.435, P = 0.015) and age of onset (r=-0.409, P = 0.022). In CMS patients, MMP-2 and TNF-α were negatively correlated with PANSS negative and total scores, and TNF-α was negatively correlated with PANSS general psychopathology scores (all P < 0.05). MMP-2 levels were positively correlated with TNF-α levels (P < 0.05), but not with cognitive function (P > 0.05). CONCLUSION: The results indicate the involvement of inflammation in the etiology of TRS and CMS. Further studies are warranted.

Asunto(s)

Esquizofrenia , Humanos , Masculino , Cognición , Inflamación , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/química , Esquizofrenia/diagnóstico , Esquizofrenia/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/química

RESUMEN

PURPOSE: To determine whether various inflammatory-, angiogenic/anti-angiogenic-, and extracellular matrix remodeling-associated proteins in plasma, alone or in combination with conventional blood-based markers, can predict intra-amniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in women with spontaneous preterm labor (PTL). METHODS: A total of 193 singleton pregnant women with PTL (23-33 weeks) were included in this retrospective cohort study. Plasma samples were obtained at the time of amniocentesis. Amniotic fluid (AF) was cultured for microorganism detection and consequent MIAC diagnosis. IL-6 levels were determined in AF and used to identify IAI (AF IL-6 ≥ 2.6 ng/mL). Endostatin, haptoglobin, IGFBP-2/3, LBP, M-CSF, MMP-2/8, pentraxin 3, PlGF, S100A8/A9, and VEGFR-1 levels were assayed in plasma samples by ELISA. CRP levels and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Plasma LBP, MMP-8, and S100A8/A9 levels, CRP levels, and NLR were significantly higher, and plasma IGFBP-2 and MMP-2 levels were significantly lower in women with IAI/MIAC than in those without this condition, whereas no baseline variables differed significantly between the two groups. Using a stepwise regression analysis, a noninvasive prediction model for IAI/MIAC was developed, which included plasma LBP, MMP-2, and MMP-8 levels (area under the curve [AUC], 0.785). The AUC for this prediction model was significantly or borderline greater than that of any single factor included in the model. CONCLUSIONS: IGFBP-2, LBP, MMP-2, MMP-8, and S100A8/A9 may represent valuable plasma biomarkers for predicting IAI/MIAC in women with PTL. Combination of LBP, MMP-2, and MMP-8 expression data can significantly improve the predictive potential for IAI/MIAC.

Asunto(s)

Líquido Amniótico , Biomarcadores , Proteína C-Reactiva , Corioamnionitis , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 8 de la Matriz , Trabajo de Parto Prematuro , Humanos , Femenino , Embarazo , Estudios Retrospectivos , Adulto , Trabajo de Parto Prematuro/microbiología , Trabajo de Parto Prematuro/sangre , Líquido Amniótico/microbiología , Líquido Amniótico/metabolismo , Metaloproteinasa 8 de la Matriz/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Biomarcadores/sangre , Corioamnionitis/microbiología , Corioamnionitis/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Metaloproteinasa 2 de la Matriz/sangre , Calgranulina A/sangre , Endostatinas/sangre , Proteínas de Fase Aguda/análisis , Interleucina-6/sangre , Amniocentesis , Componente Amiloide P Sérico/análisis , Componente Amiloide P Sérico/metabolismo , Haptoglobinas/análisis , Haptoglobinas/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Valor Predictivo de las Pruebas , Matriz Extracelular/metabolismo , Angiogénesis , Calgranulina B

RESUMEN

OBJECTIVE: To investigate the relationship between serum matrix metalloproteinase-1(MMP-1) and matrix metalloproteinase-2(MMP-2) and the formation of deep venous thrombosis(LDVT) in lower extremity patients after surgery for lower extremity fracture, and to analyze the value of MMP-1 and MMP-2 in predicting the occurrence of LDVT after lower extremity fracture. METHODS: From June 2018 to December 2021, 352 patients who planned to receive surgical treatment of lower limb fracture in our hospital were selected as the research objects. Venous blood was collected at 1, 2 and 3 days after surgery, respectively, and serum MMP-1 and MMP-2 levels were detected. The incidence of LDVT during hospitalization was analyzed, and the risk factors of postoperative LDVT in patients with lower limb fracture surgery and the predictive value of MMP-1 and MMP-2 for LDVT were analyzed. RESULTS: LDVT occurred in 40 patients (LDVT group), the incidence of LDVT was 11.36%, and 312 patients did not occurred(no occurred group). The serum levels of MMP-1 and MMP-2 in LDVT group increased gradually after surgery; the serum levels of MMP-1 and MMP-2 in the no occurred group increased slightly after surgery at 2 days and then decreased at 3 days after surgery (P<0.01);the serum levels of MMP-1 and MMP-2 in LDVT group were higher than those in the no occurred group at 2 days and 3 days after surgery (P<0.05). Serum levels of MMP-1 and MMP-2 were positively correlated with serum levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor -α (TNF-α) in LDVT patients at 2 days and 3 days postoperatively (P<0.05). Operative time, MMP-1 and MMP-2 postoperative 3 days were related to the occurrence of LDVT after lower limb fracture (P<0.01). The area under the curve(AUC) predicted by MMP-1 and MMP-2 postoperative 3 days for LDVT after lower limb fracture was 0.738 and 0.744 respectively, and the AUC predicted by combined MMP-1 and MMP-2 was 0.910, which was higher than that predicted by single indicator(Z=2.819 and 2.025, P<0.05). CONCLUSION: High levels of MMP-1 and MMP-2 after lower extremity fracture are closely related to the occurrence of LDVT, and 3 d mMP-1 and MMP-2 after surgery maybe used as evaluation indexes for LDVT risk prediction.

Asunto(s)

Fracturas Óseas , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 2 de la Matriz , Trombosis de la Vena , Humanos , Extremidad Inferior/cirugía , Metaloproteinasa 1 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/sangre , Factores de Riesgo , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiología , Fracturas Óseas/cirugía

RESUMEN

OBJECTIVE@#To investigate the relationship between serum matrix metalloproteinase-1(MMP-1) and matrix metalloproteinase-2(MMP-2) and the formation of deep venous thrombosis(LDVT) in lower extremity patients after surgery for lower extremity fracture, and to analyze the value of MMP-1 and MMP-2 in predicting the occurrence of LDVT after lower extremity fracture.@*METHODS@#From June 2018 to December 2021, 352 patients who planned to receive surgical treatment of lower limb fracture in our hospital were selected as the research objects. Venous blood was collected at 1, 2 and 3 days after surgery, respectively, and serum MMP-1 and MMP-2 levels were detected. The incidence of LDVT during hospitalization was analyzed, and the risk factors of postoperative LDVT in patients with lower limb fracture surgery and the predictive value of MMP-1 and MMP-2 for LDVT were analyzed.@*RESULTS@#LDVT occurred in 40 patients (LDVT group), the incidence of LDVT was 11.36%, and 312 patients did not occurred(no occurred group). The serum levels of MMP-1 and MMP-2 in LDVT group increased gradually after surgery; the serum levels of MMP-1 and MMP-2 in the no occurred group increased slightly after surgery at 2 days and then decreased at 3 days after surgery (P<0.01);the serum levels of MMP-1 and MMP-2 in LDVT group were higher than those in the no occurred group at 2 days and 3 days after surgery (P<0.05). Serum levels of MMP-1 and MMP-2 were positively correlated with serum levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor -α (TNF-α) in LDVT patients at 2 days and 3 days postoperatively (P<0.05). Operative time, MMP-1 and MMP-2 postoperative 3 days were related to the occurrence of LDVT after lower limb fracture (P<0.01). The area under the curve(AUC) predicted by MMP-1 and MMP-2 postoperative 3 days for LDVT after lower limb fracture was 0.738 and 0.744 respectively, and the AUC predicted by combined MMP-1 and MMP-2 was 0.910, which was higher than that predicted by single indicator(Z=2.819 and 2.025, P<0.05).@*CONCLUSION@#High levels of MMP-1 and MMP-2 after lower extremity fracture are closely related to the occurrence of LDVT, and 3 d mMP-1 and MMP-2 after surgery maybe used as evaluation indexes for LDVT risk prediction.

Asunto(s)

Humanos , Extremidad Inferior/cirugía , Metaloproteinasa 1 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/sangre , Factores de Riesgo , Trombosis de la Vena/etiología , Fracturas Óseas/cirugía

RESUMEN

INTRODUCTION: Matrix metalloproteinases (MMPs) of atherosclerotic tissue contribute to plaque rupture triggering acute coronary syndromes (ACS). Several MMPs, including MMP-2, are also contained in platelets and released upon activation. An increase in circulating levels of MMP-2 has been reported in patients undergoing percutaneous coronary interventions (PCI), but its time-course and origin remain unclear. Aims of our study were to assess the time-course of MMP-2 release in blood of stable and unstable coronary artery disease patients undergoing PCI and to unravel the possible contribution of platelets to its release. METHODS: Peripheral blood samples were drawn immediately before, 4 and 24 h after PCI from patients with ACS (NSTEMI or STEMI, n = 21) or with stable angina (SA, n = 21). Platelet-poor plasma and washed platelet lysates were prepared and stored for subsequent assay of MMP-2 and ß-thromboglobulin (ß-TG), a platelet-specific protein released upon activation. RESULTS: Plasma MMP-2 and ß-TG increased significantly 4 h after PCI and returned to baseline at 24 h in ACS patients, while they did not change in SA patients. Platelet content of MMP-2 and ß-TG decreased significantly 4 h after PCI in patients with ACS, compatible with intravascular platelet activation and release, while they did not change in patients with SA. CONCLUSIONS: PCI triggers the release of MMP-2 in the circulation of ACS patients but not in that of patients with SA. Platelets activated by PCI contribute to the increase of plasma MMP-2 releasing their MMP-2 content. Given that previous mechanicistic studies have shown that MMP-2 may sustain platelet activation and unstabilize downstream-located plaques and in the long term favour restenosis and atherosclerosis progression, these data may encourage the search for therapeutic agents blocking MMP-2 release or activity in ACS.

Asunto(s)

Síndrome Coronario Agudo , Aterosclerosis , Metaloproteinasa 2 de la Matriz/sangre , Intervención Coronaria Percutánea , Síndrome Coronario Agudo/tratamiento farmacológico , Aterosclerosis/metabolismo , Plaquetas/metabolismo , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Activación Plaquetaria

RESUMEN

BACKGROUND: Cardiopulmonary bypass (CPB) leads to shedding of the glycocalyx of endothelial cells, resulting in a series of complications such as tissue edema and coagulatory and microcirculatory dysfunctions. Matrix metalloproteinases (MMPs) can cause glycocalyx shedding in a variety of pathological processes, but their role in the process of CPB is still unclear. We hypothesized that the MMPs inhibitor doxycycline would reduce glycocalyx shedding by inhibiting MMPs during CPB. METHODS: Thirty-six patients were randomized to receive either 100 mg oral doxycycline (an MMPs inhibitor) or a matching placebo pill twice a day for three days before CPB. The primary outcome was the concentration of plasma syndecan-1. Secondary outcomes included heparan sulphate, MMP-2, MMP-9, ratio of urinary albumin to creatinine, and short-term clinical outcomes. In order to further prove that MMPs in plasma caused the glycocalyx shedding, human umbilical vein endothelial cells were cultured with plasma obtained from cardiac surgery patients before or after CPB (with or without MMPs inhibitor GM6001). The change in glycocalyx content was detected by immunofluorescence. RESULTS: CPB resulted in an increase of MMPs and shedding of the glycocalyx. Plasma syndecan-1 was higher in the control group than in the doxycycline group (median difference:15.04 µg/L; 95% CI: 9.14-20.94 µg/L; P < 0.001). Similar to syndecan-1, plasma heparan sulphate, MMP-2, and MMP-9 concentrations in the doxycycline group were significantly lower than those in the control group during CPB. Doxycycline was also correlated with a reduction in the ratio of urinary albumin to creatinine and improved the short-term clinical outcomes of patients. Endothelial cells cultured with plasma from patients after CPB showed significant shedding of syndecan-1 and heparan sulphate (post-CPB group vs pre-CPB group, P < 0.001). GM6001 was shown to reduce shedding of syndecan-1 and heparan sulphate by inhibiting MMPs (post-CPB + GM6001 group vs post-CPB group, P < 0.001). CONCLUSION: Doxycycline can reduce glycocalyx shedding by inhibiting MMPs during CPB.

Asunto(s)

Puente Cardiopulmonar , Doxiciclina , Glicocálix , Sindecano-1 , Albúminas , Creatinina , Doxiciclina/uso terapéutico , Células Endoteliales , Heparitina Sulfato , Humanos , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/sangre , Microcirculación , Sindecano-1/sangre