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1.
Medicine (Baltimore) ; 98(45): e17920, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702672

RESUMO

There is little information concerning the predictive ability of the preoperative platelet to albumin ratio (PAR) in hepatocellular carcinoma (HCC) patients after liver resection. In the current study, we aimed to assess the prognostic power of the PAR in HCC patients without portal hypertension (PH) following liver resection.Approximately 628 patients were included in this study. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of the PAR for both recurrence-free survival (RFS) and overall survival (OS). Univariate and multivariate analyses were used to identify the independent risk factors for both RFS and OS.During the follow-up period, 361 patients experienced recurrence, and 217 patients died. ROC curve analysis suggested that the best cut-off value of the PAR for RFS was greater than 4.8. The multivariate analysis revealed that microvascular invasion (MVI), tumor size >5 cm, high aspartate aminotransferase-to-platelet count ratio index (APRI) and high PAR were four independent risk factors for both RFS and OS. Patients with a low PAR had significantly better RFS and OS than those with a high PAR.The PAR may be a useful marker to predict the prognosis of HCC patients after liver resection. HCC patients with a high preoperative PAR had a higher recurrent risk and lower long-term survival rate than those with a low preoperative PAR.


Assuntos
Albuminas/metabolismo , Plaquetas/metabolismo , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Adulto , Biomarcadores/sangue , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatectomia/mortalidade , Hepatectomia/estatística & dados numéricos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Período Pré-Operatório , Intervalo Livre de Progressão , Curva ROC
2.
Biochemistry (Mosc) ; 84(10): 1213-1219, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694517

RESUMO

Diabetes mellitus is characterized by increased platelet activation which is determined by many factors including changes in the expression of membrane proteins. The aim of this study was to investigate the sensitivity of human platelets to the insulin-like growth factor (IGF) system in patients with poorly controlled type 2 diabetes mellitus (DM2). Ligand binding was analyzed using 125I-labelled IGF-1 and insulin, and relative expression of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) was evaluated by Western blotting. Platelet aggregation in the presence of IGF-1 was studied by the plate aggregometry assay. We found that platelets from DM2 patients exhibited significantly higher IGF-1 binding and upregulation of IGF-1R expression in comparison with healthy individuals. Both insulin binding and IR expression were lower in the DM2 group, but the differences with the healthy control were statistically insignificant. The potentiating effect of IGF-1 on the thrombin-induced activation of platelets was detected in both groups but was significantly more pronounced in the DM2 patients. The initial rate of platelet activation in the presence of IGF-1 positively correlated with the concentration of glycated hemoglobin. Platelets isolated from DM2 patients displayed elevated expression of the IGF-1R subunits, which might have contributed to the higher sensitivity of these cells to IGF-1 in thrombin-initiated aggregation by increasing the rate of platelet activation. However, further experiments are needed to investigate the role of IGF-1 in thrombotic complications that usually accompany diabetes.


Assuntos
Plaquetas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fator de Crescimento Insulin-Like I/isolamento & purificação , Masculino , Pessoa de Meia-Idade
3.
Medicine (Baltimore) ; 98(43): e17394, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651841

RESUMO

Child-Pugh (CP) grade A patients with early stage hepatocellular carcinoma (HCC) are candidates for curative surgery, while some patients still have a poor outcome. The aim of this study was to investigate the prognostic values of 2 new evaluation models for liver function, named albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) grades, in CP grade A patients with HCC.In this retrospective cohort study, we reviewed 134 cases of CP grade A patients with hepatitis B-associated HCC who underwent radical surgery. ALBI and PALBI grades were calculated based on preoperative serologic examinations. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier curve and Cox regression. The prognostic performances of the models were estimated by using the concordance index (C-index).During a median follow-up time of 27 months, 27.6% (37/134) of patients died and 26.1% (35/134) experienced recurrence. Kaplan-Meier analyses showed that ALBI and PALBI grades were significantly associated with OS and RFS. Multivariate analyses further revealed that both ALBI and PALBI grades were independent predictors for survival. Furthermore, the prognostic values of the combination of tumor size with ALBI (C-index = 0.754, 95% confidence interval [CI]: 0.675-0.849) or with PALBI (C-index = 0.762, 95% CI: 0.664-0.844) may be comparable with both Barcelona Clinic Liver Cancer and Cancer of Liver Italian Program staging systems.The ALBI and PALBI grades, in particular the combination with tumor size, are effective models for discriminating survival in CP grade A patients with HCC.


Assuntos
Bilirrubina/sangue , Plaquetas/metabolismo , Carcinoma Hepatocelular/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Albumina Sérica/análise , Adulto , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/virologia , Feminino , Hepatite B/complicações , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
4.
J Cancer Res Clin Oncol ; 145(11): 2713-2723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552488

RESUMO

BACKGROUND: During the development of tumors, tumors "educate" platelets causing changes in their mRNAs expression profiles and phenotypes, thereby, tumor-educated platelet (TEP) mRNA profile has the potential to diagnose lung cancer. The current study aimed to examine whether TEPs might be a potential biomarker for lung cancer diagnostics. METHODS: Platelet precipitation was obtained by low-speed centrifugation and subjected to Trizol for total RNA extraction. Platelet MAX, MTURN, and HLA-B mRNA were selected by microarray, validated by qPCR, and analyzed combined with related clinical factors. RESULTS: Our results showed that a three-platelet mRNA set: MAX, MTURN, and HLA-B was significantly up-regulated in lung cancer patients as well as in early-stage lung cancer patients compared with those from healthy donors, the area under the curve (AUC) was 0.734, 0.787, respectively, among which platelet MTURN mRNA processed a dramatically high diagnostic efficiency in female patients with lung cancer, its AUC for female was 0.825. More importantly, the three-platelet mRNA set: MAX, MTURN, and HLA-B was associated with chemotherapeutic effect, low mRNA expression of this three-platelet set was correlated with "favorable" first chemotherapy response. CONCLUSIONS: A three-platelet mRNA set: MAX, MTURN and HLA-B enables blood-based lung cancer diagnosis and chemotherapy response prediction.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Plaquetas/metabolismo , Antígenos HLA-B/genética , Neoplasias Pulmonares/diagnóstico , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Feminino , Perfilação da Expressão Gênica , Antígenos HLA-B/sangue , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/sangue , Prognóstico , RNA Mensageiro/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/genética
5.
Bratisl Lek Listy ; 120(9): 630-635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475544

RESUMO

OBJECTIVES: To test the hypothesis if mitochondrial bioenergetic function analyzed in circulating platelets may represent peripheral signature of mitochondrial dysfunction in nephropathy associated to non-communicable human diseases such as cardiovascular diseases, diabetes and with statins treatment. METHODS: High-resolution respirometry was used for analysis of mitochondrial bioenergetics in human platelets isolated from peripheral blood. This method is less-invasively compared to skeletal muscle biopsy. Patients with nephropathies and in combination with non-communicable diseases were included in the study. RESULTS: This pilot study showed platelet mitochondrial bioenergy dysfunction in patients with nephropathies and non-communicable diseases. Positive effect of treatment with 10 mg atorvastatin on platelet mitochondrial respiratory chain Complex I-linked respiration and ATP production in patients with nephropathies, diabetes and 80 mg atorvastatin in patient with nephropathy and dialysis was found. Positive effect of 80 mg fluvastatin treatment, and negative effect of thrombocytopenia and renal transplantation on platelet mitochondrial bioenergy was determined. CONCLUSION: High-resolution respirometry allowed detection of small changes in platelet mitochondrial function. This method could be used as a sensitive bioenergetic test of mitochondrial function for diagnosis and monitoring the therapy in patients with nephropathy (Tab. 1, Fig. 3, Ref. 39).


Assuntos
Plaquetas/metabolismo , Metabolismo Energético , Nefropatias/metabolismo , Mitocôndrias/metabolismo , Doenças não Transmissíveis , Respiração Celular , Humanos , Projetos Piloto
6.
Medicine (Baltimore) ; 98(32): e16801, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393410

RESUMO

BACKGROUND: Contrast-induced nephropathy (CIN) is acute renal failure observed after administration of iodinated contrast media during angiographic or other medical procedures. In recent years, many studies have focused on biomarkers that recognize CIN and/or predict its development in advance. One of the many biomarkers studied is the platelet-to-lymphocyte ratio (PLR). We performed a systematic review and meta-analysis to evaluate the correlation between PLR level and CIN. METHODS: Relevant studies were searched in PUBMED, EMBASE, and Web of Science until September 15, 2018. Case-control studies reporting admission PLR levels in CIN and non-CIN group in patients with acute coronary syndrome (ACS) were included. The pooled weighted mean difference (WMD) and 95% confidence intervals (95%CI) were calculated to assess the association between PLR level and CIN using a random-effect model. RESULTS: Six relevant studies involving a total of 10452 ACS patients (9720 non-CIN controls and 732 CIN patients) met our inclusion criteria. A meta-analysis of 6 case-control studies showed that PLR levels were significantly higher in CIN group than those in non-CIN group (WMD = 33.343, 95%CI = 18.863 to 47.823, P < .001, I = 88.0%). CONCLUSION: For patients with ACS after contrast administration, our meta-analysis shows that on-admission PLR levels in CIN group are significantly higher than those of non-CIN group. However, large and matched cohort studies are needed to validate these findings and assess whether there is a real connection or just an association.


Assuntos
Síndrome Coronariana Aguda/epidemiologia , Lesão Renal Aguda/induzido quimicamente , Plaquetas/metabolismo , Meios de Contraste/efeitos adversos , Linfócitos/metabolismo , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/cirurgia , Angiografia Coronária/efeitos adversos , Angiografia Coronária/métodos , Humanos , Contagem de Linfócitos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos
7.
Medicine (Baltimore) ; 98(34): e16793, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441851

RESUMO

Osteoporosis is a chronic, progressive disease in which early diagnosis is very important. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been reported as new predictors in inflammatory and immune diseases including osteoporosis. No studies have reported the relationship between monocyte-to-lymphocyte ratio (MLR) and osteoporosis patients.To investigated the ability of MLR to predict osteoporosis.Three hundred sixteen osteoporosis patients and 111 healthy control subjects were enrolled. Patients' laboratory and clinical characteristics were recorded. MLR, NLR, and PLR levels were calculated. The differences were compared and the diagnostic values of MLR were analyzed.There were 76 male and 105 female patients included, with a mean age of 56.57 ±â€Š9.95 years. The levels of MLR, NLR, and PLR in osteoporosis patients were all higher than those in healthy control subjects. The area under the curve of MLR was higher than those of NLR and PLR. Multivariate linear regression analysis showed that T-score was affected by age and MLR. MLR was positively correlated with C-reactive protein, erythrocyte sedimentation rate, red blood cell distribution width, age, sex, and inversely with hemoglobin. MLR and PLR levels were significantly higher in osteoporosis patients than in osteopenia patients (P < .05).The present study shows that MLR had a higher diagnostic value for osteoporosis. MLR may be a reliable, inexpensive, and novel potential predictor of osteoporosis.


Assuntos
Linfócitos/metabolismo , Monócitos/metabolismo , Osteoporose/sangue , Adulto , Fatores Etários , Idoso , Plaquetas/metabolismo , Sedimentação Sanguínea , Proteína C-Reativa/biossíntese , Estudos Transversais , Feminino , Hemoglobinas/análise , Humanos , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
8.
Chem Biol Interact ; 311: 108796, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421116

RESUMO

Lambda-cyhalothrin (LCT) is a broad-spectrum pesticide widely used in agriculture throughout the world. This pesticide is considered a potential contaminant of surface and underground water as well as food, posing a risk to ecosystems and humans. In this sense, we decided to evaluate the activity of enzymes belonging to the purinergic system, which is linked with regulation of extracellular nucleotides and nucleosides, such as adenosine triphosphate (ATP) and adenosine (Ado) molecules involved in the regulation of inflammatory response. However, there are no data concerning the effects of LCT exposure on the purinergic system, where extracellular nucleotides act as signaling molecules. The aim of this study was to evaluate nucleotide hydrolysis by E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase), Ecto-NPP (ecto-nucleotide pyrophosphatase/phosphodiesterase), ecto-5'-nucleotidase and ecto-adenosine deaminase (E-ADA) in platelets and liver of adult rats on days 7, 30, 45 and 60 after daily gavage with 6.2 and 31.1 mg/kg bw of LCT. Gene expression patterns of NTPDases1-3 and 5'-nucleotidase were also determined in those tissues. In parallel, lambda-cyhalothrin metabolites [3-(2-chloro-3,3,3- trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic acid (CFMP), 4-hydroxyphenoxybenzoic acid (4-OH-3-PBA), and 3-phenoxybenzoic acid (3-PBA)] were measured in plasma. Results showed that exposure rats to LCT caused a significant increase in the assessed enzymes activities. Gene expression pattern of ectonucleotidases further revealed a significant increase in E-NTPDase1, E-NTPDase2, and E-NTPDase3 mRNA levels after LCT administration at all times. A dose-dependent increase in LCT metabolite levels was also observed but there no significant variations in levels from weeks to week, suggesting steady-steady equilibrium. Correlation analyses revealed that LCT metabolites in the liver and plasma were positively correlated with the adenine nucleotides hydrolyzing enzyme, E-ADA and E-NPP activities in platelets and liver of rats exposed to lambda-cyhalothin. Our results show that LCT and its metabolites may affect purinergic enzymatic cascade and cause alterations in energy metabolism.


Assuntos
Plaquetas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nitrilos/farmacologia , Nucleotidases/genética , Nucleosídeos de Purina/metabolismo , Piretrinas/farmacologia , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Plaquetas/enzimologia , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Hidrólise , Fígado/enzimologia , Fígado/metabolismo , Masculino , Espectrometria de Massas , Nitrilos/sangue , Nitrilos/metabolismo , Nucleotidases/metabolismo , Piretrinas/sangue , Piretrinas/metabolismo , Pirofosfatases/genética , Pirofosfatases/metabolismo , Ratos , Ratos Wistar
9.
Ann Hematol ; 98(10): 2257-2265, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440871

RESUMO

Vascular complications of sickle cell anemia (SCA) are influenced by many factors. Elevated plasma homocysteine (Hcy) is supposed to be an independent risk factor and is either genetic or nutritional origin. The present study evaluated the plasma Hcy level, MTHFR C677T gene polymorphism, effect of folic acid (FA) supplementation' and hemato-biochemical parameters in SCA and their effect on the vaso-occlusive crisis (VOC) in SCA patients of an Asian-Indian haplotype population. One hundred twenty cases of SCA (HbSS) and 50 controls with normal hemoglobin(HbAA) were studied. It was found that the plasma Hcy level is significantly higher (p < 0.0001) in patients with SCA (22.41 ± 7.8 µmol/L) compared to controls (13.2 ± 4.4 µmol/L). Moreover, patients without FA supplementation had a significantly (p < 0.001) higher Hcy level (27 ± 7 µmol/L) compared to those with supplementation (17.75 ± 5.7 µmol/L). Turkey-Kramer multiple comparison tests show that there is a significant difference (p < 0.05) in HbF percent, hemoglobin (Hb), platelet count, serum bilirubin (direct:Bil-D and total:Bil-T), aspartate transaminase (AST), lactate dehydrogenase (LDH), and plasma Hcy levels between mild and severe VOC. Between moderate VOC and severe VOC, there was a significant difference (p < 0.05) in HbF%, Bil-D, AST, Hcy. Pearson correlation revealed that plasma Hcy had a significantly (p < 0.05) positive correlation with AST, serum bilirubin (indirect and total), LDH, jaundice, stroke, VOC per year, and hospitalization per year whereas it was inversely correlated with HbF percentage, Hb level, and FA treatment. In the study population, increased plasma Hcy level, hemolysis, and platelet activation were found to influence VOC in SCA.


Assuntos
Anemia Falciforme , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Doenças Vasculares , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia Falciforme/genética , Anemia Falciforme/fisiopatologia , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Plaquetas/metabolismo , Feminino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Hemólise , Homocisteína/genética , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Pessoa de Meia-Idade , Ativação Plaquetária , Contagem de Plaquetas , Doenças Vasculares/sangue , Doenças Vasculares/etiologia , Doenças Vasculares/genética , Doenças Vasculares/fisiopatologia
10.
Medicine (Baltimore) ; 98(30): e16565, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348282

RESUMO

BACKGROUND: We aimed to assess the association between red cell distribution width-to-platelet ratio (RPR) and hepatic fibrosis in nonalcoholic fatty liver disease. METHODS: The 388 subjects fulfilling the diagnostic criteria of Nonalcoholic fatty liver disease (NAFLD) were enrolled in this cross-sectional study. Red cell distribution, platelet, and other clinical and laboratory parameters were measured. RESULTS: NAFLD patients with advanced fibrosis had significantly higher RPR than those without fibrosis (P < .001). Spearman correlation analysis showed that RPR were significantly correlated with age, sex, creatinine, hemoglobin, white blood cell, and advanced fibrosis (all with P < .05). Multivariate logistic regression analysis showed that RPR was an independent factor predicting advanced fibrosis (fibrosis-4 calculator ≥1.3) in NAFLD patients (OR: 5.718, 95%CI: 3.326-9.830, P < .001). CONCLUSIONS: Our findings suggested that RPR were significantly associated with advanced fibrosis in nonalcoholic fatty liver disease patients.


Assuntos
Plaquetas/metabolismo , Índices de Eritrócitos , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Índice de Gravidade de Doença , Adulto , Estudos Transversais , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Contagem de Plaquetas
11.
J Stroke Cerebrovasc Dis ; 28(9): 2398-2406, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31311696

RESUMO

BACKGROUND: Coated-platelets are a subset of highly procoagulant platelets observed after dual agonist stimulation with collagen and thrombin. Coated-platelet levels are increased in acute stroke compared to controls, and higher levels are associated with stroke recurrence. We examined whether coated-platelet levels measured at the time of the stroke correlate with cognitive scores at 3 months following the brain infarction. METHODS: Coated-platelets were assayed in consecutive patients with nonlacunar stroke. Cognitive screening was performed using the Mini-Mental State Examination (MMSE) at 3 months after discharge. Linear regression, with adjustment for individual covariates, was used to model the association between coated-platelet levels and MMSE scores. RESULTS: One hundred and twenty-eight patients with a mean MMSE score of 26 points (range 14-30, standard deviation [SD] 3.1) and mean coated-platelet levels of 40.9% (range 5.2-76.2, SD 13.3), completed cognitive screening. An inverse linear association was found between coated-platelet levels and MMSE score, with higher levels seen in patients with lower MMSE scores (r = -.34, R2 = .12, P < .0001). This association remained despite adjustment for potential confounding factors. In the final model, higher coated-platelet levels (coefficient -.078, 95% confidence interval [CI]: -.12 to -.041, P < .0001), presence of hypertension (coefficient -2.42, 95% CI: -3.90 to -.95, P = .0015), and anticoagulant use at discharge (coefficient -1.48, 95% CI: -2.56 to -.39, P = .0079) were predictive of lower MMSE. CONCLUSIONS: These findings support a link between increased platelet procoagulant potential at the time of the stroke and development of cognitive impairment following cerebral infarction.


Assuntos
Coagulação Sanguínea , Plaquetas/metabolismo , Isquemia Encefálica/complicações , Transtornos Cognitivos/etiologia , Cognição , Ativação Plaquetária , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/psicologia , Transtornos Cognitivos/sangue , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Projetos Piloto , Contagem de Plaquetas , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/psicologia , Fatores de Tempo
12.
Inflammopharmacology ; 27(5): 863-869, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31309484

RESUMO

The failure of mechanisms of natural anti-coagulation either due to genetic impairment or due to severe external injuries may result in a condition called thrombosis. This is believed to be the primary cause for a variety of life-threatening conditions such as: heart attack, stroke, pulmonary embolism, thrombophlebitis, and deep venous thrombosis (DVT). The growing number of these incidents requires an alternative anti-coagulant or anti-thrombotic agent that has minimal side effects and improved efficiency. For decades, plant polyphenols, especially flavonoids, were known for their vital role in preventing various diseases such as cancer. Mitigating excessive oxidative stress caused by reactive oxygen species (ROS) with anti-oxidant-rich flavonoids may reduce the risk of hyper-activation of platelets, cardiovascular diseases (CVD), pain, and thrombosis. Furthermore, flavonoids may mitigate endothelial dysfunction (ED), which generally correlates to the development of coronary artery and vascular diseases. Flavonoids also reduce the risk of atherosclerosis and atherothrombotic disease by inhibiting excessive tissue factor (TF) availability in the endothelium. Although the role of flavonoids in CVD is widely discussed, to the best of our knowledge, their role as anti-thrombotic lead has not been discussed. This review aims to focus on the biological uses of dietary flavonoids and their role in the treatment of various coagulation disorders, and may provide some potential lead to the drug discovery process in this area.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Inflamação/tratamento farmacológico , Trombose/tratamento farmacológico , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doenças Cardiovasculares/metabolismo , Humanos , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Trombose/metabolismo
13.
Life Sci ; 231: 116522, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158377

RESUMO

AIM: Liver fibrosis is a serious health problem which is a critical cause of morbidity and mortality worldwide. It is the main complication of untreated chronic inflammatory liver diseases which can progress to liver cirrhosis, hepatocellular carcinoma, and finally death. Coagulation cascade plays a mechanistic role in the pathogenesis of different chronic inflammatory disease including atherosclerosis, stroke, and tissue fibrosis. The current study was designed to investigate the effect of inhibition of coagulation cascade on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. MATERIAL AND METHODS: The study was conducted in rats. Rats were treated with CCl4 subcutaneously for 6 consecutive weeks to determine the onset of coagulation system activation in relation to development of fibrosis. To investigate the effects of coagulation system inhibition in CCl4-induced liver fibrosis, the anticoagulants drugs dabigatran and clopidogrel were administrated orally concurrently with CCl4 treatment. KEY FINDINGS: The results of our study revealed that during the first week, there were significant elevations of fibrin, tissue factor expressions, and prothrombin time (PT) coupled with neutropenia without significant changes in liver fibrosis markers such as TGF-ß, α-SMA and collagen deposition. Starting from the second week, tissue injury markers including the oxidative, inflammatory and fibrosis markers as well as histopathological changes became evident progressively. Intriguingly, dabigatran and clopidogrel significantly normalized the biochemical and pathological changes. SIGNIFICANCE: In conclusion, activation of coagulation cascade is a triggering stimulus in the initiation of CCl4-induced liver fibrosis and the anticoagulant drugs may exert promising anti-fibrotic effect.


Assuntos
Clopidogrel/farmacologia , Dabigatrana/farmacologia , Cirrose Hepática/tratamento farmacológico , Animais , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Tetracloreto de Carbono/farmacologia , Clopidogrel/metabolismo , Dabigatrana/metabolismo , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Trombina/efeitos dos fármacos , Trombina/metabolismo
14.
Gen Physiol Biophys ; 38(4): 325-334, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241044

RESUMO

Seasonal variations in temperature may influence the physiological and pathological metabolic pathways, concentrations of antioxidants, degree of oxidative stress and mitochondrial function. The aim of this study was to evaluate platelet mitochondrial function in human subjects during seasonal variations in temperature. Two groups of healthy young subjects were enroled in the study. Winter group, mean outside temperature was 4.77°C and Spring group, mean outside temperature was 24.32°C. High-resolution respirometry method was used for determination of mitochondrial respiration and oxidative phosphorylation in platelets. Concentrations of coenzyme Q10 (CoQ10) and tocopherols were determined in platelets, blood and plasma. Our data showed slightly (not significantly) reduced respiration in intact platelets, basal and ADP-stimulated mitochondrial respiration at Complex I, as well as CoQ10-TOTAL and α-tocopherol concentrations in winter. The concentration of γ-tocopherol was higher in winter. Platelet mitochondrial ATP production depended on platelet CoQ10-TOTAL concentration in winter, not in spring. We conclude that seasonal temperature participates in the mechanism of platelet mitochondrial respiratory chain function and oxidative phosphorylation that depends on their CoQ10-TOTAL concentration at lower winter outside temperature. CoQ10 supplementation may improve platelets mitochondrial ATP production at winter season. High-resolution respirometry offers sensitive method for detection of changes of platelets mitochondrial respiratory function.


Assuntos
Plaquetas/citologia , Mitocôndrias/fisiologia , Estações do Ano , Ubiquinona/análogos & derivados , Antioxidantes/análise , Plaquetas/metabolismo , Humanos , Ubiquinona/sangue
15.
J Stroke Cerebrovasc Dis ; 28(8): 2302-2310, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174954

RESUMO

BACKGROUND: Aggregation of platelets is a trigger for additional development of larger thrombi. This study aimed to identify factors that may affect platelet aggregability and their role in clinical outcomes in acute ischemic stroke. METHODS: Consecutive acute ischemic stroke patients (n = 352) who were transferred within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure platelet aggregability and other parameters. RESULTS: Mean values of spontaneous small-sized platelet aggregates and collagen- or adenosine diphosphate (ADP)-induced large-sized aggregates were elevated in acute ischemic stroke. In atherothrombotic stroke (n = 178), collagen and ADP-induced large-sized aggregates were positively correlated with HbA1c, respectively. High incidence of the modified Rankin Scales (mRS) 5-6 at discharge was associated with diabetes complication (odds ratio [OR] 8.77, 95% confidence interval [CI] 1.32-57.56). The proportion of patients who were functionally independent (the mRS 0-2) at discharge was lower in the middle tertile of collagen and ADP-induced large-sized aggregates than their low tertile (OR 2.46, 95% CI 1.09-5.58; OR 2.43, 95% CI 1.05-5.59, respectively). Prestroke administration of aspirin recovered the proportion of independence at discharge (OR 0.25, 95% CI 0.06-0.99), and ameliorated incidence of the mRS 5-6. On logistic regression analysis, diabetes, HbA1c, collagen-induced large-sized aggregates, and prestroke administration of aspirin remained independent predictors of clinical outcomes in atherothrombotic stroke. In cardioembolic and lacunar stroke, no relations with clinical outcomes were found. CONCLUSIONS: High plasma level of HbA1c is involved in enhanced platelet aggregability in acute atherothrombotic stroke patients, and prestroke administration of aspirin may be beneficial to clinical outcomes.


Assuntos
Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Diabetes Mellitus/sangue , Hemoglobina A Glicada/metabolismo , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Biomarcadores/sangue , Plaquetas/metabolismo , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Comorbidade , Estudos Transversais , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Avaliação da Deficiência , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/efeitos adversos , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
16.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216638

RESUMO

Thrombus formation in hemostasis or thrombotic disease is initiated by the rapid adhesion, activation, and aggregation of circulating platelets in flowing blood. At arterial or pathological shear rates, for example due to vascular stenosis or circulatory support devices, platelets may be exposed to highly pulsatile blood flow, while even under constant flow platelets are exposed to pulsation due to thrombus growth or changes in vessel geometry. The aim of this study is to investigate platelet thrombus formation dynamics within flow conditions consisting of either constant or variable shear. Human platelets in anticoagulated whole blood were exposed ex vivo to collagen type I-coated microchannels subjected to constant shear in straight channels or variable shear gradients using different stenosis geometries (50%, 70%, and 90% by area). Base wall shears between 1800 and 6600 s-1, and peak wall shears of 3700 to 29,000 s-1 within stenoses were investigated, representing arterial-pathological shear conditions. Computational flow-field simulations and stenosis platelet thrombi total volume, average volume, and surface coverage were analysed. Interestingly, shear gradients dramatically changed platelet thrombi formation compared to constant base shear alone. Such shear gradients extended the range of shear at which thrombi were formed, that is, platelets became hyperthrombotic within shear gradients. Furthermore, individual healthy donors displayed quantifiable differences in extent/formation of thrombi within shear gradients, with implications for future development and testing of antiplatelet agents. In conclusion, here, we demonstrate a specific contribution of blood flow shear gradients to thrombus formation, and provide a novel platform for platelet functional testing under shear conditions.


Assuntos
Fenômenos Biomecânicos , Resistência ao Cisalhamento , Trombose/etiologia , Algoritmos , Coagulação Sanguínea , Plaquetas/metabolismo , Constrição Patológica , Humanos , Modelos Biológicos , Adesividade Plaquetária , Agregação Plaquetária , Trombose/metabolismo , Trombose/patologia
17.
Int J Mol Sci ; 20(11)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163690

RESUMO

Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10-80 µM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2-PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.


Assuntos
Plaquetas/metabolismo , Trombose/etiologia , Trombose/prevenção & controle , Umbeliferonas/uso terapêutico , Biomarcadores , Plaquetas/efeitos dos fármacos , Humanos , Fosfolipase C gama/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/química , Umbeliferonas/farmacologia
18.
Nat Commun ; 10(1): 2402, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160588

RESUMO

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to  stat1-/- mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.


Assuntos
Plaquetas/metabolismo , Vírus da Dengue/imunologia , Dengue/imunologia , Vesículas Extracelulares/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Receptores de Superfície Celular/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Citocinas/imunologia , Dengue/virologia , Exossomos/imunologia , Exossomos/metabolismo , Armadilhas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Humanos , Inflamação , Lectinas Tipo C/genética , Camundongos , Camundongos Knockout , Ativação Plaquetária , Receptores de Superfície Celular/genética , Fator de Transcrição STAT1/genética , Taxa de Sobrevida
19.
Int J Mol Sci ; 20(11)2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181592

RESUMO

Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α2ß1. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca2+. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)n and Horm-type collagen evoked Syk-dependent Ca2+ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)n sequence.


Assuntos
Plaquetas/metabolismo , Colágeno/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quinase Syk/metabolismo , Trombose/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Células Cultivadas , Colágeno/química , Cicloexilaminas/farmacologia , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Agregação Plaquetária , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinase Syk/antagonistas & inibidores
20.
Vasc Health Risk Manag ; 15: 143-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239692

RESUMO

Introduction: Conventional venous blood collection requires a puncture with a needle through the endothelium of a vessel. The endothelial injury causes activation of circulating platelets and the release of thromboxane A2. The aim of the study was to investigate if platelets continue to form thromboxane A2 in the blood tube after sample collection, but such synthesis would give false information about the actual circulating thromboxane A2 value. Methods: Thromboxane B2 is a biologically inactive but stable metabolite of thromboxane A2 and can be measured in blood samples by a standard enzyme immunoassay. Thromboxane B2 measurements reflect thromboxane A2 concentration. Blood samples were collected in 3.2% sodium citrate vials and EDTA vials from ten individuals and centrifuged and frozen at different time points (0, 30, and 120 minutes). Plasma aliquots were transferred to and frozen in 1.8 mL polypropylene tubes and the citrate samples were also transferred to and frozen in propylene tubes containing indomethacin. Results: Concentrations of thromboxane B2 in plasma samples collected in citrate vials and stored in propylene tubes increased very rapidly as the samples were left for longer after sampling and allowed to stand at room temperature. After 120 minutes, the amount of thromboxane B2 was 400% higher than in the reference sample at time zero. In comparison, thromboxane B2 concentration was about 200% higher in the 120-minute samples compared to the reference in samples collected in citrate vials but stored in indomethacin tubes. In samples collected in EDTA vials, a 10% reduction in thromboxane B2 concentration in the 120-minute samples was observed. Conclusion: Storage conditions, type of sampling vial and time from sampling until sample processing (centrifuging) has a major impact on thromboxane B2 stability.


Assuntos
Plaquetas/metabolismo , Coleta de Amostras Sanguíneas/métodos , Tromboxano A2/sangue , Tromboxano B2/sangue , Adulto , Biomarcadores/sangue , Centrifugação , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Tempo , Adulto Jovem
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