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1.
Medicine (Baltimore) ; 99(4): e18683, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977858

RESUMO

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel.Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.


Assuntos
Fenilacetatos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiofenos/farmacologia , Adulto , Clopidogrel/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Fenilacetatos/administração & dosagem , Fenilacetatos/efeitos adversos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Adulto Jovem
2.
Biosci Biotechnol Biochem ; 84(1): 85-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794329

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates collagen-mediated platelet activation through its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). However, the function of CEACAM1's extracellular cleavage fragments is currently unknown. In the present study, we used mass spectrometry (MS) to identify 9 cleavage fragments shed by matrix metallopeptidase 12 (MMP-12), and then we synthesized peptides with sequences corresponding to the fragments. QLSNGNRTLT (QLSN), a peptide from the A1-domain of CEACAM1, significantly attenuated collagen-induced platelet aggregation. QLSN also attenuated platelet static adhesion to collagen. Additionally, QLSN reduced human platelet secretion and integrin αIIbß3 activation in response to glycoprotein VI (GPVI)-selective agonist, convulxin. Correspondingly, QLSN treatment significantly decreased convulxin-mediated phosphorylation of Src, protein kinase B (Akt), spleen tyrosine kinase (Syk) and phospholipase Cγ2 (PLCγ2) in human platelets. These data indicate that the CEACAM1-derived peptide QLSN inhibits GPVI-mediated human platelet activation. QLSN could potentially be developed as a novel antiplatelet agent.


Assuntos
Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Colágeno/metabolismo , Oligopeptídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Plaquetas/metabolismo , Adesão Celular/efeitos dos fármacos , Venenos de Crotalídeos/farmacologia , Humanos , Motivo de Inibição do Imunorreceptor Baseado em Tirosina/fisiologia , Lectinas Tipo C , Metaloproteinase 12 da Matriz/metabolismo , Oligopeptídeos/síntese química , Fosfolipase C gama/metabolismo , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/agonistas , Domínios Proteicos/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinase Syk/metabolismo
3.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(11): 103-108, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31851180

RESUMO

Platelets are an easily accessible model for the study of biochemical mechanisms of mental diseases, including schizophrenia and depression. This literature review addresses a role of platelet activation in the pathogenesis of mental diseases. Platelet activation observed in patients with schizophrenia, depression and other mental illnesses is associated with the development of cardiovascular disease and an increased risk of thrombotic complications, which can be the main cause of morbidity and mortality in patients with mental disorders. A deeper understanding of the biochemical mechanisms of mental disorders will help in the study of clinical consequences of these disorders and in choosing the right therapeutic strategy for patients.


Assuntos
Transtornos Mentais , Ativação Plaquetária , Trombose , Plaquetas , Fibrinólise , Hemostasia , Humanos , Transtornos Mentais/complicações , Transtornos Psicóticos/complicações , Trombose/complicações
4.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3520-3525, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602917

RESUMO

The effect of triptolide( TP) on VEGFA,SDF-1,CXCR4 pathway were investigated in vitro to explore the mechanism in improving platelet activation in patients with ankylosing spondylitis( AS). Peripheral blood mononuclear cells( PBMC) were used for the experiment and divided into 4 groups: normal group( NC),model group( MC),triptolide group( TP),and AMD3100 group. The optimal concentration of TP was measured by the MTT method. The expressions of TNF-α,IL-1ß,IL-4,IL-10,VEGFA and VEGFR were detected by ELISA. The expressions of SDF-1,CXCR4 and VEGFA were detected by real-time quantitative PCR( RT-qPCR).The expressions of SDF-1,CXCR4,VEGFA and VEGFR were detected by Western blot. The expression levels of CD62 p,CD40 L and PDGFA were detected by immunofluorescence. MTT results showed that medium-dose TP had the strongest inhibitory effect on cells at24 h. The results of ELISA and PCR showed that TP inhibited mRNA expressions of IL-1ß,TNF-α,VEGFA,VEGFR and SDF-1,CXCR4 and VEGFA. The results of Western blot indicated that TP inhibited SDF-1,CXCR4 and VEGFA,VEGFR protein expressions; immunofluorescence results indicate that TP can inhibit the expressions of CD62 p,CD40 L,PDGFA. TP may regulate platelet activation by down-regulating SDF-1,CXCR4,VEGFA and VEGFR mRNA expressions,thereby down-regulating IL-1ß and TNF-αexpressions,and up-regulating the expressions of IL-4 and IL-10 cytokines.


Assuntos
Diterpenos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Fenantrenos/farmacologia , Ativação Plaquetária , Espondilite Anquilosante , Células Cultivadas , Quimiocina CXCL12/metabolismo , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Anticancer Res ; 39(10): 5565-5572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570451

RESUMO

BACKGROUND/AIM: The aim of the study was to evaluate the status of extravasated platelet activation (EPA) surrounding podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma by neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 74 patients were enrolled in this study. We investigated CD42b and PDPN expression in the groups of untreated, gemcitabine (GEM) alone, GEM plus S-1 (GS) and GEM plus nab-paclitaxel (GnP). RESULTS: CD42b expression in surrounding CAFs was observed in 58% patients. CD42b expression was significantly correlated with PDPN expression. CD42b-positive cases were significantly lower in the group treated with GnP than in the untreated group and groups treated with GEM alone or GS. PDPN expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of PDPN-positive fibroblasts. There was a significantly lower CD42b expression and fewer PDPN-positive fibroblasts in the GnP group than in untreated, GEM alone, and GS groups, but there was no significant difference between the latter three groups. CONCLUSION: There is a significant association between EPA and PDPN-positive CAFs in pancreatic cancer stroma. Our data suggest that the GnP regimen decreases EPA through PDPN-positive CAF depletion.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/uso terapêutico , Fibroblastos Associados a Câncer/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Ácido Oxônico/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Tegafur/uso terapêutico
6.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(8): 931-934, 2019 Aug 28.
Artigo em Chinês | MEDLINE | ID: mdl-31570682

RESUMO

Platelet lineage suggests that it plays a crucial role in immune responses. In recent years, many studies have found that platelet activation is closely related to the activity of inflammatory bowel disease. Activated platelets can release inflammatory mediators, and express surface molecules that mediate inflammation, interact with leukocytes and vascular endothelial cells. It provides a theoretical basis for antiplatelet drugs to treat the inflammatory bowel disease.


Assuntos
Células Endoteliais , Doenças Inflamatórias Intestinais , Plaquetas , Humanos , Ativação Plaquetária , Inibidores da Agregação de Plaquetas
7.
Int J Nanomedicine ; 14: 7155-7171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564871

RESUMO

Background: Platelet activation and subsequent aggregation are the initial stages of thrombosis. A molecular probe that specifically targets activated platelets and remains retained under high shear stress in vivo can enhance the imaging effect to achieve early and accurate diagnosis. Methods and materials: In this study, we constructed nanoparticles (NPs) using polydopamine to carry two peptides that simultaneously bind integrin αIIbß3 and P-selectin on activated platelets to enhance the targeting of NPs to thrombus. Results: The targeting specificity and binding stability of the NPs on red and white thrombi were demonstrated in vitro using a simulated circulatory device and the targeting effect of the NPs on mixed thrombus was studied by  magnetic resonance (MR)/photoacoustic (PA) dual-modality imaging in vivo. NPs that were surface modified with both peptides have higher selectivity and retention to red and white thrombi in vitro than NPs with a single or no peptide, and the targeting effect was closely related to the number and distribution of activated platelets as well as the structure and type of thrombus. The NPs also have MR/PA dual-modality imaging functionality, significantly enhancing the imaging of mixed thrombus in vivo. Conclusion: These dual-targeted NPs have improved targeting specificity and binding stability to different thrombi under high shear stress and are beneficial for the early diagnosis of thrombosis.


Assuntos
Indóis/química , Imagem por Ressonância Magnética , Nanopartículas/química , Técnicas Fotoacústicas , Polímeros/química , Trombose/diagnóstico por imagem , Animais , Meios de Contraste/química , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Imagem Molecular , Nanopartículas/ultraestrutura , Ativação Plaquetária , Ratos Sprague-Dawley
8.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547303

RESUMO

Better understanding the mechanisms of Leonurus cardiaca L. extract (LCE) activity is necessary to prepare recommendations for the use of LCE-based herbal products for preventive/supportive purposes in case of infective endocarditis (IE) and other staphylococcal invasive infections. The aim of the study was to analyze molecular mechanisms of LCE effect on Staphylococcus aureus and blood platelets in the context of their interactions playing a pivotal role in such disorders. Using atomic force microscopy, we demonstrated that adhesion forces of S. aureus were markedly reduced after exposure to LCE at subinhibitory concentrations. The effect resulted from the impact of LCE on S. aureus cell morphology and the composition of phospholipids and fatty acids in bacterial membranes (assessed by HPLC), which modulated their stabilization, hydrophobicity, and charge. Moreover, using FACS we showed also that LCE significantly reduced GP IIb/IIIa expression on blood platelets, thus the disruption of platelet-fibrinogen interactions seems to explain antiplatelet effect of LCE. The obtained results prove the usefulness of LCE in the prevention of S. aureus adhesion, platelet activation, and vegetations development, however, also pointed out the necessity of excluding the cationic antibiotics from the treatment of S. aureus-associated IE and other invasive diseases, when motherwort herb is used simultaneously as an addition to the daily diet.


Assuntos
Endocardite Bacteriana/prevenção & controle , Leonurus/química , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/microbiologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Endocardite Bacteriana/microbiologia , Ácidos Graxos/metabolismo , Fibrinogênio/metabolismo , Humanos , Microscopia de Força Atômica , Fosfolipídeos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/química , Staphylococcus aureus/patogenicidade
9.
Mater Sci Eng C Mater Biol Appl ; 104: 109896, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499977

RESUMO

Zinc alloys have been explored as potential materials for biodegradable vascular stents due to their tolerable corrosion rates and tunable mechanical properties. However, the performances of Zn alloys were not supported with enough toxicity or biological compatibility evaluation, particularly hemocompatibility for vascular scaffolding application. In this work, the hemocompatibility of three zinc alloys (Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li) was evaluated with 316 L stainless steel and pure zinc as controls. The hemolysis ratios of 316 L stainless steel, pure Zn, Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li were 0.38 ±â€¯0.08%, 1.04 ±â€¯0.21%, 0.47 ±â€¯0.21%, 0.57 ±â€¯0.14% and 0.52 ±â€¯0.22%, respectively, for direct contact method. Platelets aggregation on the 316 L stainless steel was observed, while the adhered platelets on the Zn alloys exhibited round shape with few pseudopodia spreading. The number of adhered platelets on the three zinc alloys (Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li) had no statistically difference compared with 316 L stainless steel, while significant fewer than the pure Zn group. None remarkable platelet activation, hematocyte aggregation, coagulation or complement activation was observed in any Zn alloy group. Furthermore, the Zn alloys prolonged prothrombin time and partial thromboplastin time, demonstrating a potential function of anticoagulation. The results demonstrated that Zn alloys presented in this work are indeed meeting the hemocompatible requirements of implant and showing the promise for perspective application as biodegradable stent.


Assuntos
Ligas/química , Materiais Biocompatíveis/química , Lítio/química , Magnésio/química , Zinco/química , Implantes Absorvíveis , Ligas/administração & dosagem , Materiais Biocompatíveis/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Corrosão , Hemólise/efeitos dos fármacos , Humanos , Lítio/administração & dosagem , Teste de Materiais/métodos , Ativação Plaquetária/efeitos dos fármacos , Aço Inoxidável/química , Stents , Zinco/administração & dosagem
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1236-1240, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418386

RESUMO

OBJECTIVE: To investigate the predictive effect of platelet activation index expression before and after adenosine bisphosphate activation on bleeding risk in patients with primary immune thrombocytopenia (ITP). METHODS: Eighty-nine patients with ITP admitted in our hospital from January 2017 to October 2018 were selected and inrolled in ITP group, the bleeding scoreing and grading were performed by using the ITP-BAT for ITP patients, then 89 ITP patients were divided into 4 subgroups: nothing bleeding symptom group, mild bleeding symprom group, mode rate bleeding symptom group and severe bleeding symptom group according to bleeding scores and grades obtained from ITP-BAT detection. At the same time, 22 persons underwent the health physical examination were selected and enrolled in control group. The adenosine diphosphate (ADP) was used as activator for all patients and controls. The flow cytonetry was used to analyze the expression of platelet membranc glyco protein (GPⅠb, GPⅡb /Ⅲ a) and P-selectin before and after ADP activation, the multiple linear person's correlation analysis was used to analyze the correlation of bleeding degree of ITP patients before and after ADP acbivation with the expression levels of GPⅠb, GPⅡb/Ⅲa and P-selectin. RESULTS: After the ADP activation, the expression level of GPⅠb significantly decreased, while the expression levels of GPⅠb, GPⅡb/Ⅲ a and P-selectin significantly increased in control group, nothing bleeding symptom group and mild bleeding symptom group; but the expression level of GPⅠb significantly increased, while the expression level of GPⅡb/Ⅲ a significantly decreased in moderate and severe bleeding symptom group, the both differences were statistically significant (P<0.05). however, the expression level of P-selectin in moderate and severe bleeding symptom groups before and after ADP activation was not statistivally significant (P>0.05). Before ADP activation, the expression level of GPⅠb in ITP subgroups was lower than that in control group, the expression level of GPⅡb/Ⅲ a in ITP subgroups was higher than that in control group, the expression level of P-selectin in moderate and severe bleeding symptom groups was higher than that in control group (P<0.05). After ADP activation, the expression levels of GPⅠb and P-selectin in ITP subgroups both were lower than those in control group, the expression level of GPⅡb/Ⅲa in ITP subgroups was higher than that in control group (P<0.05). The comparison among ITP subgroups showed that before ADP activation, the expression level of GPⅠb in moderate and severe bleeding symptom groups was lower than that in nothing bleeding symotom and mild bleeding symptom groups, while the expression levels of GPⅡb/Ⅲa and P-selectin were higher than those in nothing bleeding symptom and mild bleeding symptom groups (P<0.05), however, after ADP activation, the expression level of GPⅠb in moderate and severe bleeding symptom groups was higher than that in nothing bleeding symptom and mild bleeding symptom groups, while the expression levels of GPⅡb/Ⅲ a and P-selection in moderate and severe bleeding symptom groups were lower than those in nothing and mild bleeding symptom groups (P<0.05). The correlation analysis showed that before ADP activation, the expression levels of GPⅠb and GPⅡb/Ⅲa positivdy correlated with the bleeding risk (r=0.483, 0.504), and the P-selectin not correlated with the bleeding risk (r=0.000); however, after ADP activation, the expression level of GPⅠb and GPⅡb/Ⅲ a negatively correlated with the bleeding risk (r=-0.627, -0.406, -0.108). CONCLUSION: The expression level of platelet activation indicators before and after ADP activation is of certain value for prevention of bleeding risk in ITP patients and can be used as a reference indicator for the treatment and efficacy evaluation.


Assuntos
Adenosina , Púrpura Trombocitopênica Idiopática , Plaquetas , Humanos , Selectina-P , Ativação Plaquetária , Contagem de Plaquetas
11.
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
13.
BMC Complement Altern Med ; 19(1): 224, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438931

RESUMO

BACKGROUND: Commercial herbal medicines (CHMs) marketed as immune boosters are gaining wide popularity in South Africa, in the absence of control and regulatory guidelines. These commercially packaged and labelled herbal preparations, acquired in various retail outlets, are used without consulting either a conventional health provider or a traditional health practitioner. Although they are indicated for immune-boosting purposes, they might exert many other beneficial and unwanted effects on physiological systems. Platelets are crucial in haemostasis and important for the immunological system. The aim was to investigate the effect of the CHMs used to strengthen the immune system on the activity of human platelets. METHODS: Six CHMs commonly used as African traditional medicines in Pretoria, South Africa, were tested for their effects on healthy, isolated human platelets, using a bioluminescence method. The tested herbal medicines were Intlamba Zifo™, Maphilisa™ Herbal medicine, Matla™ African medicine for all diseases, Ngoma™ Herbal Tonic Immune Booster, Stametta™ Body Healing Liquid, and Vuka Uphile™ Immune Booster and serial-diluted standards of each from 10 to 10,000 times. The luminol-enhanced luminescence activity of the platelets was measured after incubation with the herbal medicines and activation with phorbol myristate acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP). RESULTS: Five herbal medicines, namely Intlamba Zifo™, Maphilisa™ Herbal medicine, Matla™ African medicine for all diseases, Stametta™ Body Healing Liquid, and Vuka Uphile™ Immune Booster exerted comparable weak inhibitory effects on both PMA and fMLP-induced platelets, which were concentration dependent at high doses, and inversely related to concentration at low doses. Intlamba Zifo™, Matla™ African medicine for all diseases, Stametta™ Body Healing Liquid, and Vuka Uphile™ exhibited weak, but non-systematic stimulatory effects at low doses, which were not statistically significant. Ngoma™ Herbal Tonic Immune Booster had weak, inhibitory effects at high doses and weak stimulatory effects that were inversely related to concentration at low doses. CONCLUSION: The findings suggest a potential beneficial role of the CHMs in the suppression of platelets' reactivity and in enhancing the immune system. Caution, however, should be exercised as platelet inhibition and stimulation predispose to the risk of bleeding and thrombosis, respectively.


Assuntos
Plaquetas/efeitos dos fármacos , Medicina Tradicional Africana , Preparações de Plantas/farmacologia , Adulto , Células Cultivadas , Feminino , Humanos , Medições Luminescentes , Masculino , Ativação Plaquetária/efeitos dos fármacos , Acetato de Tetradecanoilforbol , Adulto Jovem
14.
Int J Mol Sci ; 20(17)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461836

RESUMO

Platelets are megakaryocyte-derived fragments lacking nuclei and prepped to maintain primary hemostasis by initiating blood clots on injured vascular endothelia. Pathologically, platelets undergo the same physiological processes of activation, secretion, and aggregation yet with such pronouncedness that they orchestrate and make headway the progression of atherothrombotic diseases not only through clot formation but also via forcing a pro-inflammatory state. Indeed, nuclear factor-κB (NF-κB) is largely implicated in atherosclerosis and its pathological complication in atherothrombotic diseases due to its transcriptional role in maintaining pro-survival and pro-inflammatory states in vascular and blood cells. On the other hand, we know little on the functions of platelet NF-κB, which seems to function in other non-genomic ways to modulate atherothrombosis. Therein, this review will resemble a rich portfolio for NF-κB in platelets, specifically showing its implications at the levels of platelet survival and function. We will also share the knowledge thus far on the effects of active ingredients on NF-κB in general, as an extrapolative method to highlight the potential therapeutic targeting of NF-κB in coronary diseases. Finally, we will unzip a new horizon on a possible extra-platelet role of platelet NF-κB, which will better expand our knowledge on the etiology and pathophysiology of atherothrombosis.


Assuntos
Plaquetas/metabolismo , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Humanos , NF-kappa B/genética , Ativação Plaquetária , Inibidores da Agregação de Plaquetas/farmacologia
15.
Rev Assoc Med Bras (1992) ; 65(7): 988-992, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31389510

RESUMO

OBJECTIVE: The objective of this study was to investigate the effects of low triiodothyronine syndrome (LT3S) on platelet function and clotting factors in patients with nephrotic syndrome(NS). METHODS: Patients with primary nephrotic syndrome were divided into two groups, normal thyroid function (group A) and LT3S (group B), based on whether they had LT3S or not. Healthy subjects were selected as the control group (group C). Blood coagulation function was detected in each group. The platelet activation function (CD62P, CD63) was determined by flow cytometry. The platelet aggregation rate was detected by an optical method using adenosine diphosphate and arachidonic acid as inducers. RESULTS: The proportion of primary nephrotic syndrome with LT3S was 23.2% (69/298). Compared with group C, group A had higher CD62P and PAgTADP, and group B had higher CD62P, CD63, PAgTAA, and PAgTADP; the difference was statistically significant (all P < 0.05). There was no significant difference in renal pathology between group A and group B (X2 = 4.957, P = 0.421). Compared with group A, the 24-hour urine protein, CD63, PAgTAA, and PAgTADP were higher in group B, and APTT and Alb were lower. The difference was statistically significant (P < 0.05). Logistic regression analysis showed that LT3S was associated with CD36 (OR: 3.516; 95% CI: 1.742~8.186; P = 0.004) and PAgTAA (OR: 0.442; 95% CI: 1.001~1.251; P = 0.037). CONCLUSION: NS patients are prone to LT3S. Patients with LT3S may have abnormal platelet activation and increase of platelet aggregation.


Assuntos
Plaquetas/fisiologia , Síndromes do Eutireóideo Doente/sangue , Síndromes do Eutireóideo Doente/fisiopatologia , Síndrome Nefrótica/sangue , Síndrome Nefrótica/fisiopatologia , Tri-Iodotironina/sangue , Adulto , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/complicações , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/fisiologia , Contagem de Plaquetas , Testes de Função Plaquetária , Valores de Referência , Análise de Regressão , Tri-Iodotironina/deficiência
16.
Mol Med Rep ; 20(3): 2916-2921, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322221

RESUMO

Microparticles are carriers of signals for intracellular signal transduction. These carriers include proteins, mRNAs, microRNAs and other bioactive substances. Platelets are a major source of circulating microparticles, and microparticles are closely associated with the development of certain cardiovascular diseases. In the present study, a method for separating, extracting and identifying platelet­derived microparticles was developed and differences in the expression of surface proteins on microparticles harvested from platelets stimulated by vortexing or treatment with thrombin was investigated. The counts, composition, sizes and inner structures of microparticles were determined using flow cytometry and transmission electron microscopy. Additionally, it was demonstrated that platelets could be readily activated, and a large quantity of microparticles with varying complex compositions, structures and sizes were derived from activated platelets. High purity platelet­derived microparticles were obtained by gradient centrifugation. However, the microparticles derived from platelets stimulated by thrombin treatment or vortexing differed significantly in the levels of CD63. The present study aimed to provide improved options for the extraction and identification of microparticles.


Assuntos
Plaquetas/citologia , Micropartículas Derivadas de Células/metabolismo , Adulto , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Micropartículas Derivadas de Células/ultraestrutura , Feminino , Citometria de Fluxo , Humanos , Masculino , Ativação Plaquetária , Trombina/metabolismo , Adulto Jovem
17.
Cancer Sci ; 110(9): 2748-2759, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301081

RESUMO

In hepatocarcinogenesis induced by diethylnitrosamine (DEN) in B6C3F1 mice, the BrafV637E mutation, corresponding to the human BRAFV600E mutation, plays a pivotal role. The livers of transgenic mice with a hepatocyte-specific human BRAFV600E mutation weighed 4.5 times more than that of normal mice and consisted entirely of hepatocytes, resembling DEN-induced preneoplastic hepatocytes. However, these transgenic mice spontaneously died 7 wk after birth, therefore this study aimed to clarify the causes of death. In the transgenic mice, the liver showed thrombopoietin (TPO) overexpression, which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in hepatic sinusoids. TPO was also overexpressed in the DEN-induced hepatic tumors, and sinusoidal platelet deposition was observed in the hepatic tumors of humans and mice. Podoplanin was expressed in some of the Kupffer cells in the liver of the transgenic mice, indicating that platelet activation occurred via the interaction of podoplanin with C-type lectin receptor 2 (CLEC-2) on the platelet membrane. Additionally, erythrocyte dyscrasia and glomerulonephropathy/interstitial pneumonia associated with platelet deposition were observed. In the transgenic mice, aspirin (Asp) administration prevented platelet activation, reduced the liver/body weight ratio, decreased the platelet deposition in the liver, kidney, and lung, and prevented erythrocyte dyscrasia and ameliorated the renal/pulmonary changes. Thrombopoietin overproduction by BRAFV600E-mutated hepatocytes may contribute to hepatocyte proliferation via thrombocytosis, platelet activation, and the interaction of platelets with hepatic sinusoidal cells, while hematologic, renal, and pulmonary disorders due to aberrant platelet activation may lead to spontaneous death in the transgenic mice.


Assuntos
Carcinogênese/genética , Neoplasias Hepáticas Experimentais/patologia , Fígado/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Trombopoetina/metabolismo , Animais , Biópsia , Plaquetas/patologia , Medula Óssea/patologia , Capilares/patologia , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Proliferação de Células/genética , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Hepatócitos/patologia , Humanos , Fígado/irrigação sanguínea , Fígado/citologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Ativação Plaquetária/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células Tumorais Cultivadas
18.
BMC Vet Res ; 15(1): 245, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307465

RESUMO

BACKGROUND: Functional Toll-like receptor 4 (TLR4) has been characterized in human and murine platelets indicating that platelets play a role in inflammation and hemostasis during sepsis. It is unclear whether canine platelets could express functional TLR4 by responding to its ligand, lipopolysaccharide (LPS). We sought to determine if dogs express functional TLR4 and if LPS-induced platelet activation requires co-stimulation with ADP or thromboxane A2 (TxA2). Canine platelets were unstimulated (resting) or activated with thrombin or ADP prior to flow cytometric or microscopic analyses for TLR4 expression. We treated resting or ADP-primed platelets with LPS in the absence or presence of acetylsalicylic acid (ASA) and inhibited TLR4 with function blocking antibody or LPS from Rhodobacter sphaeroides (LPS-RS). RESULTS: We discovered that dog platelets have variable TLR4 expression, which was upregulated following thrombin or ADP activation. LPS augmented P-selectin expression and thromboxane B2 secretion in ADP-primed platelets via TLR4. Inhibition of cyclooxygenase by ASA attenuated LPS-mediated P-selectin expression demonstrating that TLR4 signaling in platelets is partially dependent on TxA2 pathway. CONCLUSION: Expression of functional TLR4 on canine platelets may contribute to hypercoagulability in clinical septic dogs. Cyclooxygenase and TxA2 pathways in TLR4-mediated platelet activation may present novel therapeutic targets in dogs with sepsis.


Assuntos
Plaquetas/efeitos dos fármacos , Cães , Ativação Plaquetária/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Difosfato de Adenosina/farmacologia , Animais , Aspirina/farmacologia , Plaquetas/metabolismo , Lipopolissacarídeos/farmacologia , Rhodobacter sphaeroides/química , Tromboxano A2/farmacologia
19.
Thromb Res ; 180: 87-97, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271975

RESUMO

Patients with colorectal cancer (CRC) are at increased risk of venous thrombosis, but the precise mechanisms of thrombogenesis in CRC remain largely unknown. We aimed to identify the novel role of neutrophil extracellular traps (NETs) in the induction of procoagulant activity (PCA) in CRC, and to evaluate its interactions with platelets and endothelial cells (ECs). In this study, we first showed that the levels of NETs in the peripheral blood of CRC patients were increased in parallel with cancer progression and reached significance in stage II patients compared to healthy subjects. In addition, neutrophils from CRC patients were more prone to produce NETs, resulting in shortened coagulation time, significantly increased thrombin-antithrombin (TAT) complexes and fibrin fibrils compared to healthy controls. Furthermore, platelets from CRC patients stimulated healthy neutrophils to extrude NETs, which could be inhibited by the depletion of HMGB1. Conversely, NETs from CRC patients could also induce the exposure of PS on platelets, leading to markedly enhanced PCA. Importantly, ECs were also converted to a procoagulant phenotype when exposed to NETs from CRC patients. The PCA of NETs-activated platelets or ECs could be inhibited either by the cleavage of NETs with DNase1 or the blockage of histone with activated protein C (APC). Our results reveal the complex interactions between neutrophils, platelets and ECs and their potential role in the hypercoagulable state in CRC. We propose that NETs may provide new therapeutic targets to combat the thrombotic consequences of CRC.


Assuntos
Plaquetas/metabolismo , Neoplasias Colorretais/complicações , Armadilhas Extracelulares/metabolismo , Ativação Plaquetária , Trombose/etiologia , Idoso , Coagulação Sanguínea , Neoplasias Colorretais/sangue , Neoplasias Colorretais/metabolismo , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Trombose/metabolismo
20.
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
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