Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26.070
Filtrar
1.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202163

RESUMO

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC50 of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC50 value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Fenantrenos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , AMP Cíclico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Fenantrenos/química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Relação Estrutura-Atividade
2.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208633

RESUMO

The clinical application of human platelet lysate (HPL) holds promise for tissue regeneration, and the development of an efficient vehicle for its delivery is desired. Chitosan-based hydrogels are potential candidates, but they often exhibit weak mechanical properties. In this study, a chitosan/gelatin (CS-GE) hydrogel crosslinked by glyoxal was fabricated for sustained release of HPL. The influence of HPL on Hs68 fibroblast and human umbilical vein endothelial cell (HUVEC) culture was evaluated, and we found that supplementing 5% HPL in the medium could significantly improve cell proliferation relative to supplementing 10% fetal bovine serum (FBS). Moreover, HPL accelerated the in vitro wound closure of Hs68 cells and facilitated the tube formation of HUVECs. Subsequently, we fabricated CS-GE hydrogels crosslinked with different concentrations of glyoxal, and the release pattern of FITC-dextrans (4, 40 and 500 kDa) from the hydrogels was assessed. After an ideal glyoxal concentration was determined, we further characterized the crosslinked CS-GE hydrogels encapsulated with different amounts of HPL. The HPL-incorporated hydrogel was shown to significantly promote the proliferation of Hs68 cells and the migration of HUVECs. Moreover, the release pattern of transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor-BB (PDGF-BB) from hydrogel was examined in vitro, demonstrating a sustained release profile of the growth factors. Finally, the chick chorioallantoic membrane assay revealed that HPL encapsulation in the hydrogel significantly stimulated angiogenesis in ovo. These results demonstrate the great potential of the crosslinked CS-GE hydrogel to serve as an effective delivery system for HPL to promote tissue regeneration.


Assuntos
Produtos Biológicos/farmacologia , Plaquetas/metabolismo , Quitosana , Gelatina , Glioxal , Hidrogéis , Regeneração/efeitos dos fármacos , Proliferação de Células , Quitosana/química , Dextranos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Gelatina/química , Glioxal/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrogéis/química , Neovascularização Fisiológica , Porosidade , Cicatrização/efeitos dos fármacos
3.
Molecules ; 26(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069658

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of death in developed countries. Therefore, there is an increasing interest in developing new potent and safe antiplatelet agents. Coumarins are a family of polyphenolic compounds with several pharmacological activities, including platelet aggregation inhibition. However, their antiplatelet mechanism of action needs to be further elucidated. The aim of this study is to provide insight into the biochemical mechanisms involved in this activity, as well as to establish a structure-activity relationship for these compounds. With this purpose, the antiplatelet aggregation activities of coumarin, esculetin and esculin were determined in vitro in human whole blood and platelet-rich plasma, to set the potential interference with the arachidonic acid cascade. Here, the platelet COX activity was evaluated from 0.75 mM to 6.5 mM concentration by measuring the levels of metabolites derived from its activity (MDA and TXB2), together with colorimetric assays performed with the pure recombinant enzyme. Our results evidenced that the coumarin aglycones present the greatest antiplatelet activity at 5 mM and 6.5 mM on aggregometry experiments and inhibiting MDA levels.


Assuntos
Plaquetas/efeitos dos fármacos , Cumarínicos/farmacologia , Ciclo-Oxigenase 1/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Plaquetas/enzimologia , Plaquetas/metabolismo , Humanos , Técnicas In Vitro , Malondialdeído/metabolismo
4.
Jt Dis Relat Surg ; 32(2): 489-496, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34145828

RESUMO

OBJECTIVES: This study aims to evaluate the diagnostic and prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) values in patients with osteosarcoma. PATIENTS AND METHODS: A total of 172 patients (111 males, 61 females; mean age: 24.3±15.3 years; range, 7 to 82 years) diagnosed with osteosarcoma in our institution between January 2002 and December 2018 were retrospectively analyzed. A total of 165 healthy individuals (115 males, 50 females; mean age: 20.2±9.2 years; range, 10 to 65 years) who did not have infectious, rheumatological or hematological diseases or any pathological finding were assigned as the control group. The clinical, laboratory, and demographic findings of the patients were obtained from hospital records. Pre-treatment NLR, PLR, and LMR values were calculated in all patients. Diagnostic and prognostic values of pre-treatment NLR, PLR and LMR were assessed using receiver operating curve (ROC) analysis. The Kaplan-Meier method was used for survival analysis. RESULTS: For diagnostic approach, the highest significance in area under the curve (AUC) values was obtained for NLR (AUC=0.763). The AUC for PLR and LMR was statistically significant, while the statistical power was weak compared to NLR (AUC=0.681 and 0.603). The NLR, PLR, and LMR were found to be predictors of mortality. The cut-off value was found to be 3.28 for NLR, 128 for PLR, and 4.22 for LMR. The prognostic value of NLR for mortality was higher than (AUC=0.749) PLR (AUC=0.688) and LMR (AUC=0.609). The NLR, PLR, and LMR were associated with overall survival (OS). There was a significant difference in the median OS time among the NLR, PLR, and LMR values (log-rank test order p<0.001, p=0.001, and p=0.004, respectively). CONCLUSION: Based on our study results, pre-treatment NLR, PLR and MLR have diagnostic and prognostic values in osteosarcoma.


Assuntos
Plaquetas/metabolismo , Linfócitos/metabolismo , Monócitos/metabolismo , Neutrófilos/metabolismo , Osteossarcoma/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Turquia , Adulto Jovem
5.
J Clin Neurosci ; 89: 56-64, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119295

RESUMO

BACKGROUND: Red blood cell distribution width to platelet ratio (RPR), Monocyte to high-density lipoprotein ratio (MHR), and Neutrophil to lymphocyte ratio (NLR) are novel inflammatory biomarkers in laboratory tests, which are associated with clinical outcomes in malignancy, cardiovascular and cerebrovascular diseases. This study aimed to determine their predictive value for the prognosis of acute ischemic stroke after mechanical thrombectomy (MT). METHODS: A total of 286 patients with acute ischemic stroke (AIS) admitted to a tertiary stroke center in China between January 2018 and February 2020 were treated by MT. Demographic characteristics, risk factors, clinical data, laboratory parameters, and clinical outcomes were recorded. The clinical outcome was disability or death at discharge or 90 days (defined as a modified Rankin Scale score of 3-6). The relationship between RPR, MHR, and NLR and functional outcomes was investigated by binary Logistic regression analysis, and further assessed by receiver operating characteristic curve (ROC). The Kaplan-Meier method was used to analyze the survival rate of prognosis factors. RESULTS: A total of 286 patients with AIS underwent MT (median age, 70.00; Interquartile range [IQR], 63.00-77.00; 41.6% female). Patients with unfavorable outcome showed higher RPR, MHR, and NLR than those with favorable outcome (RPR, [8.63; IQR, 6.30-10.78] vs [6.17; IQR, 5.11-7.35], P < 0.001; MHR, [0.40; IQR, 0.31-0.53] vs [0.34; IQR, 0.27-0.47], P = 0.005; NLR, [5.28; IQR, 3.63-8.02] vs [3.44; IQR, 2.63-4.63], P < 0.001). In multivariate and ROC curve analysis, higher RPR (>8.565) (odds ratio [OR], 1.671; 95% confidence interval [CI], 1.127-2.479; P = 0.011) and higher MHR (>0.368) (OR, 9.374; 95% CI, 1.160-75.767; P = 0.036), higher NLR (>4.030) (OR, 1.957; 95% CI, 1.382-2.770; P < 0.001) were independently associated with unfavorable outcome. The combined predictive value of the three indexes was higher than that of a single index. Kaplan-Meier survival curve analysis showed that the 90-day survival rate (82.1% vs 66.2%) was significantly different between the low RPR group and the high RPR group (χ2 = 4.960, P = 0.026). CONCLUSION: Higher RPR, MHR, and NLR might be independent risk factors for predicting 3-month poor prognosis in patients with AIS who underwent MT.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/cirurgia , AVC Isquêmico/sangue , AVC Isquêmico/cirurgia , Leucócitos Mononucleares/metabolismo , Trombectomia/tendências , Idoso , Biomarcadores/sangue , Plaquetas/metabolismo , Isquemia Encefálica/diagnóstico , Feminino , Humanos , AVC Isquêmico/diagnóstico , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Neutrófilos/metabolismo , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
6.
Nat Commun ; 12(1): 3626, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131117

RESUMO

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.


Assuntos
Plaquetas/metabolismo , Mapeamento Cromossômico , Sequenciamento Completo do Genoma , Sequência de Bases , Proteínas de Ligação ao GTP , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Células K562 , Fenótipo , Agregação Plaquetária , Testes de Função Plaquetária , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores de Superfície Celular/genética , Trombose/genética
7.
Nat Commun ; 12(1): 3754, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145241

RESUMO

Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.


Assuntos
Aterosclerose/patologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Interferon gama/metabolismo , Placa Aterosclerótica/patologia , Animais , Plaquetas/metabolismo , Linfócitos T CD4-Positivos/citologia , Doenças Cardiovasculares/patologia , Células Dendríticas/imunologia , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/citologia , Transdução de Sinais/fisiologia , Trombose/patologia
8.
Methods Mol Biol ; 2277: 269-276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34080156

RESUMO

Platelet mitochondria can be used in the study of mitochondrial dysfunction in various complex diseases and can help in finding biological markers for diagnosing the disease, monitoring its course and the effects of treatment. The aim of this chapter was to describe in detail the method of measuring mitochondrial respiration in platelets using high-resolution respirometry. The described method was successfully used for the study of mitochondrial dysfunction in neuropsychiatric diseases.


Assuntos
Plaquetas/metabolismo , Mitocôndrias/metabolismo , Polarografia/métodos , Respiração Celular , Humanos , Polarografia/instrumentação
9.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063076

RESUMO

Platelet function is developmentally regulated. Healthy neonates do not spontaneously bleed, but their platelets are hypo-reactive to several agonists. The mechanisms underlying immature platelet function in neonates are incompletely understood. This critical issue remains challenging for the establishment of age-specific reference ranges. In this study, we evaluated platelet reactivity of five pediatric age categories, ranging from healthy full-term neonates up to adolescents (11-18 years) in comparison to healthy adults (>18 years) by flow cytometry. We confirmed that platelet hypo-reactivity detected by fibrinogen binding, P-selectin, and CD63 surface expression was most pronounced in neonates compared to other pediatric age groups. However, maturation of platelet responsiveness varied with age, agonist, and activation marker. In contrast to TRAP and ADP, collagen-induced platelet activation was nearly absent in neonates. Granule secretion markedly remained impaired at least up to 10 years of age compared to adults. We show for the first time that neonatal platelets are deficient in thrombospondin-1, and exogenous platelet-derived thrombospondin-1 allows platelet responsiveness to collagen. Platelets from all pediatric age groups normally responded to the C-terminal thrombospondin-1 peptide RFYVVMWK. Thus, thrombospondin-1 deficiency of neonatal platelets might contribute to the relatively impaired response to collagen, and platelet-derived thrombospondin-1 may control distinct collagen-induced platelet responses.


Assuntos
Envelhecimento/fisiologia , Plaquetas/metabolismo , Colágeno/farmacologia , Trombospondina 1/farmacologia , Difosfato de Adenosina/farmacologia , Adolescente , Adulto , Plaquetas/efeitos dos fármacos , Criança , Venenos de Crotalídeos/farmacologia , Exocitose/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Lectinas Tipo C , Peptídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Receptores Ativados por Proteinase/metabolismo , Trombospondina 1/química
10.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065600

RESUMO

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Monofosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Curcuma/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
Nat Commun ; 12(1): 3352, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099640

RESUMO

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1-/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.


Assuntos
Plaquetas/metabolismo , Fator Plaquetário 4/metabolismo , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Indutores da Angiogênese , Animais , Ativação do Complemento , Complemento C5a , Inflamação , Camundongos , Camundongos Knockout , Receptor da Anafilatoxina C5a/deficiência , Receptores CXCR3/genética , Transdução de Sinais
12.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947017

RESUMO

Platelets (PLTs) can modulate the immune system through the release of soluble mediators or through interaction with immune cells. Monocytes are the main immune cells that bind with PLTs, and this interaction is increased in several inflammatory and autoimmune conditions, including systemic lupus erythematosus (SLE). Our aim was to characterize the phenotypic and functional consequences of PLT binding to monocytes in healthy donors (HD) and in SLE and to relate it to the pathogenesis of SLE. We analyzed the phenotypic and functional features of monocytes with non-activated and activated bound PLTs by flow cytometry. We observed that monocytes with bound PLTs and especially those with activated PLTs have an up-regulated HLA-DR, CD86, CD54, CD16 and CD64 expression. Monocytes with bound PLTs also have an increased capacity for phagocytosis, though not for efferocytosis. In addition, monocytes with bound PLTs have increased IL-10, but not TNF-α, secretion. The altered phenotypic and functional features are comparable in SLE and HD monocytes and in bound PLTs. However, the percentages of monocytes with bound PLTs are significantly higher in SLE patients and are associated with undetectable levels of anti-dsDNA antibodies and hematuria, and with normal C3 and albumin/creatinine levels. Our results suggest that PLTs have a modulatory influence on monocytes and that this effect may be highlighted by an increased binding of PLTs to monocytes in autoimmune conditions.


Assuntos
Plaquetas/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/metabolismo , Adulto , Idoso , Anticorpos Antinucleares/sangue , Antígenos CD/biossíntese , Apoptose , Feminino , Citometria de Fluxo , Antígenos HLA-DR/biossíntese , Humanos , Interleucina-10/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Masculino , Glicoproteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Neutrófilos/patologia , Fagocitose , Fenótipo , Fator de Necrose Tumoral alfa/metabolismo
13.
Front Immunol ; 12: 616394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995345

RESUMO

In tropical and subtropical regions, mosquito-borne dengue virus (DENV) infections can lead to severe dengue, also known as dengue hemorrhage fever, which causes bleeding, thrombocytopenia, and blood plasma leakage and increases mortality. Although DENV-induced platelet cell death was linked to disease severity, the role of responsible viral factors and the elicitation mechanism of abnormal platelet activation and cell death remain unclear. DENV and virion-surface envelope protein domain III (EIII), a cellular binding moiety of the virus particle, highly increase during the viremia stage. Our previous report suggested that exposure to such viremia EIII levels can lead to cell death of endothelial cells, neutrophils, and megakaryocytes. Here we found that both DENV and EIII could induce abnormal platelet activation and predominantly necrotic cell death pyroptosis. Blockages of EIII-induced platelet signaling using the competitive inhibitor chondroitin sulfate B or selective Nlrp3 inflammasome inhibitors OLT1177 and Z-WHED-FMK markedly ameliorated DENV- and EIII-induced thrombocytopenia, platelet activation, and cell death. These results suggest that EIII could be considered as a virulence factor of DENV, and that Nlrp3 inflammasome is a feasible target for developing therapeutic approaches against dengue-induced platelet defects.


Assuntos
Plaquetas/metabolismo , Vírus da Dengue/fisiologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Dengue Grave/complicações , Trombocitopenia/etiologia , Trombocitopenia/metabolismo , Animais , Biomarcadores , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Plaquetas/imunologia , Morte Celular , Modelos Animais de Doenças , Suscetibilidade a Doenças , Metabolismo Energético , Imunofenotipagem , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Ativação Plaquetária , Domínios e Motivos de Interação entre Proteínas/imunologia , Dengue Grave/virologia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
14.
Life Sci ; 277: 119612, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33991548

RESUMO

AIM: Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in a background of chronic liver disease and prolonged inflammation. A major contributor in the complex molecular pathogenesis of HCC is the highly intertwined cross-talk between the tumor and the surrounding stromal cells, such as hepatic stellate cells, endothelial cells, macrophages and other immune cells. These tumor-stroma interactions actively fuel tumor growth and modulate the hepatic microenvironment to benefit tumor invasion and disease progression. Platelets have been reported to interact with different cell types in the tumor microenvironment, including tumor cells, stellate cells and macrophages. MATERIALS AND METHODS: Mice were treated with hepatocarcinogenic compound diethylnitrosamine for 25 weeks to induce HCC in the background of fibrosis and inflammation. From week 10, anti-platelet drug Clopidogrel was added to the drinking water and mice were given ad libitum access. KEY FINDINGS: In this study, we show that activated platelets promote tumor cell proliferation and contribute to the adverse tumor-stroma cross-talk that fuels tumor progression. We also show that inhibiting platelet activation with the P2Y12-inhibitor Clopidogrel decreases the number of tumors in a chemically induced mouse model for HCC. SIGNIFICANCE: These results suggest an important role for platelets in the pathogenesis of HCC and that the use of anti-platelet drugs may be therapeutically relevant for patients with liver cancer.


Assuntos
Plaquetas/metabolismo , Carcinoma Hepatocelular/metabolismo , Animais , Plaquetas/fisiologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Clopidogrel/farmacologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologia
15.
Nat Commun ; 12(1): 3185, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045461

RESUMO

Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury. It is also a thrombo-inflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. Here, we show that MB2mP6 peptide nanoparticles, targeting the Gα13-mediated integrin "outside-in" signaling in leukocytes and platelets, inhibited both inflammation and thrombosis without causing hemorrhage/vascular leakage. MB2mP6 improved mouse survival when infused immediately or hours after onset of severe sepsis. Furthermore, platelet Gα13 knockout inhibited septic thrombosis whereas leukocyte Gα13 knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte Gα13 knockout inhibited septic thrombosis and inflammation, further improving survival similar to MB2mP6. These results demonstrate that inflammation and thrombosis independently contribute to poor outcomes and exacerbate each other in systemic inflammation, and reveal a concept of dual anti-inflammatory/anti-thrombotic therapy without exacerbating vascular leakage.


Assuntos
Antígenos CD18/antagonistas & inibidores , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Sepse/tratamento farmacológico , Trombose/tratamento farmacológico , Animais , Anti-Inflamatórios , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Plaquetas/metabolismo , Antígenos CD18/metabolismo , Cloretos/administração & dosagem , Cloretos/toxicidade , Modelos Animais de Doenças , Compostos Férricos/administração & dosagem , Compostos Férricos/toxicidade , Fibrinolíticos , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Macrófagos , Camundongos , Camundongos Knockout , Nanopartículas/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Sepse/sangue , Sepse/complicações , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células THP-1 , Trombose/sangue , Trombose/induzido quimicamente
16.
BMC Infect Dis ; 21(1): 461, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016046

RESUMO

BACKGROUND: Tuberculosis (TB) and type 2 diabetes mellitus (DM) are global health diseases with high morbidity and mortality. Few studies have focused on platelet indices in TB-DM coinfection patients. The objective of this work was to analyze the platelet indices in TB, DM and TB-DM patients to assess the predictive value of the platelet index for the risk of these diseases. METHODS: In total, 246 patients admitted to our hospital were distributed into three groups (113 TB, 59 DM and 74 TB + DM). A total of 133 individuals were also recruited as healthy controls (HC). Platelet indices, namely, platelet count (PC), mean platelet volume (MPV), plateletcrit (PCT) and platelet distribution width (PDW), were compared among the four groups, and the relationship with inflammatory markers was explored by using statistical software. RESULTS: Our study discovered that MPV and PCT were significantly downregulated in TB + DM patients (9.95 ± 1.25 fL, 0.20 ± 0.05%, P < 0.0001, P = 0.0121, separately) compared with DM individuals (10.92 ± 1.17 fL, 0.22 ± 0.04%). Moreover, the changes in MPV were significantly higher in TB + DM patients (9.95 ± 1.25 fL, P = 0.0041) than in TB patients (9.42 ± 1.01 fL). No differences were found in PLT and PDW among the four groups (P > 0.05). The sensitivity and specificity of MPV in the differential diagnosis of DM patients vs TB + DM patients were 64.9 and 66.1% (P < 0.0001), respectively, and the sensitivity and specificity of MPV between TB patients and TB + DM patients was 60.8 and 66.4%, respectively (P = 0.003). MPV improved the diagnosis sensitivity when it was combined with clinical parameters, such as fasting blood glucose in DM and Mycobacterium tuberculosis culture result in TB (76.3% vs 64.9, 72.6% vs 60.8%, P < 0.0001, P = 0.001, respectively). In addition, the sensitivity and specificity of PCT in the differential diagnosis of DM patients vs TB + DM patients were 69.5 and 59.4%, respectively (P = 0.008). PCT improved the diagnosis sensitivity when combined with fasting blood glucose in DM (72.9% vs 64.9%, P = 0.004). In addition, MPV was linked to CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) in the TB + DM patients (r = 0.3203, P = 0.0054, r = 0.2504, P = 0.0307) but PCT was not (r = 0.1905, r = 0.008675, P > 0.05, respectively). CONCLUSIONS: Our research shows that MPV and PCT might be good clinical laboratory markers to distinguish TB + DM patients from TB or DM individuals, thus providing support for earlier clinical diagnosis, prevention, and therapy.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Volume Plaquetário Médio , Tuberculose/epidemiologia , Adulto , Biomarcadores/sangue , Plaquetas/metabolismo , Sedimentação Sanguínea , Comorbidade , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Tuberculose/sangue , Tuberculose/metabolismo
17.
Nat Commun ; 12(1): 2773, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986264

RESUMO

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Plaquetas/metabolismo , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Xantonas/farmacologia , Animais , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Neoplasias/imunologia , Neoplasias/patologia , Ativação Plaquetária/efeitos dos fármacos , Transfusão de Plaquetas
18.
Medicine (Baltimore) ; 100(20): e25944, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011073

RESUMO

ABSTRACT: At present, various researches presented how subtypes of hematological malignancies are related to stages of the immune response, because the activated immune system represents a promising form in cancer treatment. This study explores the relationship between the adaptive immune system (T cells), and the coagulation system (platelets, platelet membrane glycoproteins, platelets derivate microparticles) which seems to play an important role in host immune defense of patients with acute myeloblastic leukemia (AML) or B cell lymphoma (BCL), 2 of the most common hematological malignancies subtypes.Blood samples (n = 114) obtained from patients with AML or BCL were analyzed for platelet membrane glycoproteins (CD42b, CD61), glycoprotein found on the surface of the T helper cells (CD4+), protein complex-specific antigen for T cells (CD3+), platelet-derived microparticles (CD61 PMP) biomarkers by flow cytometry, and hematological parameters were quantified by usual methods.In patients with AML, the means of the percentage of the expressions of the molecules on platelet surfaces (CD61 and CD42b, P < .01; paired T test) were lower as compared to both control subgroups. The expression of cytoplasmic granules content (CD61 PMP) had a significantly higher value in patients with AML reported to controlling subgroups (P < .01; paired T test), which is suggesting an intravascular activation of platelets.The platelet activation status was presented in patients with low stage BCL because CD61 and CD42b expressions were significantly higher than control subgroups, but the expression of CD 61 PMP had a significantly decreased value reported to control subgroups (all P < .01; paired T test). T helper/inducer lineage CD4+ and T lymphoid lineage CD3+ expressions presented significant differences between patients with AML or low stage BCL reported to control subgroups (all P < .01; paired T test).Platelet-lymphocyte interactions are involved in malignant disorders, and CD61, CD42b present on platelet membranes, as functionally active surface receptors mediate the adhesion of active platelets to lymphocytes, endothelial cells, and cancer cells.


Assuntos
Biomarcadores Tumorais/sangue , Plaquetas/metabolismo , Leucemia Mieloide Aguda/imunologia , Linfoma de Células B/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Plaquetas/imunologia , Complexo CD3/sangue , Adesão Celular/imunologia , Micropartículas Derivadas de Células , Feminino , Citometria de Fluxo , Humanos , Integrina beta3/sangue , Leucemia Mieloide Aguda/sangue , Ativação Linfocitária , Contagem de Linfócitos , Linfoma de Células B/sangue , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/imunologia , Contagem de Plaquetas , Complexo Glicoproteico GPIb-IX de Plaquetas/análise , Romênia , Linfócitos T Auxiliares-Indutores/imunologia
19.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946341

RESUMO

Platelets are components of the blood that are highly reactive, and they quickly respond to multiple physiological and pathophysiological processes. In the last decade, it became clear that platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity. Protein composition, localization, and activity are crucial for platelet function and regulation. The current state of mass spectrometry-based proteomics has tremendous potential to identify and quantify thousands of proteins from a minimal amount of material, unravel multiple post-translational modifications, and monitor platelet activity during drug treatments. This review focuses on the role of proteomics in understanding the molecular basics of the classical and newly emerging functions of platelets. including the recently described role of platelets in immunology and the development of COVID-19.The state-of-the-art proteomic technologies and their application in studying platelet biogenesis, signaling, and storage are described, and the potential of newly appeared trapped ion mobility spectrometry (TIMS) is highlighted. Additionally, implementing proteomic methods in platelet transfusion medicine, and as a diagnostic and prognostic tool, is discussed.


Assuntos
Plaquetas/metabolismo , Espectrometria de Massas/métodos , Testes de Função Plaquetária/métodos , Proteômica/métodos , Animais , Plaquetas/citologia , Plaquetas/imunologia , COVID-19/imunologia , COVID-19/metabolismo , Humanos , Transfusão de Plaquetas , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Medicina Transfusional/métodos
20.
Biochem Med (Zagreb) ; 31(2): 020701, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33927551

RESUMO

Introduction: The aim of the present study was to determine and compare the concentration of hyaluronic acid (HA) in rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE), and its correlation with parameters of disease activity and duration. The hypothesis was that HA should be increased in rheumatic diseases. We also expected that HA could be a marker of disease activity and inflammation in some of these diseases. Materials and methods: The study group comprised 149 patients with RA, SSc and SLE hospitalized in the Department of Rheumatology and Internal Diseases, Medical University of Bialystok (Bialystok, Poland) and 30 healthy controls. The concentrations of HA, C-reactive protein (CRP) and rheumatoid factor (RF) were measured using Architect ci8200; haemoglobin, platelets on Sysmex XS-800i; and erythrocyte sedimentation rate (ESR) on Sediplus S 2000 analysers. Statistical analysis was performed using Statistica 13.3 PL. Results: Hyaluronic acid was increased in RA, SLE and SSc when compared to controls (P < 0.001, P = 0.011, and P = 0.015, respectively). There were no differences in HA between rheumatic diseases (P = 0.840). Hyaluronic acid positively correlated with SLE activity (P = 0.025). In RA, HA positively correlated with ESR (P = 0.028) and CRP (P = 0.009). However, HA was not found to correlate with the duration of rheumatic diseases. Conclusions: Hyaluronic acid concentration undergoes changes in rheumatic diseases with no difference between RA, SLE and SSc. In RA, HA concentration can be a marker of inflammation, while in SLE patients an indicator of disease activity.


Assuntos
Artrite Reumatoide/sangue , Ácido Hialurônico/sangue , Lúpus Eritematoso Sistêmico/sangue , Escleroderma Sistêmico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Plaquetas/metabolismo , Proteína C-Reativa/metabolismo , Feminino , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...