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1.
Int J Mol Sci ; 22(18)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34576124

RESUMO

Asthma is an allergic disease that causes severe infiltration of leukocytes into the lungs. Leukocyte infiltration is mediated by the binding of sialyl Lewis X (sLex) glycans present on the leukocytes to E-and P-selectins present on the endothelial cells at the sites of inflammation. Here, we found that mouse eosinophils express sLex glycans, and their infiltration into the lungs and proliferation in the bone marrow were significantly suppressed by an anti-sLex monoclonal antibody (mAb) F2 in a murine model of ovalbumin-induced asthma. The percentage of eosinophils in the bronchoalveolar lavage fluid and bone marrow and serum IgE levels decreased significantly in the F2-administered mice. Levels of T helper type 2 (Th2) cytokines and chemokines, involved in IgE class switching and eosinophil proliferation and recruitment, were also decreased in the F2-administered mice. An ex vivo cell rolling assay revealed that sLex glycans mediate the rolling of mouse eosinophils on P-selectin-expressing cells. These results indicate that the mAb F2 exerts therapeutic effects in a murine model of allergen-induced asthma, suggesting that sLex carbohydrate antigen could serve as a novel therapeutic target for allergic asthma.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Antígeno Sialil Lewis X/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Asma/complicações , Medula Óssea/patologia , Diferenciação Celular , Modelos Animais de Doenças , Eosinófilos/imunologia , Feminino , Hipersensibilidade/complicações , Imunidade , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Selectina-P/metabolismo , Ligação Proteica
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445660

RESUMO

Bortezomib (BTZ) has demonstrated its efficacy in several hematological disorders and has been associated with thrombocytopenia. There is controversy about the effect of BTZ on human platelets, so we set out to determine its effect on various types of platelet samples. Human platelets were investigated in platelet-rich plasma (PRP) and as gel-filtered platelets (GFPs). Mitochondrial inner membrane potential depolarization and phosphatidylserine (PS) and P-selectin expression levels were studied by flow cytometry, while thrombin generation was measured by a fluorescent method. In PRP, BTZ caused negligible PS expression after 60 min of treatment. However, in GFPs, PS expression was dose- and time-dependently increased in the BTZ-treated groups, as was P-selectin. The percentage of depolarized cells was also higher after BTZ pretreatment at both time points. Peak thrombin and velocity index increased significantly even with the lowest BTZ concentration (p = 0.0019; p = 0.0032) whereas time to peak and start tail parameters decreased (p = 0.0007; p = 0.0034). The difference between PRP and GFP results can be attributed to the presence of plasma proteins in PRP, as the PS-stimulating effect of BTZ could be attenuated by supplementing GFPs with purified human albumin. Overall, BTZ induces a procoagulant platelet phenotype in an experimental setting devoid of plasma proteins.


Assuntos
Apoptose , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/patologia , Bortezomib/farmacologia , Selectina-P/metabolismo , Ativação Plaquetária , Inibidores de Proteassoma/farmacologia , Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Humanos , Selectina-P/genética
3.
Cells ; 10(8)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34440807

RESUMO

Allergic asthma is a chronic and heterogeneous pulmonary disease in which platelets can be activated in an IgE-mediated pathway and migrate to the airways via CCR3-dependent mechanism. Activated platelets secrete IL-33, Dkk-1, and 5-HT or overexpress CD40L on the cell surfaces to induce Type 2 immune response or interact with TSLP-stimulated myeloid DCs through the RANK-RANKL-dependent manner to tune the sensitization stage of allergic asthma. Additionally, platelets can mediate leukocyte infiltration into the lungs through P-selectin-mediated interaction with PSGL-1 and upregulate integrin expression in activated leukocytes. Platelets release myl9/12 protein to recruit CD4+CD69+ T cells to the inflammatory sites. Bronchoactive mediators, enzymes, and ROS released by platelets also contribute to the pathogenesis of allergic asthma. GM-CSF from platelets inhibits the eosinophil apoptosis, thus enhancing the chronic inflammatory response and tissue damage. Functional alterations in the mitochondria of platelets in allergic asthmatic lungs further confirm the role of platelets in the inflammation response. Given the extensive roles of platelets in allergic asthma, antiplatelet drugs have been tested in some allergic asthma patients. Therefore, elucidating the role of platelets in the pathogenesis of allergic asthma will provide us with new insights and lead to novel approaches in the treatment of this disease.


Assuntos
Asma/patologia , Plaquetas/metabolismo , Imunidade Adaptativa , Asma/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/metabolismo , Integrinas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Selectina-P/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Biomed Res Int ; 2021: 9935752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307676

RESUMO

Objectives: To investigate the clinical efficacy and safety of Shenxiong glucose injection combined with edaravone in the treatment of acute large-area cerebral infarction. Methods: 156 patients with acute large-area cerebral infarction admitted to our hospital from July 2015 to January 2017 were included in the analysis. The patients were randomly divided into experimental (78 cases) and control (78 cases) groups. Patients in the experimental group were given a 30 mg injection of edaravone in 100 ml of 0.9% sodium chloride solution by intravenous drip, twice a day within 30 minutes and a daily 200 ml injection of Shenxiong glucose by intravenous drip. Patients in the control group were given a 30 mg edaravone injection in 100 ml of 0.9% sodium chloride solution by intravenous drip, twice a day, and the drip was completed within 30 minutes. Patients in both groups were treated for 2 weeks. The levels of fibrinogen (FIB), D-dimer, interleukin 6 (IL-6), P-selectin (CD62P), and hypersensitive C-reactive protein (hs-CRP) were evaluated in the two groups of patients. Neurological disability was evaluated using the modified Rankin scale (mRS) and the neurological deficit score (National Institute of Health Stroke Scale, NIHSS). Adverse reactions to the treatments were also recorded. Results: No significant differences in age, gender, medical histories, and blood biochemical indices were observed between the two groups before treatment (P > 0.05). After treatment, the levels of FIB, D-dimer, IL-6, CD62P, and hs-CRP were significantly lower following treatment and compared to the control group (P < 0.05). Also, the mRS and NIHSS scores were significantly lower after treatment and compared with the control group (P < 0.05). The total effective rate of the treatment in the experimental group was significantly higher compared to the control group (P < 0.05). During the treatment period, no obvious adverse reactions were observed in the two groups of patients. Conclusions: In addition to the routine basic treatment of acute large-area cerebral infarction, the addition of Shenxiong glucose injection combined with edaravone injection can improve platelet aggregation and reduce inflammation by affecting P-selectin, D-dimer, and FIB. This treatment approach promotes the recovery of nerve defect function without obvious adverse reactions in patients with acute large-area cerebral infarction.


Assuntos
Infarto Cerebral/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Edaravone/uso terapêutico , Doença Aguda , Proteína C-Reativa/metabolismo , Infarto Cerebral/sangue , Infarto Cerebral/patologia , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/efeitos adversos , Edaravone/efeitos adversos , Edaravone/farmacologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Selectina-P/metabolismo , Resultado do Tratamento
5.
Infect Immun ; 89(10): e0017821, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34228487

RESUMO

The Chagas disease parasite Trypanosoma cruzi must extravasate to home in on susceptible cells residing in most tissues. It remains unknown how T. cruzi undertakes this crucial step of its life cycle. We hypothesized that the pathogen exploits the endothelial cell programming leukocytes use to extravasate to sites of inflammation. Transendothelial migration (TEM) starts after inflammatory cytokines induce E-selectin expression and P-selectin translocation on endothelial cells (ECs), enabling recognition by leukocyte ligands that engender rolling cell adhesion. Here, we show that T. cruzi upregulates E- and P-selectins in cardiac ECs to which it binds in a ligand-receptor fashion, whether under static or shear flow conditions. Glycoproteins isolated from T. cruzi (TcEx) specifically recognize P-selectin in a ligand-receptor interaction. As with leukocytes, binding of P-selectin to T. cruzi or TcEx requires sialic acid and tyrosine sulfate, which are pivotal for downstream migration across ECs and extracellular matrix proteins. Additionally, soluble selectins, which bind T. cruzi, block transendothelial migration dose dependently, implying that the pathogen bears selectin-binding ligand(s) that start transmigration. Furthermore, function-blocking antibodies against E- and P-selectins, which act on endothelial cells and not T. cruzi, are exquisite in preventing TEM. Thus, our results show that selectins can function as mediators of T. cruzi transendothelial transmigration, suggesting a pathogenic mechanism that allows homing in of the parasite on targeted tissues. As selectin inhibitors are sought-after therapeutic targets for autoimmune diseases and cancer metastasis, they may similarly represent a novel strategy for Chagas disease therapy.


Assuntos
Selectina E/metabolismo , Células Endoteliais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Selectina-P/metabolismo , Trypanosoma cruzi/metabolismo , Animais , Adesão Celular/fisiologia , Citocinas/metabolismo , Células Endoteliais/parasitologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/parasitologia , Leucócitos/metabolismo , Leucócitos/parasitologia , Ligantes , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Migração Transendotelial e Transepitelial/fisiologia
6.
Carbohydr Polym ; 269: 118275, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34294307

RESUMO

Endogenous and exogenous sulfated polysaccharides exhibit potent biological activities, including inhibiting blood coagulation and protein interactions. Controlled chemical sulfation of alternative polysaccharides holds promise to overcome limited availability and heterogeneity of naturally sulfated polysaccharides. Here, we established reaction parameters for the controlled sulfation of the abundant cereal polysaccharide, mixed-linkage ß(1,3)/ß(1,4)-glucan (MLG), using Box-Behnken Design of Experiments (BBD) and Response Surface Methodology (RSM). The optimization of the degree-of-substitution (DS) was externally validated through the production of sulfated MLGs (S-MLGs) with observed DS and Mw values deviating less than 20% and 30% from the targeted values, respectively. Simultaneous optimization of DS and Mw resulted in the same range of deviation from the targeted value. S-MLGs with DS > 1 demonstrated a modest anticoagulation effect versus heparin, and a greater P-selectin affinity than fucoidan. As such, this work provides a route to medically important polymers from an economical agricultural polysaccharide.


Assuntos
Anticoagulantes/farmacologia , Ésteres do Ácido Sulfúrico/farmacologia , beta-Glucanas/farmacologia , Anticoagulantes/síntese química , Anticoagulantes/metabolismo , Sequência de Carboidratos , Técnicas de Química Sintética/estatística & dados numéricos , Humanos , Selectina-P/metabolismo , Tempo de Tromboplastina Parcial , Ésteres do Ácido Sulfúrico/síntese química , Ésteres do Ácido Sulfúrico/metabolismo , beta-Glucanas/síntese química , beta-Glucanas/metabolismo
7.
Curr Opin Hematol ; 28(5): 301-307, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34183536

RESUMO

PURPOSE OF REVIEW: In this review, we will describe how the combined ability of platelets and neutrophils to interact with each other drives ischemic stroke brain injury. RECENT FINDINGS: Neutrophils are one of the first cells to respond during ischemic stroke. Although animals stroke models have indicated targeting neutrophils improves outcomes, clinical trials have failed to yield successful strategies. Platelets play a critical role in recruiting neutrophils to sites of injury by acting as a bridge to the injured endothelium. After initial platelet adhesion, neutrophils can rapidly bind platelets through P-selectin and glycoprotein Ibα. In addition, recent data implicated platelet phosphatidylserine as a novel key regulator of platelet-neutrophil interactions in the setting of ischemic stroke. Inhibition of procoagulant platelets decreases circulating platelet-neutrophil aggregates and thereby reduces infarct size. Platelet binding alters neutrophil function, which contributes to the injury associated with ischemic stroke. This includes inducing the release of neutrophil extracellular traps, which are neurotoxic and pro-thrombotic, leading to impaired stroke outcomes. SUMMARY: Platelet-neutrophil interactions significantly contribute to the pathophysiology of ischemic stroke brain injury. Better understanding the mechanisms behind their formation and the downstream consequences of their interactions will lead to improved therapies for stroke patients.


Assuntos
Plaquetas/metabolismo , AVC Isquêmico/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Adesividade Plaquetária , Animais , Plaquetas/patologia , Armadilhas Extracelulares/metabolismo , Humanos , AVC Isquêmico/patologia , Neutrófilos/patologia , Selectina-P/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
8.
Sci Rep ; 11(1): 13170, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162972

RESUMO

Gene targeting of Cdc42 GTPase has been shown to inhibit platelet activation. In this study, we investigated a hypothesis that inhibition of Cdc42 activity by CASIN, a small molecule Cdc42 Activity-Specific INhibitor, may down regulate platelet activation and thrombus formation. We investigated the effects of CASIN on platelet activation in vitro and thrombosis in vivo. In human platelets, CASIN, but not its inactive analog Pirl7, blocked collagen induced activation of Cdc42 and inhibited phosphorylation of its downstream effector, PAK1/2. Moreover, addition of CASIN to washed human platelets inhibited platelet spreading on immobilized fibrinogen. Treatment of human platelets with CASIN inhibited collagen or thrombin induced: (a) ATP secretion and platelet aggregation; and (b) phosphorylation of Akt, ERK and p38-MAPK. Pre-incubation of platelets with Pirl7, an inactive analog of CASIN, failed to inhibit collagen induced aggregation. Washing of human platelets after incubation with CASIN eliminated its inhibitory effect on collagen induced aggregation. Intraperitoneal administration of CASIN to wild type mice inhibited ex vivo aggregation induced by collagen but did not affect the murine tail bleeding times. CASIN administration, prior to laser-induced injury in murine cremaster muscle arterioles, resulted in formation of smaller and unstable thrombi compared to control mice without CASIN treatment. These data suggest that pharmacologic targeting of Cdc42 by specific and reversible inhibitors may lead to the discovery of novel antithrombotic agents.


Assuntos
Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Trombose/prevenção & controle , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Músculos Abdominais/irrigação sanguínea , Trifosfato de Adenosina/metabolismo , Animais , Arteríolas , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Lasers , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
9.
Sci Rep ; 11(1): 11965, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099810

RESUMO

Colchicine inhibits coronary and cerebrovascular events in patients with coronary artery disease (CAD), and although known to have anti-inflammatory properties, its mechanisms of action are incompletely understood. In this study, we investigated the effects of colchicine on platelet activation with a particular focus on its effects on activation via the collagen glycoprotein (GP)VI receptor, P2Y12 receptor, and procoagulant platelet formation. Therapeutic concentrations of colchicine in vitro (equivalent to plasma levels) significantly decreased platelet aggregation in whole blood and in platelet rich plasma in response to collagen (multiplate aggregometry) and reduced reactive oxygen species (ROS) generation (H2DCF-DA, flow cytometry) in response to GPVI stimulation with collagen related peptide-XL (CRP-XL, GPVI specific agonist). Other platelet activation pathways including P-selectin expression, GPIIb/IIIa conformational change and procoagulant platelet formation (GSAO+/CD62P+) (flow cytometry) were inhibited with higher concentrations of colchicine known to inhibit microtubule depolymerization. Pathway specific mechanisms of action of colchicine on platelets, including modulation of the GPVI receptor pathway at low concentrations, may contribute to its protective role in CAD.


Assuntos
Colchicina/química , Doença da Artéria Coronariana/tratamento farmacológico , Glicoproteínas da Membrana de Plaquetas/metabolismo , Espécies Reativas de Oxigênio/química , Plaquetas/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Colchicina/metabolismo , Colchicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Selectina-P/metabolismo , Peptídeos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Receptores de Colágeno/genética , Receptores de Colágeno/metabolismo , Transdução de Sinais
10.
Int J Biol Macromol ; 181: 835-846, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33857519

RESUMO

Curcumin can reduce the production of brain inflammatory mediators and symptoms of brain diseases. However, a large amount of free curcumin needs to be administered to achieve an effective level in the brain because of its poor water-solubility. Fucoidan and chitosan were reported to respectively target P-selectin and acidic microenvironment expressed by pathologically inflammatory cells/tissues. Herein, the self-assembly of chitosan and fucoidan which could encapsulate curcumin was developed to form the multi-stimuli-responsive nanocarriers, and their pathological pH- and P-selectin-responsive aspects were characterized. Through intranasal delivery to the brain, these curcumin-containing chitosan/fucoidan nanocarriers with dual pH-/P-selectin-targeting properties to the brain lesions improved drug delivery, distribution, and accumulation in the inflammatory brain lesions as evidenced by an augmented inhibitory effect against brain inflammation. This promising multifunctional nanocarrier with a novel drug-delivery route should allow potential clinical biomedical uses by neurosurgeon in the future.


Assuntos
Quitosana/química , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Encefalite/tratamento farmacológico , Nanopartículas/química , Polissacarídeos/química , Administração Intranasal , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Fluorescência , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Selectina-P/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos , Difração de Raios X
11.
PLoS One ; 16(4): e0250852, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33909702

RESUMO

Aristotelia chilensis (Mol.) Stuntz, also known as maqui, is a plant native to Chile without chemical characterization and quantification of the bioactive compounds present in it. HPLC-UV and HPLC-MS/MS studies have shown the presence, at different concentrations, of phenolic and anthocyanin compounds in fruit and leave extracts of the domesticated maqui clones Luna Nueva, Morena, and Perla Negra. The extracts from leaves and unripe fruits of Luna Nueva and Morena clones significantly inhibit platelet aggregation induced by several agonists; the extracts inhibit platelet granule secretion by decreasing the exposure of P-selectin and CD63 at the platelet membrane. Reactive oxygen species formation in platelets is lower in the presence of maqui extracts. Statistical Pearson analysis supports the levels of phenolic and anthocyanin compounds being responsible for the antiaggregant maqui effects. This work is the first evidence of antiplatelet activity from Aristotelia chilensis giving added value to the use of leaves and unripe fruits from this species.


Assuntos
Antocianinas/farmacologia , Elaeocarpaceae/química , Inibidores da Agregação Plaquetária/farmacologia , Polifenóis/farmacologia , Antocianinas/química , Antocianinas/isolamento & purificação , Chile , Cromatografia Líquida de Alta Pressão , Domesticação , Frutas/química , Humanos , Selectina-P/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/isolamento & purificação , Polifenóis/química , Polifenóis/isolamento & purificação , Espectrometria de Massas em Tandem , Tetraspanina 30/metabolismo
12.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807403

RESUMO

Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies have reported the effects of pterostilbene on platelet activation. Thus, we examined the inhibitory mechanisms of pterostilbene in human platelets and its role in vascular thrombosis prevention in mice. At low concentrations (2-8 µM), pterostilbene strongly inhibited collagen-induced platelet aggregation. Furthermore, pterostilbene markedly diminished Lyn, Fyn, and Syk phosphorylation and hydroxyl radical formation stimulated by collagen. Moreover, PTE directly hindered integrin αIIbß3 activation through interfering with PAC-1 binding stimulated by collagen. In addition, pterostilbene affected integrin αIIbß3-mediated outside-in signaling, such as integrin ß3, Src, and FAK phosphorylation, and reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Furthermore, pterostilbene substantially prolonged the occlusion time of thrombotic platelet plug formation in mice. This study demonstrated that pterostilbene exhibits a strong activity against platelet activation through the inhibition of integrin αIIbß3-mediated inside-out and outside-in signaling, suggesting that pterostilbene can serve as a therapeutic agent for thromboembolic disorders.


Assuntos
Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Estilbenos/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Retração do Coágulo/efeitos dos fármacos , Colágeno , Fibrinogênio/metabolismo , Hemostasia/efeitos dos fármacos , Humanos , Integrina alfa2/efeitos dos fármacos , Integrina alfa2/metabolismo , Integrina beta3/efeitos dos fármacos , Integrina beta3/metabolismo , Integrinas/efeitos dos fármacos , Integrinas/metabolismo , Camundongos , Selectina-P/metabolismo , Fosforilação , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Trombose/metabolismo
13.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786610

RESUMO

Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE­/­ mice received a single exposure of low or high dose X­ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in vitro in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE­/­ mice increased serum growth differentiation factor­15 (GDF­15) and C­X­C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells in vitro. Sex­specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE­/­ mice demonstrated elevated intercellular adhesion molecule­1 and P­selectin at 24 h, and adiponectin and plasminogen activator inhibitor­1 at 1 month after irradiation, while female ApoE­/­ mice exhibited decreased monocyte chemoattractant protein­1 and urokinase­type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X­irradiation and to investigate whether GDF­15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy­treated patients.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/metabolismo , Quimiocina CXCL10/metabolismo , Endotélio Vascular/efeitos da radiação , Fator 15 de Diferenciação de Crescimento/metabolismo , Raios X , Animais , Apolipoproteínas E/deficiência , Aterosclerose/genética , Molécula 1 de Adesão Celular/genética , Molécula 1 de Adesão Celular/metabolismo , Linhagem Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/genética , Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Endotélio Vascular/citologia , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/genética , Selectina-P/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
14.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771989

RESUMO

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglia/metabolismo , Selectina-P/genética , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Selectina-P/antagonistas & inibidores , Selectina-P/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
15.
ACS Appl Mater Interfaces ; 13(8): 10287-10300, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33615773

RESUMO

Near-infrared (NIR)-light-modulated photothermal thrombolysis has been investigated to overcome the hemorrhage danger posed by clinical clot-busting substances. A long-standing issue in thrombosis fibrinolytics is the lack of lesion-specific therapy, which should not be ignored. Herein, a novel thrombolysis therapy using photothermal disintegration of a fibrin clot was explored through dual-targeting glycol chitosan/heparin-decorated polypyrrole nanoparticles (GCS-PPY-H NPs) to enhance thrombus delivery and thrombolytic therapeutic efficacy. GCS-PPY-H NPs can target acidic/P-selectin high-expression inflammatory endothelial cells/thrombus sites for initiating lesion-site-specific thrombolysis by hyperthermia using NIR irradiation. A significant fibrin clot-clearance rate was achieved with thrombolysis using dual-targeting/modality photothermal clot disintegration in vivo. The molecular level mechanisms of the developed nanoformulations and interface properties were determined using multiple surface specific analytical techniques, such as particle size distribution, zeta potential, electron microscopy, Fourier-transform infrared spectroscopy (FTIR), wavelength absorbance, photothermal, immunofluorescence, and histology. Owing to the augmented thrombus delivery of GCS-PPY-H NPs and swift treatment time, dual-targeting photothermal clot disintegration as a systematic treatment using GCS-PPY-H NPs can be effectively applied in thrombolysis. This novel approach possesses a promising future for thrombolytic treatment.


Assuntos
Quitosana/uso terapêutico , Heparina/uso terapêutico , Nanopartículas/uso terapêutico , Polímeros/uso terapêutico , Pirróis/uso terapêutico , Trombose/tratamento farmacológico , Animais , Quitosana/química , Células Endoteliais/metabolismo , Heparina/química , Heparina/metabolismo , Luz , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/química , Nanopartículas/efeitos da radiação , Selectina-P/metabolismo , Fototerapia/métodos , Polímeros/química , Polímeros/efeitos da radiação , Pirróis/química , Pirróis/efeitos da radiação , Terapia Trombolítica/métodos , Trombose/metabolismo
16.
Transfusion ; 61(3): 919-930, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33527430

RESUMO

BACKGROUND: Deterioration in quality of platelet concentrates (PCs) during storage results from the appearance of storage lesions affecting the hemostatic functions and posttransfusion survival of platelets. These lesions depend on the preparation and pathogen inactivation methods used, duration of storage, and platelet additive solutions (PASs) present in storage bags. METHODS: We investigated the effects of citrate contained in third-generation PAS (PAS-III) on storage lesions in buffy-coat PCs with or without photochemical (amotosalen-ultraviolet A) treatment over 7 days. RESULTS: Platelet counts were conserved in all groups during storage, as was platelet swirling without appearance of macroscopic aggregates. Glycoprotein (GP) IIbIIIa and GPVI expression remained stable, whereas GPIbα declined similarly in all groups during storage. Removal of citrate from PAS-III, resulting in global reduction of citrate from 11 to 5 mM, led to a significant decrease in glucose consumption, which largely countered a modest deleterious effect of photochemical treatment. Citrate reduction also resulted in decreased lactate generation and better maintenance of pH during storage, while photochemical treatment had no impact on these parameters. Moreover, citrate-free storage significantly reduced exposure of P-selectin and the apoptosis signal phosphatidylserine, thereby abolishing the activating effect of photochemical treatment on both parameters. Citrate reduction benefited platelet aggregation to various agonists up to Day 7, whereas PCT had no impact on these responses. CONCLUSION: Removal of citrate from PAS-III has a beneficial impact on platelet metabolism, spontaneous activation, and apoptosis, and improves platelet aggregation, irrespective of photochemical treatment, which should allow transfusion of platelets with better and longer-lasting functional properties.


Assuntos
Plaquetas/metabolismo , Preservação de Sangue/métodos , Ácido Cítrico/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Furocumarinas/farmacologia , Hemostasia/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/metabolismo , Selectina-P/metabolismo , Fosfatidilserinas , Contagem de Plaquetas , Testes de Função Plaquetária , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo
17.
Nutr. hosp ; 38(1): 121-127, ene.-feb. 2021. tab
Artigo em Inglês | IBECS | ID: ibc-198848

RESUMO

BACKGROUND: açaí is the fruit of the palm tree Euterpe oleracea Martius, which is native to the Amazon region. This fruit has been extensively studied due to its potential effects on human health. Studies have also evaluated the potential effect of açaí on the inflammatory response, but there are still few studies that have assessed this property in humans. OBJECTIVE: in this study we aimed to evaluate the effects of 200 g of açaí pulp consumption per day during four weeks on a rich panel of inflammatory biomarkers. METHODS: a prospective nutritional intervention study was conducted on forty apparently healthy women who consumed 200 g of açaí pulp per day for four weeks. A panel of serum inflammatory markers were evaluated before and after the nutritional intervention, namely, cell adhesion molecules (ICAM-1, IVAM-1, P-selectin, MCP-1, and fractalkine), interleukins (IL-1β, IL-6, IL-8, IL-10, and IL-17) and adipokines (adiponectin, leptin, visfatin, and adipsin). The data were analyzed using paired Student's t-test to evaluate the effect of the intervention using PASW Statistics, version 18.0, and a p-value of < 0.05 was considered significant. RESULTS: four weeks of açaí pulp consumption decreased p-selectin, leptin, and visfatin concentrations in the serum of the participating women. CONCLUSION: these results show that consumption of açaí pulp was able to modulate important biomarkers of the inflammatory process in apparently healthy women


INTRODUCCIÓN: el açaí es el fruto de la palmera Euterpe oleracea Martius, originaria de la región amazónica. Esta fruta ha sido ampliamente estudiada debido a sus posibles efectos sobre la salud humana. Los estudios también han evaluado el efecto potencial del açaí sobre la respuesta inflamatoria, pero todavía hay pocos estudios que hayan evaluado esta propiedad en seres humanos. OBJETIVO: en este estudio, nuestro objetivo ha sido evaluar los efectos del consumo de 200 g de pulpa de açaí por día durante cuatro semanas sobre un rico panel de biomarcadores inflamatorios. MÉTODOS: se ha realizado un estudio prospectivo de intervención nutricional en el que cuarenta mujeres aparentemente sanas han consumido 200 g de pulpa de açaí al día durante cuatro semanas. Se ha evaluado un panel de marcadores inflamatorios séricos antes y después de la intervención nutricional, a saber, moléculas de adhesión celular (ICAM-1, IVAM-1, P-selectina, MCP-1 y fractalquina), interleucinas (IL-1β, IL-6, IL-8, IL-10 e IL-17) y adipocinas (adiponectina, leptina, visfatina y adipsina). Los datos han sido analizados mediante la prueba de la t de Student pareada para evaluar el efecto de la intervención mediante el PASW Statistics, versión 18.0, y todo valor de p < 0,05 se consideró significativo. RESULTADOS: después de cuatro semanas de consumo de pulpa de açaí disminuyeron las concentraciones de p-selectina, leptina y visfatina en el suero de las mujeres participantes. CONCLUSIÓN: estos resultados muestran que el consumo de pulpa de açaí ha sido capaz de modular importantes biomarcadores del proceso inflamatorio en mujeres aparentemente sanas


Assuntos
Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Ingestão de Alimentos , Euterpe , Dietética , Selectina-P/metabolismo , Leptina/metabolismo , Nicotinamida Fosforribosiltransferase/administração & dosagem , Adesão Celular , Biomarcadores , Estudos Prospectivos , Interleucinas/sangue , Antropometria , Adipocinas
18.
Transfusion ; 61(4): 1222-1234, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33580979

RESUMO

BACKGROUND: Patients can form antibodies to foreign human leukocyte antigen (HLA) Class I antigens after exposure to allogeneic cells. These anti-HLA class I antibodies can bind transfused platelets (PLTs) and mediate their destruction, thus leading to PLT refractoriness. Patients with PLT refractoriness need HLA-matched PLTs, which require expensive HLA typing of donors, antibody analyses of patient sera and/or crossmatching. An alternative approach is to reduce PLT HLA Class I expression using a brief incubation in citric acid on ice at low pH. METHODS AND MATERIALS: Apheresis PLT concentrates were depleted of HLA Class I complexes by 5 minutes incubation in ice-cold citric acid, at pH 3.0. Surface expression of HLA Class I complexes, CD62P, CD63, phosphatidylserine, and complement factor C3c was analyzed by flow cytometry. PLT functionality was tested by thromboelastography (TEG). RESULTS: Acid treatment reduced the expression of HLA Class I complexes by 71% and potential for C3c binding by 11.5-fold compared to untreated PLTs. Acid-treated PLTs were significantly more activated than untreated PLTs, but irrespective of this increase in steady-state activation, CD62P and CD63 were strongly upregulated on both acid-treated and untreated PLTs after stimulation with thrombin receptor agonist peptide. Acid treatment did not induce apoptosis over time. X-ray irradiation did not significantly influence the expression of HLA Class I complexes, CD62P, CD63, and TEG variables on acid treated PLTs. CONCLUSION: The relatively simple acid stripping method can be used with irradiated apheresis PLTs and may prevent transfusion-associated HLA sensitization and overcome PLT refractoriness.


Assuntos
Ácido Cítrico/efeitos adversos , Antígenos de Histocompatibilidade Classe I/efeitos dos fármacos , Transfusão de Plaquetas/métodos , Imunodeficiência Combinada Severa/induzido quimicamente , Anticorpos/imunologia , Tipagem e Reações Cruzadas Sanguíneas/métodos , Plaquetas/efeitos da radiação , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/efeitos da radiação , Teste de Histocompatibilidade/economia , Teste de Histocompatibilidade/métodos , Humanos , Selectina-P/metabolismo , Transfusão de Plaquetas/efeitos adversos , Plaquetoferese/métodos , Tetraspanina 30/metabolismo , Tromboelastografia/métodos , Trombocitopenia/terapia , Regulação para Cima/genética
19.
Nat Commun ; 12(1): 312, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436622

RESUMO

The transmembrane P-glycoprotein (P-gp) pumps that efflux drugs are a major mechanism of cancer drug resistance. They are also important in protecting normal tissue cells from poisonous xenobiotics and endogenous metabolites. Here, we report a fucoidan-decorated silica-carbon nano-onion (FSCNO) hybrid nanoparticle that targets tumor vasculature to specifically release P-gp inhibitor and anticancer drug into tumor cells. The tumor vasculature targeting capability of the nanoparticle is demonstrated using multiple models. Moreover, we reveal the superior light absorption property of nano-onion in the near infrared region (NIR), which enables triggered drug release from the nanoparticle at a low NIR power. The released inhibitor selectively binds to P-gp pumps and disables their function, which improves the bioavailability of anticancer drug inside the cells. Furthermore, free P-gp inhibitor significantly increases the systemic toxicity of a chemotherapy drug, which can be resolved by delivering them with FSCNO nanoparticles in combination with a short low-power NIR laser irradiation.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Carbono/química , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Selectina-P/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Microfluídica , Nanopartículas/ultraestrutura , Neoplasias/irrigação sanguínea , Terapia Fototérmica , Polissacarídeos/química , Dióxido de Silício/química
20.
Cell Death Dis ; 12(1): 50, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33414384

RESUMO

Novel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients, p = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81, p = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03, p < 0.0001) and other adhesion molecules involved in platelet activation and platelet-leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls (p < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.


Assuntos
Plaquetas/patologia , COVID-19/complicações , Leucócitos/patologia , SARS-CoV-2/isolamento & purificação , Trombose/epidemiologia , Adulto , Plaquetas/metabolismo , Plaquetas/virologia , COVID-19/transmissão , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Alemanha/epidemiologia , Humanos , Leucócitos/metabolismo , Leucócitos/virologia , Masculino , Pessoa de Meia-Idade , Selectina-P/metabolismo , Fragmentos de Peptídeos/metabolismo , Fenótipo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombose/virologia
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