RESUMEN
Disintegrins are a class of peptides found in snake venom that inhibit the activity of integrins, which are essential cell adhesion receptors in tumor progression and development. In this work, moojecin, a RGD disintegrin, was isolated from Bothrops moojeni snake venom, and its antitumor potential in acute myeloid leukemia (AML) HL-60 and THP-1 cells was characterized. The isolation was performed using a C18 reverse-phase column in two chromatographic steps, and its molecular mass is 7417.84 Da. N-terminal and de novo sequencing was performed to identify moojecin. Moojecin did not show cytotoxic or antiproliferative activity in THP-1 and HL-60 at tested concentrations, but it exhibited significant antimigratory activity in both cell lines, as well as inhibition of angiogenesis in the tube formation assay on Matrigel in a dose-dependent manner. A stronger interaction with integrin αVß3 was shown in integrin interaction assays compared to α5ß1, and the platelet aggregation assay indicated an IC50 of 5.039 µg/mL. Preliminary evaluation of disintegrin toxicity revealed no incidence of hemolysis or cytotoxic effects on peripheral blood mononuclear cells (PBMCs) across the tested concentrations. Thus, this is the first study to report the isolation, functional and structural characterization of a disintegrin from B. moojeni venom and bring a new perspective to assist in AML treatment.
Asunto(s)
Antineoplásicos , Bothrops , Desintegrinas , Leucemia Mieloide Aguda , Humanos , Desintegrinas/farmacología , Desintegrinas/química , Desintegrinas/aislamiento & purificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Células HL-60 , Venenos de Crotálidos/química , Agregación Plaquetaria/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Serpientes VenenosasRESUMEN
The study aimed to evaluate the antithrombotic action of Acrocomia aculeata pulp oil (AAPO) in natura, in an in vitro experimental model. AAPO was obtained by solvent extraction, and its chemical characterization was performed by gas chromatography coupled to a mass spectrometer (GC-MS). In vitro toxicity was evaluated with the Trypan Blue exclusion test and in vivo by the Galleria mellonella model. ADP/epinephrine-induced platelet aggregation after treatment with AAPO (50, 100, 200, 400, and 800 µg/mL) was evaluated by turbidimetry, and coagulation was determined by prothrombin activity time (PT) and activated partial thromboplastin time (aPTT). Platelet activation was measured by expression of P-selectin on the platelet surface by flow cytometry and intraplatelet content of reactive oxygen species (ROS) by fluorimetry. The results showed that AAPO has as major components such as oleic acid, palmitic acid, lauric acid, caprylic acid, and squalene. AAPO showed no toxicity in vitro or in vivo. Platelet aggregation decreased against agonists using treatment with different concentrations of AAPO. Oil did not interfere in PT and aPTT. Moreover, it expressively decreased ROS-induced platelet activation and P-selectin expression. Therefore, AAPO showed antiplatelet action since it decreased platelet activation verified by the decrease in P-selectin expression as well as in ROS production.
Asunto(s)
Fibrinolíticos , Selectina-P , Aceites de Plantas , Agregación Plaquetaria , Especies Reactivas de Oxígeno , Animales , Agregación Plaquetaria/efectos de los fármacos , Selectina-P/metabolismo , Humanos , Aceites de Plantas/farmacología , Aceites de Plantas/química , Especies Reactivas de Oxígeno/metabolismo , Fibrinolíticos/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacosRESUMEN
Gamma-terpinene (γ-TPN) is a cyclohexane monoterpene isolated from plant essential oils, such as tea tree (Melaleuca alternifolia), oregano (Origanum vulgare), rosemary (Rosmarinus officinalis L.), thyme (Thymus vulgaris Marchand), and eucalyptus (Eucalyptus sp.). Terpenes are widely studied molecules pharmacologically active on the cardiovascular system, hemostasis, and antioxidant actions. Herein, it was investigated the cytotoxic and antiplatelet activity of γ-TPN using different non-clinical laboratory models. For in silico evaluation, the PreADMET, SwissADME, and SwissTargetPrediction softwares were used. Molecular docking was performed using the AutoDockVina and BIOVIA Discovery Studio databases. The cytotoxicity of γ-TPN was analyzed by the MTT assay upon normal murine endothelial SVEC4-10 and fibroblast L-929 cells. Platelet aggregation was evaluated with platelet-rich (PRP) and platelet-poor (PPP) plasma from spontaneously hypertensive rats (SHR), in addition to SVEC4-10 cells pre-incubated with γ-TPN (50, 100, and 200 µM) for 24 h. SHR animals were pre-treated by gavage with γ-TPN for 7 days and divided into four groups (negative control, 25, 50, and 100 mg/kg). Blood samples were collected to measure nitrite using the Griess reagent. Gamma-TPN proved to be quite lipid-soluble (Log P = +4.50), with a qualified profile of similarity to the drug, good bioavailability, and adequate pharmacokinetics. It exhibited affinity mainly for the P2Y12 receptor (6.450 ± 0.232 Kcal/mol), moderate cytotoxicity for L-929 (CC50 = 333.3 µM) and SVEC 4-10 (CC50 = 366.7 µM) cells. The presence of γ-TPN in SVEC 4-10 cells was also able to reduce platelet aggregation by 51.57 and 44.20% at lower concentrations (50 and 100 µM, respectively). Then, γ-TPN has good affinity with purinergic receptors and an effect on the reversal of platelet aggregation and oxidative stress, being promising and safe for therapeutic targets and subsequent studies on the control of thromboembolic diseases.
Asunto(s)
Monoterpenos Ciclohexánicos , Simulación del Acoplamiento Molecular , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Ratas Endogámicas SHR , Animales , Ratones , Agregación Plaquetaria/efectos de los fármacos , Monoterpenos Ciclohexánicos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Masculino , Línea Celular , Ratas , Ratas Wistar , Supervivencia Celular/efectos de los fármacos , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Monoterpenos/farmacologíaRESUMEN
Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.
Asunto(s)
Plaquetas , Hidroquinonas , Potencial de la Membrana Mitocondrial , Compuestos Organofosforados , Inhibidores de Agregación Plaquetaria , Humanos , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Hidroquinonas/farmacología , Hidroquinonas/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/química , Fosforilación Oxidativa/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Thrombosis is one of the major causes of morbidity and mortality in a wide range of vessel diseases. Several studies have been conducted to identify antithrombotic agents from medicinal plants, and phenolic compounds (PCs) have been shown to effectively inhibit plasma coagulation and platelet aggregation. OBJECTIVES: This study aimed to conduct a survey of the natural PCs with proven antithrombotic and antiplatelet activities, as well as to evaluate by computational modeling the physicochemical and toxicological properties of these compounds using drug-likeness approaches. METHODS: The data were collected from the scientific database: 'Web of Science', 'Scifinder', 'Pubmed', 'ScienceDirect' and 'Google Scholar', the different classes of PCs with antithrombotic or antiplatelet effects were used as keywords. These molecules were also evaluated for their Drug-Likeness properties and toxicity to verify their profile for being candidates for new antithrombotic drugs. RESULTS: In this review, it was possible to register 85 lignans, 73 flavonoids, 28 coumarins, 21 quinones, 23 phenolic acids, 8 xanthones and 8 simple phenols. Activity records for tannins were not found in the researched databases. Of these 246 compounds, 213 did not violate any of Lipinski's rules of five, of which 125 (59%) showed non-toxicity, being promising candidates for new potential antithrombotic drugs. CONCLUSION: This review arouses interest in the isolation of phenolic compounds that may allow a new approach for the prevention of both arterial and venous thrombosis, with the potential to become alternatives in the prevention and treatment of cardiovascular diseases.
Asunto(s)
Fibrinolíticos , Fenoles , Inhibidores de Agregación Plaquetaria , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Fibrinolíticos/farmacología , Fibrinolíticos/química , Humanos , Fenoles/química , Fenoles/farmacología , Trombosis/tratamiento farmacológico , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/aislamiento & purificación , Agregación Plaquetaria/efectos de los fármacosRESUMEN
Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic process regulated by different signaling networks. Therefore, there are now focused efforts to search for novel bioactive compounds which target receptors and pathways in the platelet activation process while preserving normal hemostatic function. The antiplatelet activity of numerous fruits and vegetables and their multiple mechanisms of action have recently been highlighted. In this review, we review the antiplatelet actions of bioactive compounds via key pathways (protein disulfide isomerase, mitogen-activated protein kinases, mitochondrial function, cyclic adenosine monophosphate, Akt, and shear stress-induced platelet aggregation) with no effects on bleeding time. Therefore, targeting these pathways might lead to the development of effective antiplatelet strategies that do not increase the risk of bleeding.
Asunto(s)
Plaquetas/metabolismo , Hemorragia/prevención & control , Fitoquímicos/uso terapéutico , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Trombosis/tratamiento farmacológico , Animales , Plaquetas/efectos de los fármacos , Hemorragia/metabolismo , Hemostasis/efectos de los fármacos , Humanos , Fitoquímicos/farmacología , Placa Aterosclerótica/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Trombosis/metabolismoRESUMEN
Infection by Proteus mirabilis causes urinary stones and catheter incrustation due to ammonia formed by urease (PMU), one of its virulence factors. Non-enzymatic properties, such as pro-inflammatory and neurotoxic activities, were previously reported for distinct ureases, including that of the gastric pathogen Helicobacter pylori. Here, PMU was assayed on isolated cells to evaluate its non-enzymatic properties. Purified PMU (nanomolar range) was tested in human (platelets, HEK293 and SH-SY5Y) cells, and in murine microglia (BV-2). PMU promoted platelet aggregation. It did not affect cellular viability and no ammonia was detected in the cultures' supernatants. PMU-treated HEK293 cells acquired a pro-inflammatory phenotype, producing reactive oxygen species (ROS) and cytokines IL-1ß and TNF-α. SH-SY5Y cells stimulated with PMU showed high levels of intracellular Ca2+ and ROS production, but unlike BV-2 cells, SH-SY5Y did not synthesize TNF-α and IL-1ß. Texas Red-labeled PMU was found in the cytoplasm and in the nucleus of all cell types. Bioinformatic analysis revealed two bipartite nuclear localization sequences in PMU. We have shown that PMU, besides urinary stone formation, can potentially contribute in other ways to pathogenesis. Our data suggest that PMU triggers pro-inflammatory effects and may affect cells beyond the renal system, indicating a possible role in extra-urinary diseases.
Asunto(s)
Proteus mirabilis/enzimología , Proteus mirabilis/patogenicidad , Ureasa/metabolismo , Ureasa/toxicidad , Secuencia de Aminoácidos , Animales , Calcio/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Técnicas In Vitro , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/microbiología , Modelos Moleculares , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/microbiología , Neurotoxinas/química , Neurotoxinas/metabolismo , Neurotoxinas/toxicidad , Señales de Localización Nuclear , Agregación Plaquetaria/efectos de los fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/toxicidad , Ureasa/química , Virulencia/fisiologíaRESUMEN
OBJECTIVES: This study was carried out to evaluate the effects of flavonoids present in leaves of Passiflora edulis fruit on complications induced by diabetes in rats. METHODS: The extract of P. edulis leaf was obtained by 70% ethanol maceration. From the dry extract, the fractions were obtained by consecutive liquid-liquid partition with hexane, ethyl acetate and n-butanol. The content of isoorientin of ethyl acetate and n-butanol fractions was determined by ultra-performance liquid chromatography coupled with electrospray and triple quadrupole ionization (TQD) analysis in tandem mass spectrometry (UPLC-ESI-Tq-MS). Only Fr-BuOH was used to treat diabetic or not Wistar rats. Biochemical parameters, platelet aggregation and production of reactive species were evaluated. KEY FINDINGS: The UPLC-ESI-Tq-MS analysis revealed the presence of several flavonoids, among which we identified five possible flavonoids c-heterosides (luteolin-7-O-pyranosyl-3-O-glucoside, apigenin-6-8-di-C-glycoside, apigenin-6-C-arabinoside-8-C-glycoside, isoorientin, isovitexin). The diabetic rats (treated intraperitoneally with alloxan, 150 mg/kg) treated with Fr-BuOH (20 mg/kg/day for 90 days) presented improvement in blood glucose, serum levels of fructosamine, lipid profile and urea. Furthermore, the Fr-BuOH reduced both platelet aggregation and the production of oxidant species in diabetic animals. CONCLUSIONS: These results suggested that flavonoid C-glycosides present in the Fr-BuOH may be beneficial for the diabetic state, preventing complications induced by diabetes.
Asunto(s)
Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Flavonoides/uso terapéutico , Glicósidos/uso terapéutico , Passiflora/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Apigenina/análisis , Apigenina/farmacología , Apigenina/uso terapéutico , Glucemia/metabolismo , Cromatografía Líquida de Alta Presión , Complicaciones de la Diabetes/sangre , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Flavonas/análisis , Flavonas/farmacología , Flavonas/uso terapéutico , Flavonoides/análisis , Flavonoides/farmacología , Fructosamina/sangre , Glucósidos/análisis , Glucósidos/farmacología , Glucósidos/uso terapéutico , Glicósidos/análisis , Glicósidos/farmacología , Luteolina/análisis , Luteolina/farmacología , Luteolina/uso terapéutico , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Agregación Plaquetaria/efectos de los fármacos , Ratas Wistar , Espectrometría de Masas en TándemAsunto(s)
Plaquetas/fisiología , Proteínas Activadoras de GTPasa/genética , Megacariocitos/citología , Regulación hacia Arriba , Animales , Plaquetas/efectos de los fármacos , Diferenciación Celular , Línea Celular , Linaje de la Célula , Células Cultivadas , Proteínas Activadoras de GTPasa/metabolismo , Silenciador del Gen , Humanos , Megacariocitos/efectos de los fármacos , Megacariocitos/metabolismo , Ratones , Selectina-P/farmacología , Agregación Plaquetaria/efectos de los fármacos , Cultivo Primario de Células , Trombina/farmacologíaRESUMEN
This study aimed to isolate, characterize chemical-structurally and evaluate the effects of polysaccharides from Caesalpinia (Libidibia) ferrea stem barks in the haemostatic system. The deproteinated-polysaccharide extract (PE-Cf) after being fractionated by ion exchange chromatography-DEAE-cellulose resulted in three fractions (FI, FII, FIII) containing total carbohydrates (14.3-38%), including uronic acid (5-16%), and polyphenols (0.94-1.7 mg/g GAE). The polysaccharide fractions presented polydisperse profile in polyacrylamide gel electrophoresis (detected by Stains-All) and molecular masses (9.5 × 104 Da-1.5 × 105 Da) identified by gel permeation chromatography. FT-IR showed absorption bands (1630 cm-1, 1396-1331 cm-1), indicative of uronic acid, and a band at 1071 cm-1, typical of COO- groups of galacturonic acid. The NMR spectra of C. ferrea polysaccharides revealed a central core composed mainly by 5-linked α-Araf and minority components as α-Rhap and α-GalAp. UV spectra of fractions revealed discrete shoulders at 269-275 nm, characteristic of polyphenolic compounds. In vitro, polysaccharides inhibited the intrinsic and/or common coagulation pathway (aPTT test) (2.0-3.7 fold) and the platelet aggregation induced by 3 µM adenosine diphosphate (25-48%) and 5 µg/mL collagen (24%), but not that induced by arachidonic acid. In vivo, the polysaccharides inhibited (36-69%) venous thrombosis induced by hypercoagulability and stasis, showing discrete hemorrhagic effect. In conclusion, the polysaccharides of C. ferrea barks, containing arabinose, galactose, rhamnose and uronic acid, possess anticoagulant, antiplatelet and antithrombotic properties of low hemorrhagic risk, suggesting potential applicability in thromboembolic disorders.
Asunto(s)
Caesalpinia/metabolismo , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Animales , Anticoagulantes/química , Coagulación Sanguínea/efectos de los fármacos , Fibrinolíticos/química , Humanos , Tiempo de Tromboplastina Parcial , Corteza de la Planta/química , Extractos Vegetales/farmacología , Agregación Plaquetaria/efectos de los fármacos , Polifenoles/farmacología , Ratas , Ratas Wistar , Trombosis de la VenaRESUMEN
Platelets are the smallest blood cells, and their activation (platelet cohesion or aggregation) at sites of vascular injury is essential for thrombus formation. Since the use of antiplatelet therapy is an unsolved problem, there are now focused and innovative efforts to develop novel antiplatelet compounds. In this context, we assessed the antiplatelet effect of an acylhydroquinone series, synthesized by Fries rearrangement under microwave irradiation, evaluating the effect of diverse acyl chain lengths, their chlorinated derivatives, and their dimethylated derivatives both in the aromatic ring and also the effect of the introduction of a bromine atom at the terminus of the acyl chain. Findings from a primary screening of cytotoxic activity on platelets by lactate dehydrogenase assay identified 19 non-toxic compounds from the 27 acylhydroquinones evaluated. A large number of them showed IC50 values less than 10 µM acting against specific pathways of platelet aggregation. The highest activity was obtained with compound 38, it exhibited sub-micromolar IC50 of 0.98 ± 0.40, 1.10 ± 0.26, 3.98 ± 0.46, 6.79 ± 3.02 and 42.01 ± 3.48 µM against convulxin-, collagen-, TRAP-6-, PMA- and arachidonic acid-induced platelet aggregation, respectively. It also inhibited P-selectin and granulophysin expression. We demonstrated that the antiplatelet mechanism of compound 38 was through a decrease in a central target in human platelet activation as in mitochondrial function, and this could modulate a lower response of platelets to activating agonists. The results of this study show that the chemical space around ortho-carbonyl hydroquinone moiety is a rich source of biologically active compounds, signaling that the acylhydroquinone scaffold has a promising role in antiplatelet drug research.
Asunto(s)
Plaquetas/efectos de los fármacos , Hidroquinonas/química , Hidroquinonas/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Plaquetas/fisiología , Humanos , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/fisiología , Relación Estructura-ActividadRESUMEN
Gliflozins (canagliflozin, dapagliflozin and empagliflozin) are the newest anti-hyperglycemic class and have offered cardiovascular and renal benefits. Because platelets are involved in the atherothrombosis process, this study is aimed to evaluate the direct effect of gliflozins on platelet reactivity. Platelet-rich plasma (PRP) or washed platelets (WP) were obtained from healthy volunteers. Aggregation, flow cytometry for glycoprotein IIb/IIIa, cyclic nucleotides and intracellular calcium levels, Western blot, thromboxane B2 (TXB2) measurement and COX-1 activity were performed in the presence of gliflozins (1-30 µM) alone or in combination with sodium nitroprusside (SNP, 10 or 100 nM) + iloprost (ILO, 0.1 or 1 nM). SGLT2 protein is not expressed on human platelets. Gliflozins produced little inhibitory effect in agonists-induced aggregation and this effect was greatly potentiated by ~10-fold in the presence of SNP + ILO, accompanied by lower levels of TXB2 (58.1 ± 5.1%, 47.1 ± 7.2% and 43.4 ± 9.2% inhibition for canagliflozin, dapagliflozin and empagliflozin, respectively). The activity of COX-1 was not affected by gliflozins. Collagen increased Ca2+ levels and α(IIb)ß(3) activation, both of which were significantly reduced by gliflozins + SNP + ILO. The intracellular levels of cAMP and cGMP and the protein expression of p-VASPSer157 and p-VASPSer239 were not increased by gliflozins while the expression of the serine-threonine kinase, AktSer473 was markedly reduced. Our results showed that the antiplatelet activity of gliflozins were greatly enhanced by nitric oxide and prostacyclin, thus suggesting that the cardiovascular protection seen by this class of drugs could be in part due to platelet inhibition.
Asunto(s)
Epoprostenol/administración & dosificación , Óxido Nítrico/administración & dosificación , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Adulto , Células Cultivadas , Sinergismo Farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/fisiología , Transportador 2 de Sodio-Glucosa/metabolismo , Adulto JovenRESUMEN
Atherosclerosis is a multifactorial chronic disease, initiated by an endothelial dysfunction. Adenosine and its analogs can change a variety of inflammatory diseases and has shown important effects at different disease models. Inosine is a stable analogous of adenosine, but its effects in inflammatory diseases, like atherosclerosis, have not yet been studied. The aim of this study was to evaluate the pharmacological properties of inosine, administered sub chronically in a hypercholesterolemic model. Male Wistar rats were divided into four groups: control group (C) and control + inosine (C + INO) received standard chow, hypercholesterolemic diet group (HCD) and HCD + inosine (HCD + INO) were fed a hypercholesterolemic diet. At 31st experimentation day, the treatment with inosine was performed for C + INO and HCD + INO groups once daily in the last 15 days. We observed that the hypercholesterolemic diet promoted an increase in lipid levels and inflammatory cytokines production, while inosine treatment strongly decreased these effects. Additionally, HCD group presented a decrease in maximum relaxation acetylcholine induced and an increase in contractile response phenylephrine induced when compared to the control group, as well as it has presented an enhancement in collagen and ADP-induced platelet aggregation. On the other hand, inosine treatment promoted a decrease in contractile response to phenylephrine, evoked an improvement in endothelium-dependent vasorelaxant response and presented antiplatelet properties. Moreover, inosine activated eNOS and reduced p38 MAPK/NF-κB pathway in aortic tissues. Taken together, the present results indicate inosine as a potential drug for the treatment of cardiovascular disorders such as atherosclerosis.
Asunto(s)
Antiinflamatorios/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Inosina/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Antiinflamatorios/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Aterosclerosis/sangre , Aterosclerosis/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/fisiología , Humanos , Inosina/farmacología , Interleucina-6/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangre , Vasodilatadores/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.
Asunto(s)
Antimaláricos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Cloroquina/farmacología , Hidroxicloroquina/farmacología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Síndrome Antifosfolípido/tratamiento farmacológico , Síndrome Antifosfolípido/inmunología , Antirreumáticos/uso terapéutico , Artritis Reumatoide/inmunología , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Erupciones por Medicamentos/etiología , Interacciones Farmacológicas , Femenino , Glucosa/metabolismo , Cardiopatías/inducido químicamente , Humanos , Lípidos/sangre , Lupus Eritematoso Cutáneo/tratamiento farmacológico , Lupus Eritematoso Cutáneo/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/mortalidad , Masculino , Pandemias , Agregación Plaquetaria/efectos de los fármacos , Neumonía Viral/tratamiento farmacológico , Embarazo , Insuficiencia Renal/prevención & control , Enfermedades de la Retina/inducido químicamente , Síndrome de Sjögren/tratamiento farmacológico , Síndrome de Sjögren/inmunologíaRESUMEN
A sulfated polysaccharide from the red algae Gelidiella acerosa (GaSP) was obtained through enzymatic extraction and subjected to chemical characterization by HPSEC, elemental microanalysis, FT-IR and NMR spectroscopies. The GaSP anticoagulant activity was investigated through APTT and PT tests and platelet aggregation assessed by turbidimetry. The antithrombotic and hemorrhagic activities were evaluated by venous thrombosis and hemorrhagic tendency models, respectively. FT-IR and NMR demonstrated that GaSP is a sulfated agaran. HPSEC and elemental microanalysis revealed a peak molar mass of 284.8 kDa and a degree of sulfation of 0.63, respectively. This molecule prolonged the coagulation time in 2.1 times and inhibited the platelet aggregation by 45%. Furthermore, it showed significant dose-dependent antithrombotic effect of 40%, 64% and 80% at 0.1, 0.5 and 1 mg/kg, respectively, without hemorrhage. These results suggest that GaSP has promising antithrombotic.
Asunto(s)
Polisacáridos/química , Polisacáridos/farmacología , Rhodophyta/química , Sulfatos/química , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Pruebas de Coagulación Sanguínea , Femenino , Fibrinolíticos/química , Fibrinolíticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Peso Molecular , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-Actividad , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/etiologíaRESUMEN
Cardiovascular diseases are the leading cause of death in the world. Platelets have a major role in cardiovascular events as they bind to the damaged endothelium activating and forming thrombi. Although some hydroquinone scaffold-containing compounds have known antiplatelet activities, currently there is a lack of evidence on the antiplatelet activity of hydroquinones carrying electron attractor groups. In this work, we evaluate the antiplatelet effect of a series of ortho-carbonyl hydroquinone derivatives on cytotoxicity and function of human platelets, using collagen and thrombin receptor activator peptide 6 (TRAP-6) as agonists. Our structure-activity relationship study shows that gem-diethyl/methyl substitutions and the addition/modifications of the third ring of ortho-carbonyl hydroquinone scaffold influence on the selective index (IC50 TRAP-6/IC50 Collagen) and the inhibitory capacity of platelet aggregation. Compounds 3 and 8 inhibit agonist-induced platelet aggregation in a non-competitive manner with IC50 values of 1.77 ± 2.09 µM (collagen) and 11.88 ± 4.59 µM (TRAP-6), respectively and show no cytotoxicity. Both compounds do not affect intracellular calcium levels and mitochondrial bioenergetics. Consistently, they reduce the expression of P-selectin, activation of glycoprotein IIb/IIIa, and release of adenosine triphosphate and CD63 from platelet. Our findings may be used for further development of new drugs in platelet-related thrombosis diseases.
Asunto(s)
Colágeno/farmacología , Hidroquinonas/farmacología , Fragmentos de Péptidos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colágeno/química , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Hidroquinonas/síntesis química , Hidroquinonas/química , Estructura Molecular , Fragmentos de Péptidos/química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Relación Estructura-ActividadRESUMEN
Rivaroxaban is a direct oral anti-factor Xa anticoagulant. It has recently been suggested that rivaroxaban may affect platelet function in vitro; however, little is known about the clinical impact of this likely antiplatelet effect and whether this probable phenomenon is dose-dependent. Our aim was to determine whether rivaroxaban at 4 different doses inhibits direct platelet aggregation. We included adult patients of both sexes and who were allocated to one of the following groups depending on the prescribed daily dose of rivaroxaban: 5, 10, 15, and 20 mg. In 80 patients (20 patients/group), the percentage of platelet aggregation was determined by means of platelet aggregometry tests before and after rivaroxaban use. Basal samples were obtained before starting rivaroxaban and 1 month after treatment, both 2 and 24 hours after the last dose of the drug (12 hours after in the case of rivaroxaban 5 mg). We used 5 platelet agonists: adenosine diphosphate, epinephrine, arachidonic acid, collagen, and thrombin. There were no significant changes in the percentage of platelet aggregation before and after rivaroxaban use independently of the dose administered and the agonist used. Our results have clearly shown that rivaroxaban, even at a high dose, does not directly affect platelet aggregation.
Asunto(s)
Inhibidores del Factor Xa/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Rivaroxabán/administración & dosificación , Adolescente , Adulto , Anciano , Inhibidores del Factor Xa/efectos adversos , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas de Función Plaquetaria , Estudios Prospectivos , Rivaroxabán/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Common chronic conditions such as metabolic syndrome and diabetes are increasingly associated to metabolic and cardiovascular complications. Although Phyllanthus tenellus leaves have been used in decoctions as a popular remedy to control blood glucose levels and hypertension, its use needs a scientific basis. This study was therefore undertaken to report a phytochemical analysis of P. tenellus leaves and to test if the main active compound has potential to simultaneously tackle several pathophysiological features of metabolic syndrome and diabetes-related metabolic and vascular disorders such as hyperglycaemia, increased platelet activation, and endothelial dysfunction. We performed a partition of the methanolic extract of P. tenellus leaves among different organic solvents followed by chromatographic separation guided by the rat liver microsomal glucose-6-phosphatase assay. Two known tannins were identified by spectroscopic methods as pinocembrin-7-O-[3â³-O-galloyl-4â³,6â³-(S)-hexahydroxydiphenoyl]-α-D-glucose, named P7OG by us, and gemin D. The structural determination of the isolated compounds was based on spectral data. The ability of the main active component, P7OG, to inhibit human platelet aggregation and to modify vascular reactivity of rat aortic rings incubated with high glucose (D-glucose 55 mM) was then evaluated. P7OG was further able to inhibit platelet aggregation induced by adenosine 5'-diphosphate and collagen, showed vasorelaxant effects in arteries precontracted with phenylephrine, and reverted the endothelium-dependent impairment effect of high glucose in rat aortic rings. In conclusion, one tannin isolated from P. tenellus showed promising metabolic, antiaggregant, and vascular effects, which suggests the potential beneficial use of P. tenellus to tackle complex cardiometabolic diseases.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Metabolismo/efectos de los fármacos , Phyllanthus/química , Extractos Vegetales/farmacología , Adulto , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Humanos , Masculino , Síndrome Metabólico/tratamiento farmacológico , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Agregación Plaquetaria/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Heart attack, stroke, and deep vein thrombosis are among the conditions that alter blood coagulation and are modulated by antithrombogenic drugs. Natural products are an important source of antithrombogenic agents and have been considered remarkable alternatives with greater efficacy and usually with fewer side effects. However, the efficacy and toxicity of many of these plants that are used in traditional medicine must be scientifically tested. Despite a large number of published articles that report that plants or plant-derived components may act as antithrombogenic agents, few studies have investigated the mechanism of action of medicinal plants. This review presents the current knowledge about the major cellular and molecular mechanisms of antithrombogenic plants and their main components. Many well-established mechanisms (e.g., platelet aggregation, coagulation factors, and thrombolysis) are related to the antithrombogenic activity of many natural products. However, the central pathways that are responsible for their activity remain unclear. Further studies are needed to clarify the central role of each of these pathways in the pleiotropic response to these agents.