RESUMO
In this study, the neuroprotective effect of an extract of Antrodia camphorata (A. camphorata), a fungus commonly used in Chinese folk medicine for treatment of viral hepatitis and cancer, alone or in combination with aspirin was investigated in a rat embolic stroke model. An ischemic stroke was induced in rats by a selective occlusion of the middle cerebral artery (MCA) with whole blood clots and then orally treated with A. camphorata (0.25 and 0.75 g/kg/day) alone and combined with aspirin (5 mg/kg/day). Sixty days later, the brains were removed, sectioned, and stained with triphenyltetrazolium chloride and analysed by a commercial image processing software program. Brain infarct volume, neurobehavioral score, cerebral blood perfusion, and subarachnoid and intracerebral hemorrhage incidence were perceived. In addition, potential bleeding side effect of the combinative therapy was assessed by measuring hemoglobin (Hb) content during intracerebral hemorrhage and gastric bleeding, prothrombin time (PT), and occlusion time (OT) after oral administration. Posttreatment with high dose A. camphorata significantly reduced infarct volume and improved neurobehavioral score (P < 0.05). Since A. camphorata alone or with aspirin did not alter the Hb level, this treatment is safe and does not cause hemorrhagic incident. Remarkably, the combination of A. camphorata and aspirin did not show a significant effect on the bleeding time, PT and OT increase suggesting that A. camphorata may have the neuroprotective effect without the prolongation of bleeding time or coagulation time. From these observations, we suggest that combinative therapy of A. camphorata and aspirin might offer enhanced neuroprotective efficacies without increasing side effects.
Assuntos
Antrodia/química , Aspirina/uso terapêutico , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Encéfalo/patologia , Quimioterapia Combinada , Hemoglobinas/metabolismo , Hemorragia/induzido quimicamente , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/isolamento & purificação , Tempo de Protrombina , Ratos Wistar , Acidente Vascular Cerebral/complicaçõesRESUMO
Xanthohumol is the principal prenylated flavonoid in the hop plant (Humulus lupulus L.). Xanthohumol was found to be a very potent cancer chemopreventive agent through regulation of diverse mechanisms. However, no data are available concerning the effects of xanthohumol on platelet activation. The aim of this paper was to examine the antiplatelet effect of xanthohumol in washed human platelets. In the present paper, xanthohumol exhibited more-potent activity in inhibiting platelet aggregation stimulated by collagen. Xanthohumol inhibited platelet activation accompanied by relative [Ca(2+)](i) mobilization, thromboxane A(2) formation, hydroxyl radical (OH(â)) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Neither SQ22536, an inhibitor of adenylate cyclase, nor ODQ, an inhibitor of guanylate cyclase, reversed the xanthohumol-mediated inhibitory effect on platelet aggregation. Furthermore, xanthohumol did not significantly increase nitrate formation in platelets. This study demonstrates for the first time that xanthohumol possesses potent antiplatelet activity which may initially inhibit the PI3-kinase/Akt, p38 MAPK, and PLCγ2-PKC cascades, followed by inhibition of the thromboxane A(2) formation, thereby leading to inhibition of [Ca(2+)](i) and finally inhibition of platelet aggregation. Therefore, this novel role of xanthohumol may represent a high therapeutic potential for treatment or prevention of cardiovascular diseases.
RESUMO
BACKGROUND: 3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin) may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved. METHODS: The aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin. RESULTS: Simvastatin (20-50 microM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin). Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca2+]i mobilization, thromboxane A2 (TxA2) formation, and phospholipase C (PLC)gamma2, protein kinase C (PKC), and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs) phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and endothelial nitric oxide synthase (eNOS) expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCgamma2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation. CONCLUSION: The most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in inhibition of the PLCgamma2-PKC-p38 MAPK-TxA2 cascade, and finally inhibition of platelet aggregation.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/sangue , Nucleotídeos Cíclicos/sangue , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Sinvastatina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Moléculas de Adesão Celular/sangue , Colágeno/farmacologia , AMP Cíclico/sangue , GMP Cíclico/sangue , Humanos , Radical Hidroxila/sangue , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas dos Microfilamentos/sangue , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/sangue , Fosfolipase C gama/sangue , Fosfoproteínas/sangue , Inibidores da Agregação Plaquetária/farmacologia , Proteína Quinase C/sangue , Transdução de Sinais/efeitos dos fármacos , Tromboxano A2/sangueRESUMO
The intracellular mechanisms underlying the signaling pathways of activated matrix metalloproteinase-9 (MMP-9) in platelets are not yet completely understood. Therefore, the aim of this study was to further examine the effects of activated MMP-9 in preventing platelet aggregation. In this study, activated MMP-9 time-dependently (3-60 min) inhibited platelet aggregation in washed human platelet suspensions stimulated by agonists. However, activated MMP-9 had no significant effect on the binding of FITC-triflavin to the platelet glycoprotein IIb/IIIa complex. Triflavin is a specific antagonist of the glycoprotein IIb/IIIa complex purified from snake venom. Moreover, activated MMP-9 (21 and 90 ng/ml) markedly decreased the fluorescence intensity of platelet membranes tagged with diphenylhexatriene. The thrombin-evoked increase in pHi was inhibited in the presence of activated MMP-9 (21 and 90 ng/ml). In addition, activated MMP-9 (21 and 90 ng/ml) markedly reduced the electron spin resonance (ESR) signal intensity of hydroxyl radicals in collagen (1 mug/ml)-activated platelets. These results indicate that the antiplatelet activity of activated MMP-9 may involve the following pathways: (1) activated MMP-9 may initially induce conformational changes in platelet membranes and hydroxyl radical formation, leading to inhibition of platelet aggregation; and (2) activated MMP-9 also inhibits the Na(+)/H(+) exchanger, leading to reduced intracellular Ca(2+) mobilization, and ultimately to inhibition of platelet aggregation. This study further provides new insights concerning the effects of activated MMP-9 on platelet aggregation.
Assuntos
Metaloproteinase 9 da Matriz/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Células Cultivadas , Humanos , Concentração de Íons de Hidrogênio , Radical Hidroxila/metabolismo , L-Lactato Desidrogenase/análise , Fluidez de Membrana/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismoAssuntos
Artrite Infecciosa/etiologia , Vacina BCG/efeitos adversos , Tuberculose/etiologia , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/diagnóstico por imagem , Artrocentese , Humanos , Lactente , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/microbiologia , Imageamento por Ressonância Magnética , Masculino , Mycobacterium bovis , Taiwan , Tuberculose/diagnóstico , Tuberculose/diagnóstico por imagemRESUMO
Five hundred ninety-eight consecutive primary low contact stress total knee replacements were done in 502 patients between 1985 and 1990. Clinical review was available for 495 knees (406 patients), 228 knees with meniscal-bearing prostheses and 267 knees with rotating-platform prostheses. The average followup was 12 years (range, 10-15 years). The average postoperative knee and functional scores were 87 points and 75 points, respectively. The average postoperative range of motion was 110 degrees. Fifty-six knees (11%) required revision for excessive wear of the tibial insert (41), dislocation (10), patellar polyethylene breakage (one), component loosening (one patellar, one tibial), and infection (two). During revision, osteolysis (20 knees), patellar polyethylene failure (33), and femoral component fracture (one) were seen. The overall survivorship was 88.1% at 15 years using Kaplan-Meier analysis. The survival rate was 83% for the meniscal-bearing prostheses and 92.1% for the rotating-platform prostheses. The Low Contact Stress mobile-bearing knee prosthesis has no superiority over that of fixed-bearing knees, especially for the meniscal-bearing design in prevention of polyethylene failure or revision. Based on the results of this study, the use of the LCS meniscal-bearing prosthesis does not appear to be justified.