RESUMO
Monosialoganglioside GM1 (GM1) has long been used as a therapeutic agent for neurological diseases in the clinical treatment of ischemic stroke. However, the mechanism underlying the neuroprotective function of GM1 is still obscure until now. In this study, we investigated the effects of GM1 in ischemia and reperfusion (I/R) brain injury models. Middle cerebral artery occlusion and reperfusion (MCAO/R) rats were treated with GM1 (60 mg·kg-1·d-1, tail vein injection) for 2 weeks. The results showed that GM1 substantially attenuated the MCAO/R-induced neurological dysfunction and inhibited the inflammatory responses and cell apoptosis in ischemic parietal cortex. We further revealed that GM1 inhibited the activation of NFκB/MAPK signaling pathway induced by MCAO/R injury. To explore its underlying mechanism of the neuroprotective effect, transcriptome sequencing was introduced to screen the differentially expressed genes (DEGs). By function enrichment and PPI network analyses, Sptbn1 was identified as a node gene in the network regulated by GM1 treatment. In the MCAO/R model of rats and oxygen-glucose deprivation and reperfusion (OGD/R) model of primary culture of rat cortical neurons, we first found that SPTBN1 was involved in the attenuation of I/R induced neuronal injury after GM1 administration. In SPTBN1-knockdown SH-SY5Y cells, the treatment with GM1 (20 µM) significantly increased SPTBN1 level. Moreover, OGD/R decreased SPTBN1 level in SPTBN1-overexpressed SH-SY5Y cells. These results indicated that GM1 might achieve its potent neuroprotective effects by regulating inflammatory response, cell apoptosis, and cytomembrane and cytoskeleton signals through SPTBN1. Therefore, SPTBN1 may be a potential target for the treatment of ischemic stroke.
Assuntos
Gangliosídeo G(M1) , Neurônios , Fármacos Neuroprotetores , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Transdução de Sinais , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Gangliosídeo G(M1)/farmacologia , Masculino , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Ratos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Espectrina/metabolismoRESUMO
Research background: Chilling injury is a major disorder affecting the quality of tropical and subtropical vegetables during low temperature storage. Snap bean (Phaseolus vulgaris L.) is sensitive to chilling injury. The main purpose of the present study is to investigate the alleviating effects of 1-methylcyclopropene (1-MCP) on chilling injury of snap bean. In addition, the related mechanisms were also detected from the perspective of the changes of antioxidant defense system. Experimental approach: Snap beans were exposed to different volume fractions of 1-MCP. After 24 h of treatment, snap beans were stored at 4 °C for up to 14 days. Chilling injury index, electrolyte leakage, titratable acidity and total soluble solids were determined. Contents of chlorophyll, ascorbic acid and malondialdehyde were assessed. The total antioxidant capacity, Fe(II) ion chelating capacity, scavenging capacities on free radicals and activities of antioxidant enzymes were detected. Total phenol content and activities of related metabolic enzymes were also determined. Results and conclusions: 1-MCP treatment reduced chilling injury index, electrolyte leakage rate and malondialdehyde content of snap beans. The amounts of total soluble solids, titratable acid, ascorbic acid and total chlorophyll in 1-MCP-treated snap beans were significantly higher than those of control. The snap beans treated with 1-MCP showed stronger total antioxidant capacity and metal chelating activity. The 1-MCP treatment enhanced scavenging effects of snap beans on superoxide, hydroxyl and 1,1-diphenyl-2-trinitrophenylhydrazine radicals. The activities of peroxidase, ascorbate peroxidase, superoxide dismutase and catalase in 1-MCP-treated group were higher than of control. The treatment also enhanced the accumulation of phenolic compounds in snap beans by regulating the activities of phenol-metabolizing enzymes such as shikimate dehydrogenase, phenylalanine ammonia lyase enzyme, cinnamic acid 4-hydroxylase and polyphenol oxidase. In conclusion, with the mechanism that involves the activation of enzymatic and non-enzymatic antioxidant systems, 1-MCP has the ability to avoid chilling injury of snap bean. Novelty and scientific contribution: This study gives insights into whether 1-MCP can regulate postharvest cold resistance in vegetables by enhancing the enzymatic antioxidant system and inducing the accumulation of non-enzymatic antioxidants. Considering the results, 1-MCP treatment could be an effective method to alleviate postharvest chilling injury of snap beans during low temperature storage.
RESUMO
To explore the micromechanism of the structural changes of anthracite due to heat accumulation by water and pyrite, during oxidation, anthracite with coal samples was selected in this work from Baijiao Coalmine, Sichuan, China. The samples were added with water of 1, 5, 10, 15, and 20 mass % and pyrite of 1, 2, 4, and 6 mass % and were conducted to experimented torts. As compared with the raw coal sample, the effects of water and pyrite on the microstructure of anthracite were studied. The results indicate that the oxygen-containing functional group of coal increases with the addition of water. The content of the aromatic structure in coal was thought to be due to water and pyrite synergistic effects. The synergistic effect of water and pyrite accelerates the oxidation process of seven types of active groups in coal samples. The water content was 10-15 mass %, and the associated pyrite content was 2-4 mass %; the contribution to the oxidation activity of the main active groups of coal was the largest under oxidizing conditions.
RESUMO
Toll-like receptor 4 (TLR4) and C5aR1 (CD88) have been recognized as potential therapeutic targets for the reduction of inflammation and secondary damage and improvement of outcome after ischemia and reperfusion (I/R). The inflammatory responses which induce cell apoptosis and necrosis after I/R brain injury lead to a limited process of neural repair. To further comprehend how these targets function in I/R state, we investigated the pathological changes and TLR4 and C5aR1 signaling pathways in vitro and in vivo models of I/R brain injury in this study. Meanwhile, we explored the roles of schisantherin A on I/R brain injury, and whether it exerted neuroprotective effects by regulating the TLR4 and C5aR1 signaling pathways or not. The results showed that schisantherin A significantly reduced the neuronal apoptosis induced by oxygen and glucose deprivation and reperfusion (OGD/R) injury in primary culture of rat cortical neurons. Also, schisantherin A alleviated neurological deficits, reduced infarct volume, attenuated oxidation stress, inflammation and apoptosis in ischemic parietal cortex of rats after middle cerebral artery occlusion and reperfusion (MCAO/R) injury. Moreover, the activated TLR4 and C5aR1 signaling pathways were inhibited by schisantherin A treatment. In conclusion, TLR4 and C5aR1 played a vital role during I/R brain injury in rats, and schisantherin A exhibited neuroprotective effects by TLR4 and C5aR1 signaling pathways. These findings also provided new insights that would aid in elucidating the effect of schisantherin A against cerebral I/R and support the development of schisantherin A as a potential treatment for ischemic stroke.
Assuntos
Isquemia Encefálica/metabolismo , Ciclo-Octanos/administração & dosagem , Dioxóis/administração & dosagem , Lignanas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Receptor da Anafilatoxina C5a/metabolismo , Traumatismo por Reperfusão/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/prevenção & controle , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Inflamação/etiologia , Inflamação/metabolismo , Necrose/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/metabolismo , Lobo Parietal/patologia , Cultura Primária de Células , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/prevenção & controle , Transdução de SinaisRESUMO
Ischemic stroke is a major disability and cause of death worldwide due to its narrow therapeutic time window. Neuroprotective agent is a promising strategy to salvage acutely ischemic brain tissue and extend the therapeutic time window for stroke treatment. In this study, we aimed to evaluate the neuroprotective effects of isoquercetin in (1) primary culture of rat hippocampal neurons exposure on oxygen and glucose deprivation and reperfusion (OGD/R) injury and (2) rats subjected to transient middle cerebral artery occlusion and reperfusion (MCAO/R) injury. The results showed that isoquercetin post-treatment reduced the infarct size, number of apoptotic cells, oxidative stress, and inflammatory response after ischemia and reperfusion injury. The underlying mechanism study indicated that the neuroprotective effects of isoquercetin were elicited via suppressing the activation of toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB) and caspase-1; the phosphorylation of ERK1/2, JNK1/2, and p38 mitogen-activated protein kinase (MAPK); and the secretion of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6. In addition, isoquercetin also effectively alleviated hippocampus neuron apoptosis by regulation of cyclic AMP responsive element-binding protein (CREB), Bax, Bcl-2, and caspase-3. Our report provided new considerations into the therapeutic action and the underlying mechanisms of isoquercetin to improve brain injury in individuals who have suffered from ischemic stroke. As a potent anti-inflammatory and anti-oxidative compound with neuroprotective capacities, the beneficial effects of isoquercetin when used to treat ischemic stroke and related diseases in humans warrant further studies.
Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/análogos & derivados , Animais , Isquemia Encefálica/patologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Células Cultivadas , Inflamação/tratamento farmacológico , Isquemia/tratamento farmacológico , Masculino , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologiaRESUMO
Brain ischemia appears to be associated with innate immunity. Recent reports showed that C3a and C5a, as potent targets, might protect against ischemia induced cell death. In traditional Chinese medicine, the fruit of Schizandra chinesis Baill (Fructus schizandrae) has been widely used as a tonic. In the present study, we sought to evaluate the neuroprotective effects of schizandrin A, a composition of S. chinesis Baill, against oxygen and glucose deprivation followed by reperfusion (OGD/R)-induced cell death in primary culture of rat cortical neurons, and to test whether C3a and C5a affected cortical neuron recovery from ischemic injury after schizandrin A treatment. The results showed that schizandrin A significantly reduced cell apoptosis and necrosis, increased cell survival, and decreased intracellular calcium concentration ([Ca(2+)]i) and lactate dehydrogenase (LDH) release in primary culture of rat cortical neurons after OGD/R. Mechanism studies suggested that the modulation of extracellular-regulated kinase (ERK), c-Jun NH2-terminal kinases (JNK), and p38, as well as caspase-3 activity played an important role on the progress of neuronal apoptosis. C5aR participated in the neuroprotective effect of schizandrin A in primary culture of rat cortical neurons after OGD/R. Our findings suggested that schizandrin A might act as a candidate therapeutic target drug used for brain ischemia and related diseases.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Ciclo-Octanos/farmacologia , Lignanas/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos Policíclicos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Cálcio/metabolismo , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glucose/metabolismo , L-Lactato Desidrogenase/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Medicina Tradicional Chinesa , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fitoterapia , Ratos , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Schisandra , Transdução de Sinais/efeitos dos fármacosRESUMO
Mulberroside A is a natural polyhydroxylated stilbene compound present at relatively high abundance in the roots and twigs of Morus alba L. It is known for its nephroprotective, hypoglycemic, and antidiabetic effects. Because its metabolite, oxyresveratrol, possessed purported anti-inflammatory and neuroprotective effects, we proposed that mulberroside A may elicit neuroprotective effects that can be used in the treatment of brain ischemic injury. Therefore, we decided to investigate the pharmacological properties of mulberroside A in primary culture of rat cortical neurons after oxygen-glucose deprivation followed by reperfusion (OGD/R), evaluating its ability to counteract the hypoxia-ischemia impairment. The results showed that mulberroside A elicited neuroprotective effects comparable to nimodipine. The mechanistic studies showed that mulberroside A decreased the expressions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 and inhibited the activation of NALP3, caspase-1, and nuclear factor-κB and the phosphorylation of extracellular signal-regulated protein kinases, the c-Jun N-terminal kinase, and p38, exhibiting anti-inflammatory antiapoptotic effects. Our results also further demonstrate that the proinflammatory cytokines of IL-1ß, IL-6, and TNF-α are promising targets for treatment of cerebral ischemic injury. Although further investigation is required for its development, all of these findings led us to speculate that mulberroside A is a candidate for the treatment of ischemic stroke, which would act as a multifactorial neuroprotectant.
Assuntos
Córtex Cerebral/citologia , Dissacarídeos/farmacologia , Glucose/deficiência , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas de Transporte , Caspase 1/metabolismo , Hipóxia Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Embrião de Mamíferos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In the present study, oxygen-glucose deprivation followed by reperfusion (OGD/R), an in vitro model of ischemia, was used to evaluate the neuroprotective effect of isoquercetin in primary culture of rat cortical neuronal cells. It was found that isoquercetin administered prior to the insult could prevent OGD/R-induced intracellular calcium concentrations ([Ca(2+)]i) increase, lactate dehydrogenase (LDH) release and cell viability decrease. For the first time, isoquercetin is described as a neuroprotective agent that potentially explains the alleviation and prevention from OGD/R-induced injury in neurons. Mechanistic studies showed that the neuroprotective effect of isoquercetin was carried out by anti-inflammatory signaling pathway of inhibiting protein expression of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB), and mRNA expression of TNF-α and IL-6, accompanied by the anti-apoptotic signaling pathway of deactivation of extracellular-regulated kinase (ERK), Jun kinase (JNK) and p38, and inhibition of activity of caspase-3. Therefore, these studies highlighted the confirmation of isoquercetin, a flavonoid compound, as an anti-inflammation and anti-apoptosis factor which might be used as a therapeutic strategy for the ischemia/reperfusion (I/R) brain injury and related diseases.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Glucose/metabolismo , Neurônios/efeitos dos fármacos , Oxigênio/metabolismo , Quercetina/farmacologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Sequência de Bases , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Primers do DNA , NF-kappa B/metabolismo , Neurônios/metabolismo , Quercetina/química , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ramulus Mori, the branch of Morus alba, is widely used in traditional Chinese medicine prescriptions to treat gout and hyperuricemia. AIM OF THIS STUDY: To evaluate the uricosuric and nephroprotective effects of ethanol extract of Ramulus Mori (ERM) and explore its possible mechanisms in hyperuricemic mice. MATERIALS AND METHODS: HPLC analysis was employed to determine the main constituents. Hyperuricemia was induced by potassium oxonate (250 mg/kg) in male mice. ERM (10, 20 and 40 mg/kg) was orally administered to hyperuricemic and normal mice for 7 days. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Simultaneously, renal mRNA and protein levels of mouse urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9), organic anion transporter 1 (mOAT1) and organic cation/carnitine transporters (mOCT1/2, mOCTN1/2) were analyzed by RT-PCR and Western blotting methods. RESULTS: ERM mainly contained mulberroside A, oxyresveratrol, 4-hydroxycinnamic acid, resveratrol, 7-hydroxycumarin and morin. ERM significantly reduced serum urate levels and increased 24h-urine urate excretion and fractional excretion of uric acid in hyperuricemic mice. It effectively restored oxonate-induced expression alteration of renal mURAT1, mGLUT9 and mOAT1, resulting in urate excretion enhancement. Moreover, ERM decreased serum creatinine and BUN levels and increased creatinine clearance, and up-regulated expression of mOCT1/2 and mOCTN1/2, contributing to kidney function improvement in this model. CONCLUSION: These results suggest that ERM exerts the uricosuric and nephroprotective actions by the regulation of these renal organic ion transporters in hyperuricemic mice, and provide scientific support for the empirical use of Ramulus Mori.
Assuntos
Hiperuricemia/tratamento farmacológico , Morus , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Creatinina/urina , Etanol/química , Hiperuricemia/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Fitoterapia , Extratos Vegetais/análise , Substâncias Protetoras/análise , Solventes/química , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
SCOPE: Stilbenes, of which, resveratrol is a representative compound in foods and plants, possess a variety of bioactivities including antioxidation, anti-inflammation, chemoprevention, and cardioprotection. This study was conducted to evaluate the antihyperuricemic and nephroprotective effects of resveratrol and its analogues and explore the possible mechanisms. The structure-activity relationships were analyzed. METHODS AND RESULTS: Potassium oxonate-induced hyperuricemic mice were dosed by gavage with eight stilbenes. Uric acid, creatinine, and blood urea nitrogen (BUN) levels in serum and urine, clearance rate of creatinine and BUN, 24-h urate excretion, and fractional excretion of uric acid, uromodulin levels in urine and kidney were determined to evaluate renal urate handling and function. Renal protein levels of organic ion transporters were detected to elucidate the possible mechanisms. Resveratrol, trans-4-hydroxystilbene, pterostilbene, polydatin, and mulberroside A were found to have antihyperuricemic activities. These compounds together with trans-2-hydroxystilbene provided nephroprotection. Trans-3,4',5-trimethoxystilbene and cis-combretastatin A-4 had no effects. CONCLUSION: The uricosuric and nephroprotective actions of resveratrol and its analogues were mediated by regulating renal organic ion transporters in hyperuricemic mice, supporting their beneficial effects for the prevention of hyperuricemia. The number and position, methoxylation and glycosylation of hydroxyl groups in these trans-stilbenes were required for their effects.
Assuntos
Supressores da Gota/farmacologia , Hiperuricemia/tratamento farmacológico , Estilbenos/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Creatinina/sangue , Creatinina/urina , Dissacarídeos/farmacologia , Regulação da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucosídeos/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/genética , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico , Ácido Oxônico , Resveratrol , Membro 5 da Família 22 de Carreadores de Soluto , Simportadores , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
OBJECTIVE: To investigate the relationship between post-stenting coronary thrombolysis in myocardial infarction (TIMI) flow and plasma von Willebrand factor (vWF) and its cleaving protease (ADAMTS-13) levels in patients with ST segment elevation myocardial infarction (STEMI). METHODS: STEMI patients who underwent primary percutaneous coronary intervention (PCI) and stenting between September, 2007 and December, 2009 were enrolled. According to the post-stenting TIMI flow, patients were divided to TIMI ≤ 2 group (n = 43) and TIMI 3 group (n = 43). Patients with chest pain or dyspnea and normal coronary angiographic results served as control group (n = 43). The levels of vWF and ADAMTS-13 were measured by ELISA at three time points: immediately after admission, beginning of PCI and 1 week after PCI. RESULTS: Levels of vWF in STEMI patients at all 3 time points were significantly higher than in control patients, and the level of vWF was significantly higher in TIMI ≤ 2 group than in TIMI 3 group [at admission: (6721.83 ± 1380.58) U/L vs. (4786.12 ± 2362.01) U/L, P < 0.05; at the beginning of PCI: (5744.65 ± 1240.71) U/L vs. (3011.33 ± 2270.40) U/L, P < 0.05 and at 1 week after PCI: (2001.48 ± 931.70) U/L vs. (1365.17 ± 724.12) U/L, P < 0.05]. ADAMTS-13 levels were similar among groups at admission and at beginning of PCI, however, the level of ADAMTS-13 at 1 week after PCI was significantly higher in TIMI ≤ 2 group than that in TIMI 3 group [(406.93 ± 101.44) mg/L vs. (270.34 ± 115.12) mg/L, P < 0.001]. Logistic regression analysis showed that both vWF at admission (OR = 1.917, P < 0.01) and vWF at the beginning of PCI (OR = 2.016, P < 0.01) were risk factors of TIMI ≤ 2. CONCLUSION: Increased vWF during peri-PCI periods was associated with post-stenting coronary TIMI ≤ 2 after primary PCI in STEMI patients, and the imbalance between vWF and ADAMTS-13 may thus play an important role in the development of slow flow post PCI.
Assuntos
Proteínas ADAM/sangue , Circulação Coronária , Infarto do Miocárdio/sangue , Fator de von Willebrand/metabolismo , Proteína ADAMTS13 , Idoso , Angioplastia Coronária com Balão , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapiaRESUMO
Mulberroside A is a major stilbene glycoside of MORUS ALBA L. (Moraceae), which is effectively used for the treatment of hyperuricemia and gout in traditional Chinese medicine. We examined whether mulberroside A had effects on renal urate underexcretion and dysfunction in oxonate-induced hyperuricemic mice and investigated the potential uricosuric and nephroprotective mechanisms involved. Mulberroside A at 10, 20, and 40 mg/kg decreased serum uric acid levels and increased urinary urate excretion and fractional excretion of uric acid in hyperuricemic mice. Simultaneously, it reduced serum levels of creatinine and urea nitrogen (10-40 mg/kg), urinary N-acetyl- ß-D-glucosaminidase activity (10-40 mg/kg), ß2-microglobulin (10-40 mg/kg) and albumin (20-40 mg/kg), and increased creatinine clearance (10-40 mg/kg) in hyperuricemic mice. Furthermore, mulberroside A downregulated mRNA and protein levels of renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1), and upregulated mRNA and protein levels of renal organic anion transporter 1 (mOAT1) and organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1, and mOCTN2) in hyperuricemic mice. This is the first study demonstrating that mulberroside A exhibits uricosuric and nephroprotective effects mediated in part by cooperative attenuation of the expression alterations of renal organic ion transporters in hyperuricemic mice. These data suggest that mulberroside A may be a new drug candidate for the treatment of hyperuricemia with renal dysfunction.
Assuntos
Dissacarídeos/farmacologia , Hiperuricemia/tratamento farmacológico , Nefropatias/prevenção & controle , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Uricosúricos/farmacologia , Acetilglucosaminidase/urina , Albuminúria/urina , Animais , Nitrogênio da Ureia Sanguínea , Proteínas de Transporte/biossíntese , Creatinina/sangue , Dissacarídeos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Morus/química , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Transportador 2 de Cátion Orgânico , Substâncias Protetoras/isolamento & purificação , Membro 5 da Família 22 de Carreadores de Soluto , Estilbenos/isolamento & purificação , Simportadores , Ácido Úrico/sangue , Ácido Úrico/urina , Microglobulina beta-2/urinaRESUMO
PURPOSE: Morin (2',3,4',5,7-pentahydroxyflavone), a plant-derived flavonoid, has beneficial effects on hyperuricemia and renal dysfunction in animals. Since the decreased renal excretion of uric acid is the hallmark of hyperuricemia, here we studied the effects of oral morin administration on renal organic ion transporters in potassium oxonate-induced hyperuricemic mice. METHODS: Hyperuricemia in mice was induced by potassium oxonate. Uric acid and creatinine concentrations in urine and serum, and fractional excretion of uric acid (FEUA) were performed to evaluate renal urate handling. Changes in expression levels of renal organic ion transporters were detected by Western blotting and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) methods. RESULTS: Morin treatment significantly increased urinary uric acid/creatinine ratio and FEUA, resulting in reduction of serum uric acid levels in hyperuricemic mice. And kidney conditions were also improved after morin treatment in this model. Protein and mRNA levels of glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) were significantly decreased, and of organic anion transporter 1 (mOAT1) were remarkably increased in the kidney of morin-treated hyperuricemic mice. Morin treatment also blocked down-regulations of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in hyperuricemic mice. CONCLUSION: These results suggest that morin exhibits the uricosuric effects via suppressing urate reabsorption and promoting urate secretion in the kidney of hyperuricemic mice and may help to attenuate deleterious effects of hyperuricemia with renal dysfunction.
Assuntos
Flavonoides/administração & dosagem , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/metabolismo , Rim/efeitos dos fármacos , Transportadores de Ânions Orgânicos/metabolismo , Ácido Úrico/urina , Animais , Creatinina/sangue , Creatinina/urina , Regulação para Baixo/efeitos dos fármacos , Flavonoides/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Hiperuricemia/induzido quimicamente , Hiperuricemia/genética , Transporte de Íons/efeitos dos fármacos , Rim/metabolismo , Testes de Função Renal , Masculino , Camundongos , Transportadores de Ânions Orgânicos/genética , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Fenômenos Fisiológicos do Sistema UrinárioRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Sanmiao wan (SMW) is widely used for the treatment of gout and hyperuricemia in traditional Chinese medicine. AIM OF THE STUDY: The aim of the present study was to investigate the hypouricemic effects of SMW and its possible mechanism in potassium oxonate-induced hyperuricemic mice. MATERIALS AND METHODS: SMW at 489, 978 and 1956 mg/kg was orally administered to hyperuricemic and normal mice, and standard drug allopurinol (2.5mg/kg) was served as a positive control. The effects of SMW on serum, urine and liver levels of uric acid, serum levels of creatinine, and activity of hepatic xanthine oxidase (XOD) were measured in mice. Moreover, the effects of SMW on the mRNA and protein levels of hepatic XOD and renal urate transporter 1 (mURAT1) in mice were analyzed by semi-quantitative RT-PCR and Western blotting methods, respectively. RESULTS: SMW significantly reduced uric acid levels in serum and liver, inhibited hepatic XOD activity, mRNA and protein levels in hyperuricemic mice. Furthermore, SMW could effectively down-regulate renal mURAT1 mRNA and protein levels of hyperuricemic mice. And it reversed oxonate-induced elevation in serum creatinine levels of mice. However, SMW did not show any effects in normal mice. CONCLUSION: These findings suggested that SMW produced dual hypouricemic actions by suppressing hepatic XOD to reduce uric acid production and down-regulating renal mURAT1 to decrease urate reabsorption and enhance urate excretion in hyperuricemic mice.
Assuntos
Alopurinol/farmacologia , Regulação para Baixo , Supressores da Gota/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Medicina Tradicional Chinesa , Transportadores de Ânions Orgânicos/metabolismo , Xantina Oxidase/metabolismo , Animais , Sequência de Bases , Western Blotting , Cromatografia Líquida de Alta Pressão , Primers do DNA , Rim/enzimologia , Fígado/enzimologia , Masculino , Camundongos , Transportadores de Ânions Orgânicos/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Magnolia bark combined with ginger rhizome is a common drug pair in traditional Chinese prescriptions for the treatment of depression. In the present study, we examined antidepressant-like effects of the mixture of honokiol and magnolol (HMM) from magnolia bark and essential oil from ginger rhizome (OGR) alone and in combination in chronic unpredictable mild stress (CUMS) of rats. Behavioral (sucrose intake, immobility time of forced swimming test) and biochemical parameters [serotonin (5-HT) in prefrontal cortex, hippocampus, and striatum, gastric mucosa cholecystokinin (CCK) and serum gastrin (GAS) levels] were simultaneously examined in the CUMS rats. 20 mg/kg HMM alone, but not OGR, significantly increased sucrose intake and reduced immobility time in the CUMS rats. Moreover, 20 mg/kg HMM and 14 mg/kg OGR in combination exhibited significant synergistic effects on sucrose intake increase and immobility time reduction in the CUMS rats. HMM elevated 5-HT levels in various brain regions, and OGR reduced gastric mucosa CCK and serum GAS levels in the CUMS rats. These results suggested that the synergistic antidepressant-like effects of compatibility of HMM with OGR might be mediated simultaneously by regulation of the serotonergic and gastroenteric system functions. These findings also provided a pharmacological basis for the clinical application of this drug pair of magnolia bark and ginger rhizome in traditional Chinese medicine.
Assuntos
Antidepressivos/farmacologia , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Óleos Voláteis/farmacologia , Zingiber officinale , Animais , Compostos de Bifenilo/administração & dosagem , Encéfalo/efeitos dos fármacos , Colecistocinina/análise , Depressão/tratamento farmacológico , Sinergismo Farmacológico , Quimioterapia Combinada , Mucosa Gástrica/química , Mucosa Gástrica/efeitos dos fármacos , Gastrinas/sangue , Lignanas/administração & dosagem , Masculino , Óleos Voláteis/administração & dosagem , Ratos , Ratos Wistar , Serotonina/análise , NataçãoRESUMO
Honokiol and magnolol are the main constituents simultaneously identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. In the present study, we reported on the antidepressant-like effects of oral administration of the mixture of honokiol and magnolol in well-validated models of depression in rodents: forced swimming test (FST), tail suspension test (TST) and chronic mild stress (CMS) model. The mixture of honokiol and magnolol significantly decreased immobility time in the mouse FST and TST, and reversed CMS-induced reduction in sucrose consumption to prevent anhedonia in rats. However, this mixture was unable to affect ambulatory or rearing behavior in the mouse open-field test. CMS induced alterations in 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions of rats. An increase in serum corticosterone concentrations and a reduction in platelet adenylyl cyclase (AC) activity were simultaneously found in the CMS rats. The mixture of honokiol and magnolol at 20 and 40 mg/kg significantly attenuated CMS-induced decreases of 5-HT levels in frontal cortex, hippocampus, striatum, hypothalamus and nucleus accumbens. And it markedly increased 5-HIAA levels in frontal cortex, striatum and nucleus accumbens at 40 mg/kg and in frontal cortex at 20 mg/kg in the CMS rats. A subsequent reduction in 5-HIAA/5-HT ratio was found in hippocampus and nucleus accumbens in the CMS rats receiving this mixture. Furthermore, the mixture of honokiol and magnolol reduced elevated corticosterone concentrations in serum to normalize the hypothalamic-pituitary-adrenal (HPA) hyperactivity in the CMS rats. It also reversed CMS-induced reduction in platelet AC activity, via upregulating the cyclic adenosine monophosphate (cAMP) pathway. These results suggested that the mixture of honokiol and magnolol possessed potent antidepressant-like properties in behaviors involved in normalization of biochemical abnormalities in brain 5-HT and 5-HIAA, serum corticosterone levels and platelet AC activity in the CMS rats. Our findings could provide a basis for examining directly the interaction of the serotonergic system, the HPA axis and AC-cAMP pathway underlying the link between depression and treatment with the mixture of honokiol and magnolol.