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1.
Rejuvenation Res ; 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-29804491

RESUMO

Terminalia chebula (TC), a kind of Combretaceae, is a widely used herb in India and East Asia to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of TC at the metabonomics level is still not clear. The present study focused on the effects of TC on metabonomics in a stroke model. Rats were divided randomly into sham, model, and TC groups. Rats in the TC group were intragastrically administered with TC for 7 days after a middle cerebral artery occlusion (MCAO) operation. The sham and the model groups received vehicle for the same length of time. Subsequently, the neuroprotective effects of TC were examined by evaluation of neurological defects, assessment of infarct volume, and identification of biochemical indicators for antioxidant and anti-inflammatory activities. Further, metabonomics technology was employed to evaluate the endogenous metabolites profiling systematically. Consist with the results of biochemical and histopathological assays, pattern recognition analysis showed a clear separation of the model group and the sham group, indicating the recovery impact of TC on the MCAO rats. Moreover, 12 potential biomarkers were identified in the MCAO model group, involving energy (lactic acid, succinic acid, and fumarate), amino acids (leucine, alanine, and phenylalanine), and glycerophospholipid (PC [16:0/20:4], PC [20:4/20:4], LysoPC [18:0], and LysoPC [16:0]) metabolism, as well as other types of metabolism (arachidonic acid and palmitoylcarnitine). Notably, it was found that metabolite levels of TC group were partially reversed to normal. In conclusion, TC could ameliorate MCAO in rats by affecting energy metabolism (glycolysis and the TCA cycle), amino acid metabolism, glycerophospholipid metabolism, and other types of metabolism.

2.
Front Cell Neurosci ; 12: 54, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29568261

RESUMO

Lamiophlomis rotata (L. rotata; Benth.) Kudo is an effective traditional herb in the clinical treatment of chronic pain syndromes in China. 8-O-acetyl shanzhiside methylester (8-OaS), a chief component in L. rotata, possesses potent immunosuppressive activities and favorable analgesic effects. This study was proposed to compare the analgesic effects of 8-OaS with those of lidocaine and ketamine in a spinal nerve ligation (SNL) model by behavioral tests, and then investigated its effects upon the expression of spinal glial fibrillary acidic protein (GFAP), phosphorylated extracellular regulated protein kinases (pERK) and tumor necrosis factor-alpha (TNF-α) via immunofluorescence staining and western blot analyses. The data showed consecutive intrathecal injection of 8-OaS for 2 weeks brought about remarkable palliation of neuropathic pain (NP), possessing similar anti-allodynia effects with those of lidocaine and ketamine. Two weeks after surgery, pERK within the spinal dorsal horn was mainly expressed in astrocytes more than neurons and microglia, and 8-OaS inhibited spinal astrocytic activation and TNF-α expression. Finally, co-treatment of 8-OaS and PD98059 (an Extracellular signal-regulated kinase, ERK inhibitor) did not lead to remarkable increase in pain relief or TNF-α expression comparing to rats treated with 8-OaS or PD98059 alone. In conclusion, the anti-nociceptive effects of 8-OaS in the condition of NP relied on the inhibition of SNL-induced astrocyte activation, probably via the down-regulation of the ERK/TNF-α pathway.

3.
Front Pharmacol ; 9: 53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29472858

RESUMO

Alisma orientale Juzepzuk (AO) is widely used for various diuretic and nephropathic treatments in traditional Chinese medicines (TCM). In a clinical setting, AO is used as both a lipid-lowering and tubular interstitial fibrosis agent. However, the mechanisms of AO for the treatment of renal interstitial fibrosis and abnormal lipid metabolism are not well-understood. In this study, pharmacological and UPLC-HDMS-based lipidomic approaches were employed to investigate the lipid-lowering and tubular interstitial fibrosis effect of AO on rats with adenine-induced chronic kidney disease (CKD). Rats with CKD showed increased serum levels of creatinine and urea, tubular damage, and tubular interstitial fibrosis. Moreover, multiple lipid species were identified in CKD rats. Among these lipids, polyunsaturated fatty acid, eicosapentaenoic acid, 8,9-epoxyeicosatrienoic acid, and docosahexaenoic acid levels were significantly decreased in CKD rats compared to control rats. In CKD rats, up-regulation of the NF-κB pathway may impair polyunsaturated fatty acid metabolism, causing renal fibrosis. In addition, CKD rats showed significantly decreased diglyceride levels and increased triglyceride levels compared to the control group. Pathway over-representation analysis demonstrated that 30 metabolic pathways were associated with lipid species. AO treatment suppressed up-regulation of inflammation, and partly restored the deregulation of polyunsaturated fatty acids and glycerolipids metabolism. Our results indicated that AO treatment attenuated renal fibrosis by down-regulating inflammation, and mitigating lipid metabolism in CKD rats. In conclusion, this study has identified the therapeutic lipid-lowering and anti-fibrosis effects of AO on CKD.

5.
Mol Med Rep ; 15(6): 3803-3809, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28393248

RESUMO

Hyperglycemia is a typical pathogenic factor in a series of complications among patients with type II diabetes. Epigallocatechin-3-gallate (EGCG) is the major polyphenol extracted from green tea and is reported to be an antioxidant. The aim of the present study was to examine the effect of EGCG on insulin resistance in human HepG2 cells pretreated with high concentrations of glucose. The protein kinase B (AKT)/glycogen synthase kinase (GSK) pathways were analyzed using western blot analysis in HepG2 cells and primary mouse hepatocytes treated with high glucose and/or EGCG. Cellular glycogen content was determined using a glycogen assay kit. Reactive oxygen species (ROS) production was determined using dihydroethidium staining and flow cytometry. c­JUN N­terminal kinase (JNK)/insulin receptor substrate 1 (IRS1)/AKT/GSK signaling was explored using western blot analysis in HepG2 cells treated with high glucose and/or EGCG or N-acetyl-cysteine. High glucose significantly decreased the levels of phosphorylated AKT and GSK in HepG2 cells and mouse primary hepatocytes. Pretreatment with EGCG significantly restored the activation of AKT and GSK in HepG2 cells and primary hepatocytes exposed to high glucose. In HepG2 cells and primary hepatocytes, glycogen synthesis was improved by EGCG treatment in a dose­dependent manner. High glucose significantly stimulated the production of ROS while EGCG protected high glucose­induced ROS production. ROS is known to serve a major role in high glucose induced­insulin resistance by increasing JNK and IRS1 serine phosphorylation. In the present study, EGCG was observed to enhance the insulin­signaling pathway. EGCG ameliorated high glucose­induced insulin resistance in the hepatocytes by potentially decreasing ROS­induced JNK/IRS1/AKT/GSK signaling.


Assuntos
Catequina/análogos & derivados , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Resistência à Insulina , Animais , Catequina/farmacologia , Linhagem Celular Tumoral , Glucose/metabolismo , Glicogênio/metabolismo , Células Hep G2 , Humanos , Insulina/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Oncotarget ; 8(70): 114816-114828, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29383122

RESUMO

The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway has been considered as a potential target for neuroprotection in stroke. The aim of present study was to determine whether corilagin, a novel Nrf2 activator, can protect against ischemia-reperfusion injury and explore the underlying mechanism involved. In vivo, rats exposed to middle cerebral artery occlusion were applied to establish an ischemic stroke model. Posttreatment of corilagin significantly reduced infarct volumes and apoptotic cells as well as improved neurologic score after reperfusion, together with increased vascular density in the ischemic penumbra. Meanwhile, posttreatment with corilagin in MCAO rats significantly decreased malondialdehyde levels, restored the superoxide dismutase and glutathione activity, elevating the Nrf2, heme oxygenase-1, the vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. However, consecutive intrathecal injection of short interference RNAs targeting Nrf2 at 24-h intervals 72 h before ischemia reduced the beneficial effects of corilagin. In primary cultured neurons, corilagin dose-dependently protected against oxygen and glucose deprivation-induced insult, but the protective effect of corilagin was attenuated by knockdown of Nrf2. In conclusion, these findings indicate that corilagin exerts protective effects against cerebral ischemic injury by attenuating oxidative stress and enhancing angiogenesis via activation of Nrf2 signaling pathway.

7.
Oncotarget ; 8(70): 115434-115443, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29383171

RESUMO

Ischemic stroke is a common cerebrovascular disease with substantial morbidity and mortality worldwide. However, therapeutic options to minimize the cerebral ischemia-reperfusion (I/R) injury are limited. In China, combination of herb Danshen (Salvia miltiorrhiza Bge) and Honghua (Carthamus tinctorius L.) is effective for stroke treatment in patients but its underlying mechanism requires further investigation. Our study was conducted to evaluate and explore the synergistic effects of two herb ingredients Danshensu and hydroxysafflor yellow A (HSYA) on cerebral ischemia-reperfusion (I/R) injury in rats. Rats were randomly assigned to the following five groups: sham group, model group, Danshensu group, HSYA group, and Danshensu+HSYA group. Under our experimental conditions in vitro, oxygen-glucose deprivation (OGD) model was established to determine the synergistic neuroprotective effects of Danshensu and HSYA. With such methods as neurological deficits scoring, TTC, HE and TUNEL staining, and ELISA detection, the results demonstrated that administration of either Danshensu or HSYA improved neurological defects and alleviated pro-inflammatory and oxidative stress reactions. Notably, combination of Danshensu and HSYA exerted more effective results than that used alone. Furthermore, western blot analysis results showed that Danshensu and HSYA combination displayed synergistic regulation on TLR4/NF-κB and Nrf2/HO-1 pathways. Consistently, Danshensu +HSYA group exhibits better neuroprotection in primary neurons with OGD model compared with Danshensu or HSYA group. Taken together, we found for the first time that Danshensu plus HSYA could achieve remarkable synergistic neuroprotective effects on I/R injury, which is related to the anti-inflammatory and antioxidant pathways.

8.
Oncotarget ; 8(67): 111608-111622, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29340078

RESUMO

Ischemic stroke is a cerebrovascular thrombotic disease with high morbidity and mortality. Qi deficiency blood stasis (QDBS) and Yin deficiency blood stasis (YDBS) are the two major subtypes of ischemic stroke according to the theories of traditional Chinese medicine. This study was conducted to distinguish these two syndromes at transcriptomics level and explore the underlying mechanisms. Male rats were randomly divided into three groups: sham group, QDBS/MCAO group and YDBS/MCAO group. Morphological changes were assessed after 24 h of reperfusion. Microarray analysis with circulating mRNA was then performed to identify differential gene expression profile, gene ontology and pathway enrichment analyses were carried out to predict the gene function, gene co-expression and pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and Tunel staining analysis. Three subsets of dysregulated genes were acquired, including 445 QDBS-specific genes, 490 YDBS-specific genes and 1676 blood stasis common genes. Our work reveals for the first time that T cell receptor, MAPK and apoptosis pathway were identified as the hub pathways based on the pathway networks, while Nfκb1, Egfr and Casp3 were recognized as the hub genes by co-expression networks. This research helps contribute to a clearer understanding of the pathological characteristics of ischemic stroke with QDBS and YDBS syndrome, the proposed biomarkers might provide insight into the accurate diagnose and proper treatment for ischemic stroke with blood stasis syndrome.

9.
Am J Cancer Res ; 6(6): 1271-86, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27429843

RESUMO

In this study, a novel adamantyl nitroxide derivative was synthesized and its antitumor activities in vitro and in vivo were investigated. The adamantyl nitroxide derivative 4 displayed a potent anticancer activity against all the tested human hepatoma cells, especially with IC50 of 68.1 µM in Bel-7404 cells, compared to the positive control 5-FU (IC50=607.7 µM). The significant inhibition of cell growth was also observed in xenograft mouse model, with low toxicity. Compound 4 suppressed the cell migration and invasion, induced the G2/M phase arrest. Further mechanistic studies revealed that compound 4 induced cell death, which was accompanied with damaging mitochondria, increasing the generation of intracellular reactive oxygen species, cleavages of caspase-9 and caspase-3, as well as activations of Bax and Bcl-2. These results confirmed that adamantyl nitroxide derivative exhibited selective antitumor activities via mitochondrial apoptosis pathway in Bel-7404 cells, and would be a potential anticancer agent for liver cancer.

10.
Oncotarget ; 7(23): 35257-69, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27153552

RESUMO

Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3'-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.


Assuntos
Carcinoma Hepatocelular/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Proteínas/metabolismo , Animais , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Glicólise/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos SCID , Prognóstico
11.
Int Immunopharmacol ; 34: 44-52, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26921731

RESUMO

Eclipta, a traditional Chinese medicine, has been used to treat liver disease for centuries. However, the chemical basis and biological mechanisms of Eclipta remain elusive. The current study aims to investigate the hepatoprotective effect of wedelolactone (WEL), a major coumarin in Eclipta, using C57BL/6 mice with carbon tetrachloride CCl4-induced acute liver injury (ALI). Our data showed that WEL markedly decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatic histopathology changes. WEL also significantly decreased the content of MDA in liver tissues, meanwhile increased the activities of antioxidant enzymes SOD and GSH-Px. In addition, WEL reduced the protein expression of TNF-α, IL-1ß and IL-6, as well as mRNA expression. Western blot results revealed that WEL repressed phosphorylation of extracellular signal-regulated kinase (ERK) and translocation of NF-κB p65 from cytoplasm to nucleus and enhanced the phosphorylation of c-Jun. N-terminal kinase (JNK). Moreover, results showed that WEL significantly inhibited CCl4-induced hepatocytes apoptosis, markedly suppressed the down-regulation of Bax and active Caspase-3 expression and accelerated the expression of Bcl-2. Overall, the findings indicate that WEL exhibits a protective effect against CCl4-induced ALI in mice by enhancing the antioxidative defense system, suppressing the inflammatory response and cell apoptosis of liver.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cumarínicos/uso terapêutico , Hepatite/prevenção & controle , Hepatócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocinas/metabolismo , Eclipta/imunologia , Hepatite/imunologia , Hepatócitos/fisiologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
12.
Biomed Chromatogr ; 30(4): 596-600, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26284315

RESUMO

A novel and selective liquid chromatographic-mass spectrometric method (LC-MS/MS) has been established and validated for simultaneous determination of subutinib and active metabolite in human urine. Urine samples were extracted by liquid-liquid extraction with ethyl acetate and separated on a Wondasil C18 (150 × 2.1 mm, 3.5 µm), with methanol-0.2% formic acid solution (73:27, v/v) as mobile phase at flow rate of 0.2 mL/min. The linear range was 0.5000-200.0 ng/mL for subutinib and active metabolite, with a lower limit of quantitation of 0.5000 ng/mL. Intra- and inter-run precisions were all <11.8 and 14.3%, and the accuracies were all <4.5 and 5.4%, with the extraction recoveries 88.8-97.5 and 93.8-99.4% for the two analytes, respectively. The carryover values were all <15% for the two anayltes. The method was successfully applied to study urinary excretion of subutinib and active metabolite in human after oral administration of subutinib maleate capsules in fed and fasting states.


Assuntos
Antineoplásicos/urina , Indóis/urina , Inibidores de Proteínas Quinases/urina , Pirróis/urina , Espectrometria de Massas em Tandem/métodos , Adulto , Antineoplásicos/metabolismo , Cromatografia Líquida/métodos , Feminino , Humanos , Indóis/metabolismo , Limite de Detecção , Masculino , Inibidores de Proteínas Quinases/metabolismo , Pirróis/metabolismo , Adulto Jovem
13.
Am J Chin Med ; 43(7): 1381-400, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26503560

RESUMO

Traditional Chinese medicine (TCM) plays a systemic role in disease treatment, targeting multiple etiological factors simultaneously. Based on clinical experience, rhubarb and Salvia miltiorrhiza are commonly prescribed together for the treatment of chronic kidney disease (CKD) and have been proven to be very effective. However, the rationale of the combination remains unclear. The major active ingredients of these two herbs are rhein (RH) and danshensu (DSS), respectively. The aim of this paper is to investigate the renoprotective effects of RH and DSS in vitro and in vivo, and the underlying mechanism. A total of 5/6 nephrectomy rats and HK-2 cells were subjected to chronic renal injury. The combination of RH and DSS conferred a protective effect, as shown by a significant improvement in the renal function, blood supply, and fibrotic degree. Proinflammatory cytokines and adhesion molecules were suppressed by RH and DSS through NK-κB signaling. The combination also inhibited apoptosis by up-regulating Bcl-2 and down-regulating Bax. Inhibiting the TGF-ß/Smad3 pathway was at least in part involved in the antifibrotic mechanism of the combination treatment of RH and DSS. This study demonstrates for the first time the renoprotective effect and the mechanism of RH and DSS combination on chronic renal injury. It could provide experimental evidence to support the rationality of the combinatorial use of TCM in clinical practices.


Assuntos
Antraquinonas/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Lactatos/administração & dosagem , Fitoterapia , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Antraquinonas/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Combinação de Medicamentos , Humanos , Mediadores da Inflamação/metabolismo , Lactatos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Rheum/química , Salvia miltiorrhiza/química , Proteína X Associada a bcl-2/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-26253807

RESUMO

A selective liquid chromatographic-mass spectrometric method (LC-MS/MS) has been established and validated for simultaneous determination of subutinib and its active metabolite in human plasma. Plasma samples were extracted by liquid-liquid extraction with ethyl acetate and separated on a Wondasil C18 (150mm×2.1mm, 3.5µm), with methanol-0.2% formic acid solution (73:27, v/v) as mobile phase at flow rate of 0.2ml/min. The linear range was 0.25-100ng/mL for subutinib and 0.125-50.0ng/mL for its active metabolite, with lower limit of quantitation of 0.25ng/mL and 0.125ng/mL, respectively. Intra- and inter-run precision were within 7.0 and 13.1%, and the accuracies (relative errors) were<7.0 and 8.0%, with the extraction recoveries 97.0-101.2% and 93.0-98.1% for the two analytes, respectively. The validated method was successfully applied to a pharmacokinetic study of subutinib and its active metabolite in human after oral administration of subutinib maleate capsules.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Indóis/sangue , Pirróis/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Antineoplásicos/farmacocinética , Área Sob a Curva , Meia-Vida , Voluntários Saudáveis , Humanos , Indóis/farmacocinética , Limite de Detecção , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Adulto Jovem
15.
Int J Infect Dis ; 37: 125-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26159843

RESUMO

OBJECTIVE: To identify specific risk factors of vancomycin-induced nephrotoxicity in China, as the relationship between vancomycin therapy (dosing and trough concentration monitoring) and nephrotoxicity has been the subject of critical debate. METHODS: The cases of 90 critically ill patients who received vancomycin therapy in Xijing Hospital in the northwest of China between March 2014 and January 2015 were reviewed retrospectively. Vancomycin dosing, blood serum trough concentration, and other independent risk factors associated with nephrotoxicity were evaluated in a multivariable model. RESULTS: Among the 90 critically ill patients, 59 were males; mean age was 46.3 years. The indications for vancomycin use were methicillin-resistant Staphylococcus aureus-associated pneumonia, central nervous system infection, and bacteremia. Clinical pharmacists prescribed weight-based dosing, ranging from 20 to 45mg/kg/day. Fourteen (15.6%) patients developed nephrotoxicity, with serum creatinine elevated significantly from a mean (standard deviation) of 90.0 (18.8) µmol/l to 133.8 (63.2) µmol/l (p = 0.015). It was found that those with a vancomycin dosage >38mg/kg/day (50.0% vs. 11.3%, p = 0.004) and a vancomycin serum trough concentration >20mg/l (57.1% vs. 12.0%, p = 0.01) were more likely to develop nephrotoxicity. CONCLUSION: The data from this study indicate that a vancomycin dosage >38mg/kg/day and a serum trough level >20mg/l are both independent factors associated with the development of nephrotoxicity, suggesting that renal function should be monitored closely during vancomycin treatment.


Assuntos
Antibacterianos/efeitos adversos , Rim/efeitos dos fármacos , Vancomicina/efeitos adversos , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Peso Corporal , China , Feminino , Humanos , Incidência , Nefropatias/epidemiologia , Masculino , Staphylococcus aureus Resistente à Meticilina , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/administração & dosagem , Vancomicina/sangue , Vancomicina/uso terapêutico
16.
J Ethnopharmacol ; 164: 334-9, 2015 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-25701750

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has traditionally been used as the medicine considered alleviating several disorders including diabetes mellitus (DM). Chikusetsu saponin IVa (CHS) has been defined as a major active ingredient of triterpenoid saponins extracted from Aralia taibaiensis. The scientific evidence of anti-diabetic effect for CHS remains unknown and the purpose of our study was to study its hypoglycemic and insulin secretagogue activities. MATERIALS AND METHODS: In vivo studies were performed on type 2 diabetic mellitus (T2DM) rats given CHS for 28 days to test the antihyperglycemic activity. The in vitro effects and possible mechanisms of CHS on the insulin secretion in pancreatic ß-cell line ßTC3 were determined. RESULTS: Oral administration of CHS dose-dependently increased the level of serum insulin and decreased the rise in blood glucose level in an in vivo treatment. In vitro, CHS potently stimulated the release of insulin from ßTC3 cells at both basal and stimulatory glucose concentrations, the effect which was changed by the removal of extracellular Ca(2+). Two methods showed that CHS enhanced the intracellular calcium levels in ßTC3 cells. CHS was capable of enhancing the phosphorylation of extracellular signal-regulated protein kinases C (PKC), which could be reversed by a PKC inhibitor (RO320432), and the insulin secretion induced by CHS was also inhibited by RO320432. Further study also showed that the insulinotropic effect, intracellular calcium levels and the phosphorylation of PKC were reduced by inhibiting G protein-coupled receptor 40 (GPR40) by a GPR40 inhibitor (DC126026). CONCLUSION: These observations suggest that the signaling of CHS-induced insulin secretion from ßTC3 cells via GPR40 mediated calcium and PKC pathways and thus CHS might be developed into a new potential for therapeutic agent used in T2DM patients.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Saponinas/uso terapêutico , Animais , Cálcio/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Insulina/sangue , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Proteína Quinase C/metabolismo , Ratos Wistar , Receptores Acoplados a Proteínas-G/antagonistas & inibidores
17.
Molecules ; 20(2): 2922-30, 2015 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-25679051

RESUMO

Well-defined unnatural dipeptide-alcohols based on a cis-2,5-disubstitued pyrrolidine backbone were synthesized from commercially available starting materials meso-diethyl-2,5-dibromoadipate, (S)-(-)-1-phenylethylamine, and phenylalaninol. The structures of these unnatural dipeptide-alcohols are supported by HRMS, 1H- and 13C-NMR spectroscopy. These unnatural dipeptide-alcohols can act as building blocks for peptidomimetics.


Assuntos
Álcoois/química , Álcoois/síntese química , Dipeptídeos/química , Dipeptídeos/síntese química , Pirrolidinas/química , Adipatos/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Peptidomiméticos , Fenetilaminas/química , Fenilalanina/análogos & derivados , Fenilalanina/química , Estereoisomerismo
18.
Int J Clin Pharmacol Ther ; 53(3): 272-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25546165

RESUMO

OBJECTIVE: The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions. METHODS: The study participants (n=12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. RESULTS: The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 hxµg/mL for the fasting state and 22.20, 5,038 hxµg/mL for the fed state, the AUC0-∞ of triflusal and HTB were 19.79, 6,333 hxµg/mL for the fasting state and 22.44, 5,632 hxµg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB. CONCLUSION: High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects.


Assuntos
Interações Alimento-Droga , Inibidores da Agregação de Plaquetas/farmacocinética , Salicilatos/farmacocinética , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Biotransformação , Cápsulas , China , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Jejum/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/sangue , Período Pós-Prandial , Salicilatos/administração & dosagem , Salicilatos/sangue , Equivalência Terapêutica , Adulto Jovem
19.
Mol Neurobiol ; 52(3): 1430-1439, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25452227

RESUMO

Oxidative stress is well known to play a pivotal role in cerebral ischemia-reperfusion injury. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. 11-Keto-ß-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata. The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague-Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway.


Assuntos
Antioxidantes/uso terapêutico , Heme Oxigenase (Desciclizante)/fisiologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fator 2 Relacionado a NF-E2/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fármacos Neuroprotetores/toxicidade , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/fisiologia , Triterpenos/toxicidade , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Boswellia/química , Encéfalo/patologia , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/prevenção & controle , Hipóxia Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Glucose/farmacologia , Heme Oxigenase (Desciclizante)/biossíntese , Heme Oxigenase (Desciclizante)/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Malondialdeído/análise , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Triterpenos/farmacologia
20.
Clin Nutr ; 34(5): 838-44, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25306426

RESUMO

BACKGROUND & AIMS: This study aims to conduct a meta-analysis to evaluate the effects of niacin on serum lipids and glucose in patients with type 2 diabetes mellitus (T2DM). METHODS: A comprehensive literature search in Medline, Scopus, AMED, Cochrane and Clinical trial registry databases was performed to identify randomized controlled trials investigating the effect of niacin on serum HDL cholesterol (HDL-c), LDL cholesterol (LDL-c), triglycerides (TG) and fasting plasma glucose (FPG). Pooled effects were measured by weighted mean difference (WMD) using fixed-effects or random-effects models. Quality assessment, and subgroup, meta-regression and sensitivity analyses were conducted using standard methods. Inter-study heterogeneity was assessed and quantified. RESULTS: The estimated pooled mean changes (95% confidence interval) with niacin were 0.27 (95% CI: 0.24 to 0.30; P < 0.001) mmol/L for HDL-c, -0.250 (95% CI: -0.47 to -0.03; P < 0.05) mmol/L for LDL-c and -0.39 (95% CI: -0.43 to -0.34; P < 0.001) mmol/L for TG compared with controls. There was a significant heterogeneity for the impact of niacin on LDL-c and FPG. Subgroup analyses revealed a significant increase in FPG 0.085 (95% CI: 0.029 to 0.141; P < 0.05) mmol/L compared with controls in patients with long term treatment. Our analysis also showed the absence of publication bias and any dose-response relations between niacin and effect size. CONCLUSIONS: Analysis of the results showed that niacin alone or in combination significantly improved lipid abnormalities in patients with TDM, but requires monitoring of glucose in long term treatment.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Niacina/administração & dosagem , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Jejum , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Triglicerídeos/sangue
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