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1.
Zhongguo Zhong Yao Za Zhi ; 48(18): 5068-5077, 2023 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-37802849

RESUMO

This study investigated the drug delivery performance of oral co-loaded puerarin(PUE) and daidzein(DAZ) mixed micelles(PUE/DAZ-FS/PMMs) from the perspectives of pharmacokinetics, pharmacodynamics, and tissue distribution. The changes in PUE plasma concentration in rats were evaluated based on PUE suspension, single drug-loaded micelles(PUE-FS/PMMs), and co-loaded micelles(PUE/DAZ-FS/PMMs). Spontaneously hypertensive rats(SHR) were used to monitor systolic blood pressure, diastolic blood pressure, and mean arterial pressure for 10 weeks after administration by tail volume manometry. The content of PUE in the heart, liver, spleen, lung, kidney, brain, and testes was determined using LC-MS/MS. The results showed that compared with PUE suspension and PUE-FS/PMMs, PUE/DAZ-FS/PMMs significantly increased C_(max) in rats(P<0.01) and had a relative bioavailability of 122%. The C_(max), AUC_(0-t), AUC_(0-∞), t_(1/2), and MRT of PUE/DAZ-FS/PMMs were 1.77, 1.22, 1.22, 1.17, and 1.13 times higher than those of PUE suspension, and 1.76, 1.16, 1.08, 0.84, and 0.78 times higher than those of PUE-FS/PMMs, respectively. Compared with the model control group, PUE/DAZ-FS/PMMs significantly reduced systolic blood pressure, diastolic blood pressure, and mean arterial pressure in SHR rats(P<0.05). The antihypertensive effect of PUE/DAZ-FS/PMMs was greater than that of PUE suspension, and even greater than that of PUE-FS/PMMs at high doses. Additionally, the distribution of PMMs in various tissues showed dose dependency. The distribution of PMMs in the kidney and liver, which are metabolically related tissues, was lower than that in the suspension group, while the distribution in the brain was higher than that in the conventional dose group. In conclusion, PUE/DAZ-FS/PMMs not only improved the bioavailability of PUE and synergistically enhanced its therapeutic effect but also prolonged the elimination of the drug to some extent. Furthermore, the micelles facilitated drug penetration through the blood-brain barrier. This study provides a foundation for the development of co-loaded mixed micelles containing homologous components.


Assuntos
Isoflavonas , Micelas , Ratos , Animais , Distribuição Tecidual , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ratos Endogâmicos SHR , Isoflavonas/farmacologia
2.
J Exp Bot ; 73(9): 2859-2874, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35560205

RESUMO

Vegetable oils are an indispensable nutritional component of the human diet as well as important raw materials for a variety of industrial applications such as pharmaceuticals, cosmetics, oleochemicals, and biofuels. Oil plant genomes are highly diverse, and their genetic variation leads to a diversity in oil biosynthesis and accumulation along with agronomic traits. This review discusses plant oil biosynthetic pathways, current state of genome assembly, polyploidy and asymmetric evolution of genomes of oil plants and their wild relatives, and research progress of pan-genomics in oil plants. The availability of complete high-resolution genomes and pan-genomes has enabled the identification of structural variations in the genomes that are associated with the diversity of agronomic and environment fitness traits. These and future genomes also provide powerful tools to understand crop evolution and to harvest the rich natural variations to improve oil crops for enhanced productivity, oil quality, and adaptability to changing environments.


Assuntos
Genoma de Planta , Poliploidia , Produtos Agrícolas/genética , Genômica
3.
Medicine (Baltimore) ; 95(16): e3214, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27100411

RESUMO

Adjuvant 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX6) are widely used for treating resected gastric cancer in clinics in China, but only few clinical trials have investigated its efficacy. Using propensity score matching, we evaluated the efficacy of adjuvant FOLFOX6 following D2 lymphadenectomy. Patients who received adjuvant FOLFOX6 following D2 lymphadenectomy (FOLFOX6, n = 113) or D2 lymphadenectomy only (surgery-only, n = 512) between 1998 and 2007 at our center were propensity score-matched; we identified a balanced 1:2 cohort, with 96 patients in the FOLFOX6 group and 192 patients in the surgery-only group. The overall survival (OS) was estimated using the Kaplan-Meier method; factors affecting survival were identified by Cox regression models. A nomogram incorporating independent prognosticators was constructed for predicting the 3-, 5-, and 7-year OS, and bootstrap validation was performed. The median follow-up was 9.3 years, and the 7-year OS was 52.1% in the FOLFOX6 group and 43.8% in the surgery-only group (P = 0.04), with an adjusted hazard ratio of 0.69 (95% confidence interval = 0.49-0.98). A prognostic nomogram was generated with the identified significant prognosticators (adjuvant FOLFOX6, number of total harvested nodes, the interaction effect between these two variables, tumor size, T and N stage). Internal validation of the nomogram revealed good predictive abilities, with a bootstrap-corrected concordance index of 0.70. Adjuvant FOLFOX6 following D2 lymphadenectomy is associated with survival benefit in resected gastric cancer. Receiving adjuvant FOLFOX6 can be developed into a nomogram with other independent prognosticators to refine OS prediction and estimation of benefit from adjuvant FOLFOX6 for resected gastric cancer.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Excisão de Linfonodo/métodos , Estadiamento de Neoplasias , Neoplasias Gástricas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Quimioterapia Adjuvante , China/epidemiologia , Feminino , Fluoruracila , Seguimentos , Gastrectomia , Humanos , Leucovorina , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Nomogramas , Compostos Organoplatínicos , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida/tendências , Fatores de Tempo
4.
Drug Metab Rev ; 47(4): 470-519, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26574146

RESUMO

With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4α binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4α-mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6.


Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Regulação Enzimológica da Expressão Gênica , Medicina de Precisão/métodos , Processamento de Proteína Pós-Traducional , Doença de Alzheimer/enzimologia , Animais , Artrite Reumatoide/enzimologia , Citocromo P-450 CYP2D6/biossíntese , Diabetes Mellitus/enzimologia , Epigenômica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Inflamação/enzimologia , Falência Renal Crônica/enzimologia , Cirrose Hepática Alcoólica/enzimologia , Hepatopatias/enzimologia , Doença de Parkinson/enzimologia , Preparações de Plantas/farmacologia , Polimorfismo Genético , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Especificidade por Substrato
5.
Drug Des Devel Ther ; 9: 2001-27, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25926716

RESUMO

A number of drugs and herbal compounds have been documented to cause hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML-12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra-large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B-induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/toxicidade , Macrófagos/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Compostos Policíclicos/toxicidade , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Ciclo-Octanos/toxicidade , Fase G1/efeitos dos fármacos , Camundongos , Mitocôndrias Hepáticas/efeitos dos fármacos , Fase S/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
6.
Drug Des Devel Ther ; 9: 1063-102, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25733819

RESUMO

Ischemic heart disease (IHD) is the leading cause of death worldwide and remains a major life-threatening factor in humans. Apoptosis has been implicated in the pathogenesis of IHD. The Chinese herbal formula Huo Luo Xiao Ling Dan (HLXLD), one of the commonly used Chinese herbal formulas, consists of Salviae miltiorrhizae, Angelica sinensis, Gummi olibanum, and Commiphora myrrha, with a wide spectrum of pharmacological activity. However, the mechanism of action and molecular targets of HLXLD in the treatment of IHD are unclear. This study aimed to computationally predict the molecular interactions between the major active components of HLXLD and key regulators of apoptosis and then examine the effect of HLXLD on coronary artery ligation-induced acute myocardial ischemia in rats. The molecular interactions between the major active components of HLXLD, including ferulic acid, ligustilide, succinic acid, vanillic acid, tanshinone IIA, tanshinone IIB, danshensu, salvianolic acid A, salvianolic acid C, protocatechuic aldehyde, and ß-boswellic acid and human protein molecules including B cell lymphoma-extra large (Bcl-xl), B cell lymphoma 2 antagonist/killer 1 (Bak1), B cell lymphoma 2 (Bcl-2), procaspase 3, and caspase 9 with regard to hydrogen bond formation, charge interaction, and π-π stacking using Discovery Studio(®) program 3.1. The 12 HLXLD components were predicted by ADMET (absorption, distribution, metabolism, excretion and toxicity) Predictor to have favorable pharmacokinetic and low hepatotoxicity profiles. The acute myocardial ischemia was established by surgical ligation of the left anterior descending coronary artery. The rats were divided into a sham operative group, a model group, a positive control group treated with 0.2 mg/kg isosorbide mononitrate, and groups treated with 2.7, 5.4, or 10.8 g/kg HLXLD. The results showed that administration of HLXLD increased mean arterial pressure, left ventricular systolic pressure, heart rate, and maximal rate of rise/descent of left ventricular pressure levels. Administration of HLXLD significantly ameliorated coronary artery ligation-induced tissue damage in the left ventricle, with restored arrangement of myocardial fibers and recovered myoplasm in rats. Furthermore, HLXLD markedly increased the expression level of Bcl-2 but decreased the level of cleaved caspase 3. Taken together, administration of HLXLD attenuated acute myocardial ischemia-induced damage in cardiomyocytes and inhibited apoptotic death of cardiomyocytes, thereby exerting a cardioprotective effect in rats with IHD. These findings suggest that HLXLD may represent a promising herbal formula for the treatment of cardiovascular disease by counteracting apoptotic cell death via multiple active compounds. More studies are warranted to fully elucidate the mechanisms of action, identify the therapeutic targets, and validate the efficacy and safety of HLXLD in the treatment of IHD.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley
7.
Drug Des Devel Ther ; 9: 241-72, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25565776

RESUMO

There is an increasing prevalence of Alzheimer's disease (AD), which has become a public health issue. However, the underlying mechanisms for the pathogenesis of AD are not fully understood, and the current therapeutic drugs cannot produce acceptable efficacy in AD patients. Previous animal studies have shown that coffee (Coff), caffeine (Caff), and melatonin (Mel) have beneficial effects on AD. Disturbed circadian rhythms are observed in AD, and chronotherapy has shown promising effects on AD. In this study, we examined whether a combination of Coff or Caff plus Mel produced a synergistic/additive effect on amyloid-ß (Aß) generation in Neuro-2a (N2a)/amyloid precursor protein (APP) cells and the possible mechanisms involved. Cells were treated with Coff or Caff, with or without combined Mel, with three different chronological regimens. In regimen 1, cells were treated with Coff or Caff for 12 hours in the day, followed by Mel for 12 hours in the night. For regimen 2, cells were treated with Coff or Caff plus Mel for 24 hours, from 7 am to 7 am the next day. In regimen 3, cells were treated with Coff or Caff plus Mel with regimen 1 or 2 for 5 consecutive days. The extracellular Aß40/42 and Aß oligomer levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. The expression and/or phosphorylation levels of glycogen synthase kinase 3ß (GSK3ß), Erk1/2, PI3K, Akt, Tau, Wnt3α, ß-catenin, and Nrf2 were detected by Western blot assay. The results showed that regimen 1 produced an additive antiamyloidogenic effect with significantly reduced extracellular levels of Aß40/42 and Aß42 oligomers. Regimen 2 did not result in remarkable effects, and regimen 3 showed a less antiamyloidogenic effect compared to regimen 1. Coff or Caff, plus Mel reduced oxidative stress in N2a/APP cells via the Nrf2 pathway. Coff or Caff, plus Mel inhibited GSK3ß, Akt, PI3K p55, and Tau phosphorylation but enhanced PI3K p85 and Erk1/2 phosphorylation in N2a/APP cells. Coff or Caff, plus Mel downregulated Wnt3α expression but upregulated ß-catenin. However, Coff or Caff plus Mel did not significantly alter the production of T helper cell (Th)1-related interleukin (IL)-12 and interferon (IFN)-γ and Th2-related IL-4 and IL-10 in N2a/APP cells. The autophagy of cells was not affected by the combinations. Taken together, combination of Caff or Coff, before treatment with Mel elicits an additive antiamyloidogenic effects in N2a/APP cells, probably through inhibition of Aß oligomerization and modulation of the Akt/GSK3ß/Tau signaling pathway.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Cafeína/farmacologia , Café/química , Melatonina/metabolismo , Multimerização Proteica/efeitos dos fármacos , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Cafeína/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Melatonina/agonistas , Camundongos , Simulação de Acoplamento Molecular , Agregação Patológica de Proteínas/tratamento farmacológico , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Drug Des Devel Ther ; 9: 33-78, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25552899

RESUMO

Lycium barbarum berries, also named wolfberry, Fructus lycii, and Goji berries, have been used in the People's Republic of China and other Asian countries for more than 2,000 years as a traditional medicinal herb and food supplement. L. barbarum polysaccharides (LBPs) are the primary active components of L. barbarum berries and have been reported to possess a wide array of pharmacological activities. Herein, we update our knowledge on the main pharmacological activities and possible molecular targets of LBPs. Several clinical studies in healthy subjects show that consumption of wolfberry juice improves general wellbeing and immune functions. LBPs are reported to have antioxidative and antiaging properties in different models. LBPs show antitumor activities against various types of cancer cells and inhibit tumor growth in nude mice through induction of apoptosis and cell cycle arrest. LBPs may potentiate the efficacy of lymphokine activated killer/interleukin-2 combination therapy in cancer patients. LBPs exhibit significant hypoglycemic effects and insulin-sensitizing activity by increasing glucose metabolism and insulin secretion and promoting pancreatic ß-cell proliferation. They protect retinal ganglion cells in experimental models of glaucoma. LBPs protect the liver from injuries due to exposure to toxic chemicals or other insults. They also show potent immunoenhancing activities in vitro and in vivo. Furthermore, LBPs protect against neuronal injury and loss induced by ß-amyloid peptide, glutamate excitotoxicity, ischemic/reperfusion, and other neurotoxic insults. LBPs ameliorate the symptoms of mice with Alzheimer's disease and enhance neurogenesis in the hippocampus and subventricular zone, improving learning and memory abilities. They reduce irradiation- or chemotherapy-induced organ toxicities. LBPs are beneficial to male reproduction by increasing the quality, quantity, and motility of sperm, improving sexual performance, and protecting the testis against toxic insults. Moreover, LBPs exhibit hypolipidemic, cardioprotective, antiviral, and antiinflammatory activities. There is increasing evidence from preclinical and clinical studies supporting the therapeutic and health-promoting effects of LBPs, but further mechanistic and clinical studies are warranted to establish the dose-response relationships and safety profiles of LBPs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Lycium/química , Polissacarídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Especificidade por Substrato
9.
Drug Des Devel Ther ; 9: 127-46, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25552902

RESUMO

Drug metabolizing enzymes (DMEs) and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC) is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE) on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2) cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(P)H: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate-cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant increase in the intracellular level of glutathione and total glutathione S-transferase content. SCE significantly elevated the messenger ribonucleic acid and protein levels of P-glycoprotein and multidrug resistance-associated protein 2 and 4, whereas the expression of organic anion transporting peptide 1A2 and 1B1 was significantly downregulated by SCE. Knockdown of Nrf2 by small interfering ribonucleic acid attenuated the regulatory effect of SCE on these DMEs and drug transporters. SCE significantly upregulated Nrf2 and promoted the translocation of Nrf2 from cytoplasm to the nuclei. Additionally, SCE significantly suppressed the expression of cytosolic Kelch-like ECH-associated protein 1 (the repressor of Nrf2) and remarkably increased Nrf2 stability in HepG2 cells. Taken together, our findings suggest that the hepatoprotective effects of SCE may be partially ascribed to the modulation of DMEs and drug transporters via Nrf2-mediated signaling pathway. SCE may alter the pharmacokinetics of other coadministered drugs that are substrates of these DMEs and transporters and thus cause unfavorable herb-drug interactions.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Preparações Farmacêuticas/metabolismo , Schisandra/química , Transdução de Sinais/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Glutamato-Cisteína Ligase/metabolismo , Glutationa Transferase/metabolismo , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Medicina Tradicional Chinesa , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , NADPH Oxidase 4 , NADPH Oxidases/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Medicines (Basel) ; 2(4): 328-330, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-28930214

RESUMO

Herbal medicines and natural products have been the most productive source of drug development and there is a large line of evidence on the applications of herbal medicines and natural products for the management of body function and the treatment of aliments. The multiple bioactive components in herbal medicines and natural products can explain the multiple targets effect in their medical applications. The increasing usage of state-of-art computational, molecular biological, and analytical chemistry techniques will promote the exploration of the pharmacological effect of previously inaccessible sources of herbal medicines and natural products. Notably, with the increasing reports on the safety issues regarding the medical use of herbal medicines and natural products, the awareness of pharmacovigilance in herbal medicines and natural products needs to be strengthened. To prevent the adverse drug reactions related to herbal medicines and natural products, physicians need to be aware of potential risks and alert patients in the use of herbal medicines and natural products.

11.
ScientificWorldJournal ; 2012: 708292, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23213296

RESUMO

Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer's disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach.


Assuntos
Berberina/farmacocinética , Biopolímeros/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Transdução de Sinais/fisiologia , Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos
12.
Xenobiotica ; 42(3): 238-55, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21970686

RESUMO

Human CYP1A2 is an important enzyme for drug metabolism and procarcinogen activation. This study aimed to explore the binding mode of ligands with CYP1A2 and to screen potential inhibitors from a library of herbal compounds using computational and in vitro approaches. The heme prosthetic group and six residues (Thr124, Phe125, Phe226, Phe260, Gly316, and Ala317) in the active site of CYP1A2 were identified as important residues for ligand binding using the LIGPLOT program. Ala317 in helix I immediately above heme was highly conserved in most human CYPs with known crystal structures. In molecular docking, 19 of the 56 herbal compounds examined were identified as potential inhibitors of CYP1A2. Up to 21 of the 56 herbal compounds were hit by the pharmacophore model of CYP1A2 inhibitors developed and validated in this study. In the in vitro inhibition study, 8 herbal compounds were identified as moderate to potent inhibitors of CYP1A2. Five of the 8 herbal compounds predicted to be potential inhibitors were confirmed as CYP1A2 inhibitors in the in vitro study. A combination of computational and in vitro approaches, represent a useful tool to identify potential inhibitors for CYP1A2 from herbal compounds.


Assuntos
Simulação por Computador , Inibidores do Citocromo P-450 CYP1A2 , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Preparações de Plantas/farmacologia , Sequência de Aminoácidos , Aminoácidos/metabolismo , Sítios de Ligação , Biocatálise/efeitos dos fármacos , Sequência Conservada , Cristalografia por Raios X , Citocromo P-450 CYP1A2/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Heme/metabolismo , Humanos , Ligantes , Dados de Sequência Molecular , Preparações de Plantas/química , Estrutura Secundária de Proteína , Reprodutibilidade dos Testes , Especificidade por Substrato/efeitos dos fármacos
13.
Comb Chem High Throughput Screen ; 15(1): 36-80, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21846324

RESUMO

We have previously examined the binding patterns of various substrates to human cytochrome P450 2D6 (CYP2D6) using a series of molecular modeling methods. In this study, we further explored the binding modes of various types of inhibitors to CYP2D6 using a combination of ligand- and protein-based modeling approaches. Firstly, we developed and validated a pharmacophore model for CYP2D6 inhibitors, which consisted of two hydrophobic features and one hydrogen bond acceptor feature. Secondly, we constructed and validated a quantitative structure-activity relationship (QSAR) model for CYP2D6 inhibitors which gave a poor to moderate prediction accuracy. Thirdly, a panel of CYP2D6 inhibitors were subject to molecular docking into the active site of wild-type and mutated CYP2D6 enzyme. We demonstrated that 8 residues in the active site (Leu213, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, and Phe483) played an important role in the binding to the inhibitors via hydrogen bond formation and/or π-π stacking interaction. Apparent changes in the binding modes of the inhibitors have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations in CYP2D6. Finally, we screened for potential binders/inhibitors from the Chinese herbal medicine Scutellaria baicalensis (Huangqin, Baikal Skullcap) using the established pharmacophore model for CYP2D6 inhibitors and molecular docking approach. Overall, 18 out of 40 compounds from S. baicalensis were mapped to the pharmacophore model of CYP2D6 inhibitors and most herbal compounds from S. baicalensis could be docked into the active site of CYP2D6. Our study has provided insights into the molecular mechanisms of interaction of synthetic and herbal compounds with human CYP2D6 and further benchmarking studies are needed to validate our modeling and virtual screening results.


Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Medicamentos de Ervas Chinesas/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Scutellaria baicalensis/química , Domínio Catalítico/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inibidores Enzimáticos/química , Humanos , Ligantes , Modelos Moleculares , Relação Estrutura-Atividade
14.
Curr Pharm Biotechnol ; 13(9): 1640-704, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22039821

RESUMO

The highly polymorphic human cytochrome P450 2D6 (CYP2D6) metabolizes about 25% of currently used drugs. In this study, we have explored the interaction of a large number of substrates (n = 120) with wild-type and mutated CYP2D6 by molecular docking using the CDOCKER module. Before we conducted the molecular docking and virtual mutations, the pharmacophore and QSAR models of CYP2D6 substrates were developed and validated. Finally, we explored the interaction of a traditional Chinese herbal formula, Fangjifuling decoction, with CYP2D6 by virtual screening. The optimized pharmacophore model derived from 20 substrates of CYP2D6 contained two hydrophobic features and one hydrogen bond acceptor feature, giving a relevance ratio of 76% when a validation set of substrates were tested. However, our QSAR models gave poor prediction of the binding affinity of substrates. Our docking study demonstrated that 117 out of 120 substrates could be docked into the active site of CYP2D6. Forty one out of 117 substrates (35.04%) formed hydrogen bonds with various active site residues of CYP2D6 and 53 (45.30%) substrates formed a strong π-π interaction with Phe120 (53/54), with only carvedilol showing π-π interaction with Phe483. The active site residues involving hydrogen bond formation with substrates included Leu213, Lys214, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, Phe483, and Phe484. Furthermore, the CDOCKER algorithm was further applied to study the impact of mutations of 28 active site residues (mostly non-conserved) of CYP2D6 on substrate binding modes using five probe substrates including bufuralol, debrisoquine, dextromethorphan, sparteine, and tramadol. All mutations of the residues examined altered the hydrogen bond formation and/or aromatic interactions, depending on the probe used in molecular docking. Apparent changes of the binding modes have been observed with the Glu216Asp and Asp301Glu mutants. Overall, 60 compounds out of 130 from Fangjifuling decoction matched our pharmacophore model for CYP2D6 substrates. Fifty four out of these 60 compounds could be docked into the active site of CYP2D6 and 24 of 54 compounds formed hydrogen bonds with Glu216, Asp301, Ser304, and Ala305 in CYP2D6. These results have provided further insights into the factors that determining the binding modes of substrates to CYP2D6. Screening of high-affinity ligands for CYP2D6 from herbal formula using computational models is a useful approach to identify potential herb-drug interactions.


Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Simulação de Acoplamento Molecular/métodos , Domínio Catalítico , Citocromo P-450 CYP2D6/química , Interações Ervas-Drogas , Medicina Herbária/métodos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Medicina Tradicional Chinesa/métodos , Mutação , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Especificidade por Substrato
15.
Zhonghua Zhong Liu Za Zhi ; 33(2): 126-9, 2011 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-21575481

RESUMO

OBJECTIVE: To evaluate the influence of two different types of digestive tract reconstruction on the life quality, nutritional status and tolerance to adjuvant chemotherapy after total gastrectomy in patients with gastric carcinoma. METHODS: The clinical data of a total of 107 patients treated in our department from January 2005 to december 2008 were analyzed retrospectively. Among them, 49 patients underwent digestive tract reconstruction with functional jejunal interposition (FJI group) and 58 patients underwent Roux en-Y jejunal P-type anastomosis (PR group) after total gastrectomy. 79 of 107 (73.8%) patients received postoperative adjuvant chemotherapy with XELOX regimen. The digestive complications and tolerance to chemotherapy were assessed respectively. RESULTS: Neither severe complications nor surgery-related or chemotherapy-related death were observed among the 107 patients. There were statistical differences in the incidence rate of emaciation, dumping syndrome and retention syndrome between the FJI and PR groups (P < 0.05), but no significant statistical difference in incidence rate of reflux esophagitis (P > 0.05). 28 of 40 (70.0%) patients in the FJI group completed all six cycles of chemotherapy, while 12 (30.0%) patients interrupted the treatment due to chemotherapy-related toxicity. 39 patients in the PR group received chemotherapy, 19 (48.7%) of them completed 6 cycles of chemotherapy but 20 (51.3%) patients interrupted. There was a significant difference in the incidence rate of grade III/IV chemotherapeutic toxicity and completion rate of chemotherapy (P < 0.05). CONCLUSIONS: Both functional jejunal interposition and Roux-Y operation are reasonable and safe procedures of digestive tract reconstruction. The incidence rates of emaciation, dumping syndrome and retention syndrome are lower in the patients with FJI, showing a better tolerance to adjuvant chemotherapy than Roux en-Y jejunal p type anastomosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia/métodos , Neoplasias Gástricas/cirurgia , Anastomose em-Y de Roux/métodos , Anastomose Cirúrgica/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Jejuno/cirurgia , Estado Nutricional , Oxaloacetatos , Período Pós-Operatório , Qualidade de Vida , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico
16.
Am J Clin Oncol ; 34(3): 309-13, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20838324

RESUMO

OBJECTIVE: To evaluate the effect of 2 regimens of postoperative combination chemotherapies on the prognosis of early stage gastric cancer patients. METHODS: A total of 268 patients with stage II gastric cancer underwent D2 resection in our Cancer Center between January 1990 and December 2006 were recruited. Among them, 34 patients received the FAM regimen (5-fluorouracil [5-FU] 600 mg/m(2) intravenous [IV] drip on days 1, 8, 29, and 36; doxorubicin 30 mg/m(2) IV bolus injection on days 1 and 29; and mitomycin-C 10 mg/m(2) IV bolus injection on day 1; repeated every 8 weeks) and 81 patients received the FOLFOX regimen (oxaliplatin 100 mg/m(2) IV drip on days 1 and 15; leucovorin 400 mg/m(2) IV drip on days 1 and 15; 5-FU 400 mg/m(2) IV bolus injection; 5-FU 2.4/3.0 mg/m(2) continuous IV infusion for 48 hours on day 1, 2, 15, and 16; repeated every 4 weeks for at least 4 cycles). Patients were followed-up until December 2008. The Kaplan-Meier method was used to compare survival rates between treatment groups. RESULTS: The 1-, 3-, 5-, and 10-year survival rates for the patients who received postoperative chemotherapy versus the patients who underwent surgery only were 98%, 84%, 58%, 18% versus 96%, 78%, 59%, 22%, respectively (P > 0.05). Furthermore, the survival rates for patients who received the FAM and FOLFOX regimens were not significantly different (P > 0.05). CONCLUSIONS: Postoperative adjuvant chemotherapy did not produce survival benefits for the patients with stage II gastric cancer. Randomized controlled clinical trials are demanded to confirm the finding from this study.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Gastrectomia/métodos , Humanos , Infusões Intravenosas , Injeções Intravenosas , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Seleção de Pacientes , Período Pós-Operatório , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Falha de Tratamento
17.
Ai Zheng ; 27(5): 505-9, 2008 May.
Artigo em Chinês | MEDLINE | ID: mdl-18479600

RESUMO

BACKGROUND & OBJECTIVE: Multiple primary colorectal carcinoma (MPCC) is not rarely seen, but it possesses a unique biological characters. This study was to investigate the clinical characteristics, diagnosis, therapeutic principle and prognosis of MPCC. METHODS: Data of 70 MPCC patients, treated by operation from 1997 to 2003, were analyzed. Of the 70 patients, 61 had synchronous carcinoma (SC) and 9 had metachronous carcinoma (MC). RESULTS: Fifty-five patients were diagnosed by colonoscopy, barium enema or CT scan pre-operationally, while 15 were diagnosed intra-operationally due to the oversized tumor at the distal end of the colon. Thirty-three patients had colorectal carcinoma accompanying with adenoma and multiple polyps. All the patients underwent surgical resection except 3, who received short-circuit operation because of unresectable lesions. Fifty-two patients received radical resection, while 15 received palliative resection due to hepatic or peritoneal metastasis. The overall 3-and 5-year survival rates were 65.7% and 45.7%. In the patients who received radical resection, the 3-and 5-year survival rates were 78.1% and 59.3%. CONCLUSIONS: The occurrence of MPCC is largely related with adenomas and polyps. The extent of resection should be individually determined by the lesion location, range, the distance of lesions as well as the general condition of the patients. Prognosis of MPCC is relatively good. The patients accompanying with adenoma and multiple polyps should be followed up intensively.


Assuntos
Carcinoma Ductal/cirurgia , Colectomia/métodos , Neoplasias do Colo/cirurgia , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Retais/cirurgia , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adenocarcinoma Papilar/diagnóstico , Adenocarcinoma Papilar/patologia , Adenocarcinoma Papilar/cirurgia , Adulto , Idoso , Carcinoma Ductal/diagnóstico , Carcinoma Ductal/patologia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/patologia , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Reto/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida
18.
Phytother Res ; 22(6): 846-50, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18389485

RESUMO

Tanshinone IIB (TSB) is a major active constituent of the roots of Salvia miltiorrhiza (Danshen) widely used in the treatment of stroke and coronary heart disease in Asian countries. This study investigated the in vitro neuroprotective effects of TSB and the underlying mechanism. Co-treatment with TSB significantly inhibited the cytotoxicity and apoptosis of rat cortical neurons induced by staurosporine in a concentration-dependent manner. Consistently, TSB significantly reduced the DNA laddering caused by staurosporine in a concentration-dependent manner. TSB also suppressed the elevated Bax protein and decreased bcl-2 and caspase-3 proteins induced by staurosporine in rat cortical neurons. These findings indicated that TSB had a neuroprotective effect via inhibition of apoptosis. Further studies are warranted to investigate the role of other apoptosis-related signaling proteins and reperfusion-related mechanisms in the protective effect of TSB on neurons.


Assuntos
Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fenantrenos/farmacologia , Salvia miltiorrhiza/química , Abietanos , Animais , Western Blotting , Caspase 3/metabolismo , Células Cultivadas , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Marcação In Situ das Extremidades Cortadas , Neurônios/citologia , Neurônios/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Estaurosporina/farmacologia , Proteína X Associada a bcl-2/metabolismo
19.
Life Sci ; 82(1-2): 68-78, 2008 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-18048062

RESUMO

Stroke is a life-threatening disease characterized by rapidly developing clinical signs of focal or global disturbance of cerebral function due to cerebral ischemia. A number of flavonoids have been shown to attenuate the cerebral injuries in stroked animal models. Glabridin, a major flavonoid of Glycyrrhiza glabra (licorice), possesses multiple pharmacological activities. This study aimed to investigate whether glabridin modulated the cerebral injuries induced by middle cerebral artery occlusion (MCAO) in rats and staurosporine-induced damage in cultured rat cortical neurons and the possible mechanisms involved. Our study showed that glabridin at 25mg/kg by intraperitoneal injection, but not at 5mg/kg, significantly decreased the focal infarct volume, cerebral histological damage and apoptosis in MCAO rats compared to sham-operated rats. Glabridin significantly attenuated the level of brain malonyldialdehyde (MDA) in MCAO rats, while it elevated the level of two endogenous antioxidants in the brain, i.e. superoxide dismutase (SOD) and reduced glutathione (GSH). Co-treatment with glabridin significantly inhibited the staurosporine-induced cytotoxicity and apoptosis of cultured rat cortical neurons in a concentration-dependent manner. Consistently, glabridin significantly reduced the DNA laddering caused by staurosporine in a concentration-dependent manner. Glabridin also suppressed the elevated Bax protein and caspase-3 proenzyme and decreased bcl-2 induced by staurosporine in cultured rat cortical neurons, facilitating cell survival. Glabridin also inhibited superoxide production in cultured cortical neurons exposed to staurosporine. These findings indicated that glabridin had a neuroprotective effect via modulation of multiple pathways associated with apoptosis. Further studies are warranted to further investigate the biochemical mechanisms for the protective effect of glabridin on neurons and the evidence for clinical use of licorice in the management of cerebral ischemia.


Assuntos
Glycyrrhiza/química , Isoflavonas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fenóis/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glutationa/metabolismo , Marcação In Situ das Extremidades Cortadas , Técnicas In Vitro , Infarto da Artéria Cerebral Média/complicações , Isoflavonas/efeitos adversos , Isoflavonas/isolamento & purificação , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/isolamento & purificação , Fenóis/efeitos adversos , Fenóis/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/etiologia , Superóxido Dismutase/metabolismo
20.
Drug Discov Today ; 12(15-16): 664-73, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17706549

RESUMO

To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Because drug-herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug-herb and herb-CYP interaction studies should be incorporated into drug development.


Assuntos
Desenho de Fármacos , Interações Ervas-Drogas , Tecnologia Farmacêutica/métodos , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Modelos Biológicos , Preparações Farmacêuticas/química , Preparações de Plantas/efeitos adversos , Preparações de Plantas/química , Tecnologia Farmacêutica/tendências
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