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1.
Biofactors ; 45(6): 950-958, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520488

RESUMO

The regeneration of proliferation potential of dermal papilla (DP) cells contributes to the treatment of hair loss disorders. Ginkgolide B (GKB) and bilobalide (BB) are two functional components isolated from Ginkgo biloba that can promote hair growth. In the current study, the effect of GKB or BB on DP cell viability and the related signaling was assessed. Hair follicles were isolated from minks, and the growth of hair follicles was measured under the administration of GKB or BB. DP cells isolated from minks were also subjected to GKB or BB. The administration of GKB or BB induced the growth of hair follicles. The viability of DP cells was also increased by GKB or BB as illustrated by methyl thiazolyl tetrazolium and flow cytometry detection. Moreover, the secretion of VEGF was enhanced by GKB or BB. At molecular level, the activities of Akt, ERK1/2, and ß-catenin were induced by GKB, whereas BB only increased the activities of Akt and ß-catenin. In conclusion, although the two components influenced the ß-catenin signaling activity in distinct mechanisms, they both increased the viability of DP cells and promoted the cycle of hair follicles.


Assuntos
Ciclopentanos/farmacologia , Furanos/farmacologia , Ginkgolídeos/farmacologia , Folículo Piloso/crescimento & desenvolvimento , Lactonas/farmacologia , Vison/crescimento & desenvolvimento , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclopentanos/química , Derme/efeitos dos fármacos , Derme/crescimento & desenvolvimento , Furanos/química , Ginkgo biloba/química , Ginkgolídeos/química , Folículo Piloso/efeitos dos fármacos , Lactonas/química , Transdução de Sinais/efeitos dos fármacos , beta Catenina/genética
2.
Colloids Surf B Biointerfaces ; 181: 910-917, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382340

RESUMO

The purpose of this study was to investigate the effects of soybean phospholipid, as a steric stabilizer, on improving dissolution rate, storage stability and bioavailability of ginkgolides. The ginkgolides coarse powder, hydroxypropyl methylcellulose (HPMC), soybean phospholipid and sodium dodecyl sulfate (SDS) were mixed and wet-milled to prepare nanosuspension S1. Nanosuspension S2 was obtained by the same technique except adding the soybean phospholipid. Results of particle size showed that particle size (D50) of S1 significantly decreased from 44.25 µm to 0.373 µm. Results of differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and transmission electron microscope (TEM) showed that ginkgolides in nanosuspension still maintained its crystallinity, and the nanoparticles were all nearly circular and uniformly dispersed. Then, pellets F1 and F2 were prepared by layering S1 and S2 onto the microcrystalline cellulose (MCC) spheres, respectively. The dissolution rate of ginkgolide A (GA) and ginkgolide B (GB) in F1 was 98.3% and 97.7% in 30 min, respectively. It was much higher than F2 (89.0% and 86.5%) and coarse powder of ginkgolides (22.3% and 24.6%). According to the results of stability test, the storage stability of F1 was improved compared with F2. In addition, compared with coarse powder of ginkgolides, the relative bioavailability of GA and GB in F1 were up to (221.84 ±â€¯106.67) % and (437.45 ±â€¯336.43) %, respectively. The above results demonstrated that soybean phospholipid added to the nanosuspension played an important role in improving drug dissolution rate, storage stability and in vivo bioavailability: (1) The amphiphilic soybean phospholipid interacted with the drug, with the hydrophobic part adsorbed on the surface of the poorly soluble drug and the hydrophilic part exposed to the aqueous medium. This increases the wettability of the nanoparticles, which ensure a good redispersibility of the drug particles. (2) It could self-assemble to form an interfacial phospholipid film by surrounding the individual nanoparticles, which can produce enough steric hindrance to prevent nanoparticles from aggregation and ensure a rapid dissolution rate. (3) Soybean phospholipid and its hydrolysate formed strong micellar solubilizing vehicles with bile salts in vivo, stimulated the absorption process of ginkgolides. Thus, soybean phospholipid was a promising steric stabilizer in nanosuspension drug delivery system.


Assuntos
Ginkgolídeos/química , Nanopartículas/química , Fosfolipídeos/química , Soja/química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Sistemas de Liberação de Medicamentos , Ginkgolídeos/administração & dosagem , Ginkgolídeos/sangue , Tamanho da Partícula , Fosfolipídeos/administração & dosagem , Fosfolipídeos/sangue , Propriedades de Superfície , Suspensões/química
3.
Molecules ; 24(11)2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181694

RESUMO

Ginkgolides are the major active component of Ginkgo biloba for inhibition of platelet activating factor receptor. An azide-alkyne Huisgen cycloaddition reaction was used to introduce a triazole nucleus into the target ginkgolide molecules. A series of ginkgolide-1,2,3-triazole conjugates with varied functional groups including benzyl, phenyl and heterocycle moieties was thus synthesized. Many of the designed derivatives showed potent antiplatelet aggregation activities with IC50 values of 5~21 nM.


Assuntos
Ginkgolídeos/síntese química , Ginkgolídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Linhagem Celular , Reação de Cicloadição , Desenho de Fármacos , Ginkgolídeos/química , Concentração Inibidora 50 , Estrutura Molecular , Ratos
4.
Biomed Pharmacother ; 115: 108885, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029888

RESUMO

BACKGROUND: Finding novel agent for cerebral ischemia therapy is urgently required. In our present study, we aimed to investigate the regulatory mechanism of Ginkgolides B (GB) in hypoxia-injured PC-12 cells. METHODS: PC-12 cells were exposed to hypoxia and administrated with GB. Cell viability was detected by MTT assay. Flow cytometry assay was conducted for the detection of cell apoptosis, ROS generation and cell cycle assay. The changes of protein levels of Bax, Pro/Cleaved-Caspase-3, CyclinD1, CDK4, CDK6, PI3K/AKT and MEK/ERK pathways were detected by Western blot. Transfection was conducted for Polo-like kinase 1 (PLK1) knockdown. RESULTS: Hypoxia-induced decrease of cell viability and increase of ROS generation, apoptosis and cell cycle arrest were ameliorated by GB. Hypoxia disposition hindered PI3 K/AKT and MEK/ERK signaling pathways while GB had the opposite effects. Then we observed that hypoxia exposure suppressed PLK1 expression while GB increased PLK1 expression dose-dependently. Knockdown of PLK1 attenuated the neuroprotective effects of GB on hypoxia-injured PC-12 cells and also inhibited PI3 K/AKT and MEK/ERK pathways. CONCLUSION: The above observations corroborated that GB alleviated hypoxia-induced PC-12 cell injury by up-regulation of PLK1 via activating PI3K/AKT and MEK/ERK pathways. These findings implied the neuro-protective impacts in hypoxia-injured PC-12 cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Oxigênio/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ginkgolídeos/química , Lactonas/química , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Estrutura Molecular , Células PC12 , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Espécies Reativas de Oxigênio
5.
Oxid Med Cell Longev ; 2019: 8636835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911351

RESUMO

Ginkgo ketoester tablets (GT) and donepezil were a clinically used combination for the treatment of Alzheimer's disease (AD). The aim of the study was undertaken to investigate the antiamnesic effects of the two drugs alone and in combination through in vivo models of the Morris water maze along with in vitro antioxidants, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The potential mechanisms were speculated by the activities of acetylcholine (ACh), AChE, superoxide dismutase (SOD), and malondialdehyde (MDA) and the protein expression of brain-derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB). The combination group showed a concentration-dependent inhibition of cholinesterase and antioxidation. As far as its mechanism was concerned, the combination of two drugs exerted excellent effects on oxidative stress, cholinergic pathway damage, and inactivation of the BDNF-TrkB signaling pathway. Additionally, to elucidate the binding mechanism of GT active ingredients into the structure of AChE, the results of molecular docking studies indicated that hydrogen and/or hydrophobic bonds might play an important role in their binding process. Thus, the combination of drugs could treat AD perfectly and further verify the scientific rationality of clinical medication.


Assuntos
Amnésia/tratamento farmacológico , Donepezila/uso terapêutico , Ginkgo biloba/química , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Acetilcolina/metabolismo , Acetilcolinesterase , Amnésia/patologia , Animais , Benzotiazóis/química , Compostos de Bifenilo/química , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Donepezila/farmacologia , Quimioterapia Combinada , Ginkgolídeos/química , Ligantes , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Picratos/química , Extratos Vegetais/farmacologia , Receptor trkB/metabolismo , Escopolamina , Ácidos Sulfônicos/química , Superóxido Dismutase/metabolismo , Comprimidos
6.
Anticancer Agents Med Chem ; 19(6): 802-819, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30514195

RESUMO

BACKGROUND: Traditional chemotherapeutics of low-molecular weight diffuse passively across intact membrane structures of normal healthy cells found in tissues and organ systems in a non-specific unrestricted manner which largely accounts for the induction of most sequelae which restrict dosage, administration frequency, and duration of therapeutic intervention. Molecular strategies that offer enhanced levels of potency, greater efficacy and broader margins-of-safety include the discovery of alternative candidate therapeutics and development of methodologies capable of mediating properties of selective "targeted" delivery. MATERIALS AND METHODS: The covalent immunopharmaceutical, dexamethasone-(C21-phosphoramidate)-[anti- EGFR] was synthesized utilizing organic chemistry reactions that comprised a multi-stage synthesis regimen. Multiple forms of analysis were implemented to vadliate the successful synthesis (UV spectrophotometric absorbance), purity and molar-incorporation-index (UV spectrophotometric absorbance, chemical-based protein determination), absence of fragmentation/polymerization (SDS-PAGE/chemiluminescent autoradiography), retained selective binding-avidity of IgG-immunoglobulin (cell-ELISA); and selectively "targeted" antineoplastic cytotoxicity (biochemistry-based cell vitality/viability assay). RESULTS: The botanicals carnosic acid, ginkgolide-B and tangeretin, each individually exerted maximum antineoplastic cytotoxicity levels of 58.1%, 5.3%, and 41.1% respectively against pulmonary adenocarcinoma (A549) populations. Dexamethasone-(C21-phosphoramidate)-[anti-EGFR] formulated at corticosteroid/ glucocorticoid equivalent concentrations produced anti-neoplastic cytotoxicity at levels of 7.7% (10-9 M), 26.9% (10-8 M), 64.9% (10-7 M), 69.9% (10-6 M) and 73.0% (10-5 M). Ccarnosic acid, ginkgolide-B and tangeretin in simultaneous dual-combination with dexamethasone-(C21-phosphoramidate)-[anti-EGFR] exerted maximum anti-neoplastic cytotoxicity levels of 70.5%, 58.6%, and 69.7% respectively. DISCUSSION: Carnosic acid, ginkgolide-B and tangeretin botanicals exerted anti-neoplastic cytotoxicity against pulmonary adenocarcinoma (A549) which additively contributed to the anti-neoplastic cytotoxic potency of the covalent immunopharmaceutical, dexamethasone-(C21-phosphoramidate)-[anti-EGFR]. Carnosic acid and tangeretin were most potent in this regard both individually and in dual-combination with dexamethasone-(C21- phosphoramidate)-[anti-EGFR]. Advantages and attributes of carnosic acid and tangeretin as potential monotherapeutics are a wider margin-of-safety of conventional chemotherapeutics which would readily complement the selective "targeted" delivery properties of dexamethasone-(C21-phosphoramidate)-[anti-EGFR] and possibly other covalent immunopharmaceuticals in addition to providing opportunities for the discovery of combination therapies that provide heightened levels of anti-neoplastic efficacy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Dexametasona/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Abietanos/síntese química , Abietanos/química , Abietanos/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Dexametasona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Flavonas/síntese química , Flavonas/química , Flavonas/farmacologia , Ginkgolídeos/síntese química , Ginkgolídeos/química , Ginkgolídeos/farmacologia , Humanos , Lactonas/síntese química , Lactonas/química , Lactonas/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Zhongguo Zhong Yao Za Zhi ; 43(20): 4093-4096, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30486536

RESUMO

The fragmentation pathways of the three ginkgolides (ginkgolides A, ginkgolides B, ginkgolides C) have been studied with high resolution and high mass accuracy using quadrupole time-of-flight mass spectrometry in negative ion mode in this paper. The results indicate that the three ginkgolides have similar fragmentation pathways, including four kinds of common cleavage pathways and one common characteristic ion. In high quality regions, the typical fragmentation pathways of the three ginkgolides are lactone ring opening with continuous loss of CO, CO2,and loss of H2O. In low quality regions, the common characteristic fragment ion of the three ginkgolides at m/z72.993 6 is formed by C rings cleavage. Also, the common fragment ions of ginkgolides A and ginkgolides B at m/z141.018 8, 125.023 8, 113.024 0, 97.029 1 are formed by A rings cleavage. The study of fragmentation pathways could be adopted for the structural identification of the ginkgolides and their metabolites.


Assuntos
Ginkgolídeos/química , Espectrometria de Massas , Espectrometria de Massas por Ionização por Electrospray
8.
Acta Pharmacol Sin ; 39(12): 1935-1946, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30054600

RESUMO

Terpene lactones are a class of bioactive constituents of standardized preparations of Ginkgo biloba leaf extract, extensively used as add-on therapies in patients with ischemic cardiovascular and cerebrovascular diseases. This investigation evaluated human pharmacokinetics of ginkgo terpene lactones and impact of their carboxylation in blood. Human subjects received oral YinXing-TongZhi tablet or intravenous ShuXueNing, two standardized ginkgo preparations. Their plasma protein-binding and platelet-activating factor antagonistic activity were assessed in vitro. Their carboxylation was assessed in phosphate-buffered saline (pH 7.4) and in human plasma. After dosing YinXing-TongZhi tablet, ginkgolides A and B and bilobalide exhibited significantly higher systemic exposure levels than ginkgolides C and J; after dosing ShuXueNing, ginkgolides A, B, C, and J exhibited high exposure levels. The compounds' unbound fractions in plasma were 45-92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6-15%. Bilobalide's bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4-7 h) after dosing ShuXueNing were shorter than their respective values (6-13 h) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5 h. Terpene lactones were roughly evenly distributed in various body fluids and tissues; glomerular-filtration-based renal excretion was the predominant elimination route for the ginkgolides and a major route for bilobalide. Terpene lactones circulated as trilactones and monocarboxylates. Carboxylation reduced platelet-activating factor antagonistic activity of ginkgolides A, B, and C. Ginkgolide J, bilobalide, and ginkgo flavonoids exhibited no such bioactivity. Collectively, differences in terpene lactones' exposure between the two preparations and influence of their carboxylation in blood should be considered in investigating the relative contributions of terpene lactones to ginkgo preparations' therapeutic effects. The results here will inform rational clinical use of ginkgo preparations.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Ginkgolídeos/farmacocinética , Lactonas/farmacocinética , Fator de Ativação de Plaquetas/antagonistas & inibidores , Adulto , Animais , Fenômenos Bioquímicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Feminino , Ginkgo biloba/química , Ginkgolídeos/sangue , Ginkgolídeos/química , Ginkgolídeos/urina , Células HEK293 , Humanos , Lactonas/sangue , Lactonas/química , Lactonas/urina , Masculino , Coelhos , Adulto Jovem
9.
Chin J Nat Med ; 16(5): 366-374, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29860998

RESUMO

Analysis errors can occur in the desorbing process of ginkgo diterpene lactone meglumine injection (GDMI) by a conventional analysis method, due to several factors, such as easily crystallized samples, solvent volatility, time-consuming sample pre-processing, fixed method, and offline analysis. Based on risk management, near-infrared (NIR) and mid-infrared (MIR) spectroscopy techniques were introduced to solve the above problems with the advantage of timely analysis and non-destructive nature towards samples. The objective of the present study was to identify the feasibility of using NIR or MIR spectroscopy techniques to increase the analysis accuracy of samples from the desorbing process of GDMI. Quantitative models of NIR and MIR were established based on partial least square method and the performances were calculated. Compared to NIR model, MIR model showed greater accuracy and applicability for the analysis of the GDMI desorbing solutions. The relative errors of the concentrations of Ginkgolide A (GA) and Ginkgolide B (GB) were 2.40% and 2.89%, respectively, which were less than 5.00%. The research demonstrated the potential of the MIR spectroscopy technique for the rapid and non-destructive quantitative analysis of the concentrations of GA and GB.


Assuntos
Química Farmacêutica/métodos , Ginkgolídeos/análise , Meglumina/análise , Gestão de Riscos , Espectrofotometria Infravermelho/normas , Química Farmacêutica/normas , Composição de Medicamentos/normas , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/normas , Ginkgolídeos/química , Ginkgolídeos/normas , Injeções , Lactonas/análise , Análise dos Mínimos Quadrados , Meglumina/química , Meglumina/normas , Reprodutibilidade dos Testes
10.
Biomed Chromatogr ; 32(6): e4212, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29516538

RESUMO

Ginkgolides are the primarily active components in Ginkgo products that are popular worldwide. However, few studies have evaluated the bioavailability of ginkgolides and the effects of food on it after oral administration of ginkgolides. In this article, pharmacokinetics and absolute bioavailability of the primary components in ginkgolide extracts were evaluated in beagle dogs. For the first time, we showed that the fed dogs had significantly increased area under the concentration-time curve and peak concentration relative to the fasted dogs based on the data from both the prototype form and total lactones of ginkgolide A (GA) and ginkgolide B (GB). In terms of the free form of the prototype ginkgolides, the absolute bioavailabilities of GA and GB were 34.8 and 5.2% in the fasted dogs, respectively, which significantly increased to an average of 78.6 and 17.0%, respectively, in the fed dogs. In terms of acidified total lactones, the absolute bioavailabilities of GA and GB were 7.5 and 14.5% in the fed dogs, and the percentages declined to 4.1 and 3.7% in the fasted dogs, respectively. It was suggested that administration of ginkgolides after meals could promote the in vivo exposure and the bioavailability of GA and GB, and hence potentially enhance therapeutic outcomes.


Assuntos
Ginkgolídeos/sangue , Ginkgolídeos/farmacocinética , Lactonas/sangue , Lactonas/farmacocinética , Extratos Vegetais , Administração Oral , Ração Animal , Animais , Disponibilidade Biológica , Cromatografia Líquida , Cães , Estabilidade de Medicamentos , Ingestão de Alimentos/fisiologia , Feminino , Ginkgolídeos/química , Lactonas/química , Modelos Lineares , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
11.
Molecules ; 23(2)2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29385087

RESUMO

Ginkgolides (GG), containing ginkgolide A (GA), ginkgolide B (GB) and ginkgolide C (GC), are mainly prescribed for ischemic stroke and cerebral infarction. However, the ginkgolides can hardly pass the blood-brain barrier (BBB) into the brain. The purpose of this study was to prepare borneol-modified ginkgolides liposomes (GGB-LPs) to study whether borneol could enhance the transport of ginkgolides across the BBB. The preparation conditions of GGB-LPs were optimized by a response surface-central composite design. Also, pharmacokinetics and biodistribution studies of GGB-LPs were conducted using UPLC-MS. The optimal preparation conditions for GGB-LP were as follows: ratio of lipid to drug (w/w) was 9:1, ratio of phospholipid to cholesterol (w/w) was 7:1, and hydrate volume was 17.5 mL. Under these conditions, the GGB-LP yield was 89.73 ± 3.45%. With GGB-LPs, borneol significantly promoted the transport of ginkgolide across the BBB. The pharmacokinetic parameters of GGB-LP were significantly improved too, with Tmax of 15 min and a high drug concentration of 3.39 µg/g in brain. Additionally, the drug targeting index and relative uptake rate of GGB-LP was increased. Borneol-modified ginkgolide liposomes can thus potentially be used to improve the BBB permeability of gingkolide formulations.


Assuntos
Barreira Hematoencefálica/metabolismo , Canfanos , Células Endoteliais/metabolismo , Ginkgolídeos , Animais , Barreira Hematoencefálica/patologia , Canfanos/química , Canfanos/farmacocinética , Canfanos/farmacologia , Linhagem Celular Transformada , Células Endoteliais/patologia , Ginkgolídeos/química , Ginkgolídeos/farmacocinética , Ginkgolídeos/farmacologia , Lipossomos , Camundongos , Permeabilidade
12.
J Pharm Biomed Anal ; 149: 151-159, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29121568

RESUMO

Nowadays, network pharmacology-based methods were increasing proposed to screen synergistic or combinatorial compounds from herbal medicines (HMs), while these researches mainly focused on structural prediction or experiment-based interaction between single compound and target protein. The proportion of each chemical in the nature and their metabolic process was ignored, which might decide an optimized composition for their synergistic effect. To exact the effective combination of HMs, a metabolic distribution-oriented network regulation strategy was developed for the identification of effective combination. Firstly, comprehensive chemical profiling and metabolic exposure of HMs in a pathological state were conducted. Then the effective combination for HMs was screened by combining network regulation and the metabolic exposure level of HMs. Finally, with the extract of Ginkgo biloba (EGB) as a case, a combination of 12 active compounds was found for treating ischemia stroke, showing bioactivity equivalence with original herb. The results also indicated that beside the well-known ginkgolides and flavonoids, trace compounds might also play an important role of the holistic effect of EGB. This method can be used as an alternative for effective combination screening.


Assuntos
Ginkgo biloba/química , Infarto da Artéria Cerebral Média/tratamento farmacológico , Redes e Vias Metabólicas/efeitos dos fármacos , Extratos Vegetais/química , Animais , Biomarcadores/análise , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Flavonoides/química , Flavonoides/farmacocinética , Flavonoides/uso terapêutico , Ginkgolídeos/química , Ginkgolídeos/farmacocinética , Ginkgolídeos/uso terapêutico , Humanos , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacocinética , Extratos Vegetais/uso terapêutico , Equivalência Terapêutica
13.
AAPS PharmSciTech ; 19(2): 541-550, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28849380

RESUMO

The purpose of this study was to prepare ginkgolide B (GB) lyophilized powder for injection with excellent appearance and stable quality through a formulation screening and by optimizing the freeze-drying process. Cremophor EL as a solubilizer, PEG 400 as a latent solvent, and mannitol as an excipient were mixed to increase the solubility of GB in water to more than 18 times (about from 2.5 × 10-4 mol/L (0.106 mg/mL) to 1.914 mg/mL). Formulation screening was conducted by orthogonal design where the content of GB in the solution before lyophilization (using external standard method of HPLC) and reconstitution time after lyophilization were the two evaluation indexes. The optimized formulations were GB in an amount of 2 mg/mL, Cremophor EL in an amount of 16% (v/v), PEG 400 in an amount of 9% (v/v), mannitol in an amount of 8% (w/v), and the solution pH of 6.5. Through four single-factor experiments (GB adding order, preparation temperature of GB solution, adding amount, and adsorption time of activated carbon), the preparation process of GB solution was confirmed. The glass transition temperature of maximally GB freeze-concentrated solution was - 17.6°C through the electric resistance method. GB lyophilized powder began to collapse at - 14.0°C, and the fully collapsed temperature was - 13.0°C, which were determined by freeze-drying microscope. When the collapse temperature was determined, the primary drying temperature was obtained. Thereby, the freeze-drying curve of GB lyophilized powder was initially identified. The freeze-drying process was optimized by orthogonal design, the qualified product appearance and residual moisture content were the two evaluation indexes. The optimized process parameters and process were (1) shelf temperature, decreased from room temperature to - 45.0°C, at 0.5°C/min in 2 h; (2) shelf temperature increased from - 45.0 to - 25.0°C, at 0.1°C/min, maintained for 3 h, and the chamber pressure was held at 10 Pa; (3) shelf temperature was increased from - 25.0 to - 15.0°C at 0.1 °C/min, maintained for 4 h, and the chamber pressure was held at 10 Pa; and (4) shelf temperature was increased from - 15.0 to 20.0°C at 1.0 °C/min, maintained for 4 h, and the chamber pressure was raised up to 80 Pa. In these lyophilization process conditions, the products complied with relevant provisions of the lyophilized powders for injection. Meanwhile, the reproducibility was satisfactory. Post-freezing annealing had no significantly beneficial effects on shortening the freeze-drying cycle and improving the quality of GB lyophilized powder.


Assuntos
Ginkgolídeos/administração & dosagem , Lactonas/administração & dosagem , Dessecação , Excipientes/química , Liofilização , Congelamento , Ginkgolídeos/química , Glicerol/análogos & derivados , Glicerol/química , Injeções , Lactonas/química , Manitol/química , Polietilenoglicóis/química , Pós , Reprodutibilidade dos Testes , Solubilidade , Solventes/química , Temperatura , Temperatura de Transição
14.
Mol Med Rep ; 16(4): 5627-5632, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28849170

RESUMO

Ginkgolide B is one of the components extracted from Folium Ginkgo. It is a natural antagonist of platelet­activating factor receptor and has multiple pharmacological applications. In the present study, the effect of ginkgolide B on the proliferation of endothelial progenitor cells (EPCs) was examined, as well as its potential underlying mechanism. EPCs were cultured in various concentrations of ginkgolide B (0, 1.25, 5, 20, 80 or 160 µg/ml) for 24 or 48 h and then numbers of viable cells, apoptosis rate and caspace­3 activity were measured. The results demonstrated that ginkgolide B treatment effectively promoted EPC growth, and suppressed cell apoptosis and caspase­3 activity compared with control cells. In addition, ginkgolide B treatment significantly induced the expression of miR­126, vascular endothelial growth factor and endothelial nitric oxide synthase, while it increased phosphorylation of AKT serine/threonine kinase 1 (Akt) and of p38 mitogen­activated protein kinase in EPCs. The present study therefore demonstrated that ginkgolide B promoted cell growth in EPCs through overexpression of miR­126 and activation of the Akt signaling pathway.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Ginkgolídeos/farmacologia , Lactonas/farmacologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ginkgolídeos/química , Lactonas/química , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Oncotarget ; 8(27): 44682-44693, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28591721

RESUMO

Ginkgolide K (GK) belongs to the ginkgolide family of natural compounds found in Ginkgo biloba leaves, which have been used for centuries to treat cerebrovascular and cardiovascular diseases. We evaluated the protective effects of GK against neuronal apoptosis by assessing its ability to sustain mitochondrial integrity and function. Co-immunoprecipitation showed that Drp1 binding to GSK-3ß was increased after an oxygen-glucose deprivation/reperfusion (OGD/R) insult in cultured neuroblastoma cells. This induced Drp1 and GSK-3ß translocation to mitochondria and mitochondrial dysfunction, which was attenuated by GK. GK also reduced mitochondrial fission by increasing Drp1 phosphorylation at Ser637 and inhibiting mitochondrial Drp1 recruitment. In addition, GK exposure induced GSK-3ß phosphorylation at Ser9 and enhanced the interaction between adenine nucleotide translocator (ANT) and p-GSK-3ß. This interaction suppressed the interaction between ANT and cyclophilin D (CypD), which inhibited mitochondrial permeability transition pore (mPTP) opening. Similarly, suppression of mitochondrial fission by Mdivi-1 also inhibited GSK-3ß-induced mPTP opening. Treating mice with GK prevented GSK-3ß and Drp1 translocation to mitochondria and attenuated mitochondrial dysfunction after middle cerebral artery occlusion. We therefore propose that by inhibiting mitochondrial fission and attenuating mPTP opening, GK exerts neuroprotective effects that mitigate or prevent neuronal damage secondary to ischemic stroke.


Assuntos
Ginkgolídeos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Lactonas/farmacologia , Dinâmica Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Dinaminas/metabolismo , Ginkgolídeos/química , Glucose/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Lactonas/química , Masculino , Camundongos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Oxigênio/metabolismo , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/patologia
16.
J Biomater Sci Polym Ed ; 28(14): 1497-1510, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28532338

RESUMO

The amphiphilic PEG-b-PCL block copolymers were synthesized by ring-opening polymerization. The specific and selective antagonists of platelet activating factor, Ginkgolide B (GB), was successfully encapsulated in the synthesized PEG-PCL nanoparticles (NPs) with high Encapsulation Efficiency and Drug Loading. The synthesis of different PEG-PCL copolymers were confirmed with FTIR and 1H NMR spectra. The morphology and particles size distribution of cargo-free PEG-PCL NPs were studied by transmission electron microscope (TEM) analysis and Malvern laser particle analyzer. The bio-distribution and pharmacodynamics studies of GB were studied with Wistar mice as the animal models via tail injecting of GB-PEG-PCL NPs. Results from Malvern laser particle analyzer and TEM analysis illustrated that the cargo-free NPs showed narrow distribution and well separated particles size of about 60 nm in diameter. The in vitro experiment of GB-PEG-PCL NPs exhibited an extended release behavior. The bio-distribution data suggested that Tween-80 covered GB-PEG-PCL NPs showed a brain-targeting behavior. The pharmacodynamics results confirmed that the GB-PEG-PCL NPs had an obvious cerebral protection effect.


Assuntos
Encéfalo/metabolismo , Desenho de Fármacos , Ginkgolídeos/química , Interações Hidrofóbicas e Hidrofílicas , Lactonas/química , Poliésteres/química , Poliésteres/metabolismo , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Animais , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Ginkgolídeos/farmacocinética , Ginkgolídeos/farmacologia , Lactonas/farmacocinética , Lactonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
17.
Drug Metab Lett ; 10(4): 228-239, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28103788

RESUMO

OBJECTIVE: This study describes the in vivo pharmacokinetics and metabolism of [14C]labeled XQ-1H in male rats. METHODS: XQ-1H is a methanesulfonate of XQ, 10-O-(N,N-dimethylaminoethyl)-ginkgolide B, a derivative of ginkgolide B (GB) with enhanced water solubility. Since it is very difficult to synthesize radiolabeled GB, the results obtained in this study may provide helpful insight to further ADME investigation of GB and its analogue compounds. After an i.v. administration of [14C]XQ-1H to male rats, XQ (the freebase form of XQ-1H) was extensively hydrolyzed, moderately metabolized, and mainly excreted in feces (71.5% of the dose) via the biliary route. RESULTS: The main enzyme mediated metabolic pathways were mono- and di-demthylation. Using the radiolabel form of XQ-1H, the temporal binding of XQ to red blood cells was observed. CONCLUSION: Binding of XQ to RBCs may lower the blood's viscosity and thus provide symptomatic improvement of ischemic stroke patients.


Assuntos
Viscosidade Sanguínea/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Eritrócitos/metabolismo , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/sangue , Radioisótopos de Carbono/química , Desmetilação , Fezes/química , Ginkgo biloba/química , Ginkgolídeos/química , Ginkgolídeos/metabolismo , Ginkgolídeos/uso terapêutico , Eliminação Hepatobiliar , Injeções Intravenosas , Lactonas/química , Lactonas/metabolismo , Lactonas/uso terapêutico , Masculino , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/sangue , Distribuição Tecidual
18.
J Pharm Biomed Anal ; 134: 181-186, 2017 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-27915195

RESUMO

Ginkgolides, the main active constituents of Ginkgo biloba, possess significant selectively inhibition on platelet-activating factor and pancreatic lipase and attract wide attention in pharmacological research area. In our study, an effective hydrogen/deuterium (H/D) exchange method was developed by exchanging the α-Hs of lactone groups in ginkgolides with Ds, which was very useful for the elucidation of the fragmentation patterns of ginkgolides in Quadrupole Time-of-flight Mass Spectrometry (Q-TOF-MS), especially in accurately distinguishing the type and position of substituent in framework of ginkgolides. Then, a systematic research strategy for qualitative and quantitative analysis of ginkgolides, based on H/D exchange, tandem solid-phase extraction and LC-Q-TOF-MS, was developed, which was successfully applied in each medicinal part of G. biloba, which indicated that ginkgolide B was the most abundant ginkgolide in the seeds of G. biloba (60.6µg/g). This research was the successful application of H/D exchange in natural products, and proved that H/D exchange is a potential method for analysis research of complex TCMs active constituents.


Assuntos
Medição da Troca de Deutério/métodos , Ginkgo biloba , Ginkgolídeos/análise , Extratos Vegetais/análise , Extração em Fase Sólida/métodos , Ginkgolídeos/química , Espectrometria de Massas/métodos , Extratos Vegetais/química , Sementes
19.
Mini Rev Med Chem ; 17(12): 988-1001, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27297674

RESUMO

BACKGROUND: FL 32608 Terpenoids are hydrocarbon compounds derived from common fivecarbon isoprene (C5H8) building blocks. They are formed through the condensation and subsequent modification of isoprene units in various ways including - among others - cyclization and/or oxygenation. Their synthesis is localized either to the chloroplast and/or to the cytoplasm/peroxisome/ endoplasmic reticulum and mitochondrion. Terpenoids represent a very large and diverse class of metabolites and play important roles in plant growth and development. In addition, they have been intensively used in human health care, disease treatment and in dietary supplements. Approximately 60% of natural products known so far are terpenoids. CONCLUSION: This review briefly summarizes the biosynthetic pathways of major plant terpenoids. Then, five well-known and medicinally important diterpenoids, including paclitaxel, tanshinone, ginkgolide, triptolide and oridonin are discussed in detail. Their structures, occurrence, extraction and identification methods, pharmacological properties and clinical uses are also reviewed. Finally, the prospects of using biotechnology to produce medicinally important terpenoids are also briefly discussed.


Assuntos
Diterpenos/metabolismo , Plantas/química , Plastídeos/química , Abietanos/biossíntese , Abietanos/química , Diterpenos/química , Diterpenos de Caurano/biossíntese , Diterpenos de Caurano/química , Compostos de Epóxi/química , Compostos de Epóxi/metabolismo , Ginkgolídeos/química , Ginkgolídeos/metabolismo , Engenharia Metabólica , Paclitaxel/biossíntese , Paclitaxel/química , Fenantrenos/química , Fenantrenos/metabolismo , Plantas/metabolismo , Plastídeos/metabolismo
20.
Bioorg Med Chem ; 24(21): 5148-5157, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27614918

RESUMO

The blood-brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a 18F-incorporated ginkgolide B ([18F]-2) and a 11C-incorporated methylbenzyl-substituted ginkgolide B ([11C]-3). PET studies in monkeys showed low uptake of [18F]-2 into the brain, but small amounts of [11C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [18F]-2 in the rat brain did not significantly change, however, the accumulation of [11C]-3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of ginkgolides.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Ginkgolídeos/farmacocinética , Lactonas/farmacocinética , Tomografia por Emissão de Pósitrons , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ginkgolídeos/síntese química , Ginkgolídeos/química , Ginkgolídeos/farmacologia , Haplorrinos , Lactonas/síntese química , Lactonas/química , Lactonas/farmacologia , Estrutura Molecular , Permeabilidade/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
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