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1.
Brain Res Bull ; 154: 32-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669104

RESUMO

Glial cell line-derived neurotrophic factor (GDNF) has neurotrophic activity for the survival of dopaminergic neurons, which is under active investigation for Parkinson's disease (PD) therapy. FLZ is a potential new drug for PD treatment. However, it is unclear whether neurotrophic activity contributes to the neuroprotective effects of FLZ. Here we found that FLZ markedly improved the function of dopaminergic neurons in primary mesencephalic neuron/glia cultures. Further investigation demonstrated that astroglia were required for FLZ to function as a neurotrophic regulator, as FLZ failed to show neurotrophic effects in the absence of astroglia. We clarified that GDNF was responsible for the neurotrophic effects of FLZ since FLZ selectively stimulated GDNF production, which was confirmed by the finding that the neurotrophic effect of FLZ was attenuated by GDNF-neutralizing antibody. Mechanistic study demonstrated that GDNF induction by FLZ was CREB-dependent and that PI3K/Akt was the main pathway regulating CREB activity, which was confirmed by in vivo studies. We also validated that the induction of GDNF by FLZ contributed to PD treatment in vivo. In conclusion, the present data provided evidence that FLZ had robust neurotrophic effects on dopaminergic neurons through sustained induction of GDNF in astroglia by activating the PI3K/Akt/CREB pathway.

2.
PhytoKeys ; 130: 183-203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534406

RESUMO

Four new species of Gesneriaceae from Yunnan, southwest China, are described and illustrated. They are Petrocosmea rhombifolia, Petrocosmea tsaii, Didymocarpus brevipedunculatus, and Henckelia xinpingensis. Diagnostic characters between the new species and their morphologically close relatives are provided. Their distribution, ecology, phenology, and conservation status are also described.

3.
Acta Pharmacol Sin ; 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142800

RESUMO

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.

4.
Biosci Biotechnol Biochem ; 83(6): 1045-1061, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935300

RESUMO

MicroRNAs (miRNAs) regulate the development and growth cycle of hair follicles (HFs). The molecular mechanism by which miRNAs determine the development of HFs in the sheep foetus remains elusive. In this study, the expression profiles of miRNAs at 11 development periods (45, 55, 65, 75, 85, 95, 105, 115, 125, 135 and 145 d) in sheep foetus skin were analysed by high-throughput sequencing and bioinformatics analysis. A total of 72 conserved miRNAs, 44 novel miRNAs and 32 known miRNAs were significantly differentially expressed. qRT-PCR results for 18 miRNAs were consistent with the sequencing data. 85 d of foetal development was the starting point for secondary hair follicle (SF) development according to tissue morphology and cluster analysis. In SF development, the prolactin signalling pathway and platelet activation played important roles, and 10 miRNAs were potential candidate miRNAs in SF initiation.


Assuntos
Desenvolvimento Fetal/genética , Perfilação da Expressão Gênica , Folículo Piloso/crescimento & desenvolvimento , MicroRNAs/genética , Ovinos/embriologia , Animais , Biologia Computacional , Regulação para Baixo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Ativação Plaquetária , Prolactina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Análise de Sequência de RNA/métodos , Transdução de Sinais , Regulação para Cima ,
5.
Acta Pharmacol Sin ; 40(8): 1106-1118, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30792487

RESUMO

Cinnamic acid and its analogues (pyragrel and ozagrel) undergo chain-shortened (ß-oxidative) and reductive metabolism on acyl side chain. In this study, we characterized the ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes, hepatic mitochondrial, and microsomal systems. A compartmental model including parent compounds and metabolites was developed to characterize in vivo ß-oxidative and reductive metabolism following an intravenous dose of parent compounds to rats. The fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred model. We showed that hepatic microsomal CYP450s did not catalyze ß-oxidative or reductive metabolism of the three compounds. Similar to ß-oxidation of fatty acids, ß-oxidative metabolism on their acyl side chain occurred mainly in mitochondria, which was highly dependent on ATP, CoA and NAD+. Fatty acids and NADH inhibited the ß-oxidative metabolism. Reductive metabolism occurred in both mitochondria and microsomes. Reduction in mitochondria was ATP-, CoA-, and NAD(P)H-dependent and reversible, which was suppressed by enoyl reductase inhibitor triclosan. Reduction in microsomes was ATP-, CoA-, and NADPH-dependent but little affected by triclosan. Both plasma concentrations of ß-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental model. The estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles, implicating significance of in vitro kinetics. These findings demonstrate the roles of hepatic mitochondria and microsomes in ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.


Assuntos
Cinamatos/metabolismo , Metacrilatos/metabolismo , Pirazinas/metabolismo , Animais , Cinamatos/química , Cinamatos/farmacocinética , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Masculino , Metacrilatos/química , Metacrilatos/farmacocinética , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Estrutura Molecular , NAD/metabolismo , Oxirredução/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacocinética , Ratos Sprague-Dawley , Triclosan/farmacologia
6.
Am J Chin Med ; 46(2): 389-405, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29433392

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Although the exact causes of AD have not yet been fully elucidated, cholinergic dysfunction, mitochondrial damage, oxidative stress and neuroinflammation have been recognized as influential factors. Current drugs that are designed to address only a single target are unable to mitigate or prevent the progression of this complicated disease, so new disease-modifying drugs are urgently needed. Chinese herbs with thousand years of effective usage might be a good source for potential drugs. Gardenia jasminoides J. Ellis (Fructus Gardenia) is a common traditional Chinese medicine with tranquilizing effects, which is an important component of widely-used traditional Chinese medicine for dementia. GJ-4 is crocin richments extracted from Gardenia jasminoides J. Ellis. In our study, we attempted to observe the effects of GJ-4 on learning and memory injury induced by amyloid-[Formula: see text] 25-35 (A[Formula: see text] injection in mice. Treatment with GJ-4 dose-dependently enhanced the memory and cognition ability of A[Formula: see text]-injected mice. Preliminary mechanistic studies revealed the protective effect of GJ-4 was related to its protection of neurons and cholinergic dysfunction. The mechanistic results also indicated that GJ-4 could enhance antioxidant capacity and attenuate neuroinflammation. Our results implied that GJ-4 might be a promising drug to improve cognitive and memory impairment, with multiple targets.


Assuntos
Peptídeos beta-Amiloides/efeitos adversos , Antioxidantes , Carotenoides/farmacologia , Carotenoides/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Gardenia/química , Fragmentos de Peptídeos/efeitos adversos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Carotenoides/isolamento & purificação , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Frutas/química , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos ICR , Extratos Vegetais/isolamento & purificação
7.
Molecules ; 23(1)2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29315271

RESUMO

Sanggenon X, an unusual tri-O-bridged Diels-Alder adduct, was isolated from Cortex Mori Radicis. Its structure was established by spectroscopic analysis, including NMR and HR-MS (High Resolution Mass Spectrometry). Sanggenon X contained three O-bridged rings, where the oxygenated bridgeheads were all quaternary carbons. Chemical methylation was carried out to deduce the linkages of the three O-bridges. The absolute configuration was determined by calculating the ECD (Electronic Circular Dichroism) using the TDDFT (Time-Dependent Density Functional Theory) method. Sanggenon X showed significant antioxidant activity against Fe2+-Cys-induced lipid peroxidation in rat liver microsomes, and was as effective as the positive control, curcumin.


Assuntos
Antioxidantes/química , Medicamentos de Ervas Chinesas/química , Compostos Heterocíclicos de Anel em Ponte/química , Microssomos Hepáticos/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Dicroísmo Circular/métodos , Medicamentos de Ervas Chinesas/farmacologia , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Casca de Planta/química , Raízes de Plantas/química , Ratos , Relação Estrutura-Atividade , Termodinâmica
8.
Mol Cell Neurosci ; 86: 58-64, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29183796

RESUMO

Neuroinflammation triggered by activation of glial cells plays an important role in the pathophysiology of several neurodegenerative diseases including Parkinson's disease (PD). Besides microglia, astrocytes are also critical in initiating and perpetuating inflammatory process associated with PD. Heat shock protein 70 (Hsp70) is originally described as intracellular chaperone, however, recent study revealed that it had anti-inflammatory effects as well. The present study is designed to investigate whether Hsp70 mediates neuroinflammation in astrocytes. By employing α-synuclein (α-Syn) (A53T) aggregates on primary cultured astrocytes of rats, we found that astrocytes were activated and neuroinflammatory response was triggered, as indicated by over-expression of glial fibrillary acidic protein (GFAP), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), increased production of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). The data also showed that the neuroinflammatory response accompanied up-regulated Hsp70 expression. Moreover, over-expression of Hsp70 through transfection of Hsp70 cDNA plasmids could significantly reduce the production of TNF-α, IL-1ß, and the expression of GFAP, COX-2 as well as iNOS. While inhibition of Hsp70 by VER155008 exacerbated neuroinflammatory response in astrocytes challenged by α-Syn aggregates. Further mechanistic study indicated that c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) signalings were responsible for the neuroinflammation, which was also regulated by Hsp70. These findings demonstrated that Hsp70 was an important modulator in astrocytes induced inflammation, and up-regulation of Hsp70 might be a potential regulating approach for neuroinflammation-related neurodegenerative diseases, such as PD.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Proteínas de Choque Térmico HSP70/biossíntese , alfa-Sinucleína/toxicidade , Animais , Células Cultivadas , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Ratos , Ratos Sprague-Dawley
9.
Zhongguo Zhong Yao Za Zhi ; 42(22): 4346-4352, 2017 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-29318833

RESUMO

The rich diversity in medicinal plants provides an important material basic for the development of Traditional Chinese medicine in China. It is important to explore the present situation of medicinal plants within special regions in order to provide scientific instructions for their sustainable protection and exploitation and utilization. In this study, we carried out the field survey according to the guideline of national survey of Chinese material medica resources and the guideline of plant species diversity survey and estimation at county level with the line transect method. With the field surveyed data, we explored the diversity and distribution of the threatened medicinal vascular plants in Lancang. We found that there were 33 species of the threatened medicinal vascular plants in this county. These species were from 23 genera and 17 families, and were composed of one critical endangered, 10 endangered and 22 vulnerable species. They were widely distributed across the whole county and were most concentrated in the town of Nuozhadu, Fazhanhe, Nuofu and Zhutang, which were located in the southeastern, southwestern and western of Lancang, respectively. We also found that the plant species richness followed a unimodal pattern along elevation. In addition, we found that the areas of Nuozhadu Nature Reserve in Lancang only covered six threatened medicinal vascular plants, while most of the regions with high species richness were not well protected. Therefore, we proposed to make more efforts to improve the protection measurements in order to better protect and utilize the medicinal plants in Lancang.


Assuntos
Biodiversidade , Plantas Medicinais/classificação , Traqueófitas/classificação , China , Conservação dos Recursos Naturais , Medicina Tradicional Chinesa
10.
Sensors (Basel) ; 14(2): 2967-80, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24531300

RESUMO

Microfluidic systems based on fluorescence detection have been developed and applied for many biological and chemical applications. Because of the tiny amount of sample in the system; the induced fluorescence can be weak. Therefore, most microfluidic systems deploy multiple optical components or sophisticated equipment to enhance the efficiency of fluorescence detection. However, these strategies encounter common issues of complex manufacturing processes and high costs. In this study; a miniature, cylindrical and hybrid lens made of polydimethylsiloxane (PDMS) to improve the fluorescence detection in microfluidic systems is proposed. The hybrid lens integrates a laser focusing lens and a fluorescence collecting lens to achieve dual functions and simplify optical setup. Moreover, PDMS has advantages of low-cost and straightforward fabrication compared with conventional optical components. The performance of the proposed lens is first examined with two fluorescent dyes and the results show that the lens provides satisfactory enhancement for fluorescence detection of Rhodamine 6G and Nile Red. The overall increments in collected fluorescence signal and detection sensitivity are more than 220% of those without lens, and the detection limits of Rhodamine 6G and Nile red are lowered to 0.01 µg/mL and 0.05 µg/mL, respectively. The hybrid lens is further applied to the detection of Nile red-labeled Chlorella vulgaris cells and it increases both signal intensity and detection sensitivity by more than 520%. The proposed hybrid lens also dramatically reduces the variation in detected signal caused by the deviation in incident angle of excitation light.

11.
Nucleic Acids Res ; 41(22): 10403-13, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23999094

RESUMO

Filamentous bacteria of the genus Streptomyces possess linear chromosomes and linear plasmids. Theoretically, linear replicons may not need a decatenase for post-replicational separation of daughter molecules. Yet, Streptomyces contain parC and parE that encode the subunits for the decatenase topoisomerase IV. The linear replicons of Streptomyces adopt a circular configuration in vivo through telomere-telomere interaction, which would require decatenation, if the circular configuration persists through replication. We investigated whether topoisomerase IV is required for separation of the linear replicons in Streptomyces. Deletion of parE from the Streptomyces coelicolor chromosome was achieved, when parE was provided on a plasmid. Subsequently, the plasmid was eliminated at high temperature, and ΔparE mutants were obtained. These results indicated that topoisomerase IV was not essential for Streptomyces. Presumably, the telomere-telomere association may be resolved during or after replication to separate the daughter chromosomes. Nevertheless, the mutants exhibited retarded growth, defective sporulation and temperature sensitivity. In the mutants, circular plasmids could not replicate, and spontaneous circularization of the chromosome was not observed, indicating that topoisomerase IV was required for decatenation of circular replicons. Moreover, site-specific integration of a plasmid is impaired in the mutants, suggesting the formation of DNA knots during integration, which must be resolved by topoisomerase IV.


Assuntos
Segregação de Cromossomos , Cromossomos Bacterianos/química , DNA Topoisomerase IV/fisiologia , Streptomyces/genética , DNA Topoisomerase IV/genética , Deleção de Genes , Plasmídeos/biossíntese , Plasmídeos/genética , Streptomyces/crescimento & desenvolvimento
12.
Int J Pharm ; 443(1-2): 17-25, 2013 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-23318366

RESUMO

Repeated injection of pegylated liposomes could elicit the disappearance of long-circulating characteristic, referred to as "accelerated blood clearance phenomenon." ABC phenomenon typically occurs when entrapped drugs are not cytotoxic, but recently it was reported that multiple doses of pegylated liposomal topotecan, a cytotoxic drug, could also induce the phenomenon in rats. To reveal whether the phenomenon could be induced in dogs and the effect of time interval between doses on the magnitude of ABC, pLT was repeatedly injected into beagle dogs with a time interval of 7, 21 and 28 days. The anti-PEG Ig M levels were detected using ELISA. It was found that ABC phenomenon could be induced in dogs by pLT. Inter-individual difference in anti-PEG antibody production could be observed, and antibody levels were directly correlated with the magnitude of ABC. Furthermore, time interval between doses had marked effect on the magnitude of ABC phenomenon. When the time interval was prolonged from 1 week to 4 weeks, ABC phenomenon could be eliminated. By comparing the pharmacokinetic profiles of lipid vesicles and entrapped topotecan, it was found that "empty pegylated vesicles" be formed in circulation, which might be responsible for the occurrence of ABC phenomenon.


Assuntos
Portadores de Fármacos/química , Polietilenoglicóis/química , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/sangue , Topotecan/administração & dosagem , Topotecan/sangue , Animais , Cães , Esquema de Medicação , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Composição de Medicamentos , Imunoglobulina M/sangue , Infusões Intravenosas , Lipossomos , Taxa de Depuração Metabólica , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Solubilidade , Propriedades de Superfície , Fatores de Tempo
13.
Mol Cancer Ther ; 11(4): 952-62, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22319204

RESUMO

Anti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such as gefitinib and erlotinib, is limited by the development of drug-resistant mutations, including the gatekeeper T790M mutation and upregulation of alternative signaling pathways. Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success. Here, we report a novel reversible EGFR inhibitor, SKLB1206, which has potent activity against EGFR with gefitinib-sensitive and -resistant (T790M) mutations. In addition, SKLB1206 has also considerable inhibition potency against some other related oncokinases, including ErbB2, ErbB4, and VEGF receptor 2 (VEGFR2). SKLB1206 exhibited highly antiproliferative activity against a range of EGFR-mutant cell lines, including gefitinib-sensitive and -resistant cell lines, and EGFR or ErbB2-overexpressing cell lines. SKLB1206 also showed a potent antiangiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 showed complete tumor regression in gefitinib-sensitive HCC827 and PC-9 xenograft models and showed a considerable antitumor effect on the gefitinib-resistant H1975 model as well as other EGFR/ErbB2-overexpressing or -dependent tumor models including A431, LoVo, and N87 established in athymic mice. SKLB1206 also showed a very good oral bioavailability (50.1%). Collectively, these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR-activating/resistance mutations or EGFR/ErbB2 overexpressed.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Mutação , Fosforilação , Quinazolinas/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-4 , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
14.
Yao Xue Xue Bao ; 45(12): 1565-9, 2010 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-21351498

RESUMO

This study is to compare the pharmacodynamics, pharmacokinetics and tissue distribution of liposomal mitoxantrone (Mit-lipo) and free mitoxantrone (Mit-free). The antineoplastic effect of Mit-lipo was evaluated on PC-3 human xenograft tumor model after repeated intravenous injection at dose levels of 1, 2 and 4 mg x kg(-1). The pharmacokinetic study of Mit-lipo and Mit-free was performed on dogs following a single intravenous injection. The tissue distribution of Mit-lipo and Mit-free was observed on S-180 bearing mice after a single intravenous injection. (1) Pharmacodynamics: Mit-lipo dose-dependently inhibited PC-3 tumor growth at a dose ranging from 1 to 4 mg x kg(-1). The antitumor effect studies showed that Mit-lipo significantly improved the therapeutic effect in comparison with free drug. (2) Pharmacokinetics: in comparison with Mit-free, the AUC and t(1/2) values of Mit-lipo at the same dose level were higher than those of Mit-free in Beagle dogs. The results showed that Mit-lipo had long circulation characteristics. (3) Tissue distribution in S-180 bearing mice: compared to Mit-free, Mit-lipo preferentially accumulated into tumor zones instead of normal tissues. Tumor AUC in Mit-lipo treated animals was 8.7 fold higher than that in mice treated with the same dose of Mit-free. The Cmax values of Mit-lipo in heart, kidney, lung, spleen and intestinal tissue in Mit-lipo were 30.2%, 161.6%, 20.2%, 27.9% and 78.3% lower than those of Mit-free, respectively. The pharmacokinetics and tissue distribution of Mit-lipo changed obviously, thus increasing therapeutic effect and improving drug therapeutic index.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Lipossomos/química , Mitoxantrona , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Área Sob a Curva , Linhagem Celular Tumoral , Cães , Relação Dose-Resposta a Droga , Portadores de Fármacos , Feminino , Humanos , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitoxantrona/administração & dosagem , Mitoxantrona/farmacocinética , Mitoxantrona/farmacologia , Transplante de Neoplasias , Neoplasias da Próstata/patologia , Sarcoma 180/patologia , Distribuição Tecidual
15.
PLoS One ; 4(10): e7462, 2009 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-19826489

RESUMO

Many but not all species of Streptomyces species harbour a bicistronic melC operon, in which melC2 encodes an extracellular tyrosinase (a polyphenol oxidase) and melC1 encodes a helper protein. On the other hand, a melC-homologous operon (melD) is present in all sequenced Streptomyces chromosomes and could be isolated by PCR from six other species tested. Bioinformatic analysis showed that melC and melD have divergently evolved toward different functions. MelD2, unlike tyrosinase (MelC2), is not secreted, and has a narrower substrate spectrum. Deletion of melD caused an increased sensitivity to several phenolics that are substrates of MelD2. Intracellularly, MelD2 presumably oxidizes the phenolics, thus bypassing spontaneous copper-dependent oxidation that generates DNA-damaging reactive oxygen species. Surprisingly, melC(+) strains were more sensitive rather than less sensitive to phenolics than melC(-) strains. This appeared to be due to conversion of the phenolics by MelC2 to more hydrophobic and membrane-permeable quinones. We propose that the conserved melD operon is involved in defense against phenolics produced by plants, and the sporadically present melC operon probably plays an aggressive role in converting the phenolics to the more permeable quinones, thus fending off less tolerant competing microbes (lacking melD) in the phenolic-rich rhizosphere.


Assuntos
Catecol Oxidase/metabolismo , Fenol/química , Streptomyces/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Sequência de Bases , Biologia Computacional , Deleção de Genes , Modelos Genéticos , Chaperonas Moleculares/genética , Dados de Sequência Molecular , Monofenol Mono-Oxigenase/química , Óperon , Oxigênio/química , Sensibilidade e Especificidade , Streptomyces/enzimologia , Especificidade por Substrato , Transativadores/genética
16.
Yao Xue Xue Bao ; 38(2): 120-3, 2003 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-12778747

RESUMO

AIM: To develop a sensitive and specific liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the determination of adefovir in monkey plasma. METHODS: Adefovir and internal standard 9-(3-phosphonylmethoxypropyl) adenine were isolated from plasma by protein precipitation with methanol, then chromatographed by using a Diamonsil C18 column. The mobile phase consisted of methanol-water-formic acid (20:80:1). Electrospray ionization (ESI) source was applied and operated in the positive ion mode. Selected reaction monitoring (SRM) mode with the transitions of m/z 274-->m/z 162 and m/z 288-->m/z 176 were used to quantify adefovir and the internal standard, respectively. RESULTS: The linear calibration curve was obtained in the concentration range of 0.02-4.00 mg.L-1. The lower limit of quantitation was 20 micrograms.L-1. The inter- and intra-day precision (RSD) was less than 5.8%, and the accuracy (relative error) was within +/- 4.5%. The method was successfully used in a pharmacokinetic study of adefovir dipivoxil in monkeys. CONCLUSION: The method is proved to be suitable for pre-clinical investigation of adefovir dipivoxil pharmacokinetics, which offers advantages of specificity and simple sample preparation compared with the previously reported methods.


Assuntos
Adenina/análogos & derivados , Adenina/sangue , Antivirais/sangue , Organofosfonatos , Adenina/farmacocinética , Animais , Antivirais/farmacocinética , Biotransformação , Cromatografia Líquida , Macaca mulatta , Espectrometria de Massas por Ionização por Electrospray
17.
Yao Xue Xue Bao ; 37(5): 362-6, 2002 May.
Artigo em Chinês | MEDLINE | ID: mdl-12579842

RESUMO

AIM: To develop a sensitive and rapid LC/MS/MS method for the determination of wogonin, an active flavonoid shown to have an inhibitory effect on the proliferation of a carcinoma cell line, in rat plasma after an oral administration. METHODS: Wogonin and daidzein (internal standard) were extracted from plasma directly with n-hexane-diethyl ether (1:4). After liquid-liquid extraction, the analytes of interest were separated on a Diamonsil C18 column. The mobile phase was acetonitrile-water-formic acid (80:20:1) with a flow rate of 0.8 mL.min-1. A Finnigan TSQ (triple stage quadruple) tandem mass spectrometer equipped with an atmospheric pressure chemical ionization (APCI) source was used as detector and was operated in positive ion mode. Selected reaction monitoring (SRM) was used and transitions selected for quantitation were: m/z 284.8-->269.5 for wogonin and m/z 254.7-->198.5 for daidzein. The mass spectrometric conditions were as follows: The temperatures of the vaporizer and heated capillary were 450 degrees C and 250 degrees C, respectively. The corona discharge current was 4.00 microA. Nitrogen was used as the sheath and auxiliary gas, whose settings were 0.6 MPa and 3 mL.min-1, respectively. Argon was used as the collision gas at a pressure of 1.4 Pa. The collision energy of 35 V was chosen for both wogonin and daidzein. RESULTS: The calibration curve was linear over the concentration range of 0.25 to 20.0 ng.mL-1. The limit of quantitation was 0.25 ng.mL-1. Within-day and between-day precision expressed by relative standard deviation (RSD) was 2.2% to 13.1% and 5.9% to 7.3%, respectively, and the accuracy expressed by RE was -0.3% to 1.3%. CONCLUSION: This method proved to be specific, accurate and sensitive enough to be applied to the pharmacokinetic studies of wogonin in rats after a single dose of 5 mg.kg-1 by oral administration.


Assuntos
Flavanonas/sangue , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Flavanonas/isolamento & purificação , Flavanonas/farmacocinética , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Plantas Medicinais/química , Ratos , Ratos Wistar , Scutellaria/química
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