Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 63(2): 804-815, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31855601

RESUMO

A series of bisthiazole-based hydroxamic acids as novel potent HDAC inhibitors was developed during our previous work. In the present work, a new series of highly potent bisthiazole-based compounds were designed and synthesized. Among the prepared compounds, compound H13, which contains an α-(S)-methyl-substituted benzyl group, displays potent inhibitory activity toward human HDACs and several cancer cells lines. Compound H13 has a favorable PK profile and high tissue distribution specificity in the colon, as well as good efficacy in the AOM-DSS mouse model for colitis-associated colonic tumorigenesis.

2.
Materials (Basel) ; 12(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795118

RESUMO

The joint surface of the 1060 aluminum and AZ31 magnesium alloy was prepared through friction stir lap welding (FSLW) under different welding process parameters. The joint surface was characterized three-dimensionally using a three-dimensional (3D) optical profiler, and the coordinate data were obtained. The fractal dimension of the joint surface was calculated by the box-width transformation method using a MATLAB program. Furthermore, the influence of the welding process parameters on the fractal dimension of the joint surface was studied. The response surface model was established based on the principle of central composite design (CCD), and analysis of variance (ANOVA) was carried out to test the accuracy of the response surface. The results showed that the joint surface morphology had fractal characteristics, and the fractal dimension could be used as an index to characterize the quality of the joint surface. The change of the welding process parameters had a great impact on the fractal dimension of the joint surface, the interaction between the parameters was small, and the fitting accuracy of the response surface model was high. The fractal dimension of the joint surface decreased with the increase in the welding and rotational speeds and the effect of the rotational speed was more significant.

3.
Cell Metab ; 30(5): 937-951.e5, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31668872

RESUMO

Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.

4.
EBioMedicine ; 49: 291-304, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31640947

RESUMO

BACKGROUND: Aortic dissection is a severe inflammatory vascular disease with high mortality and limited therapeutic options. The hallmarks of aortic dissection comprise aortic inflammatory cell infiltration and elastic fiber disruption, highlighting the involvement of macrophage. Here a role for macrophage hypoxia-inducible factor 1-alpha (HIF-1α) in aortic dissection was uncovered. METHODS: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1α in two kinds of aortic dissection models and human tissues. Metabolomics and Seahorse extracellular flux analysis were used to detect the metabolic state of macrophages involved in the development of aortic dissection. Chromatin Immunoprecipitation (ChIP), enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were employed for mechanistic studies. FINDINGS: Macrophages involved underwent distinct metabolic reprogramming, especially fumarate accumulation, thus inducing HIF-1α activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1α activation triggered vascular inflammation, extracellular matrix degradation and elastic plate breakage through increased a disintegrin and metallopeptidase domain 17 (ADAM17), identified as a novel target gene of HIF-1α. A HIF-1α specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1α. INTERPRETATION: This study reveals that macrophage metabolic reprogramming activates HIF-1α and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1α inhibition might be a potential therapeutic target for treating aortic dissection.

6.
Nat Med ; 25(8): 1225-1233, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332392

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.


Assuntos
Ácidos e Sais Biliares/metabolismo , Fator de Transcrição GATA3/fisiologia , Microbioma Gastrointestinal , Interleucinas/fisiologia , Síndrome do Ovário Policístico/etiologia , Animais , Feminino , Humanos , Inflamação/complicações , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , Ovário/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia
7.
Org Lett ; 20(15): 4486-4489, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30035549

RESUMO

A green and efficient iridium-catalyzed asymmetric transfer hydrogenation of alkynyl ketones to chiral propargylic alcohols has been developed. By using sodium formate and ethanol as hydrogen sources, a series of alkynyl ketones were hydrogenated by chiral spiro iridium catalyst ( S)-1b to provide optically active chiral propargylic alcohols with up to 98% ee under base-free conditions. This protocol provides a practical and sustainable method for the preparation of optically active propargylic alcohols.

8.
Acta Pharmacol Sin ; 39(10): 1622-1632, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29795358

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic steatosis. NAFLD is closely linked to obesity, insulin resistance and dyslipidemia. AMP-activated protein kinase (AMPK) functions as an energy sensor and plays a central role in regulating lipid metabolism. In this study, we identified a series of novel pyrazolone AMPK activators using a homogeneous time-resolved fluorescence assay (HTRF) based on the AMPKα2ß1γ1 complex. Compound 29 (C29) is a candidate compound that directly activated the kinase domain of AMPK with an EC50 value of 2.1-0.2 µmol/L and acted as a non-selective activator of AMPK complexes. Treatment of HepG2 cells with C29 (20, 40 µmol/L) dose-dependently inhibited triglyceride accumulation. Chronic administration of C29 (10, 30 mg/kg every day, po, for 5 weeks) significantly improved lipid metabolism in both the liver and the plasma of ob/ob mice. These results demonstrate that the AMPK activators could be part of a novel treatment approach for NAFLD and associated metabolic disorders.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ativadores de Enzimas/uso terapêutico , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazolonas/uso terapêutico , Proteínas Quinases Ativadas por AMP/química , Animais , Cães , Ativadores de Enzimas/química , Ativadores de Enzimas/metabolismo , Haplorrinos , Células Hep G2 , Humanos , Fígado/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Domínios Proteicos/efeitos dos fármacos , Pirazolonas/química , Pirazolonas/metabolismo , Ratos , Relação Estrutura-Atividade
9.
ISA Trans ; 62: 349-56, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26928515

RESUMO

This paper is concerned with the tracking control problem of a voice coil motor (VCM) actuated servo gantry system. By utilizing an adaptive control technique combined with a sliding mode approach, an adaptive sliding mode control (ASMC) law with friction compensation scheme is proposed in presence of both frictions and external disturbances. Based on the LuGre dynamic friction model, a dual-observer structure is used to estimate the unmeasurable friction state, and an adaptive control law is synthesized to effectively handle the unknown friction model parameters as well as the bound of the disturbances. Moreover, the proposed control law is also implemented on a VCM servo gantry system for motion tracking. Simulations and experimental results demonstrate good tracking performance, which outperform traditional control approaches.

10.
Eur J Med Chem ; 112: 81-90, 2016 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-26890114

RESUMO

Histone deacetylases (HDACs) are a class of epigenetic modulators with complex functions in histone post-translational modifications and are well known targets for antineoplastic drugs. We have previously developed a series of bisthiazole-based hydroxamic acids as novel potent HDAC inhibitors. In the present work, a new series of bisthiazole-based compounds with different zinc binding groups (ZBGs) have been designed and synthesized. Among them is compound 7, containing a trifluoromethyl ketone as the ZBG, which displays potent inhibitory activity towards human HDACs and improved antiproliferative activity in several cancer cell lines.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Halogenação , Inibidores de Histona Desacetilases/síntese química , Humanos , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Metilação , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Zinco/metabolismo
11.
Antiviral Res ; 125: 25-33, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26611395

RESUMO

During the hepatitis B virus (HBV) life cycle, nucleocapsid assembly is essential for HBV replication. Both RNA reverse transcription and DNA replication occur within the HBV nucleocapsid. HBV nucleocapsid is consisted of core protein (HBcAg), whose carboxy-terminal domain (CTD) contains an Arg-rich domain (ARD). The ARD of HBcAg does contribute to the encapsidation of pregenomic RNA (pgRNA). Previously, we reported a small-molecule, NZ-4, which dramatically reduced the HBV DNA level in an in vitro cell setting. Here, we explore the possible mechanisms by which NZ-4 inhibits HBV function. As an HBV inhibitor, NZ-4 leads to the formation of genome-free capsids, including a new population of capsid that runs faster on agarose gels. NZ-4's activity was dependent on the presence of the ARD I, containing at least one positively charged amino acid. NZ-4 might provide a new option for further development of HBV therapeutics for the treatment of chronic hepatitis B.


Assuntos
Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Tiazóis/farmacologia , Sequência de Aminoácidos , Linhagem Celular Tumoral , DNA Viral/genética , DNA Viral/metabolismo , Endorribonucleases/genética , Endorribonucleases/metabolismo , Genoma Viral , Células Hep G2 , Antígenos do Núcleo do Vírus da Hepatite B/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Humanos , Dados de Sequência Molecular , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Replicação Viral/efeitos dos fármacos
12.
ISA Trans ; 60: 206-217, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26546099

RESUMO

This paper presents a systematic modeling and control methodology for a two-dimensional flexure beam-based servo stage supporting micro/nano manipulations. Compared with conventional mechatronic systems, such systems have major control challenges including cross-axis coupling, dynamical uncertainties, as well as input saturations, which may have adverse effects on system performance unless effectively eliminated. A novel disturbance observer-based adaptive backstepping-like control approach is developed for high precision servo manipulation purposes, which effectively accommodates model uncertainties and coupling dynamics. An auxiliary system is also introduced, on top of the proposed control scheme, to compensate the input saturations. The proposed control architecture is deployed on a customized-designed nano manipulating system featured with a flexure beam structure and voice coil actuators (VCA). Real time experiments on various manipulating tasks, such as trajectory/contour tracking, demonstrate precision errors of less than 1%.

13.
Bioprocess Biosyst Eng ; 39(3): 381-90, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26684007

RESUMO

The ability of the white-rot fungus Ganoderma sp.En3 to decolorize different kinds of dyes widely applied in the textile and dyeing industry, including the anthraquinone dye Remazol Brilliant Blue R (RBBR), indigo dye indigo carmine and triphenylmethane dye methyl green, was evaluated in this study. Ganoderma sp.En3 had a strong capability of decolorizing high concentrations of RBBR, indigo carmine and methyl green. Obvious reduction of Chemical Oxygen Demand was observed after decolorization of different dyes. Ganoderma sp.En3 had a strong ability to tolerate RBBR, indigo carmine and methyl green with high concentrations. High concentrations of RBBR, indigo carmine and methyl green could also be efficiently decolorized by the crude enzyme of Ganoderma sp.En3. Different redox mediators such as syringaldehyde, acetosyringone and acetovanillone could enhance the decolorization capability for higher concentration of indigo carmine and methyl green. Different metal ions had little effect on the ability of the crude enzyme to decolorize indigo carmine and methyl green. Our study suggested that Ganoderma sp.En3 had a strong capability for decolorizing and tolerating high concentrations of different types of dyes such as RBBR, indigo carmine and methyl green.


Assuntos
Antraquinonas/metabolismo , Ganoderma/metabolismo , Índigo Carmim/metabolismo , Compostos de Tritil/metabolismo , Oxirredução
14.
Cell Discov ; 1: 15021, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27462420

RESUMO

Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of γ-secretase or ß-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and γ-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress Aß generation. Through high-throughput screening, we discovered that 3-α-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces Aß production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce Aß production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and Aß-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics.

15.
Mol Pharmacol ; 87(1): 31-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25319542

RESUMO

Retigabine (RTG, [ethyl N-[2-amino-4-[(4-fluorophenyl)methyl]amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl)(prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases.


Assuntos
Anticonvulsivantes/farmacocinética , Carbamatos/farmacocinética , Canais de Potássio KCNQ/metabolismo , Fenilenodiaminas/farmacocinética , Convulsões/tratamento farmacológico , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Células CHO , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Células Cultivadas , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Fenilenodiaminas/administração & dosagem , Fenilenodiaminas/efeitos adversos , Convulsões/induzido quimicamente
16.
ACS Med Chem Lett ; 5(6): 628-33, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24944733

RESUMO

Inspired by the thiazole-thiazoline cap group in natural product largazole, a series of structurally simplified bisthiazole-based histone deacetylase inhibitors were prepared and evaluated. Compound 8f was evaluated in vivo in an experimental autoimmune encephalomyelitis (EAE) model and found to be orally efficacious in ameliorating clinical symptoms of EAE mice.

17.
Acta Pharmacol Sin ; 35(3): 410-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24487969

RESUMO

AIM: To investigate the action of isothiafludine (NZ-4), a derivative of bis-heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus (HBV) in vitro and in vivo. METHODS: HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA (pgRNA) and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV-infected ducks were orally administered NZ-4 (25, 50 or 100 mg·kg⁻¹·d⁻¹) for 15 d. RESULTS: NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC50 value of 1.33 µmol/L, whereas the compound inhibited the cell viability with an IC50 value of 50.4 µmol/L. Furthermore, NZ-4 was active against the replication of various drug-resistant HBV mutants, including 3TC/ETV-dual-resistant and ADV-resistant HBV mutants. NZ-4 (5, 10, 20 µmol/L) concentration-dependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. CONCLUSION: NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process, thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat HBV infection.


Assuntos
Antivirais/farmacologia , Infecções por Hepadnaviridae/tratamento farmacológico , Vírus da Hepatite B do Pato/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , RNA Viral/efeitos dos fármacos , Tiazóis/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Farmacorresistência Viral Múltipla/genética , Patos , Células Hep G2 , Infecções por Hepadnaviridae/virologia , Vírus da Hepatite B do Pato/genética , Vírus da Hepatite B do Pato/crescimento & desenvolvimento , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite Viral Animal/virologia , Humanos , Mutação , Nucleocapsídeo/metabolismo , RNA Viral/biossíntese , Fatores de Tempo , Transfecção
19.
Bioorg Med Chem ; 16(20): 9212-6, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18815049

RESUMO

DZ2002 and its related stereoisomers were efficiently synthesized. The optical data of (R)- and (S)-DZ2002 were disclosed here for the first time. Their inhibitory potency was evaluated on SAHase and MLR assay in the mean time. In accordance with respective inhibitory potency of SAHase, the immunosuppressive potency order was demonstrated as (S)-DZ2002>(Rac)-DZ2002>(R)-DZ2002>(Keto)-DZ2002. These results indicate (S)-configuration of 2-chiral center in DZ2002 is important for binding with SAHase.


Assuntos
Adenina/análogos & derivados , Butiratos/síntese química , Butiratos/farmacologia , Imunossupressores/síntese química , Imunossupressores/farmacologia , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Adenosil-Homocisteinase/antagonistas & inibidores , Adenosil-Homocisteinase/metabolismo , Animais , Butiratos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imunossupressores/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Coelhos , Estereoisomerismo
20.
Proc Natl Acad Sci U S A ; 105(8): 3128-33, 2008 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-18272489

RESUMO

Noninactivating potassium current formed by KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) subunits resembles neuronal M-currents which are activated by voltage and play a critical role in controlling membrane excitability. Activation of voltage-gated potassium channels by a chemical opener is uncommon. Therefore, the mechanisms of action are worthy further investigation. Retigabine and zinc pyrithione are two activators for KCNQ channels but their molecular interactions with KCNQ channel remain largely elusive. Here we report that retigabine and zinc pyrithione recognize two different sites of KCNQ2 channels. Their agonistic actions are noncompetitive and allow for simultaneous binding of two different activators on the same channel complex, hence giving rise to combinatorial potentiation with characteristic properties of both openers. Examining their effects on mutant channels, we showed zinc pyrithione is capable of opening nonconductive channels and coapplication of zinc pyrithione and retigabine could restore a disease mutant channel similar to wild type. Our results indicate two independent activator binding sites present in KCNQ channels. The resultant combinatorial potentiation by multiple synthetic chemical openers indicates that KCNQ channels are accessible to various types and combinations of pharmacological regulation.


Assuntos
Carbamatos/metabolismo , Canais de Potássio KCNQ/agonistas , Canais de Potássio KCNQ/metabolismo , Compostos Organometálicos/metabolismo , Fenilenodiaminas/metabolismo , Piridinas/metabolismo , Animais , Sítios de Ligação/genética , Células CHO , Carbamatos/farmacologia , Cricetinae , Cricetulus , Eletrofisiologia , Canais de Potássio KCNQ/genética , Potenciais da Membrana/efeitos dos fármacos , Mutagênese , Compostos Organometálicos/farmacologia , Técnicas de Patch-Clamp , Fenilenodiaminas/farmacologia , Mutação Puntual/genética , Piridinas/farmacologia , Análise de Sequência de DNA
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA