Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Bioorg Med Chem Lett ; 27(11): 2313-2318, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28442252

RESUMO

Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Cães , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Ratos
2.
BMC Genomics ; 14: 203, 2013 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-23530833

RESUMO

BACKGROUND: Transcription factor binding is regulated by several interactions, primarily involving cis-element binding. These binding sites maintain specificity by means of their sequence, and other additional factors such as inter-motif distance and spacer specificity. The ACGT core sequence has been established as a functionally important cis-element which frequently regulates gene expression in synergy with other cis-elements. In this study, we used two monocotyledonous - Oryza sativa and Sorghum bicolor, and two dicotyledonous species - Arabidopsis thaliana and Glycine max to analyze the conservation of co-occurring ACGT core elements in plant promoters with respect to spacer distance between them. Using data generated from Arabidopsis thaliana and Oryza sativa, we also identified conserved regions across all spacers and possible conditions regulating gene promoters with multiple ACGT cis-elements. RESULTS: Our data indicated specific predominant spacer lengths between co-occurring ACGT elements, but these lengths were not universally conserved across all species under analysis. However, the frequency distribution indicated local regions of high correlation among monocots and dicots. Sequence specificity data clearly revealed a preference for G at the first and C at the terminal position of a spacer sequence, suggesting that the G-box motif is the most prevalent for the ACGT class of promoters. Using gene expression databases, we also observed trends suggesting that co-occurring ACGT elements are responsible for gene regulation in response to exogenous stress. Conservation in patterns of ACGT (N) ACGT among orthologous genes also indicated the possibility that emergence of functional significance across species was a result of parallel evolution of these cis-elements. CONCLUSIONS: Although the importance of ACGT elements has been acknowledged for several plant species, ours is the first study that attempts to compare their occurrence across four species and analyze conservation among them. The apparent preference for particular spacer distances suggest that these motifs might be implicated in important physiological functions which are yet to be identified. Variations in correlation patterns among monocots and dicots might arise out of differences in transcriptional regulation in the two classes. In accordance with literature, we established the involvement of co-occurring ACGT elements in stress responses and showed how this regulation differs with variation in the ACGT (N) ACGT motif. We believe that our study will be an essential resource in determining optimum spacer length and spacer sequence between ACGT elements for promoter design in future.


Assuntos
Arabidopsis/genética , Genoma de Planta , Glycine max/genética , Oryza/genética , Sorghum/genética , Sequência de Bases , Bases de Dados Genéticas , Regulação da Expressão Gênica de Plantas , Repetições de Microssatélites , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas , Elementos Reguladores de Transcrição/genética
3.
bioRxiv ; 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38077032

RESUMO

A typical neuron signals to downstream cells when it is depolarized and firing sodium spikes. Some neurons, however, also fire calcium spikes when hyperpolarized. The function of such bidirectional signaling remains unclear in most circuits. Here we show how a neuron class that participates in vector computation in the fly central complex employs hyperpolarization-elicited calcium spikes to invert two-dimensional mathematical vectors. When cells switch from firing sodium to calcium spikes, this leads to a ~180° realignment between the vector encoded in the neuronal population and the fly's internal heading signal, thus inverting the vector. We show that the calcium spikes rely on the T-type calcium channel Ca-α1T, and argue, via analytical and experimental approaches, that these spikes enable vector computations in portions of angular space that would otherwise be inaccessible. These results reveal a seamless interaction between molecular, cellular and circuit properties for implementing vector math in the brain.

4.
Curr Biol ; 29(22): 3887-3898.e4, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31679932

RESUMO

Critical to evolutionary fitness, animals regulate social behaviors by integrating signals from both their external environments and internal states. Here, we find that population density modulates the courtship behavior of male Drosophila melanogaster in an age-dependent manner. In a competitive mating assay, males reared in a social environment have a marked advantage in courting females when pitted against males reared in isolation. Group housing promotes courtship in mature (7-day) but not immature (2-day) males; this behavioral plasticity requires the Or47b pheromone receptor. Using single-sensillum recordings, we find that group housing increases the response of Or47b olfactory receptor neurons (ORNs) only in mature males. The effect of group housing on olfactory response and behavior can be mimicked by chronically exposing single-housed males to an Or47b ligand. At the molecular level, group housing elevates Ca2+ levels in Or47b ORNs, likely leading to CaMKI-mediated activation of the histone-acetyl transferase CBP. This signaling event in turn enhances the efficacy of juvenile hormone, an age-related regulator of reproductive maturation in flies. Furthermore, the male-specific Fruitless isoform (FruM) is required for the sensory plasticity, suggesting that FruM functions as a downstream genomic coincidence detector in Or47b ORNs-integrating reproductive maturity, signaled by juvenile hormone, and population density, signaled by CBP. In all, we identify a neural substrate and activity-dependent mechanism by which social context can directly influence pheromone sensitivity, thereby modulating social behavior according to animals' life-history stage.


Assuntos
Feromônios/metabolismo , Comportamento Sexual Animal/fisiologia , Fatores Etários , Animais , Comportamento Animal/fisiologia , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Copulação/fisiologia , Corte , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Histona Acetiltransferases/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Neurônios Receptores Olfatórios/fisiologia , Feromônios/fisiologia , Densidade Demográfica , Isoformas de Proteínas , Olfato/fisiologia , Comportamento Social , Meio Social , Fatores de Transcrição/genética
5.
Elife ; 62017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29140243

RESUMO

Several techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages. We further show that this system can be used to control in vivo gene expression levels with low background, large dynamic range, and in a reversible manner without detectable side effects on the lifespan or behavior of the animal. Additionally, we engineered tools for chemically controlling gene expression (GAL80-DD) and recombination (FLP-DD). We demonstrate the applicability of this technology in manipulating neuronal activity and for high-efficiency sparse labeling of neuronal populations.


Assuntos
Drosophila melanogaster , Entomologia/métodos , Regulação da Expressão Gênica , Biologia Molecular/métodos , Proteólise , Animais , Rede Nervosa/fisiologia , Neurônios/fisiologia
6.
Neuron ; 90(6): 1272-1285, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27263969

RESUMO

During the lifespans of most animals, reproductive maturity and mating activity are highly coordinated. In Drosophila melanogaster, for instance, male fertility increases with age, and older males are known to have a copulation advantage over young ones. The molecular and neural basis of this age-related disparity in mating behavior is unknown. Here, we show that the Or47b odorant receptor is required for the copulation advantage of older males. Notably, the sensitivity of Or47b neurons to a stimulatory pheromone, palmitoleic acid, is low in young males but high in older ones, which accounts for older males' higher courtship intensity. Mechanistically, this age-related sensitization of Or47b neurons requires a reproductive hormone, juvenile hormone, as well as its binding protein Methoprene-tolerant in Or47b neurons. Together, our study identifies a direct neural substrate for juvenile hormone that permits coordination of courtship activity with reproductive maturity to maximize male reproductive fitness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Corte , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/fisiologia , Hormônios Juvenis/fisiologia , Feromônios/fisiologia , Receptores Odorantes/fisiologia , Fatores Etários , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Copulação/efeitos dos fármacos , Copulação/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Ácido Linoleico/farmacologia , Masculino , Metoprene/farmacologia , Mutação , Feromônios/análise , Receptores Odorantes/genética , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia
7.
PLoS One ; 8(9): e73998, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24019943

RESUMO

Neutrophil granulocytes are pivotal cells within the first line of host defense of the innate immune system. In this study, we have used a gel-based LC-MS/MS approach to explore the proteome of primary marrow neutrophils from adult zebrafish. The identified proteins originated from all major cellular compartments. Gene ontology analysis revealed significant association of proteins with different immune-related network and pathway maps. 75% of proteins identified in neutrophils were identified in neutrophils only when compared to neutrophil-free brain tissue. Moreover, cross-species comparison with human peripheral blood neutrophils showed partial conservation of immune-related proteins between human and zebrafish. This study provides the first zebrafish neutrophil proteome and may serve as a valuable resource for an understanding of neutrophil biology and innate immunity.


Assuntos
Medula Óssea/metabolismo , Neutrófilos/metabolismo , Proteoma , Proteínas de Peixe-Zebra/metabolismo , Animais , Cromatografia Líquida , Sequência Conservada , Eletroforese em Gel de Poliacrilamida , Humanos , Especificidade da Espécie , Espectrometria de Massas em Tandem , Peixe-Zebra
8.
Indian J Pharmacol ; 44(6): 759-64, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23248408

RESUMO

AIM: Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent. MATERIAL AND METHODS: DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats. RESULTS: RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900-9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P<0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats. CONCLUSIONS: The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/sangue , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/sangue , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Camundongos , Camundongos Obesos , Ratos , Ratos Wistar
9.
Eur J Pharmacol ; 652(1-3): 157-63, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-20540938

RESUMO

Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC(50) values of 32, 31 and 39nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150-300 fold) and other proline-specific proteases (>200-2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect (∼25% AUC of △ blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/kg) in Wistar rats with the oral bioavailability (F(oral)) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Teste de Tolerância a Glucose , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Insulina/sangue , Insulina/uso terapêutico , Cinética , Masculino , Camundongos , Camundongos Obesos , Ratos , Ratos Wistar
10.
Indian J Pharmacol ; 42(4): 229-33, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20927248

RESUMO

OBJECTIVE: The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model. MATERIALS AND METHODS: DPP-IV enzyme assay was carried out in human plasma (10 µL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC(50) values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC(50) values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o. RESULTS: Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin. CONCLUSION: The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA