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1.
Neurooncol Adv ; 2(1): vdaa053, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32642706

RESUMO

BACKGROUND: Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown. METHODS: We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas. RESULTS: We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors. CONCLUSION: The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.

2.
ACS Med Chem Lett ; 8(1): 128-132, 2017 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28105288

RESUMO

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.

4.
Artigo em Inglês | MEDLINE | ID: mdl-23626585

RESUMO

Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet-induced obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of obesity, with an ultimate goal to identify novel anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting body-weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long-term efficacy and safety studies.

5.
Bioorg Med Chem Lett ; 21(10): 2911-5, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21493064

RESUMO

A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Receptor de Colecistocinina A/agonistas , Amidas/química , Animais , Células Cultivadas , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirimidinas/química , Relação Estrutura-Atividade
6.
Assay Drug Dev Technol ; 9(4): 373-81, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21294696

RESUMO

Mitochondrial dysfunction is increasingly associated with disease states. These organelles, responsible for adenosine triphosphate production, have been targeted for improved function in such diseases as Parkinson's, Alzheimer's, type 2 diabetes, and sarcopenia. In addition, the importance of determining if a clinical drug candidate adversely effects mitochondria function, which could lead to overt toxicity, has been recognized. Hence, assays that measure mitochondria activity have become essential in early stage drug development. Limitations of current assays that measure mitochondria membrane potential have prohibited the high-throughput performance necessary to screen current chemical space. Here, we describe a homogeneous assay to measure mitochondria membrane potential that can utilize either adherent or suspension cell types. The assay has been miniaturized to 1,536-well plate format, and was used to perform a fully automated robotic high-throughput screen of a small molecule chemical library.


Assuntos
Bioensaio/métodos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Células CHO , Carbonil Cianeto m-Clorofenil Hidrazona/metabolismo , Corantes/metabolismo , Cricetinae , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Células Jurkat , Medições Luminescentes , Miniaturização , Mitocôndrias/metabolismo , Ionóforos de Próton/metabolismo , Rodaminas/metabolismo , Fatores de Tempo
7.
PLoS Genet ; 6(5): e1000932, 2010 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-20463879

RESUMO

Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único , Animais , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Eur J Pharmacol ; 627(1-3): 258-64, 2010 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-19818748

RESUMO

Pancreatic polypeptide is released mainly from the pancreas, and is thought to be one of the major endogenous agonists of the neuropeptide Y Y(4) receptor. Pancreatic polypeptide has been shown to stimulate colonic muscle contraction, but whether pancreatic polypeptide has in vivo functional activity with respect to colonic transit is unclear. The present report investigated the effects of pancreatic polypeptide on fecal output as an index of colonic transit as well as intestinal motor activity, using wild-type (WT) and neuropeptide Y Y(4) receptor-deficient (KO) mice. Peripheral administration of pancreatic polypeptide increased fecal weight and caused diarrhea in WT mice in a dose-dependent manner (0.01-3mg/kg s.c.). Pancreatic polypeptide-induced increases in fecal weight and diarrhea completely disappeared in KO mice, while basal fecal weights did not differ between WT and KO mice. In longitudinal and circular muscles of mouse isolated colon, pancreatic polypeptide (0.01-1 microM) increased basal tone and frequency of spontaneous contraction in WT mice, but not in KO mice. Atropine did not affect pancreatic polypeptide-induced fecal output or increase in colonic muscle tone, indicating that the actions of pancreatic polypeptide are not mediated through cholinergic mechanisms. The present findings demonstrate that pancreatic polypeptide enhances colonic contractile activity and fecal output through neuropeptide Y Y(4) receptor, and a neuropeptide Y Y(4) receptor agonist might offer a novel therapeutic approach to ameliorate constipation.


Assuntos
Colo/efeitos dos fármacos , Colo/fisiologia , Fezes , Contração Muscular/efeitos dos fármacos , Polipeptídeo Pancreático/farmacologia , Receptores de Neuropeptídeo Y/metabolismo , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Colo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Neuropeptídeo Y/deficiência , Receptores de Neuropeptídeo Y/genética , Substância P/farmacologia , Água/metabolismo
9.
Eur J Pharmacol ; 624(1-3): 77-83, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19836369

RESUMO

Melanin-concentrating hormone (MCH), which is a neuropeptide expressed in the hypothalamus of the brain, is involved in regulating feeding behavior and energy homeostasis via the MCH(1) receptor in rodents. It is widely considered that MCH(1) receptor antagonists are worthy of development for medical treatment of obesity. Here we report on the development of an ex vivo receptor occupancy assay using a new radiolabeled MCH(1) receptor antagonist, [(35)S]-compound D. An MCH(1) receptor antagonist inhibited the binding of [(35)S]-compound D to brain slices in a dose-dependent manner. The result showed a good correlation between the receptor occupancy levels and plasma or brain levels of the MCH(1) receptor antagonist, suggesting that the ex vivo receptor binding assay using this radioligand is practical. Quantitative analysis in diet-induced obese mice showed that the efficacy of body weight reduction correlated with the receptor occupancy levels at 24h. Furthermore, more than 90% occupancy levels of MCH(1) receptor antagonists during 24h post-dosing are required for potent efficacy on body weight reduction. The present occupancy assay could be a useful pharmacodynamic marker to quantitatively estimate anti-obese efficacy, and would accelerate the development of MCH(1) receptor antagonists for treatment of obesity.


Assuntos
Fármacos Antiobesidade/farmacologia , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Aumento de Peso/efeitos dos fármacos , Ração Animal , Animais , Fármacos Antiobesidade/uso terapêutico , Dieta , Relação Dose-Resposta a Droga , Camundongos , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores do Hormônio Hipofisário/metabolismo , Aumento de Peso/fisiologia
10.
Assay Drug Dev Technol ; 7(4): 391-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19689207

RESUMO

beta-Galactosidase (beta-gal) (encoded by the lacZ gene) has been widely used as a transgene reporter enzyme. The ability to image lacZ expression in living transgenic animals would further extend the use of this reporter. It has been reported that 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)-beta-d-galactopyranoside (DDAOG), a conjugate of beta-galactose and 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one), is not only a chromogenic lacZ substrate but that the cleavage product has far-red fluorescence properties detectable by in vivo imaging. In an attempt to noninvasively image lacZ expression in vivo, we applied fluorescence imaging to a G protein-coupled receptor (GPR56), knockout (KO) mouse model, in which the lacZ gene is introduced in the GPR56 locus. Compared to wild-type (WT) mice, GPR56KO/LacZ mice showed three- to fourfold higher fluorescence intensity in the head area 5 min after tail-vein injection of DDAOG. beta-Gal staining in sections of whole brain showed strong lacZ expression in homozygotes, but not in WT mice, consistent with lacZ activity detected by in vivo imaging. The kidneys were also visualized with fluorescence imaging both in vivo and ex vivo, consistent with beta-gal staining findings. Our results demonstrate that fluorescence imaging can be used for in vivo real-time detection of lacZ activity by fluorescence imaging in lacZ transgenic mice. Thus, this technology can potentially be used to noninvasively image changes of certain endogenous molecules and/or molecular pathways in transgenic animals.


Assuntos
Expressão Gênica/genética , Óperon Lac/genética , Animais , Corantes , Galactosidases/química , Processamento de Imagem Assistida por Computador , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência , Fenótipo , Receptores Acoplados a Proteínas G/genética , Processamento de Sinais Assistido por Computador , Transfecção , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
11.
Peptides ; 30(11): 2008-13, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19397944

RESUMO

Melanin-concentrating hormone (MCH) is an important neuropeptide hormone involved in multiple physiological processes. Peptide derivatives of MCH have been developed as tools to aid research including potent radioligands, receptor selective agonists, and potent antagonists. These tools have been used to further understand the role of MCH in physiology, primarily in rodents. However, the tools could also help elucidate the role for MCHR1 and MCHR2 in mediating MCH signaling in higher species.


Assuntos
Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Peptídeos/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/agonistas , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Humanos , Hormônios Hipotalâmicos/química , Melaninas/química , Dados de Sequência Molecular , Peptídeos/química , Hormônios Hipofisários/química , Salmão/metabolismo
12.
Nat Genet ; 41(4): 415-23, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19270708

RESUMO

A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.


Assuntos
Proteínas de Transporte/genética , Glutationa Peroxidase/genética , Glicoproteínas/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Abdome/anatomia & histologia , Tecido Adiposo/anatomia & histologia , Animais , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Variação Genética , Humanos , Fígado/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Músculo Esquelético/anatomia & histologia , Fenótipo , Reprodutibilidade dos Testes , Transcrição Gênica , Proteínas de Transporte Vesicular
13.
Bioorg Med Chem Lett ; 19(6): 1564-8, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19243937

RESUMO

A series of spiroindoline-3,4'-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10mg/kg.


Assuntos
Química Farmacêutica/métodos , Indóis/administração & dosagem , Indóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/química , Administração Oral , Aminas/química , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Desenho de Fármacos , Concentração Inibidora 50 , Isocianatos/química , Modelos Químicos , Biblioteca de Peptídeos , Ratos , Ureia/química
14.
Bioorg Med Chem Lett ; 18(17): 4833-7, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18684621

RESUMO

The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.


Assuntos
Fármacos Antiobesidade/farmacologia , Benzodiazepinas/farmacologia , Indóis/farmacologia , Obesidade/tratamento farmacológico , Receptor de Colecistocinina A/agonistas , Tiazóis/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Quimiocinas CC , Humanos , Indóis/síntese química , Indóis/química , Metilaminas/síntese química , Metilaminas/química , Metilaminas/farmacologia , Camundongos , Piperazina , Piperazinas/química , Receptores da Colecistocinina/agonistas , Receptores da Colecistocinina/química , Tiazóis/síntese química , Tiazóis/química
15.
J Endocrinol ; 198(2): 309-15, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18523032

RESUMO

Blockade of brain melanin-concentrating hormone 1 receptor (MCH1R) significantly ameliorates fatty liver as well as obesity. However, the mode of action of this effect is unknown. This study examined the effect of a MCH1R antagonist in murine steatohepatitis models with and without obesity and clarified whether these pharmacological effects were attributed to anti-obesity effects. Steatohepatitis with concomitant obese phenotypes was developed after 52-week exposure to a high-fat diet, and steatohepatitis with reduced body weight was developed by exposure to a methionine- and choline-deficient diet for 10 days. Chronic intracerebroventricular infusion of a peptidic MCH1R antagonist reduced hepatic triglyceride contents and ameliorated steatohepatitis on histological observations in both mice models. Improvement of steatohepatitis was concomitant with amelioration of obese phenotypes such as hyperinsulinemia and hyperleptinemia in the case of the obese model, whereas body weight reduction was not associated with amelioration of steatohepatitis by the antagonist in the lean model. Reduction of hepatic gene expressions encoding cytochromes P450 4A was identified by treatment with the antagonist in both the obese and lean models. These results suggest that brain blockade of MCH1R could alleviate steatohepatitis independently from anti-obesity effects. In conclusion, MCH1R antagonist could have a new therapeutic potential for the treatment of human nonalcoholic steatohepatitis.


Assuntos
Gorduras na Dieta/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Quimiocina CCL2/genética , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/fisiopatologia , Reação em Cadeia da Polimerase , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/genética
16.
Obesity (Silver Spring) ; 16(7): 1510-5, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18421274

RESUMO

OBJECTIVE: To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice. METHODS AND PROCEDURES: Male C57BL/6 or Npy5r(-/-) mice were adapted to high-fat (HF) diet for 6-10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r(-/-) mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified. RESULTS: The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r(-/-) DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment. DISCUSSION: These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.


Assuntos
Fármacos Antiobesidade/farmacologia , Depressores do Apetite/farmacologia , Restrição Calórica , Ciclobutanos/farmacologia , Obesidade/tratamento farmacológico , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/farmacologia , Espironolactona/farmacologia , Adiposidade , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Terapia Combinada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Ingestão de Alimentos/efeitos dos fármacos , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/dietoterapia , Obesidade/metabolismo , Obesidade/fisiopatologia , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo , Espironolactona/análogos & derivados , Fatores de Tempo
17.
Nature ; 452(7186): 429-35, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18344982

RESUMO

Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.


Assuntos
Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Síndrome Metabólica/genética , Obesidade/genética , Tecido Adiposo/metabolismo , Animais , Apolipoproteína A-II/genética , Cromossomos de Mamíferos/genética , Feminino , Desequilíbrio de Ligação , Lipase Lipoproteica/genética , Fígado/metabolismo , Escore Lod , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Síndrome Metabólica/enzimologia , Síndrome Metabólica/metabolismo , Camundongos , Obesidade/enzimologia , Obesidade/metabolismo , Fenótipo , Fosfoproteínas Fosfatases/deficiência , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Locos de Características Quantitativas , Reprodutibilidade dos Testes , Proteínas Ribossômicas/genética
18.
Basic Clin Pharmacol Toxicol ; 103(1): 36-42, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18346052

RESUMO

Cytosolic malic enzyme (ME-1) is a nicotinamide adenine dinucleotide phosphate (NADP)-dependent enzyme that generates NADPH. The activity of this enzyme, the reversible oxidative decarboxylation of malate to yield pyruvate, links glycolytic pathway to citric acid cycle. The high level of ME-1 expression in liver, and its involvement in NADPH production, suggests reduced ME-1 activity might compromise hepatic production of reduced glutathione (GSH) by the NADPH-dependent enzyme glutathione reductase, and hence affect xenobiotic detoxification. The role of ME-1 in liver detoxification was evaluated in Mod1 deficient mice (mod1(-/-)) by evaluating their sensitivity to acetaminophen-induced liver injury. The results show that mod1(-/-) mice are not more sensitive to acetaminophen hepato-toxicity. Although GSH levels were initially depleted more in the mod1(-/-) liver than in wild-type controls, the GSH levels recovered quickly. In conclusion, our data indicate that ME-1 deficiency does not adversely affect GSH-dependent detoxification.


Assuntos
Acetaminofen/toxicidade , Analgésicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Fígado/enzimologia , Malato Desidrogenase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citosol/enzimologia , Genótipo , Glutationa/metabolismo , Fígado/patologia , Malato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , NADP/metabolismo
19.
Eur J Pharmacol ; 579(1-3): 215-24, 2008 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-18021763

RESUMO

We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.


Assuntos
Fármacos Antiobesidade/farmacologia , Imidazóis/farmacologia , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Animais , Autorradiografia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dexfenfluramina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Técnicas In Vitro , Masculino , Camundongos , Camundongos Knockout , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/agonistas
20.
Curr Top Med Chem ; 7(17): 1721-33, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17979781

RESUMO

A combination of pharmacological and genetic studies in mice confirmed that the Y1 and Y5 receptors mediate the potent orexigenic actions of exogenous NPY. Although the physiological role of NPY in causing obesity is less clear, potent and selective antagonists of both Y1 and Y5 have been developed. Some of the NPY antagonists have suitable pharmacokinetic (PK) properties that allowed them to be evaluated in various rodent models of obesity. Several different Y1 and Y5 antagonists cause weight loss in rodent models, though confirmation that these effects are mechanism based has been limited. One Y5 antagonist, MK-0557 was evaluated in a 1-yr clinical trial and found to cause modest weight loss. Optimal NPY antagonist therapeutics for obesity may require blockade of both the Y1 and Y5 receptors.


Assuntos
Fármacos Antiobesidade/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/fisiologia
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