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1.
Nature ; 450(7170): 712-6, 2007 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-18046409

RESUMEN

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.


Asunto(s)
Restricción Calórica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sirtuinas/agonistas , Acetilación , Sitio Alostérico , Animales , Glucemia/metabolismo , Dominio Catalítico , Línea Celular , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Drosophila melanogaster , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Insulina/metabolismo , Insulina/farmacología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Resveratrol , Sirtuina 1 , Sirtuinas/metabolismo , Estilbenos/química , Estilbenos/farmacología
2.
Bioorg Med Chem Lett ; 19(5): 1416-20, 2009 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-19181526

RESUMEN

A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model.


Asunto(s)
Benzotiazoles/química , Proteínas Portadoras/antagonistas & inhibidores , Descubrimiento de Drogas , Enterocitos/metabolismo , Animales , Benzotiazoles/farmacología , Benzotiazoles/uso terapéutico , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Enterocitos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas , Ratas Sprague-Dawley
3.
Mach Learn ; 95(1): 27-50, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-26549932

RESUMEN

Severe weather, including tornadoes, thunderstorms, wind, and hail annually cause significant loss of life and property. We are developing spatiotemporal machine learning techniques that will enable meteorologists to improve the prediction of these events by improving their understanding of the fundamental causes of the phenomena and by building skillful empirical predictive models. In this paper, we present significant enhancements of our Spatiotemporal Relational Probability Trees that enable autonomous discovery of spatiotemporal relationships as well as learning with arbitrary shapes. We focus our evaluation on two real-world case studies using our technique: predicting tornadoes in Oklahoma and predicting aircraft turbulence in the United States. We also discuss how to evaluate success for a machine learning algorithm in the severe weather domain, which will enable new methods such as ours to transfer from research to operations, provide a set of lessons learned for embedded machine learning applications, and discuss how to field our technique.

4.
J Med Chem ; 52(5): 1275-83, 2009 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-19199480

RESUMEN

A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.


Asunto(s)
Activadores de Enzimas/síntesis química , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Quinoxalinas/síntesis química , Sirtuina 1/metabolismo , Tiazoles/síntesis química , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Imidazoles/química , Imidazoles/farmacología , Ratones , Quinoxalinas/química , Quinoxalinas/farmacología , Ratas , Ratas Zucker , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología
5.
BMC Syst Biol ; 3: 31, 2009 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-19284563

RESUMEN

BACKGROUND: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation. RESULTS: Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet. CONCLUSION: CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.


Asunto(s)
Restricción Calórica , Activación Enzimática/genética , Modelos Genéticos , Transducción de Señal/genética , Sirtuinas/metabolismo , Animales , Activación Enzimática/efectos de los fármacos , Perfilación de la Expresión Génica , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Ratones , Análisis por Micromatrices , Estructura Molecular , Resveratrol , Transducción de Señal/efectos de los fármacos , Sirtuina 1 , Estilbenos/química , Estilbenos/farmacología
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