RESUMEN
BACKGROUND: Diabetes mellitus is characterized by high blood glucose levels. Pancreatic ß cell death contributes to type 1 and type 2 diabetes. Akita mice, which harbor a human permanent neonatal diabetes-linked mutation (Cys96Tyr) in the insulin gene, are well established as an animal model of diabetes caused by pancreatic ß cell exhaustion. Mutant Insulin 2 protein (Ins2(C96Y)) induces endoplasmic reticulum (ER) stress and pancreatic ß cell death in Akita mice, although the molecular mechanism of Ins(C96Y)-induced cell death remains unclear. METHODS: We investigate the mechanisms of Ins2(C96Y)-induced pancreatic ß cell death in vitro and in vivo, using p38 inhibitor (SB203580), MIN6 cell (pancreatic ß cell line), Akita mice and apoptosis signal-regulating kinase 1 (ASK1) knockout mice. RESULTS: The expression of Ins(C96Y) activated the ASK1-p38 pathway. Deletion of ASK1 mitigated Ins(C96Y)-induced pancreatic ß cell death and delayed the onset of diabetes in Akita mice. Moreover, p38 inhibitor suppressed Ins(C96Y)-induced MIN6 cell death. CONCLUSIONS: These findings suggest that ER stress-induced ASK1-p38 activation, which is triggered by the accumulation of Ins(C96Y), plays an important role in the pathogenesis of diabetes. GENERAL SIGNIFICANCE: Pancreatic ß cell death caused by insulin overload appears to be involved in the pathogenesis of type 1 and type 2 diabetes. Inhibition of the ASK1-p38 pathway may be an effective therapy for various types of diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 2/enzimología , Estrés del Retículo Endoplásmico , Células Secretoras de Insulina/enzimología , MAP Quinasa Quinasa Quinasa 5/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Sustitución de Aminoácidos , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Imidazoles/farmacología , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/patología , MAP Quinasa Quinasa Quinasa 5/genética , Ratones , Ratones Noqueados , Mutación Missense , Piridinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Parkin-associated endothelin receptor-like receptor (Pael-R) is a substrate of the E3 ubiquitin ligase Parkin, which has been implicated in the pathogenesis of Parkinson disease. Misexpression of human Pael-R in Drosophila has been shown to induce selective loss of dopaminergic neurons, a symptom of Parkinson disease. Using this model, we investigated whether thioredoxin (TRX), an evolutionarily conserved antioxidant and molecular chaperone, could suppress the neurotoxicity induced by Pael-R. The Drosophila genome contains three TRX-encoding genes, namely TrxT, Trx-2, and dhd. When each of the TRX genes was overexpressed together with Pael-R in all neurons, the number of dopaminergic neurons and level of locomotor activity were significantly increased compared with control flies. To assess the role of the antioxidant activity of TRX in this context, we generated redox-defective mutants, TrxT(C35A) and TrxT(D26A/K57I), and coexpressed each of them with Pael-R. The mutants suppressed the Pael-R neurotoxicity similarly to wild-type TrxT, although the extent of the rescue was slightly reduced for the locomotor activity. We confirmed that both mutants remained active as chaperones, suggesting that this activity may be the major cause of the suppression. In the absence of Pael-R, overexpression of TRX in all neurons increased the level of locomotor activity in aged flies and extended the mean longevity by 15%. Furthermore, overexpression of TRX suppressed neurotoxicity in a Drosophila model of Machado-Joseph disease expressing polyglutamine. These results establish that Drosophila TRX can function as an anti-aging agent and as a suppressor of Pael-R- and poly-glutamine-induced neurotoxicity.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Longevidad/fisiología , Neuronas/citología , Neuronas/metabolismo , Receptores de Endotelina/metabolismo , Tiorredoxinas/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Proteínas de Drosophila/genética , Drosophila melanogaster/citología , Drosophila melanogaster/genética , Peróxido de Hidrógeno/farmacología , Mutación/genética , Oxidación-Reducción , Fenotipo , Receptores de Endotelina/genética , Tiorredoxinas/genéticaAsunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/psicología , Diagnóstico por Imagen , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Humanos , Procesos Mentales , Índice de Severidad de la Enfermedad , Proteínas tau/análisis , Proteínas tau/líquido cefalorraquídeoRESUMEN
Post-mortem examinations of the circle of Willis in two cases of subarachnoid hemorrhage disclosed a wide spectrum of vasculopathy ranging from a minimal tear between the intima and media, and between the media and adventitia, to complete transmural disruption leading to the formation of pseudoaneurysms. The presence of coexistence of the focal lesions with complete replacement of the entire arterial wall with thick fibrous connective tissues and the vasculopathy was suggestive of the spontaneous repair of recurrent non-traumatic dissection of intracranial arteries. The patients were 58-year-old and 43-year-old females. There was no history of injury to the head or neck in either case. They were hypertensive, but the degree of atherosclerotic changes in the circle of Willis was compatible with age. There was no histological evidence of vasculitis. The role of hypertension and medial mucoid degeneration in the genesis of non-traumatic dissection of intracranial arteries was discussed.
Asunto(s)
Disección Aórtica/patología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Círculo Arterial Cerebral/patología , Adulto , Aneurisma Falso/etiología , Aneurisma Falso/patología , Femenino , Humanos , Hipertensión/complicaciones , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/patología , Lupus Eritematoso Sistémico/complicaciones , Persona de Mediana Edad , Recurrencia , Remisión Espontánea , Hemorragia Subaracnoidea/etiologíaRESUMEN
We examine the effects of feeding a high-sucrose diet on body weight gain, plasma triglycerides, and stress tolerance in rats. Feeding a high-sucrose (60%) diet for 2 weeks did not induce a greater body weight gain compared with that of standard diet when caloric intake was similar in ventromedial hypothalamic-lesioned obese and sham-operated lean animals. The high-sucrose diet elevated plasma triglycerides by increasing the triglyceride secretion rate and decreasing the fractional catabolic rate in both groups. In response to stress, feeding a high-sucrose diet for one week induced enhanced gene expressions of heat shock proteins (HSP 70 and 27) and suppressed NOx production in the brain, whereas the standard diet did not. Results suggest that feeding a high-sucrose diet does not induce obesity in lean rats or enhance weight gain in obese rats, if caloric intake is appropriate. The diet does elevate plasma triglyerides in lean and obese rats, but it may have the potential to improve stress tolerance.
Asunto(s)
Sacarosa en la Dieta/administración & dosificación , Estrés Fisiológico/fisiopatología , Triglicéridos/sangre , Aumento de Peso/efectos de los fármacos , Animales , Ingestión de Energía , Expresión Génica , Proteínas de Choque Térmico/genética , Humanos , Hipotálamo Medio/fisiopatología , Óxido Nítrico Sintasa/metabolismo , Obesidad/fisiopatologíaRESUMEN
Uncoupling proteins (UCPs) are supposed to be involved in diet-induced thermogenesis. Their activities are usually elevated by feeding and reduced by fasting in normal animals. To investigate whether fasting affects the expression of UCPs mRNA in brown adipose tissue (BAT) of bilateral ventromedial hypothalamus (VMH)-lesioned rats, we determined the gene expression of UCP1, UCP2 or UCP3 in BAT of VMH-lesioned rats and examined oxygen consumption in these rats under fed or 48-h fasted conditions. Northern blotting revealed no difference in the expression of UCPs mRNA in BAT between VMH-lesioned and sham-operated rats under the fed condition, however, expressions were increased markedly in BAT of VMH-lesioned rats under the fasted condition. Under the fed condition, no difference in oxygen consumption was observed between VMH-lesioned and sham-operated rats. Under the fasted condition, oxygen consumption decreased in both rats, however, it decreased in VMH-lesioned less than in sham operated rats. To explore the mechanism that fasting elevated BAT UCPs mRNA in VMH-lesioned rats, we measured peroxisome proliferator-activated receptor (PPAR)-gamma mRNA and protein in BAT, because PPAR-gamma agonist can elevate UCPs mRNA levels in BAT. Under the fed condition, no differences in the expression of PPAR-gamma mRNA and protein content were observed between in BAT of VMH-lesioned and sham-operated rats. Under the fasted condition, however, both increased in BAT of VMH-lesioned rats. These results suggest that VMH-lesions enhance the gene expression of UCPs in BAT under long-term fasting as a defensive reaction to inhibit the reduction of body temperature through an increase in PPAR-gamma activity.
Asunto(s)
Tejido Adiposo Pardo/fisiología , Proteínas Portadoras/metabolismo , Ayuno , Proteínas de Transporte de Membrana , Proteínas Mitocondriales , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Desacopladores/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismo , Animales , Peso Corporal , Proteínas Portadoras/genética , Femenino , Regulación de la Expresión Génica , Canales Iónicos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Oxígeno/metabolismo , Proteínas/genética , Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3 , Núcleo Hipotalámico Ventromedial/anatomía & histología , Núcleo Hipotalámico Ventromedial/patologíaAsunto(s)
Enfermedad de Alzheimer , Demencia , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Demencia/metabolismo , Demencia/fisiopatología , Diagnóstico Diferencial , Femenino , Geriatría , Humanos , MasculinoRESUMEN
It remains unclear whether adiposity plays an important role in glucose intolerance independently of insulin resistance. We investigated whether adiposity and insulin resistance had distinct roles in glucose intolerance in rats. We examined glucose tolerance and insulin resistance using ventromedial hypothalamic (VMH)-lesioned rats in the dynamic and the static phases of obesity (2 and 14 weeks after lesioning, respectively). Rats were fed either normal chow or a fructose-enriched diet (60% of total calories). The intravenous glucose tolerance test (IVGTT) was performed by bolus injection of glucose solution (1 g/kg) and blood sampling after 0, 5 10, 30, and 60 minutes. Insulin resistance was evaluated from the steady-state plasma glucose (SSPG) value during continuous infusion of glucose, insulin, and somatostatin. SSPG was not increased in VMH-lesioned rats in the dynamic phase of obesity, but increased markedly in the static phase. The area under the glucose curve (glucose AUC) during IVGTT was increased in VMH-lesioned rats in the static phase, but not in the dynamic phase, when compared with their sham-operated counterparts. A fructose-enriched diet for 2 or 14 weeks increased SSPG values to a similar extent in both sham-operated and VMH-lesioned rats without inducing excess adiposity, but glucose intolerance was only developed in the obese rats. The plasma leptin level, an excellent indicator of adiposity, was significantly related to the glucose AUC independently of the insulin level. Insulin resistance or increased adiposity alone is not sufficient to impair glucose tolerance, but increased adiposity plays an important role in the development of glucose intolerance in an insulin-resistant state.