RESUMEN
OBJECTIVE: Chronic stress promotes obesity and metabolic comorbidities. The ability of individuals to cope with stress may serve as an important parameter in the development of obesity-related metabolic outcomes. The aim of this study was to clarify whether differences in stress response affect metabolic health under obesity. METHODS: The study was performed in a selectively bred mouse model of social dominance (Dom) and submissiveness (Sub), which exhibit stress resilience or vulnerability, respectively. Mice were given a high-fat diet (HFD) or standard diet, followed by physiological, histological, and molecular analyses. RESULTS: The HFD caused hyperleptinemia, glucose intolerance, insulin resistance, steatosis of the liver and pancreas, and brown adipose tissue whitening in Sub mice, whereas Dom mice were protected from these consequences of the HFD. The HFD increased circulating levels of interleukin (IL)-1ß and induced the expression of proinflammatory genes in the liver and in epididymal white adipose tissue of Sub mice, with no changes in Dom mice. The Cox2 inhibitor celecoxib (15 mg/kg/d) reduced serum IL-1ß, improved glucose tolerance and insulin sensitivity, and prevented hepatic and brown adipose tissue whitening in HFD-fed Sub mice. CONCLUSIONS: The extent of stress resiliency is associated with inflammation and contributes to population heterogeneity in the development of healthy or unhealthy obesity.
Asunto(s)
Hígado Graso , Resistencia a la Insulina , Animales , Ratones , Ratones Obesos , Obesidad/genética , Obesidad/prevención & control , Hígado/metabolismo , Hígado Graso/metabolismo , Resistencia a la Insulina/fisiología , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Tejido Adiposo/metabolismoRESUMEN
In recent years, growing evidence has indicated the pivotal role of mitochondria in mast cell immunological activation. We have previously reported a decrease in degranulation and cytokine secretion following the inhibition of pyruvate dehydrogenase (PDH) either by CPI-613 (PDH inhibitor/anti-cancer drug) or through its interaction with mitochondrial microphthalmia-associated transcription factor (MITF). In the present study, we further explored the role played by mitochondrial MITF in mast cell exocytosis using rat basophil leukemia cells [RBL], as well as mouse bone marrow-derived mast cells (BMMCs). Here, we report that mast cell degranulation, cytokine secretion and oxidative phosphorylation (OXPHOS) activities were associated with phosphorylation of Serine 73 of mitochondrial MITF, controlled by extracellular signals regulated by protein kinase (ERK1/2) activity. Also, we report here that decreased OXPHOS activity following ERK1/2 inhibition (U0126 treatment) during IgE-Ag activation was mediated by the dephosphorylation of Serine 73 mitochondrial MITF, which inhibited its association with PDH. This led to a reduction in mast cell reactivity. In addition, a phosphorylation-mimicking mitochondrial MITF-S73D positively regulated the mitochondrial activity, thereby supporting mast cell degranulation. Thus, the present research findings highlight the prominence of mitochondrial MITF Serine 73 phosphorylation in immunologically activated mast cells.
Asunto(s)
Mastocitos , Factor de Transcripción Asociado a Microftalmía , Animales , Citocinas/metabolismo , Inmunoglobulina E/metabolismo , Mastocitos/metabolismo , Ratones , Factor de Transcripción Asociado a Microftalmía/metabolismo , Mitocondrias/metabolismo , Fosforilación Oxidativa , Ratas , Serina/metabolismoRESUMEN
The innate and adaptive immune systems play an essential role in host defense against pathogens. Various signal transduction pathways monitor and balance the immune system since an imbalance may promote pathological states such as allergy, inflammation, and cancer. Mast cells have a central role in the regulation of the innate/adaptive immune system and are involved in the pathogenesis of many inflammatory and allergic diseases by releasing inflammatory mediators such as histamines, proteases, chemotactic factors, and cytokines. Although various signaling pathways are associated with mast cell activation, our discovery and characterization of the pLysRS-Ap4A signaling pathway in these cells provided an additional important step towards a full understanding of the intracellular mechanisms involved in mast cell activation. In the present review, we will discuss in depth this signaling pathway's contribution to host defense and the pathological state.
Asunto(s)
Inmunidad Innata , Mediadores de Inflamación/inmunología , Mastocitos/inmunología , Transducción de Señal/inmunología , Animales , Humanos , Inflamación/inmunología , Inflamación/patología , Mastocitos/patologíaRESUMEN
Prostate cancer is the most common malignancy and the second leading cause of cancer death in the male population in developing countries. Ukrain is a reaction product of different alkaloids from Chelidoniummajus L. (celandine) conjugated with thiophosphoric acid, which has cytotoxic effects on various malignant cells. In the present study, cell viability was assessed using the dimethyl thiazolyl tetrazolium bromide (MTT)method in PC-3 cells after treatment with Ukrain. The IC(50) value was observed in 10 µg concentration of Ukrain. Bax, Bad, and FasL mRNA expression was analyzed by reverse transcriptase-polymerase chain reaction, and protein expressions of p-Akt, Bcl-2, and caspase 10 were determined by western-blot analysis. Nuclei were stained with 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI). Ukrain significantly increased the pro-apoptotic mRNA expression of Bad, Bax, and FasL; decreased the cell survival protein p-Akt and the anti-apoptotic protein Bcl-2; and increased the protein levels of cleaved poly(ADP)-ribose polymerase (PARP) and caspase-10.The results of this study suggest that Ukrain decreases the cell survival of androgen-independent prostate cancer cells and induces their apoptosis, thus supporting its use as a therapeutic drug for the treatment of prostate cancer