When allowed to choose between different macronutrients, most animals display a strong attraction toward carbohydrates compared with proteins. It remains uncertain, however, whether this food selection pattern depends primarily on the sensory properties intrinsic to each nutrient or, alternatively, metabolic signals can act independently of the hedonic value of sweetness to stimulate elevated sugar intake. Here we show that Trpm5 Ϫ/Ϫ mice, which lack the cellular mechanisms required for sweet and several forms of L-amino acid taste transduction, develop a robust preference for D-glucose compared with isocaloric L-serine independently of the perception of sweetness. Moreover, a close relationship was found between glucose oxidation and taste-independent nutrient intake levels, with animals increasing intake as a function of glucose oxidation rates. Furthermore, microdialysis measurements revealed nutrient-specific dopaminergic responses in accumbens and dorsal striatum during intragastric infusions of glucose or serine. Specifically, intragastric infusions of glucose induced significantly higher levels of dopamine release compared with isocaloric serine in both ventral and dorsal striatum. Intragastric stimulation of dopamine release seemed to depend on glucose utilization, because administration of an anti-metabolic glucose analog resulted in lower dopamine levels in striatum, an effect that was reversed by intravenous glucose infusions. Together, our findings suggest that carbohydrate-specific preferences can develop independently of taste quality or caloric load, an effect associated with the ability of a given nutrient to regulate glucose metabolism and stimulate brain dopamine centers.

AimsWe investigated the therapeutic efficacy of thrombopoietin (TPO) in acute and chronic rat models of heart damage and explored the mechanisms in terms of genome-wide transcriptional changes, phosphorylation signals, and bone marrow endothelial progenitor cell (EPC) levels. Methods and resultsCardiac damage was induced in rat models of (i) acute-doxorubicin (DOX) treatment: single high-dose DOX, four doses TPO, followed up for 5 days; and (ii) chronic-DOX treatment: one low-dose DOX and three doses TPO weekly for 6 weeks, followed up for 11 weeks. Our results demonstrated that TPO treatment led to significant improvements of fractional shortening, cardiac output, and morphologic parameters in both models. In the acute-DOX model, microarray and network analyses showed that DOX damage was associated with changes in a large cohort of gene expressions, of which many were inversely regulated by TPO, including modulators of signal transduction, ion transport, anti-apoptosis, protein kinase B/ p42/p44 extracellular signal-regulated kinase (AKT/ERK) pathways, cell division, and contractile protein/matrix remodelling. Many of these regulations also occurred in chronic-DOX animals, in which TPO treatment reduced morphological damage and cardiomyopathy score, and increased AKT phosphorylation of heart tissues. Thrombopoietin also increased EPC colonies in their bone marrow. ConclusionOur overall data suggest that TPO promotes cardiac protection from acute-and chronic-DOX insults, possibly mediated by multi-factorial mechanisms including AKT-and ERK-associated restoration of regulatory gene activities critical for normal heart function.--

Background/Aims: Prevention of diabetes requires maintenance of a functional beta-cell mass, the postnatal growth of which depends on beta cell proliferation. Past studies have shown evidence of an effect of an incretin analogue, Exendin-4, in promoting beta cell proliferation, whereas the underlying molecular mechanisms are not completely understood. Methods: Here we studied the effects of Exendin-4 on beta cell proliferation in vitro and in vivo through analysing BrdU-incorporated beta cells. We also analysed the effects of Exendin-4 on beta cell mass in vivo, and on beta cell number in vitro. Then, we applied specific inhibitors of different signalling pathways and analysed their effects on Exendin-4-induced beta cell proliferation. Results: Exendin-4 increased beta cell proliferation in vitro and in vivo, resulting in significant increases in beta cell mass and beta cell number, respectively. Inhibition of PI3K/Akt signalling, but not inhibition of either ERK/MAPK pathway, or JNK pathway, significantly abolished the effects of Exendin-4 in promoting beta cell proliferation. Conclusion: Exendin-4 promotes beta cell proliferation via PI3k/Akt signaling pathway.

Introduction: Previous case-control studies have suggested that the –1562C/T and R279Q polymorphisms of the matrix metalloproteinase 9 gene (MMP9) are associated with coronary heart disease (CHD). However, other studies do not confirm these relationships. The objective is to assess these relationships using meta-analysis. Methods: Databases, including PubMed and ScienceDirect, were searched to access the genetic association studies. Then data were extracted. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated. Moreover, subgroup and sensitive analysis were performed. Results: The meta-analysis of the –1562C/T polymorphism included 12 studies with 8,336 cases and 3,984 controls. The –1562T allele was significantly associated with CHD (OR 1.25, 95% CI 1.08–1.45, p = 0.004). There was heterogeneity among the 12 studies (I² = 61%, p = 0.003). The overall results were consistent and were not changed substantially by the removal of any data set. The meta-analysis of the R279Q polymorphism, including 6 studies with 6,983 cases and 3,282 controls, showed that the R279Q polymorphism was not associated with CHD (p = 0.16). Conclusions: The synthesis of available evidence supports the fact that the MMP9 –1562C/T polymorphism is a risk factor for CHD.