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Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) are calcium (Ca2+) release channels on the endo/sarcoplasmic reticulum (ER/SR). Here we summarize the latest advances in the field, describing the recently discovered mechanistic roles of intracellular Ca2+ release channels in the regulation of mitochondrial fitness and endothelial function, providing novel therapeutic options for the treatment of heart failure, hypertension, and diabetes mellitus. [ABSTRACT FROM AUTHOR]

Pancreatic endocrine β-cells derived from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have received attention as screening systems for therapeutic drugs and as the basis for cell-based therapies. Here, we used a 12-day β-cell differentiation protocol for mouse ES cells and obtained several hit compounds that promoted β-cell differentiation. One of these compounds, mycophenolic acid (MPA), effectively promoted ES cell differentiation with a concomitant reduction of neuronal cells. The existence of neural cell-derived inhibitory humoral factors for β-cell differentiation was suggested using a co-culture system. Based on gene array analysis, we focused on the Wnt/β-catenin pathway and showed that the Wnt pathway inhibitor reversed MPA-induced β-cell differentiation. Wnt pathway activation promoted β-cell differentiation also in human iPS cells. Our results showed that Wnt signaling activation positively regulates β-cell differentiation, and represent a downstream target of the neural inhibitory factor. [ABSTRACT FROM AUTHOR]

Rivo is a novel PPARgamma agonist and potent antidiabetic agent. Expression of PPARalpha target genes and genes implicated in cardiac function was studied in the liver and heart of Zucker diabetic fatty rats treated with Rivo (1mg/kg) for 2 weeks, using pioglitazone (Pio; 100mg/kg), a PPARgamma agonist, and Wy-14,643 (Wy; 100mg/kg), a PPARalpha agonist, as comparators. Rivo and Pin normalized plasma concentrations of glucose, triglycerides (TG) and free fatty acids (FFA), while Wy decreased only plasma TG and FFA. In the heart and liver, Wy strongly increased expression of typical PPARalpha target genes such as acyl-coenzyme A oxidase 1 (ACO) and pyruvate dehydrogenase kinase 4 (PDK4), which may promote beta-oxidation of FFA as an energy source (Table). Rivo and Pio did not increase expression of these genes in the liver and Rivo decreased expression of ACO. In the heart, Rivo and Pin decreased the expression of ACO and medium chain acyl-CoA dehydrogenase (MCAD), suggesting reduced beta-oxidation of FFA and oxidative stress. They reduced expression of PDK4 and upregulated that of glucose transporter 4 (GLUT4) suggesting increased utilization of glucose. In addition, Rivo and Pin did not alter the expression of myosin heavy chain alpha and beta (MHCalpha and beta) or sarco/endoplasmic reticulum Ca[sup 2+] ATPase 2 (SERCA2), implicated in cardiac function. One week of treatment with Rivo (0.1 and 1mg/kg) or Wy (100mg/kg) reduced plasma TG primarily by accelerating TG clearance and reducing hepatic TG production, respectively. These results suggest that Rivo produces antidiabetic effects without augmenting the activity of PPARalpha and may have a desirable effect on cardiac function by improving cardiac energy homeostasis. Gene expression (% of control, meanSE; n=5, (*) p<0.05 vs control, ND=determined) [ABSTRACT FROM AUTHOR]