Sexual dimorphic responses of C57BL/6 mice to Fisetin or Dasatinib and Quercetin cocktail oral treatment

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. We hypothesized that administering senotherapeutics in young adulthood of mice would slow physiological markers of aging through mid-life. C57BL/6 mice were treated monthly with either Fisetin or a Dasatinib (D) plus Quercetin (Q) cocktail from 4-13 months of age. Fisetin treated male mice had reduced senescence-associated secretory phenotype (SASP), enhanced glucose and energy metabolism, improved cognitive performance, and increased hippocampal expression of adiponectin 1 receptor and glucose transporter 4. D+Q treated females had increased SASP expression along with accumulation of white adipose tissue, reduced energy metabolism, and cognitive performance. Senotherapeutics in young adulthood, has beneficial, negligible, or detrimental effects in mice dependent upon sex and treatment.

Insulin Signaling Attenuates GLUT4 Endocytosis in Muscle Cells via GSK3α-Dyn2-Bin1 Interplay

Insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 into cells is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2), pivotal GTPase catalyzing GLUT4 internalization, is regulated by insulin signaling in muscle cells. The membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3α or the mutations of Bin1-SH3 in patients with centronuclear myopathy, elevate the activity of Dyn2 due to reduced binding affinity toward Bin1. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role of insulin signaling in glucose metabolism and muscle physiology via attenuating Dyn2 activity thus regulating GLUT4 endocytosis in muscle cell.

Davidones F and G, Two Novel Flavonoids from Sophora davidii (Franch.) Skeels

An unprecedented novel flavanone davidone F (1) with a seven-membered ring side chain, and a novel flavanonol davidone G (2), along with 11 known flavonoids, were isolated from the ethyl acetate fraction of Sophora davidii (Franch.) Skeels. Their planar structures were established by UV, IR, HRESIMS, 1D and 2D NMR data. The relative configurations of 1 and 2 were determined by calculation of NMR chemical shift values, the absolute configuration of 1 and 2 were assigned by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. Moreover, compounds 1–13 were screened for the translocation activity of glucose transporter 4 (GLUT-4), and the fluorescence intensity was increased to the range of 1.56 and 2.79 folds. Compounds 1 and 2 showed moderate GLUT-4 translocation activity with 1.64 and 1.79 folds enhancement, respectively, at a concentration of 20 μg/mL.

THE EFFECT OF GLUT4 EXPRESSION IN HIPPOCAMPAL NEURONS TO SPATIAL MEMORY OF DIABETES-INDUCED RATTUS NOVERGICUS

Background: Identification of appropriate biomarker involved in the pathophysiology of diabetes-associated cognitive decline in animal model is necessary. Glucose transporter 4 (GLUT4) is the component of insulin-dependent neuronal signaling pathway needed for maintaining cognitive function. It is highly expressed in hippocampal neurons. Objective: To investigate the effect of GLUT4 expression in hippocampal neurons on the spatial memory of diabetes-induced Rattus novergicus. Methods: This experimental study used 24 male Rattus novergicus divided into control groups terminated on day-0 (C0), 14 (C1) and 28 (C2) and diabetic groups terminated on day-0 (D0), 14 (D1) and 28 (D2). Diabetes was induced using streptozotocin injections intraperitoneally. Spatial memory (travel time) of rats was assessed on day-14 and 28. Brain tissue sampling was performed for assessment of GLUT4 expression using immunohistochemical methods. Significant differences in means of GLUT4 expression and travel time between groups on day-0, 14 and 28 as well as correlation between means of GLUT4 expression and travel time in D1 and D2 were analyzed statistically. Results: The mean of GLUT4 expression in diabetic group was significantly higher compared to control on day-14, but not on day-0 and 28. The immunohistochemical examination confirmed this results. There were no significant differences in mean of travel time between control and diabetic groups on day-14 and 28. There were no significant correlation between means of GLUT4 expression and travel time in diabetic groups on day-14 and 28. Conclusion: The GLUT4 expression of hippocampal neurons did not significantly affect spatial memory of diabetes-induced Rattus novergicus.