Circadian dysfunction in adipose tissue: Chronotherapy in metabolic diseases

Essential for survival and reproduction, the circadian timing system (CTS) regulates adaptation to cyclical changes such as the light/dark cycle, temperature change, and food availability. The regulation of energy homeostasis possesses rhythmic properties that correspond to constantly fluctuating needs for energy production and consumption. Adipose tissue is mainly responsible for energy storage and, thus, operates as one of the principal components of energy homeostasis regulation. In accordance with its roles in energy homeostasis, alterations in adipose tissue's physiological processes are associated with numerous pathologies, such as obesity and type 2 diabetes. These alterations also include changes in circadian rhythm. In the current review, we aim to summarize the current knowledge regarding the circadian rhythmicity of adipogenesis, lipolysis, adipokine secretion, browning, and non-shivering thermogenesis in adipose tissue and to evaluate possible links between those alterations and metabolic diseases. Based on this evaluation, potential therapeutic approaches, as well as clock genes as potential therapeutic targets, are also discussed in the context of chronotherapy

Diurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5 '-deoxy-5-fluorocytidine (5 ' DFCR), 5 '-deoxy-5-fluorouridine (5 ' DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma C-max and AUC(0-6h) (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5 ' DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, C-max and AUC(0-6h) values of 5 ' DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5 ' DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.Istanbul Universit

Evaluation of the Immunomodulatory Effects of C-Vx on the Innate and Adaptive "Immune" System: Preliminary Results

AbstractObjectives: In this preliminary study, the in vitro effect of C-Vx in human PBMCs and the in vivo effect of C-Vx in rats were investigated.Methods: The human part was analyzed in PBMCs isolated from healthy subjects. Apoptotic index, cytotoxic activity of CD8+ T and NK cells, and cell proliferation of CD3+, CD4+, CD8+ T and NK cells in response to different doses of C-Vx were investigated. Also the hematological and biochemical parameters of the rats administered subcutaneously in three different doses of C-Vx were monitored for 14-days.Results: Increased CD107a expression in response to C-Vx on NK cells but not on CD8+ T cells support the increasing of NK cell cytotoxicity. C-Vx alone was capable of triggering proliferation of T and NK cells. The PHA-induced proliferation of CD3+ and CD4+ T cells was diminished in response to C-Vx, while PHA-induced CD8+ T cell proliferation was up-regulated. PHA-triggered proliferation of total NK cells was enhanced with the existence of C-Vx.C-Vx was well tolerated in rats with no serious adverse effects or mortality (death) after 14-days of follow-up. Biochemical-parameters (creatinine, blood urea nitrogen, etc.) were not significantly different among treated and control groups. The levels of white blood cells and lymphocytes were increased up to two-folds in the C-Vx group (especially 0.25 ml/day) as compared to the control group.Conclusion: Taken together, these preliminary findings support the immunomodulatory effects of C-Vx. But these findings should cautiously be evaluated due to the low numbers of subjects in both human and experimental arms.Key words:Cytotoxicity, immunomodulator, immune cells, viral infectio