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Öğe Circadian dysfunction in adipose tissue: Chronotherapy in metabolic diseases(MDPI, 2023) Civelek, Erkan; Öztürk Civelek, Dilek; Akyel, Yasemin Kübra; Kaleli Durman, Deniz; Okyar, AlperEssential 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.Öğe Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice(Nature Research, 2022) Gül, Şeref; Akyel, Yasemin Kübra; Gül, Zeynep Melis; Işın, Şafak; Özcan, Onur; Korkmaz, Tuba; Selvi, Saba; Danış, İbrahim; Şavluğ İpek, Özgecan; Aygenli, Fatih; Taşkın, Ali Cihan; Akarlar, Büşra Aytül; Özlü, Nurhan; Öztürk, Nuri; Öztürk, Narin; Özer Ünal, Durişehvar; Güzel, Mustafa; Türkay, Metin; Okyar, Alper; Kavaklı, İbrahim HalilCryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53?/? mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.Öğe Diurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice(SAGE Publications Inc., 2023) Akyel, Yasemin Kübra; Öztürk Civelek, Dilek; Öztürk Seyhan, Narin; Gül, Şeref; Gazioğlu, Işıl; Pala Kara, Zeliha; Levi, Francis; Kavaklı, İbrahim Halil; Okyar, AlperThe 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.Öğe Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in mice(2024) Öztürk Civelek, Dilek; Öztürk Seyhan, Narin; Akyel, Yasemin Kübra; Gazioğlu, Işıl; Pala Kara, Zeliha; Orman, Mehmet Nurullah; Okyar, AlperBackground: Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window and shows chronotoxicity with the best time at ZT13 and worst time at ZT1 (ZT; Zeitgeber time, time after light onset) in the preclinical setting. Objectives: In the present study, we aimed to investigate whether the pharmacokinetics of everolimus vary according to dosing time and whether sex and feeding status interfere with the chronopharmacokinetics. Method: A single dosage of 5 mg/kg everolimus was administered orally to C57BL/6J male and female mice, in fed or fasted states at ZT1-rest and ZT13-activity times and blood and tissue samples were collected at 0.5, 1, 2, 4, 12, and 24 h following drug administration. Ileum, liver, plasma, and thymus concentrations of everolimus were determined. Results: Females had a greater ileum AUC0–24h than males when fed (P = 0.043). Everolimus AUC0–24h in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (P = 0.001). Plasma Cmax, AUC0–24h, and AUCtotal were not statistically significant between the groups (P = 0.098). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (P = 0.029). Conclusion: Our findings imply that the pharmacokinetics of everolimus in mice may differ according to dosing time, sex, and feeding. Greater tissue distribution of everolimus at ZT1 may be associated with the worst tolerated time of everolimus. Our research suggests that oral chronomodulated everolimus therapy may be more effective and safer for cancer patients.Öğe The impact of circadian rhythm disruption on oxaliplatin tolerability and pharmacokinetics in Cry1-/-Cry2-/- mice under constant darkness(2025) Akyel, Yasemin Kübra; Öztürk Seyhan, Narin; Gül, Şeref; Çelik, Melis; Taşkın, Ali Cihan; Selby, Christopher; Okyar, AlperCircadian rhythms, the 24-h oscillations of biological activities guided by the molecular clock, play a pivotal role in regulating various physiological processes in organisms. The intricate relationship between the loss of circadian rhythm and its influence on the tolerability and pharmacokinetic properties of anticancer drugs is poorly understood. In our study, we investigated the effects of oxaliplatin, a commonly used anticancer drug, on Cry1-/- and Cry2-/- mice (Cry DKO mice) under darkness conditions, where they exhibit free-running phenotype. We administered oxaliplatin at a dosage of 12 mg/kg/day at two distinct circadian times, CT8 and CT16, under constant darkness conditions to Cry DKO mice and their wild type littermates. Our results revealed a striking disparity in oxaliplatin tolerance between Cry DKO mice and their wild-type counterparts. Oxaliplatin exhibited severe toxicity in Cry DKO mice at both CT8 and CT16, in contrast to the wild type mice. Pharmacokinetic analyses suggested that such toxicity was a result of high concentrations of oxaliplatin in the serum and liver of Cry DKO mice after repeated dose injections. To understand the molecular basis of such intolerance, we performed RNA-seq studies using mouse livers. Our findings from the RNA-seq analysis highlighted the substantial impact of circadian rhythm disruption on gene expression, particularly affecting genes involved in detoxification and xenobiotic metabolism, such as the Gstm gene family. This dysregulation in detoxification pathways in Cry DKO mice likely contributes to the increased toxicity of oxaliplatin. In conclusion, our study highlights the crucial role of an intact molecular clock in dictating the tolerability of oxaliplatin. These findings emphasize the necessity of considering circadian rhythms in the administration of anticancer drugs, providing valuable insights into optimizing treatment strategies for cancer patients.Öğe TW68, cryptochromes stabilizer, regulates fasting blood glucose levels in diabetic ob/ob and high fat-diet-induced obese mice(Elsevier Inc., 2023) Sürme, Saliha; Ergün, Çağla; Gül, Şeref; Akyel, Yasemin Kübra; Gül, Zeynep Melis; Özcan, Onur; Şavluğ İpek, Özgecan; Akarlar, Büşra Aytül; Özlü, Nurhan; Taşkın, Ali Cihan; Türkay, Metin; Gören, Ahmet Ceyhan; Barış, İbrahim; Öztürk, Nuri; Güzel, Mustafa; Aydın, Cihan; Okyar, Alper; Kavaklı, İbrahim HalilCryptochromes (CRYs), transcriptional repressors of the circadian clock in mammals, inhibit cAMP production when glucagon activates G-protein coupled receptors. Therefore, molecules that modulate CRYs have the potential to regulate gluconeogenesis. In this study, we discovered a new molecule called TW68 that interacts with the primary pockets of mammalian CRY1/2, leading to reduced ubiquitination levels and increased stability. In cell-based circadian rhythm assays using U2OS Bmal1-dLuc cells, TW68 extended the period length of the circadian rhythm. Additionally, TW68 decreased the transcriptional levels of two genes, Phosphoenolpyruvate carboxykinase 1 (PCK1) and Glucose-6-phosphatase (G6PC), which play crucial roles in glucose biosynthesis during glucagon-induced gluconeogenesis in HepG2 cells. Oral administration of TW68 in mice showed good tolerance, a good pharmacokinetic profile, and remarkable bioavailability. Finally, when administered to fasting diabetic animals from ob/ob and HFD-fed obese mice, TW68 reduced blood glucose levels by enhancing CRY stabilization and subsequently decreasing the transcriptional levels of Pck1 and G6pc. These findings collectively demonstrate the antidiabetic efficacy of TW68 in vivo, suggesting its therapeutic potential for controlling fasting glucose levels in the treatment of type 2 diabetes mellitus.
