Person: ÖZTÜRK CİVELEK, DİLEK
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Publication Metadata only Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice(2023-02-01) Akyel Y. K.; Öztürk Civelek D.; Ozturk Seyhan N.; Gul S.; Gazioglu I.; Pala Kara Z.; Lévi F.; Kavakli I. H.; Okyar A.; ÖZTÜRK CİVELEK, DİLEKThe 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 Cmax and AUC0-6h (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, Cmax and AUC0-6h 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.Publication Metadata only Evaluation of the Immunomodulatory Effects of C-Vx on the Innate and Adaptive\"Immune\" System:Preliminary Results(2022-01-01) Oktelık F.; Cıvelek D.; Okyar A.; Aktas E.; Kucuksezer U.; Akdenız N.; Solakoglu S.; Cevık A.; Oncul O.; Denız G.; ÖZTÜRK CİVELEK, DİLEKObjectives: 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.Publication Metadata only Synthesis of flurbiprofen thiadiazole urea derivatives and assessment of biological activities and molecular docking studies(2023-01-01) ZENGİN KURT B.; Altundağ Ö.; Tokgöz M. N.; ÖZTÜRK CİVELEK D.; Tuncay F. O.; Cakmak U.; KOLCUOĞLU Y.; Akdemir A.; Sönmez F.; ZENGİN KURT, BELMA; ÖZTÜRK CİVELEK, DİLEKTotally 15 novel flurbiprofen urea derivatives were synthesized bearing the thiadiazole ring. Their inhibition effects on tyrosinase were determined. 3c was found to be the strongest inhibitor with the IC50 value of 68.0 μM against tyrosinase. The enzyme inhibition types of the synthesized compounds were determined by examining the kinetic parameters. The inhibition type of 3c was determined as uncompetitive and the Ki value was calculated as 36.3 μM. Moreover, their cytotoxic effects on hepatocellular carcinoma (HepG2), colorectal carcinoma (HT-29), and melanoma (B16F10) cell lines were evaluated. According to the cytotoxicity results, 3l (IC50 = 14.11 μM) showed the highest cytotoxicity on the HT-29 cells, while 3o (IC50 = 4.22 μM) exhibited the strongest cytotoxic effect on HepG2 cell lines. Also, 3j (IC50 = 7.55 μM strongly affected B16F10. The effects of synthesized compounds on the healthy cell line were evaluated on the CCD-986Sk cell line. Molecular modelling studies have indicated the potential binding interactions of the uncompetitive inhibitor 3c with the enzyme-substrate complex.Publication Metadata only GLP-1 RESEPTÖR AGONİSTİ LİRAGLUTİD'İN İNSAN ENDOTEL HÜCRELERİNDE YÜKSEK GLUKOZ İLE İNDÜKLENEN İNFLAMASYON İLE İLİŞKİLİ SİNYAL YOLAKLARI ÜZERİNE ETKİSİ(2023-11-25) Gökçe M.; Vidin Şen A.; Öztürk Civelek D.; Uydeş Doğan B. S.; Alp Yıldırım F. İ.; GÖKÇE, MUSTAFA; ÖZTÜRK CİVELEK, DİLEKAmaç: Diabetes Mellitus’a bağlı olarak gelişen endotel disfonksiyonu, değişen hücre sinyalizasyonu, artan oksidatif stres ve proinflamatuvar süreçlerin aktivasyonu temelinde diyabete bağlı vasküler komplikasyonların en önemli nedenidir. İnflamasyona zemin hazırlayan immün yanıtta önemli bir rol oynayan ve patern tanıma reseptörlerinin bir üyesi olan NODbenzeri-reseptör-3 (NLRP3), inflamatuvar kaspazların aktivasyonunu, pro-interlökin-18 ve pro-interlökin-1β\"nın işlenmesini sağlayan bir protein kompleksidir. NLRP3, ASC/TMS1 ve Kaspaz-1 NLRP3 inflamazom kompleksini oluşturmaktadır. Bu çalışmada, insan endotel hücre kültürlerinde GLP-1 reseptör (GLP-1R) agonisti Liraglutid’in inflamasyona zemin hazırlayan immün yanıt yolakları ile ilişkili hedef moleküller üzerine etkisinin araştırılması amaçlanmıştır. Gereç-Yöntem: HUVEC (İnsan umbilikal ven endotel hücreleri) ve HCAEC (İnsan koroner arter endotel hücreleri), normoglisemik (5.5mM) veya hiperglisemik ortamda (25 mM) 48 saat boyunca Liraglutid’in 10 nM ve 100 nM lik konsantrasyonları ile inkübe edilmiştir. Ardından LDH (laktat dehidrogeneaz) testi ile canlılık tayini yapılmıştır. RT-PCR testi ile NLRP3 inflamazom kompleksinin üyeleri olan ASC/TMS1 ve Kaspaz-1 mRNA ekspresyonları ölçülmüştür. Bulgular: HUVEC’de LDH seviyelerinde anlamlı bir değişikliğe neden olmamasına karşın Liraglutid 100 nM’de LDH seviyelerini azaltmıştır. Hiperglisemik ortam HUVEC’de Kaspaz-1 mRNA düzeylerinde artışa neden olmuşken HCAEC’de bir değişim olmamıştır. Liraglutid 10 nM’de, HCAEC’de hiperglisemi ile artan Kaspaz-1 mRNA düzeylerini baskılarken, HUVEC’de etkisiz bulunmuştur. ASC/TMS1 mRNA düzeyleri HUVEC’de hiperglisemik ortamda artarken, HCAEC’de anlamlı bir değişime neden olmamıştır. HCAEC’de ASC/TMS1 mRNA düzeylerinde gözlenen söz konusu artış Liraglutid varlığında azalırken (10 nM’de) HUVEC’de Liraglutid inkübasyonu ile bir değişiklik olmamıştır. Sonuç: Bu çalışmanın sonuçları, Liraglutid\"in insan kaynaklı venöz ve arteriyel endotel hücrelerinde hiperglisemi ile indüklenen inflamasyon ve immün yanıt aktivasyonuna bağlı olarak oluşan hücresel hasarı azaltma potansiyelinin olabileceğine işaret etmektedir. Anahtar Kelimeler: Endotel, İnflamasyon, Liraglutid, NLRP3, HiperglisemiPublication Metadata only Development of Curcumin and Turmerone Loaded Solid Lipid Nanoparticle for Topical Delivery: Optimization, Characterization and Skin Irritation Evaluation with 3D Tissue Model(2024-02-01) Aydin B.; Sagiroglu A.; Öztürk Civelek D.; Gokce M.; Bahadori F.; ÖZTÜRK CİVELEK, DİLEKPublication Metadata only Synthesis of Sorafenib−Ruthenium Complexes, Investigation of Biological Activities and Applications in Drug Delivery Systems as an Anticancer Agent(2024-03-01) Zengin Kurt B.; Öztürk Civelek D.; Çakmak E. B.; Kolcuoğlu Y.; Şenol H.; Sağlık Özkan B. N.; Dağ A.; Benkli K.; ZENGİN KURT, BELMA; ÖZTÜRK CİVELEK, DİLEK; ŞENOL, HALIL; DAĞ, AYDANPublication Metadata only Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in mice(2024-01-01) ÖZTÜRK CİVELEK D.; ÖZTÜRK SEYHAN N.; AKYEL Y. K.; Gazioglu I.; PALA KARA Z.; Orman M. N.; OKYAR A.; ÖZTÜRK CİVELEK, DİLEK; GAZİOĞLU, IŞILBackground: 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.