Person: ÖZTÜRK CİVELEK, DİLEK
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Publication Open Access The Effects of P-glycoprotein Inhibitor Zosuquidar on the Sex and Time-Dependent Pharmacokinetics of Parenterally Administered Talinolol in Mice.(2020-10-10T00:00:00Z) Kara, ZP; Ozturk, DİLEK; Ozturk, N; Okyar, A; ÖZTÜRK CİVELEK, DİLEKP-glycoprotein (P-gp) is an efflux protein that forms a tissue barrier and plays a role in the pharmacokinetics of drugs, limiting the influx of them and other xenobiotics into the cells, as expressed in various tissues such as liver, brain, intestinal mucosa and kidneys. Circadian clock controls many biological functions in mammals including xenobiotic metabolism and detoxification. Circadian rhythms of biological functions may affect the pharmacokinetics, and thus efficacy and/or toxicity of drugs. Aim of this study is to determine how the intraperitoneally administered pharmacokinetics of talinolol, as the probe substrate of P-gp, will change depending on the circadian time and sex in the presence of P-gp inhibitor zosuquidar. 20 mg/kg talinolol with or without 30 mg/kg zosuquidar was administred intraperitoneally to male and female mice at day period (ZT3) and night period (ZT15). Plasma and tissue concentrations of talinolol were determined by using validated HPLC/UV method. The protein levels of P-gp in the liver and small intestine in male and female mice were determined by PCR and Western blot techniques. P-gp protein levels in liver and ileum tissues were not different in female mice but higher in ZT15 as compared to ZT3 in male mice (p<0.05). There was no statistically significant difference in talinolol concentration depending on time and sex in the plasma and liver. There was significant time-dependent difference between ZT3 and ZT15 groups in ileum AUC0–5 h of talinolol (p<0.01). Talinolol plasma and liver AUC0–5 h were increased by zosuquidar administration regardless of dosing-time and sex (p<0.05). Our study findings are considerable in terms of revealing changes in pharmacokinetic profiles of P-gp substrates due to the time of administration in combination with P-gp inhibitors/modulators in managing polypharmacy.Publication Open Access Design of Biocompatible Multifunctional Hydrogels with Stearyl Methacrylate and Vinylpyrrolidone(2022-03-01T00:00:00Z) Kilic, Husna; TUNCABOYLU, Deniz Ceylan; Argun, Aslihan; ÖZTÜRK CİVELEK, DİLEK; TUNCABOYLU, DENIZ CEYLAN; ÖZTÜRK CİVELEK, DİLEKBiofunctionality and biocompatibility are essential when tissue or organs are supplemented or replaced with a polymer based material. Here, we prepared stearyl methacrylate (SM) and vinylpyrrolidone (VP) based biocompatible SM-x networks with self-healing and shape memory properties. The mole ratios were gradually changed from hydrophilic to hydrophobic units between 10 and 90% to obtain gels meeting the requirements in various potential bioapplications. In addition to having a time-dependent viscoelastic character, the mechanical properties of the gels can be controlled by the amount of SM introduced into the reaction medium. Low SM content gels cannot fully return to their initial modulus values, while the gels formed with concentrations >= 60% are completely reversible due to the dynamic hydrophobic interactions, which is also effective in the self-healing behavior. Moreover, all of the networks can completely recall their permanent shape in seconds. The viability of human skin fibroblast cells, seeded on SM-x hydrogels, closely related to the water contact angle of the structures, was found to be over 82% at all x values. In the light of the findings, the wide range of properties of SM-x gel samples may show significant potential to address needs in a variety of biomedical applications.Publication Open Access Association between ABCB1, ABCG2 carrier protein and COX-2 enzyme gene polymorphisms and breast cancer risk in a Turkish population(2019-01-01T00:00:00Z) Dilek, Ozturk; Ezgi, Oztas; Halil, Kara; Cihan, Uras; Gul, Ozhan; ÖZTÜRK CİVELEK, DİLEKAim: Breast cancer is the most common cancer and the second leading cause of cancer-related deaths among women. Several genetic and environmental factors are known to be involved in breast cancer pathogenesis, but the exact etiology of this disease is complicated and not completely understood. We aimed to investigate whether the gene polymorphisms of ABCB1 and ABCG2 carrier proteins and COX2 enzyme affect breast cancer risk. Method: ABCG2 C421A (rs2231142), ABCB1 C3435T (rs1045642), COX-2 T8473C (rs5275) and COX-2 G306C (rs5277) were genotyped 104 breast cancer patients and 90 healthy controls using a real-time PCR for breast cancer susceptibility. Results: Patients carrying ABCG2 C421A, the CC genotype, had a higher risk of disease compared with patients carrying any A allele (OR = 3.06; 95% CI = 1.49–6.25, p = 0.0019). The other variants showed no association with breast cancer (p > 0.05). Comparing the pathological parameters with the variants, only, the frequency of C allele of ABCB1 C3435T was significantly lower in the estrogen receptor-a (ERa) (OR = 2.25; 95% CI: 0.75–6.76; p = 0.041) and progesterone receptor (PgR) (OR = 3.67; 95% CI: 1.34–10.03; p = 0.008) positive breast cancer patients. Conclusion: ABCB1 C3435T and ABCG2 C421A might represent a potential risk factor for breast cancer for Turkish womenPublication Open Access Molecular aspects of circadian pharmacology and relevance for cancer chronotherapy(2017-10-17) ÖZTÜRK, Narin; Ozturk, DİLEK; Kavakli, Ibrahim Halil; OKYAR, Alper; ÖZTÜRK CİVELEK, DİLEKThe circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceuticsPublication Open Access Tail-Approach-Based Design and Synthesis of Coumarin-Monoterpenes as Carbonic Anhydrase Inhibitors and Anticancer Agents(2023-02-01) Kurt B. Z.; Celebi G.; Öztürk Civelek D.; Angeli A.; Akdemir A.; Sonmez F.; Supuran C. T.; ÖZTÜRK CİVELEK, DİLEK; AKDEMİR, ATİLLA; ZENGİN KURT, BELMAIn this study, sixty novel coumarin-monoterpene compounds were synthesized in two series [thirty-two compounds (12-43) bearing a triazole ring in the first series, and twenty-eight compounds (44-71) bearing an alkyl chain in the second one]. Their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I, II, IX, and XII and anticancer potentials were determined. All synthesized molecules selectively inhibited CA IX and XII. 23 and 42 were found to be the strongest inhibitors, with K i values of 1.9 nM against hCA IX. Also, 70 showed the highest inhibitory activity with a K i value of 4.9 nM against hCA XII. Moreover, their cytotoxic effects on colon adenocarcinoma (HT-29), prostate adenocarcinoma (PC-3), and breast adenocarcinoma (MCF-7) cell lines were evaluated. According to the cytotoxicity results, 14 (IC50 = 2.48 μM) and 63 (IC50 = 3.91 μM) exhibited the highest cytotoxicity on the MCF-7 cells, while 23 showed the strongest cytotoxic effect on both PC-3 (IC50 = 9.40 μM) and HT-29 (IC50 = 12.10 μM) cell lines. 14, 23, and 66 decreased CA IX and CA XII protein expression in HT-29 cells, while 23 and 66 showed the strongest reduction of both CA IX and CA XII in MCF-7 cells. All of the selected compounds increased total apoptosis in a concentration-dependent manner in HT-29 and MCF-7 cells. 14 has the strongest apoptotic effect in MCF-7 cells. 23 increased early apoptosis primarily, while 14 and 66 increased total apoptosis in HT-29. In addition, PI/Hoechst staining proves that apoptotic cells are increased in HT-29 with an effect of 14, 23, and 66. As a result of the modeling studies, it has been shown that only the open coumarin form of the compounds can interact directly with the active-site Zn2+ ion. It has been shown that coumarin-monoterpene structures with different alkyl and monoterpene groups both specifically inhibit CA IX and XII and exhibit specific cytotoxicity in different cell lines.