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Öğe Effects of Bevacizumab, Ranibizumab, and Aflibercept on MicroRNA Expression in a Retinal Pigment Epithelium Cell Culture Model of Oxidative Stress(Mary Ann Liebert, Inc, 2018) Dinc, Erdem; Ayaz, Lokman; Kurt, Akif HakanPurpose: This study aimed to evaluate the effects of bevacizumab, ranibizumab, and aflibercept on the microRNA (miRNA) expression in human retinal pigment epithelium cell (ARPE-19) culture model of oxidative stress. Methods: Control cells were cultured in the hydrogen peroxide (H2O2)-free medium. In H2O2 group ARPE-19 cells were exposed to 600M H2O2 alone for 18h. In study groups, cells were preincubated with bevacizumab, ranibizumab, and aflibercept (1.25-2.5, 0.5 and 2.0mg/mL, respectively) for 3h before H2O2 exposure. Another group of ARPE-19 cells were incubated with drugs for 3h without H2O2 exposure. Cell viability and vascular endothelial growth factor (VEGF) levels were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and enzyme-linked immunosorbent assay. The expression levels of 1,152 miRNAs were determined by quantitative real-time PCR. Results: Incubation with 600M H2O2 alone for 18h decreased cell viability by approximate to 50%. Cell viability was greater in the anti-VEGF drug groups compared with the H2O2 group, but the differences were not significant (P>0.05). VEGF levels were significantly lower in the anti-VEGF drug groups compared with the H2O2 group (P<0.05 for all study groups), with no significant differences between the study groups (P>0.05). Incubation with anti-VEGF drugs alone had no effect on miRNA expression in ARPE-19 cells. However, preincubation with bevacizumab, ranibizumab, and aflibercept significantly altered the profile of H2O2-modulated miRNA expression. Conclusions: Preincubation with anti-VEGF drugs can alter the miRNA expression profile in response to H2O2-induced oxidative stress, and these drugs may have epigenetic effects.Öğe Protective Effect of Combined Caffeic Acid Phenethyl Ester and Bevacizumab Against Hydrogen Peroxide-Induced Oxidative Stress in Human RPE Cells(Taylor & Francis Inc, 2017) Dinc, Erdem; Ayaz, Lokman; Kurt, Akif HakanPurpose: This study aimed to evaluate the protective effects of caffeic acid phenethyl ester (CAPE) and combined CAPE-bevacizumab against oxidative stress induced by hydrogen peroxide (H2O2) in human retinal pigment epithelium. Methods: ARPE-19 cells were pretreated with 5, 10, and 30 mu M CAPE alone and in combination with bevacizumab for 3 h, then exposed to H2O2 for 16 h. Cell viability was evaluated with the 3-(4,5dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Vascular endothelial growth factor (VEGF) protein levels in the medium were measured using a human VEGF ELISA kit. Total antioxidant status (TAS) and total oxidant status (TOS) were measured in ARPE-19 cells using the test kit from Rel Assay. Expression levels of VEGF, Bax, Bcl-2, cytochrome c, apoptotic protease activating factor-1 (apaf-1), and caspase-3 were determined using reverse transcription polymerase chain reaction. Results: Pretreatment of ARPE-19 cells with 30 mu M CAPE and combined CAPE-bevacizumab reduced H2O2 mediated cell death. H2O2-induced oxidative stress increased TOS and VEGF production, which was significantly inhibited by CAPE and the CAPE-bevacizumab combination. VEGF, Bax, cytochrome c, apaf-1, and caspase-3 gene expressions were significantly decreased in cells pretreated with 5, 10, and 30 mu M CAPE and combined CAPE-bevacizumab compared to the H2O2 group. In addition, Bcl-2 expression was significantly increased in both the CAPE and CAPE-bevacizumab combination groups compared to the H2O2 group. Conclusions: CAPE has a protective effect on ARPE-19 cells against oxidative stress, and VEGF protein level and expression can be decreased by incubation with different concentrations of CAPE. These results demonstrate that CAPE suppresses the mitochondria-mediated apoptosis in ARPE-19 cells under oxidative stress. In addition, the use of CAPE in combination with bevacizumab has an additive effect.Öğe A Review on the Design, Synthesis, and Structure-activity Relationships of Benzothiazole Derivatives against Hypoxic Tumors(Bentham Science Publ Ltd, 2022) Kurt, Akif Hakan; Ayaz, Lokman; Ayaz, Furkan; Seferoglu, Zeynel; Nural, YahyaThere has been a growing body of studies on benzothiazoles and benzothiazole derivatives as strong and effective anti-tumor agents against lung, liver, pancreas, breast, and brain tumors. Due to the highly proliferative nature of the tumor cells, the oxygen levels get lower than that of normal tissues in the tumor microenvironment. This situation is called hypoxia and has been associated with increased ability for carcinogenesis. For the drug design and development strategies, the hypoxic nature of the tumor tissues has been exploited more aggressively. Hypoxia itself acts as a signal initiating system to activate the pathways that eventually lead to the spread of the tumor cells into the different tissues, increases the rate of DNA damage, and eventually ends up with more mutation levels that may increase the drug resistance. As one of the major mediators of hypoxic response, hypoxia-inducible factors (HIFs) have been shown to activate angiogenesis, metastasis, apoptosis resistance, and many other protumorigenic responses in cancer development. In the current review, we will be discussing the design, synthesis, and structure-activity relationships of benzothiazole derivatives against hypoxic tumors such as lung, liver, pancreas, breast, and brain as potential anti-cancer drug candidates. The focus points of the study will be the biology behind carcinogenesis and how hypoxia contributes to the process, recent studies on benzothiazole and its derivatives as anti-cancer agents against hypoxic cancers, conclusions, and future perspectives. We believe that this review will be useful for researchers in the field of drug design during their studies to generate novel benzothiazole-containing hybrids against hypoxic tumors with higher efficacies.