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Öğe Alteration in cardiac PI3K/Akt/mTOR and ERK signaling pathways with the use of growth hormone and swimming, and the roles of miR21 and miR133(Spandidos Publ Ltd, 2019) Palabiyik, Orkide; Tastekln, Ebru; Doganlar, Zeynep Banu; Tayfur, Pinar; Dogan, Ayten; Vardar, Selma ArzuAthletes misuse recombinant human growth hormone (r-hGH) to enhance their performance. Although r-hGH is known to increase cardiac hypertrophy, the underlying molecular mechanism remains unclear. The aim of the present study was to investigate the role of r-hGH in cardiac intracellular signaling pathways and of miR-21 and miR-133 expression in rat hearts during exercise. A total of 36 adult male Sprague-Dawley rats were divided into sedentary control (SC, n=9), swimming exercise (SE, n=8), r-hGH (GH, n=10) and swimming exercise plus r-hGH (SE-GH, n=9) groups. The exercise groups completed a 1-h swimming exercise 5 times a week for 8 weeks. Subcutaneous r-hGH was administered as 0.3 mg/kg/day. Phosphoinositide-3-kinase (PI3K), serine/threonine protein kinase 1 (AKT1), extracellular signal-regulated kinase (ERK), microRNA (miR)-21 and miR-133 expression was evaluated in ventricular muscle by real-time quantitative polymerase chain reaction. Protein expression of PI3K, AKT1, ERK and mechanistic target of rapamycin (mTOR) was also assessed by immunohistochemistry. Statistical differences were analyzed by two-way ANOVA. PI3K and AKT1 expression and the gene and protein levels was notably increased in the SE-GH group compared with in SC ventricular tissues (P<0.05). mTOR protein expression was higher in the GH, SE and SE-GH groups compared with in the SC group (P<0.05, <0.05 and <0.001, respectively). ERK gene/protein expression was similar across all groups. miR-21 and miR-133 levels in ventricular muscle were higher in the SE and GH groups than those in the SC group. In summary, growth hormone application coupled with swimming exercise appeared to affect the PI3K/AKT/mTOR signaling pathway in the left ventricular tissue of rats; however, ERK signaling pathway appeared inactive in physiological left ventricular hypertrophy caused by swimming and GH administration over 8 weeks. Furthermore, GH treatment resulted in increased miR-21 and miR-133 expression. Future study by our group will aim to assess the effects of higher dose GH treatment.Öğe ANTINEOPLASTIC MULTI-DRUG CHEMOTHERAPY TO SENSITIZE TUMORS TRIGGERS MULTI-DRUG RESISTANCE AND INHIBITS EFFICIENCY OF MAINTENANCE TREATMENT IN GLIOBLASTOMA CELLS(Excli Journal Managing Office, 2022) Doganlar, Oguzhan; Doganlar, Zeynep Banu; Erdogan, Suat; Delen, EmreCombinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma mainte-nance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apopto-sis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically re-duced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tu-mors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic com-bination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients.Öğe Chronic exposure of human glioblastoma tumors to low concentrations of a pesticide mixture induced multidrug resistance against chemotherapy agents(Academic Press Inc Elsevier Science, 2020) Doganlar, Oguzhan; Doganlar, Zeynep Banu; Kurtdere, Ayse Kardelen; Chasan, Tourkian; Ok, Esma SebenRecent evidence indicates that chronic, low-dose exposure to mixtures of pesticides can cause adverse responses in a variety of cells, tissues and organs, although interactions between pesticides circulating in the blood and cancer cells remain largely unexplored. The aim of this study was to investigate the potential of a mixture of four pesticides to induce multidrug resistance against the chemotherapeutic agents cisplatin, 5-fluorouracil and temozolomide in the human U87 glioblastoma cell line, and to explore the molecular mechanisms underlying this resistance. We found that the repeated administration of the pesticide mixture (containing the insecticides chlorpyrifos-ethyl and deltamethrin, the fungicide metiram, and the herbicide glyphosate) induced a strong drug resistance in U87 cells. The resistance was durable and transferred to subsequent cell generations. In addition, we detected a significant over-expression of the ATP-binding cassette (ABC) membrane transporters P-gp/ABCB1 and BRCP/ABCG2 as well as a glutathione-S-transferase (GST)/M1-type cellular detoxification function, known to have important roles in multidrug resistance, thus providing molecular support for the acquired multidrug resistance phenotype and shedding light on the mechanism of resistance. We further determined that there was lower mortality in the resistant brain tumor cells and that the mitochondrial apoptosis pathway was activated at a lower rate after chemotherapy compared to non-resistant control cells. In addition, multidrug-resistant cells were found to have both higher motility and wound-healing properties, suggesting a greater metastatic potential. Our results suggest that the investigation of P-gp, BRCP and GST/M1 multidrug resistance gene expression and/ or protein levels in biopsy specimens of brain tumor patients who were at risk of pesticide exposure could be beneficial in determining chemotherapy dose and prolonging patient survival.Öğe The effect of growth hormone and/or swimming exercise on PI3K, AKT, PTEN and miR21 expressions in rats(Wiley-Blackwell, 2016) Palabiyik, Orkide; Tastekin, Ebru; Doganlar, Zeynep Banu; Tayfur, Pinar; Vardar, Selma Arzu[Abstract Not Available]Öğe Effects of a Mixture of Volatile Organic Compounds on Total DNA and Gene Expression of Heat Shock Proteins in Drosophila melanogaster(Springer, 2015) Doganlar, Oguzhan; Doganlar, Zeynep BanuThe genotoxic effects of a mixture of 13 volatile organic compounds (VOCs) on total DNA profiles and the expression of heat shock proteins (HSPs) HSP26, HSP60, HSP70, and HSP83 in fruit fly tissues were examined. Drosophila melanogaster Oregon R+, reared under controlled conditions on artificial diets, was treated with 13 VOCs commonly found in water at concentrations of 10, 20, 50, and 75 ppb for 1 and 5 days. Band changes were clearly detected in random amplified polymorphic DNA assay, especially at the 50- and 75-ppb exposure levels, for both treatment periods. In addition, there were clear differences in the band profiles of the treated and untreated flies with changes in the band intensity and the loss/appearance of bands. Although the genomic template stability (GTS) exhibited irregular changes at the first day, significant decreases in GTS were observed after 5 days of VOC application. The lowest GTS value (27.77 +/- A 1.96 %) was detected at the 75-ppb level after 5 days of the treatment. Quantitative real-time polymerase chain reaction analysis showed a significant increase in the relative expression of HSP26 and HSP60 after 1 and 5 days of the treatment, respectively. The expression of HSP70 increased significantly at all treatment concentrations and times. However, the greatest increase in expression level of HSP70 (4.2-fold) occurred at 20 ppb after 5 days of the treatment. HSP83 was the least affected by exposure to the VOCs. We conclude that trace levels of a mixture of VOCs can exert genotoxic effects on both total DNA and HSP levels in Drosophila.Öğe Effects of cisplatin-5-fluorouracil combination therapy on oxidative stress, DNA damage, mitochondrial apoptosis, and death receptor signalling in retinal pigment epithelium cells(Taylor & Francis Ltd, 2018) Guclu, Hande; Doganlar, Zeynep Banu; Gurlu, Vuslat Pelitli; Ozal, Altan; Dogan, Ayten; Turhan, Meryem Aysenur; Doganlar, OguzhanAim: Combination therapies of cisplatin with 5-FU (PF) are an effective solution and have been widely used for the treatment of various categories of cancer including anal, gastrointestinal, and oral cancer, as well as head and neck tumors. The effects of combined PF treatment on vital intracellular signalling pathways in nontargeted cells remain unclear. The aim of this study is to explain the possible mechanisms by which combined PF treatment results in retinal toxicity and to investigate the effects of PF on important vital signalling pathways in ARPE 19 retinal pigmented epithelial cells.Materials and methods: We analysed the cellular and molecular effects of PF on cell viability, oxidative stress, gene repair response, and induction of apoptosis in ARPE 19 cells using molecular probe fluorescent staining, cell cytometer, RAPD, qRT-PCR, and western blot assays.Results: We determined that PF causes excessive generation of reactive oxygen species (ROS) and prevents ROS scavenging by suppressing antioxidant systems. We found induction of DNA damage, particularly mismatch and double strand break repair, in ARPE 19 cells treated with PF. In this study, PF also induced both the intrinsic apoptosis pathway and death receptor signalling in ARPE 19 cells.Conclusions: Our data proved that PF causes cytotoxicity and genotoxicity, at both the cellular and molecular levels, in ARPE 19 cells following particularly prolonged treatment (48h). Additionally, our results suggest key molecular signals for prevention strategies that can be developed to reduce the severe side effects of PF chemotherapy.Öğe Effects of Expression of Matrix Metalloproteinases and Discoidin Domain Receptors in Ligamentum Flavum Fibrosis in Patients with Degenerative Lumbar Canal Stenosis(Korean Soc Spine Surgery, 2023) Torun, Yusuf Mansur; Delen, Emre; Doganlar, Oguzhan; Doganlar, Zeynep Banu; Delen, Ozlem; Orakdogen, MetinStudy Design: This is a retrospective cohort study. Purpose: This study aimed to clarify the role of crosstalk between discoidin domain receptors (DDRs) and matrix metalloproteinases (MMPs) in the ligamentum flavum (LF) fibrosis obtained from patients with degenerative lumbar canal stenosis (DLCS). Overview of Literature: The DDRs, DDR1 and DDR2, are cell surface receptors and have an essential role in collagen fiber accumulation in several fibrotic diseases. MMPs are one of the critical factors in extracellular matrix remodeling and elastic fiber degradation in LF tissues. However, the crosstalk between DDRs and MMPs and the role of this molecular signal in LF fibrosis remain unclear. Methods: A total of 35 patients were divided into two groups in this study. Spinal surgery was performed in 23 of these patients with the diagnosis of DLCS. Twelve patients with lumbar disk herniation (LDH) were included in the control group. On axial T2-weighted magnetic resonance imaging, LF thickness was measured bilaterally at the level of the facet joint. Histology, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analyses were performed on LF tissue samples. LF tissues were stained with hematoxylin and eosin. In addition, the grade of fibrosis was histologically assessed using Masson trichrome triple staining. DDR1 and DDR2 Western blot analyses were performed. DDR1, DDR2, MMP2, MMP3, MMP9, and MMP13 expression levels were measured using qRT-PCR analysis. Results: The grade of fibrosis and LF thickness were significantly higher in the DLCS patients than in the LDH patients. DDR1 and DDR2 gene expression and protein levels in LF tissues are significantly greater in DLCS samples than in control samples, according to both qRT-PCR and Western blot analyses. In addition, we detected a significant expression of the MMP3, MMP9, and MMP13, which are known to have important roles in extracellular matrix remodeling in DLCS. Furthermore, we discovered a link between DDR protein levels and LF thickness, fibrosis, and MMP3/MMP9. Conclusions: Our results indicate that DDR1, DDR2, and MMP3 and MMP9 signals can be correlated with each other in LF tissues and be promoted LF fibrosis leading to spinal canal narrowing in patients with DLCS.Öğe Effects of permissible maximum-contamination levels of VOC mixture in water on total DNA, antioxidant gene expression, and sequences of ribosomal DNA of Drosophila melanogaster(Springer Heidelberg, 2015) Doganlar, Oguzhan; Doganlar, Zeynep Banu; Tabakcioglu, KiymetIn this study, we aimed to investigate the mutagenic and carcinogenic potential of a volatile organic compound (VOC) mixture with references to the response of D. melanogaster using selected antioxidant gene expressions, RAPD assay and base-pair change of ribosomal 18S, and the internal transcribed spacer, ITS2 rDNA gene sequences. For this purpose, Drosophila melanogaster Oregon R, reared under controlled conditions on artificial diets, were treated with the mixture of thirteen VOCs, which are commonly found in water in concentrations of 10, 20, 50, and 75 ppb for 1 and 5 days. In the random amplified polymorphic DNA (RAPD) assay, band changes were clearly detected, especially at the 50 and 75 ppb exposure levels, for both treatment periods, and the band profiles exhibited clear differences between the treated and untreated flies with changes in band intensity and the loss/appearance of bands. Quantitative real-time PCR (qRT-PCR) analysis of Mn-superoxide dismutase (Mn-SOD), catalase (CAT) and glutathione-synthetase (GS) expressions demonstrated that these markers responded significantly to VOC-induced oxidative stress. Whilst CAT gene expressions increased linearly with increasing concentrations of VOCs and treatment times, the 50- and 75-ppb treatments caused decreases in GS expressions compared to the control at 5 days. Treatment with VOCs at both exposure times, especially in high doses, caused gene mutation of the 18S and the ITS2 ribosomal DNA. According to this research, we thought that the permissible maximum-contamination level of VOCs can cause genotoxic effect especially when mixed.Öğe Ehlers?Danlos syndrome-related genes and serum strontium, zinc, and lithium levels in generalized joint hypermobility: a case-control study(Taylor & Francis Inc, 2021) Tuna, Filiz; Doganlar, Zeynep Banu; Ozdemir, Hande; Kabayel, Derya Demirbag; Doganlar, OguzhanAim of the study: Generalized joint hypermobility (GJH) is a common feature of almost all Ehlers?Danlos syndrome (EDS) types; however, its genetic basis remains unclear. Therefore, it is crucial to distinguish the genetic basis of GJH from other connective tissue disorders, including the different subtypes of EDS. The aim of this study was to determine the blood EDS-related gene expressions and serum element levels in GJH and reveal their predictive characteristics and correlations with the Beighton score. Materials and Methods: A total of 39 women aged 18?23?years with GJH and 38 age- and sex-matched controls were included in the study. Inductively coupled plasma mass spectrometry was used to analyze the serum levels of zinc (Zn), strontium (Sr), and lithium (Li). The relative expression levels of the EDS-related genes were determined using quantitative real-time polymerase chain reaction (PCR). Results: Our results showed that women with GJH possessed significantly lower Li and higher Zn and Sr levels than the controls. In addition, the gene expressions of TNXB and SLC39A13 were significantly higher, whereas those of COL1A1, COL1A2, COL5A1, FKBP14, and DSE were lower in the GJH group. Pearson correlation analyses revealed a strong negative correlation between the Beighton score and B4GALT7, FKBP14, COL1A1, and Li. However, a significant positive correlation was noted between the Beighton score and SLC39A13, TNXB, Zn, Sr, and B3GALT6. Conclusion: Our findings provide valuable basal levels for conducting gene function analysis of joint hypermobility-related connective tissue disorders.Öğe Evaluation of the selective anticancer potential and the genetic mechanisms of the induction of apoptosis by walnut milk in human breast and prostate cancer cells(Allied Acad, 2016) Doganlar, Oguzhan; Doganlar, Zeynep BanuIn different cancer types, classical chemotherapy has several side effects due to the cytotoxic properties of the compounds and non-selective targeting of normal tissue. The aims of this study were to determine bioactive molecules and to investigate the genetic mechanisms of the anticancer properties of walnut special mixture, walnut milk (WM), as a potential anticancer treatment in DU145, MCF7 and TG/HA-VSMC cells. The bioactive molecules of WM were determined by LC-Q-TOF analysis. After treatment with the WM, cell viability was determined using the MTT assay and apoptosis induction was observed following cell membrane staining by annexin-V/propidium-iodide using a Tali-cytometer. The gene expression studies were carried out using a qRT-PCR assay. In the WM, we quantified five hormones, eight polyphenols, quercetin and juglone. Abscisic acid (63.07 +/- 18.70 mu g/l), gallic acid (3887.08 +/- 155.06 mu g/l), quercetin (245.26 +/- 34.12 mu g/l) and juglone (401.52 +/- 16.60 mu g/l) were major components of the quantified compounds. Our results indicated that WM dramatically reduces cell viability and selectively induces caspase-dependent apoptosis in DU145 and MCF7 cells without affecting TG/HA-VSMC non-cancerous cells by triggering intrinsic apoptotic signalling and increases in ROS production. Our results suggest that WM is a potential anticancer agent with selective apoptotic potential and special bioactive chemical constituents.Öğe Exogenous jasmonic acid induces stress tolerance in tobacco (Nicotiana tabacum) exposed to imazapic(Academic Press Inc Elsevier Science, 2016) Kaya, Armagan; Doganlar, Zeynep BanuJasmonic acid am is one of the important phytohormones, regulating the stress responses as well as plant growth and development. The aim of this study is to determine the effects of exogenous JA application on stress responses of tobacco plant exposed to imazapic. In this study, phytotoxic responses resulting from both imazapic and imazapic combined with JA treatment are investigated comparatively for tobacco plants. For plants treated with imazapic at different concentrations (0.030, 0.060 and 0.120 mM), antioxidant enzyme activities (catalase, ascorbate peroxidase, glutathione S-transferase and glutathione reductase), carotenoids, glutathione and malondialdehyte (MDA) contents, jasmonic acid, abscisic acid and indole-3-acetic acid levels as well as herbicide residue amounts on leaves increased in general compared to the control group. In the plants treated with 45 mu M jasmonic acid, pigment content, antioxidant activity and phytohormone level increased whereas MDA content and the amount of herbicidal residue decreased compared to the non-treated plants. Our findings show that imazapic treatment induces some phytotoxic responses on tobacco leaves and that exogenous jasmonic acid treatment alleviates the negative effects of herbicide treatment by regulating these responses. (C) 2015 Elsevier Inc. All rights reserved.Öğe FOLFIRI-Mediated Toxicity in Human Aortic Smooth Muscle Cells and Possible Amelioration with Curcumin and Quercetin(Humana Press Inc, 2020) Guclu, Orkut; Doganlar, Oguzhan; Yuksel, Volkan; Doganlar, Zeynep BanuSystemic chemotherapy-mediated cell toxicity is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events of the FOLFIRI (irinotecan, folinic acid and 5-fluorouracil) regimen are mainly due to DNA damage induced by antimetabolite and topoisomerase inhibition effects. However, the role of human aortic smooth muscle cells (HaVSMCs) in this process and the mechanisms of oxidative stress, DNA and protein damage and apoptosis have not been investigated. Therefore, the effects of curcumin and quercetin on HaVSMC survival in the generation of molecular and cellular toxicity by FOLFIRI treatment and the involvement of vital cellular signalling pathways were investigated. We analysed both FOLFIRI toxicity and the therapeutic potential of quercetin and curcumin in terms of HaVSMC damage using molecular probe and florescence staining, Random Amplified Polymorphic DNA (RAPD), qRT-PCR and Western blot assays. Our study presents two preliminary findings: (a) in HaVSMCs, FOLFIRI treatment significantly induces oxidative damage to both DNA and protein, leading to a dramatic increase in caspase-dependent apoptotic death through P53-mediated Caspase3-dependent mitochondrial apoptosis, and results in TNF-alpha/Caspase8-mediated necrotic death, and (b) flavonoids not only regulate the expression of genes encoding antioxidant enzymes and increase DNA damage but also limit programmed and necrotic cell death processes in HaVSMCs. Our results clearly indicate the potential for curcumin and, particularly, quercetin as preventative chemotherapeutic interventions for cardiovascular toxicity induced by the FOLFIRI regime in HaVSMCs.Öğe Genotoxic Effect and Carcinogenic Potential of a Mixture of As and Cd in Zebrafish at Permissible Maximum Contamination Levels for Drinking Water(Springer International Publishing Ag, 2016) Doganlar, Oguzhan; Doganlar, Zeynep Banu; Muranli, Fulya Dilek Gokalp; Guner, UtkuCurrently, the toxic effects and carcinogenic potential of individually treated arsenic (As) or cadmium (Cd) are well documented both in animal and human tissues. However, there are no data focusing on the genotoxicity of these heavy metals as a mixture at the very low concentrations of permissible limits for drinking water. In this study, we examine the genotoxicity and carcinogenic potential of single and combined treatments of As and Cd, as well as attempt to elucidate the mechanism of action of certain cell defense systems such as antioxidants, gene repair, heat shock, cell cycle control, and the apoptosis pathway. Zebrafish (Danio rerio), reared under controlled conditions with artificial diets, were treated with As and Cd, either individually or in combination, at concentrations commonly found in water (10 ppb for As and 5 ppb for Cd) and tenfold higher concentrations for 48 h. Our results indicate that separately, As and Cd treatments at low dose selectively induce antioxidant enzymes, gene repair, and caspaseindependent apoptosis in gill tissue, by targeting the mitochondria, leading to oxidative stress and sub-lethal levels of DNA damage. However, tenfold higher (100 ppb As + 50 ppb Cd) treatment caused significant downregulation of genes involved in double-strand break repair and molecular chaperone genes. Additionally, the highest BCL2/BAX ratio (1.6) and lowest expression levels of caspase-3 (8.4-fold) in all treated groups were observed in same condition. These results demonstrate that both single and combined exposure to As and Cd at permissible levels is potentially safe and causes repairable genotoxicity in gill tissue. However, the highest concentration is potentially carcinogenic due to ineffective DNA repair and insufficient apoptosis.Öğe Genotoxic Effects of Heavy Metal Mixture in Drosophila melanogaster: Expressions of Heat Shock Proteins, RAPD Profiles and Mitochondrial DNA Sequence(Springer International Publishing Ag, 2014) Doganlar, Zeynep Banu; Doganlar, Oguzhan; Tabakcioglu, KiymetThe genotoxic effects of four heavy metal mixtures on Drosophila melanogaster were investigated with reference to gene expressions of heat shock proteins (HSP26, HSP60, HSP70 and HSP83), DNA profiles, and mitochondrial NADH dehydrogenase sequence. Adult D. melanogaster flies were treated with a mixture of four (Fe, Cu, Cd and Pb) heavy metals (HMs) in three different concentrations, which were selected based on one higher dose (HM3) and one lower dose (HM1) relative to the permitted limits (HM2) in drinking water at 1st, 5th and 10th days. It was determined that the amount of the accumulated heavy metals and the expressions of the HSP genes were changed with increasing exposure time. The accumulations of Cd and Pb were increased with increasing exposure time; additionally, the HSP expression patterns were determined as HSP70>HSP60>HSP26>HSP83 HM1 (5th day), HM2 (5th day and 10th day), and HM3 (all exposure times). It was also determined that the application of the heavy metal mixture affected the random amplified polymorphic DNA (RAPD) profiles and the mitochondrial NADH dehydrogenase sequence of D. melanogaster. The highest base pair changes (9 bp) were determined at the HM2 concentration (permissible limits in drinking water) on the 1st day of treatment. Therefore, it was shown that mixture of four heavy metals caused a genotoxic effect and D. melanogaster is a useful model organism for heavy metal-induced genotoxicity studies.Öğe The genotoxic effects of mixture of aluminum, arsenic, cadmium, cobalt, and chromium on the gill tissue of adult zebrafish (Danio rerio, Hamilton 1822)(Taylor & Francis Ltd, 2022) Gokalp, Fulya Dilek; Doganlar, Oguzhan; Doganlar, Zeynep Banu; Guner, UtkuThe aim of this study is to investigate the genotoxic effects of mixtures of five metals on zebrafish at two different concentrations; at the permissible maximum contamination levels in drinking water and irrigation waters. The drinking water limits are as follows: 300 mu g/L for Aluminum (Al+3), 10 mu g/L for Arsenic (As+3), 5 mu g/L for Cadmium (Cd+2), 10 mu g/L for Cobalt (Co+2), and 50 mu g/L for Chromium (Cr+2). The irrigation water limits: 5000 mu g/L for Al+3, 100 mu g/L for As+3, 10 mu g/L for Cd+2, 50 mu g/L for Co+2, and 100 mu g/L for Cr+2. The zebrafish underwent chronic exposure for periods of 5, 10, and 20 days. The gene expressions for mitochondrial superoxide dismutase (SOD2), stress-specific receptor protein NCCRP1, the heat shock proteins: Hsp9, Hsp14, Hsp60, Hsp70, DNA repair (XRCC1 and EXO1), and apoptosis (BOK and BAX) were evaluated. It was found that exposure to the low- and high-concentrations of the heavy metal mixtures caused cell stress, an increased expression of the antioxidant genes, and repair proteins. As the duration of exposure was increased, the cells progressed through the apoptotic pathway. This was more evident in the high-concentration exposure groups. The results demonstrated the necessity for a reevaluation of the maximum values of heavy metal and toxic element concentrations as prescribed by the Local Standing Rules of Water Pollution Control Regulation, as well as a reevaluation of the limitations of heavy metal mixture interactions with respect to ecological balance and environmental health.Öğe Growth Hormone Affects PI3K/AKT/mTOR Signaling Pathways in the Rat Heart Subjected to Exercise(Wiley-Blackwell, 2016) Palabiyik, Orkide; Tayfur, Pinar; Tastekin, Ebru; Doganlar, Zeynep Banu; Vardar, Selma Arzu[Abstract Not Available]Öğe Inhibition of the Invasion of Human Glioblastoma U87 Cell Line by Ruxolitinib: A Molecular Player of miR-17 and miR-20a Regulating JAK/STAT Pathway(Turkish Neurosurgical Soc, 2020) Delen, Emre; Doganlar, Oguzhan; Doganlar, Zeynep Banu; Delen, OzlemAIM: To determine the interaction between ruxolitinib, JAK/STAT signalling, and two angio-microRNAs (miRs) to expose potential target molecules in the inhibition of glioblastoma invasion. MATERIAL and METHODS: The invasion properties of glioblastoma were analyzed using a cancer cell spheroid invasion assay. Following treatment of 195 nM ruxolitinib, the relative expression levels of miR-17 and miR-20a and genes of IL-6/JAK/STAT3 receptor signaling belonging to the JAK/STAT pathway were measured by qRT-PCR in treated and untreated three-dimensional tumor spheres of U87 cells. RESULTS: Our results indicated that a therapeutic dose of ruxolitinib (195 nM) significantly increased miR-17 and miR-20a expression. Ruxolitinib treatment resulted in the production of IL-6 and active formation of IL-6 receptor complex for the subsequent activation of the IL-6R/JAK2/STAT3 axis. However, ruxolitinib treatment significantly decreased the expression of JAK2 and PI3K. Pearson correlation analyses revealed a strong negative correlation of miR-17 with JAK2, STAT3, and PI3K expressions, and also miR-20a has a negative correlation with expression levels of JAK2 and PI3K. The only positive correlation was found to be between miR-20a and IL-6, gp130 expressions. CONCLUSION: The specific JAK2 inhibitor ruxolitinib plays an important role in glioblastoma angiogenesis biology via inhibiting IL-6 receptor-dependent JAK/STAT signaling. Additionally, both miR-17a-3p and miR-20a overexpression induced by ruxolitinib treatment may be playing a major role in downregulated JAK2, STAT3, and PI3K proteins. Our results suggest that miR-17-3p and miR-20a-5p may serve as new therapeutic targets for the treatment of glioblastoma.Öğe Melatonin attenuates caspase-dependent apoptosis in the thoracic aorta by regulating element balance and oxidative stress in pinealectomised rats(Canadian Science Publishing, 2019) Doganlar, Zeynep Banu; Uzun, Metehan; Ovali, Mehmet Akif; Dogan, Ayten; Ongoren, Gulin; Doganlar, OguzhanThe aim of this study was to explain the possible mechanisms by which melatonin deficiency results in cardiovascular injury and to investigate the effects of melatonin administration on important signalling pathways and element equilibrium in the thoracic aorta (TA). For this purpose, we analysed the cellular and molecular effects of melatonin deficiency or administration on oxidative stress, DNA damage, molecular chaperone response, and apoptosis induction in TA tissues of pinealectomised rats using ELISA, RAPD, qRT-PCR, and Western blot assays. The results showed that melatonin deficiency led to an imbalance in essential element levels, unfolded or misfolded proteins, increased lipid peroxidation, and selectively induced caspasedependent apoptosis in TA tissues without significantly affecting the Bcl-2/BAX ratio (2.28 in pinealectomised rats, 2.73 in pinealectomised rats treated with melatonin). In pinealectomised rats, the genomic template stability (80.22%) was disrupted by the significantly increased oxidative stress, and heat shock protein 70 (20.96-fold), TNF-alpha (1.73-fold), caspase-8 (2.03-fold), and caspase-3 (2.87-fold) were markedly overexpressed compared with the sham group. Melatonin treatment was protective against apoptosis and inhibited oxidative damage. In addition, melatonin increased the survivin level and improved the regulation of element equilibrium in TA tissues. The results of the study indicate that melatonin deficiency induces TNF-alpha-related extrinsic apoptosis signals and that the administration of pharmacological doses of melatonin attenuates cardiovascular toxicity by regulating the increase in the rate of apoptosis caused by melatonin deficiency in TA tissue of Sprague-Dawley rats.Öğe Melatonin Improves Left Ventricular Mitochondrial Dynamics in Rats(Pleiades Publishing Inc, 2022) Uzun, Metehan; Oztopuz, Ozlem; Eroglu, Huseyin Avni; Doganlar, Oguzhan; Doganlar, Zeynep Banu; Ovali, Mehmet Akif; Demir, UfukThere is increasing awareness that efficient and regular mitochondrial dynamics improvement cardiac function and affects the quality of life. Melatonin is a main pineal gland hormones and ameliorates mitochondrial dynamics in many cardiac disorders. For that purpose, we administrated melatonin to healthy rats all day long in order to investigate change in left ventricle mitochondrial dynamics both in the end of the nighttime and daytime. Twenty male Wistar rats (3-4 months age) were randomly assigned into Control (C; n = 10) and Melatonin groups (MEL; 10 mg/kg melatonin added drinking water, n = 10). On the 5th day of the study, 5 rats from the groups were randomly selected and euthanized at 08:00 AM and the remaining 5 rats were euthanized at 20:00 PM from each groups and samples of left ventricle (LV) tissue were harvested. Quantitative real-time PCR and western blot analysis demonstrated that melatonin acts preventive role on mitochondrial fusion and mitophagy through the DRP1/FIS1 and BNIP3/NIX axis, respectively. Additionally, melatonin administration significantly reduced P21 activation, induced cell cycle arrest, P27, finally regulated caspase-depended mitochondrial apoptosis signals in a time dependent manner. Our results suggest that melatonin may emerge as a therapeutic candidate to protect the bioenergetic dynamics of mitochondria in hearth.Öğe Melatonin improves the multiple stress tolerance in pepper (Capsicum annuum)(Elsevier, 2019) Kaya, Armagan; Doganlar, Zeynep BanuPlants are often simultaneously exposed to various abiotic stress factors such as herbicide and drought at agricultural areas. The aim of this study is to investigate the effects of pendimethaline (Pend) on pepper, which is a culture plant, to determine interaction of multiple stresses when Pend and drought stresses are applied simultaneously on pepper and also to establish how exogenous melatonin (MEL) application affects multiple stress interaction and antioxidant responses in pepper. The results of the study show that for peppers exposed to 10% polyethylene glycol (PEG) and Pend at different concentrations (8, 16 and 32 mM) both separately and simultaneously, total chlorophyll content and relative water content decreased while carotenoid, proline, glutathione, endogenous MEL and malondialdehyde contents, ascorbate peroxidase, glutathine S-transferase and glutathine reductase activities as well as mRNA levels increased. These changes were found to be more significant statistically for (Pend + PEG) groups treated with stress simtdtaneously. While malondialdehyde content decreased, compared to untreated plants, for plants pre-treated with 50 mu M MEL; relative water content, chlorophyll, carotenoid, proline, glutathione and endogenous MEL contents as well as niRNA levels and activities of anticacidant enzymes (ascorbate peroxidase, glutathine S-transferase and glutathine reductase) increased. Our findings show that both Pend and PEG created some phytotoxic responses on pepper plant and multiple stress treatment induced these responses. However, exogenous MEL application alleviated negative effects of herbicide and drought stresses by inducing antiwddant defense responses of pepper.
