Browsing by Author "Avci, CB"

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    Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells
    Kutbay, NO; Avci, CB; Yurekli, BS; Kurt, CC; Shademan, B; Gunduz, C; Erdogan, M
    Anaplastic cancer constitutes 1% of thyroid cancers, and it is one of the most aggressive cancers. Treatment options are external radiation therapy and/or chemotherapy. The success rate with these treatment modalities is not satisfactory. We aimed to evaluate the effects of metformin (MET) and pioglitazone (PIO) combination on apoptosis and AMP-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway in human anaplastic thyroid cancer cells. In this study, we evaluated the effects of MET and PIO individually and the combination of the two drugs on the cellular lines SW1736 and C643 ATC. Genes contained in the mTOR signaling pathway were examined using human mTOR Signalization RT(2)Profiler PCR Array. In C643 and SW1736 cell lines, IC(50)doses of MET and PIO were found out as 17.69 mM, 11.64 mM, 27.12 mu M, and 23.17 mu M. Also, the combination of MET and PIO was determined as an additive according to isobologram analyses. We have found the downregulation of the expression levels of oncogenic genes:AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, MTOR, PIK3CA, PIK3CG, PLD1, PRKCA, andRICTORgenes, in the MET and PIO combination-treated cells. In addition, expression levels of tumor suppressorgenes, DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MYO1C, PTEN, ULK1, andULK2, were found to have increased significantly. The MET + PIO combination was first applied to thyroid cancer cells, and significant reductions in the level of oncogenic genes were detected. The decreases, particularly, inAKT3, DEPTOR, EIF4E, ILK, MTOR, PIK3C, andPRKCAexpressions indicate that progression can be prevented in thyroid cancer cells and these genes could be selected as therapeutic targets.
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    EPIGALLOCATECHIN-3-GALLATE TRIGGERS AUTOPHAGY MEDIATED CELL DEATH VIA UP-REGULATION OF TMEM74 GENE EXPRESSION IN CHRONIC MYELOID LEUKEMIA CELLS
    Goker, B; Caliskan, C; Mutlu, Z; Tepedelen, BE; Korkmaz, M; Saydam, G; Gunduz, C; Avci, CB
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    Distribution and Phylogenetic Analysis of Subtypes and Alleles of Blastocystis sp. in the Stool Samples Collected from Patients with Gastrointestinal Complaints in Izmir, Turkey
    Aykur, M; Kurt, CC; Erdogan, DD; Avci, CB; Vardar, R; Aydemir, S; Girginkardesler, N; Gunduz, C; Dagci, H
    PurposeBlastocystis sp. is one of the most prevalent intestinal protozoa found in humans and many other animals. The present study aimed to examine the distribution and genetic diversity of Blastocystis sp. in stool samples from patients with gastrointestinal complaints in Izmir, Turkey.MethodsAll stool samples of 439 patients with gastrointestinal complaints were examined by native-Lugol and trichrome staining. To investigate the presence of Blastocystis sp. in stool samples, DNA was isolated, and PCR was performed with the barcode region in the SSU rRNA gene. PCR positive samples were sequenced to identify subtypes and alleles of Blastocystis sp.ResultsThe prevalence of Blastocystis sp. was found to be 16.6% (73/439) in patients with gastrointestinal complaints in Izmir, Turkey. Three different Blastocystis sp. subtypes were identified. ST3 (28/55; 51.0%) was the most common subtype followed by ST2 (19/55; 34.5%) and ST1 (8/55; 14.5%). Itching and diarrhea were the most prominent clinical symptoms in Blastocystis sp. positive patients. When clinical symptoms and subtypes were compared, diarrhea was found in 62.5%, 47.4%, and 46.4% of patients with ST1, ST2, and ST3 subtypes, respectively. In addition, itching was found in 37.5%, 32.1%, and 21.1% of patients with ST1, ST3, and ST2, respectively. Six distinct alleles were identified by allele analysis of Blastocystis 18S rRNA gene: allele 4 for ST1, alleles 9, 11, and 12 for ST2, and alleles 34 and 36 for ST3. In this study, Blastocystis sp. was detected in 16 of 21 districts, including the central and rural districts of Izmir. Although ST1 was detected in central districts, it was not found in rural districts.ConclusionThis study provides comprehensive data on the prevalence and molecular epidemiology of the genetic diversity at the level of subtypes and alleles of Blastocystis sp. in different districts of Izmir province in Turkey. To the best of our knowledge, this is the first study which evaluates the distribution of subtypes and alleles of Blastocystis sp. according to PCR and SSU rRNA gene sequencing in patients with gastrointestinal complaints in different districts of Izmir province in Turkey.
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    Investigation of cytotoxic and apoptotic effects of disodium pentaborate decahydrate on ovarian cancer cells and assessment of gene profiling
    Gunel, NS; Yildirim, N; Ozates, NP; Oktay, LM; Bagca, BG; Sogutlu, F; Ozsaran, A; Korkmaz, M; Avci, CB
    After revealing the anti-cancer properties of boron, which is included in the category of essential elements for human health by the World Health Organization, the therapeutic potential of boron compounds has been begun to be evaluated, and its molecular effect mechanisms have still been among the research subjects. In ovarian cancer, mutations or amplifications frequently occur in the PI3K/Akt/mTOR pathway components, and dysregulation of this pathway is shown among the causes of treatment failure. In the present study, it was aimed to investigate the anti-cancer properties of boron-containing DPD in SKOV3 cells, which is an epithelial ovarian cancer model, through PI3K/AKT/mTOR pathway. The cytotoxic activity of DPD in SKOV3 cells was evaluated by WST-1 test, apoptotic effect by Annexin V and JC-1 test. The gene expressions associated with PI3K/AKT/mTOR pathway were determined by real-time qRT-PCR. In SKOV3 cells, the IC50 value of DPD was found to be 6.7 mM, 5.6 mM, and 5.2 mM at 24th, 48th and 72nd hour, respectively. Compared with the untreated control group, DPD treatment was found to induce apoptosis 2.6-fold and increase mitochondrial membrane depolarization 4.5-fold. DPD treatment was found to downregulate PIK3CA, PIK3CG, AKT2, IGF1, IRS1, MAPK3, HIF-1, VEGFC, CAB39, CAB39L, STRADB, PRKAB2, PRKAG3, TELO2, RICTOR, MLST8, and EIF4B genes and upregulate TP53, GSK3B, FKBP8, TSC2, ULK1, and ULK2 genes. These results draw attention to the therapeutic potential of DPD, which is frequently exposed in daily life, in epithelial ovarian cancer and show that it can be a candidate compound in combination with chemotherapeutics.
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    Synergistic effect of ponatinib and epigallocatechin-3-gallate induces apoptosis in chronic myeloid leukemia cells through altering expressions of cell cycle regulatory genes
    Goker, B; Caliskan, C; Caglar, HO; Kayabasi, C; Balci, T; Tepedelen, BE; Aygunes, D; Susluer, SY; Mutlu, Z; Gunel, NS; Korkmaz, M; Saydarn, G; Gunduz, C; Avci, CB
    Purpose: Ponatinib (P) has been used for the treatment of chronic myeloid leukemia (CML) and it is known that inhibition of BCR-ABL fusion protein by ponatinib induces apoptosis of CML cells. Epigallocatechin-3-gallate (EGCG), which is a poly phenol in green tea, induces apoptosis in different types of cancer cells. The purpose of this study was to determine the cytotoxic and apoptotic effects of ponatinib and EGCG combination in K562 CML cell line. This study also aimed to detect alterations of the expression levels of cell cycle-regulation related genes after ponatinib and EGCG combination in K562 CML cell line. Methods: The cytotoxic effects of the compounds on K562 cells were determined in a time-and dose-dependent manner by using WST-1 analysis. The combination index (CI) isobologram was used to analyze the data. Apoptotic effects of P-EGCG were defined by flow cytometry and gene expressions were detected by RT-qPCR. Results: IC50 values of ponatinib and EGCG were 87.13 nM and 50 mu M, respectively. CI value of the P-EGCG was 0.658 and the combination showed synergistic effect (ED90 value: 28.39 nM ponatinib, 117.12 mu g/ml EGCG). Ponatinib, EGCG and P-EGCG induced apoptosis compared to control cells. CyclinD1 and CDC25A were downregulated by P-EGCG by 2.49 and 2.63-fold, respectively. TGF-beta 2 was upregulated by 4.57-fold. Conclusion: EGCG possesses cytotoxic and apoptotic properties and may cooperate with the growth inhibiting activity of ponatinib synergistically against CML cells. P-EGCG mediated apoptosis might be associated with upregulation of TGF-/32 gene and downregulation of cyclinD1 and CDC25A genes.
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    Disodium pentaborate decahydrate (DPD) induced apoptosis by decreasing hTERT enzyme activity and disrupting F-actin organization of prostate cancer cells
    Korkmaz, M; Avci, CB; Gunduz, C; Aygunes, D; Erbaykent-Tepedelen, B
    Animal and cell culture studies have showed that boron and its derivatives may be promising anticancer agents in prostate cancer treatment. Thus, DU145 cells were treated with disodium pentaborate decahydrate (DPD) for 24, 48, and 72 h in order to investigate the inhibitor effect and mechanisms of DPD. Then, cell proliferation, telomerase enzyme activity, actin polymerization, and apoptosis were detected by WST-1 assay, qRT-PCR, immunofluorescence labeling, and flow cytometry, respectively. We found that DPD inhibited the growth of human prostate cancer cell line DU145 at the concentration of 3.5 mM for 24 h. Our results demonstrated that 7 mM of DPD treatment prevented the telomerase enzyme activity at the rate of 38 %. Furthermore, DPD has an apoptotic effect on DU145 cells which were examined by labeling DNA breaks. With 7 mM of DPD treatment, 8, 14, and 41 % of apoptotic cells were detected for 24, 48, and 72 h, respectively. Additionally, immunofluorescence labeling showed that the normal organization of actin filaments was disrupted in DPD-exposed cells, which is accompanied by the alteration of cell shape and by apoptosis in targeted cells. Taken together, the results indicate that DPD may exert its cytotoxicity at least partly by interfering with the dynamic properties of actin polymerization and decreasing the telomerase activity. Eventually, for the first time, the results of this study showed that DPD suppressed the activity of telomerase in DU145 cells, and therefore, we suggested that DPD could be an important agent for its therapeutic potential in the treatment of prostate cancer.
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    Investigation of Dientamoeba fragilis Prevalence and Evaluation of Sociodemographic and Clinical Features in Patients with Gastrointestinal Symptoms
    Aykur, M; Kurt, CC; Erdogan, DD; Avci, CB; Vardar, R; Aydemir, S; Girginkardesler, N; Gündüz, C; Dagci, H
    BackgroundDientamoeba fragilis is a protozoan parasite of the human gastrointestinal tract and still controversial in association with gastrointestinal symptoms.PurposeWe present cross-sectional study of the prevalence of D. fragilis, and sociodemographic and clinical features in the patients with gastrointestinal symptoms.MethodsA total of 490 fecal specimens were collected from outpatients with gastrointestinal symptoms in the Department of Parasitology, Faculty of Medicine, Ege University and Celal Bayar University, Turkey. Fecal specimens were examined with microscopy and inoculated in Robinson medium. D. fragilis-positive samples were examined for the presence of other intestinal parasites using enzyme immunoassay. Real-time PCR analysis was performed on all samples.ResultsOf the 490 stool specimens examined by real-time PCR, 59 patients were positive for D. fragilis infection with prevalence rate of 12.04%. Forty-four of positive patients (74.5%) were found to be infected with only D. fragilis, while 23.7% were co-infected with Blastocystis and 1.7% were co-infected with Rotavirus. No statistically significant difference was found in all the examined patients in terms of D. fragilis positivity for all sociodemographic parameters. Loose stool consistency was associated with the presence of D. fragilis, with 18.3% (P=0.001). When the clinical symptoms of all the patients participating in this study were examined, diarrhea was statistically more significant in patients with the presence of D. fragilis (16.3%; P=0.001). The rate of diarrhea in D. fragilis-positive patients (84.09%; P=0.0005) was higher than that of D. fragilis-negative patients and it was statistically significant.ConclusionThis study is important for assessing the prevalence of D. fragilis and its association with other factors in symptomatic patients in a large sample group in Turkey, as well as investigating the relationship of identified symptoms with the D. fragilis pathogenicity. It is suggested that D. fragilis in this case is not a commensal parasite but a pathogenic parasite and that the most common clinical symptom is diarrhea.
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    Effect of Different Dentin Conditioning Agents on Growth Factor Release, Mesenchymal Stem Cell Attachment and Morphology
    Atesci, AA; Avci, CB; Tuglu, MI; Ay, NPO; Eronat, AC
    Introduction: EDTA has been considered the gold standard in regenerative endodontic treatments. The aim of this study was to evaluate the effects of different dentin conditioning agents other than EDTA on released growth factors, mesenchymal stem cell attachment, and morphology. Methods: Transforming growth factor beta 1, vascular endothelial growth factor, bone morphogenetic protein 2, and fibroblast growth factor 2 release from prepared dentin discs conditioned with 17% EDTA, 10% citric acid, 1% phytic acid (IP6), or 37% phosphoric acid were quantified using the enzyme-linked immunosorbent assay after final irrigation and after 3 days of adipose-derived mesenchymal stem cell (adMSC) seeding. Forty root fragments were prepared from extracted Single-rooted teeth. The morphology and attachment of adMSCs on the conditioned root fragments were observed using a scanning electron microscope. Data for growth factor quantification were analyzed using 1-way analysis. Results: The highest transforming growth factor beta 1 release was observed after citric acid treatment followed by phosphoric acid; there was no significant difference between them, but compared with EDTA and 1% IP6, there were significant differences observed. The enzyme-linked immunosorbent assay detected a very minor exposure of vascular endothelial growth factor and fibroblast growth factor 2 after dentin conditioning, but there were no significant differences between the groups. The greatest bone morphogenetic protein 2 release was observed in the 1% IP6 group, but there were no significant differences between the groups. Three days of adMSC seeding after dentin conditioning has made a dramatic increase in all of the growth factors, and phosphoric acid appeared to be the most effective agent with significant differences compared with the remaining groups. Scanning electron microscopic observations showed that none of the conditioning solutions had an adverse effect on stem cell proliferation and attachment to root dentin. Different cell morphologies like round, oblong, flat, and well-attached cells with developed filopodia were observed in the dentin-conditioned groups. Conclusions: Phosphoric acid conditioning could be useful and may have beneficial effects in regenerative endodontic treatments.
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    Origanum Sipyleum Methanol Extract in Combination with Ponatinib Shows Synergistic anti-Leukemic Activities on Chronic Myeloid Leukemia Cells
    Kayabasi, C; Susluer, SY; Okcanoglu, TB; Yelken, BO; Mutlu, Z; Bagca, BG; Kurt, CC; Saydam, G; Durmuskahya, C; Kayalar, H; Ozbilgin, A; Avci, CB; Gunduz, C
    Origanum sipyleum is used in folk medicine due to its anti-inflammatory, antimicrobial, and antioxidant properties. Ponatinib, an effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML), has severe side effects. Thus, we aimed to determine a novel herbal combination therapy that might not only increase the anti-leukemic efficacy but also reduce the dose of ponatinib in targeting CML cells. Origanum sipyleum was extracted with methanol (OSM), and secondary metabolites were determined by phytochemical screening tests. The cytotoxic effects of OSM on K562 cells were measured by WST-1 assay. Median-effect equation was used to analyze the combination of ponatinib and OSM (p-OSM). Apoptosis, proliferation, and cell-cycle were investigated by flow-cytometry. Cell-cycle-related gene expressions were evaluated by qRT-PCR. OSM that contains terpenoids, flavonoids, tannins, and anthracenes exhibited cytotoxic effects on K562 cells. The median-effect of p-OSM was found as synergistic; OSM reduced the ponatinib dose similar to 5-fold. p-OSM elevated the apoptotic and anti-proliferative activity of ponatinib. Consistently, p-OSM blocked cell-cycle progression in G(0)/G(1), S phases accompanied by regulations in TGFB2, ATR, PP2A, p18, CCND1, CCND2, and CCNA1 expressions. OSM enhanced the anti-leukemic activity of ponatinib synergistically via inducing apoptosis, suppressing proliferation, and cell-cycle. As a result, OSM might offer a potential strategy for treating patients with CML.