TR-Dizin İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/396
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Research Project Investigation of the Antitumor Effect of Targeting PI3K-AKT-mTOR Pathway and Histone Deacetylase Enzymes on Acute Myeloid Leukemia Cells(2022) Şansaçar, Merve; Akçok, Emel Başak Gencer; Okur, Tuğba; Karaca, MünevverAcute Myeloid Leukemia (AML) is a disease characterized by the accumulation of immature myeloid cells called blasts in the peripheral blood, bone marrow, spleen, and liver, eventually leading to hematopoietic malignancy. In addition to genetic abnormalities, important cellular pathways such as PI3K/AKT/mTOR, Wnt, Notch, STAT3, Hedgehog have been reported to play a role in the pathogenesis of AML. Histone deacetylase (HDAC) inhibitors have promising anticancer activity for AML. In this study, it was aimed to investigate the effect of inhibition of the PI3K/AKT/mTOR pathway and HDAC inhibition on the molecular mechanism underlying this disease using cell lines of different AML subgroups, MOLM-13 and CMK cell lines. For this purpose, the effects of PI3K inhibitor LY294002 and HDAC inhibitors (SAHA, PCI-3501 and Tubastatin A) and their combinations were investigated. Cell proliferation was determined by MTT cell cytotoxicity test and apoptosis rates were determined by Annexin-V/PI double staining method, and the effects of drugs on the cell cycle were determined by PI staining. The level of LC3B protein, a marker of autophagy, was confirmed at the molecular level by western blot. The inhibitors used decreased cell viability at low micromolar concentrations on both cell lines. It was determined that the LY294002+SAHA combination treatment showed a 50% reduction in cell proliferation in MOLM-13 cells and a 25% decrease in CMK cells. LY294002+Tubastatin A treatment has been shown to reduce cell proliferation in MOLM-13 and CMK cells by 65% and 40%, respectively. Our results showed that combinations of LY294002 and HDAC inhibitor resulted in G0/G1 phase arrest in MOLM-13 cells compared to control cells. On the other hand, CMK cells treated with combinations of LY294002+SAHA, LY294002+PCI-3501 and LY294002+Tubastatin A were arrested in G2/M, G2/M and G0/G1 phase, respectively. The effect of the combinations on apoptotic cell death was investigated. LC3B protein expression level was checked as a result of combination therapy. Considering the effects of HDAC enzymes on both AML and different cancers, HDAC inhibition is an important and high-potential target for AML. Therefore, investigation of the PI3K/AKT/mTOR pathway and inhibition of HDACs in different subgroups may provide insight into the mechanisms leading to the pathogenesis of AML. Consequently, it is hoped that this inhibition of PI3K/AKT/mTOR and HDAC will lead to a more specific combination of targeted therapy that results in the abolition of AML.Research Project Akut Myeloid Lösemi Tedavisi için Hedgehog ve Otofaji Yolaklarının Düzenlenmesi(2019) Khatıb, Mona ElAkut myeloid lösemi (AML) çeşitli moleküler aberasyonlar ve sinyal yolaklarındaki bozuklukları içeren klonal hastalıklar ile karakterize edilen bir grup heterojen malignanttır. Hedgehog (HH) sinyal yolağı birçok kanserde deregüle edilen evrimsel olarak korunan bir sinyal yolağıdır. HH sinyal yolağı lizozomal degradasyon prosesi otofajinin temel regülatörü olan PI3K/AKT/mTOR aksesini de içeren diğer sinyal yolakları ile karşılıklı iletişim halindedir. Bu sinyal yolakları AML’de deregüle edilmiştir. Birçok çalışmada otofajinin AML için bir kaçış mekanizması olabileceği ortaya konulmuştur. Bizim çalışmamızda, HH ve otofaji yolaklarının farklı AML türleri üzerine etkileri incelenmiştir. Çalışmamızda KML hücresi olan K562 ve CMK, MV4-11, MOLM-13 ve NB4 AML hücreleri GLI1 inhibitörü GANT61 ve farklı otofaji modülatörleri ile muamele edilmiştir.MTT sonuçları NB4, MOLM-13 ve MV4-11hücre proliferasyonun GLI inhibisyonu sonrasında düştüğünü ancak CMK’nin diğer AML hücre hatlarına kıyasla GLI inhibisyonuna daha az sensitif olduğunu ortaya koymuştur. Daha sonra, otofaji modülasyonunun farklı AML hücre hatlarının proliferasyonu üzerine etkileri incelenmiştir. Otofajinin gerek otofagozom-lizozom füzyonu aşamasında gerekse otofagolizozomal degradasyon aşamasında inhibisyonunun ilaç konsantrasyonu ve muamele süresine bağlı olarak AML sağkalımını azalttığı gözlemlenmiştir. Otofaji modülatörleri ve GANT61’in kombinasyonunun MOLM-13 hücre hattı üzerinde sinerjistik bir etkisinin olduğu fakat CMK hücre hattı üzerinde sinerjistik etkisinin olmadığı gözlemlenmiştir. GANT61 muamelesinin AML hücre hatlarında otofajiyi artırdığı LC3II ekspresyonu ile western blot yöntemi ile ortaya konulmuştur. Buna ek olarak, kombinasyonun MOLM-13 hücresinde LC3II’yi artırdığı gözlenirken, bu oran CMK hücre hattında daha düşüktür. AKT proteinin ekspresyonu ilaca ve hücre hattına gore farklılık göstermektedir. Sonuç olarak, HH ve otofaji sinyal yolaklarının hedeflenmesi MOLM-13 hücre hattı için umut vaatedici bir terapi iken, CMK hücre hattında benzer sonuçlara ulaşılamamıştır.Article Citation - WoS: 1Comprehensive Prediction of FBN1 Targeting Mirnas: A Systems Biology Approach for Marfan Syndrome(Galenos Publishing House, 2025-09-22) Orhan, M.E.; Demirci, Y.M.; Saçar Demirci, M.D.S.; Demirci, Muserref Duygu SacarObjective: Marfan syndrome (MFS) is a genetic connective tissue disorder primarily caused by mutations in the FBN1 gene. Emerging evidence highlights the regulatory role of microRNAs (miRNAs) in modulating gene expression in MFS, but a systematic investigation into miRNAs targeting FBN1 is lacking. This study aimed to comprehensively identify miRNAs interacting with the FBN1 transcript to reveal potential molecular regulators and therapeutic targets. Methods: Human miRNA sequences were retrieved from miRBase (Release 22.1), and the canonical FBN1 transcript (RefSeq: NM_000138.5) was used for target prediction. Computational interaction analysis was conducted using the psRNATarget server with stringent parameters to detect potential miRNA binding sites. Expression profiles and disease associations of the top candidate miRNAs were further investigated through database integration and literature review. Results: Out of 2656 human mature miRNAs analyzed, 251 were predicted to bind FBN1, with the hsa-miR-181 family exhibiting the highest number of predicted interactions. Evidence from the literature highlighted dysregulation of hsa-miR-181 expression in MFS patients, suggesting a functional role in disease pathophysiology. Conclusion: This study identifies key members of the hsa-miR-181 family as post-transcriptional regulators of FBN1, offering new insights into miRNA-driven mechanisms in MFS. These findings support the potential of RNA-based diagnostics and therapeutic strategies targeting miRNA-FBN1 interactions. ©Copyright 2025 The Author.Research Project Resvaratrol ün FLT3 Pozitif Akut Miyeloid Lösemide Terapötik Potansiyeli ve Resveratrol Tarafından Tetiklenen Apoptozda Seramid Metabzolimasının Rolü(2019) Baran, Yusuf; Adan, AysunProje ile resveratrol'ün, Ph+ ALL hücreleri üzerindeki büyümeyi inhibe edici etkisinin arkasında yatan mekanizmalar, seramid metabolizmasının hedeflenmesi ve BCR-ABL ifadesindeki değişimler ile ilişkilendirilerek araştırılmıştır. Resveratrol, SK inhibitörü (SKI II), GSS inhibitörü (PDMP), SPT inhibitörü (myriocin) ve resveratrol: inhibitör kombinasyonlarının in vitro olarak Ph+ ALL SD1 ve SUP-B15 hücreleri üzerindeki büyümeyi durdurucu ve apoptotik etkileri MTT hücre çoğalması testi, Aneksin-V/PI boyaması, kaspaz-3, PARP ifadelerinin ve sitokrom c salınımının belirlenmesi (western blot) ile, sitostatik etki (hücre döngüsü üzerindeki) ise akım sitometresi (PI boyaması) ile araştırılmıştır. Resveratrol ve sfingolipid metabolizması enzimlerini hedefleyen inhibitör kombinasyonlarının BCR-ABL protein ifadesi üzerine etkisi western blot ile belirlenmiştir. Ayrıca, resveratrol'ün SPT, SK-1/2, GSS protein ifadeleri üzerindeki etkisi western blot ile belirlenmiştir. Her iki hücre hattında resveratrol ve resveratol?ün SKI II ve PDMP ile kombinasyonları hücre büyümesini baskılamış, apoptozu tetiklemiş ve hücre döngüsünü S fazında tutmuştur. Resveratrol:myriocin kombinasyonu ise hücre büyümesi ve hücre döngüsü üzerinde hücreye özgü etkiler gösterirken apoptozu her iki hücrede tetiklemiştir. Her iki hücre tipinde resveratol ve kombinasyonları sitokrom-c salınımını, kaspaz-3 kesimini ve PARP kesimini genel olarak arttırmakla beraber hücreye özgü değişimler de saptanmıştır. Resveratrol her iki hücrede SK- 1/SK2 ve GSS ifadesini azaltırken SPT ifadesini arttırmıştır. Resveratrol, SKI II ve PDMP BCR-ABL ifadesini azaltırken myriocin arttırmıştır. Resveratrol: SKI II ve PDMP kombinasyonları BCR-ABL üzerinde artışlara neden olurken myriocin ile kombinasyon BCR- ABL ifadesini azaltmıştır. Sonuç olarak, resveratrol seramid metabolizmasını ve BCR-ABL ifadesini düzenleyerek Ph+ ALL üzerinde hücre büyümesini baskılamış ve apoptozu tetiklemiştir.Research Project PI3K-AKT-mTOR Yolağı ve Histon Deasetilaz Enzimlerinin Hedeflenmesinin Akut Myeloid Lösemi Hücreleri Üzerine Antitümör Etkisinin İncelenmesi(2022) Şansaçar, Merve; Akçok, Emel Başak Gencer; Okur, Tuğba; Karaca, MünevverAcute Myeloid Leukemia (AML) is a disease characterized by the accumulation of immature myeloid cells called blasts in the peripheral blood, bone marrow, spleen, and liver, eventually leading to hematopoietic malignancy. In addition to genetic abnormalities, important cellular pathways such as PI3K/AKT/mTOR, Wnt, Notch, STAT3, Hedgehog have been reported to play a role in the pathogenesis of AML. Histone deacetylase (HDAC) inhibitors have promising anticancer activity for AML. In this study, it was aimed to investigate the effect of inhibition of the PI3K/AKT/mTOR pathway and HDAC inhibition on the molecular mechanism underlying this disease using cell lines of different AML subgroups, MOLM-13 and CMK cell lines. For this purpose, the effects of PI3K inhibitor LY294002 and HDAC inhibitors (SAHA, PCI-3501 and Tubastatin A) and their combinations were investigated. Cell proliferation was determined by MTT cell cytotoxicity test and apoptosis rates were determined by Annexin-V/PI double staining method, and the effects of drugs on the cell cycle were determined by PI staining. The level of LC3B protein, a marker of autophagy, was confirmed at the molecular level by western blot. The inhibitors used decreased cell viability at low micromolar concentrations on both cell lines. It was determined that the LY294002+SAHA combination treatment showed a 50% reduction in cell proliferation in MOLM-13 cells and a 25% decrease in CMK cells. LY294002+Tubastatin A treatment has been shown to reduce cell proliferation in MOLM-13 and CMK cells by 65% and 40%, respectively. Our results showed that combinations of LY294002 and HDAC inhibitor resulted in G0/G1 phase arrest in MOLM-13 cells compared to control cells. On the other hand, CMK cells treated with combinations of LY294002+SAHA, LY294002+PCI-3501 and LY294002+Tubastatin A were arrested in G2/M, G2/M and G0/G1 phase, respectively. The effect of the combinations on apoptotic cell death was investigated. LC3B protein expression level was checked as a result of combination therapy. Considering the effects of HDAC enzymes on both AML and different cancers, HDAC inhibition is an important and high-potential target for AML. Therefore, investigation of the PI3K/AKT/mTOR pathway and inhibition of HDACs in different subgroups may provide insight into the mechanisms leading to the pathogenesis of AML. Consequently, it is hoped that this inhibition of PI3K/AKT/mTOR and HDAC will lead to a more specific combination of targeted therapy that results in the abolition of AML.Research Project RNA İkincil Yapılarının Çok Boyutlu Gösterimi ve Pre-MiRNA Tespiti İçin Uygulamaları(2021) Demirci, Müşerref Duygu Saçar; Demirci, Yılmaz Mehmet-Article Theoretical Investigation of Steric Effects on the S1 Potential Energy Surface of O-Carborane Derivatives(Tubitak Scientific & Technological Research Council Turkey, 2023-01-01) Alkan, FahriTDDFT scan calculations were performed for s-carborane-anthracene derivatives (o-CB-X-Ant where X=-H,-CH3,-C2H5 and tert-butyl or-tBu) in order to understand the interplay between the steric effects, S1 potential energy surface (PES) and photophysical properties. The results show that all systems exhibit three local minima on the S1 PES, which correspond to the emissive LE and TICT state, along with the nonemissive CT state respectively. In the case of the unsubstituted system (o-CB-H-Ant), and-CH3 and-C2H5 substituted cases, S1 PES is predicted to be quite flat for certain conformations indicating that it is possible for these systems to reach the nonemissive CT state without a large energy penalty. In comparison, conformational pathways for the nonemissive CT state are predicted to be energetically unfavorable for o-CB-tBu-Ant as a result of both steric and electronic effects. These results provide a mechanism for the enhanced emission of cr-CB-fluorophore molecules with bulky ligands.Article The Therapeutic Potential of Targeting Hdac6 With Tubastatin a in Tfk-1 and Egi-1 Cholangiocarcinoma Cells(2021) Yenigül, Münevver; Akcok, E. Basak GencerCholangiocarcinoma (CCA) is a highly aggressive and invasive malignancy with a poor diagnosis because of the resistance, relapse and limited therapy. Histone deacetylases (HDAC) are a class of enzyme that have important roles in epigenetic modulations. These enzymes are intensely studied and HDAC inhibitors are considered as potent anticancer agents in both solid tumors and hematological malignancies. HDAC inhibitors can affect and induce different mechanisms such as cell cycle arrest, differentiation, and cell death. In this study, we aim to investigate the cytotoxic effect of Tubastatin A, which is a selective HDAC6 inhibitor, on cholangiocarcinoma cell lines, TFK-1 and EGI-1, by MTT assay. Besides, it was aimed to examine the impact on colony formation potential of the cells. The effect of the inhibitor on cell cycle distribution was also examined by using flow cytometry. Tubastatin A has significantly decreased the colony formation and changed cell cycle progression. Taken together, our results suggest that Tubastatin A could be a potent inhibitor against cholangiocarcinoma. On the basis of these results, further mechanistic studies are required to elucidate the antineoplastic activity of Tubastatin A.Article Citation - WoS: 6Citation - Scopus: 6Sex Effect on the Correlation of Immunoglobulin G Glycosylation With Rheumatoid Arthritis Disease Activity(Tubitak Scientific & Technological Research Council Turkey, 2020-12-14) Ercan, AltanRheumatoid arthritis (RA) is a chronic autoimmune disease which affects females more than males with a presence of autoantibodies. Immunoglobulin G (IgG) produced by adaptive arm has 2 functional domains, Fc and Fab. The Fc domain binds Fc gamma receptors and C1q proteins of the innate arm. Therefore, the IgG Fc domain serves as a bridge between the innate and adaptive arms and is regulated by an evolutionarily conserved N-glycosylation with variable structures. These glycans are classified as agalactosylated G0, monogalactosylated G1, and digalactosylated G2, which are further modified by core-fucosylation (F) and bisecting N-acetylglucosamine (B) moieties such as G0F and G0FB. Interestingly, proinflammatory G0F is shown to be regulated by estrogen in vivo. Here, it is hypothesized that the regulation of G0F by estrogen contributes to sex dichotomy in RA by setting up the level of IgG-dependent inflammation and therefore, RA disease activity (Das28-CRP3). To investigate this hypothesis, IgG glycosylation was characterized in serum samples from active RA patients (n = 232) and healthy controls (n = 232) by serum N-glycan analysis using the high performance liquid chromatography. According to the results, the IgG Fc glycan phenotype originates predominantly from the structure of G0F, and both G0F and G0FB correlate with Das28-CRP3 in females, but not in males. In conclusion, IgG G0F-dependent inflammation differs in males and females, and these differences point to the differential regulation of inflammation by sex hormone estrogen via IgG glycosylation.Article Citation - WoS: 2Citation - Scopus: 3Magnetic Separation of Micro Beads and Cells on a Paper-Based Lateral Flow System(Gazi Univ, 2023-12-01) Farooqi, Muhammed Fuad; Icoz, KutayPaper based lateral flow systems are widely used biosensor platforms to detect biomolecules in a liquid sample. Proteins, bacteria, oligonucleotides, and nanoparticles were investigated in the literature. In this work we designed a magnetic platform including dual magnets and tested the flow of micron size immunomagnetic particles alone and when loaded with cells on two different types of papers. The prewetting conditions of the paper and the applied external magnetic field are the two dominant factors affecting the particle and cell transport in paper. The images recorded with a cell phone, or with a bright field optical microscope were analyzed to measure the flow of particles and cells. The effect of prewetting conditions and magnetic force were measured, and it was shown that in the worst case, minimum 90% of the introduced cells reached to the edge of the paper. The paper based magnetophoretic lateral flow systems can be used for cell assays.