TR-Dizin İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/396
Browse
9 results
Search Results
Article Glucosylceramide Synthase Is a Novel Biomarker of Midostaurin-Induced Cytotoxicity in Non-Mutant FLT3 Positive Acute Myeloid Leukemia Cells(2021) Şahin, Hande Nur; Adan, AysunAmaç: Glukozilseramid sentaz (GSS) tarafından sentezlenen gluko- zilseramid (GS) birçok kanser türünde hücre yaşamını ve proliferas- yonunu sağlamaktadır. Ancak, mutant olmayan Fms-benzeri tirozinkinase 3 (FLT3) pozitif akut miyeloid lösemi (AML) patogenezindekirolü açıklanmamıştır. Çoklu kinaz inhibitörü olan midostaurin mu- tant FLT3 AML tedavisinde etkili olmasına rağmen mutant olmayanFLT3 pozitif AML’deki klinik etkisi gözden kaçırılmıştır. Bu çalışmada,midostaurinin GSS inhibitörü ile kombinasyonunun yabanıl tip FLT3ifadesine sahip AML hücrelerindeki etkisinin belirlenmesi ve mole- küler mekanizmalarının açıklanması amaçlanmıştır. Gereç ve Yöntem: Midostaurin, PDMP (GSS inhibitörü) ve kombi- nasyonların THP1 hücreleri üzerindeki sitotoksik ve sitostatik etki- leri sırasıyla MTT testi ve PI boyaması ile akım sitometri kullanılarakbelirlenmiştir. Kombinasyon indeksleri (CI) Calcusyn programı ilehesaplanmıştır. GSS ifadesi western blot ile belirlenmiştir.Bulgular: Midostaurin GSS ifadesini baskılamıştır. FLT3 ve GSS’ınbirlikte inhibe edilmesi kontrolle karşılaştırıldığında hücre çoğal- masını baskılamıştır. Kombinasyonlar sinerjistik sitotoksik etki gös- termiştir (CI<1). Kombinasyon hücre döngüsünün G2/M fazındakihücre populasyonunu arttırmıştır. Sonuç: Mutant olmayan FLT3 AML’de GSS inhibisyonunun midosta- urin’in etkisini arttırdığı saptanmıştır. Detaylı mekanizma çalışmalarıyapıldıktan sonra kombinasyon tedavisinin midostaurin’in sınırlıklinik kullanımını arttırması açısından yeni bir yaklaşım olabileceğidüşünülmektedir.Article Design, Molecular Docking and Molecular Dynamics Simulation Studies of Novel Pyridinecarboxamide Derivatives as Potent HDAC6 Inhibitors(2025) Akçok, İsmailHiston deasetilazlar (HDACs), gen ifadesinin ve hücresel süreçlerin düzenlenmesinde önemli rol oynayan bir enzim ailesidir. HDAC enzimleri homolojilerine, hücresel lokalizasyonlarına ve yapısal özelliklerine göre dört ana sınıfa ayrılır. Sınıf IIb enzimlerinden biri olan HDAC6 enzimi, hücre göçü, bağışıklık tepkileri ve nöronal işlev gibi çeşitli fizyolojik süreçlerde önemli işlevlere sahiptir. HDAC6 aktivitesinin düzensizliği, nörodejeneratif hastalıklarda toksik protein agregatlarının birikimiyle ilişkilendirilmiştir; kanser hücrelerinde aşırı ifadesi veya değişen aktivitesi ise metastaz ve tümör oluşumuna sebep olabilmektedir. Bu çalışmada, potansiyel HDAC6 inhibitörleri tasarlanmış ve bu moleküllerin inhibisyon potansiyelleri, moleküler kenetlenme, moleküler dinamik simülasyonları ve MM-PBSA hesaplamalarını içeren in silico protokolleri kullanılarak araştırılmıştır. Tasarlanan moleküller arasında IA64, HDAC6 enzimine karşı en iyi bağlanma profilini göstermiştir ve ileri çalışmalar için öncü bir molekül olarak görülebilir.Article Developing a Label Propagation Approach for Cancer Subtype Classification Problem(TUBITAK, 2021) Güner, P.; Bakir-Güngör, B.; Coşkun, M.; Şahan, Pınar GünerCancer is a disease in which abnormal cells grow uncontrollably and invade other tissues. Several types of cancer have various subtypes with different clinical and biological implications. Based on these differences, treatment methods need to be customized. The identification of distinct cancer subtypes is an important problem in bioinformatics, since it can guide future precision medicine applications. In order to design targeted treatments, bioinformatics methods attempt to discover common molecular pathology of different cancer subtypes. Along this line, several computational methods have been proposed to discover cancer subtypes or to stratify cancer into informative subtypes. However, existing works do not consider the sparseness of data (genes having low degrees) and result in an ill-conditioned solution. To address this shortcoming, in this paper, we propose an alternative unsupervised method to stratify cancer patients into subtypes using applied numerical algebra techniques. More specifically, we applied a label propagation-based approach to stratify somatic mutation profiles of colon, head and neck, uterine, bladder, and breast tumors. We evaluated the performance of our method by comparing it to the baseline methods. Extensive experiments demonstrate that our approach highly renders tumor classification tasks by largely outperforming the state-of-the-art unsupervised and supervised approaches. © 2022 Elsevier B.V., All rights reserved.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.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 Enlightening the Molecular Mechanisms of Type 2 Diabetes With a Novel Pathway Clustering and Pathway Subnetwork Approach(Tubitak Scientific & Technological Research Council Turkey, 2022-01-01) Bakir-Gungor, Burcu; Yazici, Miray Unlu; Goy, Gokhan; Temiz, Mustafa; Ünlü Yazici, MirayType 2 diabetes mellitus (T2D) constitutes 90% of the diabetes cases, and it is a complex multifactorial disease. In the last decade, genome-wide association studies (GWASs) for T2D successfully pinpointed the genetic variants (typically single nucleotide polymorphisms, SNPs) that associate with disease risk. In order to diminish the burden of multiple testing in GWAS, researchers attempted to evaluate the collective effects of interesting variants. In this regard, pathway-based analyses of GWAS became popular to discover novel multigenic functional associations. Still, to reveal the unaccounted 85 to 90% of T2D variation, which lies hidden in GWAS datasets, new post-GWAS strategies need to be developed. In this respect, here we reanalyze three metaanalysis data of GWAS in T2D, using the methodology that we have developed to identify disease-associated pathways by combining nominally significant evidence of genetic association with the known biochemical pathways, protein-protein interaction (PPI) networks, and the functional information of selected SNPs. In this research effort, to enlighten the molecular mechanisms underlying T2D development and progress, we integrated different in silico approaches that proceed in top-down manner and bottom-up manner, and presented a comprehensive analysis at protein subnetwork, pathway, and pathway subnetwork levels. Using the mutual information based on the shared genes, the identified protein subnetworks and the affected pathways of each dataset were compared. While most of the identified pathways recapitulate the pathophysiology of T2D, our results show that incorporating SNP functional properties, PPI networks into GWAS can dissect leading molecular pathways, and it could offer improvement over traditional enrichment strategies.Article Cytotoxic and Cytostatic Effects of Targeting mTOR and Hedgehog Pathways in Acute Myeloid Leukemia(Istanbul Univ, 2022-12-29) Cicek, Enes; Kucuktas, Fulya Mina; Yenigul, Munevver; Akcok, Emel Basak GencerObjectives: Acute myeloid leukemia (AML) is a highly aggressive heterogeneous hematopoietic malignancy characterized by a rapid and abnormal proliferation of immature myeloid leukemia cells in the bone marrow and peripheral blood. Aberrant alterations in signal transduction pathways are strongly associated with the progression of AML. This study aimed to investigate cell viability and the cell cycle in AML cells by targeting the Hedgehog and mTOR signaling pathways with rapamycin and GANT61. Materials and Method: The antiproliferative effect of rapamycin and GANT61 was assessed by the MTT cell viability assay in two AML cell lines: CMK and MOLM-13. The effect of the inhibitors on cell-cycle distribution was determined using propidium iodide staining and measured with flow cytometry. Results: Rapamycin, an mTOR inhibitor, and GANT61, a Gli-1 inhibitor, decreased the cell proliferation of CMK and MOLM-13 cells. The IC20 values, which is the drug concentration that inhibits cell growth by 20%, were combined and administered to the cells. The results show the drugs to have a combinatorial inhibitory effect on CMK cells but not on MOLM-13 cells. In addition, the combination of drugs arrested the cells during the G0/G1 phase. Conclusion: This study suggests a novel combination therapy approach for AML via mTOR and Hedgehog signaling pathway inhibition using rapamycin and GANT61, respectively. It also suggest further studies be performed to reveal the mechanism of action.Article Apatinib Sensitizes Human Breast Cancer Cells Against Navitoclax and Venetoclax Despite Up-Regulated Bcl-2 and Mcl-1 Gene Expressions(Kare Publ, 2021) Kavakcioglu Yardimci, Berna; Ozgun Acar, Ozden; Semiz, Asli; Sen, Alaattin; Acar, Ozden Ozgun; Yardımcı, Berna KavakcıoğluOBJECTIVE Defects in apoptotic cell death which restrict the success of conventional cytotoxic therapies have pivotal roles in a number of pathological conditions including cancer. However, a novel drug class targeting pro-survival Bcl-2 protein family members has been developed with the understanding of the structures and interactions of Bcl-2 proteins. Within this new class, Bcl-2/Bcl-xL inhibitor Navitoclax and Bcl-2 specific inhibitor Venetoclax have been shown to demonstrate strong anticancer activities on several types of cancers. But their low affinity to other anti-apoptotic proteins limits their clinical usage. Here, we investigated the cytotoxic and apoptotic effects of Navitoclax/Venetoclax and their combinations with specific tyrosine kinase inhibitor Apatinib on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines. METHODS MTT assay was used for the evaluation of the inhibition of cancer cell proliferation. ELISA test and Quantitative real-time PCR assay was performed to determine the role of caspase-3, Bak, Bax, Bcl-2, Bcl-xL and Mcl-1 proteins in the inhibition of cell proliferation triggered by the tested agents. RESULTS We found that aggressive MDA-MB-231 cell line was more sensitive to all tested agents. Apatinib significantly enhanced Navitoclax/Venetoclax mediated inhibition of cell viability in both cancer cell lines despite up-regulation in the expression levels of Bcl-2 and Mcl-1 genes. We further demonstrated significant Bak/Bax and caspase-3 expression in less aggressive MCF-7 cells. CONCLUSION Our findings have impacts on Navitoclax/Venetoclax plus Apatinib based therapy for breast adenocarcinoma. On the other hand, further studies should be conducted to elucidate the mechanisms underlying synergistic effects of Navitoclax/Venetoclax plus Apatinib combinations.Article Citation - Scopus: 1Glucosylceramide Synthase is a Novel Biomarker of Midostaurin-Induced Cytotoxicity in Non-Mutant FLT3 Positive Acute Myeloid Leukemia Cells(Istanbul University Press, 2021-12-03) Şahin, Hande Nur; Adan, AysunObjective: Glucosylceramide (GC) synthesized by glucosylce-ramide synthase (GCS) favors cell survival and proliferation in many cancers. However, it’s role in Fms-like tyrosine kinase 3 (FLT3) non-mutant Acute Myeloid Leukemia (AML) pathogenesis is not clarified. Midostaurin, a multi-kinase inhibitor, clinically benefits FLT3-mutated AML, however, its clinical efficacy is under-estimat-ed in FLT3 non-mutant AML. This study aimed to investigate the efficacy of combination of midostaurin with GCS inhibitor in FLT3 AML cell carrying wild-type FLT3 and the underlying molecular mechanisms. Material and Method: Cytotoxic and cytostatic effects of mido-staurin, PDMP (GCS inhibitor) alone and in combination on THP1 cells were determined by MTT assay and flow cytometric propidi-um iodide (PI) staining, respectively. Calcusyn software was used to calculate combination indexes (CIs). GCS expression was checked by western blot. Results: Midostaurin downregulated GCS. Simultaneous inhibition of FLT3 and GCS resulted in suppression of cell proliferation as compared to untreated control. Combinations showed synergistic cytotoxic effects (CI<1). Co-treatments increased cell cycle population at G2/M phase. Conclusion: Inhibition of GCS enhances the efficacy of midostau-rin in FLT3 non-mutant AML, which could be a novel therapeutic approach to increase midostaurin’s limited usage in the clinic after detailed mechanistic studies. © 2023 Elsevier B.V., All rights reserved.