PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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Article Citation - WoS: 18Citation - Scopus: 20Resveratrol Triggers Anti-Proliferative and Apoptotic Effects in FLT3-LTD Acute Myeloid Leukemia Cells via Inhibiting Ceramide Catabolism Enzymes(Humana Press inc, 2022-01-20) Ersoz, Nur Sebnem; Adan, AysunResveratrol possesses well-defined anti-carcinogenic activities. However, how resveratrol exerts its anti-leukemic actions by modulating anti-apoptotic ceramide catabolism enzymes, mainly sphingosine kinase (SK-1) and glucosylceramide synthase (GCS), in FLT3-ITD AML remains unclear. Resveratrol, SKI II (SK inhibitor) and PDMP (GCS inhibitor) were evaluated alone or in combinations for their effect on cell proliferation (MTT assay), apoptosis (annexin V-FITC/PI staining by flow cytometry) and cell cycle progression (PI staining by flow cytometry) in MOLM-13 and MV4-11 cells. The combination indexes (CIs) were calculated based on cell proliferation data using CompuSyn software. Caspase-3 and PARP activation, changes in SK-1 and GCS levels by resveratrol alone or PARP cleavage in co-treatments were determined by western blot. Resveratrol and inhibitors alone inhibited cell proliferation in a dose- and time-dependent manner. Resveratrol downregulated SK-1 and GCS expression in both cell lines. It induced apoptosis by phosphatidylserine (PS) exposure together with caspase-3 and PARP cleavage and arrested the cell cycle slightly at the S phase. Co-administrations intensified resveratrol's effect by inhibiting cell proliferation synergistically (A CI of < 1) or additively (A CI 1.0-1.1) and inducing apoptosis via PS relocalization and PARP cleavage. Resveratrol plus SKI II did not affect cell cycle progression significantly, however, resveratrol plus PDMP blocked cycle progression at G0/G1 and S phases for MOLM-13 cells and MV4-11 cells, respectively. Overall, resveratrol may inhibit FLT3-ITD AML cell proliferation by inhibiting ceramide catabolism and be evaluated as a chemopreventive after detailed analysis of the crosstalk between resveratrol and ceramide catabolism pathway.Article Citation - WoS: 16Citation - Scopus: 21GeNetOntology: Identifying Affected Gene Ontology Terms via Grouping, Scoring, and Modeling of Gene Expression Data Utilizing Biological Knowledge-Based Machine Learning(Frontiers Media S.A., 2023-08-21) Ersoz, Nur Sebnem; Bakir-Gungor, Burcu; Yousef, MalikIntroduction: Identifying significant sets of genes that are up/downregulated under specific conditions is vital to understand disease development mechanisms at the molecular level. Along this line, in order to analyze transcriptomic data, several computational feature selection (i.e., gene selection) methods have been proposed. On the other hand, uncovering the core functions of the selected genes provides a deep understanding of diseases. In order to address this problem, biological domain knowledge-based feature selection methods have been proposed. Unlike computational gene selection approaches, these domain knowledge-based methods take the underlying biology into account and integrate knowledge from external biological resources. Gene Ontology (GO) is one such biological resource that provides ontology terms for defining the molecular function, cellular component, and biological process of the gene product.Methods: In this study, we developed a tool named GeNetOntology which performs GO-based feature selection for gene expression data analysis. In the proposed approach, the process of Grouping, Scoring, and Modeling (G-S-M) is used to identify significant GO terms. GO information has been used as the grouping information, which has been embedded into a machine learning (ML) algorithm to select informative ontology terms. The genes annotated with the selected ontology terms have been used in the training part to carry out the classification task of the ML model. The output is an important set of ontologies for the two-class classification task applied to gene expression data for a given phenotype.Results: Our approach has been tested on 11 different gene expression datasets, and the results showed that GeNetOntology successfully identified important disease-related ontology terms to be used in the classification model.Discussion: GeNetOntology will assist geneticists and scientists to identify a range of disease-related genes and ontologies in transcriptomic data analysis, and it will also help doctors design diagnosis platforms and improve patient treatment plans.Article Citation - WoS: 4Citation - Scopus: 4Differential in Vitro Anti-Leukemic Activity of Resveratrol Combined With Serine Palmitoyltransferase Inhibitor Myriocin in FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-LTD) Carrying AML Cells(Springer, 2022-02-14) Ersoz, Nur Sebnem; Adan, AysunTreatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) AML is restricted due to toxicity, drug resistance and relapse eventhough targeted therapies are clinically available. Resveratrol with its multi-targeted nature is a promising chemopreventive remaining limitedly studied in FLT3-ITD AML regarding to ceramide metabolism. Here, its cytotoxic, cytostatic and apoptotic effects are investigated in combination with serine palmitoyltransferase (SPT), the first enzyme of de novo pathway of ceramide production, inhibitor myriocin on MOLM-13 and MV4-11 cells. We assessed dose-dependent cell viability, flow cytometric cell death and cell cycle profiles of resveratrol in combination with myriocin by MTT assay, annexin-V/PI staining and PI staining respectively. Resveratrol's dose-dependent effect on SPT protein expression was also checked by western blot. Resveratrol decreased cell viability in a dose- dependent manner whereas myriocin did not affect cell proliferation effectively in both cell lines after 48h treatments. Although resveratrol induced both apoptosis and a significant S phase arrest in MV4-11 cells, it triggered apoptosis and non-significant S phase accumulation in MOLM-13 cells. Co-administrations reduced cell viability. Increased cytotoxic effect of co-treatments was further proved mechanistically through induction of apoptosis via phosphatidylserine relocalization. The cell cycle alteration in co-treatment was significant with an S phase arrest in MV4-11 cells, however, it was not effective on cell cycle progression of MOLM-13 cells. Resveratrol also increased SPT expression. Overall, modulation of SPT together with resveratrol might be the possible explanation for resveratrol's action. It could be an integrative medicine for FLT3-ITD AML after investigating its detailed mechanism of action in relation to de novo pathway of ceramide production.