TR Dizin İndeksli Yayınlar Koleksiyonu / TR Dizin Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/20.500.14365/4
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Article Upregulated Acute Systemic Inflammation-Related Genes Based on Endotoxin Exposure Provide ‘Survival Benefit’ or Create ‘High Risk of Death’ in Leukaemia and Colon Cancer(Istanbul University, 2024-07-10) Duran, Gizem Ayna; Duran, Assist. Prof. Dr. Gizem Ayna; Ayna Duran, GizemObjective: Although endotoxin exposure has been shown to trigger innate immune responses and promote cancer, it has also been shown to prevent cancer formation. In our study, survival analysis was performed to determine whether the upregulated genes triggered by endotoxins have hazardous effects on cancers or provide a survival benefit. Materials and Methods: Gene intensity values of control and bacterial endotoxin-administered individuals were obtained from the Gene Expression Omnibus database. Using the R "Linear Models for Microarray Data" package, differentially expressed gene analyses were conducted to determine genes that differ between healthy and bacterial endotoxin-administered samples. "ShinyGo 0.80" web-based tool was used to determine the disease types indicated by these genes. The "Kaplan-Meier Plotter" web-based tool was used to conduct survival analysis. Results: Genes that create an innate immune response to bacterial endotoxin exposure and are upregulated differently than in individuals without exposure were identified. According to gene enrichment analyses, the two main types of cancer identified were leukaemia/lymoma and colon cancer. We detected that MLF1, STAT5B, and BCL3 genes led to poor survival; however, the ARHGAP26 gene was protective for acute myeloid leukaemia patients. In the case of colon cancer, SMAD7 and TLR2 genes were determined as leading to "high risk of death". Conclusion: Once the systemic inflammation-related genes identified in our study are confirmed through laboratory experiments in samples taken from solid tissue in the case of colon cancer and at the level of genes obtained from blood samples in leukemias, genetically targeted treatments will also be possible.Article Citation - WoS: 1Citation - Scopus: 1Differential Effects of Choline on TLR2/4 Mediated Signaling Through Possible Regulation of Toll-Interacting Protein in Hepatocellular Carcinoma Cell Lines(Walter de Gruyter GmbH, 2024-05-30) Barış, Elif; Demir, Ayse BanuObjectives: Toll-like receptor (TLR) mediated inflammatory status plays an important role in development and pro- gression of hepatocellular carcinoma (HCC). Toll-interacting protein (TOLLIP) has an inhibitory effect on TLR-mediated inflammatory signalling and expression profile of TOLLIP varies between malignancies including HCC. Cholinergic anti-inflammatory pathway (CAP) is an endogenous mech- anism that controls inflammatory status via α7nicotinic acetylcholine receptors (α7nAChR). This study aims to investigate the effect of CAP-acting agent choline on TOLLIP and its related TLR-mediated inflammatory response in HCC cells with distinct differentiation stages. Methods: The expression patterns of α7nAChR, TLR2/4, TOLLIP, IL6, NFkB genes were evaluated by RT-PCR and ELISA in the presence of choline, along with the real-time cell proliferation and migration in HEP3B and SNU449 HCC cell lines. The interaction between choline and TOLLIP assessed by using in-silico analyses. Results: Choline downregulated TOLLIP in Hep3B and SNU449 cells. However, the expressions of α7nAChR, NF-κB, IL-6, TLR2 and TLR4 showed a decreased pattern in well differentiated HEP3B cells, while an increased pattern in poorly differentiated SNU449 cells. Conclusions: Choline might exert differential effects in TLR2/4-dependent signalling based on the differentiation stages of the HCC cells, suggesting its potential therapeutic effects in earlier stages of HCC which might be result of its partial modulation of TOLLIP.Article Classification of Colon Cancer Patients Into Consensus Molecular Subtypes Using Support Vector Machines(2023-12-28) Koçhan, Necla; Dayanç, Barış EmreBackground/aim: The molecular heterogeneity of colon cancer has made classification of tumors a requirement for effective treatment. One of the approaches for molecular subtyping of colon cancer patients is the consensus molecular subtypes (CMS), developed by the Colorectal Cancer Subtyping Consortium. CMS-specific RNA-Seq-dependent classification approaches are recent, with relatively low sensitivity and specificity. In this study, we aimed to classify patients into CMS groups using their RNA-seq profiles. Materials and methods: We first identified subtype-specific and survival-associated genes using the Fuzzy C-Means algorithm and log- rank test. We then classified patients using support vector machines with backward elimination methodology. Results: We optimized RNA-seq-based classification using 25 genes with a minimum classification error rate. In this study, we reported the classification performance using precision, sensitivity, specificity, false discovery rate, and balanced accuracy metrics. Conclusion: We present a gene list for colon cancer classification with minimum classification error rates and observed the lowest sensitivity but the highest specificity with CMS3-associated genes, which significantly differed due to the low number of patients in the clinic for this group.Article Exploring Pi3k Pathway Inhibitors for Acute Myeloid Leukemia: a Drug-Repurposing Approach(Istanbul University Press, 2023-12-28) Ergun, Cansu; Kiremitci, Buse Zeren; Arslantas, Gizem; Bozkurt, Busenur; Duran, Gizem Ayna; Kiraz, YağmurObjective: Acute myeloid leukemia (AML) is a malignant disease characterized by the uncontrolled growth, differentiation, and proliferation of immature hematopoietic cells. Patients with AML often have poor survival rates, which are associated with specific gene mutations in FLT3, CEBPA, and NPM1. The phosphatidylinositol 3-kinase (PI3K) pathway, a lipase pathway, is activated in many malignancies, including AML. Given the low survival rates in AML, this study identified candidate drugs that could inhibit the PI3K pathway, thereby offering a potential treatment for AML, by using a drug-repurposing approach. Materials and Methods: Online bioinformatics tools were utilized to identify pathway-related genes and FDA-approved drugs. Subsequently, molecular docking was performed to determine the binding affinity values. Important genes were identified by evaluating their impact on survival and their aberrant expression in the tumor. In this study, genes such as VAV1, GSK3B, MTOR, PDPK1, PRR5, TSC2, AKT3, and CREB1 were determined and docked with their potential inhibitors. Particular attention was paid to VAV1 because there were no known potential VAV1 inhibitors used in AML. Results: The docking results were ranked, and the proposed gene–drug pairs were identified as tideglusib and fostamatinib for the inhibition of GSK3B, pimecrolimus and fostamatinib for the inhibition of MTOR, and fostamatinib for the inhibition of PDPK1. Furthermore, nebivolol, darifenacin, dihydroergotamine, libanserin and entereg were identified as potential inhibitors of VAV1 in AML. Conclusion: To sum up, most effective gene–drug pairs according to binding affinities were proposed as candidate inhibitor drugs for AML.Article Determination of Eight Hub Genes and Functional Pathways Affecting Both the Survival of Early- and Late-Stage Colon Cancer Patients(Kare Publ, 2023) Ayna Duran, Gizem; Sert, Fatma; Duran, Assist. Prof. Dr. Gizem Ayna; Duran, Gizem AynaOBJECTIVEThe stage of colon cancer (CC) and therefore the level at which the treatment is initiated affects the survival of CC patients. In our study, we aimed to identify the common survival-related genes in both early-and late-stage CC patients.METHODSInformation on the demographic characteristics of 581 patients and microarray expression profiles (GSE39582) were obtained from the gene expression omnibus database. Survival analysis was per-formed using univariate and multivariate Cox regression methods with the help of R3.53 programming language and Kaplan-Meier graphics through the R software Survival package. ShinyGO v0.741 gene ontology enrichment analysis was performed to clarify the common and functional pathways related to both early-and late-stage CC cancer patients' data.RESULTSCox regression analysis indicated that overall survival and relapse-free survival of CC patients were strongly influenced by stage. Genes that significantly affect prognosis and survival in early-and late -stage CC patients were identified. As a result of gene enrichment analysis, arginine binding, oxidore-ductase activity, and methylcytosine dioxygenase activity and related eight hub genes (TM4SF5, NOS3, Ten eleven translocation [TET1], TET3, JMJD7, AKR1C1, prenylcysteine oxidase 1 like, Methionine sulfoxide reductase A) were identified.CONCLUSIONAccording to our results, it might be considered that developing new treatment strategies based on eight hub-genes related to arginine binding, oxidoreductase activity, and methylcytosine dioxygenase activity detected at different stages of CC might increase the success of targeted therapies.Article In Silico Approach for Identification of PI3K/MTOR Dual Inhibitors for Multiple Myeloma Treatment(Istanbul Univ, 2023-04-14) Masalaci, Ilke; Akdogan, Yaren; Mutlu, Ozge; Eyvaz, Hande; Kiraz, YagmurObjective: Multiple myeloma is a hematologic malignancy in which targeting phosphoinositide 3 kinase (PI3K) and/or the mammalian target of rapamycin (mTOR) individually has been shown to have anti-proliferative effects, however, inhibiting both proteins simultaneously has been reported to have more effective results for its treatment. The aim of this study is to determine the molecular interactions and predicted inhibitory effects of 40 different dual inhibitors on mTOR, PI3K delta, and PI3K gamma to propose potentially the most effective dual inhibitor that targets the PI3K delta and PI3K gamma isoforms as well as the mTOR proteins since those isoforms are known to be predominant in multiple myeloma patients. Therefore, the focus in this study is built around the specific targeting of the PI3K delta and PI3K gamma isoforms from the multiple myeloma perspective. Materials and Methods: In silico docking experiments were conducted to determine the binding energies for different ligands that target mTOR, PI3K delta, and PI3K gamma. Protein-dual inhibitor complexes and the amino acids and bond types were visualized to identify molecular interactions. The absorption, distribution, metabolism, and excretion properties of dual inhibitors were analyzed and evaluated. Results: The binding affinity values were found to be between -7 and -9.9 kcal/mol. The toxicity prediction values of the selected dual inhibitors were obtained from the Pro-Tox-II web tool and classified according to the globally harmonized system of classification of labeling of chemicals. Conclusion: Correspondingly, among all dual inhibitors, Vistusertib is determined to be a promising compound against multiple myeloma cells by inhibiting both PI3K delta and PI3K gamma as well as mTORC1/2.Article Citation - WoS: 1Citation - Scopus: 1Shotgun Lipidomics Elucidates the Lipidome Alterations of the Mcl-1 Inhibitor S63845 in Aml Cell Lines With a Focus on Sphingolipids(Istanbul University Press, 2022-12-30) Yandım, Melis Kartal; Bilgin, MesutObjective: Acute myeloid leukemia (AML) is a vigorous type of leukemia requiring effective treatment. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic molecule that is upregulated in AML and is studied as a target for treatment. The specific Mcl-1 inhibitor, S63845, has antiproliferative effects on AML cells. Bioactive sphingolipids have crucial roles in cells and regulate Mcl-1 stability. This study aimed to elucidate the changes in lipid profiles of AML cell lines in response to Mcl-1 inhibitor S63845 treatment, with a special focus on sphingolipids. Materials and Methods: The cytotoxic effects of S63845 were identified in the AML cell lines MV4-11, HL60, and KG1 using the MTT cell proliferation assay. Lipidome analysis was conducted by quantitative shotgun lipidomics covering 378 individual lipid species in 26 classes within the major lipid categories. Results: The IC50 values of S63845 have been calculated as 7 nM for MV4-11, 53 nM for HL60, and 479 nM for KG1. The lipidome results reveal the S63845 treatment to increase ceramide (Cer) levels in the MV4-11 and KG1 cell lines at the expense of downstream sphingolipids while increasing the hexosylceramide (HexCer) levels in the HL60 cell line at the expense of the Cer and sphingomyelin (SM). Conclusion: This study showed S63845 to be able to suppress cell proliferation by altering lipid compositions in AML cell lines. More importantly, the study suggested S63845 to differentially affect the lipid profiles of AML cell lines.Article Citation - Scopus: 1Vinorelbine Induced Serpentine Supravenous Hyperpigmentation(Türkiye Klinikleri, 2022) Yetut, Ahsen Duygu; Dirican, Ahmet; Çelik, Cumali; Erdogan, Atıke Pınar; Taş, Semra; Ekinci, FerhatSerpentine supravenous hyperpigmentation (SSH) is a rare complexity arising from antineoplastic therapy. Vinorelbine, a\rchemotherapeutic drug that is frequently used for the treatment of breast and lung cancer, contributes to the etiology of SSH. A 54 years old\rmale patient was being treated for lung adenocarcinoma. An intravenous (IV) infusion of vinorelbine was administered in the distal dorsal vein\rof the left forearm. Erythematous hyperpigmentation at the infusion area was observed a week after the administration of the chemotherapeutic\rdrug. The initial symptoms of SSH usually appear between 1 to 15 days post IV administration of a cytotoxic drug, and it spontaneously becomes\rhyperpigmented within 1-3 weeks. However, these local reactions can be prevented by applying IV infusion for a short period (15-30\rmin) along with adequate venous irrigation (75-124 mL) instead of bolus administration. The termination of the drug can also be considered.Article Citation - WoS: 6Citation - Scopus: 5Acrylamide-Encapsulated Glucose Oxidase Inhibits Breast Cancer Cell Viability(Walter De Gruyter Gmbh, 2020-08-04) Rrustemi, Trendelina; Geyik, Oyku Gonul; Ozkaya, Ali Burak; Ozturk, Taylan Kurtulus; Yuce, Zeynep; Kilinc, AliObjectives: Cancer cells modulate metabolic pathways to ensure continuity of energy, macromolecules and redoxhomeostasis. Although these vulnerabilities are often targeted individually, targeting all with an enzyme may prove a novel approach. However, therapeutic enzymes are prone to proteolytic degradation and neutralizing antibodies leading to a reduced half-life and effectiveness. We hypothesized that glucose oxidase (GOX) enzyme that catalyzes oxidation of glucose and production of hydrogen peroxide, may hit all these targets by depleting glucose; crippling anabolic pathways and producing reactive oxygen species (ROS); unbalancing redox homeostasis. Methods: We encapsulated GOX in an acrylamide layer and then performed activity assays in denaturizing settings to determine protection provided by encapsulation. Afterwards, we tested the effects of encapsulated (enGOX) and free (fGOX) enzyme on MCF-7 breast cancer cells. Results: GOX preserved 70% of its activity following encapsulation. When fGOX and enGOX treated with guanidinium chloride, fGOX lost approximately 72% of its activity, while enGOX only lost 30%. Both forms demonstrated remarkable resilience against degradation by proteinase K and inhibited viability of MCF-7 cells in an activity-dependent manner. Conclusions: Encapsulation provided protection to GOX against denaturation without reducing its activity, which would prolong half-life of the enzyme when administered intravenously.