Moleküler Biyoloji ve Genetik Bölümü Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/209

Browse

Now showing 1 - 20 of 89

Matching variants for functional characterization of genetic variants
(Oxford University Press, 2023) Cevik,Sabiha; Zhao,Pei; Zorluer,Atiyye; Pir, Mustafa S.; Bian, Wenyin; Kaplan, Oktay I.; 0000-0002-0935-1929; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Cevik, Sabiha; Zorluer, Atiye; Pir, Mustafa S.
Rapid and low-cost sequencing, as well as computer analysis, have facilitated the diagnosis of many genetic diseases, resulting in a substantial rise in the number of disease-associated genes. However, genetic diagnosis of many disorders remains problematic due to the lack of interpretation for many genetic variants, especially missenses, the infeasibility of high-throughput experiments on mammals, and the shortcomings of computational prediction technologies. Additionally, the available mutant databases are not well-utilized. Toward this end, we used Caenorhabditis elegans mutant resources to delineate the functions of eight missense variants (V444I, V517D, E610K, L732F, E817K, H873P, R1105K, and G1205E) and two stop codons (W937stop and Q1434stop), including several matching variants (MatchVar) with human in ciliopathy associated IFT-140 (also called CHE-11)//IFT140 (intraflagellar transport protein 140). Moreover, MatchVars carrying C. elegans mutants, including IFT-140(G680S) and IFT-140(P702A) for the human (G704S) (dbSNP: rs150745099) and P726A (dbSNP: rs1057518064 and a conflicting variation) were created using CRISPR/Cas9. IFT140 is a key component of IFT complex A (IFT-A), which is involved in the retrograde transport of IFT along cilia and the entrance of G protein-coupled receptors into cilia. Functional analysis of all 10 variants revealed that P702A and W937stop, but not others phenocopied the ciliary phenotypes (short cilia, IFT accumulations, mislocalization of membrane proteins, and cilia entry of nonciliary proteins) of the IFT-140 null mutant, indicating that both P702A and W937stop are phenotypic in C. elegans. Our functional data offered experimental support for interpreting human variants, by using ready-to-use mutants carrying MatchVars and generating MatchVars with CRISPR/Cas9.
Integrating Biological Domain Knowledge with Machine Learning for Identifying Colorectal-Cancer-Associated Microbial Enzymes in Metagenomic Data
(MDPI, 2025) Bakir-Gungor, Burcu; Ersoz, Nur Sebnem; Yousef, Malik; 0000-0002-2272-6270; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Bakir-Gungor, Burcu; Ersoz, Nur Sebnem
Advances in metagenomics have revolutionized our ability to elucidate links between the microbiome and human diseases. Colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide, has been associated with dysbiosis of the gut microbiome. This study aims to develop a method for identifying CRC-associated microbial enzymes by incorporating biological domain knowledge into the feature selection process. Conventional feature selection techniques often evaluate features individually and fail to leverage biological knowledge during metagenomic data analysis. To address this gap, we propose the enzyme commission (EC)-nomenclature-based Grouping-Scoring-Modeling (G-S-M) method, which integrates biological domain knowledge into feature grouping and selection. The proposed method was tested on a CRC-associated metagenomic dataset collected from eight different countries. Community-level relative abundance values of enzymes were considered as features and grouped based on their EC categories to provide biologically informed groupings. Our findings in randomized 10-fold cross-validation experiments imply that glycosidases, CoA-transferases, hydro-lyases, oligo-1,6-glucosidase, crotonobetainyl-CoA hydratase, and citrate CoA-transferase enzymes can be associated with CRC development as part of different molecular pathways. These enzymes are mostly synthesized by Eschericia coli, Salmonella enterica, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides dificile. Comparative evaluation experiments showed that the proposed model consistently outperforms traditional feature selection methods paired with various classifiers.
TextNetTopics-SFTS-SBTS: TextNetTopics Scoring Approaches Based Sequential Forward and Backward
(Springer Science and Business Media Deutschland GmbH, 2024) Voskergian, Daniel; Bakir-Gungor, Burcu; Yousef, Malik; 0009-0005-7544-9210; 0000-0002-2272-6270; 0000-0001-8780-6303; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Bakir-Gungor, Burcu
TextNetTopics is a text classification-based topic modeling approach that performs topic selection rather than word selection to train a machine learning algorithm. However, one main limitation of TextNetTopics is that its scoring component (the S component) assesses each topic independently and ranks them accordingly, neglecting the potential relationship between topics. In order to address this limitation and improve the classification performance, this study introduces an enhancement to TextNetTopics. TextNetTopics-SFTS-SBTS integrates two novel scoring approaches: Sequential Forward Topic Scoring (SFTS) and Sequential Backward Topic Scoring (SBTS), which consider topic interactions by assessing sets of topics simultaneously. This integration aims to streamline the topic selection process and enhance classifier efficiency for text classification. The results obtained across three datasets offer valuable insights into the context-dependent effectiveness of the new scoring mechanisms across diverse datasets and varying numbers of topics involved in the analysis.
Classification of Breast Cancer Molecular Subtypes with Grouping-Scoring-Modeling Approach that Incorporates Disease-Disease Association Information
(IEEE Xplore, 2024) Qumsiyeh, Emma; Bakir-Gungor, Burcu; Yousef, Malik; 0000-0002-2272-6270; AGÜ, Mühendislik Fakültesi, Bilgisayar Mühendisliği Bölümü; Bakir-Gungor, Burcu
This study uses modern sequencing technology and large biological databases to investigate the molecular intricacies of complicated diseases like cancer. Using gene expression databases and biomarkers, the research aims to improve breast cancer molecular subtype identification for better patient outcomes. Using BRCA LumAB_ Her2Basal dataset, this study compares an integrative machine learning-based strategy (GediNET) to traditional feature selection approaches across machine learning classifiers. GediNET excels at uncovering crucial disease-disease connections and potential biomarkers using the Grouping-Scoring-Modeling (GSM) approach, which favors gene groupings above individual genes. Our comparative analysis highlights GediNET's exceptional performance, notably in terms of accuracy and Area Under the Curve metrics, underscoring its effectiveness in uncovering the genetic intricacies of breast cancer. GediNET's promise to improve disease classification and biomarker identification by improving biological mechanism understanding goes beyond exceeding traditional approaches. The work shows that GediNET's integrative method can promote bioinformatics research by identifying the most informative genes associated with certain diseases, enabling focused and customized medicine.
eTNT: Enhanced TextNetTopics with Filtered LDA Topics and Sequential Forward / Backward Topic Scoring Approaches
(SCIENCE & INFORMATION-SAI ORGANIZATION LTD, 2024) Voskergian, Daniel; Jayousi, Rashid; Bakir-Gungor, Burcu; 0000-0002-2272-6270; AGÜ, Mühendislik Fakültesi, Bilgisayar Mühendisliği Bölümü; Bakir-Gungor, Burcu
TextNetTopics is a novel text classification-based topic modelling approach that focuses on topic selection rather than individual word selection to train a machine learning algorithm. However, one key limitation of TextNetTopics is its scoring component, which evaluates each topic in isolation and ranks them accordingly, ignoring the potential relationships between topics. In addition, the chosen topics may contain redundant or irrelevant features, potentially increasing the feature set size and introducing noise that can degrade the overall model performance. To address these limitations and improve the classification performance, this study introduces an enhancement to TextNetTopics. eTNT integrates two novel scoring approaches: Sequential Forward Topic Scoring (SFTS) and Sequential Backward Topic Scoring (SBTS), which consider topic interactions by assessing sets of topics simultaneously. Moreover, it incorporates a filtering component that aims to enhance topics' quality and discriminative power by removing non-informative features from each topic using Random Forest feature importance values. These integrations aim to streamline the topic selection process and enhance classifier efficiency for text classification. The results obtained from the WOS-5736, LitCovid, and MultiLabel datasets provide valuable insights into the superior effectiveness of eTNT compared to its counterpart, TextNetTopics.
Determination of promising inhibitors for N-SH2 domain of SHP2 tyrosine phosphatase: an in silico study
(SPRINGER NATURE LINK, 2024) Akcok, Emel Basak Gencer; Guner, Huseyin; Akcok, Ismail; 0000-0002-6559-9144; 0000-0002-5444-3929; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Akcok, Emel Basak Gencer; Akcok, Ismail
There are many genes that produce proteins related to diseases and these proteins can be targeted with drugs as a potential therapeutic approach. Recent advancement in drug discovery techniques have created new opportunities for treating variety of diseases by targeting disease-related proteins. Structure-based drug discovery is a faster and more cost-effective approach than traditional methods. SHP2 phosphatase, encoded by the PTPN11 gene, has been the focus of much attention due to its involvement in many types of diseases. The biological function of SHP2 is enabled mostly by protein-protein interaction through its SH2 domains. In this study, we report the identification of a potential small molecule inhibitor for the N-SH2 domain of SHP2 by structure-based drug discovery approach. We utilized molecular docking studies, followed by molecular dynamics simulations and MM/PBSA calculations, to analyze compounds retrieved from the Broad's Drug Repurposing Hub and ZINC15 databases. We selected 10 hit compounds with the best docking scores from the libraries and examined their binding properties in the N-SH2 domain. We found that compound CID 60838 (Irinotecan) was the most suitable compound with a binding free energy value of - 64.45 kcal/mol and significant interactions with the target residues in the domain.
Pi3k-Akt-Mtor Yolağı Ve Histon Deasetilaz Enzimlerinin Hedeflenmesinin Akut Myeloid Lösemi Hücreleri Üzerine Antitümör Etkisinin Incelenmesi
(TÜBİTAK, 2022) Gencer Akçok, Emel Başak; Şansaçar, Merve; Karaca, Münevver; Okur, Tuğba; 0000-0002-6559-9144; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Gencer Akçok, Emel Başak
Akut Miyeloid Lösemi (AML), periferik kan, kemik iliği, dalak ve karaciğerde blast adı verilen olgunlaşmamış miyeloid hücrelerin birikmesiyle karakterize edilen ve sonunda hematopoietik maligniteye yol açan bir hastalıktır. Genetik anormalliklerin yanı sıra PI3K/AKT/mTOR, Wnt, Notch, STAT3, Hedgehog gibi önemli hücresel yolakların AML patogenezinde rol oynadığı bildirilmiştir. Histon deasetilaz (HDAC) inhibitörleri, AML için umut verici antikanser aktiviteye sahiptir. Çalışmada, PI3K/AKT/mTOR yolunun inhibisyonunun ve HDAC inhibisyonunun farklı AML alt gruplarının hücre hatları olan MOLM-13 ve CMK hücre hatları kullanılarak bu hastalığın altında yatan moleküler mekanizma üzerindeki etkisinin araştırılması amaçlamıştır. Bu amaçla PI3K inhibitörü LY294002 ve HDAC inhibitörleri (SAHA, PCI-3501 ve Tubastatin A) ve bunların kombinasyonlarının etkisi incelenmiştir. Hücre proliferasyonu MTT hücre sitotoksisite testi ile apoptoz oranları ise Annexin-V/PI çift boyama yöntemi ile belirlenmiş, ilaçların hücre döngüsüne olan etkileri de PI boyaması ile belirlenmiştir. Otofaji belirteci olan LC3B protein seviyesi moleküler düzeyde western blot ile doğrulanmıştır. Kullanılan inhibitörler her iki hücre hattı üzerinde düşük mikromolar konsantrasyonda hücre canlılığını azaltmıştır. Sonuçlar LY294002+SAHA kombinasyon tedavisinin MOLM-13 hücrelerinde hücre proliferasyonunu %50, CMK hücrelerinde ise %25 azalma gösterdiği belirlenmiştir. LY294002+Tubastatin A tedavisi, MOLM-13 ve CMK hücrelerinde hücre proliferasyonunu sırasıyla %65 ve %40 oranında azalttığını göstermiştir. Sonuçlarımız, LY294002 ve HDAC inhibitör kombinasyonlarının kontrol hücrelerine kıyasla MOLM-13 hücrelerinde G1 fazı tutuklanmasıyla sonuçlandığını gösterdi. Öte yandan, LY294002+SAHA, LY294002+PCI-3501 ve LY294002+Tubastatin A kombinasyonları ile tedavi edilen CMK hücreleri, sırasıyla G2/M, G2/M ve G1 fazında tutuklanmıştır. Kombinasyonların apoptotik hücre ölümü üzerine etkisine bakılmış, LC3BII/I protein ifade düzeyi kombinasyon tedavisi sonucunda incelenmiştir. HDAC enzimlerinin hem AML hem de farklı kanserler üzerindeki etkileri düşünüldüğünde, HDAC inhibisyonu AML için önemli ve yüksek potansiyelli bir hedeftir. Bu nedenle PI3K/AKT/mTOR yolağı ve HDAC'lerin farklı alt gruplarda inhibisyonunun araştırılması, AML'nin patogenezine yol açan mekanizmalar hakkında fikir verebilir. Sonuç olarak, PI3K/AKT/mTOR ve HDAC'nin bu inhibisyonunun, AML'nin ortadan kaldırılmasıyla sonuçlanan daha spesifik bir kombinasyon hedefli tedaviye yol açacağı umulmaktadır.
Highly Potent New Probiotic Strains from Traditional Turkish Fermented Foods
(SPRINGER NATURE LINK, 2025) Yigit, Mehmet Burak; Cebeci, Aysun; 0000-0002-6158-8798; 0000-0002-6777-6773; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Cebeci, Aysun; Yigit, Mehmet Burak
Traditional Turkish fermented foods like boza, pickles, and tarhana are recognized for their nutritional and health benefits, yet the probiotic potential of lactic acid bacteria (LAB) strains isolated from them remains underexplored. Sixty-six LAB strains were isolated from fermented foods using bacterial morphology, Gram staining, and catalase activity. The isolates were differentiated at strain level by RAPD-PCR (Random Amplification of Polymorphic DNA-Polymerase Chain Reaction) and twenty-five strains were selected for further evaluation of acid and bile salt tolerance. Among these, ten strains exhibited high tolerance and were subsequently assessed for adhesion to Caco-2 colorectal carcinoma cells, antimicrobial activity, exopolysaccharide (EPS) production, lysozyme resistance, and hemolytic activity. Using k-means clustering, three strains: Lactiplantibacillus plantarum ES-3, Pediococcus pentosaceus N-1, and Enterococcus faecium N-2 demonstrated superior probiotic characteristics, including significant acid (100% survival at pH3.0) and 0.3% bile salt tolerance (57%, 64%, 67%), strong adhesion to intestinal cells (65%, 88%, 91%), high lysozyme resistance (88%, 88%, 77%), and produced high amounts of EPS. These strains show promising potential as probiotics and warrant further investigation to confirm their functional properties and potential applications.
Aurora Kinases: Their Role in Cancer and Cellular Processes
(Bingöl Üniversitesi Fen Bilimleri Enstitüsü, 2024) Sarı, Sibel; Özsoy, Elif Rumeysa; 0000-0002-2505-5804; 0009-0008-6040-9875; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sarı, Sibel; Özsoy, Elif Rumeysa
Aurora kinases, belonging to a highly conserved family of serine/threonine kinases with critical roles in the regulation of the cell cycle, comprise three members: Aurora kinase A, B, and C, which serve as key mitotic regulators essential for maintaining chromosome stability. Aurora kinases play crucial roles in multiple events in mitotic such as the coordination of chromosomal and cytoskeletal events, regulation of the spindle assembly checkpoint pathway and cytokinesis to ensure the smooth progression of the cell cycle. Besides their mitotic functions, Aurora kinases are also involved in the regulation of meiosis. Gene amplification/mutation and overexpression of Aurora kinases have been detected in various solid and haematological cancers. In human tumours, Aurora kinases exhibit oncogenic roles associated with their mitotic roles, which drive the cancer cell proliferation and survival. Deregulation of Aurora kinase activity causes failure in centrosome function, spindle assembly, chromosomal alignment, and cytokinesis, eventually resulting in the mitotic abnormalities and genetic instability. These findings emphasize the crucial functions of Aurora kinases in cancer, prompting their recognition as valuable targets for cancer therapy. This review provides an overview of the structures and functions of Aurora kinases and sheds light on their oncogenic roles in cancer.
Tomatidine, a Steroidal Alkaloid, Synergizes with Cisplatin to Inhibit Cell Viability and Induce Cell Death Selectively on FLT3-ITD+ Acute Myeloid Leukemia Cells
(SPRINGER NATURE Link, 2024) Ayvaz, Havva Berre; Yenigül, Münevver; Gencer Akçok, Emel Başak; 0000-0002-5873-7879; 0000-0003-0468-721X; 0000-0002-6559-9144; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Ayvaz, Havva Berre; Yenigül, Münevver; Gencer Akçok, Emel Başak
Background: Acute Myeloid Leukemia (AML) is a hematological cancer that frequently presents with a range of side effects and drug resistance during anticancer drug treatment. The current study aims to achieve increased efficacy by combining lower doses of cisplatin with increasing concentrations of tomatidine in AML cells to increase efficacy. Methods: Anti-proliferative effects of single and combination of cisplatin and tomatidine were assessed via MTT cell viability assay. The Annexin V/Propidium Iodide Double Staining method was used to measure the apoptotic effects of combined tomatidine and cisplatin treatment. Then, Western Blot analysis was performed to measure Poly (ADP-ribose) polymerase (PARP) and Caspase-3 protein expression levels. Results: Cisplatin treatment with lower concentrations displayed high cytotoxic effects on AML cells, compared with tomatidine. The combination of the Inhibitory Concentration (IC) 20 value of cisplatin and increasing doses of tomatidine exhibited a significant decrease in cell viability relative to single treatments. The combination index analysis revealed a mild synergistic effect of cisplatin IC20 and varying tomatidine doses. The apoptosis induced when cisplatin was combined with 500 µM tomatidine by almost 20%, while the percentage of apoptosis in combination with 1 mM tomatidine was measured by 50% for both cell lines. The upregulation of proapoptotic cleaved-PARP (3.2 and 1.08-fold for THP-1 and MOLM-13, respectively) and downregulation in Caspase-3 (0.23 and 0.13-fold for THP-1 and MOLM-13, respectively) was detected. Conclusions: Together, the study indicated that when tomatidine combined with cisplatin on AML cell lines, a combinatorial anti-proliferative and apoptotic effect is observed. The combination of cisplatin with tomatidine may be a promising approach.
A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings
(ELSEVIER, 2024) Khodzhaev, Khusan; Sudutan, Tugce; Erbilgin, Yucel; Saritas, Merve; Yegen, Gulcin; Bozkurt, Ceyhun; Sayitoglu, Muge; Kebudi, Rejin; 0000-0003-4753-9372; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Saritas, Merve
Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-κB pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL. The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM_003889.3:c.811G>A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased PXR expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-PCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells. Patients with homozygous PXR variant showed significantly high expression compared to PXR wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). PXR homozygous HRS cells had significantly higher PXR expression compared to PXR wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous PXR HRS cells showed increased PXR expression in nucleus (p < 0.001). PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous PXR HL cases. This study provided clinical evidence to previously reported Sxr−/− mice model that develop multifocal lymphomas, had an aberrantly increased NF-κB expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis.
CilioGenics: an integrated method and database for predicting novel ciliary genes
(Oxford University Press, 2024) Pir, Mustafa Samet; Begar, Efe; Yenisert, Ferhan; Demirci, Hasan C.; Korkmaz, Mustafa E.; Karaman, Asli; Tsiropoulou, Sofia; Firat-Karalar, Elif Nur; Blacque, Oliver E.; Oner, Sukru S.; Doluca, Osman; Cevik, Sebiha; Kaplan, Oktay Ismail; 0000-0002-4645-7626; 0000-0002-0935-1929; 0000-0002-8733-0920; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Pir, Mustafa Samet; Yenisert, Ferhan; Demirci, Hasan C.; Korkmaz, Mustafa E.; Cevik, Sebiha; Kaplan, Oktay Ismail
Uncovering the full list of human ciliary genes holds enormous promise for the diagnosis of cilia-related human diseases, collectively known as ciliopathies. Currently, genetic diagnoses of many ciliopathies remain incomplete (1–3). While various independent approaches theoretically have the potential to reveal the entire list of ciliary genes, approximately 30% of the genes on the ciliary gene list still stand as ciliary candidates (4,5). These methods, however, have mainly relied on a single strategy to uncover ciliary candidate genes, making the categorization challenging due to variations in quality and distinct capabilities demonstrated by different methodologies. Here, we develop a method called CilioGenics that combines several methodologies (single-cell RNA sequencing, protein-protein interactions (PPIs), comparative genomics, transcription factor (TF) network analysis, and text mining) to predict the ciliary capacity of each human gene. Our combined approach provides a CilioGenics score for every human gene that represents the probability that it will become a ciliary gene. Compared to methods that rely on a single method, CilioGenics performs better in its capacity to predict ciliary genes. Our top 500 gene list includes 258 new ciliary candidates, with 31 validated experimentally by us and others. Users may explore the whole list of human genes and CilioGenics scores on the CilioGenics database (https://ciliogenics.com /).
Amelioration potential of synthetic oxime chemical cores against multiple sclerosis and Alzheimer's diseases: Evaluation in aspects of in silico and in vitro experiments
(ELSEVIER, 2024) Yilmaz, Anil; Koca, Murat; Ercan, Selami; Acar, Ozden Ozgun; Boga, Mehmet; Sen, Alaattin; Kurt, Adnan; 0000-0002-8444-376X; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sen, Alaattin
Alzheimer disease (AD) and multiple sclerosis (MS) are inflammatory neurological disorders. The main symptom of AD is dementia, and the main symptoms of MS are vertigo, sexual dysfunction, cognitive problems, and fatigue. Today, millions of people are affected by AD and MS, and the number is growing day by day. However, there are not any accurate remedies for both disorders. For this reason, discovering novel drug molecules against neurological disorders such as AD and MS is essential and precious. Oximes and benzofurans exhibit many pharmacological effects including anti-inflammatory and neurological activities. Thus, several novel compounds bearing oxime and benzofuran chemical cores were designed and synthesized, and their in vitro anticholinesterase activities were investigated in our previous study. A number of the synthesized molecules showed excellent anticholinesterase activity against both AChE and BChE enzymes. The mentioned study constituted a background for this study. In this study, we picked different chemical skeletons among all the synthesized molecules to conduct further in silico and in vitro experiments. In order to support our in vitro anticholinesterase findings, we also examined in silico anti-Alzheimer activity of the selected molecules. In addition, in silico and in vitro activities against MS disease of the synthesized molecules were investigated. Molecule 4 extraordinarily showed outstanding activity against AD disease both in silico and in vitro, as well as in silico activity against MS disease. This feature makes molecule 4 a possible drug lead molecule which is very limited in the market. On the other hand, molecule 1, a less substituted oxime skeleton, demonstrated the strongest in vitro activity against MS disease through in vitro anti-inflammatory effect. As an observation, molecule 4 was determined to be the most promising molecule to focus on in the further steps.
Investigating the Impact of Birt–Hogg–Dubé Syndrome Associated Folliculin (FLCN) and Retinitis Pigmentosa 2 (RP2) Loss on Cilia Function and Morphology
(Cumhuriyet Üniversitesi, 2024) Kaplan, Oktay İsmail; 0000-0002-8733-0920; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Kaplan, Oktay İsmail
Folliculin (FLCN), a GTPase-activating protein (GAP), has been linked to Birt–Hogg–Dubé syndrome, the mTORC1 signaling pathway and cilia. Disruptions in cilia structure and function lead to a group of diseases known as ciliopathies. Birt-Hogg-Dubé syndrome is one of 35 different ciliopathy diseases and there are more than 250 genes that cause ciliopathy diseases. FLCN interacts with kinesin-2 along cilia. The specific role of FLCN in regulating Kinesin-IFT trafficking has, however, remained unclear. In the current study, we investigated the effects of flcn-1 loss (the human ortholog of FLCN) on kinesin and IFT trafficking in C. elegans. The loss of flcn-1 alone did not result in any apparent alterations to kinesin or IFT trafficking within the cilia. However, when we combined the deletion of flcn-1 with the deletion of Retinitis Pigmentosa 2 (RP2), another GAP protein, the ciliary entry of a non-ciliary membrane protein TRAM-1 (Translocation Associated Membrane Protein 1) occured. Additionally, although cilia length was unaltered, our analysis of double mutants revealed the extra branch in wing AWB cilia morphology but not the single rod-like PHA/PHB cilia. In summary, our study reveals the previously unknown functions of FLCN in ciliary gating and cilia morphology in C. elegans
Isothiocyanates as drug candidates in cancer prevention and treatment
(IGI Global, 2023) Saylan, Demet; Cebeci, Fatma; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Saylan, Demet
Cancer is the second most common cause of death worldwide. Many methods such as surgery, chemotherapy, radiation therapy, etc. are being used for treatment. Most patients have a combination treatment with chemotherapy along with surgery or radiotherapy or both. Chemotherapy kills cancer cells by preventing them from reproducing, growing, and spreading in the body. Recently, safer alternatives to chemotherapy have been discovered and developed, as most of the drugs used in cancer treatment have side effects and a serious impact on patient comfort. As an alternative, the phytochemicals found in daily consumed plants are attractive candidates for clinical/pre-clinical evaluation because of their higher safety. In this context, certain degradation products of glucosinolates (isothiocyanates) are promising agents for cancer prevention and treatment.
Pleiotropic molecular effects of dietary polyphenols resveratrol and apigenin in Leukemia
(ELSEVIER, 2018) Adan, Aysun; Oğuz, Osman; 0000-0002-3747-8580; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun; Oğuz, Osman
Resveratrol and apigenin are commonly found polyphenols in many fruits and vegetables and recognition of these dietary polyphenols for human health owing to their biological and pharmacological features including antiinflammatory and antioxidative functions has increased recently. In addition to direct antioxidative effects, they have impacts on various important signaling pathways dysregulated in cancer, genetic and epigenetic regulators, transcription factors and even on miRNAs as anticarcinogenic compounds. Numerous in vitro and in vivo studies have demonstrated their pleiotropic molecular mechanisms of action in cancer, particularly in solid tumors. However, in recent years, significant progress has been made in studying the antileukemic effects of resveratrol and apigenin at the cellular and molecular levels. Herein, we have critically discussed the main molecular targets of resveratrol and apigenin and their promising potential as chemopreventive agents as well as their limitations, with a special emphasis on leukemias.
Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches
(Dove Medical Press Ltd, 2022) Tecik, Melisa; Adan, Aysun; 0000-0002-3747-8580; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun
FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5– 10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and-independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.
Cerium Oxide Nanoparticles Biosynthesized Using Fresh Green Walnut Shell in Microwave Environment and their Anticancer Effect on Breast Cancer Cells
(John Wiley and Sons Inc, 2022) Sulak, Mine; Turgut, Gurbet Celik; Sen, Alaattin; 0000-0002-8444-376X; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sen, Alaattin
In this study, cerium oxide nanoparticles (CONPs) were synthesized using fresh green walnut shell extract in microwave environment. The morphology and structure of the CONPs were determined using ultraviolet-visible (UV/VIS), attenuated total reflection-Fourier transform infrared (ATR-FT-IR), X-ray diffraction (XRD), energy-dispersive X-ray (EDX) spectroscopy, and scanning electron microscopy (SEM). Crystal purple staining, Annexin V-FITC detection, RT-PCR, P53, and NF-κB luciferase reporter assays were performed to evaluate the mechanism of action of CONPs in breast cancer cell lines (MCF7). The biosynthesized CONPs showed cytotoxic effects and induced apoptosis in MCF7 cells. Furthermore, CONPs induced P53 expression and suppressed NF-κB gene expression, both of which were confirmed using reporter assays. Based on the present results, it was concluded that CONPs can induce apoptosis by acting on P53 at the transcriptional level and may cause cell death by suppressing NF-κB-mediated transcription.
Evaluation of Anti-Alzheimer Activity of Synthetic Coumarins by Combination of in Vitro and in Silico Approaches
(John Wiley and Sons Inc, 2022) Erdogan Orhan, Ilkay; Deniz, F. Sezer Senol; Salmas, Ramin Ekhteiari; Irmak, Sule; Acar, Ozden Ozgun; Turgut, Gurbet Celik; Sen, Alaattin; Zbancioc, Ana-Maria; Luca, Simon Vlad; Skalicka-Woźniak, Krystyna; Skiba, Adrianna; Tataringa, Gabriela; 0000-0002-8444-376X; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sen, Alaattin
Series of synthetic coumarin derivatives (1-16) were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes linked to the pathology of Alzheimer's disease (AD). Compound 16 was the most active AChE inhibitor with IC50 32.23±2.91 μM, while the reference (galantamine) had IC50=1.85±0.12 μM. Compounds 9 (IC5075.14±1.82 μM), 13 (IC50=16.14±0.43 μM), were determined to be stronger BChE inhibitors than the reference galantamine (IC50=93.53±2.23 μM). The IC50 value of compound 16 for BChE inhibition (IC50=126.56±11.96 μM) was slightly higher than galantamine. The atomic interactions between the ligands and the key amino acids inside the binding cavities were simulated to determine their ligand-binding positions and free energies. The three inhibitory coumarins (9, 13, 16) were next tested for their effects on the genes associated with AD using human neuroblastoma (SH-SY5Y) cell lines. Our data indicate that they could be considered for further evaluation as new anti-Alzheimer drug candidates.
Synthesis and Comprehensive in Vivo Activity Profiling of Olean-12-en-28-ol, 3β-Pentacosanoate in Experimental Autoimmune Encephalomyelitis: A Natural Remyelinating and Anti-Inflammatory Agent
(American Chemical Society(ACM), 2023) Senol, Halil; Ozgun-Acar, Ozden; Daǧ, Aydan; Eken, Ahmet; Guner, Hüseyin; Aykut, Zaliha Gamze; Topcu, Gulacti; Sen, Alaattin; 0000-0002-8444-376X; 0000-0002-0220-5224; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sen, Alaattin; Güner, Hüseyin
Multiple sclerosis (MS) treatment has received much attention, yet there is still no certain cure. We herein investigate the therapeutic effect of olean-12-en-28-ol, 3β-pentacosanoate (OPCA) on a preclinical model of MS. First, OPCA was synthesized semisynthetically and characterized. Then, the mice with MOG35-55-induced experimental autoimmune/allergic encephalomyelitis (EAE) were given OPCA along with a reference drug (FTY720). Biochemical, cellular, and molecular analyses were performed in serum and brain tissues to measure anti-inflammatory and neuroprotective responses. OPCA treatment protected EAE-induced changes in mouse brains maintaining blood-brain barrier integrity and preventing inflammation. Moreover, the protein and mRNA levels of MS-related genes such as HLD-DR1, CCL5, TNF-α, IL6, and TGFB1 were significantly reduced in OPCA-treated mouse brains. Notably, the expression of genes, including PLP, MBP, and MAG, involved in the development and structure of myelin was significantly elevated in OPCA-treated EAE. Furthermore, therapeutic OPCA effects included a substantial reduction in pro-inflammatory cytokines in the serum of treated EAE animals. Lastly, following OPCA treatment, the promoter regions for most inflammatory regulators were hypermethylated. These data support that OPCA is a valuable and appealing candidate for human MS treatment since OPCA not only normalizes the pro- and anti-inflammatory immunological bias but also stimulates remyelination in EAE.

Browse

Recent Submissions