Moleküler Biyoloji ve Genetik Bölümü Koleksiyonu

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

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Akut Myeloid Lösemi Tedavisi için Hedgehog Ve Otofaji Yolaklarının Düzenlenmesi
(TUBİTAK, 2019) EL KHATIB, Mona; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; EL KHATIB, Mona
Akut 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.
An answer to colon cancer treatment by mesenchymal stem cell originated from adipose tissue
(MASHHAD UNIV MED SCIENCES, VICE-CHANCELLOR FOR RES CTR OFF IJBMS, DANESHGAH ST, PO BOX 9138813944 - 445, MASHHAD, 00000, IRAN, 2018) Iplik, Elif; Ertugrul, Baris; Kozanoglu, İlknur; Baran, Yusuf; Cakmakoglu, Bedia; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü;
Objective(s): Colon cancer is risen up with its complex mechanism that directly impacts on its treatment as well as its common prevalence. Mesenchymal stem cells (MSCs) have been considered as a therapeutic candidate for conventional disease including cancer. In this research, we have focused on apoptotic effects of adipose tissue-derived MSCs in colon cancer. Materials and Methods: MSCs were obtained from adipose tissue and characterized by Flowcytometer using suitable antibodies. MSCs, HT-29, HCT-116, RKO and healthy cell line MRC5 were cultured by different seeding procedure. After cell viability assay, changes in caspase 3 enzyme activity and the level of phosphatidylserine were measured. Results: For cell viability assay, a 48 hr incubation period was chosen to seed all cells together. There was a 1.36-fold decrease in caspase 3 enzyme activity by co-treatment of RKO and MSCs in addition to 2.02-fold decrease in HT-29 and MSCs co-treatment, and 1.103-fold increase in HCT-116 and MSCs. The results demonstrated that HCT-116 led to the highest rate of apoptotic cell death (7.5%) compared with other cells. Conclusion: We suggest that MSCs might remain a new treatment option for cancer by its differentiation and repair capacity.
Apatinib Sensitizes Human Breast Cancer Cells against Navitoclax and Venetoclax Despite Up-regulated Bcl-2 and Mcl-1 Gene Expressions
(KARE PUBLCONCORD ISTANBUL, DUMLUPINAR MAH, CIHAN SK NO 15, B BLOK 162 KADIKOY, ISTANBUL, TURKEY, 2021) Kavakcioglu Yardimci, Berna; Ozgun Acar, Ozden; Semiz, Asli; Sen, Alaattin; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sen, Alaattin
OBJECTIVE 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.
Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells
(SAGE PUBLICATIONS LTD, 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND, 2016) Kiraz, Yagmur; Neergheen-Bhujun, Vidushi S.; Rummun, Nawraj; Baran, Yusuf; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü;
Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.
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.
Biochemical, pharmacological, and toxicological attributes of caper (Capparis ovata) flowering buds and berries pickles
(WILEY, 2022) Ozgun-Acar, Ozden; Celik-Turgut, Gurbet; Guner, Huseyin; Sezer, Serdar; Sen, Alaattin; 0000-0002-8444-376X; 0000-0002-0220-5224; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Güner, Hüseyin; Şen, Alaattin
Capparis ovata is a natural plant that grows widely in Turkey and its flowering buds and berry pickle are used in traditional medicine. Thus, the current study was expanded to evaluate the biochemical, pharmacological, and toxicological aspects of the Capparis ovata water extract (COWE). To determine the biochemical properties of COWE, mineral and fatty acid content, elemental analysis, flavonoid/phenolic content, radicalscavenging capacity, and pesticide analysis were performed. Furthermore, to find out whether it had anti-inflammatory properties, reverse transcription-polymerase chain reaction (RT-PCR) and nuclear factor kappa B (NF-κB) luciferase activity tests were conducted. Whole-genome transcriptomic profiling was carried out at a dose level of 500 mg/kg COWE to understand its pharmacological effect. Transaminases in serum were tested, and quantitative polymerase chain reaction (qPCR) was done using a custom design array that included the stress and molecular toxicology pathway to establish its toxicological qualities. As a result of the evaluations, it was observed that COWE has a high mineral and unsaturated fatty acid content, flavonoid/phenolic content, and radical-scavenging ability. It significantly inhibited NF-κB transcriptional activity as well as inflammatory cytokine expression in T-lymphoblast cells. Wholegenome transcriptomic profiling depicted that COWE modulates immune responses by upregulating natural killer cell activation, cellular response to type I interferon, B-cell proliferation and differentiation, and Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathways. Molecular Toxicology Pathfinder RT2 Profiler PCR array analysis revealed that COWE at or lower dose of 500 mg/kg/day did not cause a comparatively adverse effect. According to the findings, COWE is a rich source of nutrients and can be used as an adjunct therapy for various inflammatory diseases
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 /).
Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells
(De Gruyter, 2022) Adan, Aysun; Şahin, Hande Nur; 0000-0002-3747-8580; 0000-0002-2382-3160; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun; Şahin, Hande Nur
Objectives Therapeutic potential of clinically approved FLT3 inhibitor midostaurin has been neglected in wild-type FLT3 positive acute myeloid leukemia (AML). Sphingosine kinase-1 (SK-1) having anti-proliferative functions is studied in various cancers, but not in FLT3 wild-type AML. We aimed to develop new therapeutic strategies to combat FLT3 wild-type AML by combining midostaurin with SK-1 inhibitor (SKI II) in THP1 cells. Methods The anti-proliferative effects of midostaurin, SKI II and in combination on THP1 cells were determined by MTT assay. The combination indexes were calculated using calcusyn software. SK-1 expression and PARP cleavage were checked by western blot. Cell cycle distributions (PI staining) and apoptosis (annexin-V/PI dual staining) were assessed by flow cytometry for each agent alone and in combinations. Results Midostaurin decreased SK-1 protein level. Midostaurin, SKI II and certain combinations decreased cell viability in a dose dependent manner. The combined anti-leukemic effects of the aforementioned drug combination afforded additive effect. Co-administration induced both necrosis and apoptosis via phosphatidylserine externalization, PARP cleavage and cell cycle arrest at G0/G1 and S phases. Conclusions Targeting sphingosine kinase-1 together with FLT3 inhibition could be a novel mechanism to increase limited clinic response to midostaurin in wild-type FLT3 overexpressing AML after further pre-clinical studies.
Comparative Genomics of Lentilactobacillus parabuchneri isolated from dairy, KEM complex, Makgeolli, and Saliva Microbiomes
(BMC, 2022) Gumustop, Ismail; Ortakci, Fatih; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Ortakçı, Fatih; Gümüştop, İsmail
Background: Lentilactobacillus parabuchneri is of particular concern in fermented food bioprocessing due to causing unwanted gas formation, cracks, and off-flavor in fermented dairy foods. This species is also a known culprit of histamine poisonings because of decarboxylating histidine to histamine in ripening cheese. Twenty-eight genomes in NCBI GenBank were evaluated via comparative analysis to determine genomic diversity within this species and identify potential avenues for reducing health associated risks and economic losses in the food industry caused by these organisms. Result: Core genome-based phylogenetic analysis revealed four distinct major clades. Eight dairy isolates, two strains from an unknown source, and a saliva isolate formed the first clade. Three out of five strains clustered on clade 2 belonged to dairy, and the remaining two strains were isolated from the makgeolli and Korean effective microorganisms (KEM) complex. The third and fourth clade members were isolated from Tete de Moine and dairy-associated niches, respectively. Whole genome analysis on twenty-eight genomes showed similar to 40% of all CDS were conserved across entire strains proposing a considerable diversity among L. parabuchneri strains analyzed. After assigning CDS to their corresponding function, similar to 79% of all strains were predicted to carry putative intact prophages, and similar to 43% of the strains harbored at least one plasmid; however, all the strains were predicted to encode genomic island, insertion sequence, and CRISPR-Cas system. A type I-E CRISPR-Cas subgroup was identified in all the strains, with the exception of DSM15352, which carried a type II-A CRISPR-Cas system. Twenty strains were predicted to encode histidine decarboxylase gene cluster that belongs to not only dairy but also saliva, KEM complex, and unknown source. No bacteriocin-encoding gene(s) or antibiotic resistome was found in any of the L. parabuchneri strains screened. Conclusion: The findings of the present work provide in-depth knowledge of the genomics of L. parabuchneri by comparing twenty-eight genomes available to date. For example, the hdc gene cluster was generally reported in cheese isolates; however, our findings in the current work indicated that it could also be encoded in those strains isolated from saliva, KEM complex, and unknown source. We think prophages are critical mobile elements of L. parabuchneri genomes that could pave the way for developing novel tools to reduce the occurrence of this unwanted species in the food industry.
A comparative study on normal and obese mice indicates that the secretome of mesenchymal stromal cells is influenced by tissue environment and physiopathological conditions
(BMC, CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND, 2020) Ayaz-Guner, Serife; Alessio, Nicola; Acar, Mustafa B.; Aprile, Domenico; Ozcan, Servet; Di Bernardo, Giovanni; Peluso, Gianfranco; Galderisi, Umberto; 0000-0002-1052-0961; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü
Background: The term mesenchymal stromal cells (MSCs) designates an assorted cell population comprised of stem cells, progenitor cells, fibroblasts, and stromal cells. MSCs contribute to the homeostatic maintenance of many organs through paracrine and long-distance signaling. Tissue environment, in both physiological and pathological conditions, may affect the intercellular communication of MSCs. Methods: We performed a secretome analysis of MSCs isolated from subcutaneous adipose tissue (sWAT) and visceral adipose tissue (vWAT), and from bone marrow (BM), of normal and obese mice. Results: The MSCs isolated from tissues of healthy mice share a common core of released factors: components of cytoskeletal and extracellular structures; regulators of basic cellular functions, such as protein synthesis and degradation; modulators of endoplasmic reticulum stress; and counteracting oxidative stress. It can be hypothesized that MSC secretome beneficially affects target cells by the horizontal transfer of many released factors. Each type of MSC may exert specific signaling functions, which could be determined by looking at the many factors that are exclusively released from every MSC type. The vWAT-MSCs release factors that play a role in detoxification activity in response to toxic substances and drugs. The sWAT-MSC secretome contains proteins involved in in chondrogenesis, osteogenesis, and angiogenesis. Analysis of BM-MSC secretome revealed that these cells exert a signaling function by remodeling extracellular matrix structures, such as those containing glycosaminoglycans. Obesity status profoundly modified the secretome content of MSCs, impairing the above-described activity and promoting the release of inflammatory factors. Conclusion: We demonstrated that the content of MSC secretomes depends on tissue microenvironment and that pathological condition may profoundly alter its composition.
Complementary medicines used in ulcerative colitis and unintended interactions with cytochrome P450-dependent drug-metabolizing enzymes
(TUBİTAK, 2022) Şen, Alaattin; 0000-0002-8444-376X; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Şen, Alaattin
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disease with multiple genetic and a variety of environmental risk factors. Although current drugs significantly aid in controlling the disease, many people have led to the application of complementary therapies due to the common belief that they are natural and safe, as well as due to the consideration of the side effect of current drugs. Curcumin, cannabinoids, wheatgrass, Boswellia, wormwood and Aloe vera are among the most commonly used complementary medicines in UC. However, these treatments may have adverse and toxic effects due to unintended interactions with drugs or drugmetabolizing enzymes such as cytochrome P450s; thus, being ignorant of these interactions might cause deleterious effects with severe consequences. In addition, the lack of complete and controlled long-term studies with the use of these complementary medicines regarding drug metabolism pose additional risk and unsafety. Thus, this review aims to give an overview of the potential interactions of drug-metabolizing enzymes with the complementary botanical medicines used in UC, drawing attention to possible adverse effects.
Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection
(PEERJ INC, 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND, 2020) Demirci, Muserref Duygu Sacar; Adan, Aysun; 0000-0003-2012-0598; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression found in more than 200 diverse organisms. Although it is still not fully established if RNA viruses could generate miRNAs, there are examples of miRNA like sequences from RNA viruses with regulatory functions. In the case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there are several mechanisms that would make miRNAs impact the virus, like interfering with viral replication, translation and even modulating the host expression. In this study, we performed a machine learning based miRNA prediction analysis for the SARS-CoV-2 genome to identify miRNA-like hairpins and searched for potential miRNA-based interactions between the viral miRNAs and human genes and human miRNAs and viral genes. Overall, 950 hairpin structured sequences were extracted from the virus genome and based on the prediction results, 29 of them could be precursor miRNAs. Targeting analysis showed that 30 viral mature miRNA-like sequences could target 1,367 different human genes. PANTHER gene function analysis results indicated that viral derived miRNA candidates could target various human genes involved in crucial cellular processes including transcription, metabolism, defense system and several signaling pathways such as Wnt and EGFR signalings. Protein class-based grouping of targeted human genes showed that host transcription might be one of the main targets of the virus since 96 genes involved in transcriptional processes were potential targets of predicted viral miRNAs. For instance, basal transcription machinery elements including several components of human mediator complex (MED1, MED9, MED 12L, MED 19), basal transcription factors such as TAF4, TAF5, TAF7L and site-specific transcription factors such as STATI were found to be targeted. In addition, many known human miRNAs appeared to be able to target viral genes involved in viral life cycle such as S, M, N, E proteins and ORF lab, ORF3a, ORF8, ORF7a and ORF10. Considering the fact that miRNA-based therapies have been paid attention, based on the findings of this study, comprehending mode of actions of miRNAs and their possible roles during SARS-CoV-2 infections could create new opportunities for the development and improvement of new therapeutics.
COMPUTATIONAL IDENTIFICATION OF MICRORNAS FROM SSDNA VIRUSES
(Eskişehir Teknik Üniversitesi, 2018) Saçar Demirci, Müşerref Duygu; 0000-0003-2012-0598; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Saçar Demirci, Müşerref Duygu
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and the fact that they are associated with various disease phenotypes is one of the main reasons for their importance. The complexity of experimental detection of miRNAs due to their characteristics led to the development of computational methods. In this work, a machine learning based approach was applied to identify and analyze potential miRNAs that might be originated from 60 single strand DNA (ssDNA) viruses’ genomes. The results suggest that 53 of these viruses may possibly produce proper miRNA precursors. Moreover, the possibility of these candidate miRNA precursors’ ability to generate mature miRNAs that could target human genes and viral genomes has been tested. Overall, the outcomes of this research indicate that there might be another level of host-virus interaction through miRNAs which requires further experimental confirmation.
Cytotoxic and Cytostatic Effects of Targeting mTOR and Hedgehog Pathways in Acute Myeloid Leukemia
(İstanbul Üniversitesi Yayınevi, 2022) Çiçek, Enes; Kucuktas, Fulya Mina; Yenigul, Munevver; Gencer Akcok, Emel Basak; 0000-0002-7452-2253; 0000-0001-7682-4012; 0000-0003-0468-721X; 0000-0002-6559-9144; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Çiçek, Enes; Kucuktas, Fulya Mina; Yenigul, Munevver; Gencer Akcok, Emel Basak
Objectives: 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.
Cytotoxic Effects of Resveratrol and Its Combinations with Ceramide Metabolism Inhibitors on FLT3 Positive Acute Myeloid Leukemia
(DergiPark, 2020) ERSÖZ, Nur Şebnem; ADAN, Aysun; https://orcid.org/0000-0002-3747-8580; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; ADAN, Aysun
Sphingolipids determine the cell fate by regulating cell proliferation and growth. Ceramide, growth inhibitory lipid, might be produced through de novo pathway or salvage pathway, which is converted to proliferation inducers sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3 overexpressing acute myeloid leukemia (AML) cells by pharmacological targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SK inhibitor (SKI II), GCS inhibitor (PDMP) and the combinations of resveratrol with SK-1 inhibitor and GCS inhibitor on THP-1 and OCI-AML3 FLT3 overexpressing AML cells were investigated by MTT cell viability assay in a time- and concentration-dependent manner. Apoptotic effect of resveratrol was analyzed by annexin V/PI double staining using flow cytometry. Resveratrol decreased cell viability and induced apoptosis in both cell lines (p<0.05 considered significant). There were synergistic cytotoxic effects of resveratrol with co-administration of SK-1 inhibitor and GCS inhibitor at 48 h (p<0.05 considered significant). This preliminary data showed for the first time that resveratrol might inhibit the viability of FLT3 overexpressing AML cells through targeting ceramide metabolism and inducing apoptosis, which needs to be further clarified mechanistically.
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.
Dual Targeting of DNA Damage Response Proteins Implicated in Cancer Radioresistance
(Multidisciplinary Digital Publishing Institute (MDPI), 2023) Vasilopoulos, Spyridon N.; Güner, Hüseyin; Uça Apaydın, Merve; Pavlopoulou, , Athanasia; Georgakilas, Alexandros G.; 0000-0002-0220-5224; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Güner, Hüseyin
Ionizing radiation can induce different types of DNA lesions, leading to genomic instability and ultimately cell death. Radiation therapy or radiotherapy, a major modality in cancer treatment, harnesses the genotoxic potential of radiation to target and destroy cancer cells. Nevertheless, cancer cells have the capacity to develop resistance to radiation treatment (radioresistance), which poses a major obstacle in the effective management of cancer. It has been shown that administration of platinum-based drugs to cancer patients can increase tumor radiosensitivity, but despite this, it is associated with severe adverse effects. Several lines of evidence support that activation of the DNA damage response and repair machinery in the irradiated cancer cells enhances radioresistance and cellular survival through the efficient repair of DNA lesions. Therefore, targeting of key DNA damage repair factors would render cancer cells vulnerable to the irradiation effects, increase cancer cell killing, and reduce the risk of side effects on healthy tissue. Herein, we have employed a computeraided drug design approach for generating ab initio a chemical compound with drug-like properties potentially targeting two proteins implicated in multiple DNA repair pathways. The findings of this study could be taken into consideration in clinical decision-making in terms of co-administering radiation with DNA damage repair factor-based drugs
Effect of Molecular Architecture on Cell Interactions and Stealth Properties of PEG
(AMER CHEMICAL SOC1155 16TH ST, NW, WASHINGTON, DC 20036, 2017) Ozer, Imran; Tomak, Aysel; Zareie, Hadi M.; Baran, Yusuf; Bulmus, Volga; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Baran, Yusuf
PEGylation, covalent attachment of PEG to therapeutic biomolecules, in which suboptimal pharmacokinetic profiles limiting their therapeutic utility are of concern, is a widely applied technology. However, this technology has been challenged by reduced bioactivity of biomolecules upon PEGylation and immunogenicity of PEG triggering immune response and abrogating clinical efficacy, which collectively necessitate development of stealth polymer alternatives. Here we demonstrate that comb-shape poly[oligo(ethylene glycol) methyl ether methacrylate](POEGMA); a stealth polymer alternative, has a more compact structure than PEG and self-organize into nanoparticles in a molecular weight dependent manner. Most notably, we show that comb shape POEGMA promotes significantly higher cellular uptake and exhibits less steric hindrance imposed on the conjugated biomolecule than PEG. Collectively, comb-shape POEGMA offers a versatile alternative to PEG for stealth polymer-biomolecule conjugation applications.
Effects of cell-mediated osteoprotegerin gene transfer and mesenchymal stem cell applications on orthodontically induced root resorption of rat teeth
(OXFORD UNIV PRESS, GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND, 2017) Amuk, Nisa Gul; Kurt, Gokmen; Baran, Yusuf; Seyrantepe, Volkan; KARTAL YANDIM, Melis; Adan, Aysun; Akyildiz Demir, Secil; Kiraz, Yagmur; Sonmez, Mehmet Fatih; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü;
Aim: The aim of this study is to evaluate and compare therapeutic effects of mesenchymal stem cell (MSCs) and osteoprotegerin (OPG) gene transfer applications on inhibition and/or repair of orthodontically induced inflammatory root resorption (OIIRR). Materials and methods: Thirty Wistar rats were divided into four groups as untreated group (negative control), treated with orthodontic appliance group (positive control), MSCs injection group, and OPG transfected MSCs [gene therapy (GT) group]. About 100 g of orthodontic force was applied to upper first molar teeth of rats for 14 days. MSCs and transfected MSC injections were performed at 1st, 6th, and 11th days to the MSC and GT group rats. At the end of experiment, upper first molar teeth were prepared for genetical, scanning electron microscopy (SEM), fluorescent microscopy, and haematoxylin eosin-tartrate resistant acid phosphatase staining histological analyses. Number of total cells, number of osteoclastic cells, number of resorption lacunae, resorption area ratio, SEM resorption ratio, OPG, RANKL, Cox-2 gene expression levels at the periodontal ligament (PDL) were calculated. Paired t-test, Kruskal-Wallis, and chi-square tests were performed. Results: Transferred MSCs showed marked fluorescence in PDL. The results revealed that number of osteoclastic cells, resorption lacunae, resorption area ratio, RANKL, and Cox-2 were reduced after single MSC injections significantly (P < 0.05). GT group showed the lowest number of osteoclastic cells (P < 0.01), number of resorption lacunae, resorption area ratio, and highest OPG expression (P < 0.001). Conclusions: Taken together all these results, MSCs and GT showed marked inhibition and/or repair effects on OIIRR during orthodontic treatment on rats.
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.

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