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
    Virtual Drug Screening Study to Discover Novel ERAP1 Allosteric Site Inhibitors for the Treatment of Ankylosing Spondylitis (AS)
    (Marmara Univ, Fac Pharmacy, 2025-04-08) Portakal, Hüseyin Saygın; Alp, Beste; Akyol, Mertcan
    Endoplasmic reticulum aminopeptidase 1 (ERAP1) is one of the key molecules in the antigen presentation process. To date, associations of ERAP1 with Ankylosing Spondylitis (AS) have been revealed with strong data. As such, to target the allosteric site of ERAP1 exhibits a therapeutic potential in the treatment of AS. In this paper, 9,800 ligands from “FDA-Approved Drugs'', “World-not-FDA Approved Drugs'', and “Drugs in Clinical Trials'' datasets of ZINC15 database were screened to the allosteric site of ERAP1. The best scored drugs are filtered with ADME analysis, the toxicity and bioactivity profiles of the discovered drugs and the known inhibitors were investigated. Results revealed that ZINC000100052688 (Ventavis), ZINC000004217466, and ZINC000024760115 (Dactolicib) follow the Lipinski’s rule of five and have -10.0 kcal/mole, -9.8 kcal/mole, and -9.7 kcal/mole binding affinities to allosteric site of ERAP1, respectively. Furthermore, ZINC000004217466 is the most promising since it has high protease and enzyme inhibitory activity with no toxicity. Due to that to date, only few chemical ligands recognizing ERAP1 regulatory site have been synthesized, to reveal possible repurposable drugs is quite promising, and ZINC000004217466 is the best candidate among 9,800 drugs since it has rather binding affinity, proper chemical properties, no toxicity, and high bioactivity in the inhibition of ERAP1 regulatory site.
  • 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, Gizem
    Objective: 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
    Expressions of the Satellite Repeat Hsat5 and Transposable Elements Are Implicated in Disease Progression and Survival in Glioma
    (Tubitak Scientific & Technological Research Council Turkey, 2024-08-23) Köse, Sıla Naz; Yaraş, Tutku; Bursalı, Ahmet; Oktay, Yavuz; Yandım, Cihangir; Karakulah, Gökhan
    The glioma genome encompasses a complex array of dysregulatory events, presenting a formidable challenge in managing this devastating disease. Despite the widespread distribution of repeat and transposable elements across the human genome, their involvement in glioma's molecular pathology and patient survival remains largely unexplored. In this study, we aimed to characterize the links between the expressions of repeat/transposable elements with disease progression and survival in glioma patients. Hence, we analyzed the expression levels of satellite repeats and transposons along with genes in low-grade glioma (LGG) and high-grade glioma (HGG). Endogenous transposable elements LTR5 and HERV_a-int exhibited higher expression in HGG patients, along with immune response-related genes. Altogether, 16 transposable elements were associated with slower progression of disease in LGG patients. Conversely, 22 transposons and the HSAT5 satellite repeat were linked to a shorter event-free survival in HGG patients. Intriguingly, our weighted gene coexpression network analysis (WGCNA) disclosed that the HSAT5 satellite repeat resided in the same module network with genes implicated in chromosome segregation and nuclear division; potentially hinting at its contribution to disease pathogenesis. Collectively, we report for the first time that repeat and/or transposon expression could be related to disease progression and survival in glioma. The expressions of these elements seem to exert a protective effect during LGG-to-HGG progression, whereas they could have a detrimental impact once HGG is established. The results presented herein could serve as a foundation for further experimental work aimed at elucidating the molecular regulation of glioma genome.
  • Article
    Citation - WoS: 2
    Citation - Scopus: 2
    Right Vagotomy Alters Heart Rate Variability Temporarily and Increases Total Choline Levels in Rats
    (Walter de Gruyter GmbH, 2024-07-01) Barış, Elif; Ozel, Hasan Fehmı; Kazdağlı, Hasan; Özbek, Mustafa
    Objectives: The variability in the time intervals between heartbeats, known as heart rate variability (HRV), serves as a reflection of the intricate interplay between the sympathetic and parasympathetic neural systems. While the potential asymmetric effects of the left and right branches of the vagus nerve remain uncertain, this study aims to investigate the impact of unilateral, bilateral, and atropine interventions on HRV parameters and choline levels within cardiac tissue. Methods: 40 male adult Wistar albino rats were randomly assigned to the five groups (each n=8): sham-operated, atropine, right vagotomy, left vagotomy, and bilateral vagotomy. Heart rate variability (HRV) analyses were conducted, and the levels of total choline/acetylcholine in heart tissues were quantified. Statistical analyses were performed to assess the results. Results: The bilateral vagotomy and atropine groups exhibited higher heart rates and high frequency power (HF), along with reduced low frequency power (LF). Total power (TP) remained relatively unchanged. In the bilateral vagot- omy group, DFAα1 was significantly elevated while DFAα2 was reduced significantly. SD1 and SampEn were significantly lower in both the bilateral vagotomy and atropine groups. Notably, the right vagotomy group displayed significant changes primarily in the 15th minute, particularly in time- domain parameters, HF, TP, and SD1, with a significant in- crease observed in total choline levels. Conclusions: Our results revealed that asymmetrical vagal innervation induces distinct effects on heart rate variability parameters and total choline/acetylcholine levels in heart tissues. Our findings suggest that compensatory hemody- namic recovery, possibly driven by contralateral vagal overactivity, may contribute to these observed results.
  • Article
    Citation - WoS: 1
    Citation - Scopus: 1
    Differential 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 Banu
    Objectives: 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
    Identification of the Role of Tg2 on the Expression of Tgf-Β, Timp-1 and Timp-2 in Aged Skin
    (Walter De Gruyter Gmbh, 2024-02-12) Ergülen, Elvan; Akdoğan, Gül; Guner, Gul Akdogan
    Objectives Transglutaminase 2 (TG2) is a unique protein having enzymatic and nonenzymatic functions that have been implicated in various biological and pathological processes such as cell survival and apoptosis, cell signaling, differentiation, adhesion and migration, wound healing and inflammation. As reported in previous studies, TG2 expression and activity increase by age suggesting that TG2 possibly has roles in cellular aging process. In this study, we aimed to explore the role of TG2 in chronological skin aging through its impact on the expression of some important extracellular matrix (ECM) proteins including TGF-beta, TIMP-1 and TIMP-2. Methods We have compared TG2 expression and activity in young and in vitro chronologically aged human dermal fibroblasts via Western blot and in situ TG2 activity assays. Afterwards, we inhibited TG2 expression via siRNA transfection and activity via active site inhibitor of TG2 separately in aged dermal fibroblasts and monitored the expression levels of TGF-beta, TIMP-1 and TIMP-2 in these cells by Western blot and compared to that of untreated control cells. Results We obtained evidence that both TG2 expression and activity increase in aged cells. However, protein levels of TGF-beta, TIMP-1 and TIMP-2 do not exhibit any significant difference in TG2 downregulated or TG2 activity inhibited aged cells compared to control cells. Conclusions Our results indicate that changes in the expression and activity of TG2 in (in vitro) chronologically aged human dermal fibroblasts do not impact the expression patterns of TGF-beta, TIMP-1 and TIMP-2 proteins.
  • 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, Yağmur
    Objective: 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
    Experimental Intravaginal and Intrauterine Endometritis Model: Which Model Is More Useful?
    (2022-12-31) Beşeren, Hatice; Makav, Mustafa; Kuru, Mushap; Adalı, Yasemen; Coşkun, Mustafa Reha; Eroğlu, Hüseyin Avni
    This study aims to compare the newly created intravaginal endometritis model (IVM) with the intrauterine endometritis model (IUM). E. coli infusion was used as intravaginally for IVM and intrauterinally for IUM model. The animals were exeuted on the 7th day. Histopathological and biochemical analyses [malondialdehyde (MDA), glutathione (GSH), Endocan, Endoglin] were performed. A significant inflammation was determined in IVM and IUM compared to the control. A significant decrease in GSH and a significant increase in MDA and Endoglin were determined in IVM and IUM compared to the control. There was a statistically significant increase in the IUM and a numerical increase in the IVM compared to the control. Endometritis was determined by histopathological and biochemical analyses in both IUM and IVM model. It is suggested that intravaginal administration, which is easier to perform, can be used in experimental endometritis model studies.
  • Article
    Pathological and Biochemical Investigation of the Effects of L-Carnitine and Gemfibrozil on Peroxisome Proliferator Activated Receptors (ppars) and Lipidosis in Rabbits on a High-Fat Diet
    (2022-12-31) Erkılıc, Ekin Emre; Çitil, Mehmet; Tunca, Recai; Uzlu, Erdogan; Karapehlivan, Mahmut; Adalı, Yasemen; Yapar, Kürşad; Eroğlu, Huseyin Avni; Makav, Mustafa
    Obesity and fatty liver is a worldwide health problem in human with detrimental consequences where many investigations are undertaken to overcome this problem. In this study, gemfibrozil and L-carnitine were evaluated in prevention of obesity and lipidosis. The study involved 56 New-Zealand Albino rabbits, divided into 8 equal groups (n=7). The groups were as follow; group I (normal diet), II (normal diet +gemfibrozil), III (normal diet+L-carnitine) and IV (normal diet+gemfibrozil+L- carnitine), V (high fat diet), VI (high fat diet+gemfibrozil), VII (high fat diet+L- carnitine) and VIII (high fat diet+gemfibrozil+L-carnitine). Animals were blood sampled and wieght weekly during the experiment and at the end of the experiment for determination of biochemical parameters (glucose, total lipid). All rabbits were euthanised for histopathological examination and for distrubition of peroxisome proliferator activated receptors (PPARs) in tissues by immunohystochemistry. Gemfibrozil and L-carnitin treatment in rabbits given high fat diet resulted in statistically significant decrease in total lipid when compared to those only received high fat diet. Beta oxidation of high fat diet group was significantly higher than that of groups additionally received gemfibrozil and L-carnitine. Immunohistochemistry revealed an increase in PPAR, PPAR-α and β but not PPAR-γ expression in high fat diet group. On the contrary, L-carnitin administration had no effect on tissue PPAR expression. PPAR-α expression differed between groups received gemfibrozil and high fat diet and those did not. The most marked macroscopy finding was abdominal fat increase in high fat diet group (group V). On the other hand gemfibrozil administration resulted in significant abdominal fat decrease. Furthermore decreased abdominal fat was marked in gemfibrozil and L-carnitine given animals (group VIII) when compared to other groups. In conclusion, gemfibrozil and L-carnitine administration alleviated abdominal and hepatic fattening. Gemfibrozil also caused a significant increase in PPAR-α expression in the liver. It may be of use in avoiding abdominal fat (obesity) due to high fat diet by use of gemfibrozil, a synthetic PPAR-a ligand, and L-carnitine.
  • Article
    Investigation of Cyclin-D1 Immunohistochemical Expression in Bladder Urethelial Carcinoma
    (2023-06-27) Adalı, Yasemen; Ezer, Mehmet; Yılmaz Ertürk, Fatma; Beşeren, Hatice; Ertürk, Fatma Yılmaz
    Objective: Cyclin D1 is a protein that is involved in the regulation of the cell cycle and is encoded by the CCND1 gene. There are few studies on Cyclin D1 in the literature, and the results differ in the studies. In this study, the relationship between Cyclin D1 expression and prognostic factors in bladder urothelial carcinomas was investigated. Materials and Methods: Forty-six patients who underwent TUR-M at the Kafkas University Health Research and Application Hospital were included in the study. General information about the cases and pathology reports were obtained from the hospital automation system. Tumor-containing sections were selected from the Hematoxylin and Eosin stained pathology slides, and immunohistochemical staining was performed manually with Cyclin D1 primary antibody on the blocks of the selected slides. Immunostained pathology slides were evaluated under light microscope by scoring 0-4 separately as nuclear and cytoplasmic scores. Results: The age range of the cases was 51-93, and the mean age was 69.2±11.7. Twelve (26.1%) cases were female and 34 (73.9%) were male. It was observed that 29 (63.0%) of the cases were low- grade and 17 (37.0%) were high-grade. Eighteen (39.1%) of the cases were invasive and 28 (60.9%) were noninvasive. In the statistical analyzes, it was noted that invasive tumors had a significantly higher grade compared to non-invasive tumors (pTa) (p= 0.007). Similarly, the presence of lymphovascular invasion in invasive tumors was statistically <0.005 higher than that of in non- invasive tumors. (p=0.001). It was observed that nuclear cyclin D1 expression (p=0.003) was significantly higher in invasive cases. In addition, nuclear cyclinD1 expression was found to be statistically significantly higher in low-grade tumors (p=0.044). Conclusion: As a result of the study, a relationship between Cyclin D1 expression and tumor grade and invasion status was observed in patients with bladder urothelial carcinoma, but studies with larger case series are needed to use Cyclin D1 as a biomarker.