WoS İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/394
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Article Citation - WoS: 1Citation - Scopus: 1Targeting Cholinergic Dysfunction and Neuroinflammation through Rationally Designed Thieno[3,2-d]Pyrimidine Hybrids(Academic Press Inc Elsevier Science, 2026-07) Acar, Ozden Ozgun; Acar, Busra; Senol, Halil; Tokali, Feyzi Sinan; Sen, Alaattin; Demir, Yeliz; Cakir, FurkanNeurodegenerative diseases involve the convergence of cholinergic dysfunction, neuronal loss, and sustained neuroinflammatory responses, necessitating the development of multifunctional therapeutic agents. In this study, a series of novel thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids were rationally designed, synthesized, and evaluated as dual cholinesterase inhibitors with neuroprotective and anti-neuroinflammatory potential. The synthesized compounds exhibited potent inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with inhibition constants in the low nanomolar range. Among them, compounds 5 and 9 emerged as the most active derivatives, displaying Ki values of 8.79 and 14.11 nM for AChE and 7.04 and 11.75 nM for BChE, surpassing the reference inhibitors tacrine and donepezil. Molecular docking and molecular dynamics simulations supported the experimental findings, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations further confirmed their superior binding affinities compared with donepezil. Cytotoxicity profiling in SH-SY5Y neuronal cells and RAW 264.7 and THP-1 immune cells identified a narrow sub-cytotoxic concentration window (EC05-EC10 = 1.2-2.1 mu M), ensuring biological effects independent of nonspecific cell damage. Within this range, both compounds exerted pronounced antineuroinflammatory activity. Notably, compound 9 significantly downregulated pro-inflammatory mediators, reducing IL-1 beta, IL-6, and NF-kappa B1 gene expression by up to 2.78-, 3.37-, and 4.84-fold, respectively. Consistently, it suppressed nitric oxide production in LPS-stimulated macrophages to levels comparable with ascorbic acid and markedly decreased Iba1 expression in activated THP-1 cells. This integrated enzymatic, computational, and cellular investigation identifies compounds 5 and 9 as promising multifunctional lead combining dual cholinesterase inhibition with robust anti-neuroinflammatory activity. The results provide a strong foundation for future in vivo studies and further optimization toward disease-modifying agents for neurodegenerative disorders.Article Citation - WoS: 14Citation - Scopus: 15Triterpenoids and Steroids Isolated from Anatolian Capparis Ovata and Their Activity on the Expression of Inflammatory Cytokines(Taylor & Francis Ltd, 2020-01-01) Gazioglu, Isil; Semen, Sevcan; Acar, Ozden Ozgun; Kolak, Ufuk; Sen, Alaattin; Topcu, GulactiContext CapparisL. (Capparaceae) is grown worldwide. Caper has been used in traditional medicine to treat various diseases including rheumatism, kidney, liver, stomach, as well as headache and toothache. Objective To isolate and elucidate of the secondary metabolites of theC. ovataextracts which are responsible for their anti-inflammatory activities. Materials and methods Buds, fruits, flowers, leaves and stems ofC. ovataDesf. was dried, cut to pieces, then ground separately. From their dichloromethane/hexane (1:1) extracts, eight compounds were isolated and their structures were elucidated by NMR, mass spectroscopic techniques. The effects of compounds on the expression of inflammatory cytokines in SH-SY5Y cell lines were examined by qRT-PCR ranging from 4 to 96 mu M. Cell viability was expressed as a percentage of the control, untreated cells. Results This is a first report on isolation of triterpenoids and steroids fromC. ovatawith anti-inflammatory activity. One new triterpenoid ester olean-12-en-3 beta,28-diol, 3 beta-pentacosanoate (1) and two new natural steroids 5 alpha,6 alpha-epoxycholestan-3 beta-ol (5) and 5 beta,6 beta-epoxycholestan-3 beta-ol (6) were elucidated besides known compounds; oleanolic acid (2), ursolic acid (3), beta-sitosterol (4), stigmast-5,22-dien-3 beta-myristate (7) and bismethyl-octylphthalate (8). mRNA expression levels as EC(10)of all the tested seven genes were decreased, particularly CXCL9 (19.36-fold), CXCL10 (8.14-fold), and TNF (18.69) by the treatment of 26 mu M of compound1on SH-SY5Y cells. Discussion and conclusions Triterpenoids and steroids isolated fromC. ovatawere found to be moderate-strong anti-inflammatory compounds. Particularly, compounds1and3were found to be promising therapeutic agents in the treatment of inflammatory and autoimmune diseases.Article Citation - WoS: 22Citation - Scopus: 26Suppression of Inflammatory Cytokines Expression With Bitter Melon (Momordica Charantia) in TNBS-Instigated Ulcerative Colitis(Sciendo, 2020-09-01) Semiz, Asli; Acar, Ozden Ozgun; Cetin, Hulya; Semiz, Gurkan; Sen, AlaattinBackground and Objective: This study was aimed to elucidate the molecular mechanism of Momordica charantia (MCh), along with a standard drug prednisolone, in a rat model of colitis induced by trinitrobenzene sulfonic acid (TNBS). Methods: After the induction of the experimental colitis, the animals were treated with MCh (4 g/kg/day) for 14 consecutive days by intragastric gavage. The colonic tissue expression levels of C-C motif chemokine ligand 17 (CCL-17), interleukin (IL)-1 beta, IL-6, IL-23, interferon-gamma (IFN-gamma), nuclear factor kappa B (NFkB), and tumor necrosis factor-alpha (TNF-alpha), were determined at both mRNA and protein levels to estimate the effect of MCh. Besides, colonic specimens were analyzed histopathologically after staining with hematoxylin and eosin. Results: The body weights from TNBS-instigated colitis rats were found to be significantly lower than untreated animals. Also, the IFN-gamma, IL-1 beta, IL-6, Il-23, TNF-alpha, CCL-17, and NF-kB mRNA and protein levels were increased significantly from 1.86-4.91-fold and 1.46-5.50-fold, respectively, in the TNBS-instigated colitis group as compared to the control. Both the MCh and prednisolone treatment significantly reduced the bodyweight loss. It also restored the induced colonic tissue levels of IL-1 beta, IL-6, IFN-gamma, and TNF-alpha to normal levels seen in untreated animals. These results were also supported with the histochemical staining of the colonic tissues from both control and treated animals. Conclusion: The presented data strongly suggests that MCh has the anti-inflammatory effect that might be modulated through vitamin D metabolism. It is the right candidate for the treatment of UC as an alternative and complementary therapeutics.Article Citation - WoS: 4Citation - Scopus: 4Natural Diterpenoid Alysine a Isolated from Teucrium Alyssifolium Exerts Antidiabetic Effect via Enhanced Glucose Uptake and Suppressed Glucose Absorption(Tubitak Scientific & Technological Research Council Turkey, 2019-10-07) Sen, Alaattin; Ayar, Buket; Yilmaz, Anil; Acar, Ozden Ozgun; Turgut, Gurbet Celik; Topcu, GulactiTeucrium species have been used in folk medicine as antidiabetic, antiinflammatory, antiulcer, and antibacterial agents. We have explored in vitro antidiabetic impacts of 2 natural diterpenoids, alysine A and alysine B, isolated from Teucrium alyssifolium. The lactate dehydrogenase (LDH) cytotoxicity assay, glucose uptake test, glucose utilization (glycogen content) test, glucose transport test, glucose absorption (a-glucosidase activity) test, insulin secretion test, RNA isolation and cDNA synthesis assay, qPCR quantification assays, and statistical analyses were carried out in the present study. Alysine A exerted the following effects at non-cytotoxic doses: Enhanced the glucose uptake, as much as the insulin in the C2C12, HepG2, and 3T3-L1 cells Increased the glycogen content in the C2C12 and HepG2 liver cells, significantly higher than the insulin and metformin Suppressed the alpha-glucosidase and the GLUT2 expression levels in the Caco-2 cells Suppressed the SGLT1 and GLUT1-5 expression levels in the Caco-2 cells Induced the insulin receptor substrate (IRS)1 and GLUT2 expression levels of the BTC6 pancreatic cells Induced the insulin receptor (INSR), IRS2, phosphoinositide 3-kinase (PI3K), GLUT4, and protein kinase (PK) expression levels of the 3T3-L1 and C2C12 cells Increased glucose transport through the Caco-2 cell layer Did not influence insulin secretion in the pancreatic BTC6 cells Consequently, these data strongly emphasized the antidiabetic action of alysine A on the particularly critical model mechanisms that assume a part in glucose homeostasis, such as glucose uptake, utilization, and storage. Moreover, the expression level of the essential genes in glucose metabolism and insulin signaling was altered in a way that the results would be antihyperglycemic. A blend of in vitro and in situ tests affirmed the antihyperglycemic action of alysine A and its mechanism. Alysine A has exercised significant and positive results on the glucose homeostasis; thus, it is a natural and pleiotropic antidiabetic agent. Advanced in vivo studies are required to clarify the impact of this compound on glucose homeostasis completely.Article Citation - WoS: 6Citation - Scopus: 8Evaluation of Anti-Alzheimer Activity of Synthetic Coumarins by Combination of in Vitro and in Silico Approaches(Wiley-VCH Verlag GmbH, 2022-11-14) Orhan, Ilkay Erdogan; Deniz, F. Sezer Senol; Salmas, Ramin Ekhteiari; Irmak, Sule; Acar, Ozden Ozgun; Turgut, Gurbet Celik; Tataringa, Gabriela; Erdogan Orhan, IlkaySeries 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 mu M, while the reference (galantamine) had IC50=1.85 +/- 0.12 mu M. Compounds 9 (IC(50)75.14 +/- 1.82 mu M), 13 (IC50=16.14 +/- 0.43 mu M), were determined to be stronger BChE inhibitors than the reference galantamine (IC50=93.53 +/- 2.23 mu M). The IC50 value of compound 16 for BChE inhibition (IC50=126.56 +/- 11.96 mu M) 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.Article Apatinib Sensitizes Human Breast Cancer Cells Against Navitoclax and Venetoclax Despite Up-Regulated Bcl-2 and Mcl-1 Gene Expressions(Kare Publ, 2021) Kavakcioglu Yardimci, Berna; Ozgun Acar, Ozden; Semiz, Asli; Sen, Alaattin; Acar, Ozden Ozgun; Yardımcı, Berna KavakcıoğluOBJECTIVE 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.