PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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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 A Small Indole Derivative Isolated From Caper (Capparis Ovata) as an Inducer of P53-Mediated Apoptosis in Prostate Cancer: Comprehensive In Vitro and In Silico Studies(Wiley, 2025-12-31) Acar, Ozden Ozgun; Gazioglu, Isil; Oruc, Hatice; Kale, Elif; Senol, Halil; Topcu, Gulacti; Sen, AlaattinNatural products with stunning chemical diversity have been extensively researched for their anticancer potential for more than fifty years. This study aimed to determine the effect of indole derivative 1H-indole-2-hydroxy-3-carboxylic acid (IHCA), isolated as a novel alkaloid from Capparis ovata, on selected tumor suppressor, apoptotic, and cell cycle regulatory genes, which are known to be important in cancer pathophysiology, on Caco-2 and LNCaP cells in comparison with Taxol. The molecular mechanism of IHCA's anticancer activity is essentially undefined. Different concentrations of IHCA increased the expression levels of apoptosis-related genes, including BCL-2 and TNF-alpha. In addition, the tumor suppressor genes PTEN, P53, and RB were increased in LNCaP and Caco-2 cells. KRAS, an oncogenic gene, was significantly downregulated by IHCA in LNCaP cells. Western blot results showed that the protein expression levels of P53 and PTEN in LNCaP cells were increased when treated with IHCA, whereas CDK4 and TNF-alpha were decreased. Finally, IHCA and doxorubicin significantly increased P53-driven luciferase activity compared to the control. The results strongly suggest that the novel natural compound IHCA has an anticancer effect involving the regulation of the P53 gene and its networks in vitro. The molecular docking and MD simulation analyses reveal that IHCA exhibits superior binding potential to the MDM2 protein compared to Nutlin-3a. MD simulations further confirm that IHCA maintains a more stable and consistent interaction with MDM2, as indicated by lower RMSD values and reduced ligand fluctuation. These results highlight IHCA's potential as a more effective MDM2 inhibitor, suggesting its promise as a lead compound for anticancer drug development.Clinical Trial Registration: Not applicable.Article Citation - WoS: 2Citation - Scopus: 2Neuroinflammatory Human Brain Organoids Enable Comprehensive Drug Screening Studies: Fingolimod and Its Analogues in Focus(Bentham Science Publishing Ltd, 2025-10-08) Acar, Busra; Pepe, Nihan Aktas; Zivkovic, Aleksandra; Stark, Holger; Sen, AlaattinIntroduction The absence of physiologically relevant models for neuroinflammatory brain disorders, such as multiple sclerosis (MS), highlights the need for improved drug screening platforms. To bridge this gap, this study aimed to develop a human brain organoid (hBO) model incorporating essential neural cell types, including astrocytes, microglia, and oligodendrocytes.Methods hBOs were generated from H9 stem cells, and neuroinflammatory characteristics were elicited by lipopolysaccharide (LPS). The expression of specific neuronal and inflammatory markers was assessed through qRT-PCR, immunofluorescence staining (IFS), and ELISA.Results IFS of mature hBOs with anti-SOX2, anti-SATB2, anti-MAPT, anti-GFAP, anti-MBP, and anti-IBA1 antibodies and images collected with the confocal microscope confirmed the differentiation of H9 cells into cortical neurons, astrocytes, microglia, and oligodendrocyte cell types. Elevated GFAP, IBA1, NF-kappa B, and IL-6 levels, along with reduced CNPase expression with LPS treatment, were considered reflective of MS-like pathology and were used to test fingolimod and its derivatives. Fingolimod and all its derivatives, specifically ST-1505, decreased MAPT (2.1-fold in ELISA, 1.7-fold in IFS), GFAP (1.8-fold in IFS), TNF alpha (5.4-fold in qRT-PCR), and FABP (1.5-fold in ELISA) levels, and increased IL-10 (11-fold in qRT-PCR) and MBP (2.9-fold in IFS) levels.Discussion The present data collectively showed LPS to evoke neuroinflammation in the hBO model, while fingolimod and its derivatives, particularly ST-1505, exhibited significant anti-inflammatory and neuroprotective properties by counteracting these evoked changes in the hBO model.Conclusion The findings supported the applicability of brain organoids as a model system for drug screening studies for neuroinflammatory brain diseases.Article Citation - WoS: 6Citation - Scopus: 7Therapeutic Potential of Nitrogen-Substituted Oleanolic Acid Derivatives in Neuroinflammatory and Cytokine Pathways: Insights From Cell-Based and Computational Models(Wiley-VCH Verlag GmbH, 2025-04-22) Turgut, Gurbet Celik; Pepe, Nihan Aktas; Ekiz, Yagmur Ceylan; Senol, Halil; Sen, AlaattinThis study was conducted to investigate the mechanism of the potential and anti-inflammatory properties of nitrogen-substituted oleanolic acid derivatives that can be used to treat neuroinflammatory diseases. Nitrogen-containing oleanolic acid derivatives have been evaluated for their anti-neuroinflammatory effects in vitro in neuronal and monocytic cell lines at nontoxic doses, and the production of cytokines (TNF-alpha, IL-6 and IL-17), the inflammatory enzyme induced nitric oxide synthase (iNOS) and NF-kappa B signalling under LPS-stimulated conditions, and the expression of genes associated with Alzheimer's disease have been assessed. In addition, molecular docking and molecular dynamics simulation assessments are conducted in silico. Key protein markers of neurodegenerative diseases, especially Alzheimer's disease and neuroinflammation, TAU protein levels, and microglial activation, as well as ionised calcium-binding adaptor protein-1 (IBA1) levels, were significantly reduced with the addition of oleanolic acid derivatives. LPS-induced NF-kappa B luciferase reporter activity and iNOS activity were significantly inhibited, approaching the levels in uninduced controls. The mRNA expression of proinflammatory cytokines critical for neuroinflammation, such as TNF-alpha, NF-kappa B, IL-6 and IL-17, was reduced twofold to sevenfold. Furthermore, the molecular docking and MD simulation analyses revealed potential interactions with the TNF-alpha and NF-kappa B proteins. These findings underscore the potential of oleanolic acid derivatives, particularly compound 16, as candidates for further development as therapeutic agents for neurodegenerative diseases associated with chronic inflammation.Article Citation - WoS: 1Citation - Scopus: 1Synthesis, Characterization, and Comprehensive in Vitro and in Silico Evaluation of the Anti-Inflammatory Potential of Novel 1,2,3-Triazole–Arylidenehydrazide/Thiazolidinone Hybrids(Wiley-VCH verlag GmbH, 2025-09) Pepe, Nihan Aktas; Cakir, Furkan; Atalay, Tugba; Acar, Busra; Turgut, Gurbet Celik; Sen, Alaattin; Senol, HalilFive novel 1,2,3-triazole/arylidenehydrazide/thiazolidinone hybrid compounds (7-11) were synthesized and characterized using NMR, HRMS, IR, and HPLC purity analysis. The cytotoxicity of these compounds was evaluated on fibroblasts and THP-1 cells, showing that all compounds were nontoxic at the tested concentrations. The wound healing assay revealed that compounds 7, 9, and 10 significantly enhanced wound closure, with a 7.74%-32.69% improvement in treated cells. Compounds 8 and 11 showed moderate effects. Anti-inflammatory activity was assessed through qRT-PCR, demonstrating that compound 10 led to the most significant reduction in proinflammatory cytokines TNF-alpha, IL-1 beta, and NF-kappa B1. In addition, the expression of Iba1 protein in THP-1 cells confirmed that compound 8 showed the strongest anti-inflammatory effect, surpassing that of aspirin. Compound 10 showed the highest inhibition of NF-kappa B signaling and iNOS activity. Molecular docking studies revealed that compounds 10 and 11 had strong binding affinities to TNF-alpha and iNOS, with compound 11 showing the most stable interactions. Molecular dynamics simulations supported these findings, indicating that compound 11 demonstrated more stable binding to both targets. Overall, the results suggest that compounds 10 and 11 are promising anti-inflammatory candidates with potential for further development in therapeutic applications for inflammatory diseases.Article Role of Long Non-Coding RNA X-Inactive Transcript (XIST) in Neuroinflammation and Myelination: Insights From Cerebral Organoids and Implications for Multiple Sclerosis(MDPI, 2025-04-29) Pepe, Nihan Aktas; Acar, Busra; Zararsiz, Gozde Erturk; Guner, Serife Ayaz; Sen, Alaattin; Erturk Zararsiz, Gozde; Ayaz Guner, Serife; Aktas Pepe, NihanBackground/Objectives: X-inactive-specific transcript (XIST) is a factor that plays a role in neuroinflammation. This study investigated the role of XIST in neuronal development, neuroinflammation, myelination, and therapeutic responses within cerebral organoids in the context of Multiple Sclerosis (MS) pathogenesis. Methods: Human cerebral organoids with oligodendrocytes were produced from XIST-silenced H9 cells, and the mature organoids were subsequently treated with either FTY720 or DMF. Gene expression related to inflammation and myelination was subsequently analyzed via qRT-PCR. Immunofluorescence staining was used to assess the expression of proteins related to inflammation, myelination, and neuronal differentiation. Alpha-synuclein protein levels were also checked via ELISA. Finally, transcriptome analysis was conducted on the organoid samples. Results: XIST-silenced organoids presented a 2-fold increase in the expression of neuronal stem cells, excitatory neurons, microglia, and mature oligodendrocyte markers. In addition, XIST silencing increased IL-10 mRNA expression by 2-fold and MBP and PLP1 expression by 2.3- and 0.6-fold, respectively. Although XIST silencing tripled IBA1 protein expression, it did not affect organoid MBP expression. FTY720, but not DMF, distinguished MBP and IBA1 expression in XIST-silenced organoids. Furthermore, XIST silencing reduced the concentration of alpha-synuclein from 300 to 100 pg/mL, confirming its anti-inflammatory role. Transcriptomic and gene enrichment analyses revealed that the differentially expressed genes are involved in neural development and immune processes, suggesting the role of XIST in neuroinflammation. The silencing of XIST modified the expression of genes associated with inflammation, myelination, and neuronal growth in cerebral organoids, indicating a potential involvement in the pathogenesis of MS. Conclusions: XIST may contribute to the MS pathogenesis as well as neuroinflammatory diseases such as and Alzheimer's and Parkinson's diseases and may be a promising therapeutic target.Article Citation - Scopus: 1Possible Drug-Drug Interactions Between Mesalamine and Tricyclic Antidepressants Through CYP2D6 Metabolism - in Silico and in Vitro Analyses(Georg Thieme Verlag, 2025-04-01) Ozen, Melek B.; Gazioğlu, Işil; Ozgun-Acar, Özden; Guner, Hüseyin; Semiz, Gürkan; Sen, Alaattin; Ozgun Acar, OzdenMesalamine (mesalazine, 5-aminosalicylic acid, 5-ASA) is an essential anti-inflammatory agent both used for therapy and as a remission control in patients with inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). Tricyclic antidepressants (TCAs) are used to alleviate remaining symptoms in patients already receiving IBD therapy or with quiescent inflammation. The cytochrome P4502D6 enzyme is involved in the metabolism of TCAs. Hence, it is crucial to investigate the role of CYP2D6 in 5-ASA metabolism. Initially, in silico analysis involving the docking of 5-ASA to CYP2D6 and molecular dynamics simulations was conducted. Next, the rate of O-demethylation of a nonfluorescent probe 3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin (AMMC) into a fluorescent metabolite AMHC (3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-hydroxy-4-methylcoumarin) was optimized with baculosomes co-expressing human CYP2D6 and human P450 oxidoreductase (hCPR) to monitor CYP2D6 activity in a microtiter plate assay. The apparent Km and Vmax were found to be 1.30 μM and 32.68 pmol/min/mg of protein for the O-demethylation of AMMC to AMHC, and the reaction was linear for 40 min. Then, nonselective inhibition of CYP2D6 activity with various concentrations of 5-ASA was detected. Finally, the conversion of AMMC to metabolites was analyzed by HPLC-ESI-MS/MS spectrometry, and none were identified. Thus, this study suggests that concurrent use of mesalamine with TCA may lead to adverse effects, and CYP2D6 genotyping should be routinely performed on these patients to eliminate possible threats. © 2025 Elsevier B.V., All rights reserved.Article Citation - WoS: 4Citation - Scopus: 4Evaluation of Selected Plant Phenolics Via Beta-Secretase Inhibition, Molecular Docking, and Gene Expression Related to Alzheimer's Disease(MDPI, 2024-10-28) Akyurek, Tugba Ucar; Orhan, Ilkay Erdogan; Deniz, F. Sezer Senol; Eren, Gokcen; Acar, Busra; Sen, Alaattin; Şenol Deniz, F. Sezer; Uçar Akyürek, TugbaBackground: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as beta-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer's disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC50 values 4.06 +/- 0.68, 1.62 +/- 0.12, 9.87 +/- 1.01, and 3.16 +/- 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors.Article Citation - WoS: 2Citation - Scopus: 2Cinnamomum Zeylanicum Extract Incorporated Electrospun Poly(Lactic Acid)/ Gelatin Membrane as a New Wound Dressing(Elsevier, 2025-08) Tarhan, Seray Zora; Pepe, Nihan Aktas; Sen, Alaattin; Isoglu, Ismail AlperIn this study, we fabricated poly(lactic acid)/gelatin electrospun membranes containing various concentrations of Cinnamomum zeylanicum extract and evaluated them as a novel wound dressing. The electrospun membranes were chemically, morphologically, and mechanically characterized, and the results were discussed in comparison with the literature. Electrospun membranes' biodegradability, swelling, and release properties were evaluated, with the CE7.5 membrane having values of 29.60 f 7.20 and 542.1 f 48.3 % and 66.9 %, respectively. Antibacterial activity was observed in CE7.5 and CE10 membranes against E. coli and S. aureus strains. At the highest concentration (CE10), 111.7 f 5.6 % and 96 f 12.375 % cell viability were detected in fibroblasts and differentiated LPS-induced THP-1 cells. Cell viability was further evaluated by Annexin-V/PI staining, revealing that 97.95 f 1.63 % of the cells remained viable in the CE7.5-treated membranes, while only 1.85 f 1.49 % of necrotic cells were detected in the treated cell population. Fibroblasts treated with the CE7.5 membrane showed a 42 % improvement in wound closure compared to non-treated cells. The anti-inflammatory properties of the electrospun membranes were also investigated. Treatment with the conditioned CE7.5 membrane downregulated Tba1 and tau proteins by 45.1 and 51.055 %, respectively. This study concluded that the newly developed Cinnamomum zeylanicum extract incorporated poly(lactic acid)/gelatin electrospun membranes could be a promising wound dressing material.