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: 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: 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 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 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 - WoS: 20Citation - Scopus: 22Role of Cytochrome P450 Polymorphisms and Functions in Development of Ulcerative Colitis(Baishideng Publishing Group inc, 2019-06-21) Sen, Alaattin; Stark, HolgerCytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.Article Citation - WoS: 16Citation - Scopus: 15Role of AHR, NF-kB and CYP1A1 Crosstalk With the X Protein of Hepatitis B Virus in Hepatocellular Carcinoma Cells(Elsevier, 2023-02) Celik-Turgut, Gurbet; Olmez, Nazmiye; Koc, Tugba; Ozgun-Acar, Ozden; Semiz, Asli; Dodurga, Yavuz; Sen, AlaattinIn this study, it was aimed to elucidate the interaction between aryl hydrocarbon receptor (AHR), nuclear factor -kappa B (NF-kB), and cytochrome P4501A1 (CYP1A1) with hepatitis B virus X protein (HBX) in a human liver cancer cell line (HepG2) transfected with HBX. First, AHR, NF-kB, and CYP1A1 genes were cloned into the appropriate region of the CheckMate mammalian two-hybrid recipient plasmids using a flexi vector system. Renilla and firefly luciferases were quantified using the dual-luciferase reporter assay system to measure the interactions. Secondly, transient transfections of CYP1A1 and NF-kB (RelA) were performed into HBX-positive and HBX-negative HepG2 cells. The mRNA expression of CYP1A1 and NF-kB genes were confirmed with RT-PCR, and cell viability was measured by WST-1. Further verification was assessed by measuring the activity and protein level of CYP1A1. Additionally, CYP1A1/HBX protein-protein interactions were performed with co-immunoprecipitation, which demonstrated no interaction. These results have clearly shown that the NF-kB and AHR genes interact with HBX without involving CYP1A1 and HBX protein-protein interactions. The present study confirms that AHR and NF-kB interaction plays a role in the HBV mechanism mediated via HBX and coordinating the carcinogenic or inflammatory responses; still, the CYP1A1 gene has no effect on this interaction.