Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
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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: 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 - WoS: 3Citation - Scopus: 3Biochemical, Pharmacological, and Toxicological Attributes of Caper (Capparis Ovata) Flowering Buds and Berries Pickles(Wiley, 2022-07-30) Ozgun-Acar, Ozden; Celik-Turgut, Gurbet; Guner, Huseyin; Sezer, Serdar; Sen, AlaattinCapparis 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, radical-scavenging 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-kappa B) 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-kappa B transcriptional activity as well as inflammatory cytokine expression in T-lymphoblast cells. Whole-genome 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.Article Citation - Scopus: 6Amelioration Potential of Synthetic Oxime Chemical Cores Against Multiple Sclerosis and Alzheimer's Diseases: Evaluation in Aspects of in Silico and in Vitro Experiments(Elsevier B.V., 2024-12) Yilmaz, Anil; Koca, Murat; Ercan, Selami; Acar, Özden Ozgun; Boǧa, Mehmet; Sen, Alaattin; Kurt, AdnanAlzheimer disease (AD) and multiple sclerosis (MS) are inflammatory neurological disorders. The main symptom of AD is dementia, and the main symptoms of MS are vertigo, sexual dysfunction, cognitive problems, and fatigue. Today, millions of people are affected by AD and MS, and the number is growing day by day. However, there are not any accurate remedies for both disorders. For this reason, discovering novel drug molecules against neurological disorders such as AD and MS is essential and precious. Oximes and benzofurans exhibit many pharmacological effects including anti-inflammatory and neurological activities. Thus, several novel compounds bearing oxime and benzofuran chemical cores were designed and synthesized, and their in vitro anticholinesterase activities were investigated in our previous study. A number of the synthesized molecules showed excellent anticholinesterase activity against both AChE and BChE enzymes. The mentioned study constituted a background for this study. In this study, we picked different chemical skeletons among all the synthesized molecules to conduct further in silico and in vitro experiments. In order to support our in vitro anticholinesterase findings, we also examined in silico anti-Alzheimer activity of the selected molecules. In addition, in silico and in vitro activities against MS disease of the synthesized molecules were investigated. Molecule 4 extraordinarily showed outstanding activity against AD disease both in silico and in vitro, as well as in silico activity against MS disease. This feature makes molecule 4 a possible drug lead molecule which is very limited in the market. On the other hand, molecule 1, a less substituted oxime skeleton, demonstrated the strongest in vitro activity against MS disease through in vitro anti-inflammatory effect. As an observation, molecule 4 was determined to be the most promising molecule to focus on in the further steps. © 2024 Elsevier B.V., All rights reserved.