Araştırmacılar(7)

• Demir Çetinkaya, Büşra
• Gizem Yildiztekin, K.
• Ozkemahli, Gizem
• Özçelik, İbrahim
• Özkemahll, Gizem
• Yildiztekin, Gizem
• Yildiztekin, Kübra Gizem

• ArticleYalnız künye2026/r/ebyu/11105
  Comparative evaluation of the effects of bisphenol A and/or bisphenol F on oxidative stress and cytokine responses in SH-SY5Y neuroblastoma cells: in silico and in vitro

  Özçelik, İbrahim; Çakir, Deniz Arca; Yildiztekin, Kübra Gizem; Erkekoğlu, Pınar

  Bisphenol A (BPA) is a well-known endocrine-disrupting chemical, whereas bisphenol F (BPF), a common BPA substitute, is less characterized, particularly regarding neuronal-derived cells and combined BPA + BPF exposure. Human SH-SY5Y neuroblastoma cells were exposed to BPA, BPF, or BPA + BPF for 24 h. Cell viability was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and oxidative stress and cytokine endpoints were evaluated at IC20 concentrations. SwissTargetPrediction and molecular docking were used to examine potential interactions with estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR). BPA was more cytotoxic than BPF, with IC50 values of 173.2 and 456.8 µM, respectively; the BPA + BPF combination IC50 was 196.9 µM. BPA and BPA + BPF significantly increased reactive oxygen species by 15.74% and 18.32% and protein carbonyl levels by 227.69% and 172.67%, respectively. BPA markedly increased interleukin-6, whereas BPF strongly increased tumor necrosis factor-alpha. In contrast, TNF-α decreased in the BPA and BPA + BPF groups, while malondialdehyde showed a non-significant downward trend. Docking predicted interactions of both compounds with AR, ERα, and ERβ, with binding energies of −7.3 to −8.5 kcal/mol. BPA and BPF produced distinct cytotoxic, oxidative, and cytokine-response profiles after acute exposure. BPA-containing treatments were associated with greater oxidative stress-related changes, whereas BPF elicited a distinct inflammatory response. Predicted receptor interactions require functional validation, and further studies should assess chronic, low-dose, and mixed exposures.

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• ArticleYalnız künye2026/r/ebyu/10649
  Evaluation of the protective effects of different antioxidants against the toxicity of herpes simplex virus 1 glycoprotein D

  Işik, Gözde; Çakir, Deniz Arca; Yirün, Anil; Erdemli-Köse, Selinay Başak; Özçelik, İbrahim; Erkekoǧlu, Pinar

  Herpes simplex virus type 1 (HSV-1) infects an estimated 3.8 billion people under age 50 worldwide and establishes lifelong neuronal latency, leading to recurrent disease manifestations such as neonatal and genital herpes; yet no vaccine or curative therapy exists. This study evaluated the oxidative-stress-modulating effects of HSV-1 glycoprotein D (gD) alone or in combination with two antioxidant agents - ascorbic acid and sodium selenite - in a human neuroblastoma cell line. Key oxidative-stress markers - including total glutathione (GSH), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), 8-isoprostane and protein carbonyl content - were quantified following exposure to "gD,""gD plus ascorbic acid", or "gD plus sodium selenite". Additionally, molecular docking analyses compared the binding affinities of ascorbic acid and sodium selenite for gD. Results showed that co-administration of ascorbic acid or sodium selenite with gD significantly elevated reactive oxygen species (ROS) levels compared to gD, while GSH and protein carbonyl concentrations remained unchanged. Intermediate lipid-peroxidation products did not differ significantly across treatment groups. Docking studies suggested that ascorbic acid exhibits a stronger potential for biologically relevant interaction with gD than sodium selenite, indicating a more pronounced antioxidant effect. These findings underscore the complexity of gD-induced oxidative pathways and highlight the need for further in vitro and in vivo investigations to delineate the toxicological impact of HSV-1 gD, as well as to extend analysis to other viral proteins involved in oxidative stress.

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• ArticleAçık Erişim2026/r/ebyu/10133
  Testicular toxicity of Aroclor 1254 in selenium-deficient and selenium-supplemented rats; [Toksičnost Aroclora 1254 u testisa štakora s manjkom selena i u onih na nadomjesnom selenu]

  Erkekoğlu, Pınar; Balcı-Özyurt, Aylin; Zeybek, Naciye Dilara; Tezel-Yalçın, Hülya; Yaman, Ünzile; Yildiztekin, Gizem; Aydın-Dilsiz, Sevtap; Kızılgün, Murat; İşcan, Evin; Batur, Tuğçe

  Aroclor 1254 (A1254) is a mixture of polychlorinated biphenyl (PCB) congeners known to induce testicular toxicity through oxidative stress, apoptosis, and hormonal disruption. Selenium (Se), an essential trace element for male reproduction, contributes to antioxidant defence, DNA repair, and spermatogenesis. Given the worldwide prevalence of Se deficiency and its potential impact on reproductive health, this study investigated the effects of A1254 exposure on testicular function in Sprague-Dawley rats with different Se status. Rats assigned to the Se-deficient group were receiving a ≤0.05 mg/kg Se diet, while those assigned to the Se-supplemented group were receiving 1 mg/kg Se for five weeks. A1254-treated groups were receiving 10 mg/kg/day of A1254 by oral gavage for 15 consecutive days. A1254 exposure caused significant reductions in testis weight, sperm count, motility, and plasma testosterone levels, accompanied by extensive germ cell apoptosis and enhanced lipid and protein oxidation. Total antioxidant capacity also dropped significantly, confirming redox imbalance in A1254-exposed testes. These adverse effects were substantially exacerbated in the Se-deficient group, whereas Se supplementation ameliorated but did not fully prevent histological and biochemical changes induced by A1254. Our findings demonstrate that Se plays a crucial protective role against PCB-associated testicular injury, primarily by mitigating oxidative stress and apoptotic pathways. However, Se supplementation alone may not completely counteract the reproductive toxicity caused by persistent environmental contaminants such as A1254.

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• ArticleYayıncıda açık erişim2026/r/ebyu/10015
  Design and Synthesis of 4-Arylazo Pyrazole Carboxamides as Dual AChE/BChE Inhibitors: Kinetic and In Silico Evaluation

  Akocak, Suleyman; Lolak, Nebih; Duran, Hatice Esra; Demir Çetinkaya, Büşra; Hashem, Hamada; Bräse, Stefan; Türkeş, Cüneyt

  Background/Objectives: Pyrazole carboxamides are widely used as adaptable medicinal-chemistry scaffolds and have been explored as cholinesterase (ChE) inhibitor chemotypes. In this work, we prepared a new series of 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamides 5(a–m) and evaluated their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), supported by structure-based computational analyses. Methods: Thirteen derivatives 5(a–m) were synthesized, fully characterized with analytical techniques (FT-IR, H NMR, and C NMR), and tested in vitro against AChE and BChE, with tacrine (THA) used as the reference inhibitor. Docking calculations were used to examine plausible binding modes. The top-ranked complexes (7XN1–5e and 4BDS–5i) were further examined by 100 ns explicit-solvent molecular dynamics (MD) simulations in Cresset Flare, followed by RMSD/RMSF analysis and contact-persistence profiling. Predicted ADME/Tox. properties were also assessed to identify potential developability issues. Results: The series showed strong ChE inhibition, and several compounds were more potent than THA. Compound 5e (4-nitro) was the most active AChE inhibitor (KI = 20.86 ± 1.61 nM) compared with THA (KI = 164.40 ± 20.84 nM). For BChE, the KI values ranged from 31.21 to 87.07 nM and exceeded the reference compound’s activity. MD trajectories supported stable binding in both systems (10–100 ns mean backbone RMSD: 2.21 ± 0.17 Å for 7XN1–5e; 1.89 ± 0.11 Å for 4BDS–5i). Most fluctuations were confined to flexible regions, while key contacts remained in place, consistent with the docking models. ADME/Tox. predictions suggested moderate lipophilicity but generally low aqueous solubility; all compounds were predicted as non-BBB permeant, and selected liabilities were flagged (e.g., carcinogenicity for 5e/5g/5h/5i; nephrotoxicity for 5f/5g). Conclusions: The 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamide scaffold delivers low-nanomolar ChE inhibition, with docking and MD supporting stable binding modes. Future optimization should prioritize solubility improvement and mitigation of predicted toxicities and metabolic liabilities, especially given the predicted lack of BBB permeability for CNS-directed applications.

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• Review ArticleYayıncıda açık erişim2025/r/ebyu/19344
  Elektronik Sigara Kullanımının Toksikolojik Açıdan Değerlendirilmesi

  Yildiztekin, Gizem; Şen, Hatice

  Elektronik sigaralar (e-sigaralar), geleneksel tütün ürünlerine göre daha az zararlı olduğu iddiasıyla geliştirilmiş nikotin iletim sistemleri olup, özellikle adolesan bireyler arasında hızla yayılmaktadır. Ancak, e- sigaraların içerdiği kimyasallar ve aerosol bileşenlerinin toksikolojik profili hakkındaki bilgiler hala sınırlı düzeydedir. Bu çalışma, e-sigaralarda bulunan maddeleri toksikolojik açıdan değerlendirmeyi ve insan sağlığı üzerindeki potansiyel etkilerini literatür temelli olarak ortaya koymayı amaçlamaktadır. Araştırmada, e-sigaralarda yer alan nikotin, propilen glikol, gliserol, aroma maddeleri, ağır metaller ve aldehitlerin toksiste potansiyeli incelenmiştir. Elde edilen bulgular, e-sigaraların yalnızca nikotin bağımlılığını sürdürmekle kalmayıp; solunum, kardiyovasküler, ağız-diş sağlığı ve sinir sistemi üzerinde zararlı etkilere neden olabileceğini göstermektedir. Ayrıca, propilen glikol ve gliserolün ısıl bozunumu sonucu ortaya çıkan aldehitlerin, oksidatif stres ve hücresel hasar süreçlerine katkıda bulunduğu bildirilmektedir. E-sigara kullanımının yaygın hale gelmesinin ruh sağlığı üzerinde olumsuz etkiler yaratabileceği ve halk sağlığı açısından yeni tehditler oluşturabileceği sonucuna varılmıştır. Bu bağlamda, e-sigaraların bireysel ve toplumsal düzeyde sağlık riskleri taşıdığı ve düzenleyici politikaların geliştirilmesinin gerekliliği önemle vurgulanmaktadır.

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• ArticleYayıncıda açık erişim2025/r/ebyu/11967
  Comparative in vitro and in silico evaluation of the toxic effects of metformin and/or ascorbic acid, new treatment options in the treatment of Melasma

  Yalçln, Hülya Tezel; Çaklr, Deniz Arca; Yirün, Anll; Sanajou, Sonia; Işlk, Gözde; Bozdemir, Özlem; Özçelik, Ibrahim; Güdül Bacanll, Merve; Zeybek, Naciye Dilara; Baydar, Terken

  Melasma is a chronic condition that leads to the buildup of melanin pigment in the epidermis and dermis due to active melanocytes. Even though it is considered a non-life-threatening condition, pigment disorders have a negative impact on quality of life. Since melasma treatment is not sufficient and complicated, new treatment options are sought. Research on metformin and ascorbic acid suggested that they might be used against melasma in the scope of "drug repositioning."The MNT-1 human melanoma cell line was used to assess the effects of metformin, ascorbic acid, and metformin+ascorbic acid combination on cytotoxicity and oxidative stress. Melanin, cAMP, L-3,4-dihydroxyphenylalanine (L-DOPA) and tyrosinase levels were determined by commercial ELISA kits and tyrosinase gene expression was analyzed with RT-qPCR. Cytopathological evaluations were performed by phase contrast microscopy. Tyrosinase expression was determined by immunofluorescence (IF) staining of MNT-1 cells. The online service TargetNet was used for biological target screening. The parameters were not significantly altered by ascorbic acid applied at non-cytotoxic concentrations. On the contrary, metformin dramatically raised tyrosinase and intracellular ROS levels. Moreover, intracellular ROS levels and tyrosinase levels were found to be considerably elevated with the combined treatment. Also, potential metformin and ascorbic acid interactions were determined. According to the results, it can be said that these parameters were not significantly altered by ascorbic acid. On the contrary, metformin dramatically raised tyrosinase and intracellular oxidative stress levels. Moreover, intracellular oxidative stress and tyrosinase levels were elevated with the combined treatment. In conclusion, individual treatments of ascorbic acid or metformin may only provide a limited effect when treating melasma and extensive in vitro and in vivo research are required.

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• ArticleYalnız künye2025/r/ebyu/11478
  N-substituted phthalimide–carboxylic acid hybrids as dual-targeted aldose reductase inhibitors: Synthesis, mechanistic insights, and cancer-relevant profiling

  Zognjani, Blinera; Nixha, Arleta Rifati; Duran, Hatice Esra; Arslan, Mustafa; Yıldıztekin, Gizem; Ece, Abdulilah; Türkeş, Cüneyt

  Aldose reductase (ALR2; AKR1B1), a NADPH-dependent cytosolic oxidoreductase, plays a central role in the polyol pathway and is implicated in hyperglycemia-induced tissue injury. Beyond its metabolic function, elevated ALR2 expression has been reported in several malignancies, including hepatocellular and pulmonary carcinomas, highlighting its potential as a therapeutic target in metabolic-oncologic interface. In this study, a novel set of eleven N-substituted phthalimide–carboxylic acid derivatives (5a–5k) was synthesized and evaluated for ALR2 inhibition, pharmacokinetic characteristics, and cancer-selective safety. Among the series, compound 5f demonstrated the highest inhibitory potency (KI = 7.34 nM), outperforming epalrestat (KI = 232.1 nM). Glide docking positioned 5f within the ALR2 active site (GlideScore: −6.71 kcal/mol), stabilized via key contacts with Tyr48, His110, and Cys298, along with π–π stacking at Trp219. MM-GBSA analysis corroborated strong binding affinity (ΔG = −64.86 kcal/mol). DFT-derived quantum descriptors, logP, TPSA, and solvation energies supported its favorable interaction profile. ADME/Tox predictions indicated high GI absorption, no P-gp or CYP liabilities, and acceptable bioavailability. In vitro cytotoxicity assays showed negligible activity of 5f against A549 and Hep3B cancer cell lines (IC₅₀ > 160 μM) and no toxicity toward L929 fibroblasts, reflecting safety for long-term use. Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis.

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• ArticleYalnız künye2025/r/ebyu/11469
  Phthalimide–benzoic acid hybrids as potent aldose reductase inhibitors: Synthesis, enzymatic kinetics, and in silico characterization

  Hoti, Dafina; Nixha, Arleta Rifati; Duran, Hatice Esra; Arslan, Mustafa; Yıldıztekin, Gizem; Ece, Abdulilah; Türkeş, Cüneyt

  Aldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide–benzoic acid hybrids ( 5a–5m) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative5demerging as the top hit (KI = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB4JIR), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. In silico ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide–benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting in vivo evaluation and SAR-guided optimization.

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• ArticleYayıncıda açık erişim2025/r/ebyu/11228
  Plasma phthalate levels in children with speech delay

  Yaman Artunç, Nihal; Yirün, Anıl; Yıldıztekin, Gizem; Erkekoğlu, Pınar; Zengin Akkuş, Pınar; İlter Bahadur, Evin; Özdemir, Gökçenur; Özmert, Elif N.

  Speech delay is a common developmental concern. Environmental pollutants like phthalates, recognized as endocrine disruptors, may be a risk factor. We aimed to investigate the relationship between phthalates and speech delay. The study comprised 50 children with isolated speech delay and 40 healthy children of similar ages. Children were assessed for speech delay risk factors and phthalate exposure sources. High-pressure liquid chromatography examined plasma di-(2-ethylhexyl) phthalate (DEHP), mono-(2-ethylhexyl) phthalate (MEHP) and dibutyl phthalate (DBP) levels. DEHP, MEHP, and DBP levels varied between study and control groups: 0.377 (0.003–1.224 µg/ml), 0.212 (0.007–1.112 µg/ml) (p = 0.033), 0.523 (0.031–2.477 µg/ml), 0.152 (0.239–2.129 µg/ml) (p < 0.001), and 0.395 (0.062–1.996 µg/ml) and 0.270 (0.006–0.528) (p = 0.004). Multiple linear regression was used to adjust phthalate levels and speech delay risk factors. DEHP levels were did not differ significantly between the groups (p = 0.233), whereas MEHP and DBP levels were considerably higher in the study group (p < 0.001). The statistically significant rise in plasma phthalate levels in children with speech delay implies phthalate exposure may be a risk factor, but further epidemiological research is needed.

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• ArticleYalnız künye2025/r/ebyu/11194
  Fluorenyl-phthalimide hybrids as potent aldose reductase inhibitors with selective anticancer activity: Rational design, synthesis, and molecular insights

  Gundogdu, Saliha; Duran, Hatice Esra; Arslan, Mustafa; Çetinkaya, Büşra Demir; Türkeş, Cüneyt

  Metabolic reprogramming in cancer cells creates actionable vulnerabilities for precision oncology. Aldose reductase (ALR2, AKR1B1; EC 1.1.1.21), a cytosolic NADPH-dependent oxidoreductase, has emerged as a multifunctional player in tumor progression, drug resistance, and oxidative stress modulation, yet remains underexploited as a cancer target. In this study, we report the rational design, synthesis, and biological evaluation of a focused series of fluorenyl-phthalimide carboxylic-acid hybrids (5a-5l) as dual-acting agents with selective anticancer potential and potent ALR2 inhibition. Among them, compound 5a exhibited the strongest ALR2 inhibition with a KI of 8.71 ± 0.81 nM, far surpassing the clinical comparator epalrestat (KI = 232.10 ± 14.42 nM). In MCF-7 and A549 carcinoma cells, 5a demonstrated moderate antiproliferative activity (IC50 = 52.04 μM and 192.91 μM, respectively) while sparing normal bronchial epithelial cells, indicating tumor selectivity. Molecular docking and MM-GBSA calculations (ΔGbind = −44.02 kcal/mol) revealed a consistent bidentate hydrogen bonding network supporting high-affinity binding involving Tyr48, His110, and Trp111, further stabilized by crystallographic water molecules. To explore structure-activity relationships, a Random Forest regression model was developed using 24 descriptors derived from QikProp. The model achieved strong predictive performance (Q2CV = 0.71), and SHAP analysis identified water/gas partition coefficient, skin permeability, and human oral absorption as the most influential features shaping inhibitory potency. In silico ADME/Tox profiling supported the drug-like nature of compound 5a, with no major CYP or hERG liabilities predicted. Collectively, these findings position 5a as a first-in-class ALR2-targeted anticancer lead, introducing a chemically novel and mechanistically validated chemotype for further development within the framework of metabolically targeted precision therapies.

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