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Öğe Investigation into drug resistance to cisplatin in cancer stem cell-enriched population in non-small cell lung cancer(Walter de Gruyter GmbH, 2025) Dere, Egemen; Akgün, Oǧuzhan; Aztopal, Nazllhan; Ulukaya, Enginunderstanding drug resistance in cancer is of importance in treatment. Cancer stem cells are main factor for drug resistance. Therefore, the possible gene/gene interactions/proteins were explored in our study using a cancer stem cell-enriched population (H1299/S) derived from a parental non-small cell lung cancer cell line (H1299/P). response to cisplatin, which is the main drug for the treatment of lung cancer, was evaluated with the Adenosine triphosphate (ATP) viability test. As a result of the gene expression analysis, while 14 genes were not evaluated, expression profiles were obtained for 37 genes out of 51 genes. By the drug-protein interaction analyses, Topoisomerase I (TOPI), Topoisomerase 2 alpha (TOP2A), Topoisomerase 2 beta (TOP2B), Cyclin-dependent kinases 4 (CDK4), Cyclin-dependent kinases 6 (CDK6), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 1 (ABCC1), ATP binding cassette subfamily C member 3 (ABCC3), B-cell leukemia/lymphoma 2 (BCL2), Poly (ADP-ribose) polymerase 1 (PARP1), Breast cancer gene 1 (BRCA1) and Cyclin dependent kinase inhibitor 1A (CDKN1A) genes and protein products were statistically significantly found to be in association with drug resistance. in bioinformatics analyses, it was observed that 13 pathways were affected due to expression changes and 12 genes related to these pathways were determined to activate multidrug resistance mechanisms. platinum-based drugs, as well as a broad range of other agents including topoisomerase and PARP1 inhibitors, and anthracyclines, have been shown to potentially possess multiple drug resistance. © 2024 bei den Autorinnen und Autoren, publiziert von Walter de Gruyter GmbH, Berlin/Boston 2024.Öğe L-type calcium channel blocker effects on electromagnetic field exposed lung histology(Ondokuz Mayıs Üniversitesi, 2024) Köylü, Ayşe; Ayas, BülentElectromagnetic field is produced by electrically charged objects and is defined as the combination of both electric field and a magnetic field. Wireless (wifi) networks, cell phones, bluetooth devices, power lines are some of the examples which emit electromagnetic field. Calcium channel blockers are a group of medicine used to lower blood pressure. They stop calcium from entering the cells of the heart and arteries. Our aim is to observe the possible histopathologic events of lungs from rats which was given a calcium blocker, amlodipine, meanwhile received a prolong electromagnetic field. To grade the lung histopathology, we stained the slides with hematoxylin and eosin and examined them under a camera attached light microscope. © 2024 Ondokuz Mayis Universitesi. All rights reserved.Öğe Investigation of preconditioning and the protective effects of nicotinamide against cerebral ischemia-reperfusion injury in rats(Elsevier Ireland Ltd, 2024) Arslan, Ruhat; Doğanay, Songül; Budak, ÖzcanThis study investigated the antioxidant and neuroprotective effects of nicotinamide combined with ischemic preconditioning against cerebral ischemia reperfusion (CIR) injury. Thirty-five Wistar albino male rats were randomly divided into five groups: sham, preconditioned ischemia/reperfusion (IP+IR), ischemia/reperfusion (IR), preconditioned ischemia/reperfusion + nicotinamide (IP+IR+N), and ischemia/reperfusion + nicotinamide (IR+N). CIR was achieved with bilateral common carotid artery occlusion. IP+IR and IP+IR+N groups 30 min before ischemia; Three cycles of 10 sec ischemia/30 sec reperfusion followed by 20 min IR were applied. The IP+IR+N and IR+N groups received 500 mg/kg nicotinamide intraperitoneally. After 24 h of reperfusion, a neurological evaluation was performed and vertıcal pole test. Biochemically, malondialdehyde (MDA), glutathione (GSH) levels and catalase (CAT) activity were measured in blood and brain tissue samples. Rates of red neurons, sateliosis and spongiosis were determined histopathologically in the prefrontal cortex areas. After CIR, MDA levels increased significantly in serum and brain tissue in the IR group compared to the sham group, while GSH and CAT activity decreased in the brain tissue (p < 0.05). MDA levels in the tissues were found significantly decreased in the IR+N group compared to the IR group (p < 0.05). Administration of nicotinamide together with IP significantly decreased MDA levels in brain tissue and increased GSH and CAT activity (p < 0.05). Compared to the IR group, the morphological and neurological damage in the prefrontal cortex areas decreased in the IP+IR, IP+IR+N, and IR+N groups (p < 0.05). In addition, red neuron, sateliosis and spongiosis rates increased significantly in the IR group compared to the Sham, IP+IR+N, IR+N groups (p < 0.001 for all). In neurological evaluation, while the neurological score increased and the time on the vertical pole decreased significantly in the IR group, preconditioning, and nicotinamide groups reversed (p < 0.05). The study's results show that nicotinamide administration with ischemic preconditioning alleviates cerebral ischemia/reperfusion injury. © 2024 Elsevier B.V.Öğe Crocin suppresses inflammatory response in LPS-induced acute lung injury (ALI) via regulation of HMGB1/TLR4 inflammation pathway(Dokuz Eylül University institute of health sciences, 2024) Ceylan, Tayfun; Akın, Ali Tuğrul; Kaymak, Emin; Varinli, Saban; Toluk, AyşePurpose: The most significant pathogen hypothesized to be causing the formation of Acute lung injury (ALI) in sepsis is thought to be lipopolysaccharide (LPS), a key endotoxin component of gram-negative bacteria. The main objective of this study is to determine possible anti-inflammatory effects of crocin (CRO) which has many biological properties such as anti-inflammatory, antioxidant, and anti-apoptotic in LPS-induced ALI. Material and Methods: 40 Wistar albino rats were divided into four groups: Control (no treatment), CRO (given 50 mg/kg crocin for 9 days), LPS (given 30 mg/kg LPS at 9th day), LPS+CRO (given 50 mg/kg crocin for 9 days and 30 mg/kg LPS at 9th day). After experimental, rats were sacrificed and lungs were extracted. Histological examinations were performed in the lung tissue and the changes in the HMGB1 and TLR4 expressions were determined via immunohistochemical staining. Results: Hemorrhage, HMGB1 and TLR4 expressions significantly increased in the LPS group. However, CRO administrations exerted a strong protective effect on the lungs in terms of these parameters in LPS+CRO group. Conclusion: According to our results, we suggest that CRO can be considered as a protective agent against LPS induced ALI via inhibition of HMGB1/TLR4 pathway-mediated inflammatory response.Öğe Comparison of oncological and functional results of robotic and open perineal radical prostatectomy(Wiley, 2024) Çolakoğlu, Yunus; Ekşi, Mithat; Özlü, Deniz Noyan; Şimşek, Abdüllmüttalip; Tuğcu, Volkan; Taşcı, Ali İhsanObjective: We aimed to compare the functional and oncological outcomes of patients who underwent open perineal radical prostatectomy (OPP) and robotic perineal radical prostatectomy (RPP) for prostate cancer (PCa). Methods: The data of patients who underwent OPP and RPP from June 2016 to February 2019 due to localized PCa were analyzed. Demographic characteristics, perioperative data and oncological results of the patients were recorded. In addition, the incontinence status of the patients immediately after catheter removal and at the 3rd, 6th, and 12th months were compared. Potency status was evaluated among the patients with preoperative potency, and 12th month potency status was compared. Results: A total of 135 patients were included, of whom 58 (43%) were in the OPP group and 77 (57%) were in the RPP group. The operation time was statistically significantly shorter in the OPP group (83.90 +/- 15.48 vs. 110.88 +/- 28.10 min, p = 0.001). The amount of bleeding was significantly lower in the RPP group (59.51 +/- 22.04 vs. 74.06 +/- 17.66, p = 0.002). The continence rates evaluated at the early period, 3rd, 6th, and 12th months were 40.3%, 80.5%, 87.0%, and 90.9%, respectively, for the RPP group and 36.2%, 70.7%, 86.2%, and 89.7%, for the OPP group, indicating no statistically significant difference (p > 0.05). There was no statistically significant difference in the 12th month rates of postoperative potency according to the surgical technique (p > 0.05). Conclusion: Although differences were observed between the OPP and RPP techniques in terms of perioperative parameters, oncological and functional results were similar.Öğe Protective effect of Apelin-13 on D-glutamic acid-induced excitotoxicity in SH-SY5Y cell line: An in-vitro study(Churchill Livingstone, 2025) Oruç, Kadriye Yağmur; Ağtürk, Gökhan; Oruç, Aykut; Yanar, Karolin; Seymen, Hakkı OktayExcitotoxicity, resulting from excessive accumulation of glutamate in the extracellular space, leads to neuronal cell death. This study investigates the protective effects of Apelin-13 on D-Glutamic acid-induced excitotoxicity in SH-SY5Y human neuroblastoma cells, an in-vitro model for neurodegenerative diseases. Unlike the commonly studied L-glutamic acid, this research focuses on D-Glutamic acid to understand its specific impacts. SH-SY5Y cells were treated with varying concentrations of D-Glutamic acid and Apelin-13, followed by analyses at 12 and 24 h to evaluate cell viability, oxidative stress markers, and inflammatory cytokine levels. Cell viability assays revealed significant cytotoxic effects of D-Glutamic acid at doses of 10 mM and 20 mM, reducing viability by over 50 %. However, Apelin-13 treatment mitigated these effects, especially at 2 μg/ml, enhancing cell viability and reducing inflammatory cytokine levels (IL-1β and TNF-α). Apelin-13 also increased anti-inflammatory cytokine levels (IL-10 and TGF-β1) and brain-derived neurotrophic factor (BDNF), indicating its neuroprotective role. Oxidative stress markers, including ROS, AGE, AOPP, DT, T-SH, were significantly elevated by D-Glutamic acid but effectively reduced by Apelin-13. The neuroprotective mechanisms of Apelin-13 involve modulation of cAMP/PKA and MAPK signaling pathways, enhancing BDNF synthesis and suppressing oxidative stress and inflammatory responses. This study is the first to demonstrate the effects of D-Glutamic acid on SH-SY5Y cells. It highlights Apelin-13's potential as a therapeutic agent against excitotoxicity-induced neuronal damage, emphasizing its ability to modulate key molecular pathways involved in inflammation and oxidative stress. Further in-vivo studies are warranted to explore the long-term neuroprotective effects of Apelin-13 in treating neurodegenerative diseases. © 2024Öğe Inhibition of pancreatic cancer via LPAR4 receptor with a de novo drug complex design using theoretical organic chemistry: Comprehensive molecular docking, molecular dynamics(Marmara University, 2024) Agar, Soykan; Arasan, Yaren; Akkurt, Barbaros; Ulukaya, EnginThe present work relates to a de novo organic chemistry involved drug design and repurposing discovery of a Quercetin and Ascorbic Acid complex formation with the IUPAC nomenclature of ‘’3-((2S)-2-(3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl)-2-hydroxyethoxy)-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychroman-4-one’’ to suppress pancreatic cancer via the inhibition of LPAR4 receptor. This was achieved with molecular docking and molecular dynamics studies and found that Ascorbic Acid is docking manoeuvre assistant for Quercetin to form Hydrogen bonds and Covalent bonds to shut down LPAR4 receptor with excellent inhibition constant. This study may very well lead to further in vitro organic synthesis, characterization and cell line results and in vivo/ex ovo animal testing for etherical bound Quercetin and Ascorbic Acid complex. © 2024 Marmara University Press.Öğe Induction of Apoptosis through Oxidative Stress Caused by Rubus tereticaulis Leaves Extracts in A549 Cells(Istanbul University Press, 2024) Öter, Gamze Nur; Durmuş, Ezgi; Şen, Ali; Koçyiğit, AbdurrahimObjective:Plants have been used for medicinal purposes since the beginning of human history and form the basis of modern medicine, and they are also the source of most chemotherapeutic drugs for cancer treatment. This study aims to investigate for the first time the cytotoxic and apoptotic effects of the active ethanol (RTE) and chloroform (RTC) extracts of Rubus tereticaulis leaves in the A549 non-small-cell lung cancer cell line. Materials and Methods:A549 cells were treated with RTE and RTC individually. The MTT assay was used to quantitatively detect RTE and RTC's cytotoxic effects. The fluorescent signal indicator H2DCF-DA was used to detect cellular reactive oxygen species (ROS) production. Apoptosis was evaluated by fluorescence microscope after acridine orange/ethidium bromide fluorescent staining, annexin V-FITC and immunoblotting analyses, immunofluorescence, and imaging. Results:Both RTE and RTC induced cytotoxicity in A549 cells in a dose-dependently, which was accompanied with induced ROS accumulation. Both early and late apoptotic cells detected by flow cytometry were increased in the RTE- and RTC-treated cells. In addition, the results show RTC to have higher cytotoxic and apoptotic effects and increased ROS-generation capacity than RTE. Therefore, the polarity of the solvent used to exert the anticancer effect of R. tereticaulis leaves is crucial. Conclusion:This is the first anti-cancer activity study on R. tereticaulis. The results suggest R. tereticaulis leaves to have an anti-cancer effect on lung cancer cells through ROS-mediated apoptosis and RTC to be an effective therapeutic/adjuvant strategy in cancer treatment. © 2024 Istanbul University Press. All rights reserved.Öğe Capsaicin Modulates Adipocyte Cell Differentiation and Inflammatory Gene Expression(İstanbul Üniversitesi, 03.11.2024) Degırmencıoglu, Sevgın; Çetinalp, Pınar; Küçük, Sevda Tanrıkulu; Seyithanoğlu, Muhammed; Kocak, Hikmet; Iyidogan, Yıldız OnerObjective: Adipose tissue stores lipids necessary for the maintenance of nutritional homeostasis. It is also an endocrine organ that reacts to changes in inflammation and energy status. Capsaicin, the principal bioactive compound in red pepper, has garnered significant attention for its reported anti-obesity, anti-diabetic, anti-oxidant, and anti-inflammatory properties. In this study, we aimed to elucidate the influence and most efficacious dose of capsaicin on the expression of lipid metabolism-related inflammatory proteins and the inhibition of adipocyte cell differentiation. Materials and Methods: Cell viability analysis was performed using CCK-8, cell differentiation was assessed using Oil Red O, and gene expression levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding protein alpha (C/EBPα), adiponectin, leptin, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), nuclear factor kappa B1 (NF-κB1), tumor necrosis factor-alpha (TNF-α), sirtuin-1 (SIRT-1), transient receptor potential vanilloid receptor 1 (TRPV1), and uncoupling protein 2 (UCP2) were evaluated using quantitative real time polymerase chain reaction (qRT-PCR). Statistical analyses were conducted using GraphPad Prism 5. One-way ANOVA was performed to compare quantitative data between the groups. Results: Capsaicin suppressed preadipocyte-to-adipocyte differentiation and mitigated the release of pro-inflammatory cytokines, particularly at low concentrations. Capsaicin effectively suppressed adiponectin levels at all concentrations but decreased leptin levels at lower concentrations (0.5 μM and 1 μM). Capsaicin stimulated the expressions of SIRT1 and TRPV-1 in adipocytes. According to our findings, the most effective capsaicin dose for the regulation of SIRT1 and TRPV-1 expressions appears to be 20 μM. Conclusion: Capsaicin’s effect on proteins regulating adipogenesis is not dose-related, but its inhibitory effect on adiposity-dependent inflammation was more pronounced at low concentrations.Öğe Human estrogen receptor alpha (ERα) targeted cyclic peptides inhibit cell growth and induce apoptosis in MCF-7 cells(Walter de gruyter GMBH, 2024) Şentürk, Hilal; Dedeakayoğulları, Huri; Marion, İlke U.; Özçubukçu, Salih; Kesici, Mehmet S.; Beyge, Şeyma Ünsal; Acar, Muradiye; Genel, Merve Erkısa; Akbaş, Fahri; Ulukaya, EnginObjectives Human estrogen receptor alpha (ER alpha) is considered an important target, especially in the treatment of breast cancer, as it has a vital role in cancer development. ER alpha-targeted therapies generally target the ligand binding domain (LBD) of ER alpha. However, over time, cells develop resistance to this mechanism alternative approaches to inhibit ER alpha activity target ER alpha-DNA or ER alpha-cofactor interactions. Inhibitors of ER alpha-cofactor interactions are designed by targeting the hydrophobic hollow region of the receptor box LXXLL motif.Methods In this context, helix-stabilized cyclic peptides (SPs) designed with in silico approaches were obtained by solid phase peptide synthesis. The effects of SPs on MCF-7 cells were examined with MTT and ATP, and qPCR and flow cytometry were used for further analysis.Results Our results demonstrated that the SPs were effective only in MCF-7 cells expressing ER alpha. In addition, cyclic peptide combinations (SPCs) showed anti-proliferative and toxic effects on MCF-7 cells. The impact of SPCs with the highest inhibitory effect in MCF-7 cells on ER alpha-related genes and markers of apoptosis was revealed. Moreover, the flow cytometry analysis result used to examine apoptotic cells proved the apoptosis of SPCs in MCF-7 cells.Conclusions These findings suggest that our novel SPs, which inhibit coactivator interactions of ER alpha, induce apoptosis of MCF-7 cells. Thus, considering this strong effect of SPs in the inhibition of receptors, it is pointed out that they can be further developed as an alternative to current clinical treatments or as an auxiliary approach in the generating of new targeted peptide-based therapies.Öğe Poisoning by butylated hydroxytoluene quinone methide acting as a superwarfarin: first reported case in humans(Lippincott williams & wilkins, 2024) Hindilerden, Fehmi; Aksoy, Elif; Öztürkmen, Aslı Yüksel; Türker, Gamze; Gültürk, Emine; Hançer, Veysel Sabri; Mercan, SeldaSuperwarfarins are anticoagulant rodenticides nearly 100-fold potent than the parent compound. Since their development, accidental and intentional cases of superwarfarin poisoning have been reported. We report the first human case of poisoning by butylated hydroxytoluene (BHT) quinone methide acting as a superwarfarin otherwise reported to be a well tolerated food additive and preservative and used as an antioxidant, stabilizer, anti-skinning agent in various industries. We aim to highlight the possible underlying cause of this previously unreported and potentially lethal BHT-related complication in the human.Öğe Endocrine Adverse Events in Patients Treated with Immune Checkpoint Inhibitors: A Comprehensive Analysis(Multidisciplinary Digital Publishing Institute (MDPI), 2025) Dökmetaş, Meriç; Muğlu, Harun; Özcan, Erkan; Bayram Kuvvet, Buket; Helvacı, Kaan; Kalacı, Ender; Kahraman, Seda; Aykan, Musa Barış; Çiçin, İrfan; Selçukbiricik, Fatih; Ölmez, Ömer Fatih; Bilici, AhmetBackground and Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but their use is associated with a spectrum of immune-related adverse events (irAEs), including endocrine disorders. This study aims to investigate the incidence, timing, treatment modalities, and impact of ICI-related endocrine side effects in cancer patients. Materials and Methods: This retrospective study analyzed 139 cancer patients treated with ICIs between 2016 and 2022. Data regarding endocrine irAEs, including hypothyroidism, hyperthyroidism, hypophysitis, and diabetes mellitus, were collected. The study examined the timing of irAE onset, management approaches, and the association between irAEs and treatment outcomes. Results: The most common endocrine irAE was hypothyroidism (65.5%), followed by hyperthyroidism (2.3%), hypophysitis (8.6%), and diabetes mellitus (0.7%). These disorders typically emerged within the first six months of ICI therapy. Most cases were managed conservatively or with hormone replacement therapy. Patients who developed endocrine irAEs exhibited a higher objective response rate (ORR) and clinical benefit rate (CBR) compared to those without irAEs. Conclusions: Endocrine dysfunction is a significant toxicity of ICI therapy. Early recognition, prompt diagnosis, and appropriate management are crucial to minimize their impact on patient health and quality of life. This study highlights the potential association between irAEs and improved clinical outcomes. Further research is needed to elucidate the underlying mechanisms and identify predictive biomarkers for irAE development. © 2025 by the authors.Öğe Esansiyel Trombositozlu Hastalarda Kalsiyum, Fosfor Ve Arsenik Elementlerinin Analizi(27.08.2024) Karis, Denizhan; Ozkan, Tuba; Alkan, Fatma Ateş; Cetin, Guven; Ercan, Alev MeltemAmaç: Esansiyel trombositoz, trombositlerde ciddi artış ve fonksiyon bozukluğuna sebep olan kök hücre kökenli nadir bir hastalıktır. Trombositlerin fonksiyonlarındaki bozulma ve artan aktiviteleri sonucunda, yapılarında bulunan granüllerden özgün moleküller salgılanmaktadır. Esansiyel trombositozda görülen hiperkalsemi, sayıca artan ve aktiviteleri artan trombositlerden kalsiyum salgılanmasına bağlıdır. Ayrıca, esansiyel trombositoz hastalarında artan serum fosfor düzeyi pıhtılaşma sırasında hücre içinden hücre dışına salınmasıyla ilişkili olabilir. Toksik bir element olan arsenik, trombositlerin yapısal değişikliklerine bağlı olarak ateroskleroza yol açan lipit peroksidasyonunu ve oksidatif stresi tetiklemektedir. Bu çalışmanın amacı serum kalsiyum, fosfor ve arsenik düzeylerindeki değişimlerin esansiyel trombositozun patogenez ve prognozuna etkilerini araştırmaktır. Yöntem: Çalışma grupları esansiyel trombositoz tanısı alan hastalar (Grup-1, n=40), demir eksikliği anemisine bağlı reaktif trombositoz hastaları (Grup-2, n=40) ve sağlıklı kontroller (Grup-3, n=40) olarak oluşturuldu. Serum kalsiyum, fosfor ve arsenik düzeyleri indüktif eşleşmiş plazma atomik emisyon spektrofotometresi kullanılarak analiz edildi. Bulgular: Grup-1’de serum kalsiyum düzeyleri Grup-2 ve Grup-3’e göre anlamlı derecede yüksek olarak belirlendi (sırasıyla; p=0,001, p=0,006). Grup-1 ve Grup-2’nin serum arsenik düzeyleri Grup-3’ten yüksekti (p=0,000). Sonuç: Bu çalışma, değişen yapı ve fonksiyonlarıyla trombositlerin aktivitelerindeki artışı ortaya çıkardı. Esansiyel trombositoz grubunda serum kalsiyum düzeylerinin yüksek olması, aktif trombositlerden hücre dışına salgılanan kalsiyuma bağlı olabileceği düşüncesindeyiz. Benzer şekilde, trombositoz gruplarında serum arsenik düzeyinindeki artış ise, trombosit membranındaki lipit peroksidasyona bağlı olarak oksidatif strese maruz kaldığının göstergesi olabilir.Öğe Some novel 5-benzylidenethiazolo[3,2-b]-1,2,4-triazole-6(5H)-one derivatives in the battle against cancer: Design, synthesis and their biological activities(Elsevier B.V., 2025) Avcı, Ahmet; Aztopal, Nazlıhan; Gökhan Kelekçi, Nesrin; Ulukaya, Engin; Tozkoparan, BirsenConsidering the significant biological potential and the privileged status of the 1,2,4-triazole-5-thione scaffold as one of the essential building blocks in medicinal chemistry, a novel series of 30 new hybrid compounds of 1,2,4-triazole and 5-benzylidenethiazolidinone ring systems, named 5-benzilidene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-one, were designed and synthesized in an attempt to obtain antiproliferative agents and EGFR inhibitors. Synthesized thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones were investigated for their potential cytotoxic properties by cell viability, cell cycle, and cell death analyses. Compounds that exhibited more selective anti-growth activity in A549 cells were further scrutinized, revealing an accumulation in the G1 phase. Notably, compound 6e demonstrated outstanding results and was found to induce apoptosis. Molecular docking studies indicated that the designed compounds could act as EGFR inhibitors. Indeed, compounds 6i and 6j inhibited cell growth prevented EGFR-specific phosphorylation, and thus downregulated EGFR signaling, and inhibited EGFR enzyme activity with IC50 values of 2.46 μM and 4.72 μM, respectively. Additionally, druglikeness and some pharmaceutical properties of the synthesized compounds were predicted. This study underscores the promising therapeutic potential of the novel thiazolo[3,2-b]-1,2,4-triazole derivatives as EGFR inhibitors. © 2024 Elsevier B.V.Öğe The inhibition of RXRα and RXRβ receptors provides valuable insights for potential prostate cancer treatment, in silico molecular docking and molecular dynamics studies(Asian pacific organization for cancer prevention, 2024) Agar, Soykan; Akkurt, Barbaros; Ulukaya, EnginIntroduction: Prostate cancer has emerged as a widespread health concern, with systemic inflammation believed to substantially contribute to its development and progression. The presence of systemic inflammatory responses has been established as an independent predictor of unfavorable long-term outcomes in prostate cancer patients. The goal of this study is to inhibit RXRα and RXRβ receptors, which are involved in prostate cancer, with Luteolin, Formononetin, and Kaempferol, with varying success. Methods: Retinoid X receptors (RXRs) hold crucial roles within the nuclear receptor (NR) superfamily, and compelling evidence from preclinical studies underscores the therapeutic potential of targeting RXRs for treating neurodegenerative and inflammatory conditions. Consequently, the ability to regulate and modulate RXRs using phytoestrogen ligands, Formononetin, Kaempferol, and Luteolin, assume paramount importance in treatment strategies. Results: The comprehensive in silico findings of this study vividly demonstrate the remarkable efficacy of Luteolin in inhibiting and modulating RXRα and RXRβ, while Formononetin emerges as a notably potent suppressor of RXRβ. Kaempferol, as the third compound, also exhibits commendable inhibitory attributes, although its impact is slightly less pronounced compared to the other two. Discussion: These findings highlight the notable binding and inhibition capabilities to RXRα and RXRβ, offering valuable insights for potential prostate cancer treatment avenues warranting further exploration through in vitro and in vivo analyses.Öğe Developmental exposure to the Fox River PCB mixture modulates behavior in juvenile mice(Elsevier, 2024) Wilson, Rebecca J.; Suh, Youjun P.; Dursun, İlknur; Li, Xueshu; Souza, Felipe da Costa; Grodzki, Ana Cristina; Cui, Julia Y.; Lehmler, Hans-JoachimDevelopmental exposures to PCBs are implicated in the etiology of neurodevelopmental disorders (NDDs). This observation is concerning given the continued presence of PCBs in the human environment and the increasing incidence of NDDs. Previous studies reported that developmental exposure to legacy commercial PCB mixtures (Aroclors) or single PCB congeners found in Aroclors caused NDD-relevant behavioral phenotypes in animal models. However, the PCB congener profile in contemporary human samples is dissimilar to that of the legacy Aroclors, raising the question of whether human-relevant PCB mixtures similarly interfere with normal brain development. To address this question, we assessed the developmental neurotoxicity of the Fox River Mixture (FRM), which was designed to mimic the congener profile identified in fish from the PCB-contaminated Fox River that constitute a primary protein source in the diet of surrounding communities. Adult female C57BL/6 J mouse dams (8-10 weeks old) were exposed to vehicle (peanut oil) or FRM at 0.1, 1.0, or 6.0 mg/kg/d in their diet throughout gestation and lactation, and neurodevelopmental outcomes were assessed in their pups. Ultrasonic vocalizations (USVs) and measures of general development were quantified at postnatal day (P) 7, while performance in the spontaneous alternation task and the 3-chambered social approach/social novelty task was assessed on P35. Triiodothyronine (T3) and thyroxine (T4) were quantified in serum collected from the dams when pups were weaned and from pups on P28 and P35. Developmental exposure to FRM did not alter pup weight or body temperature on P7, but USVs were significantly decreased in litters exposed to FRM at 0.1 or 6.0 mg/kg/d in the maternal diet. FRM also impaired male and female pups' performance in the social novelty task. Compared to sex-matched vehicles, significantly decreased social novelty was observed in male and female pups in the 0.1 and 6.0 mg/kg/d dose groups. FRM did not alter performance in the spontaneous alternation or social approach tasks. FRM increased serum T3 levels but decreased serum T4 levels in P28 male pups in the 1.0 and 6.0 mg/kg/d dose groups. In P35 female pups and dams, serum T3 levels decreased in the 6.0 mg/kg/d dose group while T4 levels were not altered. Collectively, these findings suggest that FRM interferes with the development of social communication and social novelty, but not memory, supporting the hypothesis that contemporary PCB exposures pose a risk to the developing brain. FRM had sex, age, and dose-dependent effects on serum thyroid hormone levels that overlapped but did not perfectly align with the FRM effects on behavioral outcomes. These observations suggest that changes in thyroid hormone levels are not likely the major factor underlying the behavioral deficits observed in FRM-exposed animals.Öğe The effects of lithium, metformin and everolimus substances on cell growth in 2D and 3D Ishikawa endometrial carcinoma cell culture(Pamukkale Üniversitesi, 5 Temmuz 2024) Tural, Emine; Çil, Nazlı; Seçme, Mücahit; Mete, Gülçin Abban; Darici, Hakan; Bilir, Ayhan; Karaoz, ErdalPurpose: Our aim is to study the effects of the single and combined treatments of Everolimus, Metformin, and Lithium Chloride in two-dimensional (2D, monolayer) and three-dimensional (3D, spheroid) cell cultures of Ishikawa cells, which comprise the endometrial cancer cell line. Materials and methods: As part of the study, the effects of single and combined forms of Everolimus, Metformin, and Lithium Chloride were determined on cell viability, invasion, colony formation and apoptosis, and PI3K/AKT/mTOR pathway. Cell viability was assessed using XTT assay. CASP3, CASP8, CASP9, FASL, FADD, TNF, TRADD, BAX, P53, PI3KCA, PI3KCB, PTEN, MTOR, AKT1 genes were evaluated with RT-PCR, apoptosis was evaluated by flow cytometry and 3D spheroid results were evaluated with invert microscope analysis. Results: Everolimus, metformin, and lithium's IC50 levels were found at 48 hours to be 37.46 nM, 48.59 mM, and 100 μM, respectively. It was determined that the invasive capacities of Ishikawa cells in treatment groups, as well as cell colony formation were significantly reduced. In addition, Ishikawa spheroid cells were significantly suppressed compared with the control groups. RT-PCR results revealed that substances and their combinations affect genes associated with PI3K/AKT/mTOR pathway and apoptosis. Flow cytometry results showed notably increased apoptosis by single and combined treatments. Conclusion: As a result, the single and combination forms of everolimus, metformin, and lithium have reduced cell proliferation, induced apoptosis, and decreased mTOR activation through various mechanisms in Ishikawa cells. However, our study has shown that Eve alone and triple combination therapy (Eve+Met+Lit) are more effective than other therapies in the treatment of endometrial cancer.Öğe The Results of Untethering Procedures with Intraoperative Neuromonitoring: Occult Spinal Dysraphism and Tethered Spinal Cord Secondary to Myelomeningocele(Halil Erdem Özel, 2018) Canaz, Hüseyin; Erdoğan, Ezgi Tuna; Alataş, İbrahimINTRODUCTION: Using intraoperative neuromonitoringin both primary and secondary tethered cord operations isaccepted as a necessity for a safer operation and guidingsurgeon in complex surgeries.METHODS: Twenty four operations which were monitoredwith three modalities; transcranial motor evoked potentials(TcMEP), free-run electromyography and direct nervestimulations. In group 1, there were 14 patients underwenttethered cord operations due to occult spinal dysraphism, ingroup 2 there were 10 patients underwent tethered cordoperations secondary to previous myelomeningocele repair.RESULTS: TcMEP responses of lower extremity were elicitedin 92 % in group 1, 80 % in group 2. TcMEP responses of analsphincter were elicited in 83 % in group 1, 60 % in group 2. NoTcMEP change was observed during the surgeries in bothgroup. Postoperative urodynamic results of both group wereimproved in 1 year period (78 % in group 1, 43 % in group 2).In patients with hypoactive bladder, we could not take analsphincter responses in TcMEP.DISCUSSION and CONCLUSION: Untethering of spinal cordboth in asymptomatic occult spinal dysraphism and TCSsecondary to MMC, can improve impaired urodynamic results.Intraoperative neuromonitoring and direct stimulation providesinformation for a safer surgery and guide surgical maneuversespecially in secondary untethering. Intraoperativeneurophysiological monitoring is beneficial for operations ofMMC patients with neurological deficits, to preserve theirresidual motor functions. Since anal sphincter functions arecorrelated with bladder functions, it is possible to get no analsphincter TcMEP response if patient has hypoactive bladder.Öğe Crocin Suppresses Inflammatory Response in LPS-Induced Acute Lung Injury (ALI) Via Regulation of HMGB1/TLR4 Inflammation Pathway(Dokuz Eylul University, 31 Mayıs 2024) Ceylan, Tayfun; Akın, Ali; Kaymak, Emin; Varinli, Şaban; Toluk, AyşeBackground and Purpose: The most significant pathogen hypothesized to be causing the formation of Acute lung injury (ALI) in sepsis is thought to be lipopolysaccharide (LPS), a key endotoxin component of gram-negative bacteria. The main objective of this study is to determine possible anti-inflammatory effects of crocin (CRO) which has many biological properties such as anti-inflammatory, antioxidant, and anti-apoptotic in LPS-induced ALI. Methods: 40 Wistar albino rats were divided into four groups: Control (no treatment), CRO (given 50 mg/kg crocin for 9 days), LPS (given 30 mg/kg LPS at 9th day), LPS+CRO (given 50 mg/kg crocin for 9 days and 30 mg/kg LPS at 9th day). After experimental, rats were sacrificed and lungs were extracted. Histological examinations were performed in the lung tissue and the changes in the HMGB1 and TLR4 expressions were determined via immunohistochemical staining. Results and Conclusion: Hemorrhage, mononuclear cell infiltration and HMGB1 and TLR4 expressions significantly increased in the LPS group. However, CRO administrations exerted a strong protective effect on the lungs in terms of these parameters in LPS+CRO group. According to our results, we suggest that CRO can be considered as a protective agent against LPS induced ALI via inhibition of HMGB1/TLR4 pathway-mediated inflammatory response.Öğe Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma(Massachussetts Medical Society, 2024) Dimopoulos, Meletios Athanasios; Beksaç, Meral; Pour, LudekBACKGROUND Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse. METHODS In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed. RESULTS A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group. CONCLUSIONS Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. Copyright © 2024 Massachusetts Medical Society.
