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Öğe An in vitro pilot study investigating placenta-derived mesenchymal stem cell coating on polypropylene mesh materials(Springer London Ltd, 2024) Aslan, Erdogan; Maytalman, Erkan; Samur, Dilara Nemutlu; Kole, Emre; Gunizi, Ozlem CerenIntroduction and hypothesis: Polypropylene meshes (PM) used in pelvic organ prolapse surgery are being withdrawn from the market. Although concerns about the usage of PMs in stress incontinence surgery have been raised, it is still one of the best methods of curing stress urinary incontinence. With advancements in stem cell-based therapies, especially mesenchymal stem cells (MSCs), it is believed that coating the synthetic meshes with MSCs may minimize excessive tissue reactions ultimately leading to clinical problems such as pain, erosion or extrusion of the implanted material. In our study we tried to show the possibility of coating the PM with placenta-derived MSCs.Methods: Mesenchymal stem cells obtained from six placentas were isolated, cultured, and identified. MSCs were then soaked in either fibronectin or collagen prior to co-culturing with strips of PMs. One group is used as a control, and hence was not pretreated before co-culturing. Specimens were fixed and stained with both Gram and hematoxylin and eosin and marked with Vybran Dil and DAPI. All preparations were examined under a light microscope. The IMAGEJ program was utilized to determine the surface area of meshes coated with MSCs.Results: We clearly showed that PMs can be coated successfully with placenta-derived MSCs. The percentage of the coated area is significantly increased when meshes were pretreated with fibronectin or collagen (p<0.0001).Conclusions: Placenta-derived MSCs can successfully coat PMs. The immunomodulatory properties of MSCs, which may be of great advantage in preventing the side effects of meshes, should be tested by in vivo and hopefully human studies before clinical applications.Öğe Drug Repurposing Targeting Mitochondrial Dysfunction in Parkinson's Disease: FBXO7-Focused Approach Through Network Analysis and In Silico Molecular Docking(2025) Samur, Dilara NemutluFBXO7 is a promising but underexplored therapeutic target in Parkinson’s disease (PD), having role in mitophagy, proteasomal degradation, and synaptic function. This study aims to investigate the therapeutic potential of targeting mitochondrial dysfunction in PD through an FBXO7-centered drug repurposing approach. A protein-protein interaction (PPI) network was constructed using the STRING database, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify key pathways associated with FBXO7. Additionally, in silico molecular docking was conducted using the AutoDock Vina algorithm in SwissDock to evaluate the binding affinities of selected clinically approved drugs to FBXO7 and identify promising candidates for potential repurposing in PD treatment. Docking analysis identified several compounds with high binding affinity to FBXO7, including fluorometholone (-6.367 kcal/mol), bendroflumethiazide ( -6.354 kcal/mol), lasofoxifene (-6.173 kcal/mol), penicillin V ( -6.102 kcal/mol), hydromorphone (-6.067 kcal/mol), and cefamandole (-6.036 kcal/mol). These drugs are involved in biological pathways related to mitochondrial function, neuroinflammation, and cellular stress responses, highlighting their potential as disease-modifying agents in PD. However, limitations such as the potential for exacerbating disease progression or systemic side effects may restrict their direct repurposing. This study highlights several clinically approved drugs with high binding affinities to FBXO7, suggesting their potential for targeting mitochondrial dysfunction in PD. While some compounds may present challenges for or direct use, their molecular interactions offer valuable insights for developing novel mitochondrial-targeted therapies. Further experimental validation and structural optimization are required to enhance their therapeutic potential and minimize side effects, paving the way for novel therapeutic strategies in PD.Öğe Investigation of the effects of losartan and captopril on rotenone-induced inflammation via TLR4/NLRP3 pathway: An integrative in vitro and in silico study(Elsevier, 2025) Samur, Dilara NemutluNeuroinflammation is a key contributor to neurodegenerative diseases, including Parkinson's disease (PD). Nonmotor symptoms such as gut-derived inflammation often precede motor deficits and represent an early stage of PD pathology. We aimed to investigate the anti-inflammatory potential of losartan and captopril on rotenoneinduced inflammation in enteric glial cells (EGCs), focusing on the modulation of the TLR4/NLRP3 inflammasome signaling pathway. EGCs were treated with rotenone (1 mu M) to induce inflammation. Non-cytotoxic drug concentrations (10-100 mu M) were identified by cell viability assays. Caspase-1 and IL-1beta levels were quantified via ELISA, and mRNA expression of TLR4/NLRP3 was assessed by RT-qPCR. Molecular docking was performed to predict drug interactions with TLR4 and NLRP3 proteins. Rotenone significantly increased caspase-1 levels and TLR4/NLRP3 expression. Losartan at 10 mu M significantly reduced rotenone-induced NLRP3 mRNA expression, while captopril required a higher concentration (100 mu M) for a comparable inhibitory effect. Paradoxically, losartan and captopril alone increased caspase-1 and/or TLR4 expression, suggesting dose-dependent pro-inflammatory effects. Molecular docking showed a stronger binding affinity for losartan compared to captopril toward TLR4/NLRP3 proteins, consistent with observed biochemical effects. Our results highlight the therapeutic potential of losartan and captopril as modulators of TLR4/NLRP3-mediated inflammation.Öğe Low level laser application reduces the effect of 5 fluorouracil/leucovorin combination on human breast cancer cells(2020) Güler, Yılmaz; Övey, İshak Suat; Samur, Dilara Nemutlu; Karabulut, BayhanAim : 5-fluorouracil has been widely used in breast cancer treatment. Low level laser therapy (LLLT) has been shown to modulate biological processes and used in cancer treatment. It has been reported that apoptosis is induced by stimulation of transient receptor potential protein channels in numerous cancer cells, including breast cancer. We aimed to reveal the effects of 5-fluorouracil / Leucovorin (5-FU/LV) and . low level laser on apoptosis via transient receptor protein ancyrin 1 (TRPA1) channels. Material and Methods: Breast cancer cells (MCF-7) were cultured and cells were divided into seven main groups. Cells were incubated with 5-FU/LV and LLLT exposure separately and together performed on MCF-7 cell cultures. Cell cultures incubated with TRPV1 channel antagonist capsazepin and stimulator capsaicin. The effects of 5-FU and LLLT were investigated on all molecular pathways of apoptosis. Results: It was found that the levels of apoptosis in 5-FU/LV group were significantly increased in cancer cells compared to control group .TRPA1 channel stimulator administration resulted in significantly increased apoptosis levels compared to the control group, in 5-FU/LV + low level laser group the apoptosis level significantly reduced compared to 5-FU/LV-only group. (p<0.001) Conclusion: It has been shown that 5-FU/LV significantly increases apoptosis in breast cancer cells, however low level laser administration decreases apoptosis and suppressed apopitotic effect of 5-FU/LV significantly on breast cancer cells.Öğe Metamizole limits proliferation in chronic myeloid leukemia cells and triggers apoptosis via the bax/bcl-2/caspase-3 cascade(Humana Press Inc, 2025) Maytalman, Erkan; Samur, Dilara NemutluMetamizole is a controversial non-steroidal anti-inflammatory drug because it may cause agranulocytosis usually in long-term use. It may reduce proliferation while increasing apoptosis in some cancer cells. In our study, the effects of increasing concentrations of metamizole on chronic myeloid leukemia (CML) cell line K562 were evaluated in terms of proliferation and apoptosis. K562 cells were cultured with 1,10,50,100 mu M concentrations of metamizole in addition to the control group. The effect on cell proliferation was determined by MTT and analysis of mitotic cell counts. The apoptotic effects were analyzed by flow cytometry using Annexin V/Propidium iodide, ELISA for caspase-3 concentrations, and RT-qPCR for Bax-Bcl-2 mRNA expression levels. Evaluations were performed for 24 and 48 h of exposure. MTT assay revealed that metamizole limited the proliferation of cells at 10 mu M concentration. Caspase-3 concentrations increased in cells exposed to concentrations of 50 mu M and above. Flow cytometry results obtained using Annexin V/PI showed that especially 50 and 100 mu M concentrations promoted apoptosis compared to the control. Bcl-2 mRNA expression was also significantly decreased at concentrations of 50 and 100 mu M, while Bax mRNA expression was significantly increased only for 100 mu M. Mitotic cell numbers also decreased with increasing concentrations. The known adverse effect of metamizole, agranulocytosis, suggests it may negatively affect cell proliferation. In this study, metamizole had both antiproliferative and pro-apoptotic effects on K562. The results of our study indicate that the synergistic effects of metamizole in the treatment of CML, especially in cases resistant to tyrosine kinase inhibitors, should be evaluated with further studies under in vitro and in vivo conditions.Öğe Metamizole modulates the concentrations of cytokines and hematopoietic growth factors in an experimental model of depression(2025) Maytalman, Erkan; Kıroğlu, Olcay; Berktaş, Fatih; Samur, Dilara Nemutlu; Aksu, FazıletObjective: In recent years, evidence of antidepressant-like activity of non-steroidal anti-inflammatory drugs has been presented. Furthermore, associations between cytokines, which are important components of the immune system, as well as hematopoietic growth factors and depression have also been demonstrated. In this study, it was aimed to analyze the effect of metamizole on the expression of cytokines and hematopoietic growth factors in mice exposed to unpredictable stress models. Method: In order to develop chronic depression behaviors, an unpredictable chronic mild stress model was applied to mice. The depression group was not given any drug and other groups were given 100 and 200 mg/kg metamizole. Forced swimming test was performed to evaluate the effect of metamizole against depression. Relative concentrations of interleukin-1 alpha (IL-1?), IL-1 beta (IL-1-ß), IL-2, IL-4, IL-6, IL-10, IL-12, IL-17, Interferon gamma (IFN-?)-, tumor necrosis factor-alpha (TNF-?), Granulocyte-colony-stimulating factor (G-CSF), and Granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in serum samples of animals with semi-quantitative ELISA. Results: In the forced swimming test, the immobility time of the depression group significantly increased compared to the control group. The immobility time of groups treated with metamizole significantly decreased compared to the depression group and approached the control. Significant decreases were observed in the relative concentration levels of cytokines and hematopoietic growth factors in the groups treated with 100 and/or 200 mg/kg metamizole compared to the depression group except for IL-1?, IL-4, and IL-10. Conclusion: Evidence showing the contribution of COX enzymes to the pathophysiology of depression is increasing. In this context, the results indicate that metamizole, which can inhibit both isoforms of COX, may cause changes in cytokine levels and hematopoietic growth factors in a depression model. However, more controlled clinical studies are needed.Öğe Metamizole Reduces The Expression of OCT4, SOX2, SOX4 in Hematopoietic Stem/Progenitor Cells Directed to Differentiation in In Vitro Hematopoiesis Simulation(2025) Maytalman, Erkan; Samur, Dilara NemutluAim: Metamizole is a non-steroidal anti-inflammatory drug used for its analgesic and antipyretic effects. Metamizole-associated agranulocytosis is a significant adverse effect limiting its use in some countries, but it has also been shown to promote apoptosis in cancer cells with possible mechanisms underlying this adverse effect. The mechanisms underlying these effects have not been sufficiently elucidated. Methods: The cells obtained from stem cell product samples collected from healthy allogeneic stem cell donors were used in the study. MTT assay was used to analyse the proliferative-cytotoxic effects of metamizole on cells. CFU-Mix culture was also performed for cell differentiation to granulocyte and analysis of expression of OCT4, SOX2, SOX4. The expression fold change of transcription factors was determined by RT-qPCR. Results: Metamizole limited the proliferation of cells at increasing concentrations starting at 10 µM. The IC50 values of metamizole were significantly different between the samples. The lowest value for IC50 was 50.96±7.60 µM and the highest value was 165.5±18.21 µM. Granulocyte-macrophage colony counts and OCT4, SOX4 mRNA expressions decreased at metamizole concentrations of 10 and 100 µM. For SOX2, the decrease occurred at a concentration of 100 µM. Conclusion: Our results indicated that metamizole may limit the proliferation and differentiation of hematopoietic stem/progenitor cells via transcription factors and this effect may be responsible for possible agranulocytosis cases. NSAIDs have also been shown to have apoptotic effects on cancer cells. The ability to limit the expression of transcription factors that play important roles in cell development and differentiation may pave the way for the synergistic use of this drug with antineoplastic drugs.Öğe Mikroglial Toll-benzeri Reseptörlerin Alzheimer ve Parkinson Hastalıklarındaki Rolü(Akdeniz Üniversitesi, 2021) Samur, Dilara Nemutlu; Özbey, GülPatern tanıma reseptörleri içinde en iyi tanımlanmış olan Toll-benzeri reseptörler, santral sinir sisteminde ?makrofaj benzeri? fonksiyona sahip mikroglia hücrelerinde bulunurlar. Amiloid-beta proteini ve agrege ?-sinüklein gibi hasarla ilişkili moleküler motifleri tanıyan Toll-benzeri reseptörler, mikroglia hücrelerinin proinflamatuar fenotipe kaymasına neden olarak ve tümör nekroz faktör-alfa (TNF-?), interlökin (IL)-1, IL-6, IL-12 gibi proinflamatuar mediyatörler aracılığıyla inflamasyonu tetikler. Nörodejeneratif hastalıklarda mikroglial Toll-benzeri reseptör aracılı sinyalizasyonun önemli bir role sahip olduğu gösterildiği için Alzheimer ve Parkinson hastalıklarında (i) aşılar, (ii) küçük moleküllü inhibitörler, (iii) var olan ilaçların yeni bir endikasyon için kullanılması ve (iv) doğal bileşikler gibi Toll-benzeri reseptörleri hedef alan yeni tedavi yaklaşımları bulunmaktadır. Preklinik çalışmalarda başarılı sonuçlar göstermiş olan ilaç adaylarının birçoğu klinik fazlarda aynı başarıyı yakalayamamıştır. Buna rağmen, Toll-benzeri reseptörler ve sinyal yolakları üzerinde etkili moleküllerle ilgili çalışmaların sayısı artmaya devam etmektedir.Öğe Neuroendocrine modulation by metamizole and indomethacin: investigating the impact on neuronal markers and GnRH release(Springer, 2024) Maytalman, Erkan; Samur, Dilara NemutluPurposeSome evidence that non-steroidal anti-inflammatory drugs have neuroprotective effects indicates their potential for use in a new field. However, their effects on hormone secretion have yet to be adequately discovered. Therefore, we aimed to evaluate the effects of metamizole and indomethacin on neuronal markers as well as the GnRH expression in the GT1-7 cell line.MethodsThe effects of these drugs on proliferation were evaluated by MTT analysis. The effect of 10-50-250 mu M concentrations of the drugs also on the expression of neuronal factors and markers, including NGF, nestin and beta III Tubulin, and additionally GnRH, was determined by the RT-qPCR method.ResultsNGF and nestin mRNA expressions were increased in all concentrations of both metamizole and indomethacin. No changes were detected in beta III Tubulin. While metamizole showed an increase in GnRH mRNA expression, there was no change at 10 and 50 mu M concentrations of indomethacin, but a remarkable decrease was observed at 250 mu M concentrations.ConclusionsThe results of our study showing an increase in the expression of neuronal factors reveal that metamizole and indomethacin may have possible neuroprotective effects. Moreover, the effects on the GnRH expression appear to be different. Animal models are required to confirm these effects of NSAIDs on neurons.Öğe Sıçan Kökenli Enteroglial Hücrelerde Rotenon ile İndüklenen İnflamatuvar Değişiklikler Üzerine Vortioksetinin Etkileri: TLR4/NF?B Sinyal Yolağının Rolü(Eskişehir Osmangazi Üniversitesi, 2025) Samur, Dilara Nemutlu; Maytalman, Erkan; Zorlu, ÖyküParkinson hastalığı (PH) progresif bir nörodejeneratif hastalık olup günümüzde hastalığı durdurmaya yönelik kesin bir tedavi seçeneği bulunmamaktadır. Gastrointestinal inflamasyon, PH ile ilişkili motor-olmayan bulgulardan biridir. Son yıllarda antidepresanların potansiyel antiinflamatuvar etkileri nedeniyle nörodejeneratif hastalıkların tedavisinde kullanılabileceğine dair ilgi artmıştır. Bu çalışmada, vortioksetinin enterik glia hücrelerinde rotenon ile indüklenen inflamatuvar yanıtlar üzerindeki etkisi ve bu etkisinde TLR4/NF-?B sinyal yolağının rolü araştırılmıştır. Rotenon (10 ?M) ve vortioksetin (1 ve 5 ?M) ile muamele edilmiş hücre örneklerinde TLR4 ve NF-?B mRNA ekspresyonları RT-qPCR ile, TNF-?, IL-1? ve IL-6 düzeyleri ise ELISA yöntemiyle değerlendirilmiştir. Bulgular, rotenonun glial hücrelerin immün yanıtlarını bozarak TLR4 ve NF-?B ekspresyonunu belirgin şekilde baskıladığını ve bu etkinin 5 ?M vortioksetin uygulamasıyla daha da arttığını göstermiştir. Ayrıca rotenon gruplarında TNF-? ve IL-1? düzeylerinde gözlenen düşüş, vortioksetin uygulaması ile tersine dönmüştür. Sonuçlar, vortioksetinin enterik glia hücrelerinde TLR4/NF-?B yolakları üzerinden inflamatuvar yanıtı düzenleyebileceğini ve PH’nin bağırsak-beyin eksenine dayalı inflamasyon modelinde potansiyel bir terapötik madde olarak çalışılabileceğini göstermektedir.Öğe The effect of thymoquinone and propranolol combination on epidermoid laryngeal carcinoma cell(Springer, 2023) Sahin, Caner; Maytalman, Erkan; Samur, Dilara Nemutlu; Dogan, BoraPurpose We aimed to evaluate the effects of thymoquinone and propranolol on Hep-2 cells representing laryngeal Ca cell type in comparison with cisplatin. We also evaluated their combined effects. Methods Apoptotic effects were directly analyzed via mitochondrial membrane potential and caspase-3 assays. In addition, effects on apoptosis and cell cycle via Bcl-2, Bax, P53, and Cyclin D1 mRNA expressions and effects on angiogenesis via VEGFA mRNA expression were evaluated by RT-qPCR. Results According to our results, it was determined that the anticancer effects of thymoquinone on Hep-2 cells were higher than propranolol. Our JC-1 and caspase-3 results showed an effect close to cisplatin, especially for 50 mu M thymoquinone. Significant differences were also obtained in Bcl-2, Bax, P53, and cyclin D1 results for similar concentrations compared to the control. No effect of thymoquinone was seen for VEGFA. Propranolol alone had no significant effect on JC-1 and Caspase-3. Propranolol had an effect on Bcl-2, Bax mRNA expressions compared to the control, only at 250 mu M concentration. Propranolol and its combinations increased VEGFA mRNA expression-like cisplatin. Conclusion Thymoquinone induced apoptosis and blocked the cell cycle in Hep-2 cells. The effects of propranolol, which was reported to have an antiangiogenesis effect in some studies, on apoptosis and cell cycle were limited except at high concentrations. For this cell line, why propranolol causes an increase in VEGFA expression should be evaluated extensively. Thymoquinone shows promise for cancer therapy, but studies need to be designed in vivo to evaluate the effects more reliably.Öğe The effects of metamizole on hematopoietic progenitor cells: Suppression of hematopoiesis stimulation in vitro(2023) Maytalman, Erkan; Samur, Dilara Nemutlu; Günizi, Özlem Ceren; Kozanoğlu, lknurBACKGRAUND: There is evidence that the adverse effects of metamizole occur due to the effect of the drug on the hematopoietic stem/progenitor cells, and therefore, the disruption of hematopoiesis. Therefore, our study aimed to evaluate the effects of metamizole on hematopoietic stem/progenitor cells using cell culture techniques. MATERIAL AND METHODS: In our study, samples were taken from stem cell products of healthy allogeneic stem cell transplant donors. The colony-forming unit (CFU) assay was used for the cells obtained from these samples. In addition, the drug effects on cell proliferation were evaluated with the MTT. Furthermore, the cell colonies were labelled with immunofl uorescent antibodies and the effects of metamizole on cell types formed in culture were evaluated. RESULTS: We determined that metamizole negatively affects the proliferation of cells, especially starting from 10 ?M. As a result of the evaluation of colonization, we saw that the number of colonies decreased with increasing concentrations. Granulocyte-macrophage colonies were more affected at increasing concentrations than other colonies. As a result of the evaluations of our in vitro study, it was also shown as an important fi nding that the individual effects of the drug were highly variable. CONCLUSION: CFU method can be used as a suitable method to investigate the effects of drugs and toxic substances on hematopoiesis. We also think it may be suitable for pre-analysing hematopoietic side effects in new drug research. In addition, using stem cell samples in studies may contribute more easily to the in vitro simulation of hematopoietic differentiations (Fig. 7, Ref. 29)Öğe The possible mechanisms of protocatechuic acid-induced central analgesia(Elsevier Science Bv, 2018) Arslan, Rana; Aydın, Şule; Samur, Dilara Nemutlu; Bektaş, NurcanIt is aimed to investigate the central antinociceptive effect of protocatechuic acid and the involvement of stimulation of opioidergic, serotonin 5-HT2A/2C. alpha 2-adrenergic and muscarinic receptors in protocatechuic acid-induced central analgesia in mice. Time-dependent antinociceptive effects of protocatechuic acid at the oral doses of 75,150 and 300 mg/kg were tested in hot-plate (integrated supraspinal response) and tail-immersion (spinal reflex) tests in mice. To investigate the mechanisms of action; the mice administered 300 mg/kg protocatechuic acid (p.o.) were pre-treated with non-specific opioid antagonist naloxone (5 mg/kg, i.p.), serotonin 5-HT2A/(2c) receptor antagonist ketanserin (1 mg/kg, i.p.), alpha 2-adrenoceptor antagonist yohimbine (1 mg/kg, l.p.) and non-specific muscarinic antagonist atropine (5 mg/kg, l.p.), respectively. The antinociceptive effect of protocatechuic acid was observed at the doses of 75, 150 and 300 mg/kg in tail-immersion test, at the doses of 150 and 300 mg/kg in hot-plate test at different time interval. The enhancement in the latency of protocatechuic acid-induced response to thermal stimuli was antagonized by yohimbine, naloxone and atropine in tail-immersion test, while it was antagonized only by yohimbine and naloxone pretreatments in hot-plate test. These results indicated that protocatechuic acid has the central antinociceptive action that is probably organized by spinal mediated cholinergic and opiodiergic, also spinal and supraspinal mediated noradrenergic modulation. However, further studies are required to understand how protocatechuic acid organizes the interactions of these modulatory systems. As a whole, these findings reinforce that protocatechuic acid is a potential agent that might be used for pain relief. Additionally, the clarification of the effect and mechanisms of action of protocatechuic acid will contribute to new therapeutic approaches and provide guidance for new drug development studies. (C) 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.Öğe Transcranial direct current stimulation alleviates nociceptive behavior in male rats with neuropathic pain by regulating oxidative stress and reducing neuroinflammation(Wiley, 2023) Akcay, Guven; Samur, Dilara Nemutlu; Derin, NarinTranscranial direct curent stimulation (tDCS) and trans--spinal direct current stimulation (tsDCS) are promising therapies for pain that can alter the excitability of neuronal activity in cerebral cortex. The aim of the study is to investigate the therapeutic effects of direct current stimulation (DCS) over the spinal cord and cerebral cortex on oxidative stress and neuroinflammation in rats with chronic constriction injury (CCI). Male Wistar rats were randomly divided into four experimental groups: Sham, CCI, CCI + tDCS and CCI + tsDCS. The neuropathic pain model was induced by using the CCI model. Rats with neuropathy were treated with cathodal tDCS and tsDCS stimulations consisting of 0.5 mA for 30 min a day for 7 days from day 8 onwards. Locomotor activity was measured by open--field test and nociceptive behavior was assessed by hot--plate, tail--flick and Randall--Selitto tests. Following the behavioral experiments, total oxidant capacity ( TOC), total antioxidant capacity (TAC) and proinflammatory cytokine levels were evaluated in spinal cord and cerebral cortex tissues. The CCI model induced significant mechanical and thermal hyperalgesia. Nociceptive behaviors in rats with CCI were reversed by DCS treatment. Higher TOC and lower TAC levels were detected in the spinal cord and cerebral cortex tissues of the CCI rats compared to the control. tsDCS treatment amended oxidant/antioxidant status. Moreover, tsDCS modulated the central levels of Tumor necrosis factor--a (TNF--a), interleukin 1--beta (IL--1 ss), IL- -6 and IL--18. tsDCS stimulation showed better therapeutic effect on neuropathic pain by regulating oxidant/antioxidant levels and reducing neuroinflammation. DCS, especially at spinal level, may be a promising therapeutic strategy that can be used alone or in combination with other effective treatments for alleviating neuropathic pain.Öğe Valnoctamide: The effect on relieving of neuropathic pain and possible mechanisms(Elsevier Science Bv, 2018) Samur, Dilara Nemutlu; Arslan, Rana; Aydın, Şule; Bektaş, NurcanThe purpose of this study is to assess the possible anti-allodynic and antihyperalgesic effect of valnoctamide, an amide derivative of valproic acid, at the doses of 40, 70 and 100 mg/kg (i.p.) in neuropathic pain model induced by chronic constriction injury in rats, by using dynamic plantar test and plantar test (Hargreaves method), and to evaluate that the possible role of certain serotonin, noradrenergic, opioid and GABAergic receptors by pretreatment with 1 mg/kg (i.p.) ketanserin, yohimbine, naloxone and 0.5 mg/kg (i.p.) bicuculline, respectively. 70 and 100 mg/kg valnoctamide significantly increased the mechanical and thermal thresholds decreasing with the development of neuropathy and demonstrated anti-allodynic and antihyperalgesic activity. Limited contribution of serotonin 5-HT2A/2C receptors and alpha 2-adrenoceptors, and significant contribution of GABA(A) and opioid receptors to the anti-allodynic activity have been identified whereas remarkable contribution of opioid receptors and significant contribution of serotonin 5-HT2A/2C receptors, alpha 2-adrenoceptors, GABA(A) receptors to the antihyperalgesic activity have been identified. Based upon these findings and considering that valnoctamide has safer side-effect profile, it is possible to say that valnoctamide is a potential agent that might be used alone or in combination with the other effective therapies in the alleviating of neuropathic pain.Öğe Vortioksetinin, Enterik Sinir Sisteminde Rotenon Maruziyeti Ile Indüklenen Patofizyolojik Değişiklikler Üzerine Etkilerinde Tlr2/S100b Sinyal Yolağının Rolü(2023) Samur, Dilara Nemutlu; Özbey, Gül; Maytalman, Erkan; Tanriover, Gamze; Kalay, Merzuka; Yikit, MuratAmaç: Enterik sinir sistemi patolojisi, Parkinson hastalığında en erken görülen bulgular arasındadır. Hatta, hastalığın enterik sistemden başlayarak beyin bölgelerine yayıldığı düşünülmektedir. Enteroglial hücreler (EGC?ler), beyindeki astrositlerin eşdeğerini temsil eder. Bu hücreler inflamasyon varlığında aktive olur, S100B ve Toll-benzeri reseptör (TLR)?ler aracılığıyla proinflamatuvar sitokin salımına neden olur. Gastrointestinal semptomlar ile duygudurum bozuklukları arasındaki çift yönlü ilişki de göz önünde bulundurularak, bu çalışmada, serotonerjik bir antidepresan olan vortioksetinin ESS?de rotenon tarafından indüklenen patofizyolojik değişiklikler üzerine olan etkilerinin ve olası etki mekanizmalarının aydınlatılması amaçlandı. Yöntem: 28 gu?n boyunca rotenon (2 mg/kg/gu?n, s.c.) ve/veya vortioksetin (10 mg/kg/gu?n, s.c.) uygulanan sıçanlardan elde edilen duodenum dokularında tirozin hidroksilaz (TH), ?-sinu?klein, serin-129 bölgesinde fosforile olmuş ?-sinu?klein, TLR2 ve S100B ekspresyonlarını belirlendi. Etki mekanizması çalışmaları için, sıçanlardan dönüştürülmüş EGC?ler, rotenon (10 uM) ve/veya vortioksetin (5 uM veya 1 uM) ile muamele edildi. Kontrol, rotenon, yüksek doz vortioksetin (5 ?M, V1), düşük doz vortioksetin (1 ?M, V2), ROT+V1 ve ROT+V2 grupları oluşturuldu. Vortioksetinin etkileri, TLR2 antagonisti C29 ve S100B inhibitörü pentamidin varlığında da değerlendirildi. S100B, TLR2 ve NF?B mRNA seviyeleri RT-qPCR, proinflamatuvar sitokin seviyeleri ise ELISA yöntemi ile tayin edildi. Bulgular: İn vivo çalışmalarda, rotenon uygulaması ile duodenum dokusunda artış gösteren inflamatuvar belirteçlerin ekspresyonları vortioksetin uygulaması ile azaldı. İn vitro çalışmalarda, rotenonun toksik etkiler aracılığıyla glial hücre yanıtlarını bozarak S100B ve NF?B gibi belirteçlerin azalmasına yol açtığı, vortioksetinin ise hücresel yanıtları iyileştirerek EGC?lerin inflamatuvar molekülleri yeniden sentezleyebilmesini sağladığı gösterildi. C29 ve pentamidin uygulamalarıyla hem S100B ve NF?B mRNA ekspresyon düzeyleri hem de TNF-?, IL-1ß ve IL-6 seviyelerinde anlamlı değişiklikler meydana geldi. Sonuç: Bu çalışma, vortioksetinin duodenum dokusunda ve EGC?lerde rotenon ile indüklenen patolojik değişiklikler üzerinde yararlı etkileri olduğunu gösteren ilk çalışmadır. Vortioksetinin göstermiş olduğu bu etkilerinin bir kısmına S100B/TLR2/NF?B yolağının aracılık ettiği düşünülmektedir.Öğe Vortioxetine ameliorates motor and cognitive impairments in the rotenone-induced Parkinson's disease via targeting TLR-2 mediated neuroinflammation(Pergamon-Elsevier Science Ltd, 2022) Samur, Dilara Nemutlu; Akcay, Guven; Yildirim, Sendegul; Ozkan, Ayse; Ceker, Tugce; Derin, Narin; Tanriover, GamzeParkinson's disease (PD) is characterized by motor and non-motor symptoms associated with dopaminergic and non-dopaminergic injury. Vortioxetine is a multimodal serotonergic antidepressant with potential procognitive effects. This study aimed to explore the effects of vortioxetine on motor functions, spatial learning and memory, and depression-like behavior in the rotenone-induced rat model of PD. Male Sprague-Dawley rats were daily administered with the rotenone (2 mg kg(-1), s.c.) and/or vortioxetine (10 mg kg(-1), s.c.) for 28 days. Motor functions (rotarod, catalepsy, open-field), depression-like behaviors (sucrose preference test), anxiety (elevated plus maze), and spatial learning and memory abilities (novel object recognition and Morris water maze) were evaluated in behavioral tests. Then immunohistochemical, neurochemical, and biochemical analysis on specific brain areas were performed. Vortioxetine treatment markedly reduced rotenone-induced neurodegeneration, improved motor and cognitive dysfunction, decreased depression-like behaviors without affecting anxiety-like parameters. Vortioxetine also restored the impaired inflammatory response and affected neurotransmitter levels in brain tissues. Interestingly, vortioxetine was thought to trigger a sort of dysfunction in basal ganglia as evidenced by increased Toll-like receptor-2 (TLR-2) and decreased TH immunoreactivity only in substantia nigra tissue of PD rats compared to the control group. The present study indicates that vortioxetine has beneficial effects on motor dysfunction as well as cognitive impairment associated with neurodegeneration in the rotenone-induced PD model. Possible mechanisms underlying these beneficial effects cover TLR-2 inhibition and neuro -chemical restoration of vortioxetine.Öğe Vortioxetine attenuates rotenone-induced enteric neuroinflammation via modulation of the TLR2/S100B/RAGE signaling pathway in a rat model of Parkinson's disease(Pergamon-Elsevier Science Ltd, 2025) Samur, Dilara Nemutlu; Yildirim, Sendegul; Maytalman, Erkan; Kalay, Merzuka; Tanriover, Gamze; Ozbey, GulEmerging evidence suggests that gastrointestinal dysfunction and enteric nervous system pathology play a critical role in the early stages of Parkinson's disease. Considering the bidirectional relationship between gastrointestinal symptoms and mood disorders, this study aimed to elucidate the effects and possible mechanisms of action of vortioxetine, a serotonergic antidepressant, on the pathophysiological changes induced by rotenone in the enteroglial cells. alpha-synuclein, phosphorylated alpha-synuclein, TLR2, S100B and RAGE expression were detected in duodenal tissues of rats administered rotenone (2 mg/kg/day, s.c.) and/or vortioxetine (10 mg/kg/ day, s.c.) for 28 days. For the mechanism of action studies, rat-derived enteroglial cells were treated with rotenone (10 mu M) and/or vortioxetine (5 mu M or 1 mu M) for 24 h. The effects of vortioxetine were evaluated in the presence of the TLR2 antagonist C29, RAGE antagonist FPS-ZM1 and the S100B inhibitor pentamidine. TLR2, S100B, RAGE, and NF kappa B mRNA levels and proinflammatory cytokines via RT-qPCR and ELISA. Our results demonstrate that rotenone treatment significantly increased alpha-synuclein, pS129-alpha-synuclein, TLR2, and S100B expression while reducing RAGE levels, indicating marked enteric pathology. Vortioxetine administration attenuated these effects, reducing alpha-synuclein accumulation and proinflammatory markers. In vitro, rotenone impaired glial responses, decreasing S100B, RAGE, and NF kappa B markers, while vortioxetine improved these responses, promoting resynthesis of inflammatory molecules. Notably, S100B, NF kappa B, and cytokine levels (TNF-alpha, IL-1 beta, IL-6) were affected by C29, FPS-ZM1, and pentamidine pretreatments. Thus, vortioxetine is thought to have beneficial effects on rotenone-induced pathological changes in EGCs, and some of these effects are thought to be mediated by the TLR2/S100B/RAGE pathway.
