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Öğe A highly bioavailable curcumin formulation ameliorates inflammation cytokines and neurotrophic factors in mice with traumatic brain injury(John Wiley and Sons Inc, 2024) Şakul, Ayşe Arzu; Balçıkanlı, Zeynep; Ateş Özsoy, Nilay; Orhan, Cemal; Şahin, Nurhan; Tuzcu, Mehmet; Juturu, Vijaya; Kılıç, Ertuğrul; Şahin, KazımA novel curcumin formulation increases relative absorption by 46 times (CurcuWIN®) of the total curcuminoids over the unformulated standard curcumin form. However, the exact mechanisms by which curcumin demonstrates its neuroprotective effects are not fully understood. This study aimed to investigate the impact of a novel formulation of curcumin on the expression of brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), a main component of the glial scar and growth-associated protein-43 (GAP-43), a signaling molecule in traumatic brain injury (TBI). Mice (adult, male, C57BL/6j) were randomly divided into three groups as follows: TBI group (TBI-induced mice); TBI + CUR group (TBI mice were injected i.p. curcumin just after TBI); TBI+ CurcuWIN® group (TBI mice were injected i.p. CurcuWIN® just after TBI). Brain injury was induced using a cold injury model. Injured brain tissue was stained with Cresyl violet to evaluate infarct volume and brain swelling, analyzed, and measured using ImageJ by Bethesda (MD, USA). Western blot analysis was performed to determine the protein levels related to injury. While standard curcumin significantly reduced brain injury, CurcuWIN® showed an even greater reduction associated with reductions in glial activation, NF-?B, and the inflammatory cytokines IL-1? and IL-6. Additionally, both standard curcumin and CurcuWIN® led to increased BDNF, GAP-43, ICAM-1, and Nrf2 expression. Notably, CurcuWIN® enhanced their expression more than standard curcumin. This data suggests that highly bioavailable curcumin formulation has a beneficial effect on the traumatic brain in mice.Öğe A novel theanine complex, Mg-L-Theanine improves sleep quality via regulating brain electrochemical activity(Frontiers Media S.A., 2022) Daşdelen, Muhammed Furkan; Er, Sezgin; Kaplan, Berkan; Çelik, Süleyman; Beker, Mustafa Çağlar; Orhan, Cemal; Tuzcu, Mehmet; Şahin, Nurhan; Mamedova, Havakhanum; Sylla, Sarah; Komorowski, James; Ojalvo, Sara PerezL-Theanine is commonly used to improve sleep quality through inhibitory neurotransmitters. On the other hand, Mg2+, a natural NMDA antagonist and GABA agonist, has a critical role in sleep regulation. Using the caffeine-induced brain electrical activity model, here we investigated the potency of L-theanine and two novel Mg-L-theanine compounds with different magnesium concentrations on electrocorticography (ECoG) patterns, GABAergic and serotonergic receptor expressions, dopamine, serotonin, and melatonin levels. Furthermore, we evaluated the sleep latency and duration in the pentobarbital induced sleep model. We herein showed that L-theanine, particularly its various complexes with magnesium increases the expression of GABAergic, serotonergic, and glutamatergic receptors, which were associated with decreased ECoG frequency, increased amplitude, and enhanced delta wave powers. Besides increased dopamine, serotonin, and melatonin; decreased MDA and increased antioxidant enzyme levels were also observed particularly with Mg-complexes. Protein expression analyses also showed that Mg-L-theanine complexes decrease inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) levels significantly. In accordance with these results, Mg complexes improved the sleep latency and duration even after caffeine administration. As a result, our data indicate that Mg-L-theanine compounds potentiate the effect of L-theanine on sleep by boosting slow-brain waves, regulating brain electrical activity, and increasing neurotransmitter and GABA receptor levels.Öğe Allyl isothiocyanate attenuates oxidative stress and inflammation by modulating Nrf2/HO-1 and NF-kappa b pathways in traumatic brain injury in mice(Springer, 2019) Çağlayan, Berrak; Kılıç, Ertuğrul; Dalay, Arman; Altunay, Serdar; Tuzcu, Mehmet; Erten, Füsun; Orhan, Cemal; Günal, Mehmet Yalçın; Yuluğ, Burak; Juturu, Vijaya; Şahin, KazımTraumatic brain injury (TBI) is the leading cause of mortality and morbidity in young adults and children in the industrialized countries; however, there are presently no FDA approved therapies. TBI results in oxidative stress due to the overproduction of reactive oxygen species and overwhelming of the endogenous antioxidant mechanisms. Recently, it has been reported that antioxidants including phytochemicals have a protective role against oxidative damage and inflammation after TBI. To analyze the effects of a naturally occurring antioxidant molecule, allyl isothiocyanate (AITC), on the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-kappa B) signaling pathways in TBI, a cryogenic injury model was induced in mice. Here, we showed that AITC administered immediately after the injury significantly decreased infarct volume and blood-brain barrier (BBB) permeability. Protein levels of proinflammatory cytokines interleukin-1 beta (IL1 beta) and interleukin-6 (IL6), glial fibrillary acidic protein (GFAP) and NF-kappa B were decreased, while Nrf2, growth-associated protein 43 (GAP43) and neural cell adhesion molecule levels were increased with AITC when compared with vehicle control. Our results demonstrated that the antioxidant molecule AITC, when applied immediately after TBI, provided beneficial effects on inflammatory processes while improving infarct volume and BBB permeability. Increased levels of plasticity markers, as well as an antioxidant gene regulator, Nrf2, by AITC, suggest that future studies are warranted to assess the protective activities of dietary or medicinal AITC in clinical studies.Öğe Allyl isothiocyanate enhances brain neuronal plasticity proteins via inhibition of inflammation proteins(Lippincott Williams & Wilkins, 2018) Juturu, Vijaya; Çağlayan, Berrak; Kılıç, Ertuğrul; Dalay, Arman; Tuzcu, Mehmet; Erten, Füsun; Günal, Mehmet Yalçın; Altunay, Serdar; Orhan, Cemal; Şahin, Kazım[Abstract Not Available]Öğe Cinnamon polyphenol extract exerts neuroprotective activity in traumatic brain injury in male mice(Bentham Science Publishers Ltd, 2018) Yuluğ, Burak; Kılıç, Ertuğrul; Altunay, Serdar; Ersavaş, Cenk; Orhan, Cemal; Dalay, Arman; Tuzcu, Mehmet; Şahin, Nurhan; Juturu, Vijaya; Şahin, KazımIntroduction: Cinnamon polyphenol extract is a traditional spice commonly used in different areas of the world for the treatment of different disease conditions which are associated with inflammation and oxidative stress. Despite many preclinical studies showing the anti-oxidative and anti-inflammatory effects of cinnamon, the underlying mechanisms in signaling pathways via which cinnamon protects the brain after brain trauma remained largely unknown. However, there is still no preclinical study delineating the possible molecular mechanism of neuroprotective effects cinnamon polyphenol extract in Traumatic Brain Injury (TBI). The primary aim of the current study was to test the hypothesis that cinnamon polyphenol extract administration would improve the histopathological outcomes and exert neuroprotective activity through its antioxidative and anti-inflammatory properties following TBI. Methods: To investigate the effects of cinnamon, we induced brain injury using a cold trauma model in male mice that were treated with cinnamon polyphenol extract (10 mg/kg) or vehicle via intraperitoneal administration just after TBI. Mice were divided into two groups: TBI+vehicle group and TBI+ cinnamon polyphenol extract group. Brain samples were collected 24 h later for analysis. Results: We have shown that cinnamon polyphenol extract effectively reduced infarct and edema formation which were associated with significant alterations in inflammatory and oxidative parameters, including nuclear factor-KB, interleukin 1-beta, interleukin 6, nuclear factor erythroid 2-related factor 2, glial fibrillary acidic protein, neural cell adhesion molecule, malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. Conclusion: Our results identify an important neuroprotective role of cinnamon polyphenol extract in TBI which is mediated by its capability to suppress the inflammation and oxidative injury. Further, specially designed experimental studies to understand the molecular cross-talk between signaling pathways would provide valuable evidence for the therapeutic role of cinnamon in TBI and other TBI related conditions.Öğe Dose-dependent effect of a new biotin compound in hippocampal remyelination in rats(2025) Yuluğ, Burak; Kılıç, Ertuğrul; Oğuz, Tuba; Orhan, Cemal; Er, Beşir; Tuzcu, Mehmet; Şahin, KazımDemyelination is commonly observed in neurodegenerative disorders, including multiple sclerosis (MS). Biotin supplementation is known to stabilize MS progression. To reduce the effective dose of biotin, we synthesized a new and superior form of biotin, a complex of magnesium ionically bound to biotin (MgB) and compared its dose-dependent effect with biotin alone after inducing demyelination using lysolecithin (LPC) in rats. Myelination was assessed using luxol fast blue staining and immunostaining against MBP protein, revealing that the most significant remyelination occurred in the MgB groups. Additionally, both biotin and MgB-treated animals showed dose-dependent improvements in spatial memory. Moreover, we detected a decrease in inflammatory proteins in both treatment groups, which was more prominent in high-dose MgB-treated animals and correlated with decreased expression of NF-kappa B p65, OP, and MMP-9 proteins. Further analysis of biotin-related proteins demonstrated that both biotin and, notably, MgB reversed the demyelination-dependent reduction of these proteins. Furthermore, biotin, particularly MgB, improved neuronal transmission proteins, Synapsin-1, PSD-93, and PSD-95. Additionally, both treatment groups exhibited increased BDNF, GAP43, and ICAM levels, with significant increments observed in high-dose MgB-treated animals. Increased GFAP, indicative of reactive gliosis, was observed in LPC-treated animals, and this effect was notably reversed by high-dose MgB treatment. The current data emphasize the dose-dependent beneficial effect on the remyelination process. Furthermore, the combination of biotin with Mg resulted in a more potent effect compared to biotin by itself. The strong influence of MgB encourages proof-of-concept studies using MgB in patients with MS.Öğe Enhancement of cisplatin sensitivity in human cervical cancer: Epigallocatechin-3-gallate(Frontiers Media, 2015) Kılıç, Ülkan; Şahin, Kazım; Tuzcu, Mehmet; Başak, Nazlı; Orhan, Cemal; Elibol Can, Birsen; Kılıç, Ertuğrul; Şahin, Fikrettin; Küçük, ÖmerCisplatin is one of the effective chemotherapeutics in the treatment of several types of cancers. However, in addition to the efforts against to its toxicity, the amelioration of cisplatin sensitivity is an important point in treatment of cervical cancer. To do so, additional substances such as epigallocatechin gallate (EGCG), a polyphenol in green tea, have been used in combination with chemotherapeutics. We aimed to investigate the possible molecular pathways to potentiate cervical cancer cell (HeLa) growth inhibition by combination therapy of cisplatin and EGCG. HeLa cells were treated with EGCG (25µM), cisplatin (250 nM), and their combination for 24 h. Cell viability was determined by MTS Assay. We analyzed the expressions of NF-?B p65, COX-2, Nrf2, HO-1, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt byWestern blot analysis. Herein, we have demonstrated that EGCG works synergistic with cisplatin in inhibiting growth of cervical cancer cells. EGCG improved efficacy of cisplatin treatment in HeLa cells by regulating NF?B p65, COX-2, p-Akt, and p-mTOR pathways, whereas it increased the expression levels of Nrf2/HO-1 in combined therapy. Our observations revealed that EGCG increases the sensitization of cisplatin to cervical cancer cells by inhibiting cell survival and inducing apoptosis.Öğe Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway(Biomed Central Ltd, 2013) Kılıç, Ülkan; Kılıç, Ertuğrul; Tuzcu, Zeynep; Tuzcu, Mehmet; Özercan, İbrahim; Yılmaz, Ökkeş; Şahin, Fikrettin; Şahin, KazımBackground: Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods: Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days), cisplatin treatment (7 mg/kg b.w., i.p.) and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N) and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-kappa B and AP-1 in Western blot analysis. Results: Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin treatment increased Nrf2 accumulation in the nuclear fraction, and increased the expression of HO-1 in the cytosolic fraction as compared to the cisplatin-treated rats. Expressions of NF-kappa B p65 and AP-1 were increased significantly in the kidneys of rats treated with cisplatin compared with the expression in the kidneys from the control, melatonin-only-treated and melatonin co-treated rats. Conclusion: Our present data suggest that melatonin attenuates cisplatin-induced nephrotoxicity possibly by modulating Nrf2/HO-1 signaling.Öğe Modulation of excitability of stellate neurons in the ventral cochlear nucleus of mice by atp-sensitive potassium channels(Springer, 2018) Bal, Ramazan; Öztürk, Gürkan; Önalan Etem, Ebru; Him, Aydın; Cengiz, Nurettin; Kulo?lu, Tuncay; Tuzcu, Mehmet; Yıldırım, Caner; Tektemur, AhmetMajor voltage-activated ionic channels of stellate cells in the ventral part of cochlear nucleus (CN) were largely characterized previously. However, it is not known if these cells are equipped with other ion channels apart from the voltage-sensitive ones. In the current study, it was aimed to study subunit composition and function of ATP-sensitive potassium channels (K-ATP) in stellate cells of the ventral cochlear nucleus. Subunits of K-ATP channels, Kir6.1, Kir6.2, SUR1, and SUR2, were expressed at the mRNA level and at the protein level in the mouse VCN tissue. The specific and clearly visible bands for all subunits but that for Kir6.1 were seen in Western blot. Using immunohistochemical staining technique, stellate cells were strongly labeled with SUR1 and Kir6.2 antibodies and moderately labeled with SUR2 antibody, whereas the labeling signals for Kir6.1 were too weak. In patch clamp recordings, K-ATP agonists including cromakalim (50 A mu M), diazoxide (0.2 mM), 3-Amino-1,2,4-triazole (ATZ) (1 mM), 2,2-Dithiobis (5-nitro pyridine) (DTNP) (330 A mu M), 6-Chloro-3-isopropylamino- 4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC 55-0118) (1 A mu M), 6-chloro-3-(methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414) (1 A mu M), and H2O2 (0.88 mM) induced marked responses in stellate cells, characterized by membrane hyperpolarization which were blocked by K-ATP antagonists. Blockers of K-ATP channels, glibenclamide (0.2 mM), tolbutamide (0.1 mM) as well as 5-hydroxydecanoic acid (1 mM), and catalase (500 IU/ml) caused depolarization of stellate cells, increasing spontaneous action potential firing. In conclusion, K-ATP channels seemed to be composed dominantly of Kir 6.2 subunit and SUR1 and SUR2 and activation or inhibition of K-ATP channels regulates firing properties of stellate cells by means of influencing resting membrane potential and input resistance.Öğe Schiff base-poloxamer p85 combination prevents prostate cancer progression in c57/bl6 mice(Wiley, 2016) Do?an, Ayşegül; Demirci, Selami; Başak Türkmen, Neşe; Çağlayan, Ahmet Burak; Aydın, Safa; Telci, Dilek; Kılıç, Ertuğrul; Şahin, Kazım; Orhan, Cemal; Tuzcu, Mehmet; Doğan Ekici, Asiye Işın; Şahin, FikrettinBACKGROUNDProstate cancer which is the second most common cause of death among men has a high incidence in recent years. Current therapeutic regimens should be improved to overcome drug resistance. At the metastatic stage, tumors become refractory to established chemotherapeutic treatments and cause serious problems at the clinics. Development of new drug molecules that are able to transport through the membrane easily and kill tumor cells rapidly is of great interest. METHODIn the current study, a novel Heterodinuclear copper(II)Mn(II) Schiff base complex combined with P85 was used for prostate cancer treatment in vivo. Tramp-C1 cells injected animals were subjected to chemotherapeutic formulation treatment and results were analyzed by toxicology analysis, tumor volume measurements, and histopathological analysis. 0.5mg/kg Schiff base was selected and combined with 0.05% P85 according to the toxicology analysis showing the enzyme levels, blood parameters, and multiple organ toxicity. RESULTSResults demonstrated that Heterodinuclear copper(II)Mn(II) complex-P85 combination decreased tumor formation and tumor volume steadily over the course of experiments. CONCLUSIONSOverall, Heterodinuclear copper(II)Mn(II) complex-P85 exerted remarkable anti-cancer activity in vivo in C57/B16 mice. Prostate 76:1454-1463, 2016.Öğe The effect of a novel theanine complex (JDS-MT-003) on sleep in a caffeine-induced insomnia mouse model(Wiley, 2020) Komorowski, James; Ojalvo, Sara; Sylla, Sarah; Mamedova, Havakhanum; Orhan, Cemal; Tuzcu, Mehmet; Şahin, Kazım; Kılıç, Ertuğrul[Abstract Not Available]Öğe The effect of a novel theanine complex (JDS-MT-003) on sleep in a pentobarbital-induced sleep model in mice(Wiley, 2020) Sylla, Sarah; Ojalvo, Sara; Komorowski, James; Orhan, Cemal; Tuzcu, Mehmet; Şahin, Nurhan; Kılıç, Ertuğrul; Şahin, Kazım[Abstract Not Available]
