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Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3&beta, (GSK-3&beta, ) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP+-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPAR&gamma, ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3&beta, enzyme inhibition against MPP+. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3&beta, enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3&beta, along with PPAR&gamma, activation may be responsible for neuroprotection.

Objective: In Psephellus and Centaurea genuses a lot of species have important pharmacological activities like antipyretic, antiinflamatory, diuretic, cytotoxic etc. In Psephellus genus the endemic plant Psephellus pyrrhoblepharus (Boiss.) Wagenitz (Centaurea pyrrhoblephara) was collected from Elazığ, Turkey. Recently interest in use of plant-derived compounds for therapeutic purposes in cancer is increasing day by day. Liver cancer which is one of the cancer types is affecting millions of people all over the world. So any approach to treat liver cancer is extremely valuable. Materials and methods: We have purposed to determine the cytotoxic activity of methanol:water (1:1), n-hexane and chloroform extracts of the aerial parts of P. pyrrhoblepharus using human liver cancer cell (HepG2) by utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay in different concentrations (50, 100 ,200 µg/ml) and time points (6, 12, 24 h). Results: Regarding the cytotoxicity, cell viability was seen as decreased following extract exposures at three different time points. The highest cytotoxic activity was observed in 100 µg/ml concentrations of chloroform extract at 24 h. At 12 h chloroform extract of plant showed the highest cytotoxic activity in 200 µg/ml concentrations when compared to methanol:water and n-hexane extracts. Conclusion: It can be suggested that extracts of P. pyrrhoblepharus show dose-dependent and time-dependent cytotoxic effects in HepG2 carsinoma cells. In general, the results provide information about the threshold concentrations of P. pyrrhoblepharus extracts that might be used in different applications without the risk of toxicity., Amaç: Birçok Psephellus ve Centaurea türü antipiretik, antiinflamatuar, diüretik ve sitotoksik gibi önemli farmakolojik aktivitelere sahiptir. Endemik bir bitki olan Psephellus pyrrhoblepharus (Boiss.) Wagenitz, Elazığ, Türkiye’den toplanmıştır. Son günlerde kanserde terapötik amaçlar için bitki kaynaklı bileşiklerin kullanımına olan ilgi artmaktadır. Bir kanser türü olan karaciğer kanseri de tüm dünyada milyonlarca insanı etkilemekteyken, karaciğer kanserini tedavi etmek için herhangi bir yaklaşım son derece değerlidir. Bu çalışmada, insan karaciğer kanseri hücresi (HepG2) kullanılarak P. pyrrhoblepharus bitkisinin topraküstü kısımlarından hazırlanmış olan metanol:su (1:1), kloroform ve n-hekzan ekstrelerinin sitotoksik potansiyelini değerlendirilmesi amaçlanmıştır. Gereç ve yöntemler: 3-(4,5-dimetiltiyazol-2-il)-2,5-difenltetrazolyumbromit (MTT) metodu kullanılarak, insan karaciğer kanser hücre hatlarında (HepG2) farklı konsantrasyonlarda (50, 100, 200 ug/ml) MTT, farklı zaman noktalarında (6, 12, 24 s) çalışmalar gerçekleştirildi. Bulgular: Sitotoksisite ile ilgili olarak, farklı zaman noktalarında ekstrelerin maruziyetlerinin ardından hücre canlılığının azaldığı gözlenmiştir. Bununla birlikte, en yüksek sitotoksik aktivite, 24 saatte 100 ug/ml konsantrasyondaki kloroform ekstresinde gözlenmiştir. Bitkinin kloroform ekstresi, metanol:su ve n-hekzan ekstreleri ile karşılaştırıldığında 12 saatte 200 ug/ml konsantrasyonda en yüksek sitotoksik etkinliği göstermiştir. Sonuç: P. pyrrhoblepharus ekstrelerinin HepG2 karsinoma hücrelerinde doza ve zamana bağlı bir şekilde sitotoksik etki gösterdiği ileri sürülebilir. Genel olarak elde edilen sonuçlar, toksisite tehlikesi olmadan farklı uygulamalarda kullanılabilecek P. pyrhoblepharus ekstrelerinin eşik konsantrasyonları hakkında bilgi sağlamıştır.