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Sisplatin Nefrotoksisitesinde Nrf2/HO-1’nin Thymoquinone Tarafından Modülasyonu

Modulation of Nrf2/HO-1 by Thymoquinone During Cisplatin-Induced Nephrotoxicity

Journal Name:

  • Türk Nefroloji, Diyaliz ve Transplantasyon Dergisi

Publication Year:

  • 2013
DOI: 
10.5262/tndt.2013.1002.09

Key Words:

Keywords (Original Language):

Author NameUniversity of AuthorFaculty of Author
Abstract (2. Language): 
OBJECTIVE: Side effects of cisplatin, such as nephrotoxicity, limit its use in chemotherapeutic regimens and indicate an agent that suppresses its toxicity. Thymoquinone (TQ), the predominant bioactive constituent present in black seed oil (Nigella sativa), has antiinfl ammatory, antioxidant and antitumor effects. We propose a protective mechanism of of TQ on cisplatin-nephrotoxicity in rats that is through modulation of Nrf2-mediated antioxidant induction and reduced inflammation. MATERIAL and METHODS: Twenty-eight male Wistar rats (8 weeks-old) were divided into four groups; Control (vehicle; 0.9% saline, 1 ml/kg body wt., p.o.), TQ (10 mg/kg body weight/day in drinking water for 5 days), cisplatin (a single injection of 7mg/kg body wt, i.p.) and TQ for 5 days in drinking water then a single injection of cisplatin. On day 10, all rats were sacrifi ced by cervical dislocation, kidneys were removed, and serum urea and creatinine were collected. RESULTS: Serum urea and creatinine levels were signifi cantly higher in cisplatin-treated rats compared with control rats. TQ-treatment signifi cantly decreased serum urea and creatinine levels. Cisplatin-treatment caused signifi cant downregulation of the nuclear NF-E2-related factor-2 (Nrf2), heme oxygenase-1(HO-1) and caused an increase in the levels of nuclear factor-kappa B (NF-κB). Interestingly, TQ supplementation signifi cantly improved the changes associated with cisplatin nephrotoxicity by increasing the levels of Nrf-2 and HO-1 and decreasing the levels of NF-κB. CONCLUSION: This study demonstrates the TQ targets NRF2/HO-1 and can be used as a potential agent against cisplatin-induced nephrotoxicity.
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Abstract (Original Language): 
AMAÇ: Sisplatinin nefrotoksisite gibi sitotoksik etkileri, kemoterapi rejimlerinde kullanımını sınırlamakta ve toksik etkilerini baskılayacak bir ajana gereksinim doğmaktadır. Thymoquinone (TQ) çörek otu yağında bulunan biyoaktif bileşen olup, antiinfl amatuvar, antioksidan ve antitümör etkileri vardır. Bu çalışmada, ratlarda TQ’nin Nrf2 indüksiyonu ve antiinfl amatuvar etki yoluyla sisplatin nefrotoksisitesi üzerine olan koruyucu etkisini araştırdık. GEREÇ ve YÖNTEMLER: Bu çalışmada, TQ’in sisplatin aracılı nefrotoksisiteye etkisini ve bu süreçte in vivo olarak infl amasyonu baskılama mekanizmalarını araştırdık. Sekiz haftalık 28 erkek Wistar rat 4 gruba ayrıldı; kontrol (1 mg/kg oral %0,9’luk tuz çözeltisi), TQ (5 gün boyunca içme suyuna 10 mg/kg/gün), sisplatin (7 mg/kg, i.p. tek doz) ve içme suyuyla 5 günlük TQ uygulaması sonrası tek doz sisplatin enjeksiyonu yapılan grup. Onuncu günde tüm ratlardan servikal dislokasyon sonrası böbrek dokuları ile üre ve kreatinin ölçümü amaçlı serumları alındı. BULGULAR: Çalışmamız kontrol grubuna kıyasla sisplatin grubunda üre ve kreatinin değerlerinin anlamlı şekilde yüksek olduğunu göstermektedir (p<0,0001). TQ tedavisi serum üre ve kreatinin düzeylerini anlamlı şekilde azaltmıştır (p<0,001). Sisplatin tedavisi anlamlı biçimde (p<0,05) nükleer NF-E2 ilişkili faktör-2 (Nrf2) ve hem oksijenaz-1 (HO-1) downregülasyonuna neden olarak nükleer faktör-kappa B (NF-kB p65) düzeylerinde artmaya neden olmuştur. İlginç biçimde TQ desteği Nrf-2 ve HO-1 artışı ve NF-kB düzeylerinde anlamlı (p<0,05) azalmaya neden olarak sisplatin nefrotoksisitesine bağlı değişiklikleri düzeltmiştir. SONUÇ: Bu çalışma TQ’in NRF2/HO-1’i hedef aldığını ve sisplatin aracılı nefrotoksisiteye karşı potansiyel koruyucu bir ajan olarak kullanılabileceğini ortaya koymaktadır.
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