Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence

Autor: Anil Kumar Kalvala, Shyam Sunder Rachamalla, Ramakrishna Sistla, Bidya Dhar Sahu, Meghana Koneru, Jerald Mahesh Kumar, Madhusudana Kuncha
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Male
Flavonols
Nitric Oxide Synthase Type II
lcsh:Medicine
Pharmacology
Kidney
Toxicology
medicine.disease_cause
Antioxidants
Blood Urea Nitrogen
Rats
Sprague-Dawley
chemistry.chemical_compound
NF-KappaB Inhibitor alpha
Medicine and Health Sciences
Phosphorylation
lcsh:Science
Multidisciplinary
NADPH oxidase
biology
Caspase 3
Cytochromes c
NOX4
Caspase 9
Respiratory enzyme
Proto-Oncogene Proteins c-bcl-2
Biochemistry
Creatinine
I-kappa B Proteins
Anatomy
Signal Transduction
Research Article
medicine.drug
Histology
Antineoplastic Agents
Nephrotoxicity
Complementary and Alternative Medicine
medicine
Animals
Peroxidase
Flavonoids
Cisplatin
Tumor Necrosis Factor-alpha
lcsh:R
Transcription Factor RelA
Biology and Life Sciences
Kidney metabolism
Rats
Gene Expression Regulation
chemistry
biology.protein
lcsh:Q
Oxidative stress
Fisetin
Zdroj: PLoS ONE, Vol 9, Iss 9, p e105070 (2014)
PLoS ONE
ISSN: 1932-6203
Popis: Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.
Databáze: OpenAIRE
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