Tangeretin attenuates cisplatin-induced renal injury in rats: Impact on the inflammatory cascade and oxidative perturbations.
BACKGROUND
Despite the efficacy of cisplatin as a chemotherapeutic agent against various cancers, its clinical utility is limited by serious adverse reactions including nephrotoxicity.


OBJECTIVE
The current study aims to investigate the protective potential of tangeretin, a citrus flavone with marked antioxidant actions, against cisplatin-induced renal injury in rats.


METHODS
Tangeretin was administered at 50 and 100 mg/kg p.o. for 1 week starting one day before cisplatin (7.5 mg/kg i.p.) injection. Likewise, silymarin was administered at 100 mg/kg orally. Renal function tests, histopathology, oxidative stress and inflammatory events were investigated.


RESULTS
Tangeretin mitigated the increased levels of serum creatinine, blood urea nitrogen and histopathologic alterations evoked by cisplatin. It alleviated renal oxidative stress due to cisplatin by lowering lipid peroxides, nitric oxide and Nrf2 levels with concomitant enhancement of GSH and GPx. Tangeretin also suppressed the upregulated inflammatory response seen with cisplatin treatment by downregulation of activated NF-κB p65 protein expression together with its downstream effectors e.g., iNOS and TNF-α, with restoration of the anti-inflammatory interleukin IL-10. Additionally, it down-regulated the expression of caspase-3, an apoptotic marker, thus favoring renal cell survival. Importantly, tangeretin enhanced the cytotoxic actions of cisplatin in Hep3B and HCT-116 human cancer cell lines.


CONCLUSIONS
Together, these findings accentuate the dual benefit of tangeretin: mitigation of renal injury-induced by cisplatin and enhancement of its cytotoxic effects.
Biochemistry Division and GTMR Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Hany H
HH
Arab
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Wafaa R
WR
Mohamed
Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al Azhar University, Cairo, Egypt.
Bassant M
BM
Barakat
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Ajman University of Science and Technology, Ajman, United Arab Emirates. Electronic address: elshimaa.arafa@pharm.bsu.edu.eg.
El-Shaimaa A
el-SA
Arafa
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D003404:Creatinine / Q000097:blood; D047309:Flavones / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D016753:Interleukin-10 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D047309:Flavones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D003404:Creatinine; D005979:Glutathione Peroxidase; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D005978:Glutathione; C059006:tangeretin; D002945:Cisplatin
Apoptosis; Cisplatin; NF-κB; Nrf2; Renal injury; Tangeretin