Role of nitric oxide donor in methotrexate-induced testicular injury via modulation of pro-inflammatory mediators, eNOS and P-glycoprotein.

Methotrexate (MTX) is a widely used chemotherapeutic agent but its clinical use is challenged with different forms of toxicities including testicular injury. The aim of the current study was to evaluate the potential protective effect of potassium channel opener, nicorandil (NIC) (3 and 10 mg/kg/day) on MTX-induced testicular injury in a rat model. Rats were randomly divided into four groups (nine rats each) and treated for 2 weeks as follows: (I) normal control (CON group) received vehicle, (II) model group (MTX group) given MTX (20 mg/kg) single intraperitoneal (i.p.) injection dose on 11th day, (III) MTX + NLD group treated with NIC (3 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. dose on 11th day, and (IV) MTX + NHD group treated with NIC (10 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. injection on the 11th day. The testicular injury was assessed biochemically via serum testosterone, total antioxidant capacity, testicular oxidative stress parameters, P-glycoprotein, tumor necrosis factor-alpha, and interleukin-1ß. Furthermore, histopathological evaluation, endothelial nitric oxide synthase (eNOS) immunoexpression, and detection of p53 expression level using Western blotting were performed. Results showed that MTX induced testicular injury which was proved by both biochemical and histopathological evaluations. Our results concluded that NIC pretreatment attenuated MTX-induced testicular injury via significantly increased eNOS immunoexpression, antiapoptotic, anti-inflammatory, and antioxidant properties. Interestingly, NIC high dose is more protective than low dose.

Protective effect of febuxostat in sepsis-induced liver and kidney injuries after cecal ligation and puncture with the impact of xanthine oxidase, interleukin 1ß, and c-Jun N-terminal kinases.

Sepsis is one of the most common causes of death among hospitalized patients. Activity of xanthine oxidase (XO), a reactive oxygen species-producing enzyme, is known to be elevated in septic patients. Our aim was to investigate the possible protective role of XO inhibitor, febuxostat (FEB), in a rat model of sepsis-induced liver and kidney injures. Adult male albino rats were divided into four groups (n = 12 each): sham control, sham + FEB, cecal ligation and puncture (CLP), and CLP + FEB groups. FEB (10 mg/kg per os (p.o.)) was given once daily for 2 days and 30 min prior to laparotomy with CLP. CLP was associated with a high mortality rate accompanied by significant liver and kidney injuries indicated by elevated serum alanine aminotransferase, aspartate aminotransferase, urea, and creatinine levels and confirmed by histopathological tissue injury. Moreover, there was an increase in neutrophil gelatinase-associated lipocalin, uric acid, malondialdehyde, and nitric oxide levels and with decreased superoxide dismutase activity and total antioxidant capacity. In addition, CLP caused increased expression of the inflammatory markers tumor necrosis factor alpha, interleukin 1beta protein levels, and nuclear factor kappa B immunoexpression. Finally, CLP operated rats exhibited an upregulation in the apoptotic mediators, caspase 3, and P-C-Jun N-terminal kinases (JNK) proteins. FEB treatment of CLP rats caused a significant improvement and normalization in all measured parameters. Moreover, FEB amerliorates degenerative histopathological changes and improves the overall survival rate. In conclusion, FEB exhibited a protective effect in sepsis-induced liver and kidney injuries most probably through its anti-inflammatory, antioxidant, and antiapoptotic properties and attenuating JNK signaling pathway secondary to its XO enzyme inhibitory activity.