Zileuton alleviates acute cisplatin nephrotoxicity: Inhibition of lipoxygenase pathway favorably modulates the renal oxidative/inflammatory/caspase-3 axis.

OBJECTIVE: The current study investigated for the first time the possible beneficial effect of zileuton, a selective 5-lipoxygenase inhibitor (5-LOX), against cisplatin-induced acute renal failure. METHODOLOGY: Male Sprague-Dawley rats (180-200 g) were administered cisplatin once (5 mg/kg, i.p.) alone or combined with oral zileuton (10 mg/kg, given twice; 1 h before and 12 h after cisplatin). RESULTS: Compared with control rats, acute cisplatin administration caused significant increases of BUN (33.76 ±â€¯7.74 vs 61.88 ±â€¯11.35 mg/dl), serum creatinine (0.61 ±â€¯0.21 vs 1.56 ±â€¯0.28 mg/dl), renal levels of MDA (6.40 ±â€¯1.04 vs 20.52 ±â€¯2.18 nmol/g tissue), NOx (3.45 ±â€¯1.20 vs 17.70 ±â€¯2.27 nmol/g tissue), TNF-α (6.71 ±â€¯0.66 vs 23.71 ±â€¯3.41 pg/g tissue), MPO (0.87 ±â€¯0.09 vs 3.12 ±â€¯0.41 U/mg tissue protein) and renal caspase-3 activity (2.81 ±â€¯0.37 vs 12.70 ±â€¯2.94 U/mg tissue protein). Whereas, total SOD activity (1.99 ±â€¯0.53 vs 0.79 ±â€¯0.06 U/mg tissue protein) and IL-10 (110.98 ±â€¯19.70 vs 62.34 ±â€¯14.42 pg/g tissue) were significantly decreased. Cisplatin-induced nephrotoxicity was further confirmed histopathologically (tubular necrosis, cystic dilatation of renal tubules, vacuolar degeneration of renal tubular epithelium with perivascular oedema, and interstitial fibrosis). These changes were accompanied by alteration in 5-LOX pathway manifested as elevated renal levels of 5-LOX, LTD4 and LTB4. Simultaneous administration of zileuton to the cisplatin-treated rats reversed the deleterious renal insults and restored the measured parameters near to control values. CONCLUSIONS: These data establish the first experimental evidence that zileuton abrogates cisplatin nephrotoxicity in rats probably via the inhibition of detrimental actions of 5-LOX products, thus favorably affecting renal oxidative/inflammatory/caspase-3 axis. Based on current findings, the therapeutic prospect of zileuton for this purpose is recommended.

CTX Correlation to Disease Duration and Adiponectin in Egyptian Children with T1DM.

BACKGROUND: In this study, we investigated the relationship of adiponectin with bone marker changes in Egyptian children and adolescents with T1DM and the effect of disease duration on these markers, as well as the possible correlations between adiponectin and bone markers in these patients. METHODS: Sixty Egyptian children and adolescent patients with T1DM were studied. Serum adiponectin and collagen breakdown products (cross-linked C-terminal telopeptide of collagen type l ¼CTX«) were measured and compared to the results of 20 age-matched healthy controls. RESULTS: After adjustment for age, BMI, Tanner stage and gender; (total) adiponectin was significantly higher in all T1DM patients. Serum level of CTX and 25(OH)D showed a marked decrease in diabetics with disease duration > 5 years. Serum level of (total) calcium and inorganic phosphorus (Pi) did not show significant difference from control. CTX was inversely correlated to FBG and T1DM duration. Pi was inversely, while 25(OH)D was directly correlated to FBG. Total calcium showed an inverse correlation with HbA1c. FBG, TC, TAG, LDL-C were independent predictors of CTX in T1DM. CONCLUSIONS: Adiponectin showed no correlation with either CTX or bone homeostatic indices. FBG, TC, TAG, LDL-C were independent predictors of CTX in T1DM. We recommend further investigation of adiponectin isoforms in a population-based study, to establish a good age- and sex-related reference.