A meta-analysis of preclinical studies using antioxidants for the prevention of cisplatin nephrotoxicity: implications for clinical application.

Cisplatin is an effective chemotherapeutic drug whose clinical use and efficacy are limited by its nephrotoxicity, which affects mainly the renal tubules and vasculature. It accumulates in proximal and distal epithelial tubule cells and causes oxidative stress-mediated cell death and malfunction. Consequently, many antioxidants have been tested for their capacity to prevent cisplatin nephrotoxicity. In this study, we made a systematic review of the literature and meta-analyzed 152 articles, which tested the nephroprotective effect of isolated compounds or mixtures of natural origin on cisplatin nephrotoxicity in preclinical models. This meta-analysis identified the most effective candidates and examined the efficacy obtained by antioxidants administered by the oral and intraperitoneal routes. By comparing with a recent, similar meta-analysis performed on clinical studies, this article identifies a disconnection between preclinical and clinical research, and contextualizes, discusses, and integrates the existing preclinical information toward the optimized selection of candidates to be further explored (clinical level). Despite proved efficacy, this article discusses the barriers limiting the clinical development of natural mixtures, such as those in extracts from Calendula officinalis flowers and Heliotropium eichwaldii roots. On the contrary, isolated compounds are more straightforward candidates, among which arjunolic acid and quercetin stand out in this meta-analysis.

NOS3 Glu298Asp polymorphism interacts with virgin olive oil phenols to determine the postprandial endothelial function in patients with the metabolic syndrome.

BACKGROUND: Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene (NOS3) has been characterized as a risk factor of hypertension and coronary artery disease. Previous studies suggest that the higher risk observed in T allele carriers is due to endothelial dysfunction associated with a lower eNOS activity and that acute consumption of phenol-rich olive oil ameliorates postprandial endothelial dysfunction by reducing oxidative stress and increasing nitric oxide bioavailability. Nevertheless, how these facts may interact in a population with altered endothelial function such as metabolic syndrome patients remains unknown. OBJECTIVE: The objective of the study was to evaluate whether the presence of NOS3 Glu298Asp polymorphism interacts with the phenol content of virgin olive oil (VOO) to influence postprandial endothelial function. DESIGN: Fifty-seven subjects with metabolic syndrome received three breakfasts based on VOO with different phenolic content. Baseline, incremental area under the curve, peak, and maximum parameters of postocclusive skin reactive hyperemia (PORH) were evaluated by laser Doppler, and the nitrate/nitrite [NO((x))] and eNOS concentrations were obtained during fasting and postprandially. RESULTS: A gene-diet interaction was found on maximum PORH and NO((x)) (P = 0.039 and P = 0.043, respectively). TT subjects showed lower values of eNOS, NO((x)), and maximum PORH as compared with GG and GT subjects, especially in the postprandial measurements (all P < 0.05). However, most of these differences were attenuated when high-phenol VOO was consumed. CONCLUSION: In a population with a compromised endothelial function, concentrations of phenols in dietary VOO interact with NOS3 Glu298Asp to ameliorate the endothelial dysfunction associated to the TT genotype.

Effects of deferasirox on renal function and renal epithelial cell death.

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.