Antioxidant activity and metabolite profile of quercetin in vitamin-E-depleted rats

8 páginas, 4 figuras, 2 tablas.-- et al.Dietary antioxidants interact in a dynamic fashion, including recycling and sparing one another, to decrease oxidative stress. Limited information is available regarding the interrelationships in vivo between quercetin and vitamin E. We investigated the antioxidant activity and metabolism of quercetin (Q) in 65 F-344 rats (n=13 per group) randomly assigned to the following vitamin E (VE)-replete and -deficient diets: (a) VE replete (30 mg α-tocopherol acetate/kg diet) control ad libitum (C-AL), (b) VE replete pair fed (C-PF), (c) VE replete+5.0 g Q/kg diet (R-VE+5Q), (d) VE deplete (<1 mg/kg total tocopherols)+5.0 g Q/kg diet (D-VE+5Q) and (e) D-VE. After 12 weeks, blood and tissue were collected for measurement of plasma vitamin E, quercetin and its metabolites, serum pyruvate kinase (PK), plasma protein carbonyls, malondialdehyde (MDA) and oxygen radical absorbance capacity. D-VE diets decreased serum α-tocopherol and increased PK activity in a time-dependent manner. The D-VE diet increased plasma protein carbonyls but did not affect MDA. Dietary quercetin supplementation increased quercetin and its metabolites in plasma and liver but did not affect D-VE-induced changes in plasma α-tocopherol, PK or protein carbonyls. Plasma isorhamnetin and its disposition in muscle were enhanced by the D-VE diet, as compared to the R-VE diet. Conversely, tamarixetin disposition in muscle was decreased by the D-VE diet. Thus, quercetin did not slow vitamin E decline in vivo; neither did it provide antioxidant activity in vitamin-E-depleted rats. However, vitamin E status appears to enhance the distribution of isorhamnetin into the circulation and its disposition in muscle.This study was supported by the U.S. Department of Agriculture under Agreement No. 58-1950-7-707.Peer reviewe

Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT0028191