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Background Low concentrations of carbon monoxide (CO) protect hepatocytes against apoptosis and confers cytoprotection in several models of liver. Mitochondria are key organelles in cell death control via their membrane permeabilization and the release of pro-apoptotic factors. Results Herein, we show that CO prevents mitochondrial membrane permeabilization (MMP) in liver isolated mitochondria. Direct and indirect approaches were used to evaluate MMP inhibition by CO: mitochondrial swelling, mitochondrial depolarization and inner membrane permeabilization. Additionally, CO increases mitochondrial reactive oxygen species (ROS) generation, and their scavenging, by ß-carotene addition, decreases CO protection, which reveals the key role of ROS. Interestingly, cytochrome c oxidase transiently responds to low concentrations of CO by decreasing its activity in the first 5 min, later on there is an increase of cytochrome c oxidase activity, which were detected up to 30 min. Conclusion CO directly prevents mitochondrial membrane permeabilization, which might be implicated in the hepatic apoptosis inhibition by this gaseoustransmitter.

International audience; BACKGROUND: Limited observational evidence suggests lower antioxidant concentrations in individuals with the metabolic syndrome (MetS); few randomized controlled trials have addressed the effect of multiple antioxidants on the risk of MetS. OBJECTIVE: The objective was to examine the effect of antioxidant supplementation for 7.5 y on the incidence of MetS and the epidemiologic association between baseline serum antioxidant concentrations and the prospective risk of MetS. DESIGN: Adults (n = 5220) participating in the SUpplementation en VItamines et Minéraux AntioXydants (SU.VI.MAX) primary prevention trial were randomly assigned to receive a supplement containing a combination of antioxidants (vitamins C and E, beta-carotene, zinc, and selenium) at nutritional doses or a placebo. Subjects were free of MetS at baseline and were followed for 7.5 y. RESULTS: Antioxidant supplementation for 7.5 y did not affect the risk of MetS. Baseline serum antioxidant concentrations of beta-carotene and vitamin C, however, were negatively associated with the risk of MetS; the adjusted odds ratios (and 95% CIs) for the highest compared with the lowest tertile were 0.34 (0.21, 0.53; P for trend = 0.0002) and 0.53 (0.35, 0.80; P for trend = 0.01), respectively. Baseline serum zinc concentrations were positively associated with the risk of developing MetS; the adjusted odds ratio (and 95% CI) for the highest compared with the lowest tertile was 1.81 (1.20, 2.72; P for trend = 0.01). CONCLUSIONS: The experimental finding of no beneficial effects of antioxidant supplementation in a generally well-nourished population is consistent with recent reports of a lack of efficacy of antioxidant supplements. However, the relations observed between the risk of MetS and baseline serum antioxidant concentrations, which probably reflect associations with overall dietary patterns, do support the current recommendations to consume antioxidant-rich foods. This trial was registered at clinicaltrials.gov as NCT00272428.

To investigate whether dietary alpha-linolenic acid (ALA) content alters the effect of beta-carotene on mammary carcinogenesis, we conducted a chemically induced mammary tumorigenesis experiment in rats randomly assigned to four nutritional groups (15 rats per group) varying in beta-carotene supplementation and ALA content. Two oil formula-enriched diets (15 %) were used: one with 6 g ALA/kg diet in an essential fatty acids (EFA) ratio of linoleic acid:ALA of 5:1 w/w (EFA 5 diet), the other with 24 g ALA/kg diet in an EFA ratio of 1:1 w/w (EFA 1 diet), both designed with a similar linoleic acid content. beta-Carotene was either added (10 mg/kg diet per d) or not added to these diets. beta-Carotene supplementation led to decreased tumour incidence and tumour growth when added to the EFA 5 diet, whereas it had no effect when added to the EFA 1 diet. The decreased tumour growth did not result from an involvement of lipoperoxidation (tumour malondialdehyde content being similar between the groups) or from an inhibition of tumour cell proliferation (as there was an unchanged S phase fraction in the tumours). We concluded that an adequate content of ALA in the diet is required to allow a protective effect of beta-carotene in mammary carcinogenesis. Whether such an interaction between ALA and beta-carotene influences the risk of breast cancer in women needs to be investigated.

To investigate whether dietary alpha-linolenic acid (ALA) content alters the effect of beta-carotene on mammary carcinogenesis, we conducted a chemically induced mammary tumorigenesis experiment in rats randomly assigned to four nutritional groups (15 rats per group) varying in beta-carotene supplementation and ALA content. Two oil formula-enriched diets (15 %) were used: one with 6 g ALA/kg diet in an essential fatty acids (EFA) ratio of linoleic acid:ALA of 5:1 w/w (EFA 5 diet), the other with 24 g ALA/kg diet in an EFA ratio of 1:1 w/w (EFA 1 diet), both designed with a similar linoleic acid content. beta-Carotene was either added (10 mg/kg diet per d) or not added to these diets. beta-Carotene supplementation led to decreased tumour incidence and tumour growth when added to the EFA 5 diet, whereas it had no effect when added to the EFA 1 diet. The decreased tumour growth did not result from an involvement of lipoperoxidation (tumour malondialdehyde content being similar between the groups) or from an inhibition of tumour cell proliferation (as there was an unchanged S phase fraction in the tumours). We concluded that an adequate content of ALA in the diet is required to allow a protective effect of beta-carotene in mammary carcinogenesis. Whether such an interaction between ALA and beta-carotene influences the risk of breast cancer in women needs to be investigated.

International audience; Tumours in rodent and human colon share many histological and genetic features. To know if rodent models of colon carcinogenesis are good predictors of chemopreventive efficacy in humans, we conducted a meta-analysis of aspirin, beta-carotene, calcium, and wheat bran studies. Controlled intervention studies of adenoma recurrence in human volunteers were compared with chemoprevention studies of carcinogen-induced tumours in rats, and of polyps in Min (Apc(+/-)) mice: 6714 volunteers, 3911 rats and 458 mice were included in the meta-analyses. Difference between models was small since most global relative risks were between 0.76 and 1.00. A closer look showed that carcinogen-induced rat studies matched human trials for aspirin, calcium, carotene, and were compatible for wheat bran. Min mice results were compatible with human results for aspirin, but discordant for calcium and wheat bran (no carotene study). These few results suggest that rodent models roughly predict effect in humans, but the prediction is not accurate for all agents. Based on three cases only, the carcinogen-induced rat model seems better than the Min mouse model. However, rodent studies are useful to screen potential chemopreventive agents, and to study mechanisms of carcinogenesis and chemoprevention.

International audience; beta-Carotene is, when cleaved, an important source of flavor and aroma compounds in fruits and flowers. Among these aroma compounds, the main degradation products are beta-ionone, 5,6-epoxy-beta-ionone, and dihydroactinidiolide (DHA), which are associated by flavorists and perfumers with fruity, floral, and woody notes. These three species can be produced by degradation of beta-carotene through an attack by enzyme-generated free radicals and a cleavage at the C9-C10 bond. This study investigated the influence of cis/trans isomerism at the C9-C10 bond on the production of beta-carotene degradation compounds, first with a predictive approach and then experimentally with different isomer mixtures. beta-Carotene solutions containing high ratios of 9-cis-isomers produced more DHA, suggesting a different pathway than for the transformation of all-trans-beta-carotene to ionone and DHA. These results are important in the search for financially viable processes to produce natural carotene-derived aroma compounds.

Background: Chronic heart failure (CHF) seems to be associated with increased oxidative stress. However, the hypothesis that antioxidant nutrients may contribute to the clinical severity of the disease has never been investigated. Aims: To examine whether antioxidant nutrients influence the exercise capacity and left ventricular function in patients with CHF. Methods: Dietary intake and blood levels of major antioxidant nutrients were evaluated in 21 consecutive CHF patients and in healthy age- and sex-matched controls. Two indexes of the severity of CHF, peak exercise oxygen consumption (peak VO2) and left ventricular ejection fraction (LVEF), were measured and their relations with antioxidants were analysed. Results: Whereas plasma alpha-tocopherol and retinol were in the normal range, vitamin C (P-0.005) and beta-carotene (P-0.01) were lower in CHF. However, there was no significant association between vitamins and either peak VO2 or LVEF. Dietary intake (P

PURPOSE. To assess the associations of plasma lutein and zeaxanthin and other carotenoids with the risk of age-related maculopathy (ARM) and cataract in the population-based Pathologies Oculaires Liees a l'Age (POLA) Study. METHODS. Retinal photographs were graded according to the international classification. ARM was defined by the presence of late ARM (neovascular ARM, geographic atrophy) and/or soft indistinct drusen (>125 μm) and/or soft distinct drusen (>125 μm) associated with pigmentary abnormalities. Cataract classification was based on a direct standardized lens examination at the slit lamp, according to Lens Opacities Classification System III. Plasma carotenoids were measured by high-performance liquid chromatography (HPLC), in 899 subjects of the cohort. RESULTS. After multivariate adjustment, the highest quintile of plasma zeaxanthin was significantly associated with reduced risk of ARM (OR = 0.07; 95% CI: 0.01-0.58; P for trend = 0.005), nuclear cataract (OR = 0.23; 95% CI: 0.08-0.68; P for trend = 0.003) and any cataract (OR = 0.53; 95% CI: 0.31-0.89; P for trend = 0.01). ARM was significantly associated with combined plasma lutein and zeaxanthin (OR = 0.21; 95% CI: 0.05- 0.79; P for trend = 0.01), and tended to be associated with plasma lutein (OR = 0.31; 95% CI: 0.09-1.07; P for trend = 0.04), whereas cataract showed no such associations. Among other carotenoids, only β-carotene showed a significant negative association with nuclear cataract, but not ARM. CONCLUSIONS. These results are strongly suggestive of a protective role of the xanthophylls, in particular zeaxanthin, for the protection against ARM and cataract.