Phenolic Compounds of Red Wine Aglianico del Vulture Modulate the Functional Activity of Macrophages via Inhibition of NF-κB and the Citrate Pathway.

Phenolic compounds of red wine powder (RWP) extracted from the Italian red wine Aglianico del Vulture have been investigated for the potential immunomodulatory and anti-inflammatory capacity on human macrophages. These compounds reduce the secretion of IL-1ß, IL-6, and TNF-α proinflammatory cytokines and increase the release of IL-10 anti-inflammatory cytokine induced by lipopolysaccharide (LPS). In addition, RWP restores Annexin A1 levels, thus involving activation of proresolutive pathways. Noteworthy, RWP lowers NF-κB protein levels, promoter activity, and nuclear translocation. As a consequence of NF-κB inhibition, reduced promoter activities of SLC25A1-encoding the mitochondrial citrate carrier (CIC)-and ATP citrate lyase (ACLY) metabolic genes have been observed. CIC, ACLY, and citrate are components of the citrate pathway: in LPS-activated macrophages, the mitochondrial citrate is exported by CIC into the cytosol where it is cleaved by ACLY in oxaloacetate and acetyl-CoA, precursors for ROS, NO·, and PGE2 inflammatory mediators. We identify the citrate pathway as a RWP target in carrying out its anti-inflammatory activity since RWP reduces CIC and ACLY protein levels, ACLY enzymatic activity, the cytosolic citrate concentration, and in turn ROS, NO·, PGE2, and histone acetylation levels. Overall findings suggest that RWP potentially restores macrophage homeostasis by suppressing inflammatory pathways and activating proresolutive processes.

Evidence of oxidative stress in brain and liver of young rats submitted to experimental galactosemia.

Galactosemia is a disorder of galactose metabolism, leading to the accumulation of this carbohydrate. Galactosemic patients present brain and liver damage. For evaluated oxidative stress, 30-day-old males Wistar rats were divided into two groups: galactose group, that received a single injection of this carbohydrate (5 µmol/g), and control group, that received saline 0.9 % in the same conditions. One, twelve or twenty-four hours after the administration, animals were euthanized and cerebral cortex, cerebellum, and liver were isolated. After one hour, it was found a significant increase in TBA-RS levels, nitrate and nitrite and protein carbonyl contents in cerebral cortex, as well as protein carbonyl content in the cerebellum and in hepatic level of TBA-RS, and a significant decrease in nitrate and nitrite contents in cerebellum. TBA-RS levels were also found increased in all studied tissues, as well as nitrate and nitrite contents in cerebral cortex and cerebellum, that also present increased protein carbonyl content and impairments in the activity of antioxidant enzymes of rats euthanized at twelve hours. Finally, animals euthanized after twenty-four hours present an increase of TBA-RS levels in studied tissues, as well as the protein carbonyl content in cerebellum and liver. These animals also present an increased nitrate and nitrite content and impairment of antioxidant enzymes activities. Taken together, our data suggest that acute galactose administration impairs redox homeostasis in brain and liver of rats.

Increased susceptibility of mitochondria isolated from frontal cortex and hippocampus of vitamin A-treated rats to non-aggregated amyloid-ß peptides 1-40 and 1-42.

OBJECTIVE: Vitamin A is a redox-active molecule and its inadvertent utilisation as a preventive therapy against ageing or neurodegeneration has become a harmful habit among humans at different ages. Mitochondrial dysfunction and redox impairment may be induced by vitamin A supplementation experimentally. Nonetheless, it is still not clear by which mechanisms vitamin A elicits such effects. Then, we performed this investigation to analyse whether mitochondria isolated from frontal cortex and hippocampus of vitamin A-treated rats are more sensitive to a challenge with amyloid-ß (Aß) peptides 1-40 or 1-42. METHODS: Adult Wistar rats received vitamin A at 1000-9000 IU/kg/day orally for 28 days. Then, mitochondria were isolated and the challenge with Aß peptides 1-40 or 1-42 (at 0.2 or 0.1 µM, respectively) for 10 min was carried out before mitochondrial electron transfer chain enzyme activity, superoxide anion radical (O2 -•) production and 3-nitrotyrosine content quantification. RESULTS: Mitochondria obtained from vitamin A-treated rats are more sensitive to Aß peptides 1-40 or 1-42 than mitochondria isolated from the control group, as decreased mitochondrial complex enzyme activity and increased O2 -• production and 3-nitrotyrosine content were observed in incubated mitochondria isolated from vitamin A-treated rats. CONCLUSION: These data suggest that oral intake of vitamin A at clinical doses increases the susceptibility of mitochondria to a neurotoxic agent even at low concentrations.

Scavenging and antioxidant potential of physiological taurine concentrations against different reactive oxygen/nitrogen species.

While several studies have been conducted on the antioxidant properties of the beta-amino acid taurine, these studies all used concentrations lower than what is found physiologically. This study investigates the scavenging and antioxidant properties of physiological taurine concentrations against different reactive species. No reactivity between taurine and hydrogen peroxide was found; however, taurine exhibited significant scavenging potential against peroxyl radical, nitric oxide, and superoxide donors. This study also evaluated if taurine was able to minimize the in vitro CuZn-superoxide dismutase damage (SOD) induced by peroxynitrite. Taurine prevented both the formation of nitrotyrosine adducts and the decrease in SOD activity caused by peroxynitrite. In addition, taurine prevented the ex vivo damage caused by tert-butyl hydroperoxide in rat liver slices. These experimental data show that taurine, at different physiological concentrations efficiently scavenges many reactive oxygen and nitrogen species. This finding supports the hypothesis that the antioxidant properties of taurine may be critical for the maintenance of cellular functions, and it suggests a more important function of taurine that requires further investigation.

Impairment of the mitochondrial electron transport chain due to sleep deprivation in mice.

It has been demonstrated that sleep deprivation is associated with altered expression of genes related to metabolic processes, response to stress and inflammation, circadian sleep/wake cycles, regulation of cell proliferation and various signaling pathways. However, the molecular mechanisms underlying these changes remain poorly understood. Thus, the present study aims to characterize the function of the mitochondrial electron transport chain in the brain using an animal model of paradoxical sleep deprivation (PSD). The question of whether sleep recovery (rebound) can reverse changes found after PSD is also addressed. Adult male inbred C57BL/6J mice were randomly distributed into three groups: home-cage control, PSD and sleep rebound groups. The PSD and rebound groups were subjected to PSD for 72 h. After this sleep deprivation period, the rebound group was returned to its home cage and allowed to sleep in an undisturbed and spontaneous fashion for 24h. The mitochondrial complex I-III, complex II, succinate dehydrogenase and complex II-III activities were then measured by spectrophotometric methods in sub-mitochondrial particles extracted from the prefrontal cortex, hippocampus, striatum and hypothalamus. Our results showed a significant decrease in the activity of complex I-III in the PSD and rebound groups as compared to the control group. The complex II and II-III activity were particularly decreased in the hypothalamus of the sleep rebound group. These results are consistent with the involvement of sleep in energy metabolism and corroborate previous experiments demonstrating the importance of the hypothalamus in sleep regulation.

WITHDRAWN: Impairment of the mitochondrial electron transport chain due to sleep deprivation in mice.

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Evaluation of redox and bioenergetics states in the liver of vitamin A-treated rats.

Vitamin A is normally stored in the mammalian liver and is physiologically released depending on the need of the organism for the vitamin. However, there is a compelling evidence showing that even the liver is affected by conditions of high vitamin A intake. Based on these previously reported findings showing negative effects of vitamin A on mammalian tissues, we have investigated the effects of a supplementation with vitamin A at clinical doses (1000-9000 IU/kg day(-1)) on some rat liver parameters. We have analyzed hepatic redox environment, as well as the activity of the mitochondrial electron transfer chain in vitamin A-treated rats. Additionally, activity of the detoxifying enzyme glutathione S-transferase was checked. Also, caspase-3 and caspase-8 and tumor necrosis factor-alpha levels were quantified to assess either cell death or inflammation effects of vitamin A on rat liver. We found increased free radical production and, consequently, increased oxidative damage in biomolecules in the liver of vitamin A-treated rats. Interestingly, we found increased mitochondrial electron transfer chain activity, as well as glutathione-S-transferase enzyme activity. Neither caspases activity, nor tumor necrosis factor-alpha levels change in this experimental model. Our results suggest a pro-oxidant, but not pro-inflammatory effect of vitamin A on rat liver.