Frailty syndrome is associated with altered circulating redox balance and increased markers of oxidative stress.

Frailty syndrome (FS) is a condition described in aging and characterized by physical vulnerability to stress and lack of physiological reserve. In this study we aim to define whether circulating oxidative stress correlates to frailty in terms of glutathione balance and oxidative protein damage. In 62 elderly outpatients, classified as frail patients according to Fried's criteria, evaluation of reduced glutathione (GSH), oxidized glutathione (GSSG), tumor necrosis factor-alpha, malonaldehyde-(MDA) and 4-hydroxy-2,3-nonenal-(HNE) protein plasma adducts were performed. A significant increase in the GSSG was observed in patients with FS when compared to non-frail. No difference was shown in the GSH amount, suggesting a glutathione oxidation more than impairment of the synthesis. TNF-alpha, MDA- and HNE-adducts, were significantly higher in FS as compared to non-frail patients. A logistic regression model correlating FS with redox balance showed a close relationship between glutathione ratio (OR=1.8, 95% CI=1.2-2.5) and MDA adducts (OR=2.8, 95% CI=1.6-4.7) to frailty. Our findings show an association between oxidative imbalance and Frailty Syndrome. GSSG/GSH ratio and plasma protein adducts strongly predict the frailty conditions and seem to be reliable and easily measurable markers in the context of the multidimensional analysis of elderly patients.

Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury.

BACKGROUND: The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production. AIMS: (1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia-reperfusion in rats with NASH. METHODS: Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H(2)O(2) synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)-protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia-reperfusion injury. RESULTS: NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE-protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia-reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress. CONCLUSIONS: Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia-reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.

Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model.

BACKGROUND: Mitochondrial dysfunction is considered a key player in non-alcoholic steatohepatitis (NASH) but no data are available on the mitochondrial function and ATP homeostasis in the liver during NASH progression. In the present paper we evaluated the hepatic mitochondrial respiratory chain activity and ATP synthesis in a rodent model of NASH development. MATERIALS AND METHODS: Male Wistar rats fed a High Fat/Methionine-Choline Deficient (MCD) diet to induce NASH or a control diet (SHAM), and sacrificed after 3, 7 and 11 weeks. The oxidative phosphorylation, the F(0)F(1)ATPase (ATP synthase) and the ATP content were assessed in liver mitochondria. RESULTS: NASH mitochondria exhibited an increased rate of substrate oxidation at 3 weeks, which returned to below the normal level at 7 and 11 weeks, concomitantly with the coupling between the phosphorylation activity and the mitochondrial respiration (ADP/O). Uncoupling of NASH liver mitochondria did not allow the recovery of the maximal respiration rate at 7 and 11 weeks. The ATPase (ATP synthase) activity was similar in NASH and SHAM rats, but the mitochondrial ATP content was significantly lower in NASH livers. CONCLUSIONS: The loss of hepatic ATP stores is not dependent on the F(0)F(1)-ATPase but resides in the respiratory chain. Dysfunction of both Complex I and II of the mitochondrial respiratory chain during NASH development implies a mitochondrial adaptive mechanism occurring in the early stages of NASH.

Evidence of lower oxidative stress in the air spaces of patients with reversible COPD.

The mechanism responsible for the reversibility of airflow limitation in stable chronic obstructive pulmonary disease (COPD) patients is unknown. The aim of this study is to assess the relationship between the reversibility of airflow limitation, the redox balance and the inflammatory cells in the sputum of patients with stable COPD. For this purpose we examined 15 normal healthy control subjects and 20 nonatopic COPD patients. The COPD patients were divided into two groups: reversible COPD (increase in FEV1> 200 ml and/or > or =12> or = after 200 microg of inhaled salbutamol) or non-reversible COPD. GSH, GSSG were measured in induced sputum and blood. Protein carbonyls were evaluated by WB in sputum and IL-4 and IL-6 and TNF-alpha in plasma and sputum. GSH oxidation and protein oxidation were lower in reversible COPD patients than in those with no reversibility. The sputum eosinophil count was significantly higher in the reversible group than in the non-reversible group, and IL-4 concentration was higher in the same patients both in sputum and in plasma. In contrast, IL-6 and TNF-alpha were increased in non-reversible COPD patients in both biological samples. We conclude that airflow reversibility in COPD patients is associated with airway oxidative stress and activation of eosinophil inflammatory pattern in sputum and blood, suggesting that these patients could respond to specific pharmacological treatment.