Melatonin restores zinc levels, activates the Keap1/Nrf2 pathway, and modulates endoplasmic reticular stress and HSP in rats with chronic hepatotoxicity.

BACKGROUND: Melatonin (MLT) is a potent antioxidant molecule that is shown to have a beneficial effect in various pathological situations, due to its action against free radicals. AIM: To evaluate the effect of MLT on carbon tetrachloride (CCl4) induced liver injury in rats in terms of oxidative stress, reticular stress, and cell damage. METHODS: Twenty male Wistar rats (230-250 g) were divided into four groups: Control rats, rats treated with MLT alone, rats treated with CCl4 alone, and rats treated with CCl4 plus MLT. CCl4 was administered as follows: Ten doses every 5 d, ten every 4 d, and seven every 3 d. MLT was administered intraperitoneally at a dose of 20 mg/kg from the 10th wk to the end of the experiment (16th wk). RESULTS: MLT was able to reduce the release of liver enzymes in the bloodstream and to decrease oxidative stress in CCl4 treated rats by decreasing the level of thiobarbituric acid reactive substances and increasing superoxide dismutase activity, with a lower reduction in serum zinc levels, guaranteeing a reduction in liver damage; additionally, it increased the expression of nuclear factor (erythroid-derived 2)-like 2 and decreased the expression of Kelch-like ECH-associated protein 1. MLT also decreased the expression of the proteins associated with endoplasmic reticulum stress, i.e., glucose-regulated protein 78 and activating transcription factor 6, as well as of heat shock factor 1 and heat shock protein 70. CONCLUSION: MLT has a hepatoprotective effect in an experimental model of CCl4-induced liver injury, since it reduces oxidative stress, restores zinc levels, and modulates endoplasmic reticulum stress.

Simvastatin Reduces Hepatic Oxidative Stress and Endoplasmic Reticulum Stress in Nonalcoholic Steatohepatitis Experimental Model.

OBJECTIVE: In this study, we evaluated the efficacy of simvastatin in the treatment of nonalcoholic steatohepatitis induced by methionine and choline-deficient diet in mice and its possible effect on factors involved in the pathogenesis of the disease including oxidative stress and endoplasmic reticulum stress. METHOD: Male C57BL6 mice were fed either a normal diet (control) or a methionine and choline-deficient diet for four weeks and then treated orally with simvastatin (4 mg/kg once a day) for two final weeks. At the end of the experimental period, liver integrity, biochemical analysis, hepatic lipids, histology, DNA damage, biomarkers of oxidative stress, and endoplasmic reticulum stress were assessed. RESULTS: Simvastatin treatment was able to significantly reduce hepatic damage enzymes and hepatic lipids and lower the degree of hepatocellular ballooning, without showing genotoxic effects. Simvastatin caused significant decreases in lipid peroxidation, with some changes in antioxidant enzymes superoxide dismutase and glutathione peroxidase. Simvastatin activates antioxidant enzymes via Nrf2 and inhibits endoplasmic reticulum stress in the liver. CONCLUSIONS: In summary, the results provide evidence that in mice with experimental nonalcoholic steatohepatitis induced by a methionine and choline-deficient diet, the reduction of liver damage by simvastatin is associated with attenuated oxidative and endoplasmic reticulum stress.

Effect of 6-minute walk test on neuromuscular properties of patients with chronic obstructive pulmonary disease.

OBJECTIVE: The objective of this study was to evaluate the neuromechanical properties of the knee extensor muscles before and after the 6-minute walk test (6MWT) in chronic obstructive pulmonary disease (COPD) patients and control subjects. MATERIALS AND METHODS: COPD patients from the Department of Pulmonology of the Hospital de Clinicas de Porto Alegre and age- and sex-matched control volunteers without COPD were included in this study. Body composition and lower limb strength assessed by maximal voluntary isometric contraction (MVIC) of the knee extensors) were assessed before and after the 6MWT. The total reaction time (TRT), premotor time (PMT) and motor time (MT) were assessed using surface electromyography of the rectus femoris and vastus lateralis knee extensor muscles. RESULTS: Eighteen patients COPD patients (10 men, FEV1 36 ± 12% of predicted) and 8 control subjects (5 men, FEV1 82 ± 7% of predicted) were included. COPD patients had lower muscle strength before (21.77 ± 7.86 kg) and after the 6MWT (11.16 ± 4.70 kg) compared with control subjects (33.50 ± 14.01 kg before; 29.25 ± 16.66 kg after). After the 6MWT, COPD patients showed a significant reduction in the MVIC and a significant increase in the TRT and PMT, which did not occur in control subjects. The reaction time parameters were higher in COPD patients after the 6MWT compared with control subjects. The TRT (r = -0.535, P < 0.005) and PMT (r = -0.549, P < 0.005) were inversely correlated with the MVIC after the 6MWT. CONCLUSIONS: Neuromuscular changes associated with upper motor neuron activation contribute to MVIC impairment in COPD patients after performing a functional test.

Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression.

OBJECTIVES: To evaluate whether reduced activity of the anti-inflammatory HSP70 pathway correlates with nonalcoholic fatty liver disease (NAFLD) progression and with markers of oxidative stress because obesity activates inflammatory JNKs, whereas HSP70 exerts the opposite effect. METHODS: Adult obese patients (N = 95) undergoing bariatric surgery were divided into steatosis (ST), steatohepatitis (SH), and fibrosis (SH+F) groups. The levels of HSP70, its major transcription factor, HSF1, and JNKs were assessed by immunoblotting hepatic and visceral adipose tissue; data were confirmed by immunohistochemistry. Plasma biochemistry (lipids, HbA1c , HOMA, hepatic enzymes, and redox markers) was also evaluated. RESULTS: In both liver and adipose tissue, decreased HSP70 levels, paralleled by similar reductions in HSF1 and reduced plasma antioxidant enzyme activities, correlated with insulin resistance and with NAFLD progression (expression levels were as follows: ST > SH > SH + F). The immunohistochemistry results suggested Kupffer cells as a site of HSP70 inhibition. Conversely, JNK1 content and phosphorylation increased. CONCLUSIONS: Decreased HSF1 levels in the liver and fat of obese patients correlated with impairment of HSP70 in an NAFLD stage-dependent manner. This impairment may affect HSP70-dependent anti-inflammation, with consequent oxidative stress and insulin resistance in advanced stages of NAFLD. Possible causal effects of fat cell senescence are discussed.

Treatment with aqueous extract from Croton cajucara Benth reduces hepatic oxidative stress in streptozotocin-diabetic rats.

Croton cajucara Benth is a plant found in Amazonia, Brazil and the bark and leaf infusion of this plant have been popularly used to treat diabetes and hepatic disorders. The present study was designed to evaluate the oxidative stress as well as the therapeutic effect of Croton cajucara Benth (1.5 mL of the C. cajucara extract i.g.) in rats with streptozotocin-induced diabetes. Croton cajucara Benth was tested as an aqueous extract for its phytochemical composition, and its antioxidant activity in vitro was also evaluated. Lipid peroxidation and superoxide dismutase, catalase, and glutathione reductase activities were measured in the hepatic tissue, as well as the presence activation of p65 (NF-κB), through western blot. Phytochemical screening of Croton cajucara Benth detected the presence of flavonoids, coumarins and alkaloids. The extract exhibited a significant antioxidant activity in the DPPH-scavenging and the hypoxanthine/xanthine oxidase assays. Liver lipid peroxidation increased in diabetic animals followed by a reduction in the Croton-cajucara-Benth-treated group. There was activation of p65 nuclear expression in the diabetic animals, which was attenuated in the animals receiving the Croton cajucara Benth aqueous extract. The liver tissue in diabetic rats showed oxidative alterations related to the streptozotocin treatment. In conclusion the Croton cajucara Benth aqueus extract treatment effectively reduced the oxidative stress and contributed to tissue recovery.

Hepatic nitrosative stress in experimental diabetes.

AIM: The effects of the inhibition of nitrosative stress by aminoguanidine in an experimental model of diabetes mellitus (DM) were investigated. METHODS: Twenty-one male Wistar rats were divided into three groups: control (CO), diabetic (DM), and diabetic treated with aminoguanidine (DM+AG). Aminoguanidine (aminoguanidine hemisulfate salt, Sigma Chemical Co., St. Louis, MO, USA) was used at a dose of 50 mg/kg (i.p.) during the last 30 days of the experiment. The expression levels of liver lipoperoxidation (TBARS - nmol/mg protein), inducible oxide nitric synthase (iNOS), nitrotyrosine and the NFκB nuclear transcription factor p65 were examined using western blot analysis. RESULTS: The DM group demonstrated an increase in lipoperoxidation and in the expression of iNOS, nitrotyrosine and p65. Aminoguanidine reduced hepatic lipid peroxidation and protein expression levels of iNOS, nitrotyrosine and p65. CONCLUSION: Aminoguanidine treatment reduces liver oxidative and nitrosative stress in diabetic animals. In addition, aminoguanidine reduced the expression of p65 in the liver.

Effect of antioxidant treatment on fibrogenesis in rats with carbon tetrachloride-induced cirrhosis.

Aim. This study aimed to assess the antioxidant activity of quercetin (Q) in an experimental model of cirrhosis induced by CCl(4) inhalation. Materials and Methods. We used 25 male Wistar rats (250 g) that were divided into 3 groups: control (CO), CCl(4), and CCl(4) + Q. The rats were subjected to CCl(4) inhalation (2x/week) for 16 weeks, and they received phenobarbital in their drinking water at a dose of 0.3 g/dL as a P450 enzyme inducer. Q (50 mg/Kg) was initiated intraperitoneally at 10 weeks of inhalation and lasted until the end of the experiment. Statistical analysis was by ANOVA Student Newman-Keuls (mean ± SEM), and differences were considered statistically significant when P < 0.05. Results. After treatment with quercetin, we observed an improvement in liver complications, decreased fibrosis, as analyzed by picrosirius for the quantification of collagen, and decreased levels of matrix metalloproteinase 2 (MMP-2) compared with the CCl(4) group. It also reduced oxidative stress, as confirmed by the decrease of substances reacting to thiobarbituric acid (TBARS), the increased activity of antioxidant enzymes, and the reduced glutathione ratio and glutathione disulfide (GSH/GSSG). Conclusion. We suggest that the use of quercetin might be promising as an antioxidant therapy in liver fibrosis.

Quercetin treatment ameliorates systemic oxidative stress in cirrhotic rats.

Our aim was to investigate whether the antioxidant quercetin protects against liver injury and ameliorates the systemic oxidative stress in rats with common bile duct ligation. Secondary biliary cirrhosis was induced through 28 days of bile duct obstruction. Animals received quercetin (Q) after 14 days of obstruction. Groups of control (CO) and cirrhotic (CBDL) animals received a daily 50 mg/kg body weight i.p. injection of quercetin (CO + Q; CBDL + Q) or vehicle (CO; CBDL). Quercetin corrected the reduction in superoxide dismutase (SOD), catalase CAT, and glutathione peroxidase GPx activities and prevented the increase of thiobarbituric acid reactive substances (TBARS), aminotransferases, and alkaline phosphatase in cirrhotic animals. Quercetin administration also corrected the reduced total nitrate concentration in the liver and prevented liver fibrosis and necrosis. These effects suggest that quercetin might be a useful agent to preserve liver function and prevent systemic oxidative stress.

A classe da NYHA tem relação com a condição funcional e qualidade de vida na insuficiência cardíaca / The relationship between NYHA class and the functional condition and quality of life in heart failure

A insuficiência cardíaca (IC) é uma síndrome que se apresenta com crescente prevalência, podendo limitar o indivíduo quanto à capacidade físico-funcional, condição pulmonar e qualidade de vida. Este estudo tem como objetivo verificar as limitações pulmonares e físicas, bem como a qualidade de vida dos pacientes e compará-las com as classes funcionais da New York Heart Association (NYHA). Estudo transversal, com amostra de 66 pacientes (45 homens). Foram aplicados uma ficha de avaliação padronizada e o questionário de qualidade de vida Short Form-36 (SF-36). Foram realizados espirometria, manovacuometria e o teste da caminhada de seis minutos (TC6M). Os pacientes (classe I: 24 indivíduos, classe II: 27 e classe III: 15) possuíam uma média de idade de 57,95±10,96 anos e representaram uma amostra com características antropométricas homogêneas. Para a condição pulmonar, observou-se diferença estatística quanto a Capacidade Vital Forçada (CVF), Pico de Fluxo Expiratório e Pressão Expiratória Máxima (Pemáx). Na distância do TC6M houve diferença entre classe I e III e entre II e III (classe I: 439,27±58,85 m, classe II: 370,96±74,41 m e classe III: 268,96±83,88 m), com p<0,001. Para o SF-36, houve decréscimo da qualidade de vida conforme o agravo das classes funcionais. Pacientes com IC apresentam diminuição da condição pulmonar, capacidade físico-funcional e qualidade de vida relacionada ao aumento da classe funcional da NYHA.

Heart failure (HF) is a syndrome that presents with increasing prevalence, and can restrict the individual as to the physical-functional, lung condition and quality of life. Check the quality of life, lung and physical limitations of patients and compare them with those in New York Heart Association (NYHA) functional class. Cross-sectional study, a sample of 66 patients (45 men). It applied a form of standardized assessment, spirometry, manovacuometry, of the six minute walk test (6MWT) and questioning the quality of life Short-Form 36 (SF-36). Patients average age of 57.95±10.96 years (Class I: 24, Class II: 27 and Class III: 15) and represented a sample with anthropometric characteristics homogeneous. For the lung condition, we observed a statistical difference in forced vital capacity (FVC), expiratory peak flow and maximal expiratory pressure (MEP). In 6MWT distance significant difference between Class I and III and between II and III (Class I: 439.27±58.85 m, Class II: 370.96±74.41 m and 268.96±83.88 m Class III), with p<0001. For the SF-36, there was a decrease in quality of life as functional disorder of the classes. Patients with IC have decreased lung condition, physical and functional capacity and quality of life proportional to the increase in the NYHA functional class.

Exogenous superoxide dismutase: action on liver oxidative stress in animals with streptozotocin-induced diabetes.

AIM: To investigate the effects of exogenous antioxidant copper zinc superoxide dismutase (Cu/Zn SOD) on oxidative stress in the experimental model of diabetes mellitus (DM). METHODS: Twenty eight male Wistar rats divided in four groups were used: control (CO), controls treated with SOD (CO + SOD), diabetics (DM), and diabetics treated with SOD (DM + SOD). SOD (orgotein, 13 mg/Kg body weight was administered. DM was induced by a single streptozotocin injection (i.p., 70 mg/kg), and 60 days later, we evaluated liver oxidative stress. RESULTS: Liver lipoperoxidation was increased in the DM group and significantly decreased in the DM + SOD group. Nitrite and nitrate measures were reduced in the DM and increased in the DM + SOD group, while iNOS expression in the DM group was 32% greater than in the CO and 53% greater in the DM + SOD group than in the DM group (P < .01). P65 expression was 37% higher in the DM (P < .05), and there was no significant difference between the DM and DM + SOD groups. CONCLUSION: SOD treatment reduced liver oxidative stress in diabetic animals, even though it did not change NFκB. SOD also increased NO, probably by the increased dismutation of the superoxide radical. The iNOS expression increase, which became even more evident after SOD administration.

Aminoguanidine reduces oxidative stress and structural lung changes in experimental diabetes mellitus.

We evaluated the effect of aminoguanidine on pulmonary oxidative stress and lung structure in an experimental model of diabetes mellitus. Thiobarbituric acid reactive substances (TBARS), histology and arterial blood gases were evaluated in animals with diabetes mellitus (DM group), animals with diabetes mellitus treated with aminoguanidine (DM+AG group), and controls. The TBARS levels were significantly higher in the DM group than in the control and DM+AG groups (2.90 ± 1.12 vs. 1.62 ± 0.28 and 1.68 ± 0.04 nmol/mg protein, respectively), as was PaCO2 when compared with that of the control group (49.2 ± 1.65 vs. 38.12 ± 4.85 mmHg), and PaO2 was significantly higher in the control group (104.5 ± 6.3 vs. 16.30 ± 69.48 and 97.05 ± 14.02 mmHg, respectively). In this experimental model of diabetes mellitus, aminoguanidine reduced oxidative stress, structural tissue alterations, and gas exchange.

Effect of Agaricus blazei Murill on the pulmonary tissue of animals with streptozotocin-induced diabetes.

The present study was designed to evaluate the oxidative stress as well as the therapeutic effect of Agaricus blazei Muril (A. Blazei) in rats with streptozotocin-induced diabetes. We used 25 Wistar rats, and DM was induced by injecting streptozotocin (70 mg/Kg i.p.). Agaricus blazei Muril was administered daily starting 40 days after disease onset. A. Blazei was tested as an aqueous extract for its phytochemical composition, and its antioxidant activity in vitro was also evaluated. Lipoperoxidation (LPO), and superoxide dismutase (SOD), catalase, and glutathione peroxidase activities were measured in the pulmonary tissue, as well as the presence of inducible nitric oxide synthase (iNOS), through immunohistochemistry. An anatomopathologic study was also performed. Phytochemical screening of A. Blazei detected the presence of alkaloids and saponins. The extract exhibited a significant antioxidant activity in the DPPH-scavenging and the hipoxanthine/xanthine oxidase assays. Pulmonary LPO increased in diabetic animals (0.43 +/- 0.09; P < .001) as compared to the control group (0.18 +/- 0.02), followed by a reduction in the A. Blazei-treated group (0.33 +/- 0.04; P < .05). iNOS was found increased in the lung in diabetic rats and reduced in the A. Blazei-treated group. The pulmonary tissue in diabetic rats showed oxidative alterations related to the streptozotocin treatment. The A. Blazei treatment effectively reduced the oxidative stress and contributed to tissue recovery.

Correlations between respiratory and functional variables in heart failure.

BACKGROUND: Respiratory alterations can impact on the functional performance of patients with heart failure. AIM: To correlate maximum inspiratory muscular force and lung function variables with functional capacity in heart failure patients. METHODS: A transversal study January-July 2007 with 42 chronic heart disease patients (28 males) with no prior pulmonary illness. The patients were in New York Heart Association Functional Class I, II and III. The variables used were maximum inspiratory pressure, forced vital capacity and forced expiratory volume in the first second. Respiratory variables measured were distance covered in the six-minute walk test, NYHA functional class and the physical functioning domain of the Short Form-36 Quality of Life Questionnaire. RESULTS: Maximum inspiratory pressure correlated with the six-minute walk test (r=0.543 and p<0.001), functional capacity (r=-0.566 and p<0.001) and the physical functioning domain score of the Short Form- 36 (r=0.459 and p=0.002). The same was true of forced vital capacity and the six-minute walk test (r=0.501 and p=0.001), functional capacity (r=-0.477 and p=0.001) and Short Form-36 (r=0.314 and p=0.043) variables. Forced expiratory volume correlated with the distance covered in the six-minute walk test (r=0.514 and p<0.001) and functional capacity (r=-0.383 and p=0.012). CONCLUSION: Lung function and inspiratory muscular force respiratory variables correlated with functional variables in patients with heart failure.