Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. This study is focused on addressing the mutual relationship and early signals of these mechanisms in the D-galactosamine and lipopolysaccharide (D-GalN/LPS) hepatotoxicity model, with the help of standard liver function and biochemistry tests, histology, and measurement of gene expression by RT-PCR. Intraperitoneal injection of 400 mg/kg D-GalN and 50 μg/kg LPS was able to induce hepatotoxicity in rats, as evidenced by significant increases in liver enzymes (ALT, AST) and raised bilirubin levels in plasma. Heme oxygenase-1 and nitric oxide synthase-2 gene expressions were significantly increa sed, along with levels of their products, bilirubin and nitrite. Th e gene expression of glutathione peroxidase 1 remained unchanged, whereas a decrease in superoxide dismutase 1 gene expression was noted. Furthermore, the significant increase in the gene expression of apoptotic genes Bid, Bax and caspase-3 indicate early activation of apoptotic pathways, which was confirmed by histological evaluation. In contrast, the measured caspase-3 activity remained unchanged. Overall, the results have revealed differential oxidative stress and apoptotic responses, which deserves further investigations in this hepatotoxicity model., N. Lekić ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung damage, inflammation, oedema formation, and surfactant dysfunction leading to hypoxemia. Severe ARDS can accelerate the injury of other organs, worsening the patient´s status. There is an evidence that the lung tissue injury affects the right heart function causing cor pulmonale. However, heart tissue changes associated with ARDS are still poorly known. Therefore, this study evaluated oxidative and inflammatory modifications of the heart tissue in two experimental models of ARDS induced in New Zealand rabbits by intratracheal instillation of neonatal meconium (100 mg/kg) or by repetitive lung lavages with saline (30 ml/kg). Since induction of the respiratory insufficiency, all animals were oxygen-ventilated for next 5 h. Total and differential counts of leukocytes were measured in the arterial blood, markers of myocardial injury [(troponin, creatine kinase - myocardial band (CK-MB), lactate dehydrogenase (LD)] in the plasma, and markers of inflammation [tumour necrosis factor (TNF)α, interleukin (IL)-6], cardiovascular risk [galectin-3 (Gal-3)], oxidative changes [thiobarbituric acid reactive substances (TBARS), 3-nitrotyrosine (3NT)], and vascular damage [receptor for advanced glycation end products (RAGE)] in the heart tissue. Apoptosis of heart cells was investigated immunohistochemically. In both ARDS models, counts of total leukocytes and neutrophils in the blood, markers of myocardial injury, inflammation, oxidative and vascular damage in the plasma and heart tissue, and heart cell apoptosis increased compared to controls. This study indicates that changes associated with ARDS may contribute to early heart damage what can potentially deteriorate the cardiac function and contribute to its failure.
Exercise can improve the cardiovascular health. However, the mechanism contributing to its beneficial effect on elderly patients with myocardial infarction is obscure. 20-month-old male Sprague-Dawley rats were used to establish myocardial infarction (MI) model by permanent ligation of the left anterior descending coronary artery (LAD) of the heart, followed by 4-week interval exercise training on a motor-driven rodent treadmill. The cardiac function, myocardial fibrosis, apoptosis, oxidative stress, and inflammatory responses were determined by using pressure transducer catheter, polygraph physiological data acquisition system, Masson's trichrome staining, and ELISA to evaluate the impact of post-MI exercise training on MI. Western blot were performed to detect the activation of AMPK/SIRT1/PGC-1α signaling in the hearts of aged rats. Exercise training significantly improved cardiac function and reduced the cardiac fibrosis. In infarcted heart, the apoptosis, oxidative stress, and inflammation were significantly reduced after 4-week exercise training. Mechanistically, AMPK/SIRT1/PGC-1α pathway was activated in the myocardial infarction area after exercise training, which might participate in the protection of cardiac function. Exercise training improves cardiac function in MI rats through reduction of apoptosis, oxidative stress, and inflammation, which may mediate by the activation of AMPK/SIRT1/PGC-1α signaling pathway.
Autophagy and poly(ADP-ribose) polymerase 1 (PARP-1) are activated and involved in a series of cell processes under oxidative stress, which is associated with pathogenesis of atherosclerosis. Research on their relationship under oxidative stress has been limited. In this study, we aimed to investigate the activation, relationship, and role of autophagy and PARP-1 in vascular smooth muscle cell (VSMC) death under oxidative stress. This study ex-plored the signal molecule PARP-1 and autophagy in VSMCs using gene silencing and the hydrogen peroxide (H2O2)-stimulated oxidative stress model. We observed that H2O2 could induce autophagy in VSMCs, and the inhibition of autophagy could protect VSMCs against oxidative stress-mediated cell death. Meanwhile, PARP-1 could also be activated by H2O2. Additionally, we analysed the regulatory role of PARP-1 in oxidative stress-mediated autophagy and found that PARP-1 was a novel factor involved in the H2O2-induced autophagy via the AMPK-mTOR pathway. Finally, PARP-1 inhibition protected VSMCs against caspase-dependent apoptosis. These data suggested that PARP-1 played a critical role in H2O2-mediated autophagy and both of them were involved in apoptosis of VSMCs. and Corresponding author: Guoxian Qi
Excessive production of oxygen free radicals has been regarded as a causative common denominator of many pathological processes in the animal kingdom. Hydroxyl and nitrosyl radicals represent the major cause of the destruction of biomolecules either by a direct reaction or by triggering a chain reaction of free radicals. Scavenging of free radicals may act preventively or therapeutically. A number of substances that preferentially react with free radicals can serve as scavengers, thus increasing the internal capacity/activity of endogenous antioxidants and protecting cells and tissues against oxidative damage. Molecular hydrogen (H2) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals, in the cells, that enables utilization of its potential for preventive and therapeutic applications. H2 rapidly diffuses into tissues and cells without affecting metabolic redox reactions and signaling reactive species. H2 reduces oxidative stress also by regulating gene expression, and functions as an anti-inflammatory and anti-apoptotic agent. There is a growing body of evidence based on the results of animal experiments and clinical observations that H2 may represent an effective antioxidant for the prevention of oxidative stress-related diseases. Application of molecular hydrogen in situations with excessive production of free radicals, in particular, hydroxyl and nitrosyl radicals is relatively simple and effective, therefore, it deserves special attention., J. Slezák, B. Kura, K. Frimmel, M. Zálešák, T. Ravingerová, C. Viczenczová, Ľ. Okruhlicová, N. Tribulová., and Obsahuje bibliografii
Damage of alveolar-capillary barrier, inflammation, oxidative
injury, and lung cell apoptosis represent the key features of acute
lung injury (ALI). This study evaluated if selective
phosphodiesterase (PDE)-4 inhibitor roflumilast can reduce the
mentioned changes in lavage-induced model of ALI. Rabbits with
ALI were divided into 2 groups: ALI without therapy (A group)
and ALI treated with roflumilast i.v. (1 mg/kg; A+R group). One
group of healthy animals without ALI served as ventilated
controls (C group). All animals were oxygen-ventilated for further
4 h. At the end of experiment, total and differential counts of
cells in bronchoalveolar lavage fluid (BALF) and total and
differential counts of white blood cells were estimated. Lung
edema formation was assessed from determination of protein
content in BALF. Pro-inflammatory cytokines (TNFα, IL-6 and
IL-8) and markers of oxidation (3-nitrotyrosine, thiobarbituricacid reactive substances) were detected in the lung tissue and
plasma. Apoptosis of lung cells was investigated
immunohistochemically. Treatment with roflumilast reduced leak
of cells, particularly of neutrophils, into the lung, decreased
concentrations of cytokines and oxidative products in the lung
and plasma, and reduced lung cell apoptosis and edema
formation. Concluding, PDE4 inhibitor roflumilast showed potent
anti-inflammatory actions in this model of ALI.