A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.

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Oxygen, oxidative stress, hypoxia, and heart failure

It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell-signaling proteins (NF-κB, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca(2+) and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System.

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ROS and ROS-Mediated Cellular Signaling

Background
The aim of this study was to evaluate the ability of dual acridine orange/ethidium bromide (AO/EB) staining to detect tumor cell apoptosis. According to apoptosis-associated changes of cell membranes during the process of apoptosis, a clear distinction is made between normal cells, early and late apoptotic cells, and necrotic cells.

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Dual AO/EB Staining to Detect Apoptosis in Osteosarcoma Cells Compared with Flow Cytometry

Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNO levels of e-cigarette consumers

Mitochondria are central to energy metabolism as the source of much of the cell's ATP, as well as being a hub for cellular Ca2+ signaling. Mitochondrial Ca2+ is a positive effector of ATP synthesis, yet Ca2+ overload can lead to mitochondrial dysfunction and cell death. Moreover, Ca2+ uptake by mitochondria is involved in shaping cellular Ca2+ dynamics by regulating the concentrations of Ca2+ within microdomains between mitochondria and sarco/endoplasmic reticulum and plasma membrane Ca2+ transporters. Reactive oxygen species (ROS) generated as a consequence of ATP production in the mitochondria are important for cellular signaling, yet contribute to oxidative stress and cellular damage. ROS regulate the activity of redox sensitive enzymes and ion channels within the cell, including Ca2+ channels. For both Ca2+ and ROS, a delicate balance exists between the beneficial and detrimental effects on mitochondria. In this review we bring together current data on mitochondrial Ca2+ uptake, ROS generation, and redox modulation of Ca2+ transport proteins. We present a model for crosstalk between Ca2+ and ROS signaling pathways within mitochondrial microdomains.

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Crosstalk signaling between mitochondrial Ca2+ and ROS.

The effect of oxidative stress on the Ca2+-ATPase activity, lipid peroxidation and protein modification of cardiac sarcoplasmic reticulum (SR) membranes was investigated. Isolated SR vesicles were exposed to FeSO4/EDTA (0.2 micromol Fe2+ per mg of protein) at 37 degrees C for 1 h in the presence or absence of antioxidants. FeSO4/EDTA decreased the maximum velocity of Ca2+-ATPase reaction without a change of affinity for Ca2+ or Hill coefficient. Treatment with radical-generating system led also to conjugated diene formation, loss of sulfhydryl groups, changes in tryptophan and bityrosine fluorescences and to production of lysine conjugates with lipid peroxidation end-products. Lipid antioxidants butylated hydroxytoluene (BHT) and stobadine partially prevented inhibition of Ca2+-ATPase and decrease in tryptophan fluorescence, while the loss of -SH groups and formation of bityrosines or lysine conjugates were completely prevented. Glutathione also partially protected Ca2+-ATPase activity and decreased formation of bityrosine, but it was not able to prevent oxidative modification of tryptophan and lysine. These findings suggest that combination of amino acid modifications, rather than oxidation of amino acids of one kind, is responsible for inhibition of SR Ca2+-ATPase activity.

Free radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulum.

Carnosine, a specific constituent of excitable tissues of vertebrates, exhibits a significant antioxidant protecting effect on the brain damaged by ischemic-reperfusion injury when it was administered to the animals before ischemic episode. In this study, the therapeutic effect of carnosine was estimated on animals when this drug was administered intraperitoneally (100 mg/kg body weight) after ischemic episode induced by experimental global brain ischemia. Treatment of the animals with carnosine after ischemic episode under long-term (7-14 days) reperfusion demonstrated its pronounced protective effect on neurological symptoms and animal mortality. Carnosine also prevented higher lipid peroxidation of brain membrane structures and increased a resistance of neuronal membranes to the in vitro induced oxidation. Measurements of malonyl dialdehyde (MDA) in brain homogenates showed its increase in the after brain stroke animals and decreased MDA level in the after brain stroke animals treated with carnosine. We concluded that carnosine compensates deficit in antioxidant defense system of brain damaged by ischemic injury. The data presented demonstrate that carnosine is effective in protecting the brain in the post-ischemic period.

Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect.

Alzheimer's disease (AD) is linked to certain common brain pathologies (e.g., ischemia, stroke, and trauma) believed to facilitate its development and progression. One of the logical approaches to this problem is to study the effects of ischemia and hypoxia on the metabolism of amyloid precursor protein, which plays one of the key roles in the pathogenesis of AD. This involves an analysis of (1) proteases, which participate in proteolysis of amyloid precursor protein either by the nonamyloidogenic route (alpha-secretase) or the amyloidogenic pathway and lead to formation of toxic beta-amyloid peptides (beta- and gamma-secretases) and (2) several metallopeptidases that might play a role in degradation of beta-amyloid peptide (Abeta). The study of the effects of prenatal hypoxia and acute hypoxia in adult animals allowed us to conclude that oxygen deprivation results not only in an increase of amyloid precursor protein expression in the brain but also in a decrease in the activity of alpha-secretase. In some brain structures involved in AD pathology (the cortex and striatum), we also observed a decrease in the expression of two of the Abeta degrading enzymes, neprilysin and endothelin-converting enzyme, after hypoxia. A decrease in expression of these metalloproteases was also observed in the model of four-vessel occlusion ischemia in rats with their restoration to the control levels after reperfusion. Preconditioning to mild hypoxia both in the prenatal period and in adults appeared to have a neuroprotective effect restoring, in particular, the levels of amyloid precursor protein, activity of alpha-secretase, and expression of neprilysin and endothelin-converting enzyme to their control values.

Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes.

Primary immunodeficiencies (PID) are inherited disorders which one or several components of immune system are decreased or missing or of non-appropriate function. These diseases affect the development, function or morphology of the immune system. The group of primary immunodeficiencies comprises more than 200 different disorders and syndromes and the number of newly recognized and revealed deficiencies is still increasing. Their clinical presentation and complications depends on the type of defects and there is a great variability in the relationship between genotypes and phenotypes. A variation of clinical presentation across various age categories is also presented and children could widely differ from adult patients with PID. Respiratory symptoms and complications present a significant cause of morbidity and also mortality amongst patients suffering from different forms of PIDs and they are observed both in children and adults. They can affect primarily either upper airways (e.g. sinusitis, otitis media) or lower respiratory tract (e.g. pneumonia, bronchitis, bronchiectasis, interstitial lung diseases). The complications from lower respiratory tract are usually considered to be more important and also more specific for PIDs and they determinate patients’ prognosis. The spectrum of the causal pathogens usually demonstrates typical pattern characteristic for each PID category. The respiratory signs of PIDs can be divided into infectious (upper and lower respiratory tract infections and complications) and non-infectious (interstitial lung diseases, bronchial abnormalities – especially bronchiectasis, malignancies, benign lymphoproliferation). Early diagnosis and appropriate therapy can prevent or at least slow down the development and course of respiratory complications of PIDs.

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Pulmonary Manifestations of Primary Immunodeficiency Disorders in Children

Bronchial asthma is one of the most common chronic inflammatory diseases of the airways. In the pathogenesis of this disease, the interplay among the genes, intrinsic and extrinsic factors is crucial. Various combinations of the involved factors determine and modify the final clinical phenotype/endotype of asthma. Oxidative stress results from imbalance between the production of reactive oxygen and nitrogen species and the capacity of anti-oxidant defense mechanisms. It was shown that oxidative damage of biomolecules is strongly involved in the asthmatic inflammation. It is evident that asthma is accompanied by oxidative stress in the airways and also at systemic circulation. During the acute exacerbation or allergen challenge, the oxidative stress is more pronounced. On the other hand, the genetic variations in the genes for anti-oxidative and pro-oxidative enzymes is variably associated with various asthmatic subtypes. Whether oxidative stress is the consequence of, or the cause for, chronic changes in asthmatic airways is still being discussed. Contribution of oxidative stress to asthma pathology remains at least partially controversial, since antioxidant interventions have proven rather unsuccessful. According to current knowledge, the relationship between oxidative stress and asthmatic inflammation is bi-directional and genetic predisposition could modify the balance between these two positions – oxidative stress as a cause for or consequence of asthmatic inflammation.

Eva Babusikova

Papers

Free radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulum.

Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect.

Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes.

Pulmonary Manifestations of Primary Immunodeficiency Disorders in Children

Oxidative Stress and Bronchial Asthma in Children—Causes or Consequences?