Oxidative stress and metal carcinogenesis

Occupational and environmental exposures to metals are closely associated with an increased risk of various cancers. Although carcinogenesis caused by metals has been intensively investigated, the exact mechanisms of action are still unclear. Accumulating evidence indicates that reactive oxygen species (ROS) generated by metals play important roles in the etiology of degenerative and chronic diseases. This review covers recent advances in (1) metal-induced generation of ROS and the related mechanisms; (2) the relationship between metal-mediated ROS generation and carcinogenesis; and (3) the signaling proteins involved in metal-induced carcinogenesis, especially intracellular reduction-oxidation-sensitive molecules.     

Role of peroxisomes in ROS/RNS-metabolism: Implications for human disease

Peroxisomes are cell organelles that play a central role in lipid metabolism. At the same time, these organelles generate reactive oxygen and nitrogen species as byproducts. Peroxisomes also possess intricate protective mechanisms to counteract oxidative stress and maintain redox balance. An imbalance between peroxisomal reactive oxygen species/reactive nitrogen species production and removal may possibly damage biomolecules, perturb cellular thiol levels, and deregulate cellular signaling pathways implicated in a variety of human diseases. Somewhat surprisingly, the potential role of peroxisomes in cellular redox metabolism has been underestimated for a long time. However, in recent years, peroxisomal reactive oxygen species/reactive nitrogen species metabolism and signaling have become the focus of a rapidly evolving and multidisciplinary research field with great prospects. This review is mainly devoted to discuss evidence supporting the notion that peroxisomal metabolism and oxidative stress are intimately interconnected and associated with age-related diseases. We focus on several key aspects of how peroxisomes contribute to cellular reactive oxygen species/reactive nitrogen species levels in mammalian cells and how these cells cope with peroxisome-derived oxidative stress. We also provide a brief overview of recent strategies that have been successfully employed to detect and modulate the peroxisomal redox status. Finally, we highlight some gaps in our knowledge and propose potential avenues for further research. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.     

Cellular response to bioactive lipid peroxidation products

Reactive aldehydes, such as 4-hydroxy-2-nonenal, have been implicated as inducers in generating intracellular reactive oxygen species and activation of stress signaling pathways, that integrate with other signaling pathways to control cellular responses to the extracellular stimuli. Here, I briefly summarize a novel signaling pathway in cellular response, in which aldehyde-stimulated detoxification response is mediated by cyclooxygenase metabolites. These findings argue that lipid mediators could induce a cellular process that represents a cellular defense program against toxic compounds.     

Cellular response to bioactive lipid peroxidation products

Reactive aldehydes, such as 4-hydroxy-2-nonenal, have been implicated as inducers in generating intracellular reactive oxygen species and activation of stress signaling pathways, that integrate with other signaling pathways to control cellular responses to the extracellular stimuli. Here, I briefly summarize a novel signaling pathway in cellular response, in which aldehyde-stimulated detoxification response is mediated by cyclooxygenase metabolites. These findings argue that lipid mediators could induce a cellular process that represents a cellular defense program against toxic compounds.     

Oxidative stress and gene regulation

Reactive oxygen species are produced by all aerobic cells and are widely believed to play a pivotal role in aging as well as a number of degenerative diseases. The consequences of the generation of oxidants in cells does not appear to be limited to promotion of deleterious effects. Alterations in oxidative metabolism have long been known to occur during differentiation and development. Experimental perturbations in cellular redox state have been shown to exert a strong impact on these processes. The discovery of specific genes and pathways affected by oxidants led to the hypothesis that reactive oxygen species serve as subcellular messengers in gene regulatory and signal transduction pathways. Additionally, antioxidants can activate numerous genes and pathways. The burgeoning growth in the number of pathways shown to be dependent on oxidation or antioxidation has accelerated during the last decade. In the discussion presented here, we provide a tabular summary of many of the redox effects on gene expression and signaling pathways that are currently known to exist.     

The physiology of bilirubin: health and disease equilibrium

Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.     

Mitochondria: Biological roles in platelet physiology and pathology

Mitochondria are key regulators of cellular energy and redox metabolism, also playing a central role in cell signaling and death pathways. A number of processes occur within mitochondria, including redox-dependent ATP synthesis by oxidative phosphorylation and reactive oxygen species production. Mitochondrial permeability transition is a reversible process that may lead to cell death and is regulated by calcium and reactive oxygen species. Functional mitochondria are present in platelets, and evidence has demonstrated the direct involvement of these organelles in cellular ATP production, redox balance, as well as in platelet activation and apoptosis. Here, we review aspects of platelet physiology in which mitochondria are involved, as well as assess their function as new tools for studying a number of human diseases.     

Mitochondrial ROS--radical detoxification, mediated by protein kinase D

The mitochondrial electron transport chain is the major source for the production of oxygen radicals. Mitochondria-generated reactive oxygen species (mROS) have been implicated in decreasing the life span and contributing to age-related diseases (known as the free radical theory of aging). Recently, the serine/threonine kinase protein kinase D1 (PKD1) was identified as a mitochondrial sensor for oxidative stress. mROS-activated PKD regulates a radical-sensing signaling pathway, which relays mROS production to the induction of nuclear genes that mediate cellular detoxification and survival. This PKD regulated signaling pathway is the first known mitochondria located and mitochondrially regulated antioxidant system that protects these organelles and cells from oxidative stress-mediated damage or cell death. The identification of this and further intracellular protective signaling pathways provides an opportunity to manipulate the effects of mROS, and might provide the key to targeting aging effects and age-related diseases that have been linked to mitochondrial dysfunctions.     

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age‐related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored. Here, we review some of the mitochondrial signaling pathways that participate in establishing cellular senescence. We discuss the role of mitochondrial reactive oxygen species (ROS), mitochondrial dynamics (fission and fusion), the electron transport chain (ETC), bioenergetic balance, redox state, metabolic signature, and calcium homeostasis in controlling cellular growth arrest. We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence. Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.     

Reactive oxygen species in cell signaling

Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When cellular production of ROS overwhelms its antioxidant capacity, damage to cellular macromolecules such as lipids, protein, and DNA may ensue. Such a state of "oxidative stress" is thought to contribute to the pathogenesis of a number of human diseases including those of the lung. Recent studies have also implicated ROS that are generated by specialized plasma membrane oxidases in normal physiological signaling by growth factors and cytokines. In this review, we examine the evidence for ligand-induced generation of ROS, its cellular sources, and the signaling pathways that are activated. Emerging concepts on the mechanisms of signal transduction by ROS that involve alterations in cellular redox state and oxidative modifications of proteins are also discussed.     

Redox regulation of 4-hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins

4-Hydroxy-2-nonenal (4-HNE), one of the major biologically active aldehydes formed during inflammation and oxidative stress, has been implicated in a number of cardiovascular and pulmonary disorders. 4-HNE has been shown to increase vascular endothelial permeability; however, the underlying mechanisms are unclear. Hence, in the current study, we tested our hypothesis that 4-HNE-induced changes in cellular thiol redox status may contribute to modulation of cell signaling pathways that lead to endothelial barrier dysfunction. Exposure of bovine lung microvascular endothelial cells (BLMVECs) to 4-HNE induced reactive oxygen species generation, depleted intracellular glutathione, and altered cell-cell adhesion as measured by transendothelial electrical resistance. Pretreatment of BLM-VECs with thiol protectants, N-acetylcysteine and mercaptopropionyl glycine, attenuated 4-HNE-induced decrease in transendothelial electrical resistance, reactive oxygen species generation, Michael protein adduct formation, protein tyrosine phosphorylation, activation of ERK, JNK, and p38 MAPK, and actin cytoskeletal rearrangement. Treatment of BLMVECs with 4-HNE resulted in the redistribution of FAK, paxillin, VE-cadherin, beta-catenin, and ZO-1, and intercellular gap formation. Western blot analyses confirmed the formation of 4-HNE-derived Michael adducts with the focal adhesion and adherens junction proteins. Also, 4-HNE decreased tyrosine phosphorylation of FAK without affecting total cellular FAK contents, suggesting the modification of integrins, which are natural FAK receptors. 4-HNE caused a decrease in the surface integrin in a time-dependent manner without altering total alpha5 and beta3 integrins. These results, for the first time, revealed that 4-HNE in redox-dependent fashion affected endothelial cell permeability by modulating cell-cell adhesion through focal adhesion, adherens, and tight junction proteins as well as integrin signal transduction that may lead dramatic alteration in endothelial cell barrier dysfunction during heart infarction, brain stroke, and lung diseases.