Cell Signaling


Cells typically receive signals in chemical form via various signaling molecules. When a signaling molecule joins with an appropriate receptor on a cell surface, this binding triggers a chain of events that not only carries the signal to the cell interior, but amplifies it as well. Cells can also send signaling molecules to other cells. Some of these chemical signals — including neurotransmitters — travel only a short distance, but others must go much farther to reach their targets.


The Redox Code - Antioxidants & Redox Signaling


Central reactions of energetics and metabolism are controlled through near-equilibrium NAD reactions. The structure and function of cells, including genomics and epigenomics, are controlled through nonequilibrium reactions of the cysteine proteome. The spatiotemporal organization of complex systems is coordinated through activation/deactivation cycles of H2O2 production. Redox changes are a common feature of aging, and disruption is a common factor in disease. The concept of the redox code integrates spatiotemporal set points in cellular organization.


The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine


Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not, administration of antioxidants is ineffective, suggesting that our current understanding of the underlying regulatory processes is incomplete.


Similar to reactive oxygen species and reactive nitrogen species, reactive sulfur species are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism, and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept defined as the reactive species interactome (RSI).


Advances in metal-induced oxidative stress and human disease


Detailed studies in the past two decades have shown that redox active metals like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals undergo redox cycling reactions and possess the ability to produce reactive radicals such as superoxide anion radical and nitric oxide in biological systems. Disruption of metal ion homeostasis may lead to oxidative stress, a state where increased formation of reactive oxygen species (ROS) overwhelms body antioxidant protection and subsequently induces DNA damage, lipid peroxidation, protein modification and other effects, all symptomatic for numerous diseases, involving cancer, cardiovascular disease, diabetes, atherosclerosis, neurological disorders (Alzheimer's disease, Parkinson's disease), chronic inflammation and others. 


Redox mechanisms in hepatic chronic wound healing and fibrogenesis


Aerobic organisms have developed evolutionarily conserved mechanisms and strategies to carefully control the generation of ROS and other oxidative stress-related radical or non-radical reactive intermediates (that is, to maintain redox homeostasis), as well as to 'make use' of these molecules under physiological conditions as tools to modulate signal transduction, gene expression and cellular functional responses (that is, redox signalling). However, a derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, can play a significant role in the pathogenesis of major human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis.


Dermal wound healing is subject to redox control


At the wound site, low concentrations of H2O2 supported the healing process especially in p47phox and MCP-1 deficient mice where endogenous H2O2 generation is impaired. Higher doses of H2O2 adversely influenced healing. At low concentrations, H2O2 facilitated wound angiogenesis in vivo. H2O2 induced FAK phosphorylation both in wound-edge tissue in vivo as well as in human dermal microvascular endothelial cells (HMEC). H2O2 induced site-specific (Tyr-925 & Tyr-861) phosphorylation of FAK. Other sites, including the Tyr-397 autophosphorylation site, were insensitive to H2O2. Adenoviral gene delivery of catalase impaired wound angiogenesis and closure. Catalase over-expression slowed tissue remodeling as evident by a more incomplete narrowing of the hyperproliferative epithelium region and incomplete eschar formation.


miRNA in wound inflammation and angiogenesis


miR-146, miR-155 and miR-21 have been of particular interest for research associated with inflammatory and immune responses. These miRNAs are induced by pro-inflammatory stimuli such as IL-1β, TNFα and TLRs. The miR-146 family is composed of two members, miR-146a and miR-146b. Promoter analysis studies recognized miR-146a as a NF-κB dependent gene. Exposure to pro-inflammatory cytokines such as TNFα or IL-1β, or the ligands of TLR-2, -4 or -5 ligands (e.g., bacterial and fungal components) potently induce miR-146 expression in myeloid cells. Several aspects of angiogenesis, such as proliferation, migration, and morphogenesis of endothelial cell are modified by specific miRNAs in an endothelial-specific manner. Endothelial miRs involved in angiogenesis, also referred to as angiomirs, include miR 17-5p, cluster 17–92, miR-15b, -16, -20, -21, -23a, -23b, -24, -27a, -29a,-30a, -30c, -31, -100, -103, -106, 125a and -b, -126, -181a, -191, -199a, -221, -222, -320, and let-7 family.


Copper complexes of non-steroidal anti-inflammatory drugs: an opportunity yet to be realized


The proposed curative properties of Cu-based non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous Cu(II) complexes of NSAIDs with enhanced anti-inflammatory activity and reduced gastrointestinal (GI) toxicity compared with their uncomplexed parent drug. These low toxicity Cu drugs have yet to reach an extended human market, but are of enormous interest, because many of today’s anti-inflammatory drug therapies, including those based on the NSAIDs, remain either largely inadequate and/or are associated with problematic renal, GI and cardiovascular side effects.


Redox Signals in Wound Healing


Recent work have identified that oxygen is not only required to disinfect wounds and fuel healing but that oxygen-dependent redox-sensitive signaling processes represent an integral component of the healing cascade. Evidence demonstrating the ability of antioxidants to oppose vascularization suggests a pro-angiogenic role for oxidants. Antioxidants stall physiological angiogenesis in vivo. Numerous aspects of wound healing are subject to redox control.


Generating and Reversing Chronic Wounds in Diabetic Mice by Manipulating Wound Redox Parameters


We have been successful in creating the first chronic wound model in which biofilm forms naturally without the need of introducing bacteria grown ex vivo. In this model, excessive increase in ROS at the time of wounding provides the skin microbiota with favorable conditions to grow and be able to form biofilms. The restoration of the redox balance by application of AOA causes biofilm to disappear from the wounds, resulting in significant improvement in wound healing. The critical parameter for development of chronic wounds in diabetic humans, and perhaps others, is an excessively high level of reactive oxygen species in the local microenvironment of the wound very early after injury. In this microenvironment, normal skin bacteria that otherwise would not form biofilm colonize the wound and become biofilm producers.


Superoxide Dismutase 1 Loss Disturbs Intracellular Redox Signaling, Resulting in Global Age-Related Pathological Changes


Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body. In vivo studies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1-/- ) mice show various aging-like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation in Sod1-/- mice. This review will focus on various age-related pathologies caused by the loss of Sod1 and will discuss the molecular mechanisms underlying the pathogenesis in Sod1-/- mice.


Tolerance of the association sucralfate / Cu-Zn salts in radiation dermatitis


A topical application of the combination sucralfate / copper zinc salts can be used in the indication radiation dermatitis. The soothing effect of the combination of sucralfate/ copper zinc salts were considered satisfying or very satisfying by investigators and patients during the study, varying from 94 to 100 % of satisfaction.


Antioxidant supplementation attenuates oxidative stress in chronic hepatitis C patients


Untreated HCV patients and also those treated with the standard therapy are coping with a systemic oxidative stress. The antioxidant supplementation conferred an antioxidant protection to both supplemented groups attenuating oxidation processes related to the disease.


Antioxidant Enzymes and Human Diseases


Describes the importance of the antioxidant enzymes superoxide dismutase in the treatment of human diseases. Reactive oxygen species (ROS) are involved in the cell growth, differentiation, progression, and death. Low concentrations of ROS may be beneficial or even indispensable in processes such as intracellular signaling and defense against microorganisms. Nevertheless, higher amounts of ROS play a role in the aging process as well as in a number of human disease states, including cancer, ischemia, and failures in immunity and endocrine functions. As a safeguard against the accumulation of ROS, several non-enzymatic and enzymatic antioxidant activities exist. Therefore, when oxidative stress arises as a consequence of a pathologic event, a defense system promotes the regulation and expression of these enzymes. Thus, further efforts are necessary to fully elucidate the importance of antioxidant enzymes in the therapy of several human disease states.


Modulation of oxidative stress as an anticancer strategy


The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.


Mitochondrial Glutathione a Key Survival Antioxidant


Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST). Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults. From the evaluation of mGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.

Possible use of zinc ions for anti-pigmentation and anti-wrinkling skin care


Active studies of skin science have gradually clarified the underlying mechanisms of skin problems regarding skin beauty. The major skin problems are the alterations in appearance such as the hyperpigmentation and wrinkling caused by age. Those skin alterations are accelerated by solar light, particularly by ultraviolet rays, and it has been reported that reactive oxygen species (ROS) also involves in most of those processes. Thus, the reduction of oxidative stress induced by intracellular ROS is one approach to prevent and improve hyperpigmentation and wrinkling. Zn(2+) is well-known as an inducer of MT (metallothionein) and γGCS (γ-glutamyl cysteinyl synthetase: a rate-limiting enzyme of glutathione synthesis) via the up-regulation of their mRNAs through a metal transcription factor. The inductions of both MT and glutathione are expected to reduce oxidative stress due to the more effective scavenging of intracellular ROS. Several complexes of Zn(2+) and amino acids were synthesized and then evaluated for effects on MT synthesis in HaCaT keratinocytes. Among the complexes tested, we found a superior induction by a Zn(2+) glycine complex, Zn(Gly)(2). The anti-pigmentation and anti-wrinkling effects of Zn(Gly)(2) are introduced in this paper.


Cellular Redox Pathways as a Therapeutic Target in the Treatment of Cancer


The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage.