Redox Relays Research Articles

Spatially localized redox relays allow sensitive site-specific hydrogen peroxide signaling

Spatially localized redox relays allow sensitive site-specific hydrogen peroxide signaling

Experimental Approaches for Investigating Disulfide-Based Redox Relays in Cells.

Reversible oxidation of cysteine residues within proteins occurs naturally during normal cellular homeostasis and can increase during oxidative stress. Cysteine oxidation often leads to the formation of disulfide bonds, which can impact protein folding, stability, and function. Work in both prokaryotic and eukaryotic models over the past five decades has revealed several multiprotein systems that use thiol-dependent oxidoreductases to mediate disulfide bond reduction, formation, and/or rearrangement. Here, I provide an overview of how these systems operate to carry out disulfide exchange reactions in different cellular compartments, with a focus on their roles in maintaining redox homeostasis, transducing redox signals, and facilitating protein folding. Additionally, I review thiol-independent and thiol-dependent approaches for interrogating what proteins partner together in such disulfide-based redox relays. While the thiol-independent approaches rely either on predictive measures or standard procedures for monitoring protein-protein interactions, the thiol-dependent approaches include direct disulfide trapping methods as well as thiol-dependent chemical cross-linking. These strategies may prove useful in the systematic characterization of known and newly discovered disulfide relay mechanisms and redox switches involved in oxidant defense, protein folding, and cell signaling.

Crystal structure of plasmoredoxin, a redox-active protein unique for malaria parasites.

Plasmoredoxin is a 22 ​kDa thiol–disulfide oxidoreductase involved in cellular redox regulatory processes and antioxidant defense. The 1.6 ​Å structure of the protein, solved via X-ray crystallography, adopts a modified thioredoxin fold. The structure reveals that plasmoredoxin, unique for malarial parasites, forms a new subgroup of thioredoxin-like proteins together with tryparedoxin, unique for kinetoplastids. Unlike most members of this superfamily, Plrx does not have a proline residue within the CxxC redox motif. In addition, the Plrx structure has a distinct C-terminal domain. Similar to human thioredoxin, plasmoredoxin forms monomers and dimers, which are also structurally similar to the human thioredoxin dimer, and, as in humans, plasmoredoxin is inactive as a dimer. Monomer–dimer equilibrium depends on the surrounding redox conditions, which could support the parasite in reacting to oxidative challenges. Based on structural considerations, the residues of the dimer interface are likely to interact with target proteins. In contrast to human and Plasmodium falciparum thioredoxin, however, there is a cluster of positively charged residues at the dimer interface of plasmoredoxin. These intersubunit (lysine) residues might allow binding of the protein to cellular membranes or to plasminogen. Malaria parasites lack catalase and glutathione peroxidase and therefore depend on their other glutathione and thioredoxin-dependent redox relays. Plasmoredoxin could be part of a so far unknown electron transfer system that only occurs in these parasites. Since the surface charge of plasmoredoxin differs significantly from other members of the thioredoxin superfamily, its three-dimensional structure can provide a model for designing selective redox-modulatory inhibitors.

The Human 2-Cys Peroxiredoxins form Widespread, Cysteine-Dependent- and Isoform-Specific Protein-Protein Interactions.

Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by H2O2 acting as a second messenger. However, H2O2 actually reacts poorly with most cysteine thiols and it is not clear how H2O2 discriminates between cysteines to trigger appropriate signaling cascades in the presence of dedicated H2O2 scavengers like peroxiredoxins (PRDXs). It was recently suggested that peroxiredoxins act as peroxidases and facilitate H2O2-dependent oxidation of redox-regulated proteins via disulfide exchange reactions. It is unknown how the peroxiredoxin-based relay model achieves the selective substrate targeting required for adequate cellular signaling. Using a systematic mass-spectrometry-based approach to identify cysteine-dependent interactors of the five human 2-Cys peroxiredoxins, we show that all five human 2-Cys peroxiredoxins can form disulfide-dependent heterodimers with a large set of proteins. Each isoform displays a preference for a subset of disulfide-dependent binding partners, and we explore isoform-specific properties that might underlie this preference. We provide evidence that peroxiredoxin-based redox relays can proceed via two distinct molecular mechanisms. Altogether, our results support the theory that peroxiredoxins could play a role in providing not only reactivity but also selectivity in the transduction of peroxide signals to generate complex cellular signaling responses.

The interactome of 2-Cys peroxiredoxins in Plasmodium falciparum

Peroxiredoxins (Prxs) are crucially involved in maintaining intracellular H2O2 homeostasis via their peroxidase activity. However, more recently, this class of proteins was found to also transmit oxidizing equivalents to selected downstream proteins, which suggests an important function of Prxs in the regulation of cellular protein redox relays. Using a pull-down assay based on mixed disulfide fishing, we characterized the thiol-dependent interactome of cytosolic Prx1a and mitochondrial Prx1m from the apicomplexan malaria parasite Plasmodium falciparum (Pf). Here, 127 cytosolic and 20 mitochondrial proteins that are components of essential cellular processes were found to interact with PfPrx1a and PfPrx1m, respectively. Notably, our data obtained with active-site mutants suggests that reducing equivalents might also be transferred from Prxs to target proteins. Initial functional analyses indicated that the interaction with Prx can strongly impact the activity of target proteins. The results provide initial insights into the interactome of Prxs at the level of a eukaryotic whole cell proteome. Furthermore, they contribute to our understanding of redox regulatory principles and thiol-dependent redox relays of Prxs in subcellular compartments.

120 - ROS-targeting of melanoma cells provides immuno-protection against tumor growth

Breaking barriers in science necessitates crossing of boundaries between disciplines. An intimate link is presented that connects the fields of redox research, cancer therapy, and immunology. Immunogenic cancer cell death (ICD) provides inflammatory stimuli to elicit anti-tumor adaptive immune responses. Release of adjuvant find-me (HMGB1, ATP) and eat-me (calreticulin) signals facilitates DC maturation and cross presentation of neoantigens to T cells. Key hallmarks of ICD in tumor cells are stress of the endoplasmic reticulum and the unfolded proteins response. Both are known to be subject to redox control. Potent ICD-inducing therapies are drugs such as anthracyclines, ionizing irradiation, or photodynamic therapies. Intriguingly, these antitumor approaches are reported to show concomitant generation of reactive species that can drive signaling responses through redox relays. Hence, the importance of reactive species and specifically hydrogen peroxide signaling are underappreciated in the onset of ICD in cancer cells. Recently, a novel technology capable of generating various oxidants has not only been shown to confer remarkable effects in tumor-bearing mice but is also a potent ICD inducer. This cold physical plasma, a partially ionized gas at about body temperature, can be applied to tumors topically, and first palliative cancer patients benefited from plasma therapy. Experimental evidence will be presented that i) physical plasma is an ICD inducer in various cell types including melanoma, ii) this is concomitant with a global HMOX1 signature, and iii) plasma-derived ROS evoke an antitumor T-cell response in tumor-bearing mice.

Hydrogen peroxide metabolism and functions in plants.

Contents Summary 1197 I. Introduction 1198 II. Measurement and imaging of H2 O2 1198 III. H2 O2 and O2·- toxicity 1199 IV. Production of H2 O2 : enzymes and subcellular locations 1200 V. H2 O2 transport 1205 VI. Control of H2 O2 concentration: how and where? 1205 VII. Metabolic functions of H2 O2 1207 VIII. H2 O2 signalling 1207 IX. Where next? 1209 Acknowledgements 1209 References 1209 SUMMARY: Hydrogen peroxide (H2 O2 ) is produced, via superoxide and superoxide dismutase, by electron transport in chloroplasts and mitochondria, plasma membrane NADPH oxidases, peroxisomal oxidases, type III peroxidases and other apoplastic oxidases. Intracellular transport is facilitated by aquaporins and H2 O2 is removed by catalase, peroxiredoxin, glutathione peroxidase-like enzymes and ascorbate peroxidase, all of which have cell compartment-specific isoforms. Apoplastic H2 O2 influences cell expansion, development and defence by its involvement in type III peroxidase-mediated polymer cross-linking, lignification and, possibly, cell expansion via H2 O2 -derived hydroxyl radicals. Excess H2 O2 triggers chloroplast and peroxisome autophagy and programmed cell death. The role of H2 O2 in signalling, for example during acclimation to stress and pathogen defence, has received much attention, but the signal transduction mechanisms are poorly defined. H2 O2 oxidizes specific cysteine residues of target proteins to the sulfenic acid form and, similar to other organisms, this modification could initiate thiol-based redox relays and modify target enzymes, receptor kinases and transcription factors. Quantification of the sources and sinks of H2 O2 is being improved by the spatial and temporal resolution of genetically encoded H2 O2 sensors, such as HyPer and roGFP2-Orp1. These H2 O2 sensors, combined with the detection of specific proteins modified by H2 O2 , will allow a deeper understanding of its signalling roles.

Using in vivo oxidation status of one- and two-component redox relays to determine H2O2 levels linked to signaling and toxicity

BackgroundHydrogen peroxide (H2O2) is generated as a by-product of metabolic reactions during oxygen use by aerobic organisms, and can be toxic or participate in signaling processes. Cells, therefore, need to be able to sense and respond to H2O2 in an appropriate manner. This is often accomplished through thiol switches: Cysteine residues in proteins that can act as sensors, and which are both scarce and finely tuned. Bacteria and eukaryotes use different types of such sensors—either a one-component (OxyR) or two-component (Pap1-Tpx1) redox relay, respectively. However, the biological significance of these two different signaling modes is not fully understood, and the concentrations and peroxides driving those types of redox cascades have not been determined, nor the intracellular H2O2 levels linked to toxicity. Here we elucidate the characteristics, rates, and dynamic ranges of both systems.ResultsBy comparing the activation of both systems in fission yeast, and applying mathematical equations to the experimental data, we estimate the toxic threshold of intracellular H2O2 able to halt aerobic growth, and the temporal gradients of extracellular to intracellular peroxides. By calculating both the oxidation rates of OxyR and Tpx1 by peroxides, and their reduction rates by the cellular redoxin systems, we propose that, while Tpx1 is a sensor and an efficient H2O2 scavenger because it displays fast oxidation and reduction rates, OxyR is strictly a H2O2 sensor, since its reduction kinetics are significantly slower than its oxidation by peroxides, and therefore, it remains oxidized long enough to execute its transcriptional role. We also show that these two paradigmatic H2O2-sensing models are biologically similar at pre-toxic peroxide levels, but display strikingly different activation behaviors at toxic doses.ConclusionsBoth Tpx1 and OxyR contain thiol switches, with very high reactivity towards peroxides. Nevertheless, the fast reduction of Tpx1 defines it as a scavenger, and this efficient recycling dramatically changes the Tpx1-Pap1 response to H2O2 and connects H2O2 sensing to the redox state of the cell. In contrast, OxyR is a true H2O2 sensor but not a scavenger, being partially insulated from the cellular electron donor capacity.

P-38 - Reactive species in immunogenic cancer cell death

Immunogenic cancer cell death (ICD) provides inflammatory stimuli to elicit anti-tumor immunity. Key hallmarks of ICD are ER-stress and the unfolded proteins response, both being redox controlled. ICD-inducing therapies are drugs such as anthracyclines, ionizing irradiation, or photodynamic therapies. Intriguingly, these antitumor approaches show concomitant generation of reactive species that can drive signaling responses through redox relays. Hence, the importance of reactive species and specifically hydrogen peroxide signaling are underappreciated in the onset of ICD in cancer cells. Recently, a novel technology capable of generating various oxidants has not only been shown to confer remarkable effects in tumor-bearing mice but is also a potent ICD inducer. This cold physical plasma, a partially ionized gas, can be applied to tumors topically, and first palliative cancer patients benefited from plasma therapy. Experimental evidence will be presented that i) physical plasma is an ICD inducer in various cell types including melanoma, ii) by this it provides immunomodulatory stimuli especially in macrophages, and iii) plasma treatment is of relevance in animal tumor models.

Regulation Of Antigen-Presenting Machinery In Melanoma After Plasma Treatment

Cold physical plasmas have been shown to eliminate multiple types of cancers in vitro and in vivo [1] Although being multi-component systems, evidence suggest plasmas to be active primarily via release of a plethora of reactive oxygen and nitrogen species (ROS/RNS). These species not only damage cells via oxidation of proteins and lipids but also trigger signaling cascades via redox relays. This redox signaling is vital for a number of processes, e.g. the formation and loading of major histocompatibility class I complexes (MHC-I). Once loaded with peptides and translocated to the cell surface, MHC-I molecules are recognized by cytotoxic T lymphocytes. In cancer, high numbers of these lymphocytes often correlate with a good prognosis due to their ability to specifically recognize and kill tumor cells. Understanding whether and how MHCI loading and expression is regulated via exogenous oxidants such as produced by cold plasmas is key to delineate possible immune-modulating effects of plasmas in onco-therapy. Intracellular proteins get degraded to peptides by the proteasome before they get transported to the endoplasmatic reticulum by antigen peptide transporter TAP1 and TAP2. In endoplasmatic reticulum the peptides get associated with MHC-class I molecules via a number of proteins, such as Tapasin, ERp57 and PDI [2, 3]. Histone deacetylase inhibitors, interferones and cytokines are able to enhance the expression of TAP1, TAP2, LMP2, LMP7, and Tapasin in association with increased expression of MHC class I [4-6]. Here, we treated melanoma cells in vitro with cold plasma and investigated subsequent effects on the antigen processing machinery. We confirmed cytotoxic effects of the plasma treatment, and measured an upregulation of MHC-I on the cell surface using flow cytometry. Subsequently, we investigated quantity and activity of several proteins crucial in the antigen processing machinery, such as TAP1, TAP2, Tapasin, and ERp57, and we observed a modulation of protein targets. Trichostatin A, Interferon γ, and IL-10 served as positive controls as they promote antigen processing and presentation [5]. Our results suggest a role of plasma-derived, exogenous reactive species in the regulation of antigen presentation of tumor cells important for mounting antitumor immune responses..

Encapsulation of a Quinhydrone Cofactor in the Inner Pocket of Cobalt Triangular Prisms: Combined Light‐Driven Reduction of Protons and Hydrogenation of Nitrobenzene

The design of artificial systems that mimic highly evolved and finely tuned natural photosynthetic systems has attracted intensive research interest. A new system was formulated that encapsulates a quinhydrone (QHQ) cofactor in metal-organic hosts based on inspiration from the redox relays of photosystem II. The M6 L3 triangular prism hosts provided a special redox-modulated environment for the cofactor localized within the pocket, and the proximity effects of the host-guest interactions facilitated the formation of charge-transfer complexes that are typically very difficult to form in normal homogeneous systems. Extensive electron delocalization and well-controlled redox potential were induced to decrease the overpotential of the metal sites for proton reduction. The excellent activity and stability of the supramolecular systems allow the tandem reductions being combined to efficiently reduce nitrobenzene using active H-sources from the light activation of water.

Encapsulation of a Quinhydrone Cofactor in the Inner Pocket of Cobalt Triangular Prisms: Combined Light‐Driven Reduction of Protons and Hydrogenation of Nitrobenzene

AbstractThe design of artificial systems that mimic highly evolved and finely tuned natural photosynthetic systems has attracted intensive research interest. A new system was formulated that encapsulates a quinhydrone (QHQ) cofactor in metal–organic hosts based on inspiration from the redox relays of photosystem II. The M6L3 triangular prism hosts provided a special redox‐modulated environment for the cofactor localized within the pocket, and the proximity effects of the host–guest interactions facilitated the formation of charge‐transfer complexes that are typically very difficult to form in normal homogeneous systems. Extensive electron delocalization and well‐controlled redox potential were induced to decrease the overpotential of the metal sites for proton reduction. The excellent activity and stability of the supramolecular systems allow the tandem reductions being combined to efficiently reduce nitrobenzene using active H‐sources from the light activation of water.

The Conundrum of Hydrogen Peroxide Signaling and the Emerging Role of Peroxiredoxins as Redox Relay Hubs.

Hydrogen peroxide (H2O2) is known to act as a messenger in signal transduction. How H2O2 leads to selective and efficient oxidation of specific thiols on specific signaling proteins remains one of the most important open questions in redox biology. Recent Advances: Increasing evidence implicates thiol peroxidases as mediators of protein thiol oxidation. Recently, this evidence has been extended to include the peroxiredoxins (Prxs). Prxs are exceptionally sensitive to H2O2, abundantly expressed and capture most of the H2O2 that is generated inside cells. The overall prevalence and importance of Prx-based redox signaling relays are still unknown. The same is true for alternative mechanisms of redox signaling. It will be important to clarify the relative contributions of Prx-mediated and direct thiol oxidation to H2O2 signaling. Many questions relating to Prx-based redox relays remain to be answered, including their mechanism, structural organization, and the potential role of adaptor proteins. Antioxid. Redox Signal. 28, 558-573.

Concerted One-Electron Two-Proton Transfer Processes in Models Inspired by the Tyr-His Couple of Photosystem II.

Nature employs a TyrZ-His pair as a redox relay that couples proton transfer to the redox process between P680 and the water oxidizing catalyst in photosystem II. Artificial redox relays composed of different benzimidazole–phenol dyads (benzimidazole models His and phenol models Tyr) with substituents designed to simulate the hydrogen bond network surrounding the TyrZ-His pair have been prepared. When the benzimidazole substituents are strong proton acceptors such as primary or tertiary amines, theory predicts that a concerted two proton transfer process associated with the electrochemical oxidation of the phenol will take place. Also, theory predicts a decrease in the redox potential of the phenol by ∼300 mV and a small kinetic isotope effect (KIE). Indeed, electrochemical, spectroelectrochemical, and KIE experimental data are consistent with these predictions. Notably, these results were obtained by using theory to guide the rational design of artificial systems and have implications for managing proton activity to optimize efficiency at energy conversion sites involving water oxidation and reduction.

Electrochemical and Spectroscopic Properties of Boron Dipyrromethene–Thiophene–Triphenylamine-Based Dyes for Dye-Sensitized Solar Cells

Because of the current increase in consumption of fossil fuels and its negative impact on the environment, clean energy technologies such as solar cells are highly desirable to address this global energy challenge. Among these, dye-sensitized solar cells (DSSCs) have emerged as potential substitutes to traditional silicon-based solar cells. In this study, a series of boron dipyrromethene (BODIPY)-based dyes (1–5) which contain thiophene and/or triphenylamine (TPA) as redox relays of chromophorebridges are synthesized and characterized using electrochemical and optical spectroscopic methods for their potential applications in DSSCs. Their electrochemical and photophysical properties are investigated and compared with the computational results. DSSCs made of these BODIPY-based dyes exhibit incident photon-to-current conversion efficiencies (IPCE) that correspond to their absorption profiles. BODIPY dye 5 bearing TPA provides the highest power efficiency because of its reversible redox activities, while the dyes bearing thiophene yield a decrease in overall solar cell efficiency because of the irreversible oxidation and electropolymerization of thiophene. Despite their low overall conversion efficiencies, these dyes show interesting structural dependence in their DSSC performance. TiO2 electrodes loaded with these BODIPY dyes are characterized by X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infrared analysis to illustrate the surface bonding characteristics of these dyes.

Quantum Dot Solar Cells: Hole Transfer as a Limiting Factor in Boosting the Photoconversion Efficiency

Semiconductor nanostructures are attractive for designing low-cost solar cells with tunable photoresponse. The recent advances in size- and shape-selective synthesis have enabled the design of quantum dot solar cells with photoconversion efficiencies greater than 5%. To make them competitive with other existing thin film or polycrystalline photovoltaic technologies, it is important to overcome kinetic barriers for charge transfer at semiconductor interfaces. This feature article focuses on the limitations imposed by slow hole transfer in improving solar cell performance and its role in the stability of metal chalcogenide solar cells. Strategies to improve the rate of hole transfer through surface-modified redox relays offer new opportunities to overcome the hole-transfer limitation. The mechanistic and kinetic aspects of hole transfer in quantum dot solar cells (QDSCs), nanowire solar cells (NWSCs), and extremely thin absorber (ETA) solar cells are discussed.

Steady-state catalytic wave-shapes for 2-electron reversible electrocatalysts and enzymes.

Using direct electrochemistry to learn about the mechanism of electrocatalysts and redox enzymes requires that kinetic models be developed. Here we thoroughly discuss the interpretation of electrochemical signals obtained with adsorbed enzymes and molecular catalysts that can reversibly convert their substrate and product. We derive analytical relations between electrochemical observables (overpotentials for catalysis in each direction, positions, and magnitudes of the features of the catalytic wave) and the characteristics of the catalytic cycle (redox properties of the catalytic intermediates, kinetics of intramolecular and interfacial electron transfer, etc.). We discuss whether or not the position of the wave is determined by the redox potential of a redox relay when intramolecular electron transfer is slow. We demonstrate that there is no simple relation between the reduction potential of the active site and the catalytic bias of the enzyme, defined as the ratio of the oxidative and reductive limiting currents; this explains the recent experimental observation that the catalytic bias of NiFe hydrogenase depends on steps of the catalytic cycle that occur far from the active site [Abou Hamdan et al., J. Am. Chem. Soc. 2012, 134, 8368]. On the experimental side, we examine which models can best describe original data obtained with various NiFe and FeFe hydrogenases, and we illustrate how the presence of an intramolecular electron transfer chain affects the voltammetry by comparing the data obtained with the FeFe hydrogenases from Chlamydomonas reinhardtii and Clostridium acetobutylicum, only one of which has a chain of redox relays. The considerations herein will help the interpretation of electrochemical data previously obtained with various other bidirectional oxidoreductases, and, possibly, synthetic inorganic catalysts.

Strategic redox relay enables a scalable synthesis of ouabagenin, a bioactive cardenolide.

Here, we report on a scalable route to the polyhydroxylated steroid ouabagenin with an unusual take on the age-old practice of steroid semisynthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 milligrams of a key precursor toward ouabagenin-and ultimately ouabagenin itself-and the discovery of innovative methods for carbon-hydrogen (C-H) and carbon-carbon activation and carbon-oxygen bond homolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules. This synthesis also showcases an approach to bypass the historically challenging problem of selective C-H oxidation of saturated carbon centers in a controlled fashion.

Engineering of Glucose Oxidase for Direct Electron Transfer via Site-Specific Gold Nanoparticle Conjugation

Optimizing the electrical communication between enzymes and electrodes is critical in the development of biosensors, enzymatic biofuel cells, and other bioelectrocatalytic applications. One approach to address this limitation is the attachment of redox mediators or relays to the enzymes. Here we report a simple genetic modification of a glucose oxidase enzyme to display a free thiol group near its active site. This facilitates the site-specific attachment of a maleimide-modified gold nanoparticle to the enzyme, which enables direct electrical communication between the conjugated enzyme and an electrode. Glucose oxidase is of particular interest in biofuel cell and biosensor applications, and the approach of "prewiring" enzyme conjugates in a site-specific manner will be valuable in the continued development of these systems.

Cell signaling (mechanism and reproductive toxicity): Redox chains, radicals, electrons, relays, conduit, electrochemistry, and other medical implications

This article deals with a novel, simple, integrated approach to cell signaling involving basic biochemical principles, and their relationship to reproductive toxicity. Initially, an overview of the biological aspects is presented. According to the hypothetical approach, cell signaling entails interaction of redox chains, involving initiation, propagation, and termination. The messengers are mainly radicals and electrons that are generated during electron transfer (ET) and hydrogen atom abstraction reactions. Termination and initiation processes in the chain occur at relay sites occupied by redox functionalities, including quinones, metal complexes, and imines, as well as redox amino acids. Conduits for the messengers, comprising species with nonbonding electrons, are omnipresent. Details are provided for the various electron transfer processes. In relation to the varying rates of cell communication, rationale is based on electrons and size of radicals. Another fit is similarly seen in inspection of endogenous precursors of reactive oxygen species (ROS); namely, proteins bearing redox moieties, lipid oxidation products, and carbohydrate radicals. A hypothesis is advanced in which electromagnetic fields associated with mobile radicals and electrons play a role. Although radicals have previously been investigated as messengers, the area occupies a minor part of the research, and it has not attracted broad consensus as an important component. For the first time, an integrated framework is presented composed of radicals, electrons, relays, conduits, and electrical fields. The approach is in keeping with the vast majority of experimental observations. Cell signaling also plays an important role in reproductive toxicity. The main classes that cause birth defects, including ROS, radiation, metal compounds, medicinals, abused drugs, and miscellaneous substances, are known to participate in the signaling process. A unifying basis exists, in that both signaling and reproductive toxicity are characterized by the electron transfer-reactive oxygen species-oxidative stress (ET-ROS-OS) scheme. This article also incorporates representative examples of the extensive investigations dealing with various medical implications. There is considerable literature pointing to a role for cell communication in a wide variety of illnesses.