270,836 research outputs found

    Redox homeostasis: The Golden Mean of healthy living

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    The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of main- tenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the mis- perception that reactions in redox signaling involve “reactive oxygen species” rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically ad- dressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutri- tional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of en- dogenously produced electrophiles (parahormesis). In summary, while hormesis, although globally protective, results in setting up of a new phenotype, parahormesis contributes to health by favoring maintenance of homeostasis

    Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State

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    The mitochondrial thioredoxin system (NADPH, thioredoxin reductase, thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the thioredoxin system, while it was decreased by cyclosporin A and the thioredoxin reductase inhibitor auranofin. The redox state of cyclophilin D, thioredoxin 1 and 2 and peroxiredoxin 3 was measured in isolated rat heart mitochondria and in tumor cell lines (CEM-R and HeLa) by redox Western blot analysis upon inhibition of thioredoxin reductase with auranofin, arsenic trioxide, 1-chloro-2,4-dinitrobenzene or after treatment with hydrogen peroxide. A concomitant oxidation of thioredoxin, peroxiredoxin and cyclophilin D was observed, suggesting a redox communication between the thioredoxin system and cyclophilin. This correlation was further confirmed by i) co-immunoprecipitation assay of cyclophilin D with thioredoxin 2 and peroxiredoxin 3, ii) molecular modeling and iii) depleting thioredoxin reductase by siRNA. We conclude that the mitochondrial thioredoxin system controls the redox state of cyclophilin D which, in turn, may act as a regulator of several processes including ROS production and pro-apoptotic factors release

    Characterisation of components and mechanisms involved in redox-regulation of protein import into chloroplasts

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    The vast majority of chloroplast proteins is encoded in the nucleus and thus has to be posttranslationally imported into the organelle, a process that is facilitated by two multimeric protein machineries, the Toc and Tic complexes (translocon at the outer/inner envelope of chloroplasts). Regulation of protein import, e.g. by redox signals, is a crucial step to adapt the protein content to the biochemical requirements of the organelle. In particular, one subunit of the Tic complex, Tic62, has been proposed as a redox sensor, whose possible function is to regulate protein import by sensing and reacting to the redox state of the organelle. To elucidate a potential redox regulation of protein import, structural features, redox-dependent properties and the evolutional origin of Tic62 were investigated. The results show that Tic62 consists of two very different modules: the N-terminal part was found to be mainly -helical and possesses dehydrogenase activity in vitro. It is furthermore an evolutionary ancient domain, as it is highly conserved in all photosynthetic organisms from flowering plants to cyanobacteria and even green sulfur bacteria. In contrast to this, the C-terminus is largely disordered and interacts specifically with ferredoxin-NADP+ oxidoreductase (FNR), a key enzyme in photosynthetic electron transfer reactions. Moreover, this domain was found to exist only in flowering plants, and thus the full-length Tic62 protein seems to be one of the evolutionary youngest Tic components. The results of this study make also clear that Tic62 is a target of redox regulation itself, as its localization and interaction properties depend on the metabolic redox state: oxidized conditions lead to fast membrane binding and interaction with the Tic complex, whereas reduced conditions cause solubilization of Tic62 into the stroma and increased interaction with FNR. This novel shuttling behaviour indicates a dynamic composition of the Tic complex. The NADP+/NADPH ratio was furthermore found to be able to influence the import efficiency of many precursor proteins. Interestingly, the import of not all preproteins depends on the stromal redox state. Hence it was proposed that not a single stable Tic translocon exists, but several Tic subcomplexes with different subunit compositions, which might mediate the import of different precursor groups in a redox-dependent or -independent fashion. Another redox signal that was analyzed in regard to an impact on protein import is the reversible reduction of disulfide bridges, which was found to affect the channel and receptor proteins of the Toc complex. The import of all proteins that use the Toc translocon for entering the chloroplast was shown to be influenced by disulfide bridge formation. Thus it can be concluded that a variety of redox signals, acting both on the Toc and Tic complexes, are able to influence chloroplast protein import

    Redox-mediated reactions of vinylferrocene: Toward redox auxiliaries

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    Chemical redox reactions have been exploited to transform unreactive vinylferrocene into a powerful dienophile for the Diels–Alder reaction and reactive substrate for thiol addition reactions upon conversion to its ferrocenium state. We have further investigated the ability of these reactions to facilitate redox-auxiliary-like reactivity by further hydrogenolyisis of the Diels–Alder adduct to the corresponding cyclopentane derivative

    The thermodynamic landscape of carbon redox biochemistry

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    Redox biochemistry plays a key role in the transduction of chemical energy in all living systems. Observed redox reactions in metabolic networks represent only a minuscule fraction of the space of all possible redox reactions. Here we ask what distinguishes observed, natural redox biochemistry from the space of all possible redox reactions between natural and non-natural compounds. We generate the set of all possible biochemical redox reactions involving linear chain molecules with a fixed numbers of carbon atoms. Using cheminformatics and quantum chemistry tools we analyze the physicochemical and thermodynamic properties of natural and non-natural compounds and reactions. We find that among all compounds, aldose sugars are the ones with the highest possible number of connections (reductions and oxidations) to other molecules. Natural metabolites are significantly enriched in carboxylic acid functional groups and depleted in carbonyls, and have significantly higher solubilities than non-natural compounds. Upon constructing a thermodynamic landscape for the full set of reactions as a function of pH and of steady-state redox cofactor potential, we find that, over this whole range of conditions, natural metabolites have significantly lower energies than the non-natural compounds. For the set of 4-carbon compounds, we generate a Pourbaix phase diagram to determine which metabolites are local energetic minima in the landscape as a function of pH and redox potential. Our results suggest that, across a set of conditions, succinate and butyrate are local minima and would thus tend to accumulate at equilibrium. Our work suggests that metabolic compounds could have been selected for thermodynamic stability, and yields insight into thermodynamic and design principles governing nature’s metabolic redox reactions.https://www.biorxiv.org/content/10.1101/245811v1Othe

    Electrochemically primed functional redox mediator generator from the decomposition of solid state electrolyte.

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    Recent works into sulfide-type solid electrolyte materials have attracted much attention among the battery community. Specifically, the oxidative decomposition of phosphorus and sulfur based solid state electrolyte has been considered one of the main hurdles towards practical application. Here we demonstrate that this phenomenon can be leveraged when lithium thiophosphate is applied as an electrochemically "switched-on" functional redox mediator-generator for the activation of commercial bulk lithium sulfide at up to 70 wt.% lithium sulfide electrode content. X-ray adsorption near-edge spectroscopy coupled with electrochemical impedance spectroscopy and Raman indicate a catalytic effect of generated redox mediators on the first charge of lithium sulfide. In contrast to pre-solvated redox mediator species, this design decouples the lithium sulfide activation process from the constraints of low electrolyte content cell operation stemming from pre-solvated redox mediators. Reasonable performance is demonstrated at strict testing conditions

    A fascinating multifaceted redox-active chelating ligand: introducing the N,Nâ€Č-dimethyl-3,3â€Č-biquinoxalinium “methylbiquinoxen” platform

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    To intimately combine a chelating ligand function with the numerous properties of a viologen-like redox-active centre would offer a rare possibility to design controllable multi-redox states, whose properties arise from strongly correlated phenomena between the organic ligand as well as with any metalloid coordinated centres. Such a concept previously proved to be feasible, however is not widely applicable owing to challenges in terms of synthesis, isolation, and aerial sensitivity of both the ligand and its metal complexes. Here we report the first stable example of such a redox-active molecule, N,Nâ€Č-dimethyl-3,3â€Č-biquinoxalinium2+/˙+/0 “methylbiquinoxen, MBqn2+/˙+/0”, which shows a rich redox chemistry and chelates a metal ion in the case of the metal complex [CdCl2(MBqn0)]. This goes beyond what is possible to achieve using viologens, which are limited by not providing chelation as well as having no accessible biradicaloid state, corresponding to the neutral direduced MBqn0 open-shell behaviour we observe here

    Surface Fluorescence Studies of Tissue Mitochondrial Redox State in Isolated Perfused Rat Lungs

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    We designed a fiber-optic-based optoelectronic fluorometer to measure emitted fluorescence from the auto-fluorescent electron carriers NADH and FAD of the mitochondrial electron transport chain (ETC). The ratio of NADH to FAD is called the redox ratio (RR = NADH/FAD) and is an indicator of the oxidoreductive state of tissue. We evaluated the fluorometer by measuring the fluorescence intensities of NADH and FAD at the surface of isolated, perfused rat lungs. Alterations of lung mitochondrial metabolic state were achieved by the addition of rotenone (complex I inhibitor), potassium cyanide (KCN, complex IV inhibitor) and/or pentachlorophenol (PCP, uncoupler) into the perfusate recirculating through the lung. Rotenone- or KCN-containing perfusate increased RR by 21 and 30%, respectively. In contrast, PCP-containing perfusate decreased RR by 27%. These changes are consistent with the established effects of rotenone, KCN, and PCP on the redox status of the ETC. Addition of blood to perfusate quenched NADH and FAD signal, but had no effect on RR. This study demonstrates the capacity of fluorometry to detect a change in mitochondrial redox state in isolated perfused lungs, and suggests the potential of fluorometry for use in in vivo experiments to extract a sensitive measure of lung tissue health in real-time
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