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YbbN/CnoX are proteins that display a Thioredoxin (Trx) domain linked to a tetratricopeptide domain. YbbN from Escherichia coli (EcYbbN) displays a co-chaperone (holdase) activity that is induced by HOCl. Here, we compared EcYbbN with YbbN proteins from Xylella fastidiosa (XfYbbN) and from Pseudomonas aeruginosa (PaYbbN). EcYbbN presents a redox active Cys residue at Trx domain (Cys63), 24 residues away from SQHC motif (SQHC[N 24 ]C) that can form mixed disulfides with target proteins. In contrast, XfYbbN and PaYbbN present two Cys residues in the CXXC (CAPC) motif, while only PaYbbN shows the Cys residue equivalent to Cys63 of EcYbbN. Our phylogenetic analysis revealed that most of the YbbN proteins are in the bacteria domain of life and that their members can be divided into four groups according to the conserved Cys residues. EcYbbN (SQHC[N 24 ]C), XfYbbN (CAPC[N 24 ]V) and PaYbbN (CAPC[N 24 ]C) are representatives of three sub-families. In contrast to EcYbbN, both XfYbbN and PaYbbN: (1) reduced an artificial disulfide (DTNB) and (2) supported the peroxidase activity of Peroxiredoxin Q from X. fastidiosa, suggesting that these proteins might function similarly to the canonical Trx enzymes. Indeed, XfYbbN was reduced by XfTrx reductase with a high catalytic efficiency (k cat /K m  = 1.27 x 10 7  M -1  s -1 ), similar to the canonical XfTrx (XfTsnC). Furthermore, EcYbbN and XfYbbN, but not PaYbbN displayed HOCl-induced holdase activity. Remarkably, EcYbbN gained disulfide reductase activity while lost the HOCl-activated chaperone function, when the SQHC was replaced by CQHC. In contrast, the XfYbbN CAPA mutant lost the disulfide reductase activity, while kept its HOCl-induced chaperone function. In all cases, the induction of the holdase activity was accompanied by YbbN oligomerization. Finally, we showed that deletion of ybbN gene did not render in P. aeruginosa more sensitive stressful treatments. Therefore, YbbN/CnoX proteins display distinct properties, depending on the presence of the three conserved Cys residues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Manganese porphyrins are well-known protectors against the deleterious effects of pro-oxidant species such as superoxide ions and hydrogen peroxide. The present study investigated the antioxidant cytochrome c-like activities of Mn(III)TMPyP [meso-tetrakis (4-N-methyl pyridinium) porphyrin] against superoxide ion and hydrogen peroxide that remained unexplored for this porphyrin. The association of TMPyP with a model of the inner mitochondrial membrane, cardiolipin (CL)-containing liposomes, shifted +30 mV vs. NHE (normal hydrogen electrode) redox potential of the Mn (II) /Mn (III) redox couple. In CL-containing liposomes, Mn (III) TMPyP was reduced by superoxide ions and recycled by Fe (III) cytochrome c to the oxidized form. Similarly, isolated rat liver mitoplasts added to a sample of Mn (II) TMPyP promoted immediate porphyrin reoxidation by electron transfer to the respiratory chain. These results show that Mn (III) TMPyP can act as an additional pool of Fe (III) cytochrome c capable of transferring electrons that escape from the IV complex back into the respiratory chain. Unlike Fe (II) cytochrome c, Mn (II) TMPyP was not efficient for hydrogen peroxide clearance. Therefore, by reducing cytochrome c, Mn (II) TMPyP can indirectly contribute to hydrogen peroxide elimination., Competing Interests: Declaration of competing interest Authors declare no conflicts of interest and no competing interests., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Thimet oligopeptidase (EC 3.4.24.15, TOP) is a cytosolic mammalian zinc protease that can process a diversity of bioactive peptides. TOP has been pointed out as one of the main postproteasomal enzymes that process peptide antigens in the MHC class I presentation route. In the present study, we describe a fine regulation of TOP activity by hydrogen peroxide (H 2 O 2 ). Cells from a human embryonic kidney cell line (HEK293) underwent an ischemia/reoxygenation-like condition known to increase H 2 O 2 production. Immediately after reoxygenation, HEK293 cells exhibited a 32% increase in TOP activity, but no TOP activity was observed 2 h after reoxygenation. In another model, recombinant rat TOP (rTOP) was challenged by H 2 O 2 produced by rat liver mitoplasts (RLMt) alone, and in combination with antimycin A, succinate, and antimycin A plus succinate. In these conditions, rTOP activity increased 17, 30, 32 and 38%, respectively. Determination of H 2 O 2 concentration generated in reoxygenated cells and mitoplasts suggested a possible modulation of rTOP activity dependent on the concentration of H 2 O 2 . The measure of pure rTOP activity as a function of H 2 O 2 concentration corroborated this hypothesis. The data fitted to an asymmetrical bell-shaped curve in which the optimal activating H 2 O 2 concentration was 1.2 nM, and the maximal inhibition (75% about the control) was 1 μm. Contrary to the oxidation produced by aging associated with enzyme oligomerization and inhibition, H 2 O 2 oxidation produced sulfenic acid and maintained rTOP in the monomeric form. Consistent with the involvement of rTOP in a signaling redox cascade, the H 2 O 2 -oxidized rTOP reacted with dimeric thioredoxin-1 (TRx-1) and remained covalently bound to one subunit of TRx-1.

The effect of four trichlorotelluro-dypnones, named compounds 1, 2, 3, and 4, on the bioenergetics of isolated rat liver mitochondria (RLM) and cells was investigated. In a dose-dependent manner, the studied organotelluranes promoted Ca(2+)-dependent mitochondrial swelling inhibited by cyclosporine A and were associated with a decrease of the total mitochondrial protein thiol content. These effects characterize the opening of the classical mitochondrial permeability transition pore. Despite the reactivity with mitochondrial protein thiol groups, these compounds did not promote significant glutathione depletion. In the absence of Ca(2+), the organotelluranes promoted mitochondrial loss of ΔΨ in RLM concomitant with respiratory control decrease due to an increase of the state 4 respiration rate. In these conditions, mitochondrial swelling was absent, and thiol content was higher than that in the presence of Ca(2+). The differentiated effects observed in the presence and absence of Ca(2+) are probably related to the effects of that ion on membrane structure, with repercussions for the exposure of specific reactive protein thiol groups. In smooth muscle cells, these compounds promoted the loss of mitochondrial ΔΨ and apoptosis. The loss of ΔΨ was not preceded by a decrease of cell viability that is consistent with mitochondria as the primary targets for the action of these organotelluranes.

A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics.

The p53 protein, a transcription factor with many gene targets, can also trigger apoptosis in the cytoplasm. The disruption of cell homeostasis, such as Ca(2+) signaling and mitochondrial respiration, contributes to the loss of viability and ultimately leads to cell death. However, the link between Ca(2+) signaling and p53 signaling remains unclear. During aging, there are alterations in cell physiology that are commonly associated with a reduced adaptive stress response, thus increasing cell vulnerability. In this work, we examined the effects of a cytoplasmic p53 inhibitor (pifithrin μ) in the striatum of young and aged rats by evaluating Ca(2+) signaling, mitochondrial respiration, apoptotic protein expression, and tissue viability. Our results showed that pifithrin μ differentially modulated cytoplasmic and mitochondrial Ca(2+) in young and aged rats. Cytoplasmic p53 inhibition appeared to reduce the mitochondrial respiration rate in both groups. In addition, p53 phosphorylation and Bax protein levels were elevated upon cytoplasmic p53 inhibition and could contribute to the reduction of tissue viability. Following glutamate challenge, pifithrin μ improved cell viability in aged tissue, reduced reactive oxygen species (ROS) generation, and reduced mitochondrial membrane potential (ΔΨm). Taken together, these results indicate that cytoplasmic p53 may have a special role in cell viability by influencing cellular Ca(2+) homeostasis and respiration and may produce differential effects in the striatum of young and aged rats., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aerobic organisms are afforded with an antioxidant enzymatic apparatus that more recently has been recognized to include cytochrome c, as it is able to prevent hydrogen peroxide generation by returning electrons from the superoxide ion back to the respiratory chain. The present study investigated the glutathione peroxidase (GPx), superoxide dismutase (SOD) and cytochrome c-like antioxidant activities of para Mn(III)TMPyP in isolated rat liver mitochondria (RLM) and mitoplasts. In RLM, Mn(III)TMPyP decreased the lipid-peroxide content associated with glutathione (GSH) depletion consistent with the use of GSH as a reducing agent for high valence states of Mn(III)TMPyP. SOD and cytochrome c antioxidant activities were also investigated. Mn(II)TMPyP was able to reduce ferric cytochrome c, indicating the potential to remove a superoxide ion by returning electrons back to the respiratory chain. In antimicyn A-poisoned mitoplasts, Mn(III)TMPyP efficiently decreased the EPR signal of DMPO-OH adduct concomitant with GSH depletion. The present results are consistent with SOD and GPx activities for Mn(III)TMPyP and do not exclude cytochrome c-like activity. However, considering that para Mn(III)TMPyP more efficiently reduces, rather than oxidizes, superoxide ion; electron transfer from the Mn(II)TMPyP to the respiratory chain might not significantly contribute to the superoxide ion removal, since most of Mn(II)TMPyP is expected to be produced at the expense of NADPH/GSH oxidation. The present results suggest GPx-like activity to be the principal antioxidant mechanism of Mn(III)TMPyP, whose efficiency is dependent on the NADPH/GSH content in cells.

This paper presents studies about the molecular interactions and redox processes involved in the formation of palladium nanoparticles associated to glucose oxidase (GOx-PdNPs) in a supramolecular arrangement. The synthesis occurs in two steps, the Pd reduction and the formation of the 80 nm sized supramolecular aggregates containing multiples units of GOx associated to 3.5 nm sized PdNPs. During synthesis, GOx molecules interact with Pd salt leading to metal ion and FAD reduction probably via the thiol group of the cysteine 521 residue. For the growing of PdNPs, formic acid was necessary as a co-adjuvant reducing agent. Besides the contribution for the redox processes, GOx is also necessary for the NP stability preventing the formation of precipitates resulted from uncontrolled growing of NPs Cyclic voltammetry of the GOx-PdNPs demonstrated electroactivity of the bionanocomposite immobilized on ITO (indium-tin oxide) electrode surface and also the NP is partially blocked due to strong interaction GOx and the surface of PdNPs. Vibrational spectroscopy (FTIR) showed that significant structural changes occurred in GOx after the association to PdNP. These mechanistics and structural studies can contribute for modulation of bionanocomposites properties.

In this minireview, the more recent findings about the effects of peculiar reactive thiol drugs on mitochondria are presented. These include the following compounds: metallo meso-tetrakis porphyrins, palladacycles, telluranes and phenothiazines. Metallo meso-tetrakis porphyrins can exhibit both beneficial and deleterious effects on mitochodria that are modulated by the central metal, cell location, and availability of axial ligands. Therefore, these compounds have the versatility to be used for cell and mitochondria protection and death. The antioxidant activity of manganese porphyrins is related to a glutathione peroxidase-like activity. By attacking exclusively the membrane protein thiol groups without glutathione depletion, palladacycles are able to induce mitochondrial permeability transition (MPT) and cytochrome c release in the absence of oxidative stress. In hepatoma cells, the mitochondrial action of palladacycles was able to induce apoptotic death. As opposed to palladacycles, telluranes and phenothiazines are able to conjugate the capacity to promote the MPT in a dose-dependent manner in association with efficient antioxidant activity toward lipids. These studies demonstrated that the action of drugs on mitochondrial bioenergetics can be modulated by peculiar reactivity with thiol groups. Therefore, they contribute to studies of toxicity as well as the design of new drugs.

The antioxidant properties of the phenothiazine nucleus (PHT) associated with mitochondrial membranes and liposomes were investigated. PHT exhibited hydrophobic interaction with lipid bilayers, as shown by the quenching of excited states of 1-palmitoyl-2[10-pyran-1-yl)]-decanoyl-sn-glycero-3-phophocholine (PPDPC) incorporated in phosphatidylcholine/phosphatidylethanolamine/cardiolipin liposomes, observed even in high ionic strength; and by the spectral changes of PHT following the addition of mitochondrial membranes. Inserted into bilayers, 5 microM PHT was able to protect lipids and cytochrome c against pro-oxidant agents and exhibited spectral changes suggestive of oxidative modifications promoted by the trapping of the reactive species. In this regard, PHT exhibited the ability to scavenge DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) free radical. PHT was also able to protect rat liver mitochondria against peroxide- and iron-induced oxidative damage and consequent swelling. At the concentration range in which the antioxidant properties were observed, PHT did not cause alterations in the membrane structure and function. This study contributes to the comprehension of the correlation structure and function of phenothiazines and antioxidant properties.

Excitotoxicity represents the primary cause of neuronal death following spinal cord injury (SCI). While autophagy plays a critical and intricate role in SCI, the specific mechanism underlying the relationship between excitotoxicity and autophagy in SCI has been largely overlooked. In this study, we isolated primary spinal cord neurons from neonatal rats and induced excitotoxic neuronal injury by high concentrations of glutamic acid, mimicking an excitotoxic injury model. Subsequently, we performed transcriptome sequencing. Leveraging machine learning algorithms, including weighted correlation network analysis (WGCNA), random forest analysis (RF), and least absolute shrinkage and selection operator analysis (LASSO), we conducted a comprehensive investigation into key genes associated with spinal cord neuron injury. We also utilized protein-protein interaction network (PPI) analysis to identify pivotal proteins regulating key gene expression and analyzed key genes from public datasets (GSE2599, GSE20907, GSE45006, and GSE174549). Our findings revealed that six genes—Anxa2, S100a10, Ccng1, Timp1, Hspb1, and Lgals3—were significantly upregulated not only in vitro in neurons subjected to excitotoxic injury but also in rats with subacute SCI. Furthermore, Hspb1 and Lgals3 were closely linked to neuronal autophagy induced by excitotoxicity. Our findings contribute to a better understanding of excitotoxicity and autophagy, offering potential targets and a theoretical foundation for SCI diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Metal nanoparticles synthesized by green methods with the use of microorganisms are currently one of the most closely studied types of nanomaterials. It has accurately been shown that the characteristics of metal nanoparticles generated in the presence of different bacteria vary. For the two isogenic strains of obligate methylotrophic bacteria of the wild type (M. quaylei MTT) and its streptomycin-resistant mutant (M. quaylei SMR), the pleiotropic character of streptomycin resistance mutation in the SMR cells has been revealed. It has been shown that both cultures can generate silver nanoparticles. There is a dramatic difference in the formation of palladium nanoparticles, which are formed only in the presence of cells of the streptomycin-resistant mutant M. quaylei SMR. This study shows that closely related isogenic strains of obligate methylotrophic bacteria can be distinguished by the spectra of biogenic nanoparticles of two noble metals. While palladium nanoparticles are only generated by the cells of the streptomycin-resistant mutant M. quaylei SMR, biogenic silver nanoparticles can be generated from both cultures. Thus, the assessment of the ability of microorganisms to form biogenic nanoparticles of different metals allows the revelation of subtle metabolic differences of even close cultures. [ABSTRACT FROM AUTHOR]

Semicarbazones and thiosemicarbazones are inhibitors of DNA replication. This activity, which is explained by their chelating property of certain metal ions cofactors of enzymes involved in the replication of DNA, justifies their use as antimicrobials. Our work was aimed at synthesizing and studying the action of certain semicarbazones and thiosemicarbazones on strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus faecalis. After their synthesis, the semicarbazones and thiosemicarbazones of six arylketones were identified by their IR, 1H and 13C NMR spectra and in mass spectrometry. The biological activity of these compounds was tested in vitro against the growth of strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus faecalis. Thiosemicarbazones 1b and 5b, the most lipophilic compounds, had reproducibly exerted an inhibitory effect on the growth of the studied bacteria. [ABSTRACT FROM AUTHOR]

Thioredoxins are multifunctional oxidoreductase proteins implicated in the antioxidant cellular apparatus and oxidative stress. They are involved in several pathologies and are promising anticancer targets. Identification of noncatalytic binding sites is of great interest for designing new allosteric inhibitors of thioredoxin. In a recent work, we predicted normal mode motions of human thioredoxin 1 and identified two major putative hydrophobic binding sites. In this work we investigated noncovalent interactions of human thioredoxin 1 with three phenotiazinic drugs acting as prooxidant compounds by using molecular docking and circular dichroism spectrometry to probe ligand binding into the previously predicted allosteric hydrophobic pockets. Our in silico and CD spectrometry experiments suggested one preferred allosteric binding site involving helix 3 and adopting the best druggable conformation identified by NMA. The CD spectra showed binding of thioridazine into thioredoxin 1 and suggested partial helix unfolding, which most probably concerns helix 3. Taken together, these data support the strategy to design thioredoxin inhibitors targeting a druggable allosteric binding site. [ABSTRACT FROM AUTHOR]

(−)-Linalool, a major component of many essential oils, is widely used in cosmetics and flavoring ingredients as well as in traditional medicines. Although various in vitro and in vivo studies have shown that (−)-linalool has anti-convulsant, anti-nociceptive, anti-inflammatory and anti-oxidative properties, its anti-ischemic/hypoxic effects have yet to be determined. This study assessed the neuroprotective effects of (−)-linalool against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cortical neuronal injury, an in vitro model of ischemic stroke. (−)-Linalool significantly attenuated OGD/R-evoked cortical neuronal injury/death, although it did not inhibit N-methyl- d-aspartate (NMDA)-induced excitotoxicity. (−)-Linalool significantly reduced intracellular oxidative stress during OGD/R-induced injury, as well as scavenging peroxyl radicals (Trolox equivalents or TE = 3.8). This anti-oxidant effect was found to correlate with the restoration of OGD/R-induced decreases in the activities of SOD and catalase. In addition, (−)-linalool inhibited microglial migration induced by monocyte-chemoattractant protein-1 (MCP-1), a chemokine released by OGD/R. These findings show that (−)-linalool has neuroprotective effects against OGD/R-induced neuronal injury, which may be due to its anti-oxidant and anti-inflammatory activities. Detailed examination of the anti-ischemic mechanisms of (−)-linalool may indicate strategies for the development of drugs to treat cerebral ischemic injury. [ABSTRACT FROM AUTHOR]

Oncology patients undergoing radiation treatment and chemotherapy routinely use prescription and/or over-the counter medications either as part of pre-existing comorbid conditions or in the context of conventional treatment management. A growing amount of data suggest that commonly used pharmaceuticals possess antioxidant properties, which may also partially explain some of their therapeutic efficacy. Clinical research is continuing on how such agents interact during chemotherapy and radiation when oxidative mechanisms of action are involved. Historically, such discussions centered on the category of dietary supplements, natural health products, fruits and vegetables, along with established protectant medications. Evidence confirms that some pharmaceutical agents exhibit antioxidant properties similar to dietary supplements, protectants, and may hence hinder the efficacy of chemotherapy and radiation treatment. Awareness by both healthcare providers and patients in this area is often lacking. After reviewing some of the more common and well-established pharmaceuticals, which include those prescribed during cancer treatment, caution needs to be advised especially in regards to the use of corticosteroids, as long-term randomized outcome studies ensuring safety in this area are still outstanding. [ABSTRACT FROM AUTHOR]

Aims Oxidative stress is a direct cause of injury in various neural diseases. Manganese porphyrins (MnPs), a large category of superoxide dismutase (SOD) mimics, shown universally to have effects in numerous neural disease models in vivo. Given their complex intracellular redox activities, detailed mechanisms underlying the biomedical efficacies are not fully elucidated. This study sought to investigate the regulation of endogenous antioxidant systems by a MnP (MnTM-4-PyP) and its role in the protection against neural oxidative stress. Methods Primary cortical neurons were treated with MnTM-4-PyP prior to hydrogen peroxide-induced oxidative stress. Results MnTM-4-PyP increased cell viability, reduced intracellular level of reactive oxygen species, inhibited mitochondrial apoptotic pathway, and ameliorated endoplasmic reticulum function. The protein levels and activities of endogenous SODs were elevated, but not those of catalase. SOD2 transcription was promoted in a transcription factor-specific manner. Additionally, we found FOXO3A and Sirt3 levels also increased. These effects were not observed with MnTM-4-PyP alone. Conclusion Induction of various levels of endogenous antioxidant responses by MnTM-4-PyP has indispensable functions in its protection for cortical neurons against hydrogen peroxide-induced oxidative stress. [ABSTRACT FROM AUTHOR]

New tetracyclic and pentacyclic azaphenothiazines containing one or two quinoline rings instead of benzene rings were obtained in the original reactions of isomeric diquinodithiins, dichlorodiquinolinyl sulfides, and disulfide with aromatic amines. The type of ring fusion in the azaphenothiazine system was concluded from the H NMR spectra. The obtained azaphenothiazines were evaluated in vitro for their antioxidant activity on rat hepatic microsomal membranes for protection of non-enzymatic lipid peroxidation promoted by the Fe/ascorbic acid redox system. Most compounds exhibited a very significant antioxidant activity with IC values between 1 and 23 μM. The degree of antioxidant activity depends on the lipophilicity and molecular size as well as the (non)substitution of the thiazine nitrogen atom and type of ring system fusion. It is the first time to our knowledge that azaphenothiazines are shown to exhibit such potent antioxidant activity. [ABSTRACT FROM AUTHOR]

Mechanical loading is essential for articular cartilage homeostasis and plays a central role in the cartilage pathology, yet the mechanotransduction processes that underlie these effects remain unclear. Previously, we showed that lethal amounts of reactive oxygen species (ROS) were liberated from the mitochondria in response to mechanical insult and that chondrocyte deformation may be a source of ROS. To this end, we hypothesized that mechanically induced mitochondrial ROS is related to the magnitude of cartilage deformation. To test this, we measured axial tissue strains in cartilage explants subjected to semi-confined compressive stresses of 0, 0.05, 0.1, 0.25, 0.5, or 1.0 MPa. The presence of ROS was then determined by confocal imaging with dihydroethidium, an oxidant sensitive fluorescent probe. Our results indicated that ROS levels increased linearly relative to the magnitude of axial strains ( $$r^2 = 0.87, p < 0.05$$ ), and significant cell death was observed at strains $$>$$ 40 %. By contrast, hydrostatic stress, which causes minimal tissue strain, had no significant effect. Cell-permeable superoxide dismutase mimetic Mn(III)tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride significantly decreased ROS levels at 0.5 and 0.25 MPa. Electron transport chain inhibitor, rotenone, and cytoskeletal inhibitor, cytochalasin B, significantly decreased ROS levels at 0.25 MPa. Our findings strongly suggest that ROS and mitochondrial oxidants contribute to cartilage mechanobiology. [ABSTRACT FROM AUTHOR]

Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log kcat(O2-), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]