Significance: The thioredoxin (Trx) and glutathione (GSH) systems play important roles in maintaining the redox balance in the brain, a tissue that is prone to oxidative stress due to its high-energy demand. These two disulfide reductase systems are active in various areas of the brain and are considered to be critical antioxidant systems in the central nervous system (CNS). Various neuronal disorders have been characterized to have imbalanced redox homeostasis. Recent Advances: In addition to their detrimental effects, recent studies have highlighted that reactive oxygen species/reactive nitrogen species (ROS/RNS) act as critical signaling molecules by modifying thiols in proteins. The Trx and GSH systems, which reversibly regulate thiol modifications, regulate redox signaling involved in various biological events in the CNS. Critical Issues: In this review, we focus on the following: (i) how ROS/RNS are produced and mediate signaling in CNS; (ii) how Trx and GSH systems regulate redox signaling by catalyzing reversible thiol modifications; (iii) how dysfunction of the Trx and GSH systems causes alterations of cellular redox signaling in human neuronal diseases; and (iv) the effects of certain small molecules that target thiol-based signaling pathways in the CNS. Future Directions: Further study on the roles of thiol-dependent redox systems in the CNS will improve our understanding of the pathogenesis of many human neuronal disorders and also help to develop novel protective and therapeutic strategies against neuronal diseases. Antioxid. Redox Signal . 27, 989–1010.

Multidrug‐resistant (MDR) Gram‐negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of Escherichia coli thioredoxin and thioredoxin reductase, which are required for ribonucleotide reductase and DNA synthesis and defense against oxidative stress. The bactericidal efficacy of silver and ebselen was further verified in the treatment of mild and acute MDR E. coli peritonitis in mice. These results demonstrate that thiol‐dependent redox systems in bacteria can be targeted in the design of new antibacterial drugs. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems and might be developed for novel efficient treatments against MDR Gram‐negative bacterial infections. Synopsis Silver acts synergistically with the selenazol drug ebselen to combat five clinically most difficult‐to‐treat multidrug‐resistant Gram‐negative bacteria, by targeting thiol‐dependent antioxidant systems. Five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. Silver and ebselen can directly inhibit E. coli thioredoxin reductase, and rapidly deplete GSH, which results in elevation of ROS production and stop in DNA synthesis to induce cell death. The bactericidal efficacy of silver and ebselen was further confirmed in the treatment of mild and acute MDR E. coli peritonitis in mice. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems to be developed for novel efficient treatments against MDR Gram‐negative bacterial infections.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) is critical for defense against intracellular pathogens but may mediate inflammatory tissue damage. To elucidate the role of iNOS in neuroinflammation, infections with encephalitogenic Trypanosoma brucei parasites were compared in inos^-/- and wild-type mice. Inos^-/- mice showed enhanced brain invasion by parasites and T cells, and elevated protein permeability of cerebral vessels, but similar parasitemia levels. Trypanosome infection stimulated T cell- and TNF-mediated iNOS expression in perivascular macrophages. NO nitrosylated and inactivated pro-inflammatory molecules such as NF-κΒp65, and reduced TNF expression and signalling. iNOS-derived NO hampered both TNF- and T cell-mediated parasite brain invasion. In inos^-/- mice, TNF stimulated MMP, including MMP9 activity that increased cerebral vessel permeability. Thus, iNOS-generated NO by perivascular macrophages, strategically located at sites of leukocyte brain penetration, can serve as a negative feed-back regulator that prevents unlimited influx of inflammatory cells by restoring the integrity of the blood-brain barrier. Inflammatory responses can lead to harmful effects on the brain during many chronic parasitic infections, including those with African trypanosomes. T. brucei, the causative agent of African trypanosomiasis, that traverse the blood-brain barrier (BBB) to invade the brain, where, together with inflammatory infiltrates, they likely contribute to the neurologic disturbances of the disease. High levels of nitric oxide (NO) released by the inducible NO synthase (iNOS) are critical for defense against parasites, but also mediate inflammatory tissue damage. Using a mouse model of African trypanosomiasis, we uncovered an unexpected role of NO, preserving the integrity of the BBB and limiting the neuroinvasion of leukocytes and parasites, rather than mediating brain damage or killing of trypanosomes. iNOS-derived NO, nitrosylates molecules such as pro-inflammatory transcription factors. iNOS hampered both TNF- and T cell-mediated parasite and leukocyte brain invasion and passage of serum proteins across the BBB. In inos^-/- mice, exacerbated TNF secretion and signalling increased MMP9 activity that mediates cerebral vascular permeability. Thus, NO is crucial for maintenance of the integrity of the cerebral vessels and serves as a feed-back regulator by inhibiting leukocyte brain penetration during T. brucei infection. Consequently, therapies could target iNOS to reduce tissue damage during neuroinflammation.

Glutaredoxins (Grx) are involved in many reactions including defense against oxidative stress. However, the role of the Grx system under nitrosative stress has barely been investigated. In this study, we found that human Grxs denitrosylated both low and high molecular weight S‐nitrosothiols. Some S‐nitrosylated proteins, stable in the presence of a physiological concentration of glutathione (GSH), were denitrosylated by Grxs. Caspase 3 and cathepsin B were identified as substrates of Grx1‐catalysed denitrosylation. In addition, mono‐thiol Grxs, such as Grx5, exhibited denitrosylase activity coupled with GSH via a monothiol mechanism. Our study demonstrates the ability of Grxs to act as S‐denitrosylases and pinpoint a new mechanism for denitrosylation.

The human retina is facing a big challenge of reactive oxygen species (ROS) from endogenous and exogenous sources. Excessive ROS can cause damage to DNA, lipids, and proteins, triggering abnormal redox signaling, and ultimately lead to cell death. Thus, oxidative stress has been observed in inherited retinal diseases as a common hallmark. To counteract the detrimental effect of ROS, cells are equipped with various antioxidant defenses. In this review, we will focus on the antioxidant systems in the retina and how they can protect retina from oxidative stress. Both small antioxidants and antioxidant enzymes play a role in ROS removal. Particularly, the thioredoxin and glutaredoxin systems, as the major antioxidant systems in mammalian cells, exert functions in redox signaling regulation via modifying cysteines in proteins. In addition, the thioredoxin-like rod-derived cone viability factor (RdCVFL) and thioredoxin interacting protein (TXNIP) can modulate metabolism in photoreceptors and promote their survival. In conclusion, elevating the antioxidant capacity in retina is a promising therapy to curb the progress of inherited retinal degeneration.