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.

The blood-brain barrier (BBB), a dynamic and complex barrier formed by endothelial cells, can impede the entry of unwanted substances - pathogens and therapeutic molecules alike - into the central nervous system (CNS) from the blood circulation. Taking into account the fact that CNS-related diseases are the largest and fastest growing unmet medical concern, many potential protein- and nucleic acid-based medicines have been developed for therapeutic purposes. However, due to their poor ability to cross the BBB and the plasma membrane, the above-mentioned bio-macromolecules have limited use in treating neurological diseases. Finding effective, safe, and convenient ways to deliver therapeutic molecules into the CNS is thus urgently required. In recent decades, much effort has been expended in the development of drug delivery technologies, of which cell-penetrating peptides (CPPs) have the most promising potential. The present review covers the latest advances in CPP delivery technology, and provides an update on their use in CNS-targeted drug delivery.

The suppressor of cytokine signalling‐3 (SOCS3) is well known as a feedback inhibitor of the Janus kinases‐signal transducer and activator of transcription 3 (JAK/STAT3) signalling pathway, which mediates the signal transduction of many cytokines, growth factors and hormones during many cellular processes. The critical role of SOCS3 is manifested by its binding to both the JAK kinase and the cytokine receptor, which can result in the inhibition of STAT3 phosphorylation. STAT3 triggers variety of genes expression in response to cytokine (IL‐6 family, IL‐10) and growth factor stimulation and thus plays a critical role in many cellular biological processes involved in anti/pro‐inflammatory responses, cell growth and cell death. SOCS3 might act directly either by hampering JAK activation or by mediating the ubiquitination and subsequent proteasome degradation of the cytokine/growth factor/hormone receptor. Generally, SOCS3 is a negative regulator for cytokine or hormone signalling. But in some cases, SOCS3 regulates the inflammatory responses positively through inhibiting STAT3. An increasing number of reports showed abnormal expression levels of SOCS3/STAT3 in different myeloid and lymphoid cells as well as in various non‐hematopoietic cells, which suggested its involvement in various infection and inflammatory diseases. In this review, we described the role of SOCS3 and STAT3 expression in different cell populations in regulating the outcomes of infection and inflammatory diseases.

Thiol-dependent enzymes, including the thioredoxin (Trx) and glutathione (GSH) systems, have recently been found as promising bactericidal targets in multidrug-resistant (MDR) bacteria. We previously discovered that silver acted synergistically with ebselen in the inhibition of the Trx system and also resulted in a fast depletion of GSH in Gram-negative bacteria. Silver has been found by others to improve the sensitivity of bacteria to certain conventional antibiotics. Here, we found that the synergistic antibacterial effects of silver with four conventional antibiotics was correlated with the blockage of bacterial Trx system by silver. The synergistic antibacterial effect came along with the production of reactive oxygen species. All these results suggested that silver primarily enhanced the bactericidal activities of conventional antibiotics towards Gram-negative strains through the upregulation of ROS production.