In this study we demonstrated that while Cu I does

In this study, we demonstrated that while Cu(I) does not affect LPS induced iNOS Fluoxymesterone it inhibits NO release from microglia. Cu(I)-induced GSNOR inhibition and GSNO depletion is more in line with alternative (non-inflammatory) polarization. These results extend our previous findings that Cu(I) elicits a phenotype with characteristics of both pro-inflammatory and alternative profiles (Rossi-George et al., 2012). Because GSNO represents the main pool of biologic NO in the body, its homeostasis is critical for regulating pathogenesis in the CNS. Although our in vitro observations cannot be directly extrapolated to in vivo, Cu(I) inhibition of GSNOR and GSNO in activated microglia may have pathophysiological relevance. Recent studies suggest that GSNO administration may attenuate the severity of EAE, an animal model of multiple sclerosis (Prasad et al., 2007). High levels of Cu(I) have been found in CNS pathologies in both animal models and in humans. Thus, the disruption of GSNOR-GSNO dyad may have important implications in neuroimmunological disorders and neuroinfectious diseases. Inhibition of GSNOR by Cu(I) may represent one mechanism which leads to shifting microglia signaling in the CNS. GSNO depletion and changes in the profile of SNO-proteins may be one of the mechanisms responsible for the pathogenesis of the inflammatory process related to the disorders in the CNS. Further understanding of transient metal contributions to the regulation of RNS in the CNS may lead to the development of new strategies for treatment of neurological disorders characterized by inflammation.
Acknowledgments This investigation was supported by a grant from the National Institutes of Health R00 ES018891 to ARG.
Introduction Rhizosphere is a dynamic environment in which representatives of various species of plants and microorganisms compete for space, nutrients and water. Roots of plants, in addition to providing mechanical support, uptake of water and mineral nutrients, also play other specialized roles such as synthesis and secretion of various organic substances into the surrounding environment [1]. Compounds identified in root exudates are known to inhibit attack of herbivores or pathogens, stimulate the symbiotic interaction between plants and microorganisms, or influence growth of neighboring plants [2]. The phenomenon in which plants produce and release chemicals, affecting the development of other individuals is called allelopathy. Fescues plants (Festuca) comprises about 450 species typical for areas of moderate temperatures. They are used at golf courses, sports fields and lawns in North and South America and Europe [3]. Grasslands created with fescues do not grow other species e.g. clover (Trifolium L.), dandelion (Taraxacum F.H. Wigg.) or daisies (Bellis sp.). Almost 50 years ago it has been shown that the aqueous extracts from the dried roots of shrubs and tall fescue (Festuca arundinacea Schreb.) inhibited growth of roots of rape (Brassica nigra L.) [4]. A negative effect of fescues on seed germination, growth and development of birdsfoot trefoil (Lotus corniculatus L.) [5] or yield of red clover (T. pratensis L.) [6] was described. Allelopathic properties of fescues correspond to their root exudates. The main component of fescue roots' exudates is meta-Tyrosine (m-Tyr). The highest content of m-Tyr was recorded in F. rubra spp. Commutata and F. rubra spp. Rubra [7]. It occurs also in myrtle euphorbia (Euphorbia myrsinites L.). Moreover, m-Tyr is produced by certain strains of bacteria, and is a precursor for antibiotics such as mureidomycins, pacidamycins, and napsamycins [8], [9]. m-Tyr belongs to the group of non-protein amino acids (NPAAs). In plant cells it is produced by the enzymatic hydroxylation of phenylalanine (Phe) (in F. rubra) or transamination of m-hydroxy-phenylpyruvate (in E. myrsinites) [9]. In contrast, in animal cells, in oxidative stress conditions m-Tyr is accumulated as a result of non-enzymatic oxidation of Phe [10].