Reactive Gliosis in Neonatal Disorders: Friend or Foe for Neuroregeneration?

A developing nervous system is particularly vulnerable to the influence of pathophysiological clues and injuries in the perinatal period. Astrocytes are among the first cells that react to insults against the nervous tissue, the presence of pathogens, misbalance of local tissue homeostasis, and a lack of oxygen and trophic support. Under this background, it remains uncertain if induced astrocyte activation, recognized as astrogliosis, is a friend or foe for progressing neonatal neurodevelopment. Likewise, the state of astrocyte reactivity is considered one of the key factors discriminating between either the initiation of endogenous reparative mechanisms compensating for aberrations in the structures and functions of nervous tissue or the triggering of neurodegeneration. The responses of activated cells are modulated by neighboring neural cells, which exhibit broad immunomodulatory and pro-regenerative properties by secreting a plethora of active compounds (including interleukins and chemokines, neurotrophins, reactive oxygen species, nitric oxide synthase and complement components), which are engaged in cell crosstalk in a paracrine manner. As the developing nervous system is extremely sensitive to the influence of signaling molecules, even subtle changes in the composition or concentration of the cellular secretome can have significant effects on the developing neonatal brain. Thus, modulating the activity of other types of cells and their interactions with overreactive astrocytes might be a promising strategy for controlling neonatal astrogliosis.

The pursuit of new alternative ways to eradicate Helicobacter pylori continues: Detailed characterization of interactions in the adenylosuccinate synthetase active site.

Purine nucleotide synthesis is realised only through the salvage pathway in pathogenic bacterium Helicobacter pylori. Therefore, the enzymes of this pathway, among them also the adenylosuccinate synthetase (AdSS), present potential new drug targets. This paper describes characterization of His6-tagged AdSS from H. pylori. Thorough analysis of 3D-structures of fully ligated AdSS (in a complex with guanosine diphosphate, 6-phosphoryl-inosine monophosphate, hadacidin and Mg2+) and AdSS in a complex with inosine monophosphate (IMP) only, enabled identification of active site interactions crucial for ligand binding and enzyme activity. Combination of experimental and molecular dynamics (MD) simulations data, particularly emphasized the importance of hydrogen bond Arg135-IMP for enzyme dimerization and active site formation. The synergistic effect of substrates (IMP and guanosine triphosphate) binding was suggested by MD simulations. Several flexible elements of the structure (loops) are stabilized by the presence of IMP alone, however loops comprising residues 287-293 and 40-44 occupy different positions in two solved H. pylori AdSS structures. MD simulations discovered the hydrogen bond network that stabilizes the closed conformation of the residues 40-50 loop, only in the presence of IMP. Presented findings provide a solid basis for the design of new AdSS inhibitors as potential drugs against H. pylori.