Influence of acute cold stress on the secretion of IL-2, IL-4, IFNγ, IL-12 <i>in vivo</i> by mouse splenocytes

Current literature contains a large amount of data on the modifying effect of cold stress on the functions of immune cell system, in particular, on the secretion of cytokines by the cells of innate and adaptive immunity, mRNA expression. However, the modulatory mechanisms of cold stress effects upon immune response are still not studied in details. We have previously shown that cold stress strongly modulates innate immunity reactions, in particular, leads to increased macrophage secretion of reactive oxygen species, IL-10, but does not affect production of pro-inflammatory cytokines (IL-1β and TNFα. In this work, we aimed for evaluation of effects exerted by acute cold stress upon some adaptive immunity indices, i.e., antibody synthesis, production of IL-2, IL-4, IFNγ by murine splenocytes as well as production of IL-12 and oxygen radicals, taking into account appropriate time-dependent changes. Materials and methods. White male mice were the object of the present study. The animals were divided into the following groups: 1st (control), 2nd (cold stress exposure, at -20 °С for 10 min), 3rd (cold stress at -20 °С for 60 min). Subgroups of the animals were intraperitoneally sensitized with sheep erythrocytes (108 cells in 0.2 ml in 0.9% NaCl) one hour after ending of the cold exposure. On the day 5, the number of antibody-forming cells in the spleen was assessed by the method of local hemolysis in agarose gel. The other subgroup of animals was removed from the experiment 1 and 6 hours after the end of stress exposure, the spleen and cells were isolated from peritoneal cavity. The cytokine concentrations in supernatants were determined by means of enzyme-linked immunosorbent assay systems; production of reactive oxygen species in peritoneal cells was assessed using a luminol-dependent chemiluminescence reaction. It was established that 10- and 60-min cold stress did not have a statistically significant effect on the antibody production, spontaneous and stimulated production of IL-4 by splenocytes. However, inhibition of IL-2 production was observed 60 min following cold stress of either type. At the same time, inhibited IFNγ production was revealed after the both stress regimens. In the animals subjected to cooling for 60 min, a decrease in IL-12 production was also detected. In addition, the 60-min stress led to a pronounced and persistently increased production of oxygen radicals, which may exert negative effects on the development of immune responses. Hence, the acute cold stress led to inhibition of the production of cytokines related to the T cell immune response

Design, Synthesis, and Structure−Activity Relationship Exploration of 1-Substituted 4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one Analogues as Inhibitors of the Annexin A2−S100A10 Protein Interaction

This research was supported by grants from Cancer Research UK. H.K.M. was funded by a Biotechnology and Biological Sciences Research Council studentship.S100 proteins are small adaptors that regulate the activity of partner proteins by virtue of direct protein interactions. Here, we describe the first small molecule blockers of the interaction between S100A10 and annexin A2. Molecular docking yielded candidate blockers that were screened for competition of the binding of an annexin A2 peptide to S100A10. Several inhibitory clusters were identified with some containing compounds with potency in the lower micromolar range. We chose 3-hydroxy-1-(2-hydroxypropyl)-5-(4-isopropylphenyl)-4-(4-methylbenzoyl)-1H-pyrrol-2(5H)-one (1a) as a starting point for structure-activity studies. These confirmed the hypothetical binding mode from the virtual screen for this series of molecules. Selected compounds disrupted the physiological complex of annexin A2 and S100A10, both in a broken cell preparation and inside MDA-MB-231 breast cancer cells. Thus, this class of compounds has promising properties as inhibitors of the interaction between annexin A2 and S100A10 and may help to elucidate the cellular function of this protein interaction.Peer reviewe

Synthesis and anaigetical activity of derivatives of 1-indolilethil-3-pirrolin-2-ones

Interaction of methyl esters of acylpyruvic acides with mixture of aromatic aldehyde and tryptamine or 5-methoxytryptamine leads to 5-aryl-4-acyl-3-hydroxy-1-[2-(3-indolil)-ethyl)-2,5-dihydropyrrol-2-ones (I). The compounds (I) were transformed to 3,4-diaryl-1,4,5,6-tetrahydro-6-oxo-5-(2-(3-indolil)-ethyl)pyrrolo[3,4-c]pyrazoles (II) by reaction with hydrazine-hydrate. The structure of received compounds is established. The analgetical activity of compounds (I б-е) and (II) is investigated