Early transcriptional response in the jejunum of germ-free piglets after oral infection with virulent rotavirus

Germ-free piglets were orally infected with virulent rotavirus to collect jejunal mucosal scrapings at 12 and 18 hours post infection (two piglets per time point). IFN-gamma mRNA expression was stimulated in the mucosa of all four infected piglets, indicating that they all responded to the rotavirus infection. RNA pools prepared from two infected piglets were used to compare whole mucosal gene expression at 12 and 18 hpi to expression in uninfected germ-free piglets (n = 3) using a porcine intestinal cDNA microarray. Microarray analysis identified 13 down-regulated and 17 up-regulated genes. Northern blot analysis of a selected group of genes confirmed the data of the microarray. Genes were functionally clustered in interferon-regulated genes, proliferation/differentiation genes, apoptosis genes, cytoskeleton genes, signal transduction genes, and enterocyte digestive, absorptive, and transport genes. Down-regulation of the transport gene cluster reflected in part the loss of rotavirus-infected enterocytes from the villous tips. Data mining suggested that several genes were regulated in lower- or mid-villus immature enterocytes and goblet cells, probably to support repair of the damaged epithelial cell layer at the villous tips. Furthermore, up-regulation was observed for IFN-γ induced guanylate binding protein 2, a protein that effectively inhibited VSV and EMCV replication in vitro (Arch Virol 150:1213–1220, 2005). This protein may play a role in the small intestine’s innate defense against enteric viruses like rotavirus

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Inhibition of alpha2A-adrenoceptors ameliorates DSS-induced acute intestinal inflammation in mice

It has been hypothesized that alpha2-adrenoceptors (alpha2-ARs) may be involved in the pathomechanism of colitis, however, the results are conflicting since both aggravation and amelioration of colonic inflammation have been described in response to alpha2-AR agonists. Therefore, we aimed to analyse the role of alpha2-ARs in acute murine colitis. The experiments were carried out in wild-type (WT), alpha2A-, alpha2B- and alpha2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2 %), alpha2-AR ligands were injected intraperitoneally (i.p.). The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by ELISA and proteome profiler array, respectively. The non-selective alpha2-AR agonist clonidine induced a modest aggravation of DSS-induced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels or histological score. Clonidine induced similar changes in alpha2B- and alpha2C-AR KO mice, whereas it failed to affect the disease activity index (DAI) scores and caused only minor weight loss in alpha2A-AR KO animals. On the other hand, selective inhibition of alpha2A-ARs by BRL 44408 significantly delayed the development of colitis, reduced the colonic levels of MPO and the cytokines/chemokines CCL3, CXCL2, CXCL13 and G-CSF, and elevated that of TIMP-1. Here we report that activation of alpha2-ARs aggravates murine colitis, an effect mediated by the alpha2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation