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A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT(6) for antagonism., (Copyright 2010. Published by Elsevier Ltd.)

Some antioxidants, including butylated hydroxyanisole (BHA), tetrahydropapaveroline (THP), nordihydroguiauretic acid, and 10,11-dihydroxyaporphine (DHA), were found to be potent inhibitors of the production of tumor necrosis factor (TNF)-alpha, IL-1 beta, and IL-6 by human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS) (IC50s in the low micromolar range). Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis. Inhibition of cytokine production by PBMC was observed also when other inducers were used (staphylococci, silica, zymosan). Much higher concentrations of other antioxidants--including ascorbic acid, trolox, alpha-tocopherol, butylated hydroxytoluene, and the 5-lipoxygenase inhibitor zileuton--did not affect the production of these cytokines. The active compounds did not inhibit IL-1-induced production of IL-6 in fibroblasts, showing the cell selectivity of the effect. Antioxidant-mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs. Nuclear run-on experiments showed that THP inhibited transcription of the IL-1 beta gene. THP decreased the concentration of the transcription factors NF-kappa B and AP-1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS. THP and DHA markedly decreased the levels of TNF-alpha and IL-1 beta in the circulation of mice following LPS injection. Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro-inflammatory cytokines. Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock.

Human Langerhans cells (LC) were isolated from epidermal cell preparations by panning with mouse anti-CD1 monoclonal antibody. RNA was prepared and probed for the presence of mRNAs for various cytokines using radiolabeled cDNAs. After stimulation with phorbol myristate acetate LC express RNA for interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta) and produce proteins but do not secrete them at detectable levels. LC-associated IL-1, particularly IL-1 alpha, may play a role in antigen presentation. PMA did not induce IL-6 expression in LC. The addition of lipopolysaccharide, a muramyl dipeptide analog, ionomycin, IL-1 alpha, tumor necrosis factor-alpha, insulin-like growth factor-1 or IL-6 did not induce IL-1 mRNA in LC. UVB augmented IL-1 beta mRNA expression. Glucocorticoids did not detectably affect IL-1 alpha or IL-1 beta mRNA levels following PMA induction, however, staurosporin inhibited IL-1 beta mRNA synthesis. Thus the inducers and regulators of IL-1 formation in human LC and monocytes are not identical.

Interleukin-1 (IL-1) and transforming growth factor alpha (TGF alpha) mRNA expression was analyzed in cultured normal human keratinocytes. Keratinocytes constititively express IL-1 mRNA when cultured in keratinocyte growth medium but not in Dulbecco's minimal essential medium containing fetal bovine serum, in which the cells differentiate. The predominant form of IL-1 expressed by keratinocytes is IL-1 alpha. Addition of IL-1 alpha to keratinocytes increased IL-1 alpha and TGF alpha mRNA expression in a dose-dependent manner. TGF alpha induced a similar increase in IL-1 alpha and TGF alpha mRNA in keratinocytes. Hydrocortisone decreased the expression of both IL-1 alpha and TGF alpha mRNA in keratinocytes. These findings document an autocrine mechanism by which IL-1 alpha and TGF alpha can stimulate the proliferation of keratinocytes in the skin. It is proposed that this autocrine loop may be hyperactive in psoriasis. Antagonism of the effects of this autocrine loop may be one of the mechanisms by which glucocorticoids exert clinically useful effects in psoriasis and other diseases of the skin.

In this study 184 lactose-fermenting Salmonella strains, collected in the National Salmonella Centre from the northern and central parts of Ponad were examined. Epidemiological, serological and biochemical investigations were carried out. Apart from this, chemotherapeutic resistance and male-phage sensitivity were determined. Most of strains belonged to S. agona serotype (S. typhimurium and S. oranienburg were also presented) which apart from the lactose-fermenting ability retained all the remaining biochemical features typical of Salmonella bacilli, were male-phage M13 resistant and showed a high resistance to a wide spectrum of chemotherapeutics. In order to establish the way of the acquiring lac+ property by Salmonella bacilli P22 phage transduction and conjugation experiments, with E. coli F'lac and Hfr H as donors, were performed. S. agona lac- strains were shown to acquire the lactose-fermenting ability by mating with E. coli.