Attenuation of regulatory T cell function by type I IFN signaling in an MDA5 gain-of-function mutant mouse model

Melanoma differentiation-associated gene 5 (MDA5) is an essential viral double-stranded RNA sensor to trigger antiviral immune responses, including type I interferon (IFN) induction. Aberrant activation of this viral sensor is known to cause autoimmune diseases designated as type I interferonopathies. However, the cell types responsible for these diseases and the molecular mechanisms behind their onset and development are still largely unknown. In this study, we revealed the attenuation of regulatory T cell (Treg) function by type I IFN signaling in a mouse model expressing a gain-of-function MDA5 G821S mutant. We found that experimental colitis induced by adoptive transfer of naïve T cells in Rag2⁻/⁻ mice was rescued by simultaneous transfer of Tregs from wild-type but not from the MDA5 mutant mice. Type I IFN receptor deficiency in the MDA5 mutant mice recovered the suppressive function of MDA5 mutant Tregs. These results suggest that constitutive MDA5 and type I IFN signaling in Tregs decreases the suppressive function of Tregs, potentially contributing to the onset and exacerbation of autoimmune disorders in interferonopathies

Asymmetric syntheses of daedalin A and quercinol and their tyrosinase inhibitory activity

Stereoselective syntheses of daedalin A and quercinol, an enantiomer of daedalin A, is described. The tyrosinase inhibitory activities of daedalin A and quercinol were examined. The activity of quercinol was weaker than that of daedalin A at high concentration.ArticleBIOORGANIC & MEDICINAL CHEMISTRY LETTERS. 20(3):1063-1064 (2010)journal articl

Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells

Th17 cell differentiation is dependent on interleukin (IL)-6 and transforming growth factor (TGF)-β, and it is modulated by activation of the aryl hydrocarbon receptor (AhR). In this study, we show that differentiation of Th17 cells, but not Th1 or induced regulatory T (iT reg) cells, is increased by endogenous AhR agonists present in culture medium. Th17 development from wild-type mice is suboptimal in the presence of the AhR antagonist CH-223191, similar to the situation in AhR-deficient mice, which show attenuated IL-17 production and no IL-22 production. The presence of natural AhR agonists in culture medium is also revealed by the induction of CYP1A1, a downstream target of AhR activation. However, the most commonly used medium, RPMI, supports very low levels of Th17 polarization, whereas Iscove's modified Dulbecco's medium, a medium richer in aromatic amino acids, which give rise to AhR agonists, consistently results in higher Th17 expansion in both mouse and human cells. The relative paucity of AhR agonists in RPMI medium, coupled with the presence of factors conducive to IL-2 activation and enhanced Stat5 phosphorylation, conspire against optimal Th17 differentiation. Our data emphasize that AhR activation plays an essential part in the development of Th17 cells and provide a rational explanation for the poor in vitro polarization of Th17 cells that is reported in the majority of publications for both mouse and human cells

The Pathogenic Factors from Oral Streptococci for Systemic Diseases

The oral cavity is suggested as the reservoir of bacterial infection, and the oral and pharyngeal biofilms formed by oral bacterial flora, which is comprised of over 700 microbial species, have been found to be associated with systemic conditions. Almost all oral microorganisms are non-pathogenic opportunistic commensals to maintain oral health condition and defend against pathogenic microorganisms. However, oral Streptococci, the first microorganisms to colonize oral surfaces and the dominant microorganisms in the human mouth, has recently gained attention as the pathogens of various systemic diseases, such as infective endocarditis, purulent infections, brain hemorrhage, intestinal inflammation, and autoimmune diseases, as well as bacteremia. As pathogenic factors from oral Streptococci, extracellular polymeric substances, toxins, proteins and nucleic acids as well as vesicles, which secrete these components outside of bacterial cells in biofilm, have been reported. Therefore, it is necessary to consider that the relevance of these pathogenic factors to systemic diseases and also vaccine candidates to protect infectious diseases caused by Streptococci. This review article focuses on the mechanistic links among pathogenic factors from oral Streptococci, inflammation, and systemic diseases to provide the current understanding of oral biofilm infections based on biofilm and widespread systemic diseases

Nucleolar integrity during interphase supports faithful Cdk1 activation and mitotic entry

The nucleolus is a dynamic nuclear body that has been demonstrated to disassemble at the onset of mitosis; the relationship between cell cycle progression and nucleolar integrity, however, remains poorly understood. We studied the role of nucleolar proteins in mitosis by performing a global analysis using small interfering RNAs specific to nucleolar proteins; we focused on nucleolar protein 11 (NOL11), with currently unknown mitotic functions. Depletion of NOL11 delayed entry into the mitotic phase owing to increased inhibitory phosphorylation of cyclin-dependent kinase 1 (Cdk1) and aberrant accumulation of Wee1, a kinase that phosphorylates and inhibits Cdk1. In addition to effects on overall mitotic phenotypes, NOL11 depletion reduced ribosomal RNA (rRNA) levels and caused nucleolar disruption during interphase. Notably, mitotic phenotypes found in NOL11-depleted cells were recapitulated when nucleolar disruption was induced by depletion of rRNA transcription factors or treatment with actinomycin D. Furthermore, delayed entry into the mitotic phase, caused by the depletion of pre-rRNA transcription factors, was attributable to nucleolar disruption rather than to G2/M checkpoint activation or reduced protein synthesis. Our findings therefore suggest that maintenance of nucleolar integrity during interphase is essential for proper cell cycle progression to mitosis via the regulation of Wee1 and Cdk1

AN EFFICIENT SYNTHESIS OF PROCYANIDINS USING EQUIMOLAR CONDENSATION OF CATECHIN AND/OR EPICATECHIN CATALYZED BY YTTERBIUM TRIFLATE

Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensation of equimolar amount of catechin derivatives catalyzed by Yb(OTf)(3). The coupled products were successfully converted to procyanidins B1, B2, B3, and B4, respectively. Procyanidins B1, B2, B3, and B4 could be used as standard compounds for identifying the polyphenols in natural source.ArticleHETEROCYCLES. 79:549-563 (2009)journal articl