イミダゾキノリノン誘導体の高効率合成法に基づく新規DPP-4阻害糖尿病治療薬の創製 [論文要旨及び審査の要旨]

関西大

イミダゾキノリノン誘導体の高効率合成法に基づく新規DPP-4阻害糖尿病治療薬の創製

関西大

Influence of applied electric fields on the positive magneto-LC effects observed in the ferroelectric liquid crystalline phase of a chiral nitroxide radical compound

By measuring the electric field dependence of EPR spectra of the ferroelectric liquid crystalline (FLC) phase of (2S, 5S)-1 confined in a surface-stabilized liquid-crystal cell, two magnetic bistable states were observed. These states occur because of the anisotropy in spin–spin dipole interactions responsible for positive ‘magneto-LC effects’, which refer to the generation of a sort of spin glass-like ferromagnetic interactions (average spin–spin exchange interaction constant [J with combining macron] > 0) induced by weak magnetic fields in the various liquid crystalline (LC) phases of nitroxide radical compound 1

GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet’s disease

Abstract Background Low C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet’s disease (BD). The objective of the present study was to clarify the pathological roles of CCR1 and IL10 loci identified by previous BD genome-wide association studies (GWASs). Methods M1 and M2 macrophages (Mφ) were differentiated with granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor (M-CSF) from peripheral monocytes of healthy control subjects (HC) and patients with BD. Expression of CD68 and CD163 was evaluated to test for Mφ polarization. CCR1 and IL-10 messenger RNA (mRNA) and protein expression was compared according to CCR1 and IL10 single-nucleotide polymorphism (SNP) genotypes. The migratory ability of M1 and M2 Mφ toward CCR1 ligand macrophage inflammatory protein (MIP)-1α was compared. The ratio of M1 and M2 Mφ in skin lesions of BD and systemic sclerosis (SSc), which was reported to be M2 Mφ-dominant, was compared. To examine the plasticity of polarized Mφ, the differentiated cells were cultured with either the same or the other culture condition. Results Preferential expression of CD163, CCR1, and IL-10 was found in M2 Mφ compared with M1 Mφ. M2 Mφ migrated more sensitively to low concentrations of MIP-1α than M1 Mφ did. BD-derived M1 Mφ showed higher CCR1 surface expression than HC-derived M1 Mφ did. IL10 and CCR1 mRNA expression differences were observed by GWAS-identified SNP genotypes in polarized Mφ. BD skin lesions showed M1 Mφ predominance compared with SSc skin lesions. A plasticity assay revealed that M-CSF restored IL-10 synthesis and reduced IL-6 production by M1 Mφ. Conclusions The present study reveals that GWAS-identified SNPs contribute to M1 Mφ-predominant inflammation in BD. Our data also suggest that the skewed Mφ polarization is correctable by immunological intervention

DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells.

In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6-polycomb repressive complex 1 (PRC1), which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6-PRC1 regulates the expression of only a subset of genes repressed by MAX. Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX-DNMT and MAX-SETDB1 pathways are independent of the PCGF6-PRC1 pathway. Our findings provide insights into our understanding of MAX-based repressive mechanisms of germ cell-related genes in ESCs

Additional file 1: of GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet’s disease

Figure S1. Comparison of phenotypic features and cytokine profiles between M1 and M2 cultured cells. Figure S2. eQTL effect of rs7616215 on CCR2 and CCR1. Figure S3. Detailed results of chemotaxis of M2 Mφ toward various concentrations of MIP-1α. Figure S4. Differences in CCR1 positivity (fluorescence-activated cell sorting) between treatments. a Biologics. b Colchicine. c Prednisolone. Figure S5. The number of differentiated Mφ in vitro in HC and BD. Figure S6. eQTL effect of rs1518111 on IL-10 protein and mRNA. Figure S7. Schema showing our proposed immunological responses in BD. Table S1. Characteristics of patients with BD who participated in the study. Table S2. Characteristics of HC study participants. (DOCX 9663 kb

Additional file 1: of Dysregulated heme oxygenase-1low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons

Table S1. Primer sequences used for qRT-PCR. Figure S1. Numbers of CD68, CD163, HO-1 positive cells in the glomerulus of lupus nephritis patients (ClassI or II). Figure S2. Numbers of CD68, CD163, HO-1 positive cells in the extra-glomerulus of lupus nephritis patients. Figure S3. HO-1 mRNA expression in M1 and M2 Mϕ stimulated with various regents. Figure S4. Genomic background of congenic mice. Figure S5. Genotyping of Bach1 knockout mice. (DOCX 953 kb