Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (LCFA) and very‐long‐chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA‐GM3 increase significantly in metabolic disorders, while LCFA‐GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA‐GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4‐mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA‐GM3 and unsaturated VLCFA‐GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand‐molecular docking analysis supports that VLCFA‐GM3 and LCFA‐GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA‐GM3 is a risk factor for TLR4‐mediated disease progression.

SUMMARYRecent reports suggest that DNA methylation is involved in the cause of autoimmune disease. We investigated the alteration of DNA methylation levels in lupus strains of mice, MRUlpr as a model, which develop an age-dependent lymphadenopathy and autoimmune disease. DNA methylation levels of thymus and axillary lymph nodes in 20-week-old MRWlpr mice, which are in an autoimmune disease state, were lower than those of 4-week-old MRUlpr mice with no symptoms as yet. No significant changes were observed in MRL/+ strain mice, which seemed normal at least 20 weeks, while DNA methylation levels in the spleen of both strains of mice increased significantly from the age of 4 to 20 weeks. However, no significant changes of DNA methylation levels in peripheral blood were observed with ageing in MRL strains. Moreover, we clarified that administration of 5-azacytidine had a strong effect on longer survival of MRLJlpr mice and reduced DNA methylation levels in the axillary lymph nodes and spleen. The possible relevance of DNA methylation levels to the progression of autoimmune disease is discussed.

Queuosine is a modified nucleoside located at the first position of the tRNA anticodon, which is synthesized by tRNA-guanine transglycosylase (TGT). Although the levels of queuosine in cancer cells have been reported to be lower than those in normal cells, the expression levels of TGT remain to be determined. We determined the expression levels of a subunit of TGT (TGT60KD). Contrary of our expectations, the results revealed higher levels of expression of TGT60KD than that in normal cells, and the level of queuosine in the tRNA fraction corresponded with that of TGT60KD expression. These results suggest the possibilities that the expression levels of TGT60KD regulate TGT activity and the levels of queuosine, and that TGT60KD plays significant roles in carcinogenesis. To our knowledge, this is a first report of increased expression levels of TGT60KD in human cancer cells.

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Aim:To identify signs predictive of pneumonia development that can be recognized at nursing homes where limited medical staff and equipmentare available. Methods: Subjects were 761 elderly individuals needing nursing care (172 men 594 women; mean age, 86.8±7.2 years), from 42 nursing homes across Japan who could eat orally and had not received antibiotic treatment during the previous three months.Dental hygienists examined each subject for wet hoarseness during and after eating a meal as a sign of impaired swallowing function, prolongation of mealtime length, refusal of oral care, dry mouth and halitosis. Data on the subjects' activities of daily living, body mass index (BMI) calculated from body height and weight as a measure of nutritional status, and underlying diseases were transcribed from the medical records kept at each nursing home. Results:During the study period, pneumonia occurred in 116 subjects (44 men, 72 women). Significant associations with pneumonia development were identified for nutritional status (P=0.007) and swallowing function (P=0.002). Analysis including comorbid conditions further identified heart disease (P=0.03). Conclusion:In this study, decreased BMI and wet hoarseness during and after eating a meal were identified as signs of pneumonia risk at nursing homes.