Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity.

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

Quercetin attenuates adipogenesis and fibrosis in human skeletal muscle.

Age-associated increase in ectopic fat degeneration and fibrosis in the skeletal muscle contribute to muscle degradation and weakness. Quercetin is a bioactive flavonoid with anti-inflammatory and anti-obesity effects. Thus, we aimed to investigate the effects of quercetin on adipogenesis and fibrosis in the human skeletal muscle, which have not yet been elucidated. Human muscle-derived PDGFRα+/CD201+ cells (mesenchymal progenitors) were incubated with various concentrations of quercetin (0, 0.3, 1, and 3 µM) under adipogenic or fibrogenic conditions. Lipid accumulation was visualized via Oil Red O staining. The expression of genes implicated in adipocyte or fibroblast differentiation and activation of signaling pathways was analyzed. The quercetin-treated PDGFRα+/CD201+ cells showed attenuated lipid accumulation and adipogenic gene expression (CEBPA and ADIPOQ) via the inhibition of CREB phosphorylation under adipocyte differentiation conditions. Additionally, quercetin treatment significantly attenuated the expression of fibrogenic genes (TIMP1, ACTA2, COL1A1 and COL3A1) by inhibiting Smad2 phosphorylation. Quercetin suppressed the differentiation of muscle-derived PDGFRα+/CD201+ cells to adipocytes and fibroblasts at concentrations achievable by dietary and dietary supplement intake, which indicated its preventive or therapeutic effect against the loss of muscle quality.

Annexin A1 accounts for an anti-inflammatory binding target of sesamin metabolites.

Sesamin [(7α,7'α,8α,8'α)-3,4:3',4'-bis(methylenedioxy)-7,9':7',9-diepoxylignane] is a major lignan in sesame seeds. Sesamin is converted to the catechol metabolite, SC1 [(7α,7'α,8α,8'α)-3',4'-methylenedioxy-7,9':7',9-diepoxylignane-3,4-diol] with anti-inflammatory effects after oral administration. However, its molecular target remains unknown. Analysis using high-performance affinity nanobeads led to the identification of annexin A1 (ANX A1) as an SC1-binding protein. SC1 was found to bind to the annexin repeat 3 region of ANX A1 with a high-affinity constant (Kd = 2.77 µmol L-1). In U937 cells, SC1 exhibited an anti-inflammatory effect dependent on ANX A1. Furthermore, administration of sesamin or SC1 attenuated carbon tetrachloride-induced liver damage in mice and concurrently suppressed inflammatory responses dependent on ANX A1. The mechanism involved SC1-induced ANX A1 phosphorylation at serine 27 that facilitates extracellular ANX A1 release. Consequently, the ANX A1 released into the extracellular space suppressed the production of tumor necrosis factor α. This study demonstrates that ANX A1 acts as a pivotal target of sesamin metabolites to attenuate inflammatory responses.

Administration timing and duration-dependent effects of sesamin isomers on lipid metabolism in rats.

Metabolism of lipids such as cholesterol and triglycerides has daily variations and is controlled by a circadian clock. Sesamin isomers, a mixture of sesamin and episesamin (SE), are types of lignans in sesame seed that have shown the improvement of lipid metabolism with various diseases in an animal model. We therefore tested whether the effects of SE on lipid metabolism are influenced by timing of administration. High-fat diet (HFD)-loaded rat was administered SE in the ZT13 or 14 (at the beginning of the active phase) or ZT23 or 22 (at the end of the active phase) every day for 7 or 28 days, and the effects on lipid metabolism were evaluated. The effects of SE were enhanced by duration-dependency: 28-day administration of SE strongly affected some parameters related to lipid metabolism, particularly cholesterol metabolism, as compared to 7-day administration. In particular, in 28-day administration, the analysis of serum and liver cholesterol levels revealed that SE administration decreases more effectively at the beginning of the active phase when compared to at the end of that. Furthermore, quantitative real-time polymerase chain reaction (QRT-PCR) and functional analysis indicated that suppression of cholesterol synthesis in the liver and promotion of cholesterol excretion from the liver, as well as inhibition of the functional activity and gene expression of sterol response element-binding protein 2 (Srebp2), which is a transcriptional factor and controls the gene expression involved in cholesterol-metabolism enzymes, contribute to enhancement of SE's effects at this administration timing. No significant differences were observed in triglyceride metabolism with regard to timing of SE administration. After 28-day administration of SE, administration at the beginning of the active phase only affected the expression of clock genes in the liver with phase-advance. In the pharmacokinetic study, administration time had no effect on the level of sesamin, episesamin or their metabolites in the liver after administration of SE for 28 days. The present results suggest that continuous long administration of SE at the beginning of the active phase is preferable for obtaining beneficial effects on lipid metabolism.