Research into the metabolism of fats may reveal potential targets for developing pharmaceutical approaches to obesity and related disorders. Such research may be limited, however, by the cost and time involved in using mammalian subjects or developing suitable cell lines. To determine whether invertebrates could be used to carry out such research more efficiently, we investigated the ability of Caenorhabditis elegans (C. elegans) to accumulate body fat following the consumption of excess calories and the mechanisms it uses to metabolize fat. C. elegans worms were grown on media containing various sugars and monitored for changes in body fat and expression of sbp-1, a homolog of the mammalian transcription factor SREBP-1c, which facilitates fat storage in mammals. The fat content increased markedly in worms exposed to glucose. In situ analysis of gene expression in transgenic worms carrying the GFP-labeled promoter region of sbp-1 revealed that sbp-1 mRNA was strongly expressed in the intestine. An sbp-1 knockdown caused a reduction in body size, fat storage, and egg-laying activity. RT-PCR analysis revealed a considerable decrease in the expression of fatty acid synthetic genes (including elo-2, fat-2, and fat-5) and a considerable increase of starvation-inducible gene acs-2. Normal egg-laying activity and acs-2 expression were restored on exposure to a polyunsaturated fatty acid. These findings suggest that SBP-1 and SREBP regulate the amount and composition of fat and response to starvation in a similar manner. Thus, C. elegans may be an appropriate subject for studying the metabolism of fats.

After introducing biological DMARDs, increase of ccfDNA at 8 weeks was associated with improvement of disease activities. Compared with biomarkers reported, ccfDNA is able to predict the early therapeutic effects of biological DMARDs in RA patients.

It is well understood that sir2 (sirtuin), an NAD-dependent deacetylase, is essential for the extension of lifespan under caloric restriction. However, the mechanism underlying activation of sir2 is unclear. Life extension through caloric restriction requires the sir2 ortholog sir-2.1 in nematodes but occurs independently of the forkhead-type transcription factor DAF-16. We aimed here to elucidate the correlation between life extension in nematodes and NAD-dependent activation of sirtuin by analyzing the relationship between NAD and DAF-16.Lifespan was extended when C. elegans were bred using medium containing NAD. An RNA interference experiment revealed that life extension by NAD was sir-2.1 dependent. However, life extension by NAD did not occur in daf-16-RNAi nematodes, suggesting that NAD-dependent longevity requires daf-16. This result suggested that different signaling pathways are involved in life extension resulting from caloric restriction and from NAD addition.Expression of sod-3, a target gene of daf-16, and increased oxidative-stress resistance and adiposity were observed in response to NAD addition, indicating that NAD activated daf-16 in each phenotype. These results suggest that NAD affected lifespan through the activation of SIR-2.1 and DAF-16 along a signaling pathway, namely insulin-like signalling pathway (at least parts of it), different from that associated with caloric restriction.

Among the symptoms of patients with rheumatoid arthritis (RA), joint stiffness is influenced by diurnal rhythm and reaches peak in the morning, which is a common complaint and reflects the circadian nature of disease manifestation. In addition, inflammatory cytokines, which reach peak secretion early in the morning are major players causing the morning stiffness. In this review, we explore the link between the circadian clock and inflammation, focusing on the interactions of various clock genes with the immune-pathways underlying the pathology of rheumatoid arthritis.

Recently, it was reported that a deficit in the mouse stearoyl-CoA desaturase 1 gene decreases biosynthesis and accumulation of fatty acid and revitalizes the beta-oxidation of fatty acid. To examine the physiological role of fatty acid desaturase (FAT) and elongase (ELO)-gene transduction in ontogeny, fatty acid accumulation and individual lifespan, we performed bacteria-mediated RNA interference (RNAi) in the nematode Caenorhabditis elegans. Suppression of the expression of FAT-2 gene mRNA caused a drastic decrease in the amount of body fat and defects in egg-hatching. The amount of body fat was markedly decreased, and body size reduced, by down regulation of FAT-6 and FAT-7, whereas lifespan was drastically reduced. RNAi of the FAT-2 gene caused a remarkable increase of the beta-oxidation-related gene expression and the DAF-16 transcriptional activity, whereas, ELO-2 RNAi caused a remarkable decrease in fatty acid biosynthesis-related gene expression. Additionally, RNAi of FAT-6 decreased the mRNA levels of the genes involved in fatty acid synthesis, and FAT-7 RNAi increased the mRNA levels of beta-oxidation system genes. These results indicated that the elongation and desaturation of fatty acids are integral to various phenomena such as ontogeny and lifespan and play important roles in fatty acid accumulation and consumption.

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BackgroundEndogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.MethodsWe enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction before and after the initiation of immunosuppressive therapy. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure of eosinophil extracellular traps (EETs) and neutrophil extracellular traps (NETs) and stability against DNase were assessed in vitro. Platelet adhesion of EETs were also assessed.ResultsSerum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. The structure of EETs showed bolder net-like chromatin threads in vitro and EETs showed greater stability against DNase than NETs. EETs provided a scaffold for platelet adhesion.ConclusioncfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs in small-vessel thrombi might contribute to higher concentration of cfDNA and the occurrence of immunothrombosis in EGPA.

Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, and mutations. Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis, and treatment of RA has highly varied outcomes. cfDNA in patients with RA is elevated in peripheral blood and synovial fluid and is associated with disease activity. Profiling of cfDNA in patients with RA may then be utilized in various aspects of clinical practice, such as the prediction of prognosis and treatment responses; monitoring disease state; and as a diagnostic marker. In this review, we discuss cfDNA in patients with RA, particularly the sources of cfDNA and the correlation of cfDNA with RA pathogenesis. We also highlight the potential of analyzing cfDNA profiles to guide individualized treatment approaches for RA.