Triglyceride-rich lipoproteins prevent septic death in rats.

Triglyceride-rich lipoproteins bind and inactive bacterial endotoxin in vitro and prevent death when given before a lethal dose of endotoxin in animals. However, lipoproteins have not yet been demonstrated to improve survival in polymicrobial gram-negative sepsis. We therefore tested the ability of triglyceride-rich lipoproteins to prevent death after cecal ligation and puncture (CLP) in rats. Animals were given bolus infusions of either chylomicrons (1 g triglyceride/kg per 4 h) or an equal volume of saline for 28 h after CLP. Chylomicron infusions significantly improved survival (measured at 96 h) compared with saline controls (80 vs 27%, P < or = 0.03). Chylomicron infusions also reduced serum levels of endotoxin, measured 90 min (26 +/- 3 vs 136 +/- 51 pg/ml, mean +/- SEM, P < or = 0.03) and 6 h (121 +/- 54 vs 1,026 +/- 459 pg/ml, P < or = 0.05) after CLP. The reduction in serum endotoxin correlated with a reduction in serum tumor necrosis factor, measured 6 h after CLP (0 +/- 0 vs 58 +/- 24 pg/ml, P < or = 0.03), suggesting that chylomicrons improve survival in this model by limiting macrophage exposure to endotoxin and thereby reducing secretion of inflammatory cytokines. Infusions of a synthetic triglyceride-rich lipid emulsion (Intralipid; KabiVitrum, Inc., Alameda, CA) (1 g triglyceride/kg) also significantly improved survival compared with saline controls (71 vs 27%, P < or = 0.03). These data demonstrate that triglyceride-rich lipoproteins can protect animals from lethal polymicrobial gram-negative sepsis

Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

Analyzing and Mapping Sweat Metabolomics by High-Resolution NMR Spectroscopy

The content of human sweat is studied by high-resolution NMR, and the majority of organic components most often found in sweat of conditionally healthy people are identified. Original and simple tools are designed for sweat sampling from different areas of human body. The minimal surface area needed for sampling is in the range of 50–100 cm2. On all the surface parts of the human body examined in this work, the main constituents forming a sweat metabolic profile are lactate, glycerol, pyruvate, and serine. The only exception is the sole of the foot (planta pedis), where trace amounts of glycerol are found. An attempt is made to explain the presence of specified metabolites and their possible origin

Fine Tuning of Globin Gene Expression by DNA Methylation

Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the γ(A) and γ(G) genes are expressed in fetal liver, both are silenced in adult erythrocytes. In order to decipher the role of DNA methylation in this process, we generated a YAC transgenic mouse system that allowed us to control γ(A) methylation during development. DNA methylation causes a 20-fold repression of γ(A) both in non-erythroid and adult erythroid cells. In erythroid cells this modification works as a dominant mechanism to repress γ gene expression, probably through changes in histone acetylation that prevent the binding of erythroid transcription factors to the promoter. These studies demonstrate that DNA methylation serves as an elegant in vivo fine-tuning device for selecting appropriate genes in the globin locus. In addition, our findings provide a mechanism for understanding the high levels of γ-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate γ-globin expression in patients with β-hemoglobinopathies

Association between anxiety and non-coding genetic variants of the galanin neuropeptide

Galanin, an inhibitory neuropeptide and cotransmitter has long been known to co-localize with noradrenaline and serotonin in the central nervous system. Several human studies demonstrated altered galanin expression levels in major depressive disorder and anxiety. Pharmacological modulation of galanin signaling and transgenic strategies provide further proof for the involvement of the galanin system in the pathophysiology of mood disorders. Little is known, however, on the dynamic regulation of galanin expression at the transcriptional level. The aim of the present study was to seek genetic association of non-coding single nucleotide variations in the galanin gene with anxiety and depression.Six single nucleotide polymorphisms (SNP) occurring either in the regulatory 5' or 3' flanking regions or within intronic sequences of the galanin gene have been genotyped with a high-throughput TaqMan OpenArray qPCR system in 526 healthy students (40% males). Depression and anxiety scores were obtained by filling in the Hospital Anxiety and Depression Scale (HADS) questionnaire. Data were analyzed by ANCOVA and Bonferroni correction was applied for multiple testing. Linkage disequilibrium (LD) analysis was used to map two haploblocks in the analyzed region.A single-locus and a haplotype genetic association proved to be statistically significant. In single-marker analysis, the T allele of the rs1042577 SNP within the 3' untranslated region of the galanin gene associated with greater levels of anxiety (HADS scores were 7.05±4.0 vs 6.15±.15; p = 0.000407). Haplotype analysis revealed an association of the rs948854 C_rs4432027_C allele combination with anxiety [F(1,1046) = 4.140, p = 0.042141, η2 = 0.004, power = 0.529]. Neither of these associations turned out to be gender-specific. These promoter polymorphisms are supposed to participate in epigenetic regulation of galanin expression by creating potentially methylatable CpG dinucleotides. The functional importance of the rs1042577_T allele remains to be elucidated

Chronic Oral Infection with Porphyromonas gingivalis Accelerates Atheroma Formation by Shifting the Lipid Profile

BACKGROUND: Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We orally infected C57BL/6 and C57BL/6.KOR-Apoe(shl) (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages. CONCLUSIONS/SIGNIFICANCE: Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease