The ethanolamide metabolite of DHA, docosahexaenoylethanolamine, shows immunomodulating effects in mouse peritoneal and RAW264.7 macrophages: evidence for a new link between fish oil and inflammation

Several mechanisms have been proposed for the positive health effects associated with dietary consumption of long-chain n-3 PUFA (n-3 LC-PUFA) including DHA (22 : 6n-3) and EPA (20 : 5n-3). After dietary intake, LC-PUFA are incorporated into membranes and can be converted to their corresponding N-acylethanolamines (NAE). However, little is known on the biological role of these metabolites. In the present study, we tested a series of unsaturated NAE on the lipopolysaccharide (LPS)-induced NO production in RAW264.7 macrophages. Among the compounds tested, docosahexaenoylethanolamine (DHEA), the ethanolamide of DHA, was found to be the most potent inhibitor, inducing a dose-dependent inhibition of NO release. Immune-modulating properties of DHEA were further studied in the same cell line, demonstrating that DHEA significantly suppressed the production of monocyte chemotactic protein-1 (MCP-1), a cytokine playing a pivotal role in chronic inflammation. In LPS-stimulated mouse peritoneal macrophages, DHEA also reduced MCP-1 and NO production. Furthermore, inhibition was also found to take place at a transcriptional level, as gene expression of MCP-1 and inducible NO synthase was inhibited by DHEA. To summarise, in the present study, we showed that DHEA, a DHA-derived NAE metabolite, modulates inflammation by reducing MCP-1 and NO production and expression. These results provide new leads in molecular mechanisms by which DHA can modulate inflammatory processes

Effect of Maillard induced glycation on protein hydrolysis by lysine/arginine and non-lysine/arginine specific proteases

Enzymatic protein hydrolysis is sensitive to modifications of protein structure, e.g. Maillard reaction. In early stages of the reaction glycation takes place, modifying the protein primary structure. In later stages protein aggregation occurs. The specific effect of glycation on protein hydrolysis was studied using α-lactalbumin glycated with D-glucose at 50 °C (0–10 h). This resulted in proteins with different degrees of glycation (DG = 0–63%) without changes in secondary, tertiary and quaternary structure. These glycated proteins were hydrolyzed by lysine/arginine specific proteases (bovine and porcine trypsin) or by non-lysine/arginine specific proteases (Bacillus licheniformis protease (BLP), α-chymotrypsin and subtilisin A). For bovine and porcine trypsin, the maximal degree of hydrolysis decreased linearly with 65% from untreated to maximal glycated protein (DG = 63%). This means trypsin cannot hydrolyze glycated cleavage sites. BLP and subtilisin A hydrolyses were independent of glycation, while α-chymotrypsin cannot hydrolyze cleavage sites with glycated binding sites. This means for non-lysine/arginine specific proteases, the effect of glycation depends on the enzyme sensitivity towards modifications on binding sites. Since not all cleavage sites are efficiently used by the enzymes, the extent of the effects depends on the enzyme selectivity towards cleavage sites (for trypsin) or cleavage sites near glycation sites (for α-chymotrypsin). Combining the results of all proteases, an equation was derived describing the effect of modification of protein primary structure on the extent of hydrolysis based on the enzyme specificity, selectivity and binding site sensitivity

It’s worth the wait: optimizing questioning methods for effective intraoperative teaching

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138426/1/ans14046_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138426/2/ans14046.pd

Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer

AbstractThe physiological function initially attributed to the oligosaccharide moieties or glycans on inflammatory glycoproteins was to improve protein stability. However, it is now clear that glycans play a prominent role in glycoprotein structure and function and in some cases contribute to disease states. In fact, glycan processing contributes to pathogenicity not only in autoimmune disorders but also in atherosclerotic cardiovascular disease, diabetes and malignancy. While most clinical laboratory tests measure circulating levels of inflammatory proteins, newly developed diagnostic and prognostic tests are harvesting the information that can be gleaned by measuring the amount or structure of the attached glycans, which may be unique to individuals as well as various diseases. As such, these newer glycan-based tests may provide future means for more personalized approaches to patient stratification and improved patient care.Here we will discuss recent progress in high-throughput laboratory methods for glycomics (i.e. the study of glycan structures) and glycoprotein quantification by methods such as mass spectrometry and nuclear magnetic resonance spectroscopy. We will also review the clinical utility of glycoprotein and glycan measurements in the prediction of common low-grade inflammatory disorders including cardiovascular disease, diabetes and cancer, as well as for monitoring autoimmune disease activity

Higher Sodium Intake Assessed by 24 Hour Urinary Sodium Excretion Is Associated with Non-Alcoholic Fatty Liver Disease:The PREVEND Cohort Study

A higher sodium intake is conceivably associated with insulin resistant conditions like obesity, but associations of non-alcoholic fatty liver disease (NAFLD) with a higher sodium intake determined by 24 hours (24 h) urine collections are still unclear. Dietary sodium intake was measured by sodium excretion in two complete consecutive 24 h urine collections in 6132 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Fatty Liver Index (FLI) >= 60 and Hepatic Steatosis Index (HSI) >36 were used as proxies of suspected NAFLD. 1936 (31.6%) participants had an FLI >= 60, coinciding with the increased prevalence of type 2 diabetes (T2D), metabolic syndrome, hypertension and history of cardiovascular disease. Sodium intake was higher in participants with an FLI >= 60 (163.63 +/- 61.81 mmol/24 h vs. 136.76 +/- 50.90 mmol/24 h, p = 60 was positively associated with a higher sodium intake when taking account for T2D, a positive cardiovascular history, hypertension, alcohol intake, smoking and medication use (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.44-1.64, p 36 showed similar results. Associations remained essentially unaltered after adjustment for body surface area or waist/hip ratio. In conclusion, suspected NAFLD is a feature of higher sodium intake. Insulin resistance-related processes may contribute to the association of NAFLD with sodium intake

Higher Free Triiodothyronine Is Associated With Higher HDL Particle Concentration and Smaller HDL Particle Size

Context Thyroid function status has effects on the development of atherosclerotic cardiovascular disease by affecting lipid metabolism, but associations of high-density lipoprotein (HDL) particle concentrations and subfractions with thyroid hormone levels within the reference range remain elusive. Objective The aim of the present study was to determine the associations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels with HDL particle characteristics in euthyroid individuals. Methods This cross-sectional study on the associations of thyroid hormones with HDL particle concentrations, HDL subfractions, and HDL particle size included 5844 euthyroid individuals (FT3, FT4, and TSH levels within the reference range and no medication use affecting thyroid function), participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. HDL particles and subfractions were measured by nuclear magnetic resonance using an optimized version of the NMR LipoProfile Test (LP4). Results In multivariable linear regression analyses, FT3 was positively associated with total HDL particle concentration (std.beta = 0.14; P < 0.001) and with small (std.beta = 0.13; P < 0.001) and medium-sized HDL particles (std.beta = 0.05; P = 0.001). Conversely, FT3 was inversely associated with large HDL particles (std.beta = -0.07; P < 0.001) and with HDL particle size (std.beta = -0.08; P < 0.001). Such associations with FT4 or reciprocally with TSH were less pronounced or nonsignificant. Conclusion In euthyroid individuals, higher FT3 is cross-sectionally associated with higher total HDL particle concentration and with lower HDL particle size. These associations may be relevant to better understand the role of HDL in thyroid function-associated atherosclerotic cardiovascular disease

Broadband Meter-Wavelength Observations of Ionospheric Scintillation

Intensity scintillations of cosmic radio sources are used to study astrophysical plasmas like the ionosphere, the solar wind, and the interstellar medium. Normally these observations are relatively narrow band. With Low Frequency Array (LOFAR) technology at the Kilpisj\"arvi Atmospheric Imaging Receiver Array (KAIRA) station in northern Finland we have observed scintillations over a 3 octave bandwidth. ``Parabolic arcs'', which were discovered in interstellar scintillations of pulsars, can provide precise estimates of the distance and velocity of the scattering plasma. Here we report the first observations of such arcs in the ionosphere and the first broad-band observations of arcs anywhere, raising hopes that study of the phenomenon may similarly improve the analysis of ionospheric scintillations. These observations were made of the strong natural radio source Cygnus-A and covered the entire 30-250\,MHz band of KAIRA. Well-defined parabolic arcs were seen early in the observations, before transit, and disappeared after transit although scintillations continued to be obvious during the entire observation. We show that this can be attributed to the structure of Cygnus-A. Initial results from modeling these scintillation arcs are consistent with simultaneous ionospheric soundings taken with other instruments, and indicate that scattering is most likely to be associated more with the topside ionosphere than the F-region peak altitude. Further modeling and possible extension to interferometric observations, using international LOFAR stations, are discussed.Comment: 11 pages, 17 figure

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events

Background:The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population.Methods:HDL anti-inflammatory capacity was determined as its ability to suppress TNF alpha (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNF alpha effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls.Results:HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; PConclusions:The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.</p

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events

Background: The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population. Methods: HDL anti-inflammatory capacity was determined as its ability to suppress TNF alpha (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNF alpha effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls. Results: HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; P Conclusions: The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction

A Newly Developed Diabetes Risk Index, Based on Lipoprotein Subfractions and Branched Chain Amino Acids, is Associated with Incident Type 2 Diabetes Mellitus in the PREVEND Cohort

Objective: Evaluate the ability of a newly developed diabetes risk score, the Diabetes Risk Index (DRI), to predict incident type 2 diabetes mellitus (T2D) in a large adult population. Methods: The DRI was developed by combining the Lipoprotein Insulin Resistance Index (LP-IR), calculated from 6 lipoprotein subspecies and size parameters, and the branched chain amino acids, valine and leucine, all of which have been shown previously to be associated with future T2D. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2D. Results: During a median follow-up of 8.5 years, 306 new T2D cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2D with the hazard ratio (HR) for the highest versus lowest quartile being 12.07 (95% confidence interval: 6.97-20.89, p <0.001). After additional adjustment for body mass index (BMI), family history of T2D, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 3.20 (1.73-5.95), p = 0.001). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 (1.14-1.65), p <0.001). The Kaplan-Meier plot demonstrated that patients in the highest quartile of DRI scores presented at higher risk (p-value for log-rank tes