Synthesis and biology of oligoethylene glycol linked naphthoxylosides.

Proteoglycans (PGs) are important macromolecules in mammalian cells, consisting of a core protein substituted with carbohydrate chains, known as glycosaminoglycans (GAGs). Simple xylosides carrying hydrophobic aglycons can enter cells and act as primers for GAG chain synthesis, independent of the core protein. Previously it has been shown that aromatic aglycons can be separated from the sugar residue by short linkers without affecting the GAG priming ability. To further investigate the effects of the xylose-aglycon distance on the GAG priming ability, we have synthesized xyloside derivatives with 2-naphthyl and 2-(6-hydroxynaphthyl) moieties connected to xylose, directly, via a methylene bridge, or with oligoethylene glycol linkers of three different lengths. The GAG priming ability and the antiproliferative activity of the xylosides, as well as the composition of the xyloside-primed GAG chains were investigated in a matched pair of human breast fibroblasts and human breast carcinoma cells. An increase of the xylose-aglycon distance from 0.24 to 0.37nm resulted in an increased GAG priming ability in both cell lines. Further increase of the xylose-aglycon distance did not result in any pronounced effects. We speculate that by increasing the xylose-aglycon distance, and thereby the surface area of the xyloside, to a certain level would make it more accessible for enzymes involved in the GAG synthesis. The compositions of the primed GAG chains varied with different xylosides, independent of the xylose-aglycon distance, probably due to various affinities for enzymes and/or different cellular uptake. Furthermore, no correlations between the antiproliferative activities, the xylose-aglycon distances, and the amounts or compositions of the GAG chains were detected suggesting involvement of other factors such as fine structure of the GAG chains, effects on endogenous PG synthesis, or other unknown factors for the antiproliferative activity

Self-Reported Health as Predictor of Allostatic Load and All-Cause Mortality: Findings From the Lolland-Falster Health Study

Objectives: The aim was to determine the association between self-reported health (SRH), allostatic load (AL) and mortality.Methods: Data derived from the Lolland-Falster Health Study undertaken in Denmark from 2016–2020 (n = 14,104). Median follow-up time for death was 4.6 years where 456 participants died. SRH was assessed with a single question and AL by an index of ten biomarkers. Multinomial regression analysis were used to examine the association between SRH and AL, and Cox regression to explore the association between SRH, AL and mortality.Results: The risk of high AL increased by decreasing level of SRH. The ratio of relative risk (RRR) of having medium vs. low AL was 1.58 (1.11–2.23) in women reporting poor/very poor SRH as compared with very good SRH. For men it was 1.84 (1.20–2.81). For high vs. low AL, the RRR was 2.43 (1.66–3.56) in women and 2.96 (1.87–4.70) in men. The hazard ratio (HR) for all-cause mortality increased by decreasing SRH. For poor/very poor vs. very good SRH, the HR was 6.31 (2.84–13.99) in women and 3.92 (2.12–7.25) in men.Conclusion: Single-item SRH was able to predict risk of high AL and all-cause mortality

Association between Neonatal Whole Blood Iron Content and Cytokines, Adipokines, and Other Immune Response Proteins

(1) Background: High iron associates with inflammation and type 1 diabetes (T1D). Iron is essential not only for neonatal development but also for infectious microorganisms. The neonatal immune system is immature, and innate immunity prevails before immunocompetence develops. (2) Methods: In 398 newborns from the Danish Newborn Screening Biobank, we examined if whole blood iron (WB-Iron) content were associated with cytokines, adipokines, C-reactive protein (CRP), and mannose-binding lectin (MBL) in non-infected healthy neonates, and if these associations differed in newborns who later developed T1D (cases) (n = 199). WB-Iron was quantified using laser ablation inductively coupled plasma mass spectrometry on the neonatal dried blood spots. For each analyte, the relative change (RC) in the mean level was modeled by robust log-normal regression. (3) Results: A one unit increase in neonatal WB-Iron was associated with a 38% decrease in mean interleukin (IL)-6 levels (0.62; 95% CI: 0.40–0.95, p = 0.03), and a 37% decrease in mean MBL levels (0.63; 95% CI: 0.41–0.95, p = 0.03), but was not statistically significant after correction for multiple testing. (4) Conclusions: In summary, we found that higher neonatal WB-iron content was inversely associated with IL-6 and MBL, which may increase susceptibility to infections

Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study.

Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials