A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P= 1.2 × 10−4). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer(LC;P= 4.0 × 10−4), chronic obstructive pulmonary disease (COPD;P= 9.3 × 10−4), peripheral artery disease (PAD;P= 0.090) and abdominal aortic aneurysms (AAAs; P= 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49,P= 2.2 × 10−4), COPD (OR = 3.22,P= 2.9 × 10−4), PAD (OR = 3.47,P= 9.2 × 10−3) and AAA (OR = 6.44, P= 6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P= 6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation

The effects of smoking in pregnancy on factors influencing fetal growth

To access Publisher full text version of this article. Please click on the hyperlink in Additional Links fieldAIM: To evaluate the influence of maternal smoking during pregnancy on factors influencing fetal growth. METHODS: Thirty newborns of smoking mothers were prospectively compared with 60 newborns of non-smoking mothers. Pre-albumin, albumin, triglycerides, glucose, insulin, insulin-like growth factor I, IGF binding protein 3, pH, lactic acid, erythropoietin and hemoglobin concentrations were measured in umbilical cord blood. RESULTS: Infants of smoking mothers had a significantly lower birth weight (3418 +/- 533 vs. 3863 +/- 503 g; p < 0.001), length (50.5 +/- 2,6 vs. 52.3 +/- 1.9 cm; p < 0.001) and head circumference (34.6 +/- 1.8 vs. 35.8 +/- 1.1 cm; p < 0.001) than controls. They also had significantly lower insulin (3.2 (2.0-4.9) vs. 5.8 (4.6-7.1) mU/L; p = 0.008), insulin-like growth factor I (54.4 +/- 32.5 vs. 93.8 +/- 54.5 microg/L; p = 0.001) and IGF binding protein 3 (1664 +/- 432 vs. 1943 +/- 421 microg/L; p = 0.01) concentrations, than controls. Infants of smoking mothers also had significantly higher hemoglobin (167 +/- 14 vs. 157 +/- 13 g/L; p = 0.002) and erythropoietin (42.3 (25.1-72.4) vs. 26.3 (21.9-30.9) U/L; p = 0.03) than controls, but not pH or lactate concentrations. There was no significant difference in pre-albumin, albumin, triglycerides and glucose concentrations. CONCLUSIONS: Smoking during pregnancy causes symmetrical fetal growth impairment, possibly due to decreased oxygen transport to the fetus and decreased concentrations of fetal insulin, insulin-like growth factor I and IGF binding protein 3

6-Bromoindole Derivatives from the Icelandic Marine Sponge Geodia barretti: Isolation and Anti-Inflammatory Activity

An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge Geodia barretti. This includes three new metabolites, namely geobarrettin A⁻C (1⁻3) and four known compounds, barettin (4), 8,9-dihydrobarettin (5), 6-bromoconicamin (6), and l-6-bromohypaphorine (7). The chemical structures of compounds 1⁻7 were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A (1) was assigned by ECD analysis and Marfey's method employing the new reagent l-Nα-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both 2 and 3 reduced DC secretion of IL-12p40, but 3 concomitantly increased IL-10 production. Maturing DCs treated with 2 or 3 before co-culturing with allogeneic CD4⁺ T cells decreased T cell secretion of IFN-γ, indicating a reduction in Th1 differentiation. Although barettin (4) reduced DC secretion of IL-12p40 and IL-10 (IC50 values 11.8 and 21.0 μM for IL-10 and IL-12p40, respectively), maturing DCs in the presence of 4 did not affect the ability of T cells to secrete IFN-γ or IL-17, but reduced their secretion of IL-10. These results indicate that 2 and 3 may be useful for the treatment of inflammation, mainly of the Th1 type

Geobarrettin D, a Rare Herbipoline-Containing 6-Bromoindole Alkaloid from <i>Geodia barretti</i>

Geobarrettin D (1), a new bromoindole alkaloid, was isolated from the marine sponge Geodia barretti collected from Icelandic waters. Its structure was elucidated by 1D, and 2D NMR (including 1H-15N HSQC, 1H-15N HMBC spectra), as well as HRESIMS data. Geobarrettin D (1) is a new 6-bromoindole featuring an unusual purinium herbipoline moiety. Geobarrettin D (1) decreased secretion of the pro-inflammatory cytokine IL-12p40 by human monocyte derived dendritic cells, without affecting secretion of the anti-inflammatory cytokine IL-10. Thus, compound 1 shows anti-inflammatory activity

Bromotryptamine and Imidazole Alkaloids with Anti-inflammatory Activity from the Bryozoan .

To access publisher's full text version of this article click on the hyperlink belowChemical investigation of the marine bryozoan Flustra foliacea collected in Iceland resulted in isolation of 13 new bromotryptamine alkaloids, flustramines Q-W (1-7) and flustraminols C-H (8-13), and two new imidazole alkaloids, flustrimidazoles A and B (14 and 15), together with 12 previously described compounds (16-27). Their structures were established by detailed spectroscopic analysis using 1D and 2D NMR and HRESIMS. Structure 2 was verified by calculations of the 13C and 1H NMR chemical shifts using density functional theory. The relative and absolute configurations of the new compounds were elucidated on the basis of coupling constant analysis, NOESY, [α]D, and ECD spectroscopic data, in addition to chemical derivatization. The compounds were tested for in vitro anti-inflammatory activity using a dendritic cell model. Eight compounds (1, 3, 5, 13, 16, 18, 26, and 27) decreased dendritic cell secretion of the pro-inflammatory cytokine IL-12p40, and two compounds (4 and 14) increased secretion of the anti-inflammatory cytokine IL-10. Deformylflustrabromine B (27) showed the most potent anti-inflammatory effect (IC50 2.9 μM). These results demonstrate that F. foliacea from Iceland expresses a broad range of brominated alkaloids, many without structural precedents. The potent anti-inflammatory activity in vitro of metabolite 27 warrants further investigations into its potential as a lead for inflammation-related diseases.University of Iceland AVS R&D Fund of The Ministry of Fisheries and Agriculture in Icelan