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- Alsehli, Ahmed M., et al.
(författare)
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Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
- 2021
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Ingår i: Frontiers in Bioscience-Landmark. - : Frontiers Media S.A.. - 2768-6701 .- 2768-6698. ; 26:12, s. 1453-1463
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.
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| 3. |
- de Ruijter, Markus J. T., et al.
(författare)
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Association of Diligence and Sociability with Stroke : A UK Biobank Study on Personality Proxies
- 2022
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Ingår i: FRONTIERS IN BIOSCIENCE-LANDMARK. - : IMR Press. - 2768-6701 .- 2768-6698. ; 27:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a growing interest in how personality may be related to the risk of developing disease. Associations between personality and stroke have so far only been studied in relation to stroke mortality. However, many stroke survivors suffer severe impairment of quality of life due to sequelae such as aphasia, hemiparesis, depression and anxiety. In this study we assess the association between personality and risk of stroke, regardless of mortality. Methods: Using self-reported data on psychological factors, mental health and social support, proxies for the Big Five personality traits were developed for 482,535 participants in the UK Biobank. Logistic regression and Cox proportional hazard models, with 95% confidence intervals (CI), were used to estimate odds ratios (OR) and hazard ratios (HR) between each personality trait and stroke prevalence (N = 6793) and incidence (N = 3312), respectively. Models were adjusted for demographic, health-related, and lifestyle factors. Results: Diligence and sociability were associated with a lower risk of stroke incidence in the fully adjusted model (respectively: [HR = 0.92; 95% CI = (0.88, 0.96)], [HR = 0.93; 95% CI = (0.89, 0.97)]). However, nervousness, curiosity and warmth were not significantly associated with a risk of stroke incidence. Conclusions: Individuals with higher levels of diligence and sociability may be at a reduced risk of developing stroke. With respect to the debated role of neuroticism in relation to cardiovascular disease, we did not find evidence of an association between nervousness and risk of developing stroke.
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| 4. |
- Hamada-Kawaguchi, Noriko, 1978-, et al.
(författare)
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Exposure to Therapeutic BTK Inhibitors Induces Phenocopying of Btk29A Mutants in the Fruit Fly Drosophila melanogaster
- 2023
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Ingår i: Frontiers in Bioscience-Landmark. - 2768-6701 .- 2768-6698. ; 28:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bruton’s tyrosine kinase (BTK) is a non-receptor type tyrosine kinase originally identified as the genetic signature responsible for X-linked agammaglobulinemia (XLA) when mutated. Its functional form is required for B lymphocyte maturation in both humans and mice, whereas loss-of-function causes a different form of developmental defect in the fruit fly, Drosophila melanogaster. Methods: Ibrutinib and other therapeutic inhibitors of BTK have been extensively used to successfully treat various leukemias and lymphomas. Btk29A type 2 is the ortholog of BTK in the fruit fly. We show that feeding wild-type flies an ibrutinib-containing diet induces phenocopying of Btk29A mutants, i.e., failure in the fusion of left and right halves of the dorsal cuticles, partial loss of wing tissues and dysregulation of germ cell production. Results: We have previously reported that Btk29A phosphorylates Drosophila Arm (β?-catenin), and ibrutinib reduces phosphorylation at Tyrosine142 of endogenously expressed β?-catenin in Cos7 cells transfected with Btk29A type 2 cDNA. Conclusions: Thus, Drosophila is suitable for screens of novel BTK inhibitor candidates and offers a unique in vivo system in which the mode of action of BTK inhibitors can be examined at the molecular, cellular, and organismal levels.
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| 8. |
- Sangsuwan, Traimate, 1981-, et al.
(författare)
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Oxidative Stress Levels and DNA Repair Kinetics in Senescent Primary Human Fibroblasts Exposed to Chronic Low Dose Rate of Ionizing Radiation
- 2023
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Ingår i: Frontiers in Bioscience Landmark. - 2768-6701. ; 28:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Exposure to low dose rate (LDR) radiation may accelerate aging processes. Previously, we identified numerous LDR-induced pathways involved in oxidative stress (OS) and antioxidant systems, suggesting that these pathways protect against premature senescence (PS). This study aimed to investigate if there are differences between young replicative senescent (RS) and PS cells considering DNA repair kinetics, OS, and DNA damage localized in the telomeres. Methods: We established PS cells by culturing and passaging young primary fibroblasts exposed to LDR. Then, RS cells were established by culturing and passaging young fibroblasts until they stopped proliferating. Senescence was characterized by analyzing telomere length and senescence-associated β-galactosidase (SA-β-gal) staining. DNA damage and repair were evaluated with γH2AX foci formation; telomere identification was carried out using the fluorescence in situ hybridization (FISH) probe; and oxidative stress was assessed by measuring 8-oxo-dG in the medium. Results: The data indicate the following: young cells have a better ability to cope with LDR-induced oxidative stress; RS and PS have higher steady-state levels of DNA damage; RS have slower DNA repair kinetics; and PS/RS have elevated levels of telomeric DNA damage. Conclusion: Our main conclusion is that PS and RS differ regarding DNA repair kinetics and SA-β-gal levels.
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| 9. |
- Vimali, Jaisheela, et al.
(författare)
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Chronic Viral Infection Compromises the Quality of Circulating Mucosal-Associated Invariant T Cells and Follicular T Helper Cells via Expression of Inhibitory Receptors
- 2024
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Ingår i: FRONTIERS IN BIOSCIENCE-LANDMARK. - : IMR PRESS. - 2768-6701. ; 29:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic viral infection results in impaired immune responses rendering viral persistence. Here, we compared the quality of T-cell responses among chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-infected individuals by examining the levels of expression of selected immune activation and exhaustion molecules on circulating MAIT cells and Tfh cells. Methods: Cytokines were measured using a commercial Bio-plex Pro Human Cytokine Grp I Panel 17-plex kit (BioRad, Hercules, CA, USA). Inflammation was assessed by measuring an array of plasma cytokines, and phenotypic alterations in CD4(+) T cells including circulating Tfh cells, CD8(+) T cells, and TCR iV alpha 7.2(+) MAIT cells in chronic HBV, HCV, and HIV-infected patients and healthy controls. The cells were characterized based on markers pertaining to immune activation (CD69, ICOS, and CD27) proliferation (Ki67), cytokine production (TNF-alpha, IFN-gamma) and exhaustion (PD-1). The cytokine levels and T cell phenotypes together with cell markers were correlated with surrogate markers of disease progression. Results: The activation marker CD69 was significantly increased in CD4(+hi) T cells, while CD8(+) MAIT cells producing IFN-gamma were significantly increased in chronic HBV, HCV and HIV infections. Six cell phenotypes, viz., TNF-alpha(+)CD4(+lo) T cells, CD69(+)CD8(+) T cells, CD69(+)CD4(+) MAIT cells, PD-1(+)CD4(+hi) T cells, PD-1(+)CD8(+) T cells, and Ki67(+)CD4(+) MAIT cells, were independently associated with decelerating the plasma viral load (PVL). TNF-alpha levels showed a positive correlation with increase in cytokine levels and decrease in PVL. Conclusion: Chronic viral infection negatively impacts the quality of peripheral MAIT cells and Tfh cells via differential expression of both activating and inhibitory receptors.
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