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Strong increase of leukocyte apha-galactosidase A activity in two male patients with Fabry disease following oral chaperone therapy.
Lamari, F, Mauhin, W, Koraichi, F, Khrouf, W, Bordet, C, London, J, Lidove, O, Charron, P
Molecular genetics & genomic medicine. 2019;(9):e894
Abstract
BACKGROUND Fabry disease (OMIM 301500) is an X-linked disorder caused by alpha-galactosidase A (α-Gal A) deficiency. The administration of a pharmacologic chaperone (migalastat) in Fabry patients with amenable mutations has been reported to improve or stabilize organ damages and reduce lyso-Gb3 plasma level. An increase of α-Gal A activity has been observed in vitro in cells expressing amenable GLA mutations when incubated with migalastat. The impact of the drug on α-Gal A in vivo activity has been poorly studied. METHODS We conducted a retrospective analysis of two unrelated male Fabry patients with p.Asn215Ser (p.N215S) variant. RESULTS We report the important increase of α-Gal A activity in blood leukocytes reaching normal ranges of activity after about 1 year of treatment with migalastat. Cardiac parameters improved or stabilized with the treatment. CONCLUSION We confirm in vivo the effects of migalastat that have been observed in N215S carriers in vitro. The increase of α-Gal A activity may be the strongest marker for biochemical efficacy. The normalization of enzyme activity could become the new therapeutic target to achieve.
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Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.
Kalstad, AA, Tveit, S, Myhre, PL, Laake, K, Opstad, TB, Tveit, A, Schmidt, EB, Solheim, S, Arnesen, H, Seljeflot, I
BMC geriatrics. 2019;(1):376
Abstract
BACKGROUND Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients. METHODS The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used. RESULTS Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI. CONCLUSIONS In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging. TRIAL REGISTRATION Clinical trials no. NCT01841944, registration date April 29, 2013.
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Effect of mate tea (Ilex paraguariensis) on the expression of the leukocyte NADPH oxidase subunit p47phox and on circulating inflammatory cytokines in healthy men: a pilot study.
Panza, VP, Brunetta, HS, de Oliveira, MV, Nunes, EA, da Silva, EL
International journal of food sciences and nutrition. 2019;(2):212-221
Abstract
Increased superoxide production by phagocytic NADPH oxidase has been associated with inflammatory conditions. Growing evidences suggest that dietary polyphenols may modulate the expression of NADPH oxidase subunits. Herein, we examined whether soluble mate tea (SMT) consumption - a polyphenol-rich beverage - affects the expression of the leukocyte NADPH oxidase protein p47phox and/or circulating biomarkers of inflammation and antioxidant biomarkers in humans. In a two-phase study, nine men were requested to drink water (control) for 8 d and then follow a second 8-d period drinking SMT. Blood samples were analysed for p47phox protein in CD16+/CD14- cells, interleukin (IL)-1β (IL-1β), tumour necrosis factor-alpha (TNF-α), IL-6, total phenols, and reduced and oxidised glutathione (GSH and GSSG, respectively) after each study phase. After SMT intake, CD16+/CD14- cells' p47phox protein and serum TNF-α and IL-6 levels were significantly attenuated (P < .05) while plasma phenolic compounds and blood GSH:GSSG ratio were significantly enhanced (P < .05). Consumption of SMT favourably affected leukocytes' p47phox expression and inflammatory cytokine and antioxidants levels in peripheral blood, which may help decrease oxidative stress and low-grade inflammation.
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Immunomodulatory effects of probiotics: Can they be used to treat allergies and autoimmune diseases?
Dargahi, N, Johnson, J, Donkor, O, Vasiljevic, T, Apostolopoulos, V
Maturitas. 2019;:25-38
Abstract
As a person ages, physiological, immunological and gut microbiome changes collectively result in an array of chronic conditions. According to the 'hygiene hypothesis' the increasing prevalence of immune-mediated disorders may be related to intestinal dysbiosis, leading to immune dysfunction and associated conditions such as eczema, asthma, allergies and autoimmune diseases. Beneficial probiotic bacteria can be utilized by increasing their abundance within the gastrointestinal lumen, which in turn will modulate immune cells, such as, T helper (Th)-1, Th2, Th17, regulatory T (Treg) cells and B cells, which have direct relevance to human health and the pathogenesis of immune disorders. Here, we describe the cross-talk between probiotics and the gastrointestinal immune system, and their effects in relation to inflammatory bowel disease, multiple sclerosis, allergies and atopic dermatitis.
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Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.
Agha, G, Mendelson, MM, Ward-Caviness, CK, Joehanes, R, Huan, T, Gondalia, R, Salfati, E, Brody, JA, Fiorito, G, Bressler, J, et al
Circulation. 2019;(8):645-657
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Abstract
BACKGROUND DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
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Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients.
Gosselt, HR, van Zelst, BD, de Rotte, MCFJ, Hazes, JMW, de Jonge, R, Heil, SG
Arthritis research & therapy. 2019;(1):157
Abstract
BACKGROUND Low-dose methotrexate (MTX) is the first-line therapy in early rheumatoid arthritis (eRA). Up to 40% of eRA patients do not benefit from MTX therapy. MTX has been shown to inhibit one-carbon metabolism, which is involved in the donation of methyl groups. In this study, we investigate baseline global DNA methylation and changes in DNA methylation during treatment in relation to clinical non-response after 3 months of MTX treatment. METHODS Two hundred ninety-four blood samples were collected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, ISRCTN26791028), a multicenter, stratified single-blind clinical trial of eRA patients. Global DNA (hydroxy)methylation was quantified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and validated with a global DNA LINE-1 methylation technique. MTX response was determined as ΔDAS28. Additionally, patients were stratified into two response groups according to the European League Against Rheumatism (EULAR) response criteria. Associations between global DNA methylation and response were examined using univariate regression models adjusted for baseline DAS28, baseline erythrocyte folate levels, and body mass index (BMI). RESULTS Higher baseline global DNA methylation was associated with less decrease of DAS28 (β = 0.15, p = 0.013) and with MTX non-response (OR = 0.010, 95% CI = 0.001-0.188). This result was validated in LINE-1 elements (β = 0.22, p = 0.026). Changes in global DNA (hydroxy)methylation were not associated with MTX response over 3 months. CONCLUSIONS These results show that higher baseline global DNA methylation in treatment naïve eRA patients is associated with decreased clinical response after 3 months of treatment of eRA patients and can be further evaluated as a predictor for MTX therapy non-response. TRIAL REGISTRATION ISRCTN, ISRCTN26791028 , registered 23 August 2007-retrospectively registered.
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Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.
Perrier, F, Viallon, V, Ambatipudi, S, Ghantous, A, Cuenin, C, Hernandez-Vargas, H, Chajès, V, Baglietto, L, Matejcic, M, Moreno-Macias, H, et al
Clinical epigenetics. 2019;(1):57
Abstract
BACKGROUND There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.
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The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial.
Freitas-Simoes, TM, Cofán, M, Blasco, MA, Soberón, N, Foronda, M, Corella, D, Asensio, EM, Serra-Mir, M, Roth, I, Calvo, C, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(2):958-961
Abstract
BACKGROUND & AIMS Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. DESIGN Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. RESULTS In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023). CONCLUSION An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.
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Childhood obesity and leucocyte telomere length.
Lamprokostopoulou, A, Moschonis, G, Manios, Y, Critselis, E, Nicolaides, NC, Stefa, A, Koniari, E, Gagos, S, Charmandari, E
European journal of clinical investigation. 2019;(12):e13178
Abstract
BACKGROUND Obesity in adulthood is associated with decreased leucocyte telomere length (LTL), which is associated with cardiovascular disease and diabetes mellitus type 2. The aim of our study was to investigate whether increased body mass index (BMI) is associated with decreased LTL in children and adolescents, and to identify other risk factors of shorter LTL in this population. MATERIALS AND METHODS A cross-sectional study was conducted among 919 Greek children aged 9-13 years (The Healthy Growth Study). Participants were classified as obese (n = 124), overweight (n = 276) or of normal BMI (n = 519). LTL was determined by monochrome multiplex quantitative real-time polymerase chain reaction. Univariate and multivariable linear regression analyses were applied to determine the predictive factors of LTL. RESULTS Both overweight and obese children had significantly shorter LTL than their normal-BMI counterparts. Following adjustment for age, sex, total daily energy intake and average weekly physical activity (average total steps per day), increasing weight category was inversely associated with LTL in children and adolescents (β: -0.110 ± 0.035; P = .002). CONCLUSION Overweight and obesity in childhood and adolescence are associated with shorter LTL, even following adjustment for potential confounding effects. Therefore, the increased BMI in childhood and adolescence may be associated with accelerated biological ageing and may have an adverse impact on future health in adulthood.
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Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial.
Freitas-Simoes, TM, Cofán, M, Blasco, MA, Soberón, N, Foronda, M, Serra-Mir, M, Roth, I, Valls-Pedret, C, Doménech, M, Ponferrada-Ariza, E, et al
Nutrients. 2018;(12)
Abstract
Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63⁻79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.