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A Comprehensive, Multidisciplinary, Personalized, Lifestyle Intervention Program Is Associated with Increased Leukocyte Telomere Length in Children and Adolescents with Overweight and Obesity.
Paltoglou, G, Raftopoulou, C, Nicolaides, NC, Genitsaridi, SM, Karampatsou, SI, Papadopoulou, M, Kassari, P, Charmandari, E
Nutrients. 2021;(8)
Abstract
Leucocyte telomere length (LTL) is a robust marker of biological aging and is associated with obesity and cardiometabolic risk factors in childhood and adolescence. We investigated the effect of a structured, comprehensive, multidisciplinary, personalized, lifestyle intervention program of healthy diet and physical exercise on LTL in 508 children and adolescents (239 males, 269 females; 282 prepubertal, 226 pubertal), aged 10.14 ± 0.13 years. Participants were classified as obese (n = 267, 52.6%), overweight (n = 174, 34.2%), or of normal BMI (n = 67, 13.2%) according to the International Obesity Task Force (IOTF) cutoff points and were studied prospectively for one year. We demonstrated that LTL increased significantly after 1 year of the lifestyle interventions, irrespective of gender, pubertal status, or body mass index (BMI). Waist circumference was the best negative predictor of LTL at initial assessment. The implementation of the lifestyle interventions also resulted in a significant improvement in clinical (BMI, BMI z-score and waist to height ratio) and body composition indices of obesity, inflammatory markers, hepatic enzymes, glycated hemoglobin (HbA1C), quantitative insulin sensitivity check index (QUICKI), and lipid profile in all participants. These findings indicate that the increased LTL may be associated with a more favorable metabolic profile and decreased morbidity later in life.
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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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Expression of inflammation-related miRNAs in white blood cells from subjects with metabolic syndrome after 8 wk of following a Mediterranean diet-based weight loss program.
Marques-Rocha, JL, Milagro, FI, Mansego, ML, Zulet, MA, Bressan, J, Martínez, JA
Nutrition (Burbank, Los Angeles County, Calif.). 2016;(1):48-55
Abstract
OBJECTIVES The aim of this study was to evaluate the influence of a dietary strategy for weight loss (the RESMENA [reduction of metabolic syndrome in Navarra, Spain] diet) on the expression of inflammation-related microRNAS (miRNAs) and genes in white blood cells (WBC) from individuals with metabolic syndrome (MetS). METHODS The clinical, anthropometric, and biochemical characteristics of 40 individuals with MetS (20 men and 20 women; age: 48.84 ± 10.02 y; body mass index: 35.41 ± 4.42 kg/m(2)) were evaluated before and after an 8-wk hypocaloric diet based on the Mediterranean dietary pattern. Nutrient intake was assessed with a food frequency questionnaire and 48-h weighed food records. Total RNA was isolated from WBC and the expression of some inflammation-related miRNAs and mRNAs (IL-6, TNF-α, ICAM-1, IL-18, SERPINE1, VCAM-1, GAPDH) was assessed by quantitative polymerase chain reaction. RESULTS The RESMENA nutritional intervention improved most anthropometric and biochemical features. The expression of miR-155-3p was decreased in WBC, whereas Let-7b was strongly upregulated as a consequence of the dietary treatment. However, they were not correlated with the expression of the proinflammatory genes in the same cells. The changes in the expression of let-7b, miR-125b, miR-130a, miR-132-3p, and miR-422b were significantly associated with changes in diet quality when assessed by the Healthy Eating Index. Moreover, low consumption of lipids and saturated fat (g/d) were associated with higher expression of let-7b after the nutritional intervention. CONCLUSIONS The Mediterranean-based nutritional intervention was able to induce changes in the expression of let-7b and miR-155-3p in WBC from patients with MetS after 8 wk. Moreover, the quality of the diet has an important effect on the miRNAs expression changes. These results should be highlighted because these miRNAs have been associated with inflammatory gene regulation and important human diseases.
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Insulin resistance and inflammation predict kinetic body weight changes in response to dietary weight loss and maintenance in overweight and obese subjects by using a Bayesian network approach.
Kong, LC, Wuillemin, PH, Bastard, JP, Sokolovska, N, Gougis, S, Fellahi, S, Darakhshan, F, Bonnefont-Rousselot, D, Bittar, R, Doré, J, et al
The American journal of clinical nutrition. 2013;(6):1385-94
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Abstract
BACKGROUND The ability to identify obese subjects who will lose weight in response to energy restriction is an important strategy in obesity treatment. OBJECTIVE We aimed to identify obese subjects who would lose weight and maintain weight loss through 6 wk of energy restriction and 6 wk of weight maintenance. DESIGN Fifty obese or overweight subjects underwent a 6-wk energy-restricted, high-protein diet followed by another 6 wk of weight maintenance. Network modeling by using combined biological, gut microbiota, and environmental factors was performed to identify predictors of weight trajectories. RESULTS On the basis of body weight trajectories, 3 subject clusters were identified. Clusters A and B lost more weight during energy restriction. During the stabilization phase, cluster A continued to lose weight, whereas cluster B remained stable. Cluster C lost less and rapidly regained weight during the stabilization period. At baseline, cluster C had the highest plasma insulin, interleukin (IL)-6, adipose tissue inflammation (HAM56+ cells), and Lactobacillus/Leuconostoc/Pediococcus numbers in fecal samples. Weight regain after energy restriction correlated positively with insulin resistance (homeostasis model assessment of insulin resistance: r = 0.5, P = 0.0002) and inflammatory markers (IL-6; r = 0.43, P = 0.002) at baseline. The Bayesian network identified plasma insulin, IL-6, leukocyte number, and adipose tissue (HAM56) at baseline as predictors that were sufficient to characterize the 3 clusters. The prediction accuracy reached 75.5%. CONCLUSION The resistance to weight loss and proneness to weight regain could be predicted by the combination of high plasma insulin and inflammatory markers before dietary intervention.
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Rho-kinase activation in patients with heart failure.
Do e, Z, Fukumoto, Y, Sugimura, K, Miura, Y, Tatebe, S, Yamamoto, S, Aoki, T, Nochioka, K, Nergui, S, Yaoita, N, et al
Circulation journal : official journal of the Japanese Circulation Society. 2013;(10):2542-50
Abstract
BACKGROUND Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. METHODS AND RESULTS Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19 ± 0.06 vs. 0.97 ± 0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14 ± 0.02 vs. 0.77 ± 0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. CONCLUSIONS Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder.
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Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility.
Reinius, LE, Acevedo, N, Joerink, M, Pershagen, G, Dahlén, SE, Greco, D, Söderhäll, C, Scheynius, A, Kere, J
PloS one. 2012;(7):e41361
Abstract
Methylation of cytosines at CpG sites is a common epigenetic DNA modification that can be measured by a large number of methods, now even in a genome-wide manner for hundreds of thousands of sites. The application of DNA methylation analysis is becoming widely popular in complex disorders, for example, to understand part of the "missing heritability". The DNA samples most readily available for methylation studies are derived from whole blood. However, blood consists of many functionally and developmentally distinct cell populations in varying proportions. We studied whether such variation might affect the interpretation of methylation studies based on whole blood DNA. We found in healthy male blood donors there is important variation in the methylation profiles of whole blood, mononuclear cells, granulocytes, and cells from seven selected purified lineages. CpG methylation between mononuclear cells and granulocytes differed for 22% of the 8252 probes covering the selected 343 genes implicated in immune-related disorders by genome-wide association studies, and at least one probe was differentially methylated for 85% of the genes, indicating that whole blood methylation results might be unintelligible. For individual genes, even if the overall methylation patterns might appear similar, a few CpG sites in the regulatory regions may have opposite methylation patterns (i.e., hypo/hyper) in the main blood cell types. We conclude that interpretation of whole blood methylation profiles should be performed with great caution and for any differences implicated in a disorder, the differences resulting from varying proportions of white blood cell types should be considered.
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Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans.
Friebe, D, Neef, M, Kratzsch, J, Erbs, S, Dittrich, K, Garten, A, Petzold-Quinque, S, Blüher, S, Reinehr, T, Stumvoll, M, et al
Diabetologia. 2011;(5):1200-11
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AIMS/HYPOTHESIS Nicotinamide phosphoribosyltransferase (NAMPT) is a multifunctional protein potentially involved in obesity and glucose metabolism. We systematically studied the association between circulating NAMPT, obesity, interventions and glucose metabolism and investigated potential underlying inflammatory mechanisms. METHODS Fasting morning NAMPT serum levels were measured in cohorts of lean vs obese children, cohorts of intervention by lifestyle, exercise and bariatric surgery, and during an OGTT. In addition, mRNA expression, protein production and enzymatic activity of NAMPT were assessed from isolated leucocytes and subpopulations. RESULTS Circulating NAMPT was significantly elevated in obese compared with lean children and declined after obesity interventions concomitantly with the decline in BMI, high-sensitivity C-reactive protein (hsCrP) and leucocyte counts. Circulating NAMPT significantly correlated with glucose metabolism and cardiovascular variables in univariate analyses, but only the association with glucose response during an OGTT was independent from BMI. We therefore assessed the NAMPT dynamic following an oral glucose load and found a significant decline of NAMPT levels to 77.0 ± 0.1% as a function of time, and insulin-to-glucose ratio during an OGTT in obese insulin-resistant adolescents. Circulating NAMPT was, however, most strongly associated with leucocyte counts (r = 0.46, p < 0.001). The leucocyte count itself determined significantly and independently from BMI insulin resistance in multiple regression analyses. We systematically evaluated NAMPT expression among several tissues and found that NAMPT was predominantly expressed in leucocytes. In subsequent analyses of leucocyte subpopulations, we identified higher NAMPT protein concentrations in lysates of granulocytes and monocytes compared with lymphocytes, whereas granulocytes secreted highest amounts of NAMPT protein into cell culture supernatant fractions. We confirmed nicotinamide mononucleotide enzymatic activity of NAMPT in all lysates and supernatant fractions. In monocytes, NAMPT release was significantly stimulated by lipopolysaccharide (LPS) exposure. CONCLUSIONS Leucocytes are a major source of enzymatically active NAMPT, which may serve as a biomarker or even mediator linking obesity, inflammation and insulin resistance.
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Plasma choline depletion is associated with decreased peripheral blood leukocyte acetylcholine in children with cystic fibrosis.
Innis, SM, Davidson, AG, Bay, BN, Slack, PJ, Hasman, D
The American journal of clinical nutrition. 2011;(3):564-8
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Abstract
BACKGROUND Choline is an important constituent of acetylcholine. Choline is needed for acetylcholine in the nonneuronal acetylcholine system that includes epithelial cells of the lung and intestine, endothelial cells, and immune cells. Plasma free choline concentrations are low in children with cystic fibrosis (CF), but the implications for acetylcholine are unknown. OBJECTIVE We determined the relation between plasma free choline and related metabolites and leukocyte acetylcholine in children with CF and in a control group of healthy children without CF. DESIGN This was a cross-sectional study in 34 children with CF who were pancreatic insufficient and taking pancreatic enzyme-replacement therapy and in 16 healthy children. Plasma free choline, betaine, dimethylglycine, methionine, homocysteine, and leukocyte acetylcholine concentrations were quantified by using isotope-dilution HPLC-tandem mass spectrometry. RESULTS Mean (±SE) plasma free choline was 9.30 ± 0.37 and 6.54 ± 0.38 μmol/L (P < 0.05) and leukocyte acetylcholine was 1.21 ± 0.016 and 0.077 ± 0.011 pmol leukocyte acetylcholine/10(6) cells (P < 0.05) in control children and children with CF, respectively. Leukocyte acetylcholine was positively correlated with plasma free choline concentration in children with CF (r = 0.412, P < 0.05) but not in control children. Plasma betaine, dimethylglycine, and methionine concentrations were also lower in children with CF than in control children (P < 0.05). CONCLUSIONS A low free choline and methyl status in children with CF is associated with reduced acetylcholine in leukocytes. Whether these changes are explained by a mutation in the CF transmembrane conductance regulator or disturbances in choline metabolism and the implications for immune cell dysfunction in CF are unknown. This trial was registered at clinicaltrials.gov as NCT01150136.
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Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.
Chavez-Blanco, A, Segura-Pacheco, B, Perez-Cardenas, E, Taja-Chayeb, L, Cetina, L, Candelaria, M, Cantu, D, Gonzalez-Fierro, A, Garcia-Lopez, P, Zambrano, P, et al
Molecular cancer. 2005;(1):22
Abstract
BACKGROUND The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. METHODS Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. RESULTS All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6-170.49 microg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid. CONCLUSION Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
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Diagnosing infection in the failed joint replacement: a comparison of coincidence detection 18F-FDG and 111In-labeled leukocyte/99mTc-sulfur colloid marrow imaging.
Love, C, Marwin, SE, Tomas, MB, Krauss, ES, Tronco, GG, Bhargava, KK, Nichols, KJ, Palestro, CJ
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2004;(11):1864-71
Abstract
UNLABELLED The objectives of this study were to investigate (18)F-FDG imaging, using a coincidence detection system, for diagnosing prosthetic joint infection and to compare it with combined (111)In-labeled leukocyte/(99m)Tc-sulfur colloid marrow imaging in patients with failed lower extremity joint replacements. METHODS Fifty-nine patients--with painful, failed, lower extremity joint prostheses, 40 hip and 19 knee--who underwent (18)F-FDG, labeled leukocyte, and bone marrow imaging, and had histopathologic and microbiologic confirmation of the final diagnosis, formed the basis of this investigation. (18)F-FDG images were interpreted as positive for infection using 4 different criteria: criterion 1: any periprosthetic activity, regardless of location or intensity; criterion 2: periprosthetic activity on the (18)F-FDG image, without corresponding activity on the marrow image; criterion 3: only bone-prosthesis interface activity, regardless of intensity; criterion 4: semiquantitative analysis--a lesion-to-background ratio was generated, and the cutoff value yielding the highest accuracy for determining the presence of infection was determined. Labeled leukocyte/marrow images were interpreted as positive for infection when periprosthetic activity was present on the labeled leukocyte image without corresponding activity on the marrow image. RESULTS Twenty-five (42%) prostheses, 14 hip and 11 knee, were infected. The sensitivity, specificity, and accuracy of (18)F-FDG, by criterion, were as follows: criterion 1: 100%, 9%, 47%; criterion 2: 96%, 35%, 61%; criterion 3: 52%, 44%, 47%; criterion 4: 36%, 97%, 71%. The sensitivity, specificity, and accuracy of labeled leukocyte/marrow imaging were 100%, 91%, and 95%, respectively. WBC/marrow imaging, which was more accurate than any of the (18)F-FDG criteria for all prostheses, as well as for hips and knees separately, was significantly more sensitive than criterion 3 (P < 0.001) and criterion 4 (P < 0.001) and was significantly more specific than criterion 1 (P < 0.001), criterion 2 (P < 0.001), and criterion 3 (P < 0.001). CONCLUSION Regardless of how the images are interpreted, coincidence detection-based (18)F-FDG imaging is less accurate than, and cannot replace, labeled leukocyte/marrow imaging for diagnosing infection of the failed prosthetic joint.