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Magnesium transport and homeostasis-related gene expression in skeletal muscle of young and old adults: analysis of the transcriptomic data from the PROOF cohort Study.
Coudy-Gandilhon, C, Gueugneau, M, Taillandier, D, Combaret, L, Polge, C, Roche, F, Barthélémy, JC, Féasson, L, Maier, JA, Mazur, A, et al
Magnesium research. 2019;(3):72-82
Abstract
Magnesium (Mg2+) is critical for a number of biological processes and 25% body Mg2+ is located in the skeletal muscle. Mg2+ transport and homeostasis systems (MgTHs) regulate intracellular Mg2+ concentration and muscle MgTHs are thus related to whole body Mg2+ homeostasis. Nonetheless, few studies have investigated the regulation of muscle MgTHs under (patho)physiological conditions. Herein, we assessed the relationship between the expression of MgTHs genes (Trpm6, Trpm7, Magt1, Mrs2, Cnnm1-4, Slc41a1-3) and relevant pathways in human sarcopenia, which is one of the most dramatic physiologic changes affecting the human body. Transcriptomic data were compared between young adult (YO, 22 y, n = 11) and old (EL, 73 y, n = 13) men from the PROOF cohort. MgTH mRNA levels did not change with aging, with the exception of a slight decrease for Slc41a3. Nevertheless, interindividual variations of mRNA levels revealed strong correlations between MgTHs in the YO group, while few were maintained in the EL muscle. Moreover, in the YO muscle, different clusters of MgTH mRNAs strongly correlated with divers physiological (BMI, blood pressure) and muscle characteristics (intramyocellular droplets, capillarization); however, most correlations changed or disappeared in the EL muscle. Further investigations of the whole transcriptome identified several sets of mRNAs correlated with defined MgTHs. There again was a sharp difference between YO and EL muscles, as the number of mRNAs correlated with MgTHs strongly decreased with aging. Gene ontology analyses of these sets of correlated mRNAs revealed 6 biological processes common to YO and EL, 3 specific to the YO (RNA processing, translation, respiration), and 2 (regulation of catabolic process, Wnt signaling) to the EL muscle. Overall, these observations lead to questions about potential resilience to muscle Mg2+ homeostasis in the elderly.
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H. pylori eradication with antibiotic treatment causes changes in glucose homeostasis related to modifications in the gut microbiota.
Martín-Núñez, GM, Cornejo-Pareja, I, Coin-Aragüez, L, Roca-Rodríguez, MDM, Muñoz-Garach, A, Clemente-Postigo, M, Cardona, F, Moreno-Indias, I, Tinahones, FJ
PloS one. 2019;(3):e0213548
Abstract
BACKGROUND H. pylori infection and eradication cause perturbations of the gut microbiome. The gut microbiota has been identified as a potential contributor to metabolic diseases. We evaluate whether these alterations in intestinal microbiota composition produced by H. pylori infection and its posterior eradication with antibiotic treatment could be associated with glucose homeostasis in metabolically healthy subjects. METHODS Forty adult patients infected with H. pylori and 20 control subjects were recruited. The infected subjects were evaluated before and two months after eradication treatment (omeprazole, clarithromycin, amoxicillin). The microbiota composition in fecal samples was determined by 16S rRNA gene (V3-V4) sequencing using Illumina Miseq. RESULTS Patients (pre- and post-H. pylori eradication) showed a decreased bacterial richness and diversity with respect to controls. There was an improvement in glucose homeostasis in subjects two months after H. pylori eradication treatment. Changes in the amount of Rikenellaceae, Butyricimonas, E. biforme, B. fragilis, and Megamonas were inversely associated with changes in the glucose level or related parameters (Hb1ac) in H. pylori eradication subjects. CONCLUSIONS H. pylori infection and eradication with antibiotic treatment causes alteration of the human gut microbiome. The increase in SCFA-producing bacteria and glucose-removing bacteria, specifically members of Megamonas, Rikenellaceae and Butyricimonas, has been related with an improvement in glucose homeostasis after H. pylori eradication with antibiotic treatment.
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Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients.
Margerie, D, Lefebvre, P, Raverdy, V, Schwahn, U, Ruetten, H, Larsen, P, Duhamel, A, Labreuche, J, Thuillier, D, Derudas, B, et al
BMC medical genomics. 2019;(1):80
Abstract
BACKGROUND Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. METHODS An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. RESULTS We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60-4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. CONCLUSIONS A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. TRIAL REGISTRATION NCT01129297 . Registered May 242,010 (retrospectively registered).
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Dynamic thiol/disulphide homeostasis in acute pancreatitis.
Köseoğlu, H, Alışık, M, Başaran, M, Tayfur Yürekli, Ö, Solakoğlu, T, Tahtacı, M, Ersoy, O, Erel, Ö
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2018;(3):348-353
Abstract
BACKGROUND/AIMS: The dynamic thiol/disulfide homeostasis plays pivotal roles in many physiological mechanisms in an organism. We aimed to investigate whether dynamic thiol/disulfide homeostasis changes among patients with acute pancreatitis. MATERIALS AND METHODS This prospective trial contained 45 patients with acute pancreatitis and 45 sex-and age-matched healthy volunteers as control group. Thiol/disulfide homeostasis parameters were measured by a novel and automated assay, and detected results were compared between the two groups. RESULTS Disulfide/total thiol percent ratio and disulfide/native thiol percent ratios were significantly higher in acute pancreatitis group; besides the native thiol, total thiol levels and native thiol/total thiol percent ratios were significantly lower (for all p < 0.001). CONCLUSION The thiol/disulfide homeostasis is impaired in acute pancreatitis with a shift toward the oxidative status, and this deficiency might be a pathogenic factor in acute pancreatitis. The correction of this thiol/disulfide imbalance may be a new target in the management of acute pancreatitis.
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Markers of metabolic health in children differ between weekdays--the result of unhealthier weekend behavior.
Hjorth, MF, Damsgaard, CT, Michaelsen, KF, Astrup, A, Sjödin, A
Obesity (Silver Spring, Md.). 2015;(4):733-6
Abstract
OBJECTIVE The aim of this study was to investigate whether indicators of metabolic health fluctuate during the week in a group of children posing unhealthier physical activity, sedentary time, and sleep during weekends compared to weekdays. METHODS A total of 807 eight- to eleven-year-old children had valid metabolic health markers from one, two, or three measurements contributing 2190 to 2240 observations of metabolic health markers. The weekly variation was tested using linear mixed models. RESULTS Homeostatic model assessment of insulin resistance (HOMAIR), triglycerides, leptin (all P < 0.001), and adiponectin (P = 0.03) decreased from Monday to Friday, whereas ghrelin increased (P < 0.001). HOMAIR , triglycerides, and leptin were 35%, 28%, and 33% higher on Mondays compared to Fridays, respectively, and ghrelin was 7% lower on Mondays compared to Fridays (all P < 0.001). CONCLUSIONS The large weekly variation in HOMAIR , triglycerides, and leptin was likely the result of unhealthier behaviors during weekends. These findings have public health relevance and raise methodological issues that should ideally be taken into account in future studies.
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Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation.
Terrier, B, Derian, N, Schoindre, Y, Chaara, W, Geri, G, Zahr, N, Mariampillai, K, Rosenzwajg, M, Carpentier, W, Musset, L, et al
Arthritis research & therapy. 2012;(5):R221
Abstract
INTRODUCTION Systemic lupus erythematosus (SLE) is a T and B cell-dependent autoimmune disease characterized by the appearance of autoantibodies, a global regulatory T cells (Tregs) depletion and an increase in Th17 cells. Recent studies have shown the multifaceted immunomodulatory effects of vitamin D, notably the expansion of Tregs and the decrease of Th1 and Th17 cells. A significant correlation between higher disease activity and lower serum 25-hydroxyvitamin D levels [25(OH)D] was also shown. METHODS In this prospective study, we evaluated the safety and the immunological effects of vitamin D supplementation (100,000 IU of cholecalciferol per week for 4 weeks, followed by 100,000 IU of cholecalciferol per month for 6 months.) in 20 SLE patients with hypovitaminosis D. RESULTS Serum 25(OH)D levels dramatically increased under vitamin D supplementation from 18.7±6.7 at day 0 to 51.4±14.1 (p<0.001) at 2 months and 41.5±10.1 ng/mL (p<0.001) at 6 months. Vitamin D was well tolerated and induced a preferential increase of naïve CD4+ T cells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells. Vitamin D also induced a decrease of memory B cells and anti-DNA antibodies. No modification of the prednisone dosage or initiation of new immunosuppressant agents was needed in all patients. We did not observe SLE flare during the 6 months follow-up period. CONCLUSIONS This preliminary study suggests the beneficial role of vitamin D in SLE patients and needs to be confirmed in randomized controlled trials.
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miR-183-96-182 cluster is overexpressed in prostate tissue and regulates zinc homeostasis in prostate cells.
Mihelich, BL, Khramtsova, EA, Arva, N, Vaishnav, A, Johnson, DN, Giangreco, AA, Martens-Uzunova, E, Bagasra, O, Kajdacsy-Balla, A, Nonn, L
The Journal of biological chemistry. 2011;(52):44503-11
Abstract
Decreased zinc levels are a hallmark of prostate cancer tumors as zinc uniquely concentrates in healthy prostate tissue. Increased dietary zinc correlates with decreased risk of advanced prostate cancer and decreased mortality from prostate cancer. The mechanisms of prostatic zinc homeostasis are not known. Lower zinc levels in the tumor are correlated directly with decreased expression of the zinc transporter hZIP1. We report identification of a microRNA cluster that regulates multiple zinc transporters, including hZIP1. Screening in laser capture microdissected prostate cancer tumors identified miR-182 as a potential regulator of hZIP1. Regulation of hZIP1 by miR-182 via two binding sites was confirmed in primary prostate cell cultures. miR-96 and miR-183 are expressed as a cluster with miR-182 and share similar sequences. Array profiling of tissue showed that miR-183, -96, and -182 are higher in prostate cancer tissue compared with normal prostate. Overexpression of the entire miR-183-96-182 cluster suppressed five additional zinc transporters. Overexpression of miR-183, -96, and -182 individually or as a cluster diminished labile zinc pools and reduced zinc uptake, demonstrating this miR cluster as a regulator of zinc homeostasis. We observed regulation of zinc homeostasis by this cluster in prostate cells and HEK-293 cells, suggesting a universal mechanism that is not prostate-specific. To our knowledge, this is the first report of a miR cluster targeting a family of metal transport proteins. Individually or as a cluster, miR-183, -96, and -182 are overexpressed in other cancers too, implicating this miR cluster in carcinogenesis.
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Clinical and biochemical indicators of homeostasis model assessment-estimated insulin resistance in postmenopausal women.
Lin, KH, Liou, TL, Hsiao, LC, Hwu, CM
Journal of the Chinese Medical Association : JCMA. 2011;(10):442-7
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Abstract
BACKGROUND Homeostasis model assessment of insulin resistance (HOMA-IR) is a surrogate estimate of directly measured insulin resistance that been robustly proven to be associated with diabetes and cardiovascular disease. The purpose of this study was to evaluate the use of several simple indicators to identify postmenopausal women with insulin resistance estimated by HOMA-IR. METHODS We recruited 262 naturally postmenopausal women without overt diabetes for the study. HOMA-IR values were calculated from fasting glucose and insulin levels. Multiple linear regression analyses were carried out to detect determinants of HOMA-IR. Insulin resistance was conventionally defined as the upper quartile of the HOMA-IR values. The diagnostic power of clinical and biochemical markers for insulin resistance was assessed using receiver operating characteristic curves. RESULTS Some 90% of the women with HOMA-IR ≥ 2.8 (75th percentile as cutoff) showed abnormal glucose metabolism and 45% of them had silent diabetes (odds ratio 6.09, 95% CI 3.17 - 11.73 vs. those with HOMA-IR < 2.8). Results revealed that uric acid, body mass index, waist circumference, alanine aminotransferase, triglycerides, and high-density lipoprotein cholesterol were important determinants of HOMA-IR in these women. Using uric acid ≥ 5.0 mg/dL as a cutoff point, we could diagnose insulin resistance with 75.4% sensitivity and 73.1% specificity. CONCLUSION Postmenopausal women with HOMA-IR-estimated insulin resistance were at high risk of glucose abnormalities in this study. High HOMA-IR values were significantly associated with six clinical and biochemical indicators. Among these, high serum uric acid levels seemed to be a useful marker identifying postmenopausal women with insulin resistance. This study was registered at clinicaltrials.gov as NCT00945271.
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Meat and soy protein affect calcium homeostasis in healthy women.
Kerstetter, JE, Wall, DE, O'Brien, KO, Caseria, DM, Insogna, KL
The Journal of nutrition. 2006;(7):1890-5
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Abstract
We showed that increasing dietary protein from omnivorous sources increases intestinal calcium absorption and urinary calcium, whereas a low-protein diet decreases calcium absorption and lowers urinary calcium. To assess the effect of soy protein on this relation, we substituted soy for meat in high- and low-protein diets fed to healthy women. The study consisted of a 2-wk adjustment period followed by a 4-d experimental period in which 20 healthy women consumed, in random order, the following 4 diets: high-protein soy-based, low-protein soy-based, high-protein meat-based, low-protein meat-based. Measures of calcium homeostasis were evaluated at baseline and after 4 d of the experimental period. At 24 h, net acid excretion was higher during the high- compared with the low-protein intervention (P < 0.05), and during the meat compared with the soy intervention (P < 0.05). The high-protein diets increased 24-h urinary calcium (P < 0.001), but urinary calcium did not differ due to the type of protein. Serum concentrations of parathyroid hormone and calcitriol, and urinary nephrogenous cAMP were higher during the low- compared with the high-protein intervention and during the soy compared with the meat protein (P < 0.05). In a subset of subjects, intestinal calcium absorption tended to be lower (P = 0.1) when they consumed the soy diets rather than the meat diets. These data indicate that when soy protein is substituted for meat protein, there is an acute decline in dietary calcium bioavailability.
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Long-term high copper intake: effects on copper absorption, retention, and homeostasis in men.
Turnlund, JR, Keyes, WR, Kim, SK, Domek, JM
The American journal of clinical nutrition. 2005;(4):822-8
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Abstract
BACKGROUND Numerous studies have examined the effect of low and adequate intakes of copper on absorption and retention, but little information is available on the regulation of absorption and retention of copper when intake is high. OBJECTIVE A study was conducted in men to determine the effect of long-term high copper intake on copper absorption, retention, and homeostasis. DESIGN Nine men were confined to a metabolic research unit (MRU) for 18 d and were fed a 3-d rotating menu containing an average of 1.6 mg Cu/d. They continued the study under free-living conditions for 129 d, supplementing their usual diets with 7 mg Cu/d. They then returned to the MRU for 18 d and consumed the same diet as during the first period, except that copper intake was 7.8 mg/d. The stable isotope (63)Cu was fed to 3 subjects and infused into the other 6 on day 7 of each MRU period, and complete urine and stool collections were made throughout the study. Total copper and (63)Cu were determined by inductively coupled plasma mass spectrometry. Copper absorption, excretion, and retention were calculated on the basis of dietary, urinary, and fecal copper and (63)Cu. RESULTS Results were as follows when comparing the high copper intake with the usual intake: fractional copper absorption was significantly lower, but the amount absorbed was significantly higher; excretion of the infused (63)Cu was significantly faster; and total retention was significantly higher. CONCLUSIONS Homeostatic regulation of copper absorption and retention helped to minimize the amount of copper retained with high copper intake but was not sufficient to prevent retention of >0.6 mg Cu/d.