TY - JOUR A1 - Vetrivel, Sharmilee A1 - Zhang, Ru A1 - Engel, Mareen A1 - Oßwald, Andrea A1 - Watts, Deepika A1 - Chen, Alon A1 - Wielockx, Ben A1 - Sbiera, Silviu A1 - Reincke, Martin A1 - Riester, Anna T1 - Characterization of adrenal miRNA-based dysregulations in Cushing's syndrome JF - International Journal of Molecular Sciences N2 - MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing's syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing's disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes. KW - cortisol KW - ACTH KW - miRNA KW - Cushing's KW - hypercortisolism KW - pituitary Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284394 SN - 1422-0067 VL - 23 IS - 14 ER - TY - JOUR A1 - Vetrivel, Sharmilee A1 - Zhang, Ru A1 - Engel, Mareen A1 - Altieri, Barbara A1 - Braun, Leah A1 - Osswald, Andrea A1 - Bidlingmaier, Martin A1 - Fassnacht, Martin A1 - Beuschlein, Felix A1 - Reincke, Martin A1 - Chen, Alon A1 - Sbiera, Silviu A1 - Riester, Anna T1 - Circulating microRNA Expression in Cushing’s Syndrome JF - Frontiers in Endocrinology N2 - Context Cushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging. Objective Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes. Methods We included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls. Results NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression. Outcome In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself. KW - cortisol KW - ACTH KW - miRNA KW - biomarker KW - cortisol-producing adenoma KW - miR-182-5p KW - hypercortisolism KW - miR-183 cluster Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229761 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - Altieri, Barbara A1 - Di Dato, Carla A1 - Modica, Roberta A1 - Bottiglieri, Filomena A1 - Di Sarno, Antonella A1 - Pittaway, James F.H. A1 - Martini, Chiara A1 - Faggiano, Antongiulio A1 - Colao, Annamaria T1 - Bone metabolism and vitamin D implication in gastroenteropancreatic neuroendocrine tumors JF - Nutrients N2 - Patients affected by gastroenteropancreatic–neuroendocrine tumors (GEP–NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP–NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP–NET, focusing on vitamin D and its role in GEP–NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis. KW - bone KW - vitamin D KW - neuroendocrine tumor KW - osteoporosis KW - mineral bone density KW - cortisol KW - serotonin KW - miRNA KW - MEN1 KW - therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203823 SN - 2072-6643 VL - 12 IS - 4 ER - TY - JOUR A1 - Zopf, Kathrin A1 - Frey, Kathrin R. A1 - Kienitz, Tina A1 - Ventz, Manfred A1 - Bauer, Britta A1 - Quinkler, Marcus T1 - \(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency JF - Endocrine Connections N2 - Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR). Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH. Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented. Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)). Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC. KW - medicine KW - adrenal crisis KW - adrenal insufficiency KW - cortisol KW - hydrocortisone KW - polyglandular autoimmune syndrome Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173276 VL - 6 IS - 8 ER - TY - JOUR A1 - Born, Dennis-Peter A1 - Zinner, Christoph A1 - Sperlich, Billy T1 - The mucosal immune function is not compromised during a period of high-intensity interval training. Is it time to reconsider an old assumption? JF - Frontiers in Physiology N2 - Purpose: The aim of the study was to evaluate the mucosal immune function and circadian variation of salivary cortisol, Immunoglobin-A (sIgA) secretion rate and mood during a period of high-intensity interval training (HIIT) compared to long-slow distance training (LSD). Methods: Recreational male runners (n = 28) completed nine sessions of either HIIT or LSD within 3 weeks. The HIIT involved 4 × 4 min of running at 90–95% of maximum heart rate interspersed with 3 min of active recovery while the LSD comprised of continuous running at 70–75% of maximum heart rate for 60–80 min. The psycho-immunological stress-response was investigated with a full daily profile of salivary cortisol and immunoglobin-A (sIgA) secretion rate along with the mood state on a baseline day, the first and last day of training and at follow-up 4 days after the last day of training. Before and after the training period, each athlete's running performance and peak oxygen uptake (V·O\(_{2peak}\)) was determined with an incremental exercise test. Results: The HIIT resulted in a longer time-to-exhaustion (P = 0.02) and increased V·O\(_{2peak}\) compared to LSD (P = 0.01). The circadian variation of sIgA secretion rate showed highest values in the morning immediately after waking up followed by a decrease throughout the day in both groups (P < 0.05). With HIIT, the wake-up response of sIgA secretion rate was higher on the last day of training (P < 0.01) as well as the area under the curve (AUC\(_{G}\)) higher on the first and last day of training and follow-up compared to the LSD (P = 0.01). Also the AUC\(_{G}\) for the sIgA secretion rate correlated with the increase in V·O\(_{2peak}\) and running performance. The AUC\(_{G}\) for cortisol remained unaffected on the first and last day of training but increased on the follow-up day with both, HIIT and LSD (P < 0.01). Conclusion: The increased sIgA secretion rate with the HIIT indicates no compromised mucosal immune function compared to LSD and shows the functional adaptation of the mucosal immune system in response to the increased stress and training load of nine sessions of HIIT. KW - high-volume training KW - periodization KW - circadian rhythm KW - cortisol KW - diurnal profile KW - endurance KW - immunoglobin-A Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158025 VL - 8 IS - 485 ER - TY - JOUR A1 - Pishva, Ehsan A1 - Drukker, Marjan A1 - Viechtbauer, Wolfgang A1 - Decoster, Jeroen A1 - Collip, Dina A1 - van Winkel, Ruud A1 - Wichers, Marieke A1 - Jacobs, Nele A1 - Thiery, Evert A1 - Derom, Catherine A1 - Geschwind, Nicole A1 - van den Hove, Daniel A1 - Lataster, Tineke A1 - Myin-Germeys, Inez A1 - van Os, Jim A1 - Rutten, Bart P. F. A1 - Kenis, Gunter T1 - Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study JF - PLOS ONE N2 - Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery. KW - DNA methylation KW - de-novo methylation KW - psychotic experiences KW - DNMT3A KW - glucocorticoid receptor KW - stress KW - mammalian development KW - psychiatry KW - cortisol KW - cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115956 SN - 1932-6203 VL - 9 IS - 6 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Ritz, Eberhard A1 - Tomaschitz, Andreas A1 - Pilz, Stefan A1 - Schönfeld, Stephan A1 - Blouin, Katja A1 - Bidlingmaier, Martin A1 - Hammer, Fabian A1 - Krane, Vera A1 - März, Winfried A1 - Allolio, Bruno A1 - Fassnacht, Martin A1 - Wanner, Christoph T1 - Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients JF - European Heart Journal N2 - Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials. KW - mortality KW - kidney disease KW - cardiovascular events KW - sudden cardiac death KW - cortisol KW - aldosterone Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132562 VL - 34 ER -