Hospitalized patients are frequently deprived of contact with natural light and constantly exposed to artificial lighting, losing biological synchronism. However, few studies have been conducted to ...assess the consequences of inadequate exposure to light in hospital environments, whether related to insufficient light in the period daytime, or to light peaks at night. This study assesses the effect of daytime exposure to different monochromatic lights on the excretion of 6-sulfatoxymelatonin (aMT6s), a hormone that reflects variations in the light/dark cycle. The light intensity was adjusted to 300 lx. Forty voluntary patients under transfusion were randomly assigned into five groups of light exposure for five hours, during the day. The concentration of aMT6s was determined in the urine samples collected at four intervals in a period of 24 hours during two days (before and at intervention). Exposure to green light resulted in significant acute melatonin reduction; blue light, in delay of night secretion; red, yellow and white light, kept it unaltered. These findings indicate that exposure to light during the day can lead to changes in the pattern of melatonin secretion. This research can be useful in artificial lighting environments, such as hospitals, to maintain adequate lighting and preserve the sleep/wake cycle.
Abstract
The postnatal synchronization of the circadian variation of the adrenal clock genes in mammals remains unknown. We evaluated the postnatal ontogeny of daily variation of clock genes ...(Clock/Bmal1/Per1/Per2/Per3/Cry1/Cry2/Rorα/Rev-Erbα) and steroidogenesis-related genes (Star and Mc2r) in rat adrenals and its relationship with the emergence of plasma corticosterone rhythm using cosinor analysis. Plasma corticosterone circadian rhythm was detected from postnatal day (P)1, with morning acrophase, between zeitgeber time (ZT)0 and ZT2. From P14, there was a nocturnal acrophase of corticosterone at ZT20, which was associated with pups’ eye opening. From P3 there was a circadian variation of the mRNA expression of Bmal1, Per2, Per3, and Cry1 genes with morning acrophase, whereas Rev-Erbα had nocturnal acrophase. From P14, Bmal1, Per2, Per3, and Cry1 acrophases advanced by approximately 10 hours, as compared with early neonatal days, becoming vespertine-nocturnal. In all postnatal ages, Per2 and Cry1 circadian profiles were synchronized in phase with the circadian rhythm of plasma corticosterone, whereas Bmal1 was in antiphase. An adult-like Star circadian rhythm profile was observed only from P21. In conclusion, our original data demonstrated a progressive postnatal maturation of the circadian variation of the adrenal clock genes in synchrony with the development of the corticosterone circadian rhythm in rats.
In rat adrenals, the assessment of clock genes expression ontogeny revealed a progressive postnatal maturation of clock genes circadian variation in synchrony with corticosterone circadian rhythm.
The circadian rhythm of glucocorticoids has long been recognised within the last 75 years. Since the beginning, researchers have sought to identify basic mechanisms underlying the origin and ...emergence of the corticosteroid circadian rhythmicity among mammals. Accordingly, Young, Hall and Rosbash, laureates of the 2017 Nobel Prize in Physiology or Medicine, as well as Takahashi’s group among others, have characterised the molecular cogwheels of the circadian system, describing interlocking transcription/translation feedback loops essential for normal circadian rhythms. Plasma glucocorticoid circadian variation depends on the expression of intrinsic clock genes within the anatomic components of the hypothalamic–pituitary–adrenal axis, which are organised in a hierarchical manner. This review presents a general overview of the glucocorticoid circadian clock mechanisms, highlighting the ontogeny of the pituitary–adrenal axis diurnal rhythmicity as well as the involvement of circadian rhythm abnormalities in the physiopathology and diagnosis of Cushing’s disease.
Epigenetic control of adamantinomatous craniopharyngiomas Marrero-Gutiérrez, Junier; Bueno, Ana Carolina; Martins, Clarissa Silva ...
The journal of clinical endocrinology and metabolism,
2024-Jan-05, 2024-01-05, 20240105
Journal Article
Recenzirano
Odprti dostop
Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking.
To identify methylation signatures in ACPs regarding clinical presentation and outcome.
Clinical ...and pathology data were collected from 35 ACP patients (54% male; 18.1 years 2-68). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses.
Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation.
Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.
Summary
Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, ...we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2.
Objective
To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations.
Design, patients and measurements
Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11βHSD isoforms expression were assessed by qPCR.
Results
Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA‐IR, triglycerides, TNF‐α, IL‐1β, IL‐6 and IL‐10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRβ overexpression in PBMC was observed in female patients compared with female controls.
Conclusions
Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRβ overexpression leading to a more severe phenotype in female.
Context: MicroRNAs (miRNAs) are small noncoding RNAs, functioning as antisense regulators of gene expression by targeting mRNA and contributing to cancer development and progression. More than 50% of ...miRNA genes are located in cancer-associated genomic regions or in fragile sites of the genome.
Objective: The aim of the study was to analyze the differential expression of let-7a, miR-15a, miR-16, miR-21, miR-141, miR-143, miR-145, and miR-150 in corticotropinomas and normal pituitary tissue and verify whether their profile of expression correlates with tumor size or remission after treatment.
Material and Methods: ACTH-secreting pituitary tumor samples were obtained during transphenoidal surgery from patients with Cushing disease and normal pituitary tissues from autopsies. The relative expression of miRNAs was measured by real-time PCR using RNU44 and RNU49 as endogenous controls. Relative quantification of miRNA expression was calculated using the 2−ΔΔCt method.
Results: We found underexpression of miR-145 (2.0-fold; P = 0.04), miR-21 (2.4-fold; P = 0.004), miR-141 (2.6-fold; P = 0.02), let-7a (3.3-fold; P = 0.003), miR-150 (3.8-fold; P = 0.04), miR-15a (4.5-fold; P = 0.03), miR-16 (5.0-fold; P = 0.004), and miR-143 (6.4-fold; P = 0.004) in ACTH-secreting pituitary tumors when compared to normal pituitary tissues. There were no differences between miRNA expression and tumor size as well as miRNA expression and ratio of remission after surgery, except in patients presenting lower miR-141 expression who showed a better chance of remission.
Conclusion: Our results support the possibility that altered miRNA expression profile might be involved in corticotrophic tumorigenesis. However, the lack of knowledge about miRNA target genes postpones full understanding of the biological functions of down-regulated or up-regulated miRNAs in corticotropinomas.
MicroRNAs (miRNAs) are underexpressed in corticotropinomas without association with tumor size; however, lower miR-141 expression was associated with a better chance of Cushing’s disease remission.
Canonical and non-canonical Wnt pathways are involved in the genesis of multiple tumors; however, their role in pituitary tumorigenesis is mostly unknown.
This study evaluated gene and protein ...expression of Wnt pathways in pituitary tumors and whether these expression correlate to clinical outcome.
Genes of the WNT canonical pathway: activating ligands (WNT11, WNT4, WNT5A), binding inhibitors (DKK3, sFRP1), β-catenin (CTNNB1), β-catenin degradation complex (APC, AXIN1, GSK3β), inhibitor of β-catenin degradation complex (AKT1), sequester of β-catenin (CDH1), pathway effectors (TCF7, MAPK8, NFAT5), pathway mediators (DVL-1, DVL-2, DVL-3, PRICKLE, VANGL1), target genes (MYB, MYC, WISP2, SPRY1, TP53, CCND1); calcium dependent pathway (PLCB1, CAMK2A, PRKCA, CHP); and planar cell polarity pathway (PTK7, DAAM1, RHOA) were evaluated by QPCR, in 19 GH-, 18 ACTH-secreting, 21 non-secreting (NS) pituitary tumors, and 5 normal pituitaries. Also, the main effectors of canonical (β-catenin), planar cell polarity (JNK), and calcium dependent (NFAT5) Wnt pathways were evaluated by immunohistochemistry.
There are no differences in gene expression of canonical and non-canonical Wnt pathways between all studied subtypes of pituitary tumors and normal pituitaries, except for WISP2, which was over-expressed in ACTH-secreting tumors compared to normal pituitaries (4.8x; p = 0.02), NS pituitary tumors (7.7x; p = 0.004) and GH-secreting tumors (5.0x; p = 0.05). β-catenin, NFAT5 and JNK proteins showed no expression in normal pituitaries and in any of the pituitary tumor subtypes. Furthermore, no association of the studied gene or protein expression was observed with tumor size, recurrence, and progressive disease. The hierarchical clustering showed a regular pattern of genes of the canonical and non-canonical Wnt pathways randomly distributed throughout the dendrogram.
Our data reinforce previous reports suggesting no activation of canonical Wnt pathway in pituitary tumorigenesis. Moreover, we describe, for the first time, evidence that non-canonical Wnt pathways are also not mis-expressed in the pituitary tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Objective Studies on the influence of genetic factors on the ontogeny of cortisol circadian rhythm in infants are lacking. This study evaluated the influence of twinning and the heritability ...on the age of emergence of salivary cortisol rhythm.
Design and subjects A longitudinal study was performed using salivary samples obtained during morning and night, at 2, 4, 8, 12, 16, 20 and 24 weeks of postnatal life in 34 infants, 10 monozygotic (MZ) and 7 dizygotic (DZ) twin pairs. Salivary cortisol was determined by radioimmunoassay (RIA). Zigosity was verified by DNA analysis of at least 13 short tandem repeat polymorphisms. Difference of the emergence of cortisol circadian rhythm, within each twin pair, the intraclass correlation coefficient and the heritability index (h2) were calculated.
Results The mean (± SEM) age of emergence of salivary cortisol circadian rhythm was similar in MZ and DZ (7·8 ± 1·0 vs 7·4 ± 1·3 weeks). Seven pairs showed coincidence of the emergence of cortisol rhythm. Ten pairs were not coincident; among them the within‐pair difference of emergence of salivary circadian rhythm was similar in both MZ and DZ groups. The intraclass correlation coefficients were rMZ = 0·60, P = 0·02; and rDZ = 0·65, P = 0·03, respectively. The heritability index (h2) was 0·21 (ns).
Conclusions Salivary circadian rhythm appeared at the same postnatal age in MZ and DZ twin infants. Although several physiological aspects might be involved, the heritability index, obtained in the present study, suggests less genetic than environmental impact on the age of the onset of the cortisol circadian rhythm. Our data also indicated that each twin‐pair show synchrony because they probably shared prenatal and postnatal environmental synchronizers.
IntroductionCortisol awakening response (CAR) is a rapid increase of cortisol levels within 30–45 min after awakening.ObjectiveThis study evaluates CAR compared with cortisol circadian rhythm in ...active and in remission Cushing's disease (CD).Materials and methodsWe evaluated healthy controls (HC, n=19), obese (OB, n=10), in remission (n=08), and active CD patients (n=10). Salivary free cortisol (SF) was determined at 0800, 1100, 1700, 2000, and 2300 h on the first day. CAR was obtained the next morning immediately upon awakening and at 15, 30, 45, and 60-min post-wake up.ResultsWe observed differences in SF levels throughout the day in HC, OB, and in remission CD (ANOVA P=0.0001) but not in active CD (P=0.2). We demonstrated SF increment after awakening in HC, OB, and in remission CD (ANOVA P=0.007), with no effect of time on SF in active CD. The relative increment of SF obtained at the peak after awakening (CARi%) in the active CD (67±57%) was lower than in HC (154±107%), OB (240±188%), and in remission CD (186±184%) patients (P=0.009). There was a negative correlation between the SF at awakening and the CARi% in HC (r=−0.8), OB (r=−0.78), and in remission CD (r=−0.74) but not in active CD (r=−0.35; P=0.31).ConclusionThis study originally described a blunted CAR in active CD in contrast to its presence in HC, OB, and in remission CD. This subtle dysfunction of the hypothalamus–pituitary–adrenal axis may represent a distinct and additional physiopathological phenomenon superimposing the dysregulated cortisol circadian rhythm in this disease.
ObjectiveACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to ...segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis of MC2R, MRAP, and AAAS genes in five Brazilian patients with ACTH resistance syndrome.Design and methodsGenomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R.ResultsAll five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in the MC2R gene in one patient and p.Met1Ile mutation in the MRAP gene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of the AAAS gene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation in MC2R, MRAP, or AAAS gene.ConclusionsIn conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.