Relationship of oxidative stress to visceral adiposity in youth and role played by vitamin D.

BACKGROUND: Visceral adipose tissue (VAT) accumulation is a major cardiometabolic risk factor, associated with increased inflammation. Oxidative stress (OS) is also associated with inflammation and cardiometabolic issues, yet mainly through general obesity. Both OS and obesity were linked to vitamin D deficiency. OBJECTIVES: To investigate whether OS increase is associated with VAT accumulation in youth, and whether in the presence of VAT accumulation, a higher vitamin D status is associated with lower OS. METHODS: One hundred and fifty-eight youth with overweight/obesity, 7 to 17 years old, were recruited (Pediatric Clinic, Luxembourg). We assessed visceral and subcutaneous abdominal adipose tissues by magnetic resonance imaging, OS by DNA/RNA oxidative damage with ELISA and vitamin D by high-performance liquid chromatography. RESULTS: VAT was the body fat compartment the most strongly associated with OS (RPearson : 0.298; P < 10-4 ). The general linear (GLM) models assessing the relationship between OS, VAT and vitamin D concentrations showed that "Log10 OS = (0.003 × VAT) + 3.911 (R2adjusted : 0.083; P-value < 10-4 )"; "Log10 OS = (0.003 × VAT) - (0.156 × log10 vitamin D) + 4.110 (R2adjusted : 0.101; P-value < 10-4 )". After back-transformation of the log-values into normal values, the GLM showed that, for a person with an average value of VAT (40.7 cm2 ), a 10 cm2 increase in VAT would increase OS by approx. 771.833 pg/mL, after age, gender, Tanner stage and physical activity adjustment. An approximate increase of 9 ng/mL of vitamin D would counterbalance this negative effect of increased VAT. CONCLUSION: Dietary strategies improving vitamin D status should be investigated to tackle VAT and OS increase.

Premature Ovarian Failure in French Canadian Leigh Syndrome.

In all surviving girls with Leigh syndrome, French Canadian variety, a mitochondrial disease, we detected premature ovarian failure, manifested as absent or arrested breast development, lack of menarche, high follicle-stimulating hormone, a prepubertal uterus, and small ovaries. Pubertal onset and progression should be evaluated in girls with mitochondrial diseases.

Severe aldosterone synthase deficiency in a nine-day old Lebanese boy: the importance of functional studies to establish pathogenicity of seemingly benign variants in CYP11B2.

Introduction Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in CYP11B2. Case Presentation A boy, born in Montreal to Lebanese parents who are first cousins, was referred at nine days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D). In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement. Conclusion If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negative.

Factors contributing to the resistance of the thyrocyte to hydrogen peroxide.

We studied the mechanism that may explain the relative resistance of thyrocytes to H2O2 compared to other cell types. Ability to degrade H2O2, glutathione peroxidase (GPx) activity, heme oxygenase-1 (HO-1) expression, cell survival and capacity to repair DNA damage after H2O2 exposure or irradiation were measured in human thyrocytes in primary culture and compared to the values obtained in human T-cells and different cell lines. Compared to other cell types, thyrocytes presented a low mortality rate after H2O2 exposure, rapidly degraded extracellular H2O2 and presented a high basal seleno-dependent GPx activity. Only in thyrocytes, H2O2 up-regulated GPx activity and expression of HO-1 mRNA. These effects were not reproduced by irradiation. DNA damage caused by H2O2 was more slowly repaired than that caused by irradiation and not repaired at all in T-cells. Our study demonstrates that the thyrocyte has specific protective mechanisms against H2O2 and its mutagenic effects.

From Bioinactive ACTH to ACTH Antagonist: The Clinical Perspective.

The adrenocorticotropic hormone (ACTH) is a pituitary hormone derived from a larger peptide, the proopiomelanocortin (POMC), as are the MSHs (α-MSH, ß-MSH, and γ-MSH) and the ß-LPH-related polypeptides (Figure 1A). ACTH drives adrenal steroidogenesis and growth of the adrenal gland. ACTH is a 39 amino acid polypeptide that binds and activates its cognate receptor [melanocortin receptor 2 (MC2R)] through the two regions H6F7R8W9 and K15K16R17R18P19. Most POMC-derived polypeptides contain the H6F7R8W9 sequence that is conserved through evolution. This explains the difficulties in developing selective agonists or antagonists to the MCRs. In this review, we will discuss the clinical aspects of the role of ACTH in physiology and disease, and potential clinical use of selective ACTH antagonists.

Comparative analysis of the thyrocytes and T cells: responses to H2O2 and radiation reveals an H2O2-induced antioxidant transcriptional program in thyrocytes.

CONTEXT: Radiation is an established cause of thyroid cancer, and growing evidence supports a role for hydrogen peroxide (H2O2) in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyrocytes. OBJECTIVE: The purpose of this study was to compare the responses of thyrocytes and T cells to H2O2 and radiation. METHODS: We profiled the DNA damage and cell death induced by γ-radiation (0.1-5 Gy) and H2O2 (0.0025-0.3 mM) in primary human thyrocytes and T cells. We next prepared thyroid and T-cell primary cultures from 8 donors operated for noncancerous thyroid pathological conditions and profiled their genome-wide transcriptional response 4 hours after (1) exposure to 1-Gy radiation, (2) treatment with H2O2 and (3) no treatment. Two H2O2 concentrations were investigated, calibrated in each cell type to elicit levels of single- and double-strand breaks equivalent to 1-Gy γ-radiation. RESULTS: Although thyrocytes and T cells had comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses inducing double-strand breaks, cell death occurred after 24 hours in T cells but not in thyrocytes. The transcriptional responses of thyrocytes and T cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also up-regulated antioxidant genes in thyrocytes, including glutathione peroxidases and heme oxygenase at the double-strand breaks-inducing concentration. In contrast, a transcriptional storm involving thousands of genes was raised in T cells. Finally, we showed that inhibiting glutathione peroxidases activity increased the DNA damaging effect of H2O2 in thyrocytes. CONCLUSION: We propose that high H2O2 production in thyrocytes is matched with specific transcriptionally regulated antioxidant protection.

Early transient hypoglycemia is associated with increased albumin nitration in the preterm infant.

BACKGROUND: The clinical significance of early transient hypoglycemia (ETH), a frequent event in preterm newborns, is a highly controversial issue. In experimental models, hypoglycemia has been reported to cause oxidative stress. Among the reactive species, early generated peroxynitrite is responsible for protein nitration and lipid peroxidation, a process referred to as nitrative stress. OBJECTIVES: The aim of the present study is to investigate whether ETH is associated with protein nitration in the preterm newborn. METHODS: Using a novel highly sensitive ELISA, we quantified plasma nitroalbumin (PNA) as a marker of peroxynitrite generation in 72 preterm newborns (28-36 weeks), among which 25 had a glycemia level of <2.5 mmol/l during the first hour of life (H1). RESULTS: PNA was significantly higher in ETH than in normoglycemic infants at H1 [median = 6.3 (3.8-8.8) vs. 3.4 ng/ml (2.1-5.1), p = 0.027] and at day 1 [median = 6.6 (5.6-15.3) vs. 3.9 ng/ml (2.3-4.6), p = 0.014]. PNA was inversely correlated with glycemia at H1 (r = -0.30, p = 0.01) and at day 1 (r = -0.63, p = 0.001). In ETH infants, lactatemia was inversely correlated with PNA. At day 1, PNA was higher in ETH infants treated by gavage than in those treated with intravenous dextrose [median = 8.9 ng/ml (7.1-10.4) vs. 4.4 ng/ml (2.6-5.7), p = 0.008]. CONCLUSIONS: These results indicate that ETH is associated with increased peroxynitrite generation resulting in systemic protein nitration in premature newborns. Treatment of ETH with intravenous dextrose is associated with lower PNA levels than gavage.

Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ.

DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H(2)O(2)) is still controversial. In this work, we studied whether the high levels of H(2)O(2) produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H(2)O(2) (0.1-0.5 mmol/l) as well as irradiation (1-10 Gy) provoked a large number of SSBs ( approximately 2-3 times control DNA damage values) but also high levels of DSBs (1.2-2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. L-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H(2)O(2)-induced DNA damage. Moreover, we showed that DNA breaks induced by H(2)O(2) were more slowly repaired than those induced by irradiation. In conclusion, H(2)O(2) causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H(2)O(2) in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.