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Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress

Evidence of obesity-induced oxidative stress in adults has emerged in the past several years, and similar evidence has been demonstrated in children more recently. The reactive species of oxygen or nitrogen can chemically alter all major classes of biomolecules by modifying their structure and function. Organisms have developed mechanisms to protect biomolecules from the deleterious effects of free radicals. These include the enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as water and lipid-soluble antioxidants, such as glutathione, ascorbate (vitamin C), α-tocopherol (vitamin E), and β-carotene. Obesity creates oxidant conditions that favor the development of comorbid diseases. Energy imbalances lead to the storage of excess energy in adipocytes, resulting in both hypertrophy and hyperplasia. These processes are associated with abnormalities of adipocyte function, particularly mitochondrial stress and disrupted endoplasmic reticulum function. In this sense, oxidative stress can also be induced by adipocyte associated inflammatory macrophages. There is a close link among obesity, a state of chronic low-level inflammation, and oxidative stress. In addition, the dysregulation of adipocytokines, which are secreted by adipose tissue and promoted by oxidative stress, act synergistically in obesity-related metabolic abnormalities. Adipocytokines link the local and systemic inflammation responses in the context of obesity. It is thought that the evaluation of oxidative status may allow for the identification of patients at an increased risk of complications. Decreasing the levels of chronic inflammation and oxidative stress in childhood may decrease cardiovascular morbidity and mortality in adulthood.

Long-term follow-up of growth in height after successful liver transplantation

Quantitative assessment of growth in height during the long-term follow-up of children who underwent orthotopic liver transplantation was done to allay concerns related to the progress of the children in terms of normal relationships with peers. Height curves were constructed for 119 children who received transplants at Bicêtre and Cochin Hospitals and were followed for more than 1 year. Poor linear growth was observed during the first 6 months after transplantation, during which time children received corticosteroids daily. The onset of catch-up growth was observed between 6 and 24 months after transplantation, and its magnitude did not differ between male and female patients. Both boys and girls underwent a normal pubertal growth spurt and normal development of secondary sexual characteristics. All adolescent girls had regular menstrual cycles, and one delivered a normal infant 6 years after transplantation. Patients who received transplants before the age of 2 years had poor average growth velocity by the third year after transplantation. Linear growth improved in almost all children and was not affected by the cause of the liver disease that existed before the liver transplantation except that fulminant hepatic failure was associated with poor growth. Long-term improvement of growth in height usually is obtained after liver transplantation in most children with chronic liver diseases. The use of low doses of corticosteroids, administered on an alternate-day basis, contributes to this improvement. Young age of the patient, but not the cause of the chronic liver disease, appears to influence the long-term outcome of linear growth.

Nitric oxide production is increased in severely obese children and related to markers of oxidative stress and inflammation.

OBJECTIVE Nitric oxide (NO) is the major endothelium-derived relaxing factor. The aim of the present study was to evaluate NO synthesis and metabolism in severely obese children with different degrees of metabolic risk and to ascertain their relation with the parameters of oxidative stress and inflammation. METHODS The study involved 60 obese children evaluated with respect to metabolic risk factors (MRFs) (32<4 MRFs and 28 ≥ 4 MRFs) and 50 normal weight children between 7 and 14 years of age. Nutritional status was assessed by clinical and anthropometric examination. MRFs (serum lipid profile, insulin resistance indexes, blood pressure) in addition to uric acid, homocysteine, leptin, and inflammatory markers were measured. Plasma nitrite, nitrate and nitrotyrosine concentrations, and urinary nitrate were determined as markers of NO production and nitrosative stress. Malondialdehyde, 8-isoprostane F(2α), and advanced oxidation protein products were analyzed in plasma to assess oxidative stress. RESULTS Compared with healthy controls, the obese children had significantly increased concentrations of markers of NO synthesis and nitrosative and oxidative stress that were correlated with each another. Increased NO production in obese children was associated with MRFs; plasma nitrate to waist circumference (r=0.388, p=0.003), uric acid (r=0.404, p<0.001), and tumor necrosis factor α (r=0.302, p=0.021), and plasma nitrite to triglycerides (r=0.432, p<0.001). CONCLUSION NO synthesis and nitrosative stress are increased in severely obese children and correlated with anthropometric parameters indicative of abdominal obesity, oxidative stress and inflammatory markers.

Vitamin D Status is Linked to Biomarkers of Oxidative Stress, Inflammation, and Endothelial Activation in Obese Children

OBJECTIVE To examine vitamin D, parathyroid hormone, and serum calcium-phosphorus levels relationships to biomarkers of oxidative/nitrosative stress, inflammation, and endothelial activation, potential contributors for vascular complications in obese children. STUDY DESIGN Cross-sectional clinical study of 66 obese Caucasian children aged 7 to 14 years. Cardiovascular risk factors were assessed. Malondialdehyde and myeloperoxidase as measures of oxidative stress, and plasma nitrite+nitrate, urinary nitrate, and 3-nitrotyrosine as markers of nitrosative stress were measured. Adipocytokines, inflammatory molecules (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α), endothelial activation molecules (soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule 1 [sVCAM-1]), E-selectin, and vascular endothelial growth factor were also investigated. Serum 25-hydroxy-cholecalciferol [25(OH)D], intact parathormone, and calcium-phosphorus levels were determined in these children and in a comparison group of 39 non-obese children. RESULTS Obese children had a significantly lower 25(OH)D level (P = .002) and a higher intact parathormone (P = .011) than non-obese children. Phosphorus and the calcium-phosphorus product were also significantly higher (P < .0001). Insufficient serum concentrations of 25(OH)D (<20 ng/mL) were detected in 5% of normal children and in 30% of the obese children. In the obese children with vitamin D insufficiency, malondialdehyde, myeloperoxidase, 3-nitrotyrosine, interleukin-6, and sVCAM-1 were substantially elevated. A partial correlation analysis showed an inverse relationship of 25(OH)D levels with 3-nitrotyrosine (r = -0.424, P = .001), and sVCAM-1 (r = -0.272, P = .032). CONCLUSIONS Insufficient 25(OH)D levels were detected in severely obese children with increased markers of oxidative/nitrosative stress, inflammation, and endothelial activation.

Is obesity associated with oxidative stress in children

OBJECTIVE We evaluated the presence of oxidative stress in obese children without co-morbidities. METHODS The study population included 68 children (30 girls, 38 boys), between 6 and 14 years of age. The levels of markers of oxidative damage (malondialdehyde [MDA], and plasma carbonyl groups [CG]) and measures of antioxidant defense, such as the enzyme glutathione peroxidase (GPx) and low molecular scavengers (erythrocyte-reduced glutathione [GSH], alpha-tocopherol and beta-carotene) were determined. Children were categorized in groups by the standard deviation score of body mass index (SDS-BMI). Twenty children were non-obese (SDS-BMI< or =1.33), and the 48 obese children (SDS-BMI> or =2) were further divided into two groups: SDS-BMI> or =3 (22 children) and > or =2 SDS-BMI<3 (26 children). RESULTS The levels of MDA and CG were significantly higher (p<0.05) in children with SDS-BMI> or =3. The GPx activity was increased, while the GSH concentration was lower in obese children compared with non-obese children (p<0.01). There were no differences in serum alpha-tocopherol and beta-carotene levels between groups. MDA was the sole marker of oxidative damage that was positively correlated with SDS-BMI, (r=0.35, p=0.015), and negatively with high-density lipoprotein cholesterol (HDL-C) (r=- 0.32, p=0.027). GPx was inversely related to total cholesterol (r=- 0.34, p=0.019). In multiple regression analysis, we confirmed that SDS-BMI and HDL-C were determinants of MDA. CONCLUSIONS Severe childhood obesity is associated with oxidative stress. Thus, providing foods with high antioxidant capacity in addition to a hypocaloric diet is crucial for the treatment of obese children.

Intestinal Microbiota and Celiac Disease: Cause, Consequence or Co-Evolution?

It is widely recognized that the intestinal microbiota plays a role in the initiation and perpetuation of intestinal inflammation in numerous chronic conditions. Most studies report intestinal dysbiosis in celiac disease (CD) patients, untreated and treated with a gluten-free diet (GFD), compared to healthy controls. CD patients with gastrointestinal symptoms are also known to have a different microbiota compared to patients with dermatitis herpetiformis and controls, suggesting that the microbiota is involved in disease manifestation. Furthermore, a dysbiotic microbiota seems to be associated with persistent gastrointestinal symptoms in treated CD patients, suggesting its pathogenic implication in these particular cases. GFD per se influences gut microbiota composition, and thus constitutes an inevitable confounding factor in studies conducted in CD patients. To improve our understanding of whether intestinal dysbiosis is the cause or consequence of disease, prospective studies in healthy infants at family risk of CD are underway. These studies have revealed that the CD host genotype selects for the early colonizers of the infant’s gut, which together with environmental factors (e.g., breast-feeding, antibiotics, etc.) could influence the development of oral tolerance to gluten. Indeed, some CD genes and/or their altered expression play a role in bacterial colonization and sensing. In turn, intestinal dysbiosis could promote an abnormal response to gluten or other environmental CD-promoting factors (e.g., infections) in predisposed individuals. Here, we review the current knowledge of host-microbe interactions and how host genetics/epigenetics and environmental factors shape gut microbiota and may influence disease risk. We also summarize the current knowledge about the potential mechanisms of action of the intestinal microbiota and specific components that affect CD pathogenesis.

Resistin: Insulin resistance to malignancy

Adipose tissue is recognized as an endocrine organ that secretes bioactive substances known as adipokines. Excess adipose tissue and adipose tissue dysfunction lead to dysregulated adipokine production that can contribute to the development of obesity-related co-morbidities. Among the various adipokines, resistin, which was initially considered as a determinant of the emergence of insulin resistance in obesity, has appeared as an important link between obesity and inflammatory processes. Several experimental and clinical studies have suggested an association between increased resistin levels and severe conditions associated with obesity such as cardiovascular disease and malignancies. In this review, we present the growing body of evidence that human resistin is an inflammatory biomarker and potential mediator of obesity-associated diseases. A common pathway seems to involve the combined alteration of immune and inflammatory processes that favor metabolic disturbances, atherosclerosis and carcinogenesis. The mode of action and the signaling pathways utilized by resistin in its interactions with target cells could involve oxidative and nitrosative stress. Therefore, resistin could function as a key molecule in the complications of obesity development and could potentially be used as a diagnostic and prognostic marker.

Elevated advanced oxidation protein products (AOPPs) indicate metabolic risk in severely obese children

BACKGROUND AND AIMS The assessment of oxidative stress may aid in the identification of subsequent metabolic risk in obese children. The objective of this study was to determine whether the plasma level of advanced oxidation protein products, analyzed with a recently proposed modified assay that involves a delipidation step (mAOPPs), was related to metabolic risk factors (MRFs) in severely obese children. METHODS AND RESULTS The plasma levels of mAOPPs were determined by spectrophotometry in 54 severely obese and 44 healthy children. We also measured lipid peroxidation biomarkers (thiobarbituric acid-reactive substances, malondialdehyde, and 8-isoprotane F(2α)) and sulfhydryl groups, a marker of antioxidant defense. Protein oxidation and lipid peroxidation markers were higher and sulfhydryl levels were lower in obese children compared with controls. Taking metabolic risk into account, obese children were subdivided according to the cutoff point (53.2 μmol/L) obtained for their mAOPPs values from the ROC curve. Anthropometric measures and the existence of hypertension did not differ between groups. The presence of dyslipidemia and insulin resistance was significantly higher in the group with higher mAOPPs levels. The highest levels of mAOPPs were found in the children with ≥3 MRFs. The level of mAOPPs was positively correlated with triglycerides and negatively correlated with high-density lipoprotein cholesterol. There was no correlation of this marker of protein oxidation with biomarkers of lipid peroxidation. CONCLUSION The determination of mAOPPs in delipidated plasma is an easy way to evaluate protein oxidation. It may be useful in severely obese children for better cardiovascular risk assessment.

Oxidative markers in children with severe obesity following low-calorie diets supplemented with mandarin juice

Aim:  To evaluate the effect of supplementing a hypocaloric diet with mandarin juice, a food with a high content of antioxidants (vitamin C, flavonoids and carotenoids), on biomarkers of oxidant/antioxidant status of severe obese children.

Mandarin Juice Improves the Antioxidant Status of Hypercholesterolemic Children

Background: Oxidative stress has been linked to such degenerative diseases as atherosclerosis, and it has been suggested that increased dietary intake of antioxidants may reduce its progression. Objective: To determine the effect of mandarin juice consumption on biomarkers related to oxidative stress in hypercholesterolemic children. Materials and Methods: The diet of 48 children with plasma cholesterol >200 mg/dL and low-density lipoprotein cholesterol >130 mg/dL was supplemented for 28 days with 500 mL/day of pure (100%) mandarin juice (Citrus clementina Hort. ex Tan.). The composition of the mandarin juice was analyzed, and its antioxidant antiradical activity was evaluated in vitro. Malondialdehyde, carbonyl groups, vitamins E and C, erythrocyte-reduced glutathione, and plasma lipids were measured at the onset and at the end of the supplementation period. The paired Student t test was used to compare values before and after supplementation. Results: Mandarin juice exerted a strong antioxidant effect mainly due to its high hydroxyl activity and, to a lesser extent, to its superoxide scavenger activity. At the end of the study, levels of the plasma biomarkers of oxidative stress were significantly decreased (malondialdehyde −7.4%, carbonyl groups −29.1%, P < 0.01), whereas the plasma antioxidants vitamin E and C (13.5%, P < 0.001 and 68.2%, P < 0.00001, respectively) and intraerythrocyte glutathione level (36.7%, P < 0.00001) were significantly increased. Plasma lipids and antibodies to oxidized low-density lipoproteins remained unchanged. Conclusions: Regular ingestion of mandarin juice significantly reduces plasma biomarkers of lipid and protein oxidation and enhances the antioxidant status of consumers.