Gestational Diabetes Mellitus and its Effects on the Developing Cerebellum: A Narrative Review on Experimental Studies.

Diabetes mellitus during pregnancy is a common complication of gestation, but its effects on the offspring's development are poorly understood. Recently, some studies reported that gestational diabetes mellitus (GDM) impairs cerebellar development, and some genetic alterations have been described as consequences. Cerebellum, one of the hindbrain derived structures in the posterior cranial fossa, plays a crucial role in cognition and behavioral functions. In recent years, some surveys stated that gestational diabetes has adverse effects on the fetus's cerebellum. Disruption of cerebellar cortex morphogenesis, reduce the volume of the cerebellum, reduce the thickness of cerebellar cortex layers, and its neuronal cells and effects on the expression of synaptophysin, insulin, and insulin-like growth factor -1 receptors are some of the maternal diabetes effects on developing cerebellum. On other hand, GDM, as a neurotoxic agent, impaired cerebellar development and could be a cause for the behavioral, functional, and structural anomalies observed in pups of diabetic mothers. Based on the literature review, most studies have pointed out that administering insulin in patients with GDM decreased the cellular and molecular alterations that induced by GDM in the developing cerebellum. Undoubtedly, screening strategies for all pregnant women are necessary.

The Effectiveness of Glutathione Redox Status as a Possible Tumor Marker in Colorectal Cancer.

The role of oxidative stress (OS) in cancer is a matter of great interest due to the implication of reactive oxygen species (ROS) and their oxidation products in the initiation of tumorigenesis, its progression, and metastatic dissemination. Great efforts have been made to identify the mechanisms of ROS-induced carcinogenesis; however, the validation of OS byproducts as potential tumor markers (TMs) remains to be established. This interventional study included a total of 80 colorectal cancer (CRC) patients and 60 controls. By measuring reduced glutathione (GSH), its oxidized form (GSSG), and the glutathione redox state in terms of the GSSG/GSH ratio in the serum of CRC patients, we identified significant changes as compared to healthy subjects. These findings are compatible with the effectiveness of glutathione as a TM. The thiol redox state showed a significant increase towards oxidation in the CRC group and correlated significantly with both the tumor state and the clinical evolution. The sensitivity and specificity of serum glutathione levels are far above those of the classical TMs CEA and CA19.9. We conclude that the GSSG/GSH ratio is a simple assay which could be validated as a novel clinical TM for the diagnosis and monitoring of CRC.

Vitamin D receptor gene ApaI and FokI polymorphisms and its association with inflammation and oxidative stress in vitamin D sufficient Caucasian Spanish children.

BACKGROUND: Vitamin D has gone from being just one vitamin to being an important prohormone with multiple effects on different tissue types. The mechanism of action of the active form or calcitriol is mediated by the intracellular vitamin D receptor (VDR). The interaction of the VDR with calcitriol modulates the expression of target genes involved in cell proliferation and cytokine production. Several studies have explored the effects of vitamin D deficiency in inflammatory disorders. Furthermore, some mutations in the VDR can affect its functionality. The focus of this study was to explore associations between VDR single nucleotide polymorphisms (SNPs) and markers of inflammation and oxidative stress in vitamin D sufficient children. METHODS: This is a cross-sectional study of a Caucasian Spanish population including 155 healthy children (87 males, 68 females) aged 10 to 14 years. FokI, ApaI and TaqI SNPs of the VDR gene were genotyped. Routine biochemistry, serum levels of interleukin-6, tumor necrosis factor-α, interferon-γ, 8-isoprostaglandin F2α and nitrates were determined. RESULTS: The homozygous major allele AA in the FokI SNP was associated with increased levels of high-density lipoprotein cholesterol in a recessive inheritance mode (P=0.025). The minor allele A of ApaI was significantly associated with decreased serum tumor necrosis factor-α and 8-isoprostaglandin F2α in an additive mode (P=0.016 and P=0.020 respectively). No significant associations were observed between the TaqI SNP and any of the parameters evaluated. Haplotype analysis confirmed the significance of the relationships between ApaI and FokI SNPs and parameters associated with inflammation and oxidative stress. CONCLUSIONS: Genetic variations of VDR are associated with subtle changes in metabolic, inflammatory and oxidative stress markers. These results may provide a better understanding of the relationships between vitamin D and these clinical parameters.

Molecular aspects of pancreatic ß-cell dysfunction: Oxidative stress, microRNA, and long noncoding RNA.

Metabolic syndrome is known as a frequent precursor of type 2 diabetes mellitus (T2D). This disease could affect 8% of the people worldwide. Given that pancreatic ß-cell dysfunction and loss have central roles in the initiation and progression of the disease, the understanding of cellular and molecular pathways associated with pancreatic ß-cell dysfunction can provide more information about the underlying pathways involved in T2D. Multiple lines evidence indicated that oxidative stress, microRNA, and long noncoding RNA play significant roles in various steps of diseases. Oxidative stress is one of the important factors involved in T2D pathogenesis. This could affect the function and survival of the ß cell via activation or inhibition of several processes and targets, such as receptor-signal transduction, enzyme activity, gene expression, ion channel transport, and apoptosis. Besides oxidative stress, microRNAs and noncoding RNAs have emerged as epigenetic regulators that could affect pancreatic ß-cell dysfunction. These molecules exert their effects via targeting a variety of cellular and molecular pathways involved in T2D pathogenesis. Here, we summarized the molecular aspects of pancreatic ß-cell dysfunction. Moreover, we highlighted the roles of oxidative stress, microRNAs, and noncoding RNAs in pancreatic ß-cell dysfunction.

Molecular aspects of diabetes mellitus: Resistin, microRNA, and exosome.

Diabetes mellitus (DM) is known as one of important common endocrine disorders which could due to deregulation of a variety of cellular and molecular pathways. A large numbers studies indicated that various pathogenesis events including mutation, serin phosphorylation, and increasing/decreasing expression of many genes could contribute to initiation and progression of DM. Insulin resistance is one of important factors which could play critical roles in DM pathogenesis. It has been showed that insulin resistance via targeting a sequence of cellular and molecular pathways (eg, PI3 kinases, PPARγ co-activator-1, microRNAs, serine/threonine kinase Akt, and serin phosphorylation) could induce DM. Among of various factors involved in DM pathogenesis, microRNAs, and exosomes have been emerged as effective factors in initiation and progression of DM. A variety of studies indicated that deregulation of these molecules could change behavior of various types of cells and contribute to progression of DM. Resistin is other main factor which is known as signal molecule involved in insulin resistance. Multiple lines evidence indicated that resistin exerts its effects via affecting on glucose metabolism, inhibition of fatty acid uptake and metabolism with affecting on a variety of targets such as CD36, fatty acid transport protein 1, Acetyl-CoA carboxylase, and AMP-activated protein kinase. Here, we summarized various molecular aspects are associated with DM particularly the molecular pathways involved in insulin resistance and resistin in DM. Moreover, we highlighted exosomes and microRNAs as effective players in initiation and progression of DM.

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.

Plasma resistin levels are associated with homocysteine, endothelial activation, and nitrosative stress in obese youths.

OBJECTIVE: To evaluate whether serum resistin levels are related to cardiovascular risk in obese children. DESIGN AND METHODS: Cross-sectional study of 110 children (40 normal weight and 70 severely obese). Clinical and biochemical parameters, including lipid profile, fasting glucose and insulin, and homocysteine, were determined. The levels of adipokines (adiponectin, leptin, and resistin), markers of inflammation (high-sensitivity C-reactive protein (hs-CRP)), endothelial activation (serum concentrations of soluble intercellular and vascular cellular adhesion molecule-1 (sICAM-1, sVCAM-1)), and oxidative/nitrosative stress (malondialdehyde and urinary nitrate/nitrite) were measured. RESULTS: A partial correlation adjusted by gender, Tanner stage, and body mass index in obese children showed that resistin was significantly related to central obesity (p<0.002), insulin resistance (p<0.005), and homocysteine (p<0.001). No association was found with other metabolic risk factors or hs-CRP levels. Malondialdehyde (p<0.043) and sVCAM-1 (p<0.002) were positively correlated whereas urinary nitrate/nitrite was negatively correlated (p<0.007). In multiple regression analysis homocysteine, sVCAM-1, and urinary nitrate/nitrite remained independent determinants of resistin levels (R(2) adjusted=0.347, p=0.000). CONCLUSIONS: Resistin could be considered as a promising marker for future cardiovascular disease in obese children.

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.

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 ß-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.

Polyamines are increased in obese children and are related to markers of oxidative/nitrosative stress and angiogenesis.

CONTEXT: Polyamines (putrescine, spermidine, and spermine) are polycationic amines derived from arginine, which is the precursor of nitric oxide (NO). Due to the close relationship between the metabolism of polyamines and NO metabolism, the alteration in polyamine homeostasis can affect the NO bioavailability at the endothelium. OBJECTIVES: The objective of the study was to test the hypothesis that childhood obesity is associated with a significant modification of blood polyamines and to investigate the presence of correlation between these molecules, circulating markers of oxidative and nitrosative stress, and endothelial dysfunction. DESIGN AND SETTING: This was an observational analytical case-control study conducted at one tertiary care center. PATIENTS AND METHODS: The study was performed with 102 children aged 7-14 yr (60 obese, 42 nonobese). Blood polyamines were measured by HPLC. Metabolites of the NO pathway, oxidative stress parameters, inflammatory markers, adhesion molecules, and adipocytokines were also determined. RESULTS: Polyamine levels were significantly higher in obese children. Among them, spermine was the polyamine with the more discriminatory power, taking into account the obesity. In all children, spermine levels were related to biomarkers of oxidative/nitrosative stress, inflammation, and leptin and to adhesion molecules, soluble E-selectin, and soluble intercellular adhesion molecule-1. Only in obese children was there a positive correlation with vascular endothelial growth factor and a negative correlation with 3'-nitrotyrosine levels. CONCLUSIONS: Polyamine levels are increased in childhood obesity and correlated to markers of oxidative/nitrosative stress and angiogenesis. This finding implicates polyamine metabolism in the complications of obesity. Their potential utility as a clinical tool remains to be elucidated.

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.

La arginina en su contexto metabólico y fisiológico / Arginine on its metabolic and physiological context

La L-arginina es uno de los aminoácidos más versátiles desde el punto de vista metabólico y fisiológico. Entre sus funciones conocidas se incluyen: sustrato de la biosíntesis de proteínas y de péptidos bioactivos, participación en la detoxificación de amonio, liberación de hormonas, y biosíntesis de poliaminas y creatina. Las funciones de la arginina se han visto recientemente incrementadas con el descubrimiento de su papel como sustrato precursor del óxido nítrico, un efector multifuncional implicado en la vasodilatación, neurotransmisión, y con actividad antimicrobiana y antitumoral. Desde el punto de vista nutricional, la arginina es un aminoácido "condicionalmente esencial" para los mamíferos. Sus requerimientos se cubren gracias al aporte dietético y la síntesis endógena, siendo ésta última en el hombre, al parecer, suficiente para cubrir las necesidades fisiológicas habituales pero insuficiente en períodos o condiciones de elevada demanda del aminoácido. Tal situación sugiere un potencial uso terapéutico para la arginina que está comenzando a ser analizado. Esta revisión pretende resumir los conocimientos actuales sobre la síntesis de arginina y sus principales destinos metabólicos (AU)

La arginina en su contexto metabólico y fisiológico / Arginine on its metabolic and physiological context

La L-arginina es uno de los aminoácidos más versátiles desde el punto de vista metabólico y fisiológico. Entre sus funciones conocidas se incluyen: sustrato de la biosíntesis de proteínas y de péptidos bioactivos, participación en la detoxificación de amonio, liberación de hormonas, y biosíntesis de poliaminas y creatina. Las funciones de la arginina se han visto recientemente incrementadas con el descubrimiento de su papel como sustrato precursor del óxido nítrico, un efector multifuncional implicado en la vasodilatación, neurotransmisión, y con actividad antimicrobiana y antitumoral. Desde el punto de vista nutricional, la arginina es un aminoácido "condicionalmente esencial" para los mamíferos. Sus requerimientos se cubren gracias al aporte dietético y la síntesis endógena, siendo ésta última en el hombre, al parecer, suficiente para cubrir las necesidades fisiológicas habituales pero insuficiente en períodos o condiciones de elevada demanda del aminoácido. Tal situación sugiere un potencial uso terapéutico para la arginina que está comenzando a ser analizado. Esta revisión pretende resumir los conocimientos actuales sobre la síntesis de arginina y sus principales destinos metabólicos