Daniel Prá

Iron and genome stability: an update.

Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7mg/day to 18mg/day depending on life stage and gender. Pregnant women need 27mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40-45mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.

A Possible Link Between Iron Deficiency and Gastrointestinal Carcinogenesis

There is definitive evidence that iron overload induces oxidative stress and DNA damage, which can enhance carcinogenic risk. However, other evidence suggests that iron deficiency and anemia also increase oxidative stress and DNA damage, which might increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. The aim of this review is to provide essential background information for the accurate interpretation of future research on iron deficiency and increased GI cancer risk. Based on clinical, epidemiological, and experimental evidence, we discuss how iron deficiency might contribute to increased cancer risk through the impairment of several iron-dependent metabolic functions that are related to genome protection and maintenance (e.g., immune responses against cancer-initiated cells, metabolism of toxic compounds, and redox regulation of DNA biosynthesis and repair). Some epidemiological studies have indicated increased risk of GI tumors among individuals with low iron intake or low somatic iron stores, and in vivo data from rodent cancer models indicates the early progression of GI tumors during iron deficiency. Given the preliminary but consistent evidence relating iron deficiency to cancer risk and the fact that iron deficiency affects about one third of the worlds population, further studies are needed to define the extent to which iron deficiency might increase GI cancer risk.

Uma análise entre índices pressóricos, obesidade e capacidade cardiorrespiratória em escolares

FUNDAMENTO: Durante a infância e adolescencia, o sedentarismo, o excesso de peso e a alimentacao inadequada sao fatores de risco para doencas cronicas, sobretudo obesidade, hipertensao arterial sistemica e diabete melito. A intervencao precoce pode prevenir o desenvolvimento dessas complicacoes. OBJETIVO: Verificar a presenca de fatores de risco cardiovasculares (obesidade e hipertensao arterial) e suas possiveis interacoes com a capacidade cardiorrespiratoria. Metodos: Estudo transversal composto de amostra estratificada por conglomerados, de 1.666 escolares, com idades entre 7 e 17 anos, 873 (52,4%) do sexo masculino e 793 (47,6%) do sexo feminino. Avaliaram-se as pressoes arteriais sistolica (PAS) e diastolica (PAD), indice de massa corporal (IMC), percentual de gordura (%G) e capacidade cardiorrespiratoria. Ainda, PAS e PAD foram correlacionadas com circunferencia da cintura (CC), relacao cintura-quadril (RCQ), somatorio de dobras cutâneas (ΣDC) e capacidade cardiorrespiratoria. RESULTADOS: A avaliacao do IMC dos escolares evidenciou 26,7% de sobrepeso ou obesidade e 35,9% com o percentual de gordura acima de moderadamente alto. Com relacao aos niveis pressoricos, encontraram-se 13,9% e 12,1% de escolares limitrofes e hipertensos, para PAS e PAD, respectivamente. Houve associacao entre hipertensao, obesidade e capacidade cardiorrespiratoria. Observou-se correlacao significativa em relacao a PAS e PAD, para todas as variaveis analisadas, apresentando, ainda, uma relacao fraca a moderada com as variaveis idade, peso, estatura, IMC e circunferencia da cintura. CONCLUSAO: A presenca da hipertensao arterial associada a obesidade e seu reflexo na capacidade cardiorrespiratoria reforcam a importância de se propor, ja na infância, um estilo de vida mais ativo e saudavel.

Relationship between anthropometric measures and cardiovascular risk factors in children and adolescents.

Background Obesity has been identified as an important risk factor in the development of cardiovascular diseases; however, other factors, combined or not with obesity, can influence cardiovascular risk and should be considered in cardiovascular risk stratification in pediatrics. Objective To analyze the association between anthropometry measures and cardiovascular risk factors, to investigate the determinants to changes in blood pressure (BP), and to propose a prediction equation to waist circumference (WC) in children and adolescents. Methods We evaluated 1,950 children and adolescents, aged 7 to 18 years. Visceral fat was assessed by WC and waist hip relationship, BP and body mass index (BMI). In a randomly selected subsample of these volunteers (n = 578), total cholesterol, glucose and triglycerides levels were evaluated. Results WC was positively correlated with BMI (r = 0.85; p < 0.001) and BP (SBP r = 0.45 and DBP = 0.37; p < 0.001). Glycaemia and triglycerides showed a weak correlation with WC (r = 0.110; p = 0.008 e r = 0.201; p < 0.001, respectively). Total cholesterol did not correlate with any of the variables. Age, BMI and WC were significant predictors on the regression models for BP (p < 0.001). We propose a WC prediction equation for children and adolescents: boys: y = 17.243 + 0.316 (height in cm); girls: y = 25.197 + 0.256 (height in cm). Conclusion WC is associated with cardiovascular risk factors and presents itself as a risk factor predictor of hypertension in children and adolescents. The WC prediction equation proposed by us should be tested in future studies.

Biomonitoring genotoxicity and cytotoxicity of Microcystis aeruginosa (Chroococcales, Cyanobacteria) using the Allium cepa test

Water pollution caused by toxic cyanobacteria is a problem worldwide, increasing with eutrophication. Due to its biological significance, genotoxicity should be a focus for biomonitoring pollution owing to the increasing complexity of the toxicological environment in which organisms are exposed. Cyanobacteria produce a large number of bioactive compounds, most of which lack toxicological data. Microcystins comprise a class of potent cyclic heptapeptide toxins produced mainly by Microcystis aeruginosa. Other natural products can also be synthesized by cyanobacteria, such as the protease inhibitor, aeruginosin. The hepatotoxicity of microcystins has been well documented, but information on the genotoxic effects of aeruginosins is relatively scarce. In this study, the genotoxicity and ecotoxicity of methanolic extracts from two strains of M. aeruginosa NPLJ-4, containing high levels of microcystin, and M. aeruginosa NPCD-1, with high levels of aeruginosin, were evaluated. Four endpoints, using plant assays in Allium cepa were applied: rootlet growth inhibition, chromosomal aberrations, mitotic divisions, and micronucleus assays. The microcystin content of M. aeruginosa NPLJ-4 was confirmed through ELISA, while M. aeruginosa NPCD-1 did not produce microcystins. The extracts of M. aeruginosa NPLJ-4 were diluted at 0.01, 0.1, 1 and 10 ppb of microcystins; the same procedure was used to dilute M. aeruginosa NPCD-1 used as a parameter for comparison, and water was used as the control. The results demonstrated that both strains inhibited root growth and induced rootlet abnormalities. The strain rich in aeruginosin was more genotoxic, altering the cell cycle, while microcystins were more mitogenic. These findings indicate the need for future research on non-microcystin producing cyanobacterial strains. Understanding the genotoxicity of M. aeruginosa extracts can help determine a possible link between contamination by aquatic cyanobacteria and high risk of primary liver cancer found in some areas as well as establish water level limits for compounds not yet studied.

Iron intake, red cell indicators of iron status, and DNA damage in young subjects

OBJECTIVE This study evaluated the association between primary DNA damage and chromosomal damage with iron intake and red blood cell parameters of iron status in a sample of healthy children and adolescents from a low-socioeconomic community. METHODS The level of primary DNA damage was assessed using an alkaline comet assay and the level of chromosomal damage was assessed using the cytokinesis-block micronucleus assay. A automated complete blood count was used to evaluate red blood cell status. The intake of iron was measured using a food-recall questionnaire. RESULTS According to hemoglobin levels, only 1 of the 30 subjects evaluated was anemic. Nevertheless, 43% of the sampled subjects showed decreased mean corpuscular volume in addition to an increased amount of primary DNA damage (P < 0.05). Mean corpuscular volume was negatively correlated with primary DNA damage (r = -0.429, P = 0.020) but not with chromosomal damage. The association between iron and primary DNA damage showed a U-shaped curve, indicating that an intake of approximately 15 mg of iron per day (up to two-fold of the dietary recommended intake) could minimize primary DNA damage in this age group. The frequency of micronuclei and nucleoplasmic bridges, indicators of chromosomal breakage/loss and chromosomal end-fusions, respectively, showed a negative correlation with iron intake. These results indicate that an intake of iron >15 mg/d could increase genomic stability in binucleated lymphocytes of the same group. CONCLUSION An intake of iron ≥ 15 mg/d can decrease DNA damage in young subjects.

Antioxidant Activity and Phenolic and Mineral Content of Rose Grape Juice

There are many studies related to the antioxidant activity of grape products; however, they concern only purple and white grape varieties. Up to now, there are no reports of studies on the Goethe rose grape variety, either on its antioxidant activity or on its phenolic and mineral quantification. Thus, the purpose of this study was to evaluate in vitro and in vivo antioxidant activity, as well as to quantify total phenolic compounds, ascorbic acid, and mineral content, in a Goethe rose grape juice. The results obtained showed that the Goethe rose grape juice is a great polyphenol source, which contains catechin, epicatechin, and procyanidins (B(1), B(2), B(3), and B(4)). Of all metals analyzed, potassium, calcium, magnesium, and iron showed the highest values. We found that this rose grape juice shows an important antioxidant activity in in vitro (2,2-diphenyl-1-picrylhydrazyl radical scavenging activity) and in vivo (using the Saccharomyces cerevisiae yeast cells) assays. The antioxidant activity could be explained by the significant phenolic content and ascorbic acid levels found in the juice. The results showed that rose grape juice is an excellent antioxidant source, which could contribute to the prevention of many diseases related to oxidative stress, such as atherosclerosis and Parkinsons disease.

DNA damage and cytotoxicity in adult subjects with prediabetes.

Prediabetes (intermediate hyperglycemia) is a high-risk state for diabetes that is defined by higher than normal glycemic levels that are below the level required for a diagnosis of diabetes. Prediabetes is characterized by oxidative stress, yet the associated DNA damage and cytotoxicity remain unknown to date. Therefore, we evaluated the relationship between glycemic alterations, DNA damage and cytotoxicity in the lymphocytes of individuals with pre-diabetes. Fasting plasma glucose (FPG) and glycated hemoglobin (A1C) levels were quantified and used as inclusion criteria. Anthropometric parameters were also evaluated. The cytokinesis-block micronucleus cytome assay (CBMN Cyt) was used to evaluate DNA damage and cytotoxicity. FPG correlated with A1C (r=0.562, p=0.002). Because A1C is the best predictor of diabetes complications, the association between A1C and the evaluated variables was assessed. The waist-hip ratio correlated with A1C (p<0.01). Regarding DNA damage, the frequency of nucleoplasmic bridges correlated with A1C (p<0.05). Both apoptosis and necrosis correlated with A1C (p<0.05). The overall frequency of DNA damage and cytotoxicity also correlated with A1C (p<0.01). Additional studies evaluating cell cycle and cell death patterns in prediabetes are necessary.

Biological functions of selenium and its potential influence on Parkinson's disease

Parkinsons disease is characterized by the death of dopaminergic neurons, mainly in the substantia nigra, and causes serious locomotor dysfunctions. It is likely that the oxidative damage to cellular biomolecules is among the leading causes of neurodegeneration that occurs in the disease. Selenium is an essential mineral for proper functioning of the brain, and mainly due to its antioxidant activity, it is possible to exert a special role in the prevention and in the nutritional management of Parkinsons disease. Currently, few researchers have investigated the effects of selenium on Parkinson´s disease. However, it is known that very high or very low body levels of selenium can (possibly) contribute to the pathogenesis of Parkinsons disease, because this imbalance results in increased levels of oxidative stress. Therefore, the aim of this work is to review and discuss studies that have addressed these topics and to finally associate the information obtained from them so that these data and associations serve as input to new research.

Length of treatment and dose as determinants of mutagenicity in sickle cell disease patients treated with hydroxyurea.

Hydroxyurea (HU) is an antineoplastic drug widely used in the clinical management of patients with sickle cell disease (SCD), and many questions related with its use remain unresolved. Given the severity of SCD, HU benefits, although not thoroughly confirmed, seem to outweigh its potential carcinogenicity. This study aimed to assess the genotoxicity associated with HU dose and treatment length by evaluating mutagenicity in patients with SCD treated with HU (SCHU) using the cytokinesis-block micronucleus assay (CBMN) in white cells. The study was conducted with 35 individuals in the SCHU group and 34 controls matched according to age, sex and smoking habit. CBMN results showed an increase (p=0.032) in the number of micronuclei (MN), but not of nucleoplasmic bridges (NPB) or nuclear buds (NBUD) in the SCHU group. The increased frequency of MN in the SCHU group was significantly correlated with treatment length and final HU dose, which confirms that patients with SCD treated with HU should be carefully monitored to reduce the risk of carcinogenicity.