Maternal Melatonin Programs the Daily Pattern of Energy Metabolism in Adult Offspring

Background: Shift work was recently described as a factor that increases the risk of Type 2 diabetes mellitus. In addition, rats born to mothers subjected to a phase shift throughout pregnancy are glucose intolerant. However, the mechanism by which a phase shift transmits metabolic information to the offspring has not been determined. Among several endocrine secretions, phase shifts in the light/dark cycle were described as altering the circadian profile of melatonin production by the pineal gland. The present study addresses the importance of maternal melatonin for the metabolic programming of the offspring. Methodology/Principal Findings: Female Wistar rats were submitted to SHAM surgery or pinealectomy (PINX). The PINX rats were divided into two groups and received either melatonin (PM) or vehicle. The SHAM, the PINX vehicle and the PM females were housed with male Wistar rats. Rats were allowed to mate and after weaning, the male and female offspring were subjected to a glucose tolerance test (GTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Pancreatic islets were isolated for insulin secretion, and insulin signaling was assessed in the liver and in the skeletal muscle by western blots. We found that male and female rats born to PINX mothers display glucose intolerance at the end of the light phase of the light/dark cycle, but not at the beginning. We further demonstrate that impaired glucose-stimulated insulin secretion and hepatic insulin resistance are mechanisms that may contribute to glucose intolerance in the offspring of PINX mothers. The metabolic programming described here occurs due to an absence of maternal melatonin because the offspring born to PINX mothers treated with melatonin were not glucose intolerant. Conclusions/Significance: The present results support the novel concept that maternal melatonin is responsible for the programming of the daily pattern of energy metabolism in their offspring.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)CNPq (Conselho Nacional de Aperfeicoameno Cientifico)CNPq (Conselho Nacional de Aperfeicoameno Cientifico

Zika virus infection in pregnancy and infant growth, body composition in the first three months of life: a cohort study.

The implications of Zika Virus exposure in pregnancy for early infant growth remains poorly described. The main goal of this study is to compare the growth, body composition, and feeding modality of infants in the first three months of life by prenatal Zika Virus exposure status. We selected an analytical cohort of 115 infants born without microcephaly, comprising 56 infants with qRT-PCR confirmed exposure to ZIKV during gestation and 59 infants born to women with presumptively no evidence of ZIKV in pregnancy. Infants were evaluated at birth, 1 and 3 months of age in terms of anthropometrics, body composition All the results were adjusted by maternal age, maternal BMI and gestational age. We observe no differences between anthropometric measurements at birth. Mothers in exposed group showed higher BMI. At 1 month and 3 months of age there were differences in mid arm circumference, arm muscle circumference and fat free mass. Weight and length was less in the ZIKV exposed in pregnancy infants and statistically different at 3 month of age. The findings of this investigation provide new evidence that ZIKV exposure in pregnancy may be associated with differences in body composition

Environmental control of biological rhythms: effects on development, fertility and metabolism

Internal temporal organisation properly synchronised to the environment is crucial for health maintenance. This organisation is provided at the cellular level by the molecular clock, a macromolecular transcription-based oscillator formed by the clock and the clock-controlled genes that is present in both central and peripheral tissues. In mammals, melanopsin in light-sensitive retinal ganglion cells plays a considerable role in the synchronisation of the circadian timing system to the daily light/dark cycle. Melatonin, a hormone synthesised in the pineal gland exclusively at night and an output of the central clock, has a fundamental role in regulating/timing several physiological functions, including glucose homeostasis, insulin secretion and energy metabolism. As such, metabolism is severely impaired after a reduction in melatonin production. Furthermore, light pollution during the night and shift work schedules can abrogate melatonin synthesis and impair homeostasis. Chronodisruption during pregnancy has deleterious effects on the health of progeny, including metabolic, cardiovascular and cognitive dysfunction. Developmental programming by steroids or steroid-mimetic compounds also produces internal circadian disorganisation that may be a significant factor in the aetiology of fertility disorders such as polycystic ovary syndrome. Thus, both early and late in life, pernicious alterations of the endogenous temporal order by environmental factors can disrupt the homeostatic function of the circadian timing system, leading to pathophysiology and/or disease.This work was supported by grants 1110220 from FONDECYT and ACT1116 from CONICYT, Chile (to HGR); Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Tecnológico e Científico (CNPq; Brazil, to AMC, FGA and JCN); Pro-Reitoria de Pesquisa Universidade Federal de Minas Gerais, Brazil (to MOP); fellowship 21120472 from CONICYT (Chile) to (NM) and an NIEHS sponsored Pilot Grant from the Department of Environmental Medicine at the University of Rochester School of Medicine to MTS

Reactive Oxygen Species Production and Mitochondrial Dysfunction Contribute to Quercetin Induced Death in Leishmania amazonensis

BACKGROUND: Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compound with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 hours of treatment and with maximum growth inhibition observed at 96 hours. The IC(50) for quercetin at 48 hours was 31.4 µM. Quercetin increased ROS generation in a dose-dependent manner after 48 hours of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addition, quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential. CONCLUSIONS/SIGNIFICANCE: The effects of several drugs that interfere directly with mitochondrial physiology in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chemical agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function

A population-based surveillance study on severe acute maternal morbidity (near-miss) and adverse perinatal outcomes in Campinas, Brazil: The Vigimoma Project

BACKGROUND: Auditing of sentinel health events based on best-practice protocols has been recommended. This study describes a population-based investigation on adverse perinatal events including severe acute maternal morbidity (near-miss), maternal and perinatal mortality, as a health intervention to help improve the surveillance system. METHODS: From October to December 2005, all cases of maternal death (MD), near-miss (NM), fetal deaths (FD), and early neonatal deaths (END), occurring in Campinas, Brazil, were audited by maternal mortality committees. RESULTS: A total of 4,491 liveborn infants (LB) and 159 adverse perinatal events (35.4/1000 LB) were revised, consisting of 4 MD (89/100.000 LB) and 95 NM (21.1/1000 LB), 23.7 NM for each MD. In addition, 32 FD (7.1/1000 LB) and 28 END (6.2/1000 LB) occurred. The maternal death/near miss rate was 23.7:1. Some delay in care was recognized for 34%, and hypertensive complications comprised 57.8% of the NM events, followed by postpartum hemorrhage. CONCLUSION: Auditing near miss cases expanded the understanding of the spectrum from maternal morbidity to mortality and the importance of promoting adhesion to clinical protocols among maternal mortality committee members. Hypertensive disorders and postpartum hemorrhage were identified as priority topics for health providers training, and organization of care

The Genomic Ancestry of Individuals from Different Geographical Regions of Brazil Is More Uniform Than Expected

Based on pre-DNA racial/color methodology, clinical and pharmacological trials have traditionally considered the different geographical regions of Brazil as being very heterogeneous. We wished to ascertain how such diversity of regional color categories correlated with ancestry. Using a panel of 40 validated ancestry-informative insertion-deletion DNA polymorphisms we estimated individually the European, African and Amerindian ancestry components of 934 self-categorized White, Brown or Black Brazilians from the four most populous regions of the Country. We unraveled great ancestral diversity between and within the different regions. Especially, color categories in the northern part of Brazil diverged significantly in their ancestry proportions from their counterparts in the southern part of the Country, indicating that diverse regional semantics were being used in the self-classification as White, Brown or Black. To circumvent these regional subjective differences in color perception, we estimated the general ancestry proportions of each of the four regions in a form independent of color considerations. For that, we multiplied the proportions of a given ancestry in a given color category by the official census information about the proportion of that color category in the specific region, to arrive at a “total ancestry” estimate. Once such a calculation was performed, there emerged a much higher level of uniformity than previously expected. In all regions studied, the European ancestry was predominant, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of six million Europeans to Brazil in the 19th and 20th centuries - a phenomenon described and intended as the “whitening of Brazil” - is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. These findings, of both clinical and sociological importance for Brazil, should also be relevant to other countries with ancestrally admixed populations