Inhibition of placental mTOR signaling provides a link between placental malaria and reduced birthweight

BACKGROUND: Placental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone. Fetal growth (and therefore birthweight) is dependent on placental amino acid transport, which is impaired in placental malaria-associated intervillositis. Here, we tested the hypothesis that mechanistic target of rapamycin (mTOR) signaling, a pathway known to regulate amino acid transport, is inhibited in placental malaria-associated intervillositis, contributing to lower birthweight. METHODS: We determined the link between intervillositis, mTOR signaling activity, and amino acid uptake in tissue biopsies from both uninfected placentas and malaria-infected placentas with and without intervillositis, and in an in vitro model using primary human trophoblast (PHT) cells. RESULTS: We demonstrated that (1) placental mTOR activity is lower in cases of placental malaria with intervillositis, (2) placental mTOR activity is negatively correlated with the degree of inflammation, and (3) inhibition of placental mTOR activity is associated with reduced placental amino acid uptake and lower birthweight. In PHT cells, we showed that (1) inhibition of mTOR signaling is a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake and (2) constitutive mTOR activation partially restores amino acid uptake. CONCLUSIONS: Our data support the concept that inhibition of placental mTOR signaling constitutes a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake, which may contribute to lower birthweight. Restoring placental mTOR signaling in placental malaria may increase birthweight and improve neonatal survival, representing a new potential therapeutic approach

Corticotropin-releasing hormone as the homeostatic rheostat of feto-maternal symbiosis and developmental programming In utero and neonatal life

A balanced interaction between the homeostatic mechanisms of mother and the devel- oping organism during pregnancy and in early neonatal life is essential in order to ensure optimal fetal development, ability to respond to various external and internal challenges, protection from adverse programming, and safeguard maternal care availability after parturition. In the majority of pregnancies, this relationship is highly effective resulting in successful outcomes. However, in a number of pathological settings, perturbations of the maternal homeostasis disrupt this symbiosis and initiate adaptive responses with unpre- dictable outcomes for the fetus or even the neonate. This may lead to development of pathological phenotypes arising from developmental reprogramming involving interaction of genetic, epigenetic, and environmental-driven pathways, sometimes with acute conse- quences (e.g., growth impairment) and sometimes delayed (e.g., enhanced susceptibility to disease) that last well into adulthood. Most of these adaptive mechanisms are activated and controlled by hormones of the hypothalamo-pituitary adrenal axis under the influ- ence of placental steroid and peptide hormones. In particular, the hypothalamic peptide corticotropin-releasing hormone (CRH) plays a key role in feto-maternal communication by orchestrating and integrating a series of neuroendocrine, immune, metabolic, and behavioral responses. CRH also regulates neural networks involved in maternal behavior and this determines efficiency of maternal care and neonate interactions. This review will summarize our current understanding of CRH actions during the perinatal period, focusing on the physiological roles for both mother and offspring and also how external challenges can alter CRH actions and potentially impact on fetus/neonate health

Diet Enriched with Olive Oil Attenuates Placental Dysfunction in Rats with Gestational Diabetes Induced by Intrauterine Programming

Scope: Offspring from rats with mild diabetes develop gestational diabetes mellitus (GDM). We tested the hypothesis that an olive oil-supplemented diet attenuates placental oxidative stress/inflammation, activation of mTOR signaling, and inhibition of peroxisome proliferator-activated receptor γ (PPARγ) and fetal overgrowth in GDM offspring from mild diabetic rats. Methods and results: Female offspring from rats with mild diabetes (group that developed GDM) and controls were fed with either a standard diet or a 6% olive oil-supplemented diet during pregnancy. On day 21 of pregnancy, plasma glucose levels in mothers and fetuses were increased in the GDM group independently of the diet. Fetal overgrowth and activation of placental mTOR signaling were partially prevented in the olive oil-treated GDM group. Placental PPARγ protein expression was decreased in GDM rats, independently of the diet. However, increases in placental lipoperoxidation, connective tissue growth factor, and matrix metalloproteinase 2 levels were prevented by the olive oil-enriched diet. Conclusion: Diets enriched with olive oil attenuate placental dysfunction and fetal overgrowth in rats with GDM induced by intrauterine programming.Fil: Capobianco, Evangelina Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Gomez Ribot, Dalmiro Leonardo Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Fornes, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Powell, Theresa L.. Universidad de Colorado, Denver; Estados UnidosFil: Levieux, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Jansson, Thomas. State University of Colorado at Boulder; Estados UnidosFil: Jawerbaum, Alicia Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

The Problem with Using the Birthweight: Placental Weight Ratio as a Measure of Placental Efficiency

Introduction The ratio of birthweight to placental weight (BW:PW) is often used as a measure of placental efficiency in humans and animals. However, ratios have properties that are known to lead to spurious results. An alternative approach is the use of residuals from regression, which reflect whether birthweight is higher or lower than expected for a given placental weight, given the population pattern. We hypothesized that biologically meaningful measures of placental efficiency would differ between placentas with and without pathology, and between adverse and normal perinatal and postnatal outcomes. Methods We examined associations between measures of placental efficiency (BW:PW ratio or residuals) and placental pathology, Apgar scores and infant death using National Collaborative Perinatal Project data (4645 preterm births and 28497 term births). Results BW:PW ratios and residuals were significantly lower in placentas showing pathologies including signs of large infarcts or hemorrhage, although many of these differences were small. Low BW:PW ratios and residuals were also associated with low Apgar scores and increased risk of postnatal death. Whereas residuals were lower in term placentas that appeared immature by microscopic examination, the opposite was true for BW:PW ratios. Conclusion The BW:PW ratio produced an artefact whereby histologically less mature placentas at term appeared to be more “efficient” than mature placentas, illustrating a known problem with the use of ratios. For other traits, residuals generally showed differences between placentas with and without pathology that were as great as those seen with BW:PW ratios, and often showed stronger associations with adverse outcomes. &nbsp

Role of Myeloid Cell-Specific TLR9 in Mitochondrial DNA-Induced Lung Inflammation in Mice

Mitochondrial dysfunction is common in various pathological conditions including obesity. Release of mitochondrial DNA (mtDNA) during mitochondrial dysfunction has been shown to play a role in driving the pro-inflammatory response in leukocytes including macrophages. However, the mechanisms by which mtDNA induces leukocyte inflammatory responses in vivo are still unclear. Moreover, how mtDNA is released in an obese setting has not been well understood. By using a mouse model of TLR9 deficiency in myeloid cells (e.g., macrophages), we found that TLR9 signaling in myeloid cells was critical to mtDNA-mediated pro-inflammatory responses such as neutrophil influx and chemokine production. mtDNA release by lung macrophages was enhanced by exposure to palmitic acid (PA), a major saturated fatty acid related to obesity. Moreover, TLR9 contributed to PA-mediated mtDNA release and inflammatory responses. Pathway analysis of RNA-sequencing data in TLR9-sufficient lung macrophages revealed the up-regulation of axon guidance molecule genes and down-regulation of metabolic pathway genes by PA. However, in TLR9-deficient lung macrophages, PA down-regulated axon guidance molecule genes, but up-regulated metabolic pathway genes. Our results suggest that mtDNA utilizes TLR9 signaling in leukocytes to promote lung inflammatory responses in hosts with increased PA. Moreover, TLR9 signaling is involved in the regulation of axon guidance and metabolic pathways in lung macrophages exposed to PA

FOOD RESOURCE DECISION-MAKING IN A PHILIPPINE PEASANT COMMUNITY

The way peasants make decisions about how to allocate time and household resources and to make food choices is examined. Ecological, demographic, socioeconomic, and cultural contexts of decision-making are presented. Data for this research come from multiple sources: municipal records, a field survey, and a range of ethnographic procedures such as participant observation and key informant interviewing. A number of underlying premises frequently found in studies of peasants served to direct this research. One suggests that peasants are not economically rational. A second suggests that transnational corporations contribute to the increasing ecological deterioration and progressive impoverishment of their host country. A third premise is that agricultural development tends to restrict the range of food choices, resulting in a change in consumption habits and the eventual lowering of nutritional status. Data from this research indicate that the peasants in Alae, Mantibugao and MENZI choose among alternatives in order to maximize economic benefits under the constraining environmental and socioeconomic circumstances. They set higher priorities on security rather than profit-maximization. Independent small farmers express priorities in production technology, distribution strategies and food consumption practices. Plantation workers express priorities in terms of choice of occupation. Differences between and within groups are evident. Independent small farmers and plantation workers differ in demographic characteristics, scales of priorities and quantity and quality of food intake. Within each group, members can be internally differentiated according to size of landholding, number of alternative sources of income and psychological factors such as attitudes, perceptions, motivations and values. This study concludes that there are causal links between structural dissimilarities and degree of integration to plantation economy, on one hand, and the way independent small farmers and plantation workers manage their food resources and allocate their time and household budget, on the other hand

NUTRITIONAL QUALITY AND PROTEIN FRACTIONS OF MODIFIED OPAQUE-2 MAIZE WITHVARYING PROTEIN AND LYSINE CONTENTS.

Abstract not availabl

Placental mTOR signaling and fetal growth restriction in placental malaria

© 2017 Dr. Kris Genelyn Bernardino DimasuayBackground: Low birthweight is a major global health issue contributing to about 70% of all neonatal deaths. Malaria in pregnancy is a leading cause of low birthweight responsible for ~900,000 low birthweight deliveries and ~200,000 infant deaths annually. Placental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone. In malaria-endemic regions, almost 50% of all low birthweight cases are attributed to fetal growth restriction. The underlying mechanisms of fetal growth restriction in placental malaria are still unknown but a study implicated impaired placental amino acid transport in placenta malaria-associated intervillositis. Fetal growth is highly dependent on placental amino acid transport. Placental mechanistic target of rapamycin (mTOR) signaling is a nutrient sensing pathway that regulates the expression and activity of amino acid transporters in the syncytiotrophoblast, the nutrient transporting epithelium of the placenta. Decreased placental mTOR signaling has been associated with reduced activity of placental amino acid transporters that lead to decreased fetal growth in animal models and human cases. Here, the present study investigated the potential role of placental mTOR signaling in the pathogenesis of fetal growth restriction in placental malariaassociated intervillositis by putting emphasis on reduced amino acid uptake. Also, the present study investigated the possible contribution of placental autophagy, a process negatively regulated by mTOR, to alter amino acid uptake in placental malariaassociated intervillositis. Methods: Placental villous tissue biopsies sampled at delivery from Malawian women were grouped into uninfected placentas (n = 17) and placental malaria without (n = 7) and with (n = 14) intervillositis. Western blotting was done to quantify levels of expression of mTOR downstream targets (rps6, 4EBP-1 and Akt) and autophagic markers (LC3-II:LC3-I ratio, Rab7, ATG4B and p62). Immunofluorescence staining coupled with image analysis were used to quantify the density of autophagosomes (LC3B puncta), lysosomes (LAMP1 puncta), and their colocalization in the syncytiotrophoblast. In addition, an in vitro model of placental malaria-associated intervillositis was developed, using trophoblast cells and monocyte-malaria infected red blood cell co-cultures, to establish mTOR signaling as a mechanistic link between placental malaria-associated intervillositis and reduced amino acid uptake. Results: The first study provided evidence that 1) placental mTOR activity is lower in cases of placental malaria with intervillositis; and 2) decreased placental mTOR activity is associated with reduced placental amino acid uptake and lower birthweight. Using the trophoblast cell in vitro model, it was demonstrated that 1) placental mTOR signaling is a possible mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake; and 2) constitutive mTOR activation partially restores amino acid uptake. These results suggest that placental mTOR signaling inhibition mediates the decrease in amino acid uptake in placental malariaassociated intervillositis. The second study provided evidence that 1) decreased placental mTOR activity (such as we found in placental malaria with intervillositis) is associated with increased autophagosome formation; 2) there were more LC3B and LAMP1 puncta in the syncytiotrophoblast from women with placental malaria with intervillositis, although there was no biologically relevant increase in colocalization of these different puncta; and 3) expression of Rab7, a protein that mediates autophagosome and lysosome fusion, was lower in placental malaria with intervillositis. These results seem to indicate a block in the late stage of autophagy. Conclusion: This thesis provides strong support for the hypothesis that inhibition of placental mTOR signaling mechanistically links inflammation in placental malaria and reduced placental amino acid uptake and this may contribute to the pathogenesis of fetal growth restriction in placental malaria. Furthermore, this thesis demonstrated the detrimental impact of placental malaria-associated intervillositis on placental autophagy. Dysregulated placental autophagy could negatively affect amino acid uptake and could worsen placental inflammation, and thereby may also contribute to the pathogenesis of fetal growth restriction. There is an urgent need to identify mechanisms linking placental malaria to LBW. The work presented in this thesis will facilitate the development of interventions aimed at minimizing the effect of malaria on birthweight that could be used to complement existing malaria control measures. Interventions involving possible mTOR agonists may enhance placental nutrient uptake, which could improve fetal growth and pregnancy outcomes in women with malaria