The activity and inhibition of the food vacuole plasmepsin from the rodent malaria parasite Plasmodium chabaudi

Funding Information: This work received financial support from the Biotechnology and Biological Sciences Research Council (DW), the British Council Treaty of Windsor Anglo-Portuguese Joint Research Programme (CB & AD) and by FCT/POCTI/FEDER, Project PROTINIB, POCTI/43637/99 (TM & AD).The rodent malaria parasite Plasmodium chabaudi encodes one food vacuole plasmepsin - the aspartic proteinases important in haemoglobin degradation. A recombinant form of this enzyme was found to cleave a variety of peptide substrates and was susceptible to a selection of naturally occurring and synthetic inhibitors, displaying an inhibition profile distinct from that of aspartic proteinases from other malaria parasites. In addition, inhibitors of HIV proteinase that kill P. chabaudi in vivo were also inhibitors of this new plasmepsin. P. chabaudi is a widely used model for human malaria species and, therefore, the characterisation of this plasmepsin is an important contribution towards understanding its biology.publishersversionpublishe

Vastus medialis cross-sectional area is positively associated with patella cartilage and bone volumes in a pain-free community-based population

INTRODUCTION: Although vastus medialis and lateralis are important determinants of patellofemoral joint function, their relationship with patellofemoral joint structure is unknown. The aim of this study was to examine potential determinants of vastus medialis and lateralis cross-sectional areas and the relationship between the cross-sectional area and patella cartilage and bone volumes. METHODS: Two hundred ninety-seven healthy adult subjects had magnetic resonance imaging of their dominant knee. Vastus medialis and lateralis cross-sectional areas were measured 37.5 mm superior to the quadriceps tendon insertion at the proximal pole of the patella. Patella cartilage and bone volumes were measured from these images. Demographic data and participation in vigorous physical activity were assessed by questionnaire. RESULTS: The determinants of increased vastus medialis and lateralis cross-sectional areas were older age (P <or= 0.002), male gender (P < 0.001), and greater body mass index (P <or= 0.07). Participation in vigorous physical activity was positively associated with vastus medialis cross-sectional area (regression coefficient [beta] 90.0; 95% confidence interval [CI] 38.2, 141.7) (P < 0.001) but not with vastus lateralis cross-sectional area (beta 10.1; 95% CI -18.1, 38.3) (P = 0.48). The cross-sectional area of vastus medialis only was positively associated with patella cartilage volume (beta 0.6; 95% CI 0.23, 0.94) (P = 0.001) and bone volume (beta 3.0; 95% CI 1.40, 4.68) (P < 0.001) after adjustment for potential confounders. CONCLUSIONS: Our results in a pain-free community-based population suggest that increased cross-sectional area of vastus medialis, which is associated with vigorous physical activity, and increased patella cartilage and bone volumes may benefit patellofemoral joint health and reduce the long-term risk of patellofemoral pathology

Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue

Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue

Something Smells Fishy: How Lipid Mediators Impact the Maternal–Fetal Interface and Neonatal Development

Normal pregnancy relies on inflammation for implantation, placentation, and parturition, but uncontrolled inflammation can lead to poor maternal and infant outcomes. Maternal diet is one modifiable factor that can impact inflammation. Omega-3 and -6 fatty acids obtained through the diet are metabolized into bioactive compounds that effect inflammation. Recent evidence has shown that the downstream products of omega-3 and -6 fatty acids may influence physiology during pregnancy. In this review, the current knowledge relating to omega-3 and omega-6 metabolites during pregnancy will be summarized

Something Smells Fishy: How Lipid Mediators Impact the Maternal-Fetal Interface and Neonatal Development

Normal pregnancy relies on inflammation for implantation, placentation, and parturition, but uncontrolled inflammation can lead to poor maternal and infant outcomes. Maternal diet is one modifiable factor that can impact inflammation. Omega-3 and -6 fatty acids obtained through the diet are metabolized into bioactive compounds that effect inflammation. Recent evidence has shown that the downstream products of omega-3 and -6 fatty acids may influence physiology during pregnancy. In this review, the current knowledge relating to omega-3 and omega-6 metabolites during pregnancy will be summarized

Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth

Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography-tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman\u27s correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (\u3e30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value \u3c 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes

Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth

Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography–tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman’s correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (\u3e30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value \u3c 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes

Intrauterine Transfer of Polyunsaturated Fatty Acids in Mother–Infant Dyads as Analyzed at Time of Delivery

Polyunsaturated fatty acids (PUFAs) are essential for fetal development, and intrauterine transfer is the only supply of PUFAs to the fetus. The prevailing theory of gestational nutrient transfer is that certain nutrients (including PUFAs) may have prioritized transport across the placenta. Numerous studies have identified correlations between maternal and infant fatty acid concentrations; however, little is known about what role maternal PUFA status may play in differential intrauterine nutrient transfer. Twenty mother–infant dyads were enrolled at delivery for collection of maternal and umbilical cord blood, and placental tissue samples. Plasma concentrations of PUFAs were assessed using gas chromatography (GC-FID). Intrauterine transfer percentages for each fatty acid were calculated as follows: ((cord blood fatty acid level/maternal blood fatty acid level) × 100). Kruskal–Wallis tests were used to compare transfer percentages between maternal fatty acid tertile groups. A p-value \u3c 0.05 was considered significant. There were statistically significant differences in intrauterine transfer percentages of arachidonic acid (AA) (64% vs. 65% vs. 45%, p = 0.02), eicosapentaenoic acid (EPA) (41% vs. 19% vs. 17%, p = 0.03), and total fatty acids (TFA) (27% vs. 26% vs. 20%, p = 0.05) between maternal plasma fatty acid tertiles. Intrauterine transfer percentages of AA, EPA, and TFA were highest in the lowest tertile of respective maternal fatty acid concentration. These findings may indicate that fatty acid transfer to the fetus is prioritized during gestation even during periods of maternal nutritional inadequacy