Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Charles Dent was one of the first physicians to recognize the teratogenic effects of maternal phenylalanine (Phe) on the fetus in 1956. This article describes the clinical experiences of women with phenylketonuria (PKU) within the unit that was established by Dent in the United Kingdom. Between 1977 and 2002, 79 infants were born to women with PKU. Of the 79, 18 (23%) were conceived while the women were on a normal diet with high blood Phe levels. The mean birth weight was 2.89 kg, and head circumference was 32.8 cm. At 1 year, the mean developmental quotient was 105.5 and at 4 years was 82.3. Four of these infants had congenital heart disease (2 of whom died as a result). In the remaining 61 infants, Phe-restricted diet started before conception. None of them had congenital heart disease. The mean birth weight was 3.23 kg, and head circumference was 34.0 cm. At 1 year, mean developmental quotient was 108.0 and at 4 years was 90.9. They continue to be followed up with additional neuropsychometric assessments at 8 and 14 years of age. This cohort is a proportion of infants who were born to mothers with PKU in the United Kingdom. Between 1978 and 1997, 255 live births were reported. Of these, 56% were conceived on unrestricted diet with subsequently poor outcome. This relatively high rate of conception off PKU diet is likely to reflect the scarcity of medical services for adults with metabolic disorders. We conclude that many features of the maternal PKU syndrome can be prevented but still occur because of the lack of appropriate resources to care for at-risk women. The precise targets for blood Phe and other nutrients during pregnancy are not entirely clear, neither are the reasons that some offspring are spared the harmful effects of Phe. The impact of the postnatal environment in which these infants find themselves requires additional assessment, too.
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PMID:Maternal phenylketonuria: experiences from the United Kingdom. 1465 64

The results of the International Collaborative Study of Maternal phenylketonuria have shown that dietary phenylalanine restriction of women with hyperphenylalaninemia during pregnancy decreases the incidence of mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation in their offspring. The best results are achieved when treatment is initiated before conception. Psychosocial problems are the most pervasive obstacle to the achievement of optimum dietary treatment. Novel, nondietary approaches to the treatment of maternal phenylketonuria are under development.
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PMID:The Maternal Phenylketonuria Project: a summary of progress and challenges for the future. 1465 70

trans-Resveratrol (t-RVT) has been shown to have a wide range of anti-inflammatory properties, some of which have been suggested to contribute to the molecular explanation of the French Paradox, a possible reason for the low incidence of heart disease in France. The ability of t-RVT to inhibit the production of reactive oxygen species (ROS) from monocytes (differentiated U937) was investigated using isoluminol, luminol, lucigenin, and 2',7'-dichlorofluorescein (DCF). t-RVT (0.1-50 microM) was found to significantly inhibit cellular ROS production stimulated by f-Met-Leu-Phe (fMLP), 12-phorbol 13-myristate, and arachidonic acid after a 1-h preincubation. The efficacy of t-RVT could be increased if it was added directly into the assay. NADPH-dependent superoxide production was measured in cell homogenates and t-RVT (10-50 microM) was found to have no effect on this activity. The majority of these redox probes require a peroxidase to be oxidized; therefore, the inhibitory effect of t-RVT on ROS measured by these probes is complicated by its ability to be oxidized by peroxidase enzymes and thus compete with the probe. t-RVT, known to be oxidized by the horseradish peroxidase (HRP)/H(2)O(2) system, was found to inhibit the HRP-dependent oxidation of the fluorescent probe DCF and the chemiluminescent probe isoluminol. However, using a redox probe that did not require oxidation by a peroxidase (lucigenin), significant inhibition was still observed. Moreover, the inhibitory effects of t-RVT on fMLP-induced ROS production correlated with significant inhibitory effects on fMLP-induced phosphatidylinositol 3-kinase (PI3K) activity at 50 microM and Akt phosphorylation (10-50 microM). Other known inhibitors of both PI3K and Akt were also found to inhibit this response. Therefore, inhibition of signaling through the PI3K to NADPH oxidase by t-RVT might represent an important anti-inflammatory mechanism.
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PMID:Inhibition of the respiratory burst by resveratrol in human monocytes: correlation with inhibition of PI3K signaling. 1592 84

More women with phenylketonuria are becoming pregnant and need appropriate management to avoid the effects of raised phenylalanine on the fetus: facial dysmorphism, microcephaly, growth retardation, developmental delay and congenital heart disease. Here we describe our experiences from a single centre gained over almost three decades. A series of six cases is presented to illustrate key points in management. Ideally, phenylalanine-restricted diet is started before conception in a planned fashion, but some women present pregnant and blood phenylalanine must be lowered rapidly. The aims of management are to maintain blood phenylalanine concentration in the target range (100-250 micromol/L) before and throughout the pregnancy, and to ensure adequate maternal nutrition and appropriate weight gain. Blood phenylalanine is monitored twice, three times a week, before and after conception respectively. Weight is monitored on a weekly basis and key micronutrients are monitored every 6-8 weeks in clinic. From the second trimester onwards, dietary phenylalanine intake has to be promptly increased, as phenylalanine tolerance increases rapidly. Postnatal management includes a neurological assessment of the infant at 4-8 weeks and an echocardiogram for infants conceived off diet. Subsequently, offspring are seen at 1 year, 4 years, 8 years and 14 years for neuropsychometric evaluations. Regular follow-up of the mother remains important whether on or off a phenylalanine-restricted diet.
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PMID:A practical approach to maternal phenylketonuria management. 1735 26

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU are caused by mutations in the PAH gene. Untreated PKU is associated with an abnormal phenotype, which includes growth failure, seizures, global developmental delay and severe intellectual impairment. The maternal PKU (MPKU) syndrome is caused by high blood Phe concentrations during pregnancy and presents with serious foetal anomalies, especially microcephaly, congenital heart disease and mental retardation. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. We present the case of a 33-year-old woman who had been diagnosed as having PKU only after a pregnancy with MPKU embryopathy, to emphasize that undiagnosed maternal phenylketonuria still exists. On that ground, we reviewed updated literature on the pathogenesis of this syndrome, possibility of prophylaxis and treatment.
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PMID:Undiagnosed maternal phenylketonuria: own clinical experience and literature review. 1955 60

Elevated phenylalanine (Phe) levels in pregnant women with PKU are teratogenic. Fetal damage due to elevated maternal Phe levels during pregnancy is known as maternal phenylketonuria (MPKU). The risk of birth defects in MPKU, including global developmental delays, microcephaly, congenital heart disease, and low birth weight, can be dramatically reduced by controlling Phe levels during pregnancy (metabolic control). Phe levels should be maintained in the range of 120-360 micromol/L, ideally starting before pregnancy begins (i.e., when planning a pregnancy). If control is not achieved before pregnancy (e.g., if the pregnancy was unplanned), good outcomes are still possible if metabolic control is established by 8 weeks of pregnancy. Unfortunately, metabolic control before and during pregnancy can be poor. As well, many mothers stop treatment after pregnancy, which can decrease the mother's ability to focus on her child and increase her risk of behavioral and psychological problems. This can have a negative effect on the home environment. Many factors affect adherence to the strict diet used to control Phe levels, including poor access to medical care, lack of reimbursement for medical foods (in some regions, such as parts of the United States), practical difficulties with implementing the diet, financial constraints, demographics, and psychosocial issues. A comprehensive treatment approach that begins prior to pregnancy and continues after the infant is born may help to improve the management of MPKU. This approach should include education of girls about MPKU at an early age, interventions to prevent unplanned pregnancies, psychosocial support, improved treatment access and reimbursement for medical foods, and treatment guidelines. Treatments such as sapropterin may also have a role in improving metabolic control during pregnancy.
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PMID:Psychosocial issues and outcomes in maternal PKU. 2012 74

The development and evolution of PKU can be prevented by prescribing an appropriate diet at an early age. A systematic neonatal screening has been set up in most countries. However, young women suffering from PKU give birth to very severely malformed children (PKU embryopathy: microcephaly, mental retardation, hypotrophy, cardiopathy) unless they again take up the specific diet, until the PHE level has lowered down to normal, before the beginning of gestation. The treatment has to be continued at least during the first months of gestation. This management is very unpleasant and sometimes not easily accepted. The mechanism of this embryopathy is still unknown. It is possible that (1) the excess of PHE or the presence of abnormal metabolites, or (2) serotonin deficiency (which is a feature of PKU) could be responsible for the maldevelopment of the embryo. Some authors consider that serontonin has a morphogenetic role in normal embryogenesis. Previously we described an experimental animal model using in vitro culture of rat embryos in human PKU sera. Mouse embryos have been subsequently used, since they show a greater sensitivity. Malformations, consisting essentially of neural tube defects, were present in almost 100% of the embryos cultured in serum from PKU patients. Using this animal model, we tested the hypothesis of serotonin deficiency. For this purpose, mouse embryos were cultured in human serum depleted of serotonin. Under these conditions, 100% of the embryos showed oculo-neural malformations characteristic of the experimental embryopathy. These results indicate the importance of serotonin deficiency in the occurrence of PKU embryopathy.
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PMID:Serotonin deficiency in phenylketonuria embryopathy. 2065 Jan 41

Untreated maternal phenylketonuria (MPKU) is a major cause of microcephaly, congenital heart disease, intrauterine growth retardation and mental retardation in the offspring of mothers who have the disease. There is evidence, however, that dietary restriction of phenylalanine in the mother before conception and throughout the pregnancy will reduce the risk of these congenital anomalies in the fetus. It is important to be alert to this preventable cause of developmental retardation and congenital abnormalities in all pregnancies until the stage is reached where every woman of child-bearing age has been through the neonatal PKU-screening program. Family physicians are advised to consider prenatal or premarital screening for PKU of all female patients of child-bearing age for the next generation.
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PMID:Maternal Phenylketonuria (MPKU). 2126 27

Resveratrol, a polyphenol compound found in grape skins, has been proposed to account for the beneficial effects of red wine against heart disease. To produce resveratrol in Saccharomyces cerevisiae, four heterologous genes were introduced: the phenylalanine ammonia lyase gene from Rhodosporidium toruloides, the cinnamic acid 4-hydroxylase and 4-coumarate:coenzyme A ligase genes both from Arabidopsis thaliana, and the stilbene synthase gene from Arachis hypogaea. When this recombinant yeast was cultivated by batch fermentation in YP medium containing 2% galactose, it produced 2.6 mg/L p-coumaric acid and 3.3 mg/L resveratrol. In order to increase the pool of malonyl-CoA, a key precursor in resveratrol biosynthesis, the acetyl-CoA carboxylase (ACC1) gene was additionally overexpressed in the yeast by replacing the native promoter of the ACC1 gene with the stronger GAL1 promoter and this resulted in enhanced production of resveratrol (4.3 mg/L). Furthermore, when tyrosine was supplemented in the medium, the concentration of resveratrol increased up to 5.8 mg/L. This result illustrates a possible strategy for developing metabolically engineered yeast strain for the economical production of resveratrol from cheap amino acids.
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PMID:Production of resveratrol from tyrosine in metabolically engineered Saccharomyces cerevisiae. 2288 55

Equilibrative nucleoside transporters are a unique family of proteins that enable uptake of nucleosides/nucleobases into a wide range of eukaryotes and internalize a myriad of drugs used in the treatment of cancer, heart disease, AIDs, and parasitic infections. In previous work we generated a structural model for such a transporter, the LdNT1.1 nucleoside permease from the parasitic protozoan Leishmania donovani, using ab initio computation. The model suggested that aromatic residues present in transmembrane helices 1, 2, and 7 interact to form an extracellular gate that closes the permeation pathway in the inward-open conformation. Mutation of residues Phe-48(TM1) and Trp-75(TM2) abrogated transport activity, consistent with such prediction. In this study cysteine mutagenesis and oxidative cross-linking were combined to analyze proximity relationships of helices 1, 2, and 7 in LdNT1.1. Disulfide bond formation between introduced paired cysteines at the interface of such helices (A61C(TM1)/F74C(TM2), A61C(TM1)/G350C(TM7), and F74C(TM2)/G350C(TM7)) was analyzed by transport measurement and gel mobility shifts upon oxidation with Cu (II)-(1,10-phenanthroline)(3). In all cases cross-linking inhibited transport. However, if LdNT1.1 ligands were included during cross-linking, inhibition of transport was reduced, suggesting that ligands moved the three gating helices apart. Moreover, all paired cysteine mutants exhibited a mobility shift upon oxidation, corroborating the formation of a disulfide bond. These data support the notion that helices 1, 2, and 7 constitute the extracellular gate of LdNT1.1, thus further validating the computational model and the previously demonstrated importance of F48(TM1) and Trp-75(TM2) in tethering together helices that are part of the gate.
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PMID:Cysteine cross-linking defines the extracellular gate for the Leishmania donovani nucleoside transporter 1.1 (LdNT1.1). 2315 Jun 61


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