Foetal glutamate as a possible precursor of placental glutamine in the guinea pig.
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ABSTRACT:
SUBMITTER: Bloxam DL
PROVIDER: S-EPMC1163262 | biostudies-other | 1981 Aug
REPOSITORIES: biostudies-other
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Project description:1. The pathways and the fate of glutamate carbon and nitrogen were investigated in isolated guinea-pig kidney-cortex tubules. 2. At low glutamate concentration (1 mM), the glutamate carbon skeleton was either completely oxidized or converted into glutamine. At high glutamate concentration (5 mM), glucose, lactate and alanine were additional products of glutamate metabolism. 3. At neither concentration of glutamate was there accumulation of ammonia. 4. Nitrogen-balance calculations and the release of 14CO2 from L-[1-14C]glutamate (which gives an estimation of the flux of glutamate carbon skeleton through alpha-oxoglutarate dehydrogenase) clearly indicated that, despite the absence of ammonia accumulation, glutamate metabolism was initiated by the action of glutamate dehydrogenase and not by transamination reactions as suggested by Klahr, Schoolwerth & Bourgoignie [(1972) Am. J. Physiol. 222, 813-820] and Preuss [(1972) Am. J. Physiol. 222, 1395-1397]. Additional evidence for this was obtained by the use of (i) amino-oxyacetate, an inhibitor of transaminases, which did not decrease glutamate removal, or (ii) L-methionine DL-sulphoximine, an inhibitor of glutamine synthetase, which caused an accumulation of ammonia from glutamate. 5. Addition of NH4Cl plus glutamate caused an increase in both glutamate removal and glutamine synthesis, demonstrating that the supply of ammonia via glutamate dehydrogenase is the rate-limiting step in glutamine formation from glutamate. NH4Cl also inhibited the flux of glutamate through glutamate dehydrogenase and the formation of glucose, alanine and lactate. 6. The activities of enzymes possibly involved in the glutamate conversion into pyruvate were measured in guinea-pig renal cortex. 7. Renal arteriovenous-difference measurements revealed that in vivo the guinea-pig kidney adds glutamine and alanine to the circulating blood.
| S-EPMC1161972 | biostudies-other
Project description:Several neurodegenerative diseases are linked to expanded repeats of glutamine residues, which lead to the formation of amyloid fibrils and neuronal death. The length of the repeats correlates with the onset of Huntington's disease, such that healthy individuals have <38 residues and individuals with >38 repeats exhibit symptoms. Because it is difficult to obtain atomic-resolution structural information for poly(l-glutamine) (polyQ) in aqueous solution experimentally, we performed molecular dynamics simulations to investigate the conformational behavior of this homopolymer. In simulations of 20-, 40-, and 80-mer polyQ, we observed the formation of the "alpha-extended chain" conformation, which is characterized by alternating residues in the alpha(L) and alpha(R) conformations to yield a sheet. The structural transition from disordered random-coil conformations to the alpha-extended chain conformation exhibits modest length and temperature dependence, in agreement with the experimental observation that aggregation depends on length and temperature. We propose that fibril formation in polyQ may occur through an alpha-sheet structure, which was proposed by Pauling and Corey. Also, we propose an atomic-resolution model of how the inhibitory peptide QBP1 (polyQ-binding peptide 1) may bind to polyQ in an alpha-extended chain conformation to inhibit fibril formation.
| S-EPMC1224618 | biostudies-literature
Project description:Fetal growth restriction (FGR) is a significant risk factor for stillbirth, neonatal complications and adulthood morbidity. Compared with those of appropriate weight for gestational age (AGA), FGR babies have smaller placentas with reduced activity of amino acid transporter systems A and L, thought to contribute to poor fetal growth. The amino acids glutamine and glutamate are essential for normal placental function and fetal development; whether transport of these is altered in FGR is unknown. We hypothesised that FGR is associated with reduced placental glutamine and glutamate transporter activity and expression, and propose the mammalian target of rapamycin (mTOR) signaling pathway as a candidate mechanism. FGR infants [individualised birth weight ratio (IBR) < 5th centile] had lighter placentas, reduced initial rate uptake of 14C-glutamine and 14C-glutamate (per mg placental protein) but higher expression of key transporter proteins (glutamine: LAT1, LAT2, SNAT5, glutamate: EAAT1) versus AGA [IBR 20th-80th]. In further experiments, in vitro exposure to rapamycin inhibited placental glutamine and glutamate uptake (24 h, uncomplicated pregnancies) indicating a role of mTOR in regulating placental transport of these amino acids. These data support our hypothesis and suggest that abnormal glutamine and glutamate transporter activity is part of the spectrum of placental dysfunction in FGR.
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Project description:Lipid synthesis as measured by the incorporation of acetate or 3H2O into slices of foetal liver, is much higher than in slices of adult liver and shows a peak at about two-thirds of gestation. At this time the synthesis from glucose was low and reached a peak 10 days later. The changes in the activity of ATP citrate lyase, which mirrored acetate incorporation, and the effect of glucose and pyruvate on acetate corporation into lipid suggests that some of the lipid synthesis occurs via intramitochondrial acetyl-CoA production from acetate. Despite this, lipid synthesis was not inhibited by (-)-hydroxycitrate. The low rate of synthesis from glucose at two-thirds of gestation is ascribed to the low activity of pyruvate carboxylase at this time and a role for a phosphoenolpyruvate carboxykinase in providing oxaloacetate for lipogenesis is proposed. The activity of fatty acid synthetase broadly agreed with the changes in lipid synthesis, whereas the activity of acetyl-CoA carboxylase was barely sufficient to account for the rates of lipid synthesis in vivo. Acetate and short-chain fatty acids are likely to be the major precursors for lipid synthesis in vivo.
| S-EPMC1172686 | biostudies-other
Project description:Human cytomegalovirus (HCMV) infects the placenta, and these placental infections can cause fetal injury and/or demise. The timing of maternal HCMV infection during pregnancy is a determinant of fetal outcomes, but how development affects the placenta's susceptibility to infection, the likelihood of placental injury post-infection, and the frequency of transplacental HCMV transmission remains unclear. In this study, guinea pig cytomegalovirus (GPCMV) was used to model primary maternal infection and compare the effects of infection at two different times on the placenta. When guinea pigs were infected with GPCMV at either 21- or 35-days gestation (dGA), maternal and placental viral loads, as determined by droplet digital PCR, were not significantly affected by the timing of maternal infection. However, when the transcriptomes of gestational age-matched GPCMV-infected and control placentas were compared, significant infection-associated changes in gene expression were only observed after maternal infection at 35 dGA. Notably, transcripts associated with immune activation (e.g. Cxcl10, Ido1, Tgtp1, and Tlr8) were upregulated in the infected placenta. A GPCMV-specific in situ hybridization assay detected rare infected cells in the main placenta after maternal infection at either time, and maternal infection at 35 dGA also caused large areas of GPCMV-infected cells in the junctional zone. As GPCMV infection after mid-gestation is known to cause high rates of stillbirth and/or fetal growth restriction, our results suggest that the placenta becomes sensitized to infection-associated injury late in gestation, conferring an increased risk of adverse pregnancy outcomes after cytomegalovirus infection.
| S-EPMC8239309 | biostudies-literature
Project description:1. Glutamine was found to be the main carbon and nitrogen product of the metabolism of aspartate in isolated guinea-pig kidney-cortex tubules. Glutamate, ammonia and alanine were only minor products. 2. Carbon-balance calculations and the release of 14CO2 from [U-14C]aspartate indicate that oxidation of the aspartate carbon skeleton occurred. 3. A pathway involving aspartate aminotransferase, glutamate dehydrogenase, glutamine synthetase, phosphoenolpyruvate carboxykinase, pyruvate kinase, pyruvate dehydrogenase and enzymes of the tricarboxylic acid cycle is proposed for the conversion of aspartate into glutamine. 4. Evidence for this pathway was obtained by: (i) inhibiting aspartate removal by amino-oxyacetate, an inhibitor of transaminases, (ii) the use of methionine sulphoximine, an inhibitor of glutamine synthetase, which induced a large increase in ammonia release from aspartate, (iii) the use of quinolinate, an inhibitor of phosphoenolpyruvate carboxykinase, which inhibited glutamine synthesis from aspartate, (iv) the use of alpha-cyano-4-hydroxycinnamate, an inhibitor of the mitochondrial transport of pyruvate, which caused an accumulation of pyruvate from aspartate, and (v) the use of fluoroacetate, an inhibitor of aconitase, which inhibited glutamine synthesis with concomitant accumulation of citrate from aspartate.
| S-EPMC1131451 | biostudies-other
Project description:Neuronal activity is accompanied by transmembranous ion fluxes that cause cell volume changes. In whole mounts of the guinea pig retina, application of glutamate resulted in fast swelling of neuronal cell bodies in the ganglion cell layer (GCL) and the inner nuclear layer (INL) (by approximately 40%) and a concomitant decrease of the thickness of glial cell processes in the inner plexiform layer (IPL) (by approximately 40%) that was accompanied by an elongation of the glial cells, by a thickening of the whole retinal tissue, and by a shrinkage of the extracellular space (by approximately 18%). The half-maximal effect of glutamate was observed at approximately 250 mum, after approximately 4 min. The swelling was caused predominantly by AMPA-kainate receptor-mediated influx of Na+ into retinal neurons. Similar but transient morphological alterations were induced by high K+ and dopamine, which caused release of endogenous glutamate and subsequent activation of AMPA-kainate receptors. Apparently, retinal glutamatergic transmission is accompanied by neuronal cell swelling that causes compensatory morphological alterations of glial cells. The effect of dopamine was elicitable only during light adaptation but not in the dark, and glutamate and high K+ induced strong ereffects in the dark than in the light. This suggests that not only the endogenous release of dopamine but also the responsiveness of glutamatergic neurons to dopamine is regulated by light-dark adaptation. Similar morphological alterations (neuronal swelling and decreased glial process thickness) were observed in whole mounts isolated immediately after experimental retinal ischemia, suggesting an involvement of AMPA-kainate receptor activation in putative neurotoxic cell swelling in the postischemic retina.
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Project description:Antioxidant defences are comparatively low during foetal development making the brain particularly susceptible to oxidative stress during antioxidant deficiencies. The brain is one of the organs containing the highest concentration of vitamin C (VitC) and VitC deficiency during foetal development may place the brain at risk of redox status imbalance. In the present study, we investigated the developmental pattern and effect of VitC deficiency on antioxidants, vitamin E and superoxide dismutase (SOD), assessed oxidative damage by measuring malondialdehyde (MDA), hydroxynonenal (HNE) and nitrotyrosine (NT) and analysed gene and protein expression of apoptosis marker caspase-3 in the guinea pig foetal brain at two gestational (GD) time points, GD 45/pre-term and GD 56/near term following either a VitC sufficient (CTRL) or deficient (DEF) maternal dietary regime. We show that except for SOD, antioxidants and oxidative damage markers are differentially expressed between the two GDs, with high VitC (p<0.0001), NT modified proteins (p<0.0001) and active caspase-3 levels (p<0.05) at pre-term and high vitamin E levels (p<0.0001), HNE (p<0.0001) and MDA (p<0.0001) at near term. VitC deficiency significantly increased SOD activity (p<0.0001) compared to CTRLs at both GDs indicating a compensatory response, however, low levels of VitC significantly elevated MDA levels (p<0.05) in DEF at near term. Our results show a differential regulation of the investigated markers during late gestation and suggest that immature brains are susceptible to oxidative stress due to prenatal vitC deficiency in spite of an induction of protective adaptation mechanisms.
| S-EPMC3926113 | biostudies-literature
Project description:The rate of lipid biosynthesis in vivo was determined in pregnant guinea pigs after maternal and foetal injections of 3H2O. Synthesis in the maternal tissues was low and in the foetal liver and adipose tissues relatively high. In the foetal liver it reached a peak at about two-thirds of gestation, whereas that in the foetal adipose tissue occurred later. These results were used to support the view that lipid synthesis in the foetal guinea-pig liver at two-thirds of gestation is largely from short-chain fatty acids, whereas in foetal adipose tissue glucose is probably the major substrate.
| S-EPMC1172687 | biostudies-other
Project description:1. Lysosome-rich fractions were obtained from foetal liver tissues as early as 35 days uterine age. Foetal lysosomes showed the same ;structure-linked latency' and acid hydrolytic potentiality characteristic of their adult counterparts. 2. The osmotic stability of lysosome-rich fraction from foetal guinea-pig liver tissue was greater than that of the corresponding adult lysosome fractions, p-nitrophenyl-phosphatase being used as marker enzyme. 3. The observation was confirmed by using beta-glycerophosphatase and phenolphthalein beta-glucuronidase as alternative marker enzymes. p-Nitrophenyl phosphate and beta-glycerophosphate appear to act as substrates for the same enzyme. 4. By using p-nitrophenylphosphatase activity measurements it was shown that the osmotic stability of foetal lysosomal fractions decreased with increasing foetal age, but at no time achieved the degree of osmotic instability characteristic of adult lysosomal fractions. 5. The correlation of these findings with the intracellular environment of lysosomes is discussed.
| S-EPMC1187570 | biostudies-other