The conversion of orotic acid into uridine 5'-monophosphate by isolated perfused normal and regenerating rat livers.
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ABSTRACT:
SUBMITTER: Fausto N
PROVIDER: S-EPMC1174226 | biostudies-other | 1972 Oct
REPOSITORIES: biostudies-other
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Project description:Hereditary orotic aciduria (HOA) is a very rare inborn error of pyrimidine metabolism. It results from a defect of the uridine-5-monophosphate synthase (UMPS) gene. To date, only about twenty patients have been described. We report a case of HOA with a novel variant in the UMPS gene. A 17-year-old Emirati girl was born to first-cousin parents. During the first year, she had recurrent, severe infections including disseminated varicella. After evaluation for immunodeficiency, an impression of immunodeficiency of unknown etiology was presumed. Frequent episodes of pancytopenia were also noted. Bone marrow biopsy showed trilineage megaloblastoid maturation with dysplastic changes that were refractory to hematinic therapy. Also, she was noted to have failure to thrive, developmental delay and epilepsy. She was referred to the Genetics clinic where whole-exome sequencing (WES) was done and showed a novel homozygous variant in the UMPS gene confirming a diagnosis of HOA. She was started on uridine triacetate after which she showed clinical, hematologic and biochemical improvement. Although extremely rare, hereditary orotic aciduria should be suspected in any child with megaloblastic bone marrow, immunodeficiency or when developmental delay and anemia coexist.
| S-EPMC7807243 | biostudies-literature
Project description:Background and purposePurinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up(4)A) as a novel and highly potent endothelial-derived contracting factor. Up(4)A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X(1) receptor activation. However, other purinoceptors are also involved and were analysed here.Experimental approachThe rat isolated perfused kidney was used to characterize vasoactive actions of Up(4)A.Key resultsAfter desensitization of the P2X(1) receptor by ?,?-methylene ATP (?,?-meATP), Up(4)A showed dose-dependent P2Y(2)-mediated vasoconstriction. Continuous perfusion with Up(4)A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X(1) receptor desensitization. In addition, there is a long-lasting P2Y(2)-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up(4)A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X(1) receptor desensitization by ?,?-meATP, and the remaining P2Y(2)-mediated vasoconstriction was only inhibited by suramin. The Up(4)A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y(1) and P2Y(2) receptor activation.Conclusions and implicationsUp(4)A activated P2X(1) and P2Y(2) receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y(1/2) receptor activation. Up(4)A might be of relevance in the physiology and pathophysiology of vascular tone regulation.
| S-EPMC2990153 | biostudies-literature
Project description:1. At 1h after operation livers from partially hepatectomized rats showed a 60-100% increase in the capacity to concentrate (3)H radioactivity from orotate, thymidine or uridine with respect to the radioactivity in plasma. Uptake of [(3)H]cytidine into liver was unaffected, as was entry of any precursor studied into any tissue other than liver. 2. This increase in intracellular radioactivity was detectable 10min after operation with both orotate and thymidine. With orotate the augmentation had disappeared by 3 days, but with thymidine it was still evident 8 days after partial hepatectomy, when [(3)H]thymidine incorporation into DNA was no longer increased. Competition studies established that orotate was not entering the liver by the same mechanism as thymidine. 3. In the soluble fraction of the liver all the (3)H radioactivity from orotate was present as uridine nucleotides. Thymidine was not phosphorylated, and was believed to be catabolized.
| S-EPMC1177558 | biostudies-other
Project description:Isolated liver perfusion systems have been used to characterize intrinsic metabolic changes in liver as a result of various perturbations, including systemic injury, hepatotoxin exposure, and warm ischemia. Most of these studies were done using hyperoxic conditions (95% O(2)) but without the use of oxygen carriers in the perfusate. Prior literature data do not clearly establish the impact of oxygenation, and in particular that of adding oxygen carriers to the perfusate, on the metabolic functions of the liver. Therefore, herein the effects of oxygen delivery in the perfusion system on liver metabolism were investigated by comparing three modes of oxygenation. Rat livers were perfused via the portal and hepatic veins at a constant flow rate of 3 mL/min/g liver in a recirculating perfusion system. In the first group, the perfusate was equilibrated in a membrane oxygenator with room air (21% O(2)) before entering the liver. In the second group, the perfusate was equilibrated with a 95% O(2)/5% CO(2) gas mixture. In the third group, the perfusate was supplemented with washed bovine red blood cells (RBCs) at 10% hematocrit and also equilibrated with the 95% O(2)/5% CO(2) gas mixture. Oxygen and CO(2) gradients across the liver were measured periodically with a blood gas analyzer. The rate of change in the concentration of major metabolites in the perfusate was measured over time. Net extracellular fluxes were calculated from these measurements and applied to a stoichiometric-based optimization problem to determine the intracellular fluxes and active pathways in the perfused livers. Livers perfused with RBCs consumed oxygen at twice the rate observed using hyperoxic (95% O(2)) perfusate without RBCs, and also produced more urea and ketone bodies. At the flow rate used, the oxygen supply in perfusate without RBCs was just sufficient to meet the average oxygen demand of the liver but would be insufficient if it increased above baseline, as is often the case in response to environmental perturbations. Metabolic pathway analysis suggests that significant anaerobic glycolysis occurred in the absence of RBCs even using hyperoxic perfusate. Conversely, when RBCs were used, glucose production from lactate and glutamate, as well as pathways related to energy metabolism were upregulated. RBCs also reversed an increase in PPP fluxes induced by the use of hyperoxic perfusate alone. In conclusion, the use of oxygen carriers is required to investigate the effect of various perturbations on liver metabolism.
| S-EPMC3193557 | biostudies-literature
Project description:Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I, and their glucuronide and sulfate conjugates that can be found in urine and feces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urine using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I, and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules, whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate, whereas the conjugated metabolites are almost exclusively secreted to the urine.
| S-EPMC3276251 | biostudies-literature
Project description:The crystal structure of the title compound, which is also known as vitamin B(13) (systematic name: 2,6-dioxo-1,2,3,6-tetra-hydro-pyrimidine-4-carboxylic acid monohydrate), C(5)H(4)N(2)O(4)·H(2)O, was reported for the first time by Takusagawa & Shimada [Bull. Chem. Soc. Jpn (1973 ▶), 46, 2011-2019]. The present redetermination provides more precise values of the mol-ecular geometry. The asymmetric unit comprises a planar diketo tautomer and a solvent water mol-ecule. In the crystal structure, mol-ecules are connected by O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds involving NH groups, two carbonyl O atoms and the solvent water mol-ecule.
| S-EPMC2961056 | biostudies-literature
Project description:Adeno-associated virus (AAV) vectors generated with five different capsids were intravenously injected into human livers undergoing normothermic machine perfusion (NMP). To assess the tropism of the five AAV vectors in the human livers, single-cell suspensions of hepatocytes and non-parenchymal cells (NPCs) were analyzed by single-cell RNA sequencing (scRNAseq). Differentially expressed genes were identified in AAV vector-transduced hepatocytes and unique cell populations.
2024-11-12 | GSE228000 | GEO
Project description:Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is an essential component of membrane phosphatides and has been implicated in cognitive functions. Low levels of circulating or brain DHA are associated with various neurocognitive disorders including Alzheimer's disease (AD), while laboratory animals, including animal models of AD, can exhibit improved cognitive ability with a diet enriched in DHA. Various cellular mechanisms have been proposed for DHA's behavioral effects, including increases in cellular membrane fluidity, promotion of neurite extension and inhibition of apoptosis. However, there is little direct evidence that DHA affects synaptic structure in living animals. Here we show that oral supplementation with DHA substantially increases the number of dendritic spines in adult gerbil hippocampus, particularly when animals are co-supplemented with a uridine source, uridine-5'-monophosphate (UMP), which increases brain levels of the rate-limiting phosphatide precursor CTP. The increase in dendritic spines (>30%) is accompanied by parallel increases in membrane phosphatides and in pre- and post-synaptic proteins within the hippocampus. Hence, oral DHA may promote neuronal membrane synthesis to increase the number of synapses, particularly when co-administered with UMP. Our findings provide a possible explanation for the effects of DHA on behavior and also suggest a strategy to treat cognitive disorders resulting from synapse loss.
| S-EPMC2140951 | biostudies-literature
Project description:Understanding the intermolecular interactions between nucleotides and artificial receptors is crucial to understanding the role of nucleic acids in living systems. However, direct structural evidence showing precise interactions and bonding features of a nucleoside monophosphate (NMP) with a macrocycle-based synthetic molecule has not been provided so far. Herein, we present two novel crystal structures of uridine monophosphate (UMP) and thymidine monophosphate (TMP) complexes with a macrocycle-based dinuclear receptor. Structural characterization of these complexes reveals that the receptor recognizes UMP through coordinate-covalent interactions with phosphates and π-π stackings with nucleobases and TMP through coordinate-covalent interactions with phosphate groups. Furthermore, the receptor has been shown to effectively bind nucleoside monophosphates in the order of GMP > AMP > UMP > TMP > CMP in water at physiological pH, as investigated by an indicator displacement assay.
| S-EPMC5709781 | biostudies-literature
Project description:Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low-density lipoproteins (VLDL) contain oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL oxylipins. A compartmental model of deuterium-labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several oxylipins by a similar amount (13-HOTrE, 35% [4%,55%], -1.3 nM; 9(10)-EpODE, 29% [3%,49%], -2.0 nM; 15(16)-EpODE, 29% [2%,49%], -1.6 nM; AA-derived diols, 32% [5%,52%], -2.4 nM; 19(20)-DiHDPA, 31% [7%,50%], -1.0 nM). However, the EPA-derived epoxide, 17(18)-EpETE, was decreased by 75% [49%,88%], (-0.52 nM) with LPS, double the suppression of other oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)-EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.
| S-EPMC7903942 | biostudies-literature