Biomedical subjects

J Shi

Publications and source records attributed to J Shi.

At least 19 recordsLinked to original sources

PubMed2001

Snapshots of catalysis: the structure of fructose-1,6-(bis)phosphate aldolase covalently bound to the substrate dihydroxyacetone phosphate.

Fructose-1,6-bis(phosphate) aldolase is an essential glycolytic enzyme found in all vertebrates and higher plants that catalyzes the cleavage of fructose 1,6-bis(phosphate) (Fru-1,6-P(2)) to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP). Mutations in the aldolase genes in humans cause hemolytic anemia and hereditary fructose intolerance. The structure of the aldolase-DHAP Schiff base has been determined by X-ray crystallography to 2.6 A resolution (R(cryst) = 0.213, R(free) = 0.249) by trapping the catalytic intermediate with NaBH(4) in the presence of Fru-1,6-P(2). This is the first structure of a trapped covalent intermediate for this essential glycolytic enzyme. The structure allows the elucidation of a comprehensive catalytic mechanism and identification of a conserved chemical motif in Schiff-base aldolases. The position of the bound DHAP relative to Asp33 is consistent with a role for Asp33 in deprotonation of the C4-hydroxyl leading to C-C bond cleavage. The methyl side chain of Ala31 is positioned directly opposite the C3-hydroxyl, sterically favoring the S-configuration of the substrate at this carbon. The "trigger" residue Arg303, which binds the substrate C6-phosphate group, is a ligand to the phosphate group of DHAP. The observed movement of the ligand between substrate and product phosphates may provide a structural link between the substrate cleavage and the conformational change in the C-terminus associated with product release. The position of Glu187 in relation to the DHAP Schiff base is consistent with a role for the residue in protonation of the hydroxyl group of the carbinolamine in the dehydration step, catalyzing Schiff-base formation. The overlay of the aldolase-DHAP structure with that of the covalent enzyme-dihydroxyacetone structure of the mechanistically similar transaldolase and KDPG aldolase allows the identification of a conserved Lys-Glu dyad involved in Schiff-base formation and breakdown. The overlay highlights the fact that Lys146 in aldolase is replaced in transaldolase with Asn35. The substitution in transaldolase stabilizes the enamine intermediate required for the attack of the second aldose substrate, changing the chemistry from aldolase to transaldolase.

Animals↗

PubMed2001

Reversibly bound and covalently attached ligands induce conformational changes in the omega loop, Cys69-Cys96, of mouse acetylcholinesterase.

We have used a combination of cysteine substitution mutagenesis and site-specific labeling to characterize the structural dynamics of mouse acetylcholinesterase (mAChE). Six cysteine-substituted sites of mAChE (Leu(76), Glu(81), Glu(84), Tyr(124), Ala(262), and His(287)) were labeled with the environmentally sensitive fluorophore, acrylodan, and the kinetics of substrate hydrolysis and inhibitor association were examined along with spectroscopic characteristics of the acrylodan-conjugated, cysteine-substituted enzymes. Residue 262, being well removed from the active center, appears unaffected by inhibitor binding. Following the binding of ligand, hypsochromic shifts in emission of acrylodan at residues 124 and 287, located near the perimeter of the gorge, reflect the exclusion of solvent and a hydrophobic environment created by the associated ligand. By contrast, the bathochromic shifts upon inhibitor binding seen for acrylodan conjugated to three omega loop (Omega loop) residues 76, 81, and 84 reveal that the acrylodan side chains at these positions are displaced from a hydrophobic environment and become exposed to solvent. The magnitude of fluorescence emission shift is largest at position 84 and smallest at position 76, indicating that a concerted movement of residues on the Omega loop accompanies gorge closure upon ligand binding. Acrylodan modification of substituted cysteine at position 84 reduces ligand binding and steady-state kinetic parameters between 1 and 2 orders of magnitude, but a similar substitution at position 81 only minimally alters the kinetics. Thus, combined kinetic and spectroscopic analyses provide strong evidence that conformational changes of the Omega loop accompany ligand binding.

Acetylcholinesterase↗

PubMed2001

Role of the liver in regulating numbers of circulating neutrophils.

Neutrophils (polymorphonuclear leukocytes [PMNs]) carry potent destructive enzymes that can destroy invasive bacteria or damage normal tissue. PMNs have a half-life of only 6 hours in the blood, but the details of this homeostasis are unknown. In a rat model of endotoxemia, P-selectin was selectively up-regulated in hepatic sinusoids and veins where it was necessary for phagocytosis of PMNs by Kupffer cells in the liver, as opposed to the spleen or the lungs. Apoptotic PMNs appeared in the lungs and spleen only after inactivation of Kupffer cells by gadolinium chloride (GdCl(3)). Blocking of Fas protein reduced the number of apoptotic cells in the liver; binding of annexin V to phosphatidylserine (PS) reduced the number of PMNs phagocytosed by Kupffer cells. The results support a clearance pathway in which apoptosis and phagocytosis are effected by Kupffer cells after P-selectin-mediated sequestration. (Blood. 2001;98:1226-1230)

Animals↗

PubMed2001

Developmental depression of glutamate neurotransmission by chronic low-level activation of NMDA receptors.

Slabs of slow-release plastic (Elvax) containing NMDA or solvent were implanted over the rat colliculus beginning on postnatal day 8 (P8). Whole-cell patch clamping in the superficial superior collicular layers (sSCs) from P10 to P21 demonstrated a severe decrease in spontaneous EPSC frequency after chronic NMDA treatment. The decrease was not attributable to an increase in GABA(A) receptor-mediated inhibition and was present only when NMDA receptor (NMDAR) current was blocked by Mg(2+). Analysis of miniature EPSCs indicated that many active sites on NMDA-treated neurons lacked functional AMPA and kainate receptor (AMPA/KAR) currents, and AMPA/KAR:NMDAR current ratios of evoked EPSCs were also significantly reduced. In addition, the normal downregulation of NMDAR decay time in sSC neurons at P11 was absent after NMDA treatment. Nevertheless, neither AMPA nor NMDA receptor subunit expression was altered by NMDA treatment, and experiments with the NMDAR antagonist ifenprodil suggested that incorporation of NR2A-containing NMDARs at the sSC synapses was unperturbed. Thus, disrupting but not blocking NMDARs suppresses the development of AMPA/KAR currents. The absence of the P11 NMDAR current downregulation is likely a secondary effect resulting from the reduction of AMPA/KAR function. Chronic agonist application reduces but does not eliminate NMDAR conductances. Therefore these data support an active role for NMDAR currents in synaptic development. Prolonged NMDA treatment in vivo, which couples reduced postsynaptic Ca(2+) responses with normally developing afferent activity, produces a long-lasting synaptic depression and stalls glutamatergic synaptogenesis, suggesting that the correlation between robust NMDAR activation and afferent activity is an essential component during normal development.

Aging↗

PubMed2001

Identification of dopamine responsive mRNAs in glial cells by suppression subtractive hybridization.

Recent studies have established that glial cells are important targets of the neurotransmitter dopamine (DA), but the regulatory effects of DA on glial cells have not been extensively studied. In the present study, we have investigated the influence of DA on gene transcription in glial cells. Two-directional (forward and backward) suppression subtraction hybridization (SSH) was performed on astrocytes cultured from rat cerebral tissues in standard media or in culture media treated with DA. PCR-select differential screening was used to further verify the differentially expressed cDNA clones, positive clones were sequenced, and the mRNAs were re-examined on Northern blots. Fourteen sequences were identified of which eleven are homologous to known genes, three are homologous to expressed sequence tags (ESTs). Three novel full-length cDNAs were isolated using the EST fragments as probes to screen a cDNA library constructed from human brain. Analysis of these sequences suggested that complex intracellular signaling pathways, involving crosstalk with growth factor pathways, steroid hormone pathways, and an interferon-regulated 2-5 A pathway, are responsive to DA in astrocytes. The responsive proteins downstream from the signaling pathways were found to fall into at least three groups, including a series of metabolic enzymes, stress proteins, transfer proteins, etc. In addition, several of them have established their relationships with specific neurodegenerative diseases, showing that there is overlap in the pathogenic mechanisms of different diseases. Our results have provided a foundation for better understanding of the molecular basis of glial cell functions in dopaminergic transmission and an approach to find possible medication for the related disorders.

Animals↗

PubMed2001

FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties.

FUGUE, a program for recognizing distant homologues by sequence-structure comparison (http://www-cryst.bioc.cam.ac.uk/fugue/), has three key features. (1) Improved environment-specific substitution tables. Substitutions of an amino acid in a protein structure are constrained by its local structural environment, which can be defined in terms of secondary structure, solvent accessibility, and hydrogen bonding status. The environment-specific substitution tables have been derived from structural alignments in the HOMSTRAD database (http://www-cryst.bioc. cam.ac.uk/homstrad/). (2) Automatic selection of alignment algorithm with detailed structure-dependent gap penalties. FUGUE uses the global-local algorithm to align a sequence-structure pair when they greatly differ in length and uses the global algorithm in other cases. The gap penalty at each position of the structure is determined according to its solvent accessibility, its position relative to the secondary structure elements (SSEs) and the conservation of the SSEs. (3) Combined information from both multiple sequences and multiple structures. FUGUE is designed to align multiple sequences against multiple structures to enrich the conservation/variation information. We demonstrate that the combination of these three key features implemented in FUGUE improves both homology recognition performance and alignment accuracy.

Algorithms↗

PubMed2001

Synthesis of a series of oligo(ethylene glycol)-terminated alkanethiol amides designed to address structure and stability of biosensing interfaces.

A strategy for the synthesis of a series of closely related oligo(ethylene glycol)-terminated alkanethiol amides (principally HS(CH(2))(m)CONH(CH(2)CH(2)O)(n)H; m = 2, 5, 11, 15, n = 1, 2, 4, 6, 8, 10, 12) and analogous esters has been developed. These compounds were made to study the structure and stability of self-assembled monolayers (SAMs) on gold in the prospect of designing new biosensing interfaces. For this purpose, monodisperse heterofunctional oligo(ethylene glycols) with up to 12 units were prepared. Selective monoacylation of the symmetrical tetra- and hexa(ethylene glycol) diols as their mesylates with the use of silver(I) oxide was performed. The synthetic approach was based on carbodiimide couplings of various oligo(ethylene glycol) derivatives to omega-(acetylthio) carboxylic acids via a terminal amino or hydroxyl function. SAM structures on gold were studied with respect to thickness, wettability (water contact angles approximately 30 degrees ), and conformation. A good fit was obtained for the relation between monolayer thickness (d) and the number of units in the oligo(ethylene glycol) chain (n): d = 2.8n + 21.8 (A). Interestingly, the corresponding infrared spectroscopy analysis showed a dramatic change in conformation of the oligomeric chains from all-trans (n = 4) to helical (n > or = 6) conformation. A crystalline helical structure was observed in the SAMs for n > 6.

Journal Article↗

PubMed2001

[The study of point mutation of muscular mitochondrial DNA from patients with mitochondrial encephalomyopathies].

OBJECTIVE: To study the relation between the point mutation at nt3243 and nt8344 of muscular mitochondrial DNA from patient with mitochondrial encephalomyopathies and phenotypes. METHODS: The total DNA was extracted from muscle specimens from 5 patients with mitochondrial encephalomypathies and amplified by PCR method using corresponding oligonucleotide primers. The DNA fragments were digested with the restriction enzyme Bgl I and Apa I, then the digested DNA fragments were analyzed with electrophoresed method. RESULTS: The point mutation at nt3243 of mtDNA was found in 2 patients, 1 with MELAS and another with MERRF. The point mutation at nt8344 was found in 2 patients with MERRF, including the one with point mutation at nt3243. CONCLUSIONS: There was a correlation of the point mutation of DNA at nt3243 with MELAS,and at nt8344 with MERRF. In addition, The detection of point matation at both nt3243 and nt8344 in patient with MERRF shows the association of matation with diversity in clinical manifestion of mitichondrial encephalomypathies.

Adolescent↗

PubMed2001

Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1.

Nox1, a homologue of gp91phox, the catalytic moiety of the superoxide (O(2)(-))-generating NADPH oxidase of phagocytes, causes increased O(2)(-) generation, increased mitotic rate, cell transformation, and tumorigenicity when expressed in NIH 3T3 fibroblasts. This study explores the role of reactive oxygen species (ROS) in regulating cell growth and transformation by Nox1. H(2)O(2) concentration increased approximately 10-fold in Nox1-expressing cells, compared with <2-fold increase in O(2)(-). When human catalase was expressed in Nox1-expressing cells, H(2)O(2) concentration decreased, and the cells reverted to a normal appearance, the growth rate normalized, and cells no longer produced tumors in athymic mice. A large number of genes, including many related to cell cycle, growth, and cancer (but unrelated to oxidative stress), were expressed in Nox1-expressing cells, and more than 60% of these returned to normal levels on coexpression of catalase. Thus, H(2)O(2) in low concentrations functions as an intracellular signal that triggers a genetic program related to cell growth.

Animals↗

PubMed2001

Detection of multivalent interactions through two-tiered energy transfer.

A method based on two-tiered fluorescence resonant energy transfer (FRET) has been developed for selective and sensitive detection of species involved in a multivalent interaction. Pentavalent binding between cholera toxin and ganglioside GM1 is used as a model system to demonstrate the advantage of the two-tiered FRET over one-stage FRET in both conventional fluorimeter and flow cytometer. In the system, three fluorescent probes (namely, fluorescence donor, acceptor, and intermediate) are covalently tagged to receptors, and the intermediate is used to bridge the energy transfer between the donor and acceptor even though the donor's fluorescence spectrum does not overlap with absorption spectrum of the acceptor. One of the most significant improvements of the scheme over one-stage FRET is a dramatic decrease in the background fluorescence of the acceptor fluorescence, which, theoretically and practically, increases the detection sensitivity.

Binding Sites↗

PubMed2001

Effect of cigarette smoke extract on neonatal porcine vascular smooth muscle cells.

RATIONALE: Cigarette smoke exposure in the perinatal period increases the risk of various prenatal and postnatal complications, including sudden infant death syndrome (SIDS) and persistent pulmonary hypertension of the newborn (PPHN). We investigated the cellular effects of cigarette smoke extract (CSE) in the developing vasculature. METHODS: Vascular smooth muscle cells (VSMC) were isolated from neonatal porcine carotid arteries, splenic arteries, and main and resistance pulmonary arteries. Effects of CSE on VSMC proliferation, viability, apoptosis, and media nitrates and nitrites were evaluated. The effects of known constituents of CSE (nicotine, benzopyrene, acrolein, acetaldehyde), aged CSE, CSE with added hemoglobin, devolatilized CSE, CSE with added dithiothreitol (DTT), and reduced glutathione (GSH) on cell proliferation and viability were assessed. RESULTS: CSE caused a dose- and time-dependent decrease in neonatal VSMC numbers isolated from all four sites, mainly as a result of increased cell necrosis and not apoptosis. Nitrates and nitrites were below the threshold of detection. Nicotine and benzopyrene did not affect cell counts, while acrolein and acetaldehyde decreased cell counts in a dose-dependent manner. Addition of hemoglobin, devolatilization, and the addition of DTT or GSH slightly decreased CSE inhibition. CONCLUSIONS: CSE causes necrosis of neonatal VSMC, and this toxicity is mediated mainly by volatile components such as acrolein and acetaldehyde, possibly in association with nitric oxide and carbon monoxide.

Acetaldehyde↗

PubMed2001

Mutation of the hematopoietic cell phosphatase (Hcph) gene is associated with resistance to gamma-irradiation-induced apoptosis in Src homology protein tyrosine phosphatase (SHP)-1-deficient "motheaten" mutant mice.

To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptotic response and cell cycle function in irradiated spleen cells of motheaten (me/me) mice. The defect in me/me mice has been attributed to mutations of the HCPH: gene, which encodes SHP-1. Homozygotes develop severe systemic autoimmune and inflammatory disease, whereas heterozygotes live longer and develop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)-me/me and B6-+/+ controls were analyzed after gamma-irradiation from a (137)Cs source. B6-me/me cells were significantly more resistant than B6-+/+ cells to gamma-irradiation-induced apoptosis exhibiting a higher LD(50). The defective apoptosis response of the B6-me/me cells was exhibited by T and B cells and macrophages. Of the Bcl-2 family members analyzed, a significant difference was observed in the transcription of Bax mRNA, which was up-regulated early after irradiation in B6-+/+ cells, but not B6-me/me cells. Analysis of 3,3'-dihexyloxacarbocyanine iodide revealed resistance to the gamma-irradiation-induced mitochondrial transmembrane permeability transition in the B6-me/me cells. The blocking of the cell cycle in the G(0)/G(1) phase characteristic of the irradiated B6-+/+ cells was not observed in the B6-me/me cells. There was decreased phosphorylation of p38 mitogen-activated protein kinase and increased phosphorylation of p53 from spleen cell lysates of irradiated B6-me/me mice compared with wild-type mice. These data suggest that SHP-1 plays an important role in regulation of apoptosis and cell cycle arrest after a gamma-irradiation-induced stress response.

Animals↗

PubMed2001

Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds.

The host defense roles of neutrophil elastase in a porcine skin wound chamber model were explored. Analysis of wound fluid by acid-urea polyacrylamide gel electrophoresis, Western blot, and bacterial overlay confirmed that the neutrophil-derived protegrins constituted the major stable antimicrobial polypeptide in the wound fluid. The application to the wound of 0.10 and 0.25 mM N-methoxysuccinyl-alanine-alanine-proline-valine (AAPV) chloromethyl ketone, a specific neutrophil elastase inhibitor (NEI), blocked the proteolytic activation of protegrins and diminished the associated antimicrobial activity as detected by radial diffusion assay against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans or by bacterial gel overlay against S epidermidis and E coli. The application of the related cathepsin G inhibitor (CGI), benzyloxycarbonyl-glycine-leucine-phenylalanine (ZGLF) chloromethyl ketone, had no effect. In wound chambers that received 10(6) colony-forming unit (CFU)/mL of S epidermidis, the presence of NEI significantly decreased the 24-hour clearance of bacteria from the wound compared to wounds treated with CGI or solvent only. Neither inhibitor, at 0.10 or 0.25 mM concentration, affected leukocyte accumulation or degranulation in the wound chambers. The in vitro microbicidal decrement due to NEI was restored by an amount of the specific protegrin (PG-1), which was equivalent to the measured difference of protegrin between control and inhibited chambers. Administration of 1 microg/mL exogenous PG-1 4 hours after chamber preparation was sufficient to normalize in vivo antimicrobial activity. Although pharmacologic NEIs are promising candidates as anti-inflammatory drugs, they may impair host defense in part by inhibiting the activation of cathelicidins by neutrophil elastase.

Animals↗

PubMed2001

Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence: efficacy of contingency management and significant other involvement.

BACKGROUND: Contingency management (CM) and significant other involvement (SO) were evaluated as strategies to enhance treatment retention, medication compliance, and outcome for naltrexone treatment of opioid dependence. METHODS: One hundred twenty-seven recently detoxified opioid-dependent individuals were randomly assigned to 1 of 3 conditions delivered for 12 weeks: (1) standard naltrexone treatment, given 3 times a week; (2) naltrexone treatment plus contingency management (CM), with delivery of vouchers contingent on naltrexone compliance and drug-free urine specimens; or (3) naltrexone treatment, CM, plus significant other involvement (SO), where a family member was invited to participate in up to 6 family counseling sessions. Principal outcomes were retention in treatment, compliance with naltrexone therapy, and number of drug-free urine specimens. RESULTS: First, CM was associated with significant improvements in treatment retention (7.4 vs 5.6 weeks; P =.05) and in reduction in opioid use (19 vs 14 opioid-free urine specimens; P =.04) compared with standard naltrexone treatment. Second, assignment to SO did not significantly improve retention, compliance, or substance abuse outcomes compared with CM. Significant effects for the SO condition over CM on retention, compliance, and drug use outcomes were seen only for the subgroup who attended at least 1 family counseling session. The SO condition was associated with significant (P =.02) improvements in family functioning. CONCLUSION: Behavioral therapies, such as CM, can be targeted to address weaknesses of specific pharmacotherapies, such as noncompliance, and thus can play a substantial role in broadening the utility of available pharmacotherapies.

Adult↗

PubMed2001

Sequence-structure homology recognition by iterative alignment refinement and comparative modeling.

Our approach to fold recognition for the fourth critical assessment of techniques for protein structure prediction (CASP4) experiment involved the use of the FUGUE sequence-structure homology recognition program (http://www-cryst.bioc.cam.ac.uk/fugue), followed by model building. We treat models as hypotheses and examine these to determine whether they explain the available data. Our method depends heavily on environment-specific substitution tables derived from our database of structural alignments of homologous proteins (HOMSTRAD, http://www-cryst.bioc.cam.ac.uk/homstrad/). FUGUE uses these tables to incorporate structural information into profiles created from HOMSTRAD alignments that are matched against a profile created for the target from multiple sequence alignment. In addition, environment-specific substitution tables are used throughout the modeling procedure and as part of the model evaluation. Annotation of sequence alignments with JOY, to reflect local structural features, proved valuable, both for modifying hypotheses, and for rejecting predictions when the expected pattern of conservation is not observed. Our stringency in rejecting incorrect predictions led us to submit a relatively small number of models, including only a low number of false positives, resulting in a high average score.

Amino Acid Sequence↗

PubMed2001

Detection of red blood cell-bound immunoglobulin G by flow cytometry and its application in the diagnosis of autoimmune hemolytic anemia.

Detection of autoantibodies to erythrocytes is of fundamental importance in the diagnosis of autoimmune hemolytic anemia (AIHA). The routinely used direct antiglobulin test (DAT) has the disadvantage of low sensitivity. In this study, we investigated the optimal test conditions of measurement of red blood cell (RBC)-bound immunoglobulin (Ig) G by flow cytometry (FCM). We studied 64 patients with AIHA, 30 anemic patients diagnosed with other diseases, and 36 healthy individuals. In 33 AIHA patients who were found to have RBC-bound IgG, both the mean fluorescence intensity (MFI) and percentage of fluorescence-activated RBCs were remarkably increased and results of both were considered positive. In the remaining 31 AIHA patients who had positive results for RBC-bound complement C3d, the MFI and the percentage of fluorescence-activated RBCs was also increased and 17 patients (54.8%) were considered to have a positive result by this method. In anemic patients with negative DATs the results of FCM were always negative. These results could be confirmed by enzyme-linked immunosorbent assay (ELISA), and the values obtained by FCM and ELISA corresponded to titration scores of the DAT. Additionally, in 3 of the other 8 patients who were suspected to have DAT-negative AIHA, RBC-bound IgG was detected by FCM and ELISA. Our investigation demonstrates that FCM is a precise, reliable, and sensitive method of detecting RBC-bound autoantibodies and could be used as a new routine diagnostic technique for AIHA and other immune hemolytic anemias.

Adolescent↗

PubMed2001

Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy.

PURPOSE: The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the oral bioavailability of uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). METHODS: PTAU was administered orally to mice alone or with uridine. The plasma levels of PTAU as well as those of uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. RESULTS: Co-administration of PTAU with uridine elevated the concentration of plasma uridine in a dose-dependent manner over that resulting from the administration of the same dose of uridine alone, and reduced the clearance of uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 micromol x h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg uridine by 2.2-, 2.6- and 3.2-fold, respectively. CONCLUSION: The effectiveness of PTAU in improving the oral bioavailability of uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of uridine.

Administration, Oral↗

PubMed2001

A polymorphism in the promoter region of catalase is associated with blood pressure levels.

Catalase is an important antioxidant enzyme that detoxifies H2O2 into oxygen and water and thus limits the deleterious effects of reactive oxygen species (ROS). Because chronic exposure to excess ROS may contribute to vascular damage, we investigated whether genetic variation in catalase was associated with susceptibility to essential hypertension (EHYT) in 324 individuals (at least 50 years old) who were randomly sampled from an isolated population living in Xiangchang, China. They were screened for genetic variation in the promoter of catalase by direct sequencing. In total, four single nucleotide polymorphisms (SNPs) were identified. The association between the SNPs and EHYT was investigated by a linear regression model under phenotypic selection; in our analyses, we used both SBP>150 mmHg and SBP>160 mmHg as thresholds. A SNP 844 bp upstream of the start codon (SNP-844) demonstrated strong evidence of association with EHYT (SBP>150 mmHg: F=5.09, P=0.008; SBP>160 mmHg: F=7.13, P=0.002). This is the first study to implicate genetic variation in catalase in susceptibility to EHYT and suggests that polymorphisms in promoter regions may be particularly relevant to the study of complex diseases.

Aged↗