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PubMed1983

A multicomponent analysis of amino acid transport systems in human lymphocytes. 1. Kinetic parameters of the A and L systems and pathways of uptake of naturally occurring amino acids in blood lymphocytes.

We have determined the kinetic parameters of natural and system-specific synthetic amino acid transport by human blood lymphocytes, using a multi-component computer analysis that separates carrier-mediated uptake from diffusion. These studies were initiated in order to provide the basis for studies of human blood T and B lymphocytes and malignant lymphocytes. Methylaminoisobutyric acid (methyl-AIB) and 2-amino-2-carboxy-bicyclo (2,2,1) heptane (BCH) uptakes into lymphocytes were measured as prototypes of A- and L-system amino acid transport. The Michaelis constant for methyl-AIB uptake was 540 microM; the maximal velocity of uptake was 28 mumol/L cell water/min, and the diffusion coefficient was .004 min-1. In contrast, the Michaelis constant for BCH uptake was 63 microM; the maximal velocity was 969 mumol/L cell water/min, and the diffusion coefficient was .141 min-1. The transport of the naturally occurring amino acids, alanine, proline, and leucine was defined by studies of: (1) competitive inhibition with the system-specific synthetic amino acids, methyl-AIB and BCH, (2) the effect of the transcellular sodium gradient on transport, and (3) evaluation of the time-dependent increase of transport in amino acid-deficient medium (adaptation). Alanine was transported principally (approximately 70%) by the ASC-system, and leucine was transported principally (70%) by the L-system in lymphocytes. The analysis of proline transport was more complex because of a large component of uptake by diffusion even at low amino acid concentrations. Taken together, the kinetics of sodium-sensitive uptake and the results of competitive inhibition studies indicated that proline was transported by the A-system (30%), the ASC system (30%), and also by the L-system (15%).

Amino Acids↗

PubMed1987

Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine.

Cysteine and cystine transport activities of resting and activated mouse spleen lymphocytes were characterized in order to examine the contributions of cysteine and cystine to intracellular glutathione contents. Following stimulation with lipopolysaccharide, the lymphocytes markedly increased their capacity to transport cysteine. The uptake of cysteine was mediated mainly by the ASC system (Na+-dependent neutral amino acid transport system especially reactive with alanine, serine, and cysteine). On the other hand, both the resting and the activated lymphocytes had extremely low cystine transport activities. Because of the instability of cysteine, the culture media usually contained cystine but not cysteine. Therefore, both the resting and the activated lymphocytes rapidly decreased their glutathione contents owing to their poor capacities to take up cystine. The effects of freshly added cysteine on the cellular glutathione contents were examined in the presence of bathocuproinedisulfonate, a nontoxic copper-specific chelator that inhibits autoxidation of cysteine. Cysteine added at 25-400 microM only partially prevented the rapid decrease of the glutathione contents in fresh resting lymphocytes. In the lipopolysaccharide-activated cells, however, cysteine enhanced the cellular glutathione contents in a dose-dependent manner. These results indicate that the enhanced activity of the ASC system increases the level of intracellular glutathione in the presence of cysteine.

Animals↗

PubMed1990

Characterization of glutamine transport into resting and concanavalin A-stimulated peripheral human lymphocytes.

Characteristics of glutamine transport, its substrate specificity, and its pattern of competitive and non-competitive inhibition in response to amino acid analogues were determined in peripheral human lymphocytes, incubated with or without concanavalin A (Con A). Maximum capacity of transport (Vmax) at 37 degrees C and 136.9 mM Na+ was 30 pmol/10(6) cells/30 seconds, while the apparent Km was 142 microM. In cells exposed to 10 mM histidine, asparagine, serine, or leucine transport of glutamine declined to 28%, 15%, 17%, and 21%, respectively, of the rates in controls. Inhibition by histidine (Ki = 0.58 mM) and serine (Ki = 0.25 mM) was competitive, by leucine was non-competitive (Ki = 0.64), while alpha-methylamino-isobutyric acid and 2-amino carboxy-bicyclo (2.2.1)-heptane had no effect. In cells cultured for 24 hours with or without 10 micrograms/ml Con A, the apparent Km was 70 microM vs. 89 microM and Vmax 73 vs. 26 pmol/10(6) cells/30 seconds. Sodium depletion (9.0 mM NaCl) greatly diminished glutamine transport in resting and stimulated cells. Inhibition of glutamine transport by serine was sodium sensitive, while inhibition by histidine and asparagine was not. Serine had no competitive effect in sodium-depleted media. The data demonstrate what appear to be two carrier systems for glutamine, sodium sensitive and sodium insensitive. It is suggested that glutamine transport into lymphocytes occurs via processes similar to System N and System ASC described in other cells, with System ASC as the sodium-sensitive component. Con A augments the capacity rather than the affinity of glutamine transporting systems.

Adult↗

PubMed2007

Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features.

Promoter CpG island hypermethylation is an important carcinogenic event in prostate adenocarcinoma. Regardless of tissue type, human cancers have in common both focal CpG island hypermethylation and global genomic hypomethylation. The present study evaluated CpG island loci hypermethylation and LINE-1 and Alu repeat hypomethylation in prostate adenocarcinoma, analysed the relationship between them, and correlated these findings with clinicopathological features. We examined 179 cases of prostate adenocarcinoma and 30 cases of benign prostate hypertrophy for the methylation status of 22 CpG island loci and the methylation levels of LINE-1 and Alu repeats using methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. The following 16 CpG island loci were found to display cancer-related hypermethylation: RASSF1A, GSTP1, RARB, TNFRSF10C, APC, BCL2, MDR1, ASC, TIG1, RBP1, COX2, THBS1, TNFRSF10D, CD44, p16, and RUNX3. Except for the last four CpG island loci, hypermethylation of each of the remaining 12 CpG island loci displayed a close association with one or more of the prognostic parameters (ie preoperative serum prostate specific antigen level, Gleason score sum, and clinical stage). Prostate adenocarcinoma with hypermethylation of each of ASC, COX2, RARB, TNFRSF10C, MDR1, TIG1, RBP1, NEUROG1, RASSF1A, and GSTP1 showed a significantly lower methylation level of Alu or LINE-1 than prostate adenocarcinoma without hypermethylation. In addition, hypomethylation of Alu or LINE-1 was closely associated with one or more of the above prognostic parameters. These data suggest that in tumour progression a close relationship exists between CpG island hypermethylation and the hypomethylation of repetitive elements, and that CpG island hypermethylation and DNA hypomethylation contribute to cancer progression.

Adenocarcinoma↗

PubMed2004

Use of isotopically labelled octanoic acid to assess the effect of meal size on gastric emptying.

It has been proposed that the (13)C-octanoic acid breath test (OBT) provides a safe, non-radioactive means of measuring gastric emptying. However, deuterated octanoic acid provides a better marker when compared with scintigraphy, as the kinetics are less complex than those of the (13)C label. The appearance of (2)H in saliva is modelled as a two-compartment body water system, using an asymmetric triangular gastric emptying function. This study compared the (2)H-octanoic acid saliva test (OST) with the OBT in measuring altered states of gastric emptying in the nutritional context of diet manipulation. Gastric emptying was measured using the OST and OBT in a three-way crossover study involving 12 healthy male and female subjects (mean BMI = 23.4 kg/m(2), aged 24-57 years). Following an overnight fast, subjects were given an egg meal, labelled with 10 microL/kg body weight (2)H-octanoic acid and 100 microL (13)C-octanoic acid. The meal was nutritionally manipulated to provide a 1 MJ, 2 MJ or 3 MJ meal. Breath and saliva samples were collected at regular intervals for 6 h, with further saliva samples being collected over four subsequent days. (2)H isotopic enrichment in saliva and (13)C isotopic enrichment in breath were analysed using isotope ratio mass spectrometry and the data fitted to the respective gastric emptying models. The half excretion time (T(1/2) (D)), time to maximum emptying rate (T(1) (D)) and time when emptying is complete (T(2) (D)) were calculated from the (2)H saliva test data, and the lag time (T(lag) (C)), half excretion time (T(1/2) (C)), latency phase (T(lat) (C)) and ascension time (T(asc) (C)) were calculated from the (13)C breath test data. Overall, the OBT correlated well with the OST, with a significant relationship between T(1/2) (C) and T(1/2) (D), a significant relationship between T(lat) (C) and T(1) (D) and finally a significant relationship between T(asc) (C) and T(2) (D). Gastric emptying measured using the OST was significantly faster with the 1 MJ meal (DeltaT(1/2) (D) = -0.77 h vs. 2 MJ, p = 0.004). Increases were also seen when the meal size was increased from 2 MJ to 3 MJ (DeltaT(1/2) (D) = +0.44 h vs. 2 MJ), but these were not significant. These trends were mirrored in the OBT data, with significant differences between 1 MJ and 2 MJ (DeltaT(1/2) (C) = -0.63 h vs. 2 MJ, p = 0.013) and non-significant increases with the larger 3 MJ meal (DeltaT(1/2) (C) = +0.10 h vs. 2 MJ). Total meal calorie content was shown to have an effect on gastric emptying using both the OBT and the OST. The deuterium method allows the direct calculation of the gastric emptying function and could be used as an alternative to gamma scintigraphy, allowing further validation of the (13)C-octanoic acid breath test.

Adult↗

PubMed1996

Application of glutamate in the cortex of rats: a microdialysis study.

Glutamate, a major neurotransmitter in the brain, is also involved in pathophysiological processes resulting in secondary lesions following ischaemia or trauma. In the present study we investigated the relationship between glutamate excitotoxicity free radical induction (indicated by ascorbic acid level) and glucose-lactate metabolism. Monosodium glutamate was applied through microdialysis probes (500 mM in perfusate) into the cortex of rats for 30 minutes and ascorbic acid (ASC), glucose (GLUC) and lactate (LAC) were measured in dialysates. Glutamate produced a cortical lesion with an average volume of 12.7 +/- 1.4 mm3. Analysis of dialysates revealed a significant increase of ASC (325 +/- 52% of baseline) and LAC (677 +/- 86%) in the core lesion. In the lesion periphery a non-significant and short-lasting elevation was measured for both parameters with a second microdialysis probe (about 1.3 mm frontally to the first probe). A concomitant decrease of GLUC was found in both probes, reaching 29 +/- 8% and 60 +/- 7% of basal levels in the core and periphery of the lesion, respectively. In addition, we studied the delivery characteristics of several glutamate concentrations (10, 100 or 1000 mM in perfusate) during a 90-minute application into the cortex. The delivery of glutamate from the perfusate to the brain was about 33-38% in the first 30 min and afterwards 11 25% of the total in the perfusate. The results show that cortical application of glutamate changes the composition of the extracellular fluid, which could contribute to the development of the lesion.

Animals↗

PubMed1993

Glycine uptake by trout (Salmo trutta) red blood cells.

The present study demonstrates the presence of different amino acid carriers in the membrane of trout red cells. Most glycine is taken up through the Na(+)-dependent system ASC, although the nearly specific Gly system is also active. Besides these carriers, glycine is taken up by means of Na(+)-independent transporters, system L being the most important. A system asc of high affinity and low capacity has been found, and band 3 is unable to transport glycine under physiological conditions. These results suggest that although all these carriers are already present in primitive vertebrates, several differences exist in their properties with respect to those found in mammalian cells.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed1995

Inheritance and genetic mapping of resistance to Alternaria alternata f. sp. lycopersici in Lycopersicon pennellii.

The fungal pathogen Alternaria alternata f. sp. lycopersici produces AAL-toxins that function as chemical determinants of the Alternaria stem canker disease in the tomato (Lycopersicon esculentum). In resistant cultivars, the disease is controlled by the Asc locus on chromosome 3. Our aim was to characterize novel sources of resistance to the fungus and of insensitivity to the host-selective AAL-toxins. To that end, the degree of sensitivity of wild tomato species to AAL-toxins was analyzed. Of all members of the genus Lycopersicon, only L. cheesmanii was revealed to be sensitive to AAL-toxins and susceptible to fungal infection. Besides moderately insensitive responses from some species, L. pennellii and L. peruvianum were shown to be highly insensitive to AAL-toxins as well as resistant to the pathogen. Genetic analyses showed that high insensitivity to AAL-toxins from L. pennellii is inherited in tomato as a single complete dominant locus. This is in contrast to the incomplete dominance of insensitivity to AAL-toxins of L. esculentum. Subsequent classical genetics, RFLP mapping and allelic testing indicated that high insensitivity to AAL-toxins from L. pennellii is conferred by a new allele of the Asc locus.

Alternaria↗

PubMed1990

Osmotic state of lenses in three dominant murine cataract mutants.

Three newly detected dominant cataract mutations (Asc-1, Cat-3vao, Tcm) were investigated for effects on osmotic alterations in the lenses of heterozygotes. The lens wet weight was reduced in two mutant lines (Cat-3vao and Tcm), and the water content in the lenses of the Cat-3vao mice was increased. Moreover, in the cataractous lenses from Cat-3vao mice, the sodium-potassium-adenosine triphosphatase (Na(+)-K(+)-ATPase) activity was enhanced and the ATP concentration, correspondingly decreased. The osmotic variations observed in the Cat-3vao mutants might have been due to a metabolic response to the yet unknown, primary pathological event. The lenses of the other two mutant lines (Asc-1 and Tcm) revealed no alterations that could be related to osmotic stress. In no mutant line investigated could a decrease in Na(+)-K(+)-ATPase activity be demonstrated that was similar to the causative factor in the Nakano mutant line. The Cat-3vao mice exhibited some similarities to the Philly mutant line.

Adenosine Triphosphate↗

PubMed1982

Isolation of a spontaneous CHO amino acid transport mutant by a combination of tritium suicide and replica plating.

A spontaneous transport mutant of Chinese hamster ovary cells, CHY-1, was isolated by a combination of [3H]proline suicide and replica plating. The mutant took up less tritium than the parent, resulting in a lower killing rate during storage. Transport by four separate amino acid transport systems (A, ASC, L, Ly+) was examined. The CHY-1 mutant exhibited normal uptake via the ASC, L, and Ly+ systems. By contrast, uptake of the most specific substrate of the A system, 2-(methylamino)-isobutyric acid, was significantly reduced at low, but not high, concentrations, due to a 3.5-fold increase in Km and a 1.5-fold increase in Vmax. Taken together, these data suggest that the CHY-1 mutation may be in the structural gene coding for the A transport protein. The tritium suicide procedure is discussed, and general equations are derived to predict the maximum storage time for the survival of one mutant cell and the optimum size of the cell population for maximum mutant enrichment.

Amino Acids↗

PubMed1987

Complementation studies with clinical and biochemical characterizations of a new variant of multiple sulphatase deficiency.

A patient with a new variant of multiple sulphatase deficiency (MSDv) is reported. Unlike the usual type, onset was late and progress was slow. The phenotypic changes were those usually seen in multiple sulphatase deficiency but much milder. Cytoplasmic accumulations were found in skin fibroblasts, and urinary mucopolysaccharides and sulphatides were high. Arylsulphatases A, B and C (ASA, B and C), heparan N-sulphatase sulphoiduronate sulphatase, and N-acetylgalactosamine 6-sulphatase all had low activity in lymphocytes and cultured skin fibroblasts. Complementation for ASA activity was found in hybrids between MSDv and metachromatic leukodystrophy (MLD) as well as between multiple sulphatase deficiency (MSD) and MLD. Complementation for ASC activity was also seen in hybrids between MSDv and X-linked ichthyosis (XLI), and between MSD and XLI. However, neither ASA nor ASC activity increased in hybrid cells of MSDv and MSD. These results suggested that the mutations of MSDv and of MSD were allelic, although of different phenotypes.

Adult↗

PubMed1989

Electrophysiological investigation of the amino acid carrier selectivity in epithelial cells from Xenopus embryo.

The electrical responses induced by external applications of neutral amino acids were used to determine whether different carriers are expressed in the membrane of embryonic epithelial cells of Xenopus laevis. Competition experiments were performed under voltage-clamp conditions at constant membrane potential. Gly, L-Ala, L-Pro, L-Ser, L-Asn and L-Gln generate electrical responses with similar apparent kinetic constants and compete for the same carrier.They are [Na]o and voltage-dependent, insensitive to variations in [Cl]o and [HCO3]o, inhibited by pHo changes, by amiloride and, for a large fraction of the current, by MeAIB. The increase in [K]o at constant and negative membrane potential reduces the response, whereas lowering [K]o augments it. L-Leu, L-Phe and L-Pro appear to compete for another carrier. They generate electrogenic responses insensitive to amiloride and MeAIB, as well as to alterations of membrane potential, [Na]o and [K]o. Lowering [Cl]o decreases their size, whereas increasing [HCO3]o at neutral pHo increases it. It is concluded that at least two and possibly three transport systems (A, ASC and L) are expressed in the membrane of the embryonic cells studied. An unexpected electrogenic character of the L system is revealed by the present study and seems to be indirectly linked to the transport function. L-Pro seems to be transported by system A or ASC in the presence of Na and by system L in the absence of Na. MeAIB induces an inward current.

Amino Acid Transport Systems↗

PubMed1989

Differentiation of second messenger systems in mast cell activation.

Pretreatment of rat peritoneal mast cells with either Staurosporine or an analog K-252a, lead to a dose-related inhibition of histamine release when stimulated with Anti-IgE (IC50: Staurosporine = 110 nM; K-252a = 100 nM). In contrast, the two PKC inhibitors (1-1000 nM) failed to inhibit histamine release induced by compound 48/80 (0.5-1 micrograms/ml). Exposure of Anti-Asc-IgE sensitized mouse bone marrow derived mast cells to Asc-BSA lead to the release of both histamine (510 ng +/- 12.6 ng/10(6) cells) and immunoreactive Leukotriene C4 (27.0 +/- 12.6 ng/10(6) cells). LTC4 release was inhibited by Staurosporine and K-252a with an IC50 of 75 nM for both compounds. Pretreatment of rat peritoneal mast cells with PMA 100 nM lead to a small but significant release of histamine (18.3 +/- 3.6%). Pretreatment of these cells with K-252a or Staurosporine lead to a dose related inhibition of histamine release with an ED50 of 10 nM for Staurosporine and 60 nM for K-252a. Treatment of rat peritoneal mast cells with the calcium ionophore A23187 lead to a significant release of histamine which was not inhibited by either of the two kinase inhibitors (0.1-1000 nM). The two kinase inhibitors also inhibited mouse bone marrow derived mast cell proliferation in response to IL-3 with IC50 of 80 nM for Staurosporine and 270 nM for K-252a.

Alkaloids↗

PubMedDate not supplied

Problems of the analysis of altered states of consciousness.

It is assumed on the basis of data that have been obtained that altered states of consciousness (ASC) arise during the performance of operator activity under conditions of monotony, when modulating influences in the minute range of fluctuations are experienced in the process. This modulation promotes the attenuation or intensification of the degree of ASC; this is reflected in corresponding shifts in attention and in the quality of operator actions relating to recognition of visual images. These results point to the important role of the modulating system of the brain, and of its infraslow wave manifestations in the activity of consciousness whose content is determined by informational processes.

Adult↗

PubMed1990

Changes of pre-S1 and pre-S2 antigens in sera of patients with hepatitis B virus infection.

Polypeptides encoded by the pre-S1 and pre-S2 genes of hepatitis B virus (HBV) (pre-S1 antigen and pre-S2 antigen) were detected by enzyme-linked immunosorbent assay (ELISA) in 137 serum samples of patients with HBV infection. The HBV-DNA level closely correlated with the titer of pre-S antigens. However, HBV-DNA levels more closely correlated with the titer of the pre-S1 antigen [HBV-asymptomatic carrier (ASC): n = 40, r = 0.800, P less than 0.01; chronic hepatitis B (CH): n = 60, r = 0.730, P less than 0.01] than with the titer of the pre-S2 antigen [ASC: r = 0.675, P less than 0.01; CH: r = 0.575, P less than 0.01]. Thirty patients with CH, in whom hepatitis e antigen (HBeAg) was cleared after acute exacerbation (AE) [alanine aminotransferase (ALT) level greater than 200 IU/L] and the ALT level normalized, were followed for 12 months and classified into two groups: Group 1, those in whom HBeAg reappeared with an elevated ALT level within 12 months, and Group 2, those in whom HBeAg was persistently cleared from the serum and a normal ALT level continued. Of the 30 patients, 24 (80%) were classified into Group 1 and 6 (20%) were classified into Group 2. Changes in serum levels of HBV markers a month before and after AE were observed. The HBV-DNA level and DNA-P activity became negative after AE in both groups. The titer of pre-S1 antigen also decreased after AE, and no significant differences were observed between Group 1 and Group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA, Viral↗

PubMed1991

Analysis of neutral amino acid transport systems in the small intestine: a study of brush border membrane vesicles.

Transport of L-proline, L-leucine and L-cysteine was studied in brush border membrane vesicles prepared from guinea pig ileum. Concentrative transport of L-proline, L-leucine and L-cysteine was obtained in the presence of an Na+ gradient from, outside to inside of the vesicles, which indicated contribution of either system A (alanine-preferring) or system ASC (alanine-, serine- and cysteine-preferring) to the transport. When Na+ was replaced by Li+, L-leucine and L-cysteine maintained the same concentrative transport. However, the concentrative transport of L-proline was markedly decreased by Li+ -for-Na+ substitution. Strong exchange properties of L-leucine transport via system L (leucine-preferring) was observed with brush border membrane vesicles, in which preloaded L-methionine could be exchanged with labeled L-leucine added outside the vesicles. These results suggest that the small intestine of the guinea pig possesses classical neutral amino acid transport systems such as systems A, ASC and L.

Alanine↗

PubMed1997

Nasal lymphoid tissue, intranasal immunization, and compartmentalization of the common mucosal immune system.

Mucosal application of vaccines with an appropriate adjuvant can induce immune responses at both systemic and mucosal sites, and therefore may prevent not only infectious disease, but also colonization of mucosal surfaces. Intranasal is more effective than intragastric immunization at generating earlier and stronger mucosal immune response. Nasal lymphoid tissue (NALT) and its local draining lymph nodes may retain long-term immune memory. IgA isotype switching, and the differentiation and maturation of IgA antibody-secreting cells (ASC) may occur before these cells migrate out of NALT, whereas IgG ASC responses require passage of the cells through draining lymph nodes of the NALT. Knowledge of whether immune memory cells can recirculate to and reside in the inductive sites other than their origin after encountering antigen will be helpful for understanding the compartmentalization of the common mucosal immune system as well as for determining the best route for delivering a mucosal vaccine against a particular pathogen.

Administration, Intranasal↗

PubMed2004

An extensive microarray analysis of AAL-toxin-induced cell death in Arabidopsis thaliana brings new insights into the complexity of programmed cell death in plants.

A T-DNA knockout of the Arabidopsis homologue of the tomato disease resistance gene Asc was obtained. The asc gene renders plants sensitive to programmed cell death (PCD) triggered by the fungal AAL toxin. To obtain more insights into the nature of AAL-toxin-induced cell death and to identify genes of potential importance for PCD, we carried out transcription profiling of AAL-toxin-induced cell death in this knockout with an oligonucleotide array representing 21,500 Arabidopsis genes. Genes responsive to reactive oxygen species (ROS) and ethylene were among the earliest to be upregulated, suggesting that an oxidative burst and production of ethylene played a role in the activation of the cell death. This notion was corroborated by induction of several genes encoding ROS-generating proteins, including a respiratory burst oxidase and germin oxalate oxidase. Cytochemical studies confirmed the oxidative burst and, in addition, showed synthesis of callose, a feature of the hypersensitive response. A diverse group of transcription factors was also induced. These events were followed by repression of most of the auxin-regulated genes known to be involved in growth and developmental responses. All photosynthesis-related genes were repressed. Blocking the synthesis of ethylene or NO significantly compromised cell death. In addition, we identified a heterogeneous group of early-induced genes, some of them never before associated with PCD. The group of early-induced genes included a number of proteases that were previously implicated in developmentally regulated types of PCD, suggesting a more principal role for these proteases in the PCD process. These findings provide new insights into the molecular mechanisms of plant PCD.

Apoptosis↗