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At least 1,567 records · Page 87Linked to original sources
PubMed1991

The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs.

The substituted glucopyranose ring structure 2-hydroxypropyl-beta-cyclodextrin (CDEX) increases the solubility of molecules by inclusion of the agent in the lipophilic interior of the ring. This property is of particular use for the administration of molecules by the intracerebral (ICV) or intrathecal (IT) routes. In concentrations up to 40% w/v (isotonic), this agent (10 microliters) effect upon nociceptive or motor function after IT injection or on EEG and general behavior after ICV injection in rats. Using 20% CDEX, there is no change in the ED50 as compared to saline on the hot plate (HP) after IT injection of morphine, D-Ala2-D-Leu5 enkephalin or Tyr-Aib-Gly-gPhe-mAib-NH2, (Aib: alpha-aminoisobutyric acid) although there is an increase in their respective durations of effect. Cyclic peptide opioids: Tyr-c[D-A2bu-Gly-D-beta Nal(1)-D-Leu] (A2bu: alpha, gamma-diaminobutyric acid; beta-Nal(1): beta-naphthylalanine(1)) or Tyr-c[DA2bu-Gly-beta Nal(1)-D-Leu] are insoluble in saline but are readily dissolved in CDEX, and display a naloxone-sensitive antinociception following spinal administration. In other studies, saline insoluble capsaicin is administered in 25% dimethylsulfoxide (DMSO) or 20% CDEX (15 microliters; 5 mg/ml) which result in a significant reduction in the spinal levels of substance P and calcitonin gene related peptide and an increase in the HP latency. DMSO alone, but not CDEX alone, reduces the levels of the two peptides. These data emphasize the utility of complexation with CDEX for intracerebral drug delivery and compatibility with brain and spinal tissue.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1978

Spontaneous Fanconi syndrome in the dog.

Three dogs with spontaneous renal tubular defects similar to idiopathic Fanconi syndrome are characterized. Renal clearance studies revealed a fractional reabsorption of glucose ranging from 31% to 82%. Abnormal glucose thulium values were present in all dogs. A generalized aminoaciduria occurred in two dogs while one had aminoaciduria characteristic of canine cystinuria. Fractional reabsorption of phosphate ranged from 47% to 79%. In vitro uptake of alpha-methyl-D-glucoside was significantly depressed (p less than 0.001). In vitro uptake of amino isobutyric acid was similar to controls. Renal biopsy revealed nonspecific interstitial change in two dogs and normal histology in the other. These animals represent a useful new model for the study of renal tubular transport defects.

Amino Acids↗
PubMed1989

Glyburide but not ciglitazone enhances insulin action in the liver independent of insulin receptor kinase activation.

To test the hypothesis that sulfonylureas enhance insulin action by activating the insulin receptor tyrosine kinase, the effects of glyburide, a second generation sulfonylurea, and ciglitazone, a nonsulfonylurea hypoglycemic agent, were determined in primary cultures of rat hepatocytes on insulin action and insulin receptor structure and function. Twenty hours of preincubation with glyburide (1 microgram/mL) resulted in increased insulin (1 X 10(-7) mol/L) stimulation of [14C] acetate incorporation into lipids and [14C] alpha-aminoisobutyric acid uptake without any change in basal activity. Ciglitazone (1 microgram/mL) was without any effect. Glyburide's actions were mediated without altering the following: (1) 125I-insulin binding; (2) the electrophoretic mobility of the affinity labeled alpha-subunit or the autophosphorylated beta-subunit of the insulin receptor; and (3) the insulin-stimulated insulin receptor kinase activity using histone or the beta-subunit of the insulin receptor as phosphoacceptors. These data suggest that the action of sulfonylureas is distal to the insulin receptor tyrosine kinase. Ciglitazone in vitro is ineffective in the liver, which suggests the peripheral tissues as the possible site of action.

Animals↗
PubMed1985

Hyperphagia induced by 2-deoxy-D-glucose in the presence of the delta-opioid antagonist ICI 174,864.

The effect of the selective delta-opioid antagonist ICI 174,864 (N,N-bisallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib=alpha-aminoisobutyric acid) on the hyperphagia induced by 2-deoxy-D-glucose (2-DG) was investigated in non-deprived rats. The increase in food intake produced by 2-DG (500 mg/kg i.p.) was not reduced by ICI 174,864 at a dose (3 micrograms/rat i.c.v.) which totally abolished the feeding response to the delta-agonist D-Ala2-D-Leu5-enkephalin (10 micrograms/rat i.c.v.). These findings suggest that the appetitive effects of 2-DG are not mediated by an enkephalinergic/delta-receptor system. They do not, however, preclude the possible involvement of endogenous opioids acting at other sub-types of opioid receptor in this glucoprivic ingestional response, which is suppressed by less specific opioid antagonists such as naloxone.

Animals↗
PubMed1983

Ultrastructural changes of bovine pulmonary artery endothelial cells irradiated in vitro with a 137Cs source.

Bovine pulmonary artery endothelial cells in culture were evaluated by phase-contrast and electron microscopy at various times after being irradiated with 137Cs in vitro. Cells irradiated prior to reaching confluency showed vacuolization aand increased numbers of lysosomes beginning at 48 hr after irradiation with 300-500 rad and at 24 hr after irradiation with 1500-5000 rad. After 7 days the morphological changes appeared to be reversible for cells receiving the lower doses, but were progressive for higher doses of radiation. The same qualitative changes, with a delayed onset, were observed for cells irradiated at confluency. An observed decrease in the endoplasmic reticulum and polysomes occurred only late in the course of radiation injury. There was no observable structural alteration of mitochondria even when there was evidence of otherwise marked cytoplasmic injury. We conclude that structural changes of the lysosomes constitute an early phase of injury by irradiation of the endothelial cell in culture, while decreases in endoplasmic reticulum and polysomes occur relatively late. The mitochondrial structure of the endothelial cell appears to be relatively resistant to radiation. All morphological changes occur subsequent to impaired transport of alpha-aminoisobutyric acid, which is observed within 6 hr as previously reported.

Animals↗
PubMed1984

Neutral amino acid transport and in vitro aging.

Human fibroblasts possess five distinguishable systems for amino acid transport. Initial rates for three of these decline with in vitro age. The decline most noticeably affects the L system, whose rate for L-phenylalanine transport at 10 microM declines by 44% between the 27th and 39th population doubling levels. Accumulation of L-phenylalanine is similarly affected. The insensitivity of older cells to reduction of the amino acid concentration in culture medium casts doubt on possible interpretation of the transport decline as a causal factor in limiting growth.

Alanine↗
PubMed1981

The regulatory influence of prostaglandins on protein synthesis in the human non pregnant cervix.

Cervical connective tissue was obtained from non pregnant fertile women undergoing hysterectomy. Tissue specimens were mechanically chopped into 1 mm thick slices which were preincubated in Krebs-Ringer bicarbonate buffer containing PGE2 or PGF2 alpha (300 ng/ml). After 60 min the slices were transferred into fresh buffer with the corresponding PG-concentration and 3H-labelled proline or hydroxyproline. Following incubation (60 min) the protein bound radioactivity was determined and related either to the dry weight or to the protein content of each slice. The two methods used did not show any qualitative differences. The experiments showed that PG:s had a marked effect on protein synthesis in the cervical tissue. During the follicular phase incubation with both types of PG:s was followed by a decreased incorporation indicating decreased net synthesis of collagen while there was an increased incorporation and hence increased synthesis in the luteal phase. There was no significant influence on the distribution of the model amino acid 14C-AIB in the presence of PG:s neither in the follicular nor in the luteal phase. The present data point to an acute effect of PGE2 and PGF2 alpha on cervical collagen metabolism and indicate furthermore that the process is steroid hormone dependent. It is concluded that these substances may exert their effect by modulating the incorporation of amino acids into protein.

Amino Acids↗
PubMed1977

Catabolism of thymidine during the lymphocyte cell cycle.

Concanavalin A-stimulated lymphocytes degrade thymidine to beta-aminoisobutyric acid. Thymidine-catabolizing enzymes are active in the cells during G1, G2 and mitosis, but activity falls to very low levels just prior to the onset of S and remains low throughout the S period. The data suggest that cell pools of thymidine are regulated by degradation.

Cell Cycle↗
PubMedDate not supplied

Maternal tobacco smoking and changes in amino acid uptake by human placental villi: induction of uptake systems, gammaglutamyltranspeptidase and membrane fluidity.

Maternal smoking depressed the active uptake of amino acids by human placentae and lowered their levels in the placenta and umbilical vein. During starvation of cells for amino acids, more amino acid carriers are induced and incorporated into the plasma membrane. A question arises whether there could be similar changes due to maternal smoking in the placental amino acid uptake carrier systems. Therefore, the characteristics of (a) the uptake of 2-amino[I-14C]-isobutyric acid (AIB) by isolated placental villi, (b) gammaglutamyltranspeptidase (GGTP), a critical enzyme of the gammaglutamyl cycle (GGC) for the uptake of amino acids in human placenta, and (c) lipid structural parameters (reciprocal of fluidity), by steady state fluorescence polarization of plasma membrane vesicles of microvilli (MV) and microsomal membranes (MM) of umbilical and chorionic plate arteries of placentae of smoking and non-smoking mothers were investigated. The above investigations gave the following results: (a) Washed placental villi of smokers exhibited higher capacity for AIB uptake than those of non-smokers. The higher uptake capacity was mainly due to increase in Vmax for AIB uptake in smokers. Km increased for placental AIB uptake in smokers. (b) Maternal smoking lowered GGTP activity of MV by decreasing its Vmax. Therefore, maternal smoking decreases the formation of gammaglutamyl-amino acid (GGAA) on the surface of trophoblast which are absorbed by the trophoblast. The degree of absorption of GGAA is considered as an inverse environmental signal for the cell to regulate amino acid transport systems. Maternal smoking seems to decrease the formation and absorption of GGAA and thereby induce the formation of new carriers for AIB uptake. (c) Maternal smoking increased the values for lipid structural order parameters and microviscosity of MV and induced tolerance against fluidization by ethyl alcohol in MM of umbilical and chorionic arteries. The alterations could increase Km for AIB uptake system and decrease the sensitivity of umbilical and chorionic arteries to vasoconstrictive substances like 5-hydroxytryptamine and catecholamine which are released by nicotine. All these changes tend to overcome the deficits produced in placental amino acid transport and satisfy the demands of the growing fetus for amino acids.

Amino Acids↗
PubMedDate not supplied

Na(+)-dependent amino acid uptake by human placental microvillous membrane vesicles: importance of storage conditions and preservation of cytoskeletal elements.

Human placental microvillous membrane vesicles (MMV) were purified by precipitation of non-microvillous membrane with MgCl2. Two aspects of MMV preparation were found to be important to the interpretation of amino acid transport studies: (1) storage conditions, and (2) preservation of cytoskeletal elements. In non-frozen MMV, MeAIB uptake was stimulated by an inward Na+ gradient and showed 'overshoot'. The initial Na(+)-dependent uptake rate was concentration-dependent with a Vmax of 640 +/- 80 pmol/mg/30 sec and a Km of 0.44 +/- 0.77 mM. Na(+)-stimulated cysteine uptake (65 +/- 23 pmol/mg/30 sec), previously thought to be very low or absent in the human placenta, was comparable to MeAIB, although there was no 'overshoot'. Cysteine uptake was partially stimulated by Li+. In general, freezing and storage at either -80 degrees C or -196 degrees C markedly reduced Na(+)-dependent uptake of several amino acids, compared to vesicles stored at 4 degrees C. The greatest reduction was seen with storage at -80 degrees C, especially with cysteine. There was no effect of storage temperature on Na(+)-independent amino acid uptake. For frozen vesicles, there was no difference in uptake for 12 versus 60 h storage. Removal of cytoskeletal proteins with the chaotropic agent, KSCN, resulted in greater enrichment of MMV marker proteins, but the preparation lost the capacity for active MeAIB uptake. These data, especially with regard to storage conditions, highlight the importance of precise definition of preparation and storage conditions when interpreting results of amino acid uptake by human placental MMV.

Amino Acids↗
PubMedDate not supplied

Selective delta-opioid receptor antagonism by ICI 174,864 in the central nervous system.

The effects of the novel gamma-opioid receptor antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib = alpha-aminoisobutyric acid) have been examined in the CNS in vivo using spontaneous reflex contractions of the rat urinary bladder as an index of activity. Bladder contractions were inhibited by equipotent intracerebroventricular (ICV) doses of the selective mu-agonist DAGO [D-Ala2, MePhe4,Gly-(ol)5]enkephalin and the delta-agonist DPDPE[D-Pen2, D-Pen5]enkephalin. ICI 174,864 (1-3 micrograms) administered by the same route produce a selective and reversible antagonism of DPDPE effects. At higher doses (6-15 micrograms, ICV) ICI 174,864 exhibited marked agonistic activity, producing inhibition of bladder contractions that were resistant to ICV naloxone (1-2 micrograms). Thus ICI 174,864 was considered a selective central delta-opioid receptor antagonist but its usefulness was limited by additional agonistic properties.

Animals↗
PubMed1994

Biological activity and receptor binding properties of some analogues of pQDPFLRFamide.

To investigate the role of the N-terminal region of the heptapeptide FMRFamide-like peptide, pQDPFLRFamide, three analogues were synthesized. The analogues [pQNPFLRFamide, pQDAibFLRFamide (Aib = aminoisobutyric acid) and pQDGFLRFamide] contained modifications at amino acid residues 2 and 3, which we believed might be critical for maintaining the bioactive conformation of the heptapeptide. The analogues were tested for their ability to bind to receptors in membranes from Helix aspersa circumoesophageal ganglia and for their biological effects on the isolated Helix heart, the Helix tentacle retractor muscle, and extensor-tibiae neuromuscular preparation of the locust. Schistocerca gregaria. The substitution of Asn for Asp2 and that of Aib for Pro3 were conservative with respect to retention of heptapeptide-like biological activity, whereas the substitution of Gly for Pro3 significantly improved the binding affinity of the peptide for the FMRFamide receptors and conferred on the peptide some characteristic FMRFamide-like biological activity. Thus, pQDPFLRFamide bioactivity may depend on a bent conformation in solution.

Amino Acid Sequence↗
PubMed1989

System A amino acid transport in a rat submandibular ductal cell line.

1. Neutral amino acid transport was studied in an established cell line derived from rat submandibular glands, RSMTx. 2. The greatest portion of alpha-amino isobutyrate (AIB) transport is mediated by system A. This component is Na+ dependent, pH sensitive, markedly inhibited by methyl AIB and enhanced 2-5-fold by amino acid depletion. 3. Evidence for the presence of other neutral amino acid transport systems, presumably ASC and L, was also found in these cells.

Adaptation, Physiological↗