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PubMed1988

Abscisic acid and water-stress induce the expression of a novel rice gene.

We have identified a novel rice gene, called RAB 21, which is induced when plants are subject to water-stress. This gene encodes a basic, glycine-rich protein (mol. wt 16,529) which has a duplicated domain structure. Immunoblots probed with antibodies raised against beta-galactosidase/RAB 21 fusion protein detect RAB 21 protein only in cytosolic cell fractions. RAB 21 mRNA and protein accumulate in rice embryos, leaves, roots and callus-derived suspension cells upon treatment with NaCl (200 mM) and/or the plant hormone abscisic acid (10 microM ABA). The effects of NaCl and ABA are not cumulative, suggesting that these two inducers share a common response pathway. Induction of RAB 21 mRNA accumulation by ABA is rapid (less than 15 min in suspension cells) and does not require protein synthesis, indicating that preformed nuclear and/or cytosolic factors mediate the response to this hormone. We have characterized the RAB 21 gene by determining the complete nucleotide sequence of a nearly full-length cDNA and corresponding genomic copy, and by mapping the start site of its major transcript. The proximal promoter region contains various GC-rich repeats.

Abscisic Acid↗
PubMed2001

Role of specific aminotransferases in de novo glutamate synthesis and redox shuttling in the retina.

In this study aminotransferase inhibitors were used to determine the relative importance of different aminotransferases in providing nitrogen for de novo glutamate synthesis in the retina. Aminooxyacetate, which inhibits all aminotransferases, blocked de novo glutamate synthesis from H(14)CO(3)(-) by more than 60%. Inhibition of neuronal cytosolic branched chain amino acid transamination by gabapentin or branched chain amino acid transport by the L-system substrate analog, 2-amino-bicyclo-(2,2,1)-heptane-2-carboxylic acid, lowered total de novo synthesis of glutamate by 30%, suggesting that branched chain amino acids may account for half of the glutamate nitrogen contributed by transamination reactions. L-cycloserine, an inhibitor of alanine aminotransferase, inhibited glutamate synthesis less than 15% when added in the presence of 5 mM pyruvate but 47% in the presence of 0.2 mM pyruvate. Although high levels of pyruvate blunted the inhibitory effectiveness of L-cycloserine, the results indicate that, under physiological conditions, alanine as well as branched chain amino acids are probably the predominant sources of glutamate nitrogen in ex vivo retinas. The L-cycloserine results were also used to evaluate activity of the malate/aspartate shuttle. In this shuttle, cytosolic aspartate (synthesized in mitochondria) generates cytosolic oxaloacetate that oxidizes cytosolic NADH via malate dehydrogenase. Because L-cycloserine inhibits cytosolic but not mitochondrial aspartate aminotransferase, L-cycloserine should prevent the utilization of aspartate but not its generation, thereby increasing levels of (14)C-aspartate. Instead, L-cycloserine caused a significant decline in (14)C-aspartate. The results suggest the possibility that shuttle activity is low in retinal Müller cells. Low malate/aspartate shuttle activity may be the molecular basis for the high rate of aerobic glycolysis in retinal Müller cells.

Acetates↗
PubMed1983

Differences in uptake kinetics of cis-3-aminocyclohexane carboxylic acid into neurons and astrocytes in primary cultures.

The uptake of [3H]ACHC and [3H]GABA into cultured neurons and astrocytes was studied. [3H]ACHC uptake was less efficient than that of GABA in both cell types and Km values for ACHC uptake into neurons and astrocytes were 40.3 microM and 210.8 microM, respectively. The corresponding Vmax values were 0.321 and 0.405 nmol . min-1 . mg-1 cell protein, respectively. Kinetic studies of the effects of GABA on ACHC uptake and vice versa showed that GABA is a linear competitive inhibitor of ACHC uptake in both cell types with a Ki value of 15 microM. On the other hand, ACHC turned out to be a complex inhibitor of astrocytic GABA uptake being competitive at lower concentrations and non-competitive at higher concentrations. ACHC inhibited GABA uptake into neurons competitively with a Ki of 69 microM. It is concluded that ACHC acts primarily on neuronal GABA uptake sites but its uptake is much more complicated than hitherto anticipated.

Amino Acids↗
PubMed1992

Neuronal and glial gamma-aminobutyric acid+ transporters are distinct proteins.

In the central nervous system, two subtypes of sodium- and chloride-coupled GABA transporter exist. One is sensitive to ACHC, the other to beta-alanine. They are thought to be of neuronal and glial origin, respectively. GABA transport in membrane vesicles derived from astroglial cells was found to be sodium- and chloride-dependent, electrogenic and much more sensitive to beta-alanine than to ACHC. Immunoblotting with antibodies directed against a variety of sequences of the ACHC-sensitive transporter indicated that none of these epitopes was shared by the glial transporter.

Amino Acids↗
PubMed1983

Interactions between dopamine and gamma-aminobutyrate in the substantia nigra: implications for the striatonigral output hypothesis.

Experiments employing a rodent circling model were conducted to test the predictive capacity of the theory which states that striatonigral gamma-aminobutyrate neurones transmit striatal information influencing the animal's locomotion and orientation. In agreement with this proposal, blocking nerve conduction in one substantia nigra with procaine, or nigral gamma-aminobutyrate receptors with bicuculline administered stereotaxically, frequently forced rats to move ipsiversively to systemic apomorphine, as though the treatment had impaired striatonigral transmission on that side of the brain. Attempts to reverse the direction of apomorphine circling by stimulating gamma-aminobutyrate receptors with muscimol, by facilitating the amino acid's action with flurazepam, or by increasing its synaptic concentration either with a breakdown inhibitor (ethanolamine O-sulphate or 4-amino-hex-5-enoic acid) or an uptake blocker (cis-1,3-aminocyclohexane carboxylic acid) in one nigra, proved unsuccessful. In fact, ethanolamine O-sulphate, flurazepam and muscimol all gave the appearance of hindering rather than enhancing the passage of striatal-derived motor information through the nigra. Broadly speaking, these drugs gave predictable behavioral responses from the ventromedial thalamus, suggesting they were acting in accordance with known mechanisms. The anomalous behaviour with ethanolamine O-sulphate may be attributed to its elevating gamma-aminobutyrate levels in other brain areas, since similar ipsiversive rotations occurred if gamma-aminobutyrate catabolism was prevented at a wide variety of extranigral sites. A simple explanation for the paradoxical ipsiversive behaviours produced by intranigral flurazepam or muscimol in combination with systemic or intracerebral injection of dopamine agonists, is that they act via presynaptic receptors to inhibit the release of endogenous gamma-aminobutyrate and thereby impede striatonigral outflow ipsilaterally.

Amino Acids↗
PubMed1993

[3H]gabapentin may label a system-L-like neutral amino acid carrier in brain.

The ability of large neutral amino acids to interact with a site in mouse and pig brain labelled by [3H]gabapentin was examined. As previously described for rat tissue, [3H]gabapentin bound to synaptic plasma membranes prepared from mouse or pig cerebral cortex with high affinity (Kinetically derived KD = 14 and 17 nM for mouse and pig, respectively). Equilibrium binding in each species was inhibited by gabapentin and a range of large neutral amino acids. L-leucine (IC50 = 80 nM), L-isoleucine (IC50 = 72 nM), L-norleucine (IC50 = 40 nM) and L-methionine (IC50 = 50 nM) were the most potent of those tested. Binding was also inhibited by L-phenylalanine (IC50 = 380 nM), L-valine (IC50 = 310 nM) and the selective system-L substrate 2-amino-2-carboxy-bicycloheptane (IC50 = 420 nM) but not by the sodium-dependent System-A substrate methylaminoisobutyric acid. The presence of a submaximal concentration of leucine reduced [3H]gabapentin binding affinity but did not affect the maximum number of binding sites, suggesting a competitive interaction between leucine and the binding protein. The results suggest [3H]gabapentin may label a site in brain that resembles the large neutral amino acid transporter described in other tissues.

Acetates↗
PubMed2006

The phosphodiesterase type IV inhibitor cilomilast decreases pro-inflammatory cytokine production from primary bronchial epithelial cells in lung transplantation patients.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the major cause of long-term morbidity and mortality after lung transplantation, and new therapeutic measures are needed. We speculated that cilomilast might reduce mediators of airway inflammation and angiogenesis from the airway epithelium, supporting a potential value in the treatment of BOS. We used an ex vivo primary bronchial epithelial cell culture (PBEC) model to investigate this hypothesis. Increasing evidence suggests the epithelium is central in stimulating both inflammatory and proliferative responses in the airway. METHODS: Bronchial brushings were taken from 7 stable lung allograft recipients and were used to establish sub-confluent PBECs. The effect of incubation for 48 hours with 0.1 to 10 micromol/liter cilomilast on basal production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor (GMCSF), and vascular endothelial growth factor (VEGF) were assayed by multiplex analyser. RESULTS: There was a dose dependent fall in basal IL-8 and GMCSF levels with cilomilast. Median change for IL-8 was -25% (range, -66% to 5%; p = 0.035) at 1 micromol/liter , and -40% (range, -72% to -20; p = 0.022) at 10 micromol/liter. Median GMSCF change was -34% (range, -70% to 16%; p = 0.05) at 1 micromol/liter, and 37% (range, -80% to -8%; p = 0.04) at 10 micromol/liter. There were no effects on VEGF. CONCLUSION: The phosphodiesterase type IV inhibitor cilomilast reduced IL-8 and GMCSF release from PBECs. These cytokines are associated with the persistence of airway neutrophilic inflammation and airway remodelling seen in obliterative bronchiolitis. These ex vivo results suggest a potential for cilomilast in the treatment of BOS, which would need to be evaluated in appropriate clinical studies.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors.

Over-expression of matrix metalloproteinases by lung fibroblasts has been blamed for much of the tissue destruction associated with airway inflammation. Because cyclic AMP is known to regulate fibroblast proliferation, as well as cytokine and extracellular matrix protein production, the current study was designed to evaluate the ability of three selective phosphodiesterase (PDE) type 4 inhibitors, rolipram, cilomilast and CI-1044, to inhibit extracellular matrix degradation. Using zymography and ELISA, we found that pro-MMP-2 release was enhanced following 24 h treatment of human lung fibroblast (MRC-5) with TGF-beta1 (10 ng/ml) or TNF-alpha (10 ng/ml), whereas PMA (0.02 microM) had no effect. One hour of pre-incubation with PDE4 inhibitors (10 microM) induced an inhibition of TNF-alpha-stimulated pro-MMP-2 release. Zymography and immunoblotting revealed that fibroblasts cultured with PMA or TNF-alpha released increased amounts of pro-MMP-1, whereas TGF-beta1 had no effect. Incubation with CI-1044 or cilomilast significantly prevented the TNF-alpha increase in pro-MMP-1. These results suggest that PDE4 inhibitors are effective in inhibiting the pro-MMP-2 and pro-MMP-1 secretion induced by TNF-alpha and might underline a potential therapeutic benefit of selective PDE4 inhibitors in lung diseases associated with abnormal tissue remodelling.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Determination of tranexamic acid in human serum by high-performance liquid chromatography using selective pre-column derivatization with phenyl isothiocyanate.

A high-performance liquid chromatographic method for determination of tranexamic acid in human serum using a selective derivatization has been developed. Tranexamic acid in the sample was allowed to react with phenyl isothiocyanate to form the phenylthiocarbamoyl derivative. Interfering alpha-amino acids in the sample were eliminated by selective derivatization to phenylthiohydantoin derivatives by acid treatment of the phenylthiocarbamoyl derivatives followed by solvent extraction. Then, the sample was analysed by conventional high-performance liquid chromatography with ultraviolet detection. The limit of detection of this method for serum sample was 0.2 micrograms/ml at a signal-to-noise ratio of 2. This method gave results comparable with those obtained by amino acid analysis (regression line: y = 0.4531x-0.02596, r = 0.9998, n = 21).

Amino Acids↗