| 1. |
- Eghbali, M, et al.
(författare)
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Hippocampal GABA(A) channel conductance increased by diazepam
- 1997
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 388:6637, s. 71-75
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Tidskriftsartikel (refereegranskat)abstract
- Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Here we show that the benzodiazepine diazepam can also increase the conductance of GABAA channels activated by low concentrations of GABA (0.5 or 5 microM) in rat cultured hippocampal neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAA channels tonically activated by low ambient concentrations of GABA in the extracellular environment may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.
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| 2. |
- Bond, C. A., et al.
(författare)
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International pharmacy
- 1995
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Ingår i: Pharmacotherapy. - 0277-0008 .- 1875-9114. ; 15:5, s. 586-591
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Tidskriftsartikel (refereegranskat)
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| 3. |
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| 4. |
- Ahmed, A. Ahmed, et al.
(författare)
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Eudesmane derivatives from Laggera crispata and Pluchea carolonesis
- 1998
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Ingår i: Phytochemistry. - : Elsevier. - 0031-9422 .- 1873-3700. ; 49:8, s. 2421-2424
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Tidskriftsartikel (refereegranskat)abstract
- Investigation of the aerial parts of Laggera crispata and Pluchea carolonesis afforded in addition to several known compounds, three new eudesmane derivatives, 3β,4α-dihydroxy-7-epi-eudesm-11(13)-ene, 3α-(2′,3′-dihydroxy-2′-methylbutanoyl)-4,11-dihydroxy-6,7-dehydroeudesman-8-one and 3α-(3′-chloro-2′-hydroxy-2′-methylbutanoyl)cuauhtemone. The structures were elucidated by spectroscopic methods
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| 5. |
- Araya, Zufan
(författare)
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Cytochrome P450 enzymes in the biosynthesis and metabolism of bile acids and active forms of vitamin D
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cytochrome P450 enzymes catalyzing hydroxylations in the biosynthesis and metabolism of bile acids and active forms of vitamin D3 were studied.A microsomal cytochrome P450 enzyme with a molecular mass of 53 kDa, catalyzing the 6α-hydroxylation of taurochenodeoxycholic acid was purfied from pig liver microsomes and characterized with respect to catalytic and electrophoretic properties as well as polyclonal antibodies. The enzyme was also characterized by N-terminal and some internal amino acid sequencings. These sequences showed similarities with those of mammalian cytochromes P450 (CYP) in the CYP4A subfamily. .CYP3A4, a major drug-metabolizing enzyme in human liver, was found to be active in and responsible for a major part of the 6α-hydroxylation of taurochenodeoxycholic acid and lithocholic acid in human liver microsomes.Purified CYP27A from pig kidney mitochondria was shown to catalyze 1α-and 27-hydroxylaton but not 24-hydroxylation of 25-hydroxyvitamin D3. The same enzyme was found to convert 25-hydroxyvitamin D3 into another hydroxylated major metabolite. Recombinantly expressed human CYP27A was able to catalyze the same hydroxylations.Regulation of rabbit liver CYP7A and CYP27A enzymes by cholic acid and cholestyramine was studied. There was no coordinate regulation of CYP7A and CYP27A at a transcriptional level. In contrast to CYP7A, CYP27A was not subject to a negative feedback control by bile acids neither at a transcriptional nor at a post-transcriptional level.A 5 kb DNA fragment of the human CYP27A gene, upstream from the translation initiation codon, was studied using luciferase reporter constructs in HepG2 cells. The DNA fragment was found to contain a functional promotor. Three fragments of the 5 kb DNA obtained after Sma I digestion were analyzed for promotor activity. DNA sequence analysis of two of the fragments revealed the presence of possible promotor sequences (TATA) in both fragments. The response of the human CYP27A-luciferase plasmid to dexamethasone, growth hormone, 1α,25-dihydroxyvitamin D3 and bile acids was studied. The transcriptional activity was induced two-fold by growth hormone and three-fold by dexamethasone. 1α,25-Dihydroxyvitamin D3 or bile acids had no significant effects on the expression of the human CYP27A gene.
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| 6. |
- Cappendijk, Susanne L T, et al.
(författare)
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A heroin-, but not a cocaine expecting, self-administration state preferentially alters brain endogenous peptides
- 1999
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Ingår i: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 365:2-3, s. 175-182
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session ('acute drug on board' state), and just before the next scheduled session ('drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the 'acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the 'drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.
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| 7. |
- Franck, Johan, et al.
(författare)
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Met-enkephalin inhibits 5-hydroxytryptamine release from the rat ventral spinal cord via delta opioid receptors
- 1996
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 35:6, s. 743-749
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Tidskriftsartikel (refereegranskat)abstract
- The effect of opioid receptor agonists and antagonists on the electrically evoked release of endogenous serotonin (5-hydroxytryptamine, 5-HT) was studied in superfused slices of the rat ventral lumbar spinal cord. Met-ENK (1 x 10(-8)M-1 x 10(-6)M) and DPDPE (1 x 10(-8)M-1 x 10(-6)M) reduced the evoked 5-Ht release in a concentration dependent fashion. DAMGO (1 x 10(-8)-1 x 10(-6)) and (-)-trans-(1S,2S)-U-50488 (1 x 10(-6)M) had no effect on the 5-HT release. The inhibitory effect of met-ENK was completely abolished by ICI-174,864, but neither by naloxonazine nor nor-binaltorphimine. Following i.c.v. treatment with 5,7-dihydroxytryptamine (5,7-DHT), the tissue concentration of 5-HT was reduced by 97%, whereas the concentration of noradrenaline was reduced by only 5%. The tissue concentration of met-ENK, as measured by radioimmunoassay, was not significantly altered. The results suggest that met-ENK is present in the rat ventral spinal cord mainly in non-serotonergic nerve terminals and exerts an inhibitory action on 5-HT release via delta opioid receptors.
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| 8. |
- Gibreel, Amera
(författare)
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Characterization of resistance to quinolones, sulfonamide and trimethoprim in Campylobacter jejuni as well as to macrolides in the related bacterium, Helicobacter pylori
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gastroenteritis caused by C. jejuni is usually a mild to moderate self-limiting disease. Treatment is recommended in some cases. In recent years, quinolones have been increasingly used to treat acute bacterial enteritis. Quinolone resistance in clinical isolates of C. jejuni in Sweden increased more than 20-fold at the beginning of 1990s. Quinolone resistance in C. jejuni was found to be associated with chromosomal mutations leading to a Thr-86-to Ile substitution in the gyrA gene and an Arg-139-to Gln substitution in the parC gene.Sulfonamides and trimethoprim have always been considered as inefficient antimicrobial agents for the treatment of Campylobacter infections. Detailed studies regarding the molecular basis of resistance to sulfonamide and trimethoprim in C. jejuni are lacking. Further data about the molecular basis of resistance might be a good contribution to the general understanding of the nathogenicity of C. jejuni. Resistance of C. jejuni to a high-level of trimethoprim was found to be due to the acquisition of dfr genes expressing-drug-resistant variants of the target enzyme, dihydrofolate reductase (DHFR). The most commonly found gene was dfr1 but another gene, dfr9,was also detected. These genes were observed to be chromosomally located in an integron and a transposon context, respectively. In some cases, a 90 bp repeat-containing variant of the dfr1 gene was detected. Moreover, in 5% of the examined C. jejuni strains, the repeat-containing dfr 1 variant was found to occur in the form of two cassettes in tandem located in an integron context. The existence of the 90 bp repeat within the coding sequence of the dfr 1 gene was found to play a role in the adaptability of C. jejuni isolates to the variation in the selection pressure induced by trimethoprim.The acquisition of sulfonamide resistance, however, was found to be associated with the mutational substitution of four amino acid residues in the chromosomal folP gene of C. jejuni. Kinetic measurements established different affinities of sulfonamide for the DHPS enzyme isolated from the resistant and susceptible strains.Treatment regimen with clarithromycin has been found to cure H. pylori infection efficiently. The development of macrolide resistance should be monitored during the course of the treatment. Transition mutations in the 23S rRNA gene at locations corresponding to macrolide resistance in other bacteria were observed. No other mechanisms of resistance were detected.
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| 9. |
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| 10. |
- Hansson, Karin
(författare)
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Characterization of a site-specific gene-transfer mechanism in bacteria
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Integrons capture and rearrange single genes borne on mobile units called cassettes using site-specific recombination. The integrons increase the variation of antibiotic resistance among bacterial plasmids and may also reorganize clustered genes in bacterial genomes.The integrons consist of a conserved sequence coding for a recombinase of the lambda phage integrase family, and adjacent cassettes in tandem. Palindromic recombination sites, attC, occur 3' of all cassettes but the conserved sequence is joined to the cassettes by another type of site, attI. All sites contain a core with the reactive sequence GTT.Constructed deletions and point mutations were used to characterize attC and attI. Evidence was found that attC contains two symmetrical and co-operating subsites. The subsite containing the core was 1000-fold more reactive than that containing an inverse core. Mutations in the inverse core reduced recombination at the remote core strongly which suggests that the low-reactive end in attC has significance for the assembly of a synaptic nucleoprotein complex. The low-reactive end of attC could furthermore be used to fuse the site to sequences in the process of being recruited to new cassettes.Most integrations of cassettes occurred at attI. Recombination between two attI sites responded to upstream deletions progressing closer than 9-14 bp from the core. Recombination with an attC-site required another area of the conserved sequence 32 bp from the core of attI. The cross-over point was localized between G and TT in the core.Nucleotide sequencing of integrons documented new cassettes harboring ORFS, the dihydrofolate reductase gene dfr2a and a new spectinomycin resistance gene aadA4.The integron of class 2 in Tn7 was sequenced and functionality was demonstrated after mutagenesis of an internal stop codon in the integrase gene. Also the third class of integron was shown to be functional. Limited cross-specificity between the three integron classes was observed.The integrases of integron classes 1 and 3 were expressed as polyhistidine conjugates and purified by metal ion affinity chromatography. The purified recombinases catalyzed site-specific recombination in cell-free reactions stimulated by the architectural proteins HU and IHF.
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