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D J Reynolds

Publications and source records attributed to D J Reynolds.

At least 55 records · Page 3Linked to original sources
PubMed1993

Characterization of metal ion-induced [3H]inositol hexakisphosphate binding to rat cerebellar membranes.

The binding of [3H]inositol hexakisphosphate ([3H] InsP6) to rat cerebellar membranes has been characterized with the objective of establishing the role, if any, of a membrane protein receptor. In the presence of EDTA, we have previously identified an InsP6-binding site with a capacity of approximately 20 pmol/mg protein (Hawkins, P. T., Reynolds, D. J. M., Poyner, D. R., and Hanley, M. R. (1990) Biochem. Biophys. Res. Commun. 167, 819-827). However, in the presence of 1 mM Mg2+, the capacity of [3H]InsP6 binding to membranes was increased approximately 9-fold. This enhancing effect of Mg2+ was reversed by addition of 10 microM of several cation chelators, suggesting that the increased binding required trace quantities of other metal cations. This is supported by experiments where it was possible to saturate binding by addition of excess membranes, despite not significantly depleting radioligand, pointing to removal of some other factor. Removal of endogenous cations from the binding assay by pretreatment with chelex resin also prevents the Mg(2+)-induced potentiation. Consideration of the specificity of the chelators able to abolish this potentiation suggested involvement of Fe3+ or Al3+. Both these ions (but not several others) were able to increase [3H]InsP6 binding to chelex-pretreated membranes at concentrations of 1 microM. It is possible to demonstrate synergy between Fe3+ and Mg2+ under these conditions. We propose that [3H]InsP6 may interact with membranes through non-protein recognition, possibly via phospholipids, in a manner dependent upon trace metals. The implications of this for InsP6 biology are considered.

Animals↗
PubMed1993

Terephthalic acid in Sprague-Dawley rats as a hypolipidemic agent.

Terephthalic acid at 20 mg/kg/day in lowered serum cholesterol and triglyceride levels in rats. The cholesterol content was lowered in the lipoprotein fractions. The effects of the agents on de novo lipid synthesis showed that similar enzymes were affected in rat liver and small intestinal mucosa cells as when compared to in vitro tissue culture cells from rats and humans, e.g. reduction of acyl CoA cholesterol acyl transferase and elevation of neutral cholesterol ester hydrolase activities suggest that net cholesterol esters deposition in foam cells should be reduced and plaque growth should be slowed. The suppression of LDL receptor binding and degradation by the drug suggest that less apoB lipoproteins are taken up by peripheral tissues. The elevated HDL receptor binding and internalization in the liver suggest that the drug accelerates cholesterol return to the liver. Additional studies show that cholesterol and bile acid secretion in the bile is elevated. However, the bile acids secreted are not lithogenic. Acute toxicity studies show that the agent appears to be safe in rodents. Two observations of increased serum alkaline phosphatase levels and increased liver vacuolation suggest some alteration of hepatic cell morphology, which requires further investigation.

Animals↗
PubMed1993

The hypolipidemic effects of 2-furoic acid in Sprague-Dawley rats.

2-Furoic acid was shown to be effective in lowering both serum cholesterol and serum triglyceride levels significantly in rats with an elevation of HDL cholesterol level at 20 mg/kg/day orally. LDL receptor activity was reduced in hepatocytes, aorta foam cells, small intestinal epithelium cells and fibroblasts. HDL receptor activity was elevated in the rat hepatocytes and small intestinal cells. These activities were correlated with inhibition of acyl CoA cholesterol acyl transferase activity. Neutral cholesterol ester hydrolase activity was elevated in rat hepatocytes and human fibroblasts. Thus, 2-furoic acid appears to interfere directly with activity of intracellular enzymes rather than affecting high affinity-mediated lipoprotein membrane receptors. In vivo treatment with 2-furoic acid led to reduction in the liver and small intestine ATP dependent citrate lyase, acetyl CoA synthetase, acyl CoA cholesterol acyl transferase, sn-glycerol 3-phosphate acyl transferase, phosphatidylate phosphohydrolase and heparin induced lipoprotein lipase activities. 2-Furoic acid reduced biliary cholesterol levels but the agent increased bile salts which are lithogenic. Acute toxicity studies in mice suggest that the agent has some hepatic toxicity effects. The LD50 was relatively low at 250 mg/kg IP in mice.

Animals↗
PubMed1993

Hypolipidemic effects of 6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid in rats and tissue culture cells.

6-Amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid (AMMPCA) was found to be a potent hypolipidemic agent at oral doses of 10 and 20 mg/kg/day in rodents. This agent was observed to affect de novo lipid synthesizing enzyme activities in a manner that resulted in lower lipid levels in tissues including the aorta wall. Very low density lipoprotein and low density lipoprotein cholesterol levels were reduced, whereas high density lipoprotein cholesterol levels were significantly increased. AMMPCA interfered with low density receptor activity, suggesting that the drug blocked lipid uptake by peripheral tissue while stimulating binding of lipid to the high density lipoprotein receptor, which should accelerate lipid clearance from the tissues and blood. A second mode of action of the drug is enhanced biliary excretion of lipids, but there was no evidence of a lithogenic effect. Acute toxicity studies in rodents support the fact that AMMPCA is safe in its therapeutic dose range.

Animals↗
PubMed1993

Comparison between 6,7-dihydro-5H-dibenz(c,e)azepine and lovastatin as hypolipidemic agents in rats.

6,7-Dihydro-5H-dibenz(c,e)azepine (azepine) and lovastatin were investigated for their hypolipidemic activity in Sprague-Dawley male rats. Azepine lowered both serum total cholesterol and serum triglyceride levels, whereas lovastatin only lowered serum total cholesterol levels significantly. Lovastatin also elevated lipid levels in tissues, whereas azepine in general did not have a similar effect. High-density lipoprotein cholesterol levels were significantly elevated and low-density lipoprotein cholesterol levels were reduced after treatment with both agents. Concentrations of ApoE and ApoAl of high-density lipoprotein were increased after treatment, a result that should enhance the reverse cholesterol transport process of returning cholesterol to the liver for excretion. Azepine appeared to be safe in its therapeutic range in rodents.

Administration, Oral↗
PubMed1993

Identification of T-cell stimulatory antigens of Chlamydia trachomatis using synovial fluid-derived T-cell clones.

Chlamydia trachomatis is a major cause of sexually transmitted disease, infertility and reactive arthritis in the Western world, and of trachoma in the developing world. There is evidence that the chronic inflammatory reaction seen in diseases associated with chlamydiae represents a delayed-type hypersensitivity response to chlamydial antigens. Little is known about which chlamydial antigens elicit T-cell responses yet such information could have important implications in terms of both immunopathological understanding of these diseases and immunoprophylaxis design. In this study, 61 chlamydia-specific T-cell clones have been produced from the synovial fluid of an individual with sexually acquired reactive arthritis (SARA). Ten clones have been characterized in detail and used to identify T-cell stimulatory antigens of chlamydiae by means of T-cell immunoblotting. Two distinct antigenic fractions have been identified, one recognized by three of the clones (molecular weight 18,000), the other recognized by six of the clones (molecular weight 30,000). The fractions are distinct from the major outer membrane protein, the 57,000 MW stress protein and the 60,000 MW cysteine-rich membrane protein of chlamydiae. The major histocompatibility complex (MHC) restriction of the response to these antigens differed: clones recognizing the 18,000 MW antigen required antigen-presenting cells expressing DR1 subtype DRB1*0101 or DRB1*0102 which only differ at amino acids 85 and 86 on the DR beta-chain; by contrast clones recognizing the 30,000 MW antigen were presented to only by antigen-presenting cells from DRB1*0101 individuals, reflecting extreme sensitivity of these clones to the polymorphism at positions 85 and 86 on the DR beta-chain.

Adult↗
PubMed1992

Pharmacology of the 5-hydroxytryptamine-induced depolarization of the ferret vagus nerve in vitro.

Grease-gap recordings revealed that 5-hydroxytryptamine (5-HT) depolarized the ferret vagus nerve (pEC50 = 4.9). This response was mimicked by 2-methyl-5-HT and 1-phenylbiguanide, but not by 5-carboxamidotryptamine. Paroxetine (1 microM) or ketamine (10 microM) did not potentiate the response. Ketanserin (1 microM) did not reduce the depolarization, but four 5-HT3 receptor antagonists did. It is concluded that 5-HT depolarizes the ferret vagus nerve via 5-HT3 receptors, but these receptors may differ pharmacologically from those in other species.

Animals↗
PubMed1992

Di- and triester prodrugs of the varicella-zoster antiviral agent 6-methoxypurine arabinoside.

6-Methoxypurine arabinoside (9-beta-D-arabinofuranosyl-6-methoxy-9H-purine, 1) has potent and selective activity against varicella-zoster virus in vitro. An unfavourable metabolic profile observed with oral dosing in the rat led to the preparation of a variety of 2',3',5'-triesters (2a-n) and several 2',3'-, 2',5'-, and 3',5'-diesters of this arabinoside (3a-n, 4a-f, and 5a-j, respectively). The compounds were evaluated as prodrugs by measuring the urinary levels of 1 in rat urine after oral dosing. With the exception of triacetate 2a, the triesters failed to significantly enhance bioavailability. Administration of compound 2a resulted in a 3-fold increase in systemic availability of 1, possibly because of its increased water solubility (1.6 times more soluble than 1) and only slightly increased relative log P value (1.93 vs 0.50 for 1). The longer chain aliphatic triesters and aromatic triesters had lower water solubilities and increased lipophilic partitioning. These factors might account for the lower systemic bioavailability of these compounds. In contrast, the diesters, especially the aliphatic diesters, showed significantly improved systemic availability. This might be a consequence of the higher aqueous solubilities and enhanced partition coefficients seen with these compounds. 2',3'-Diacetate 3a showed the best combination of high systemic availability and water solubility of all the prodrugs of 1.

Administration, Oral↗
PubMed1992

The effects of N(4-methylphenyl)diphenimide on lipid metabolism of Sprague Dawley rats.

N(4-Methylphenyl)diphenimide proved to be an effective hypolipidemic agent in rats at 10 and 20 mg/kg/day. Both serum cholesterol and triglyceride levels were reduced significantly. Decreases in tissue lipids as well as VLDL cholesterol levels were observed. HDL-cholesterol was elevated even at 10 mg/kg/day. The agent was equally effective in hyperlipidemic diet-induced rats, lowering serum lipids and VLDL- and LDL-cholesterol while elevating HDL-cholesterol levels. The drug interfered with the incorporation of 3H-cholesterol and 3H-palmitic acid into chylomicrons, VLDL, and LDL. The two precursors were incorporated at a higher rate into HDL. 3H-Leucine was incorporated into chylomicrons, VLDL, and LDL at a higher rate, but not into HDL. Reduced uptake of the precursor for lipid synthesis was noted in tissues after treatment with the drug.

Animals↗
PubMed1992

The effects on lipid metabolism of 4-phenyl-5,5-dicarbethoxy-2-pyrrolidenone in Sprague Dawley rats.

4-Phenyl-5,5-dicarbethoxy-2-pyrrolidenone [XIV] treatment in Sprague Dawley rats caused significant reduction of serum cholesterol and triglyceride levels with reduction of VLDL and LDL cholesterol levels. The compound significantly reduced regulatory enzyme activities, e.g. ATP dependent citrate lyase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha-hydroxylase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. In tissue cultured cells, the compound suppressed LDL receptor activity and degradation, and elevated HDL receptor activity and HDL degradation. Rat bile cholesterol and phospholipids were elevated; however, overall bile acids were reduced. In situ loop studies suggest that the agent interfered with interhepatic reabsorption of cholesterol and cholic acids. At the therapeutic dose of compound XIV, no deleterious effects were demonstrated in mice.

Animals↗
PubMed1991

Cisplatin-evoked induction of c-fos protein in the brainstem of the ferret: the effect of cervical vagotomy and the anti-emetic 5-HT3 receptor antagonist granisetron (BRL 43694).

We have monitored the expression of c-fos protein in the medulla oblongata of the ferret, using immunocytochemistry, to identify the brainstem pathways involved in the mediation of nausea and vomiting caused by the antineoplastic drug cisplatin. Cisplatin administration resulted in c-fos-like immunoreactivity (FLI) in the area postrema, the nucleus of the solitary tract, and in scattered cells within the ependymal lining of the fourth ventricle. Unilateral cervical vagotomy greatly reduced FLI in the ipsilateral nucleus of the solitary tract but did not significantly affect reactivity in the contralateral solitary tract nucleus or in the area postrema. Pretreatment of the animals with the 5-HT3 antagonist granisetron (BRL 43694) abolished the retching and vomiting caused by cisplatin and markedly reduced the cisplatin-evoked FLI in the nucleus of the solitary tract; treatment with this drug had no significant effect on cisplatin-evoked FLI in the area postrema. The results suggest that cisplatin induces c-fos gene expression in the nucleus of the solitary tract by an action involving vagal afferent pathways and also by a vagally independent, direct action on the area postrema. The anti-emetic 5-HT3 antagonist drug granisetron mimicked the effect of vagotomy on c-fos protein induction suggesting that it may act via 5-HT3 receptors known to be associated with vagal afferent terminals. The FLI seen in the area postrema was neither vagally dependent nor was it abolished by granisectron.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Zoonoses and other findings in hedgehogs (Erinaceus europaeus): a survey of mortality and review of the literature.

A survey of mortality in hedgehogs (Erinaceus europaeus) was carried out between July 1976 and November 1986. Most were from Norfolk. Of the 74 examined, 35 (47.3 per cent) were road casualties, one of which yielded Salmonella typhimurium phage type (PT) 104. Of the remaining 39, 13 (33.3 per cent) had salmonellosis due to S enteritidis PT 11. This organism, which appears to be common and widespread in hedgehogs in England was found in 10 separate incidents. The only other zoonosis was ringworm (Trichophyton erinacei infection). Other findings included ectoparasitic infestations with mange mites (Caparinia tripilis), fleas (Archaeopsylla erinacei) and ticks (Ixodes hexagonus). Helminths comprised Crenosoma striatum lungworms (associated with Bordetella bronchiseptica infection in one animal), intestinal nematodes (Capillaria species), cestodes (Rodentolepis erinacei), trematodes (Brachylaemus erinacei) and acanthocephalans (Prosthoryhnchus species). Metaldehyde poisoning was diagnosed in three animals. Over a 10 year period 370 carcases were counted on a stretch of 18 miles of road in Norfolk. The major causes of mortality are probably road casualties and hypothermia during the winter months. In December 1988 S enteritidis PT 11 was isolated from three of four carcases examined in Berkshire and the zoonosis pseudotuberculosis (Yersinia pseudotuberculosis infection) was diagnosed in two of them.

Animals↗