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Biomedical subjects

C K Lau

Publications and source records attributed to C K Lau.

32 records · Page 2Linked to original sources
PubMed1991

Rapid induction of the c-jun protooncogene in the avian oviduct by the antiestrogen tamoxifen.

This report describes a rapid regulation of the expression of the c-jun protooncogene by the antiestrogen tamoxifen (Tam). The c-jun protooncogene codes for an important component of the AP-1 transcription factor complex, which regulates the expression of many unlinked genes. Repeated experiments have shown that Tam rapidly increases the steady-state c-jun mRNA levels in the avian oviduct but decreases the levels in the liver. The Tam effects are time- and dose-dependent. These results are supported by other studies that have demonstrated that 17 beta-estradiol decreases steady-state levels of c-jun protooncogene mRNA in oviducts of animals fully withdrawn from estradiol. The effect of Tam in the avian oviduct is in contrast to the reported effects of Tam on the expression of practically all other genes in the avian oviduct and other animal tissues. Transcription analyses using nuclear runoff experiments with oviduct nuclei demonstrate a decrease in the c-jun gene transcription within minutes after Tam treatment with a return to 75% of control values by 4 hr. The fact that Tam transiently decreases the transcription of the c-jun gene but increases the steady-state c-jun mRNA levels suggests that Tam must alter both transcriptional and post-transcriptional events. The results support a role of the c-jun protooncogene as a regulatory gene in the cascade model for steroid action whereby steroids rapidly regulate the regulatory genes, which in turn regulate many other structural genes.

Animals↗
PubMed1991

Effect of azelastine and ketotifen on the bronchial and skin responses to platelet-activating factor in humans.

In a randomized, double-blind placebo-controlled study we investigated the effect of single oral doses of 8 mg azelastine and 2 mg ketotifen on the immediate response to platelet-activating factor (PAF) inhalation and to increasing doses of PAF injected intradermally. Bronchial provocation with 100 micrograms of PAF resulted in marked bronchoconstrictor responses, but neither azelastine nor ketotifen had any significant effect on these responses. Intradermal injection of PAF (100, 200 and 400 ng) resulted in a dose-related weal and flare response. Azelastine and ketotifen both caused significant reductions in this response (P less than 0.002-P less than 0.01). There was no significant difference between the effect of the two drugs.

Adult↗
PubMed1990

Rapid inhibition of the c-jun proto-oncogene expression in avian oviduct by estrogen.

The c-jun proto-oncogene codes for an important component of the AP-1 transcription factor complex which regulates the expression of many genes. This paper demonstrates that the steady state c-jun mRNA level in the avian oviduct is markedly decreased to 50% of control values within 30 minutes after estrogen injection into the animals. In the avian liver, the level is rapidly increased over 10 fold. Nuclear run-off transcription analysis demonstrates that the decrease in the c-jun mRNA levels in the avian oviduct occurs at least in part at the level of transcription. These changes are reproducible in repeat experiments. This response in the avian oviduct is unique since 1) it is the first demonstration of a steroid effect on c-jun expression in any animal system, 2) the changes in c-jun mRNA occur much more rapidly than most steroid responsive genes, and 3) it is the rare demonstration of an estrogen inhibition of the expression of a gene. A role for the c-jun proto-oncogene as an early regulatory gene in the cascade model for steroid action is proposed.

Animals↗
PubMed1989

Synthesis and structure-activity relationships of a novel class of 5-lipoxygenase inhibitors. 2-(Phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans: the development of L-656,224.

The synthesis of a series of 2-(phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans and their inhibitory effects against leukotriene biosynthesis and 5-lipoxygenase activity in vitro are described. Many compounds in this series were found to be potent inhibitors of LTB4 production by human polymorphonuclear leukocytes with IC50 values ranging from 7 to 100 nM. Structure-activity relationships of the series are presented. Within this series, 2-[(4'-methoxyphenyl)methyl]-4-hydroxy-3-methyl-5-propyl-7-chlorobenz ofuran (L-656,224) showed extremely potent activity, inhibiting leukotriene biosynthesis in intact human leukocytes (IC50 = 11 nM), as well as the 5-lipoxygenase reaction catalyzed by cell-free preparations from rat leukocytes (IC50 = 36 nM), human leukocytes (IC50 = 0.4 microM), and the purified enzyme from porcine leukocytes (IC50 = 0.4 microM). The compound also shows oral activity in a number of animal models in vivo.

Adult↗
PubMed1989

Steroid action on gene expression: possible roles of regulatory genes and nuclear acceptor sites.

There has been exciting progress in the understanding of the mechanism of action of steroid hormones. The structures and functions of the various receptor protein domains as well as the various domains of steroid-regulated genes, including steroid response elements, are currently being elucidated. The roles of transcription factors in the steroid-altered regulation of gene transcription are just being defined. The nature of the nuclear acceptor sites, i.e. nuclear-binding sites, for steroid receptors are under investigation. The composition, location, and function of these nuclear acceptor sites for steroid receptors is crucial for understanding the mechanism of steroid regulation of gene expression. Possible roles of specific, DNA-binding, chromatin proteins in these acceptor sites have been suggested. A very rapid action of steroids on the expression of proto-oncogenes that code for nuclear regulatory proteins has recently been described. Using this information, we have proposed a novel steroid action model utilizing "regulatory genes" whereby the steroids would rapidly alter the expression of regulatory genes (early genes) whose protein products would return to the nucleus to regulate the expression of structural genes (late genes). The latter would occur via binding of these regulatory proteins (e.g. transcription factors) to the steroid-regulatory elements neighboring these late genes. This model would explain many of the characteristics reported from many laboratories on the action of steroid hormones on gene expression.

Animals↗
PubMed1989

Rapid inhibition of c-myc gene expression by a glucocorticoid in the avian oviduct.

The glucocorticoid dexamethasone (DEX) causes a rapid, reversible reduction in c-myc mRNA level in the oviducts of estrogen-treated, immature chickens. The c-myc mRNA level begins to decrease by 5 min after injection of 0.5 mg DEX, reaches a minimum of 10% of the control value by 30 min, and returns to 30-40% of the control value by 4 h post injection. This rapid effect of DEX on the c-myc mRNA level occurs in both diethylstilbestrol-stimulated and diethylstilbestrol-withdrawn oviducts. The effect is dose dependent, with reduction of the c-myc mRNA measured with as little as 10 micrograms DEX injection (0.03 micrograms/g BW). The effect of the steroid is gene specific with H2B histone mRNA displaying a significantly reduced response. The effect is also tissue specific with liver displaying an increase of 170% of control values in c-myc mRNA level by 30 min after injection of 0.5 mg DEX. The reduction of avian oviduct c-myc mRNA levels by DEX may play a role in glucocorticoid inhibition of cell proliferation in this tissue. The rapidity of the steroid effects on c-myc expression makes it likely that the steroid-induced reduction of c-myc mRNA levels represents a direct primary action of the steroid-receptor complex on the c-myc gene expression.

Animals↗
PubMed1987

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3- methyl-5-propyl-4-benzofuranol): a novel, selective, orally active 5-lipoxygenase inhibitor.

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol) was a potent inhibitor of leukotriene biosynthesis in intact rat and human leukocytes and CXBG mastocytoma cells (IC50 values, 18-240 nM) and of crude human leukocyte and highly purified porcine leukocyte 5-lipoxygenase (IC50 value, 4 X 10(-7) M). The selectivity of L-656,224 for 5-lipoxygenase was shown through the relative lack of activity of the compound on 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase, catalase, and myeloperoxidase. The compound showed (i) oral activity against hyperalgesia induced in the rat paw by injection of yeast or platelet-activating factor, (ii) dyspnea in sensitized inbred rats induced by an aerosol of antigen, and (iii) bronchoconstriction induced by an aerosol of Ascaris in squirrel monkeys, suggesting a role for 5-lipoxygenase inhibitors in the treatment of asthma and peripheral pain.

Animals↗
PubMed1983

Antimicrobial action of compound 48/80--II mechanism of action.

The mixture of compounds called compound 48/80 had been shown to have antimicrobial activity against a wide variety of microorganisms. In this paper it is shown that its primary site of attack appears to be on the membrane of the cell. In its presence, Tetrahymena became much more sensitive to osmotic stress, and alpha-methylglucose was rapidly released from preloaded Escherichia coli cells. The drug also had effects on cell viability, respiration, cell division, and the release of material absorbing at 260 nm. In general, its effects paralleled those of polymyxin B, although its structure is quite different except for the presence of amino groups and hydrophobic regions in both molecules. The activity of 48/80 was not due to detergent-like, surface-active properties and was antagonized by magnesium and other cations and by phosphatidylserine. Purification of the active principle might provide a relatively simple and readily modifiable probe of membrane function and possibly a new family of useful antimicrobial compounds.

Animals↗
PubMed1983

Synthetic leukotriene B4 is a potent chemotaxin but a weak secretagogue for human PMN.

We have examined the effects of very pure (greater than 99.8%) chemically synthesized leukotriene B4 of verified structure on the chemotactic and secretory behavior of human polymorphonuclear leukocytes (PMN). The synthetic material is highly chemotactic and shows the same concentration dependence of this activity as does natural LTB4. Synthetic LTB4 is also a weak degranulating agent in cytochalasin B treated PMN. Maximally it released 11%, 17% and 26% as much N-acetyl-beta-D-glucosaminidase, myeloperoxidase and lysozyme as did N-formyl-methionine-leucine-phenylalanine (fMLP). Thus LTB4 differs significantly from other chemotaxins, such as C5a and fMLP, in that it is a poor secretagogue for enzymes of the specific and azurophilic granules of human PMN.

Acetylglucosaminidase↗
PubMed1979

Histon-histone interactions within chromatin. Preliminary location of multiple contact sites between histones 2A, 2B, and 4.

The contact-site cross-linkers tetranitromethane, UV light, formaldehyde, and a monofunctional imido ester have been used to generate a collection of histone-histone dimers and trimers from nuclei and chromatin. Four different H2B-H4 dimers have been isolated. Preliminary CNBr peptide mapping has shown that all are cross-linked at different positions that are apparently clustered within the C-terminal regions of these histones. Similarily, two different H2A-H2B dimers and two different H2A-H2B-H4 trimers have been partially characterized. The data suggest a functional map for H2B in which the N-terminal third interacts with DNA, the middle third interacts with H2A, and the C-terminal third interacts with H4. We hope, by pursuing this type of analysis, to develop a detailed understanding of each histone-histone binding interaction through saturation cross-linking of the binding sites.

Animals↗
PubMed1977

The site of action of the histamine releaser compound 45/80 in causing mast cell degranulation.

A primary amine analog of compound 48/80 (nor-48/80) was purified and attached to Sepharose beads through an albumin link. Suspensions of rat peritoneal cells were passed over the beads in an affinity chromatography column, and the proportion of the mast cells that was retained by the beads was determined. Sixty-seven percent of the mast cells were found to be retained by the column, indicating the existence of a binding site for nor-48/80 on the exterior of mast cells. The beads were larger than the cells, and hence precluded the entry of the nor-48/80 into the cells. Neither the Sepharose beads nor the albumin link was responsible for this amount of binding because control beads without nor-48-80 retained only 22% of the mast cells. Mast cells incubated with large quantities of the beads in a batch procedure released up to 53% of the mast cell histamine, whereas control beads without the polymer released only 18%. This release could not be attributable to soluble nor-48/80 because only trace amounts of radioactive nor-48/80 were released from beads soaked overnight, and these supernatants released insignificant amounts of histamine when incubated with mast cells. These studies indicate the presence of a receptor for 48/80 on the mast cell membrane which can trigger histamine release.

Animals↗