Search PubMed⌕ Search

Biomedical subjects

G Beck

Publications and source records attributed to G Beck.

At least 91 records · Page 5Linked to original sources
PubMed1991

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Adolescent↗
PubMed1991

Purification and biochemical characterization of an invertebrate interleukin 1.

Interleukin 1 (IL-1) is a major immunoregulatory protein released by macrophages with many host defense related properties. That IL-1 has been found in the invertebrates attests to its importance in homeostasis. The first step in comparing the vertebrate protein to its invertebrate correlate is to purify the protein to study. We have purified to homogeneity IL-1 isolated from the coelomic fluid of the starfish Asterias forbesi. The IL-1 had isoelectric points of 7.4, 5.4 and 4.8. The pI 4.8 species had a molecular weight of 22,000 and the pI 7.4 and 5.4 species both had Mr of 17,000. Higher Mr forms were also found. These molecules were biologically active in the human melanoma A375 cytotoxicity assay for IL-1, and were also able to stimulate murine dermal fibroblast proliferation, protein synthesis, and PGE2 production. The pI 4.8 and 5.4 forms were purified to homogeneity and the amino acid composition was determined. The pI 4.8 and 5.4 species were purified more than 200-fold to specific activities of 3 x 10(6) and 1 x 10(6) units mg-1, respectively. The pI 7.4 form was isolated and partial N-terminal sequence analysis was performed. The similarities of molecular weight, isoelectric points and biological properties between vertebrate and invertebrate IL-1 show that it is an important, evolutionarily stable host defense molecule.

Amino Acid Sequence↗
PubMed1991

Primitive cytokines: harbingers of vertebrate defense.

The evolution of the immune system has awarded cytokines a key role as coordinators of the immune response. The exquisite action of cytokines in fine tuning and controlling the response raises the question of whether or not these molecules have been highly conserved through evolution. Gregory Beck and Gail Habicht have isolated and characterized two major cytokines, interleukin 1 and tumor necrosis factor, from invertebrates. In this article, they speculate on the possible function of these molecules and on the existence of other cytokines in invertebrates.

Animals↗
PubMed1991

Inhibition of growth by the antihormone RU486 in different hepatoma cell lines.

The synthetic steroid RU486 (17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-estra-4,9-dien-3-one), which has been shown to display antiprogestin and antiglucocorticoid properties in different systems, exerts antiglucocorticoid effects and inhibits the cell growth in a concentration-dependent manner on Reuber rat hepatoma cell variants. This effect can be observed on glucocorticoid-sensitive cells, containing glucocorticoid receptors, and on glucocorticoid-resistant cells displaying a very low level of dexamethasone binding. Metabolization of RU486 occurs in different glucocorticoid-resistant hepatoma variants; these cells are less sensitive to the growth inhibitory effect of the antihormone than the steroid-sensitive cells which do not metabolize RU486. Thus, metabolization of RU486 must also be taken into account for the efficacy of this antagonist on cell growth.

Aminoglutethimide↗
PubMed1991

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.

A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.

Animals↗
PubMed1991

Mediators, initiating the inflammatory response, released in organ culture by full-thickness human skin explants exposed to the irritant, sulfur mustard.

Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so, because injury to the skin can be made in vitro, eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies, the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then, the explants were cultured in small Petri dishes, usually for 18 h at 36 degrees C, and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme, trypsin-like and chymotrypsin-like proteases, acid phosphatase, beta-glucuronidase, beta-galactosidase, lysozyme, deoxyribonuclease, ribonuclease, interleukin 1, and lactic dehydrogenase. However, the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity, and often prostaglandin E2, when compared to culture fluids from control explants. After 3 to 4 d in culture, full-thickness human skin explants, when exposed to 0.2% SM (but not when exposed to 1.0% SM), sometimes showed separation of the epidermis and increased collagenase activity (i.e., hydroxyproline release). Thus, histamine (from local mast cells), and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.

Administration, Cutaneous↗
PubMed1991

Evidence for a functional glucocorticoid responsive element in the Epstein-Barr virus genome.

Glucocorticoids induce the expression of Epstein-Barr virus early antigens in latently infected Daudi cells. By sequence analysis, we found that fragment C of the BamHI digested Epstein-Barr virus B95-8 genome contains a region with a large degree of homology to the glucocorticoid responsive element of known glucocorticoid-regulated genes. By transfection experiments in Daudi and HeLa cells, different lengths of this region, cloned in front of the bacterial chloramphenicol acetyl transferase linked to the Herpes Simplex virus thymidine kinase promoter (pBLCAT.2), were assayed for their responsiveness to dexamethasone; our results led us to the conclusion that the hormonal effect observed was mediated by a minimal sequence of 15 base pairs presenting 85% homology with the consensus glucocorticoid responsive element sequence.

Base Sequence↗
PubMed1990

Effect of phenobarbital on the glucocorticoid receptor in rat hepatoma cells.

Phenobarbital is a potent inducer of several liver-specific genes such as those encoding detoxication enzymes, including cytochromes P450. However, the mechanisms of action of the barbiturate are poorly understood. Since both, phenobarbital and glucocorticoids, are capable of inducing the same cytochrome P450 species, we asked whether the glucocorticoid receptor could participate to the phenobarbital induced responses. The results presented here show that phenobarbital was able to induce a two-fold increase in the affinity of the glucocorticoid receptor for the binding of dexamethasone, as well as a 30% increase of the receptor number in Reuber rat hepatoma cells of the Fao line. These effects may have a biological significance since they were paralleled by an enhancement of the dexamethasone-induced tyrosine aminotransferase activity, a glucocorticoid inducible function in rat hepatoma cells and in rat liver. To our knowledge, phenobarbital is the first compound shown to be able to induce, in intact cells, an increase in the affinity of the glucocorticoid receptor for the binding of its ligand.

Animals↗
PubMed1990

The processed pseudogene of mouse thymidine kinase is active after transfection.

Aside of the gene coding for cytoplasmic thymidine kinase, the genome of mouse cells carries two pseudogenes. Both are inactive in situ. One of the pseudogenes is a processed pseudogene in which a two base pair deletion caused a shift of the reading frame and a shortening of the gene product from the 233 amino acids of thymidine kinase to 177 amino acids in the pseudogene product. We report here that introduction of this pseudogene into LTK- cells gave rise to cells with a thymidine kinase positive phenotype. The transformed cells carried multiple copies of the pseudogene the upstream region of which exhibited low but measurable promoter activity. Replacement of the upstream region of the pseudogene by a promoter of Simian virus 40 or of the mammary tumor virus resulted in high transfection efficiencies and in cell lines exhibiting high thymidine kinase activities.

Animals↗
PubMed1990

The steroid antagonist RU38486 is metabolized by the liver microsomal P450 mono-oxygenases.

Microsomal preparations from adult male rat liver actively oxidized RU38486 into the 11 beta-monodemethylated, 11 beta-didemethylated and 17 alpha-hydroxylated derivatives, metabolites which are known to be formed in vivo. These oxidative reactions were inhibited at different degrees by P450 chemical inhibitors. Pretreatment of the animals by P450 mono-oxygenase prototype inducers led to drastic changes in RU38486 metabolization. Methylcholanthrene treatment carried out a significant decrease while phenobarbital markedly increased the metabolic activity of the liver microsomes. Moreover, antibodies to methylcholantrene-inducible P450 forms did not affect the metabolic activity while a complete blockade-of RU38486 oxidation was observed in the presence of antibodies to phenobarbital- inducible forms. The present results demonstrate that liver P450 mono-oxygenases are engaged in different oxidative steps of RU38486 metabolism and that phenobarbital-inducible but not methylcholanthrene-inducible P450 forms are active in RU38486 degradation.

Aging↗
PubMed1990

Isolation, preliminary chemical characterization, and biological activity of Borrelia burgdorferi peptidoglycan.

Peptidoglycan (PG), an essential cell wall polymer of most bacteria, has been isolated from many species of spirochetes. Our interest in the host response to Borrelia burgdorferi led us to isolate and characterize its PG. Extracted cells were solubilized with warm 1% SDS followed by digestion with proteases. Amino acid analysis of the isolated PG demonstrated the presence of alanine, glycine, glutamic acid, and ornithine as occurs in other spirochetes and bacteria. Intense erythematous reactions were observed after id injection of 10 micrograms of PG into normal human skin. PG was not mitogenic for human peripheral blood mononuclear cells. Murine splenocytes of certain strains responded to the PG, but only at concentrations of 25 micrograms/ml or more. PG stimulated macrophages to produce interleukin 1. Sixteen micrograms of PG injected iv into rabbits produced biphasic fevers. These observations on the in vitro and in vivo activities associated with the cellular components of the B. burgdorferi spirochete give further insight to how a small number of invading organisms can cause a multisystemic disease such as Lyme disease.

Amino Acids↗
PubMed1990

Interaction of C1q with its receptor on cultured cell lines induces an anti-proliferative response.

The receptor for human C1q (C1qR) is expressed on a wide variety of somatic cells, including cultured cell lines of different lineages such as Raji, Daudi, Wil2WT, U937, and Molt4. In this report, we present evidence which shows that culturing of C1qR-expressing cell lines with C1q inhibits their growth. When each of the different cell lines were cultured for 5 days with or without various concentrations (5-50 micrograms/ml) of micro-filtered (0.22 micron) C1q, cell proliferation was inhibited in a dose-dependent manner with maximal inhibition (90%) occurring at a concentration of 50 micrograms/ml at Day 4 of culture. This anti-proliferative effect of C1q was inhibited when 30 micrograms/ml of F(ab')2 anti-C1q was included in the culture with C1q while the antibody alone did not have any effect. The specificity of this interaction was further substantiated by the finding that neither macromolecular C1, or subcomponents C1r and C1s, nor human or murine IgG nor IgM had any inhibitory activity when cultured with these cell lines. That this C1q-induced inhibition of cell growth is mediated by C1qR was deduced from experiments in which (i) culturing of cells in the presence of two IgM monoclonal antibodies II1/D1 and II1/B5, directed against the C1q-binding site of C1qR resulted in the inhibition of cell growth while nonimmune murine IgM did not, and (ii) the collagenous portion of C1q (c-C1q) which contains the intact, C1qR-binding domain was also capable of inhibiting cell proliferation in a manner similar to intact C1q. The effect of C1q was not cytotoxic but cytostatic since the number of dead cells in the C1q-treated cultures was not significantly different than that in the untreated cells (5% vs 4%), a figure which represents the normal wear and tear of tissue culture conditions. On the basis of these findings we propose that the C1qR alone or in conjunction with other cellular factors may function as a molecule which supports cell growth. Upon ligand binding, however, the ligand-receptor interaction may suppress postreceptor events which are necessary for cell proliferation.

Carrier Proteins↗
PubMed1990

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids.

Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.

Acetates↗
PubMed1990

Vascular stenting in normal and atherosclerotic rabbits. Studies of the intravascular endoprosthesis of titanium-nickel-alloy.

Percutaneous transluminal balloon angioplasty would be more effective if the rate of recurrent stenosis were reduced. To evaluate the prevention of restenosis after percutaneous transluminal angioplasty, intravascular endoprosthetic stents of titanium-nickel-alloy were implanted transluminally in seven normal and 21 atherosclerotic rabbits. In normal rabbits, a 3.5-mm diameter stent was implanted in the aorta and a 2.5-mm diameter stent in the right iliac artery, which were followed with serial angiograms from 6 weeks (n = 7) to 8 months (n = 4). There was a mean stenosis of 13.1% in the 2.5-mm and 13.6% in the 3.5-mm stent. There was no significant narrowing compared with the adjacent control segments of artery; histopathology showed a thin, fibrous neointima with smooth muscle cells. Each atherosclerotic rabbit was balloon dilated at two separate stenotic sites; each site was 2.0 cm in length. The aortic site (with 28.8 +/- 13.8% mean stenosis [+/- SD]) was dilated with a 3.5-mm balloon, and the iliac site (with 36.5 +/- 14.2% stenosis) was dilated with a 2.5-mm balloon. In each site, an intravascular stent of corresponding diameter and 7-mm length was implanted in one half of the dilated segment, assigned randomly, and the other half served as the angioplasty control. Angiographically observed restenosis rates and the corresponding histopathology were similar in the atherosclerotic segments that had angioplasty alone versus the atherosclerotic segments that had angioplasty plus stenting. The mean neointimal thickness in the aortas and iliac arteries, respectively, measured 247 +/- 181 microns (+/- SD) and 218 +/- 77 microns after 6 weeks (n = 8) versus 321 +/- 168 and 308 +/- 189 microns after 20 weeks (n = 5, p = NS). At 20 weeks follow-up, there was 29.1 +/- 29.8% (median, 16.4%) stenosis in the aortic stent versus 38.9 +/- 24.1% (median, 34.0%) stenosis in the percutaneous transluminal angioplasty control segment of aorta (n = 5, p = NS) and 81.4 +/- 25.5% stenosis in the iliac artery stent versus 89.3 +/- 15.3% stenosis in the PTA control segment of the right iliac artery (n = 5, p = NS). Comparing stenotic arterial segments treated with angioplasty alone with angioplasty plus intravascular stenting in the atherosclerotic rabbits showed that there was no significant difference in either the histopathologic changes or the restenosis rates.

Alloys↗
PubMed1990

[Characterization of liver tyrosine aminotransferase in rats using an immunoaffinity technic].

Antisera directed against synthetic peptides with sequences that correspond to selected regions of tyrosine aminotransferase may react with the protein without affecting its biological activity. The antiserum against the theoretical N-terminal dodecapeptide recognizes the enzyme and makes it possible to detect a blocked form of the enzyme. Another form shortened by seven aminoacids and starting with Thr 8 has been found. The isolation of tyrosine aminotransferase by one step affinity chromatography is now made possible; nevertheless the elution procedure remains a critical point. The strategy described should have further applications and allow the detailed exploration of the essential domains of aminotransferases, especially those involved in the function and the degradation of pyridoxal phosphate requiring enzymes.

Animals↗
PubMed1989

Role of leukotrienes and platelet activating factor in acute gastric mucosal lesions in rats.

Leukotriene C4 (LTC4) and platelet activating-factor (PAF) were found to affect gastric microcirculation and mucosal integrity but their role in acute gastric damage has not been established. The present study with rats confirms that exogenous LTC4 (10 micrograms/kg.h s.c.) or PAF (10 micrograms/kg i.p.) alone caused only mild gastric mucosal injury but greatly augmented mucosal lesions produced by other irritants such as absolute ethanol, taurocholate, aspirin or stress. These acute lesions were accompanied by a significant increase in mucosal generation of LTC4, and the addition of PAF further increased it. Pretreatment with BN 52021, a PAF receptor antagonist, abolished PAF-induced gastric lesions and reduced LTC4 generation in tests with PAF plus ethanol. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, and FPL 55712, an LTC receptor-antagonist, reduced dose dependently the extent of gastric damage in various models of gastric lesions. Again, these protective effects were accompanied by a reduction in mucosal LTC4 formation. In addition, the protection induced by nordihydroguaiaretic acid was reversed in part by the pretreatment with indomethacin, suggesting that it could be attributed to increased biosynthesis of protective PG. The results indicated that LTC4 biosynthesis is increased in various forms of gastric damage and that LTC4 may be involved in the pathogenesis of this damage.

Animals↗
PubMed1989

The frog palate mucosa as a model for studying bacterial adhesion to mucus-coated respiratory epithelium.

Most of the methods proposed to quantify bacterial adherence to respiratory mucosa differ mainly from in vivo conditions in the absence of the mucus blanket and in the exposure of the sub-mucosal connective tissue (SMCT) to the micro-organisms. We propose the frog palate as a model to study bacterial adhesion to the respiratory mucosa, with a system which allows the mucus to be preserved and the bacterial adhesion to be quantified in a standardized mucosal area, where mucociliary transport is still active. In order to evaluate the role of respiratory mucus in bacteria-mucosa interaction, we compared the adhesion of radiolabelled pneumococci to 12 mucus-coated and 10 non-mucus-coated frog palate mucosae. The presence or absence of mucus was controlled by scanning electron microscopy (SEM). After a 10 min incubation period, the bacterial adhesion to mucus-coated palate mucosa was five times greater (P less than 0.01) than that to uncoated mucosa. By SEM, bacteria were never seen attached to ciliated cells but could be detected on small areas where mucus was not totally eliminated. Even after a 120 min contact of bacteria to uncoated mucosa, bacterial adhesion remained only half that to mucus-coated epithelium. In order to ascertain whether the exposure of the SMCT represented a means of attraction to bacteria, we incubated the frog palate mucosa face-down with radiolabelled Pseudomonas aeruginosa. As much as 44 per cent of added bacteria adhered to exposed SMCT and, by SEM, numerous micro-organisms were seen attached to connective tissue. In contrast, only a few bacteria were observed adhering to the mucosa, mainly to granules of mucus.

Animals↗