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Biomedical subjects

A Faller

Publications and source records attributed to A Faller.

At least 19 recordsLinked to original sources
PubMed2002

CD23 shedding: requirements for substrate recognition and inhibition by dipeptide hydroxamic acids.

CD23 (low affinity IgE receptor, FcepsilonRII) is expressed as a Type II extracellular protein on a variety of cells such as B cells, monocytes and macrophages and is cleaved from the cell surface to generate several distinct fragments. The expression of CD23 on the cell surface as well as the generation of soluble fragments of CD23 has been shown to be involved in regulation of IgE synthesis. CD23 is released from the cell surface by a metalloprotease, analogous to the cleavage of other cell surface molecules such as TNF-alpha. This activity has been extensively studied with respect to biochemical characterization and ability to cleave specific mutants of CD23. Both local sequence and distal domains have been shown to affect cleavage of CD23. Selective dipeptide hydroxamic acid inhibitors of CD23 processing have been identified and demonstrated to very potently and selectively inhibit CD23 processing.

Binding Sites↗
PubMed2000

Inhibition of CD23 processing correlates with inhibition of IL-4-stimulated IgE production in human PBL and hu-PBL-reconstituted SCID mice.

BACKGROUND: CD23, the low affinity serum immunoglobulin E (IgE) receptor, is upregulated on B cells following interleukin (IL)-4 stimulation and is concomitantly cleaved to generate soluble CD23 (sCD23) fragments with cytokine-like activity. OBJECTIVE: Compounds that selectively inhibit the proteolytic release of CD23 to generate sCD23 were assessed for their ability to inhibit IgE production in order to evaluate the contribution of sCD23 in the production of human IgE as well as the ability of such compounds to block IgE production. METHODS: IgE production was measured in IL-4-stimulated human peripheral blood lymphocytes (PBL) and PBL-reconstituted SCID mice in the presence of a broad-spectrum matrix metalloprotease (MMP) inhibitor, a compound selective for inhibition of CD23 processing over MMPs and an anti-CD23 mAb, MHM6. RESULTS: The two compounds were equipotent in inhibiting IgE production without inhibition of IgG production by IL-4/anti-CD40-stimulated PBL. Soluble CD23 release was also shown to precede IgE accumulation in the cell-free medium. Addition of compound at later times other than day 0 in the 14 day assay resulted in progressively less inhibition of both IgE and sCD23, and exactly paralleled the effect of an anti-CD23 mAb, MHM6 on IgE levels. Both compounds also inhibited the release of CD23 from human RPMI 8866 cells adoptively transferred i. p. to mice. Doses required for inhibition of CD23 correlated well with the doses required for inhibition of IgE production in IL-4-challenged hu-PBL-SCID mice. IgE was selectively inhibited over total IgG in the SCID mice as well. CONCLUSIONS: Inhibition of CD23 processing alone is sufficient to inhibit IL-4-stimulated IgE production both in vitro and in vivo.

Animals↗
PubMed1999

Selective inhibition of low affinity IgE receptor (CD23) processing: P1' bicyclomethyl substituents.

Using a variety of alpha-hydroxy hydroxamic acid derivatives, the size and shape of the S1' pocket for the CD23 processing metalloprotease has been explored. It has been demonstrated that a P1' 2-naphthylmethyl group occupies most of the available space and gives excellent selectivity against fibroblast collagenase (matrix metalloproteinase-1, MMP-1) and other MMPs.

Bridged Bicyclo Compounds↗
PubMed1998

Hydroxamate-based inhibitors of low affinity IgE receptor (CD23) processing.

A series of hydroxamic acids related to the non-selective matrix metalloprotease inhibitor Batimastat is described, which inhibits the proteolytic cleavage of the low affinity IgE receptor from cell membrane preparations. Limited SAR studies suggest that the structural requirements for effective inhibition are distinct from those required for the inhibition of collagenase.

Humans↗
PubMed1998

Selective inhibition of low affinity IgE receptor (CD23) processing.

A series of hydroxamic acids related to the non-selective matrix metalloproteinase inhibitor Batimastat has been prepared, some members of which are potent inhibitors of the processing of the low affinity IgE receptor (CD 23). Increased activity is obtained by appropriate substitution at the alpha-position, whilst selectivity is gained by use of a P1' benzyl group in conjunction with a C-terminal primary amide.

Hydroxamic Acids↗
PubMed1997

Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor.

PURPOSE: The present study was aimed at evaluating early changes in glycolysis, the redox state of free cytosolic NAD(P)-couples, and the adenine nucleotide system in lens in both control and 50% galactose-fed rats, with the possibility of preventing these with an aldose reductase inhibitor (ARI). METHODS: Experiments were performed on male Sprague-Dawley rats fed the galactose diet for 2-14 days. The levels of glucose, galactose, glycolytic intermediates, alpha-glycerophosphate, malate, NAD, ATP, ADP, AMP were assayed spectrofluorometrically in individual lenses by enzymatic procedures, while galactitol and myo-inositol were quantified by GC-MS. Free cytosolic NAD+/NADH, NADP+/NADPH, and ATP/ADP x P(i) (phosphate potential) were estimated from lactate dehydrogenase, malic enzyme, and triose phosphate isomerase-glyceraldehyde 3-phosphate dehydrogenase-3-phosphoglycerate kinase systems. Lactate and pyruvate production by lenses of both control and galactose-fed rats was measured in a set of in vitro incubation studies (2 hr, 37 degrees C, Krebs bicarbonate-Hepes buffer, pH 7.45, with 5mM glucose or 5mM glucose + 30 mM galactose, respectively). RESULTS: Lens galactitol levels in 2, 4, 6, 8, 10, and 14-day galactose-fed rats were 48 +/- 8, 58 +/- 9, 68 +/- 8, 73 +/- 5, 81 +/- 20, and 75 +/- 11 mmol/g wet weight (mean +/- SD), respectively. NAD+/NADH ratios were indistinguishable from controls after 2-6 days on the galactose diet, but fell dramatically between 8 and 10 days, and did not correlate with polyol accumulation per se. The pattern of glycolytic intermediates (no change in G6P, F6P, and 3-PG, increase in GA3P, decrease in FDP, PEP, pyruvate, and lactate), as well as reduced in vitro lactate and pyruvate production, suggest inhibition of glycolysis at the sites of phosphofructokinase, glyceraldehyde 3-phosphate dehydrogenase, enolase, and pyruvate kinase. ATP levels as well as total ATP/ADP, ATP/ADP x Pi, adenylate charge, and cytosolic phosphate potential were decreased in galactose-fed rats, while galactose 1-phosphate and a-glycerophosphate levels as well as NADP+/NADPH ratio were increased. Lens galactitol levels were reduced approximately 57% in 10-day galactose-fed rats treated with the ARI (tolrestat, 100 mg/kg bwt/day, 6-day pretreatment); the changes in the lower segment of glycolysis, alpha-glycerophosphate levels, redox state of NAD-couples, and energy metabolism were partially prevented while NADP+/ NADPH ratios were unchanged and galactose 1-phosphate levels were further increased. CONCLUSIONS: Depressed glycolysis in lens in galactose-fed rats is consistent with decreased NAD+/NADPH and adenine nucleotide phosphorylation. Early changes in lens glucose utilization, redox state of NAD-couples, and energy metabolism in this model of galactosemia are similar to those in diabetes, are at least in part mediated by aldose reductase involved mechanisms, and can be partially prevented by an aldose reductase inhibitor.

Aldehyde Reductase↗
PubMed1991

Relaxant activity of 6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carboxamides and -thiocarboxamides and their analogues in guinea pig trachealis.

Structural modifications of the potassium channel activator cromakalim (1) are described in which the amide moiety at C-4 has been replaced by carboxamide and thiocarboxamide functions. Analogues in which the hydroxyl group at C-3 has been oxidized or removed are also disclosed. Such analogues display an interesting profile of smooth muscle relaxant activity in the guinea pig isolated trachea, not all of which appears to result from the opening of potassium channels, but few compounds retain useful in vivo activity. However, one compound in particular, 6-cyano-2,2-dimethyl-N-methyl-2H-1-benzopyran-4-thiocarboxamide (13) was shown to be a potent potassium channel activator in vitro and to provide prolonged protection to guinea pigs from the respiratory effects of inhaled histamine.

Animals↗
PubMed1985

Splenic architecture reflected in the connective tissue structure of the human spleen.

An analysis of the connective-tissue structure of the human spleen can give us information about the basic architecture of the organ. The most important part of the spleen is the lienic center around which the subcapsular zone forms an envelope, like a mantle. This zone has but little depth and develops superficially. The tangential radial beam net ('Tangentialbalkennetz') is formed partly by the radial trabeculae of the capsule and partly by the outer branches of the arbor trabecularis. This arbor divides into 5-6 branching orders. The branches of orders 1 to 3 surround the parenchyma of the spleen center's inner layer. The lienic lobuli which are found between the branches are relatively large and are connected very extensively with their parenchyma. The branches of orders 4, 5, and 6 enclose the lienic lobuli of the outer layer of the spleen center. The splenic lobuli are defined by the vascular course. Mostly they are provided with one or two arterial influxes and, as a rule, with only one venous drain. Their mutual delimitation is more of a functional than of a morphological nature. This led von Herrath to coin the term 'functional spleen lobuli'. The lienic envelope lies between the inside of the capsule and the outermost branchings of the arbor trabecularis. This arbor is subdivided, by the radial trabeculae, which never have any vessels, into elongated lobuli and serves first and foremost to regulate pressure. The lattice fibers are of high tensile strength and are extensions of the collagenous fibers seen at the microscopic level.

Connective Tissue↗
PubMed1983

Muscle capillary basement membrane in identical twins discordant for insulin-dependent diabetes.

Although hereditary factors clearly modulate susceptibility to develop diabetes, their role as determinants of vascular complications associated with diabetes remains unclear. These studies were undertaken to further assess the extent to which capillary basement membrane thickening (CBMT) is governed by metabolic derangements associated with relative or absolute insulin deficiency versus genetic determinants of vascular disease closely linked to but independent of those modulating susceptibility to develop relative or absolute insulin deficiency. Quadriceps muscle capillary basement membranes obtained by needle biopsy were examined in eight pairs of identical twins discordant for insulin-dependent diabetes (IDD) for 11-29 yr. Biopsy material from one of the diabetic twins was technically unsuitable for study. The average CBM width of the IDD twins was found to be significantly thicker than that of their nondiabetic (ND) twin mates (t = 2.50, P less than 0.025). Three IDD, but none of the ND twins, had basement membrane width values in excess of 95% upper tolerance intervals for age- and sex-matched controls with no family history of diabetes. The absence of CBMT in all of the ND twins and in four of the IDD twins with diabetes of 15-24 yr duration argues against the existence, in this group of subjects, of hereditary determinants of diabetic vascular disease linked to those governing susceptibility to develop diabetes. In addition, the absence of CBMT in four subjects with IDD of 15-24 yr duration is consistent with evidence from other studies indicating that diabetic microangiopathy is not an inevitable consequence of the diabetic milieu.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1981

Modified oxidase and benzidine tests for separation of staphylococci from micrococci.

Two simple and rapid methods for the separation of staphylococci from micrococci are described. They are based on modified oxidase and benzidine tests. Micrococci and Staphylococcus sciuri yield a blue color with a 6% solution of tetramethylphenylenediamine in dimethyl sulfoxide, whereas all of the other staphylococci exhibit no coloration. Best's results were obtained with overnight cultures on blood agar. The presence of c-type cytochromes i micrococci and S. sciuri could be detected with benzidine; all noncovalently linked heme groups are removed before the addition of the benzidine reagent. The oxidase test is the simplest and most rapid method for the separation of staphylococci (except S. sciuri) from micrococci, if the nutritional requirements and the time of incubation are strictly followed. This test is especially recommended for the examination of clinical material in which S. sciuri is usually not found.

Bacteriological Techniques↗
PubMed1978

[Energetic swelling and lysis of mitochondria].

B1 avitaminosis presents a typical example of energetic mitochondrial degeneration. The alterations--swelling and lysis of mitochondria--are accompanied by dilatation with formation of megamitochondria, by appearance of blebs and tearings of the mitochondrial membranes, by progressive fading of the matrix, by swelling of the mitochondrial membranes with lysis of the cristae advancing from centre towards periphery, by vacuolar transformation of the cell and by development of onionoid bodies (corpora cepiformia).

Animals↗