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Biomedical subjects

A D Horowitz

Publications and source records attributed to A D Horowitz.

13 recordsLinked to original sources
PubMed1995

Exclusion of SP-C, but not SP-B, by gel phase palmitoyl lipids.

The interactions of the hydrophobic pulmonary surfactant proteins, SP-C and SP-B, with lipid bilayers were assessed by fluorescence energy transfer. SP-C and SP-B were labeled with the fluorescent probe, succinimidyl nitrobenzoxadiazolyl amino hexanoate (NBD). Fluorescence energy transfer from NBD-SP-C and NBD-SP-B to four distinct indocarbocyanine probes (CnDiI) was utilized to determine the association of the surfactant proteins with various lipid acyl chains. In lipid mixtures including DPPC and DPPG, SP-C was associated with shorter chain and unsaturated lipids below the bulk lipid phase transition. Longer chain saturated CnDiI were excluded from SP-C aggregates. In contrast, SP-B demonstrated little acyl chain preference. The association of SP-C with shorter chain and unsaturated lipids below the bulk phase transition is interpreted to arise from a mismatch in the length of the hydrophobic region of the SP-C alpha-helix relative to the length of the hydrophobic region of dipalmitoyl lipids in the gel phase.

Animals↗
PubMed1995

Human surfactant protein B: structure, function, regulation, and genetic disease.

Elucidation of the structure and function of the hydrophobic surfactant protein (SP-B) and the SP-B gene has provided critical insight into surfactant homeostasis and control of respiratory epithelial cell gene expression. Surfactant protein B, in concert with surfactant protein A (SP-A), surfactant protein C (SP-C), and surfactant phospholipids, contributes to the structure and function of surfactant particles, determining surface activities and pathways by which surfactant phospholipids and proteins are processed, routed, packaged, and secreted from lamellar bodies by type II epithelial cells. After secretion, SP-B plays an essential role in determining the structure of tubular myelin, the stability and rapidity of spreading, and the recycling of surfactant phospholipids. The biochemical and structural signals underlying the homeostasis of alveolar surfactant are likely mediated by interactions between the surfactant proteins and phospholipids producing discrete structural forms that vary in size, aproprotein, and phospholipid content. Distinctions in structure, protein, and size are likely to determine the function of surfactant particles, their catabolism, or recycling by alveolar macrophages and airway epithelial cells. Analysis of the genetic controls governing the SP-B gene has led to the definition of DNA-protein interactions that determine respiratory epithelial cell gene expression in general. The important role of SP-B in lung function was defined by the study of a lethal neonatal respiratory disease, hereditary SP-B deficiency, caused by mutations in the human SP-B gene.

Disease Models, Animal↗
PubMed1993

Lipid effects on aggregation of pulmonary surfactant protein SP-C studied by fluorescence energy transfer.

The self-association of pulmonary surfactant protein SP-C in lipid vesicles was studied using fluorescence energy transfer. Bovine SP-C was labeled with two fluorescent probes, succinimidyl 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoate and eosin isothiocyanate, on the amino terminus of the protein, producing NBD-SP-C and EITC-SP-C, respectively. The N-terminus of SP-C was relatively immobile between 20 and 37 degrees C, as demonstrated by high fluorescence anisotropy of NBD-SP-C and EITC-SP-C. The mobility increased at the transition of the lipid to the fluid phase. Using fluorescence energy transfer, with NBD-SP-C as the donor and EITC-SP-C as the acceptor, a high degree of SP-C/SP-C association was found below 25 degrees C, decreasing to very little self-association above 42 degrees C in 7:1 1,2-dipalmitoylphosphatidylcholine-1,2-dipalmitoylphosphatidylglycerol (DPPC-DPPG) vesicles. The fraction of SP-C aggregated below 37 degrees C in 7:1 DPPC-DPPG was estimated from the observed energy transfer to be more than 70% of total SP-C. In various lipid mixtures, self-association of SP-C was dependent on the presence of at least some gel-phase lipids. In a lipid mixture resembling pulmonary surfactant, gradually increasing self-association was observed below 38 degrees C. The relation of the present data to the state of aggregation of SP-C in pulmonary surfactant is discussed.

Animals↗
PubMed1992

Effects of lung surfactant proteolipid SP-C on the organization of model membrane lipids: a fluorescence study.

Lipid-protein interactions of pulmonary surfactant-associated protein SP-C in model DPPC/DPPG and DPPC/DPPG/eggPC vesicles were studied using steady-state and time-resolved fluorescence measurements of two fluorescent phospholipid probes, NBD-PC and NBD-PG. These fluorescent probes were utilized to determine SP-C-induced lipid perturbations near the bilayer surface, and to investigate possible lipid headgroup-specific interactions of SP-C. The presence of SP-C in DPPC/DPPG membrane vesicles resulted in (1) a dramatic increase in steady-state anisotropy of NBD-PC and NBD-PG at gel phase temperatures, (2) a broadening of the gel-fluid phase transition, (3) a decrease in self-quenching of NBD-PC and NBD-PG probes, and (4) a slight increase in steady-state anisotropy of NBD-PG at fluid phase temperatures. Time-resolved measurements, as well as steady-state intensity measurements indicate that incorporation of SP-C into DPPC/DPPG or DPPC/DPPG/eggPC vesicles results in a increase in the fraction of the long-lifetime species of NBD-PC. The results presented here indicate that SP-C orders the membrane bilayer surface, disrupts acyl chain packing, and may increase the lateral pressure within the bilayer.

Animals↗
PubMed1983

Comparative effects of aplysiatoxin, debromoaplysiatoxin, and teleocidin on receptor binding and phospholipid metabolism.

We have compared the activities of aplysiatoxin and debromoaplysiatoxin, two polyacetate marine algae toxins, with teleocidin, a tumor-promoting indole alkaloid from Streptomyces, with respect to inhibition of specific binding of epidermal growth factor, and phorbol-12,13-dibutyrate to their respective receptors and ability to stimulate the release of radioactivity from cells prelabeled with choline or arachidonic acid. Although these compounds have chemical structures that are quite different from the phorbol esters, both aplysiatoxin and teleocidin are essentially equipotent with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate in all four assays. The fact that aplysiatoxin and teleocidin inhibit phorbol-12,13-dibutyrate-receptor binding suggests that their biological activities are mediated by binding to the same receptors utilized by the phorbol esters. Debromoaplysiatoxin, a debrominated form of aplysiatoxin, is about 10-fold weaker than aplysiatoxin in inhibiting epidermal growth factor and phorbol-12,13-dibutyrate-receptor binding, but is equipotent with aplysiatoxin in stimulating the release of lipid metabolites from the prelabeled cells. The results are discussed in terms of possible heterogeneity of cellular receptors for this group of compounds.

Alkaloids↗
PubMed1982

Inhibition of phorbol ester-receptor binding by a factor from human serum.

The inhibition of receptor binding of [3H]phorbol-12,13-dibutyrate (PDBu) by a factor from human serum was characterized. The serum factor inhibited [3H]PDBu binding in intact monolayer cultures of the rat embryo cell line CREF N and in a subcellular system containing membranes from these cells. Inhibition occurred at both 37 and 4 degrees C and was rapid and reversible. An analysis of [3H]PDBu binding in the presence of the serum factor indicated that inhibition of [3H]PDBu binding by the serum factor was noncompetitive. Using gel filtration to separate the serum factor from free [3H]PDBu, we obtained evidence that the serum factor does not act by binding or trapping the [3H]PDBu. Unlike the phorbol ester tumor promoters, the serum factor alone did not stimulate the release of choline or arachidonic acid from cellular phospholipids, nor did it inhibit the binding of 125I-labeled epidermal growth factor to cellular receptors. The factor did, however, antagonize the inhibition of epidermal growth factor binding induced by PDBu. Sera from pregnant women were, in general, more inhibitory of [3H]PDBu binding than were those from nonpregnant women, which were more inhibitory than those from men. During these studies we found that CREF N cells responded to being grown in the presence of PDBu by partial down regulation of the phorboid receptor. The 50% effective dose for down regulation was 8 nM PDBu, and the maximum effect occurred after 6 h. Taken together, our results indicate that the serum factor inhibits [3H]PDBu binding by a direct physical effect at the level of the phorboid receptors or their associated membranes. It would appear that if this factor acts in vivo, then it might antagonize certain effects of this class of tumor promoters.

Animals↗
PubMed1981

Identification of receptors for phorbol ester tumor promoters in intact mammalian cells and of an inhibitor of receptor binding in biologic fluids.

Utilizing [3H]phorbol dibutyrate [P(Bu)2], we have developed an assay for high-affinity phorbol ester receptors in intact rat embryo fibroblasts. At 37 degrees C, binding of [3H]P(Bu)2 reached a maximum within 10 min and was rapidly reversible. The tumor promoters 12-O-tetradecanoyl-phorbol 13-acetate, teleocidin B, and mezerein were potent inhibitors of [3H]P(Bu)2 binding. Phorbol and 4-alpha-phorbol didecanoate, which lack tumor-promoting activity, did not inhibit [3H]P(Bu)2 binding. Epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, arginine and lysine vasopressin, luteinizing-hormone releasing hormone, and diazepam did not inhibit [3H]P(Bu)2 binding. A Scatchard analysis was compatible with two classes of binding sites, one with Kd = 8 nM and about 1--2 x 10(5) sites per cell and the other with Kd = 710 nM and about 3 x 10(6) sites per cell. Sera from various species, human amniotic fluid, and certain tissue extracts inhibited specific binding of [3H]P(Bu)2. Fractionation of human serum led to 135-fold purification of an inhibitory factor with a molecular weight in the range 40,000 to 80,000.

Animals↗
PubMed1977

Sampson S. Hecht.

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Dentistry↗