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At least 451 records · Page 25Linked to original sources
PubMed1995

Permeability of the blood-brain barrier to the neurotensin8-13 analog NT1.

Neurotensin (NT) has been suggested to be a neuropeptide with therapeutic potential. We used multiple-time regression analysis to measure the unidirectional influx constant (Ki) of a tritiated analog of NT8-13, NT1, with improved metabolic stability. The Ki of [3H]NT1 across the blood-brain barrier (BBB) was 5.12(10(-4)) ml/g-min and was decreased 66% by unlabeled NT1 system. The amount of NT1 crossing the BBB, 0.087% of the injected dose per gram of brain, is consistent with its exerting central effects after peripheral administration. The stable [3H]NT1 crossed the BBB in intact form as assessed by HPLC and completely crossed the endothelial cells that comprise the BBB as assessed by the capillary depletion method. The presence of a transport system could be important for the development of NT analogs.

Animals↗
PubMed1989

Influence of the carcinogenic pollutant benzo[a]pyrene on plant development: fern gametophytes.

Polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are known to be biologically active in mammalian systems and are accumulated by plants. A few reports suggest that PAHs stimulate growth in plants and induce morphogenesis in plant tissue in culture. To investigate the growth altering abilities of PAHs in plants, polypodiaceous fern gametophytes were grown under sterile conditions on media containing a biologically active PAH, benzo[a]pyrene (BaP), at doses ranging from 0.1 to 10.0 micrograms/ml. The growth pattern of polypodiaceous fern gametophytes enables alterations in growth and morphogenesis to be observed at the cellular level in an intact plant. Doses of BaP in the range 0.1--3.2 micrograms/ml enhanced the onset of the morphological transitions from 1-dimensional (1D) to 2-dimensional (2D) growth. This transition for BaP treated plants occurred after fewer cell divisions than the corresponding solvent and untreated controls. The low (0.1 and 0.32 micrograms) and high (1.0 and 3.2 micrograms) doses of BaP were found to accelerate and inhibit cell proliferation, respectively. The 10.0 microgram dose was toxic and resulted in decreased germination of spores and reduced survival of plants. A slight but significant decrease in survival was also observed in ferns treated with 3.2 micrograms. This is the first example of PAH influencing cell differentiation in a whole plant system.

Benzo(a)pyrene↗
PubMed1990

Conjugation of benzo[a]pyrene metabolites by freshwater green alga Selenastrum capricornutum.

Benzo[a]pyrene (BaP) undergoes metabolic transformation in mammals via oxidative, hydrolytic, and conjugative processes; however, little is known concerning BaP conjugation in freshwater algae. It has been shown in this laboratory that BaP is metabolized by Selenastrum capricornutum via a dioxygenase pathway. This study describes the conjugation of BaP metabolites by a green alga, Selenastrum capricornutum. Cultures were exposed to 1160 micrograms/l [14C]BaP for 4 days at 23 degrees C under gold fluorescent lights on a diurnal cycle of 16 h light, 8 h dark. Of the total metabolites in the algal culture, 89% were present in media. BaP and non-conjugated metabolites were separated from conjugated metabolites by chromatography on neutral alumina columns using solvents of increasing polarity. Seventy-one percent of the BaP metabolites were conjugates of which 12.2%, 12.0% and 12.4% were sulfate ester and alpha- and beta-glucose conjugates, respectively. Conjugates that coeluted with sulfate esters were hydrolyzed with arylsulfatase, alpha- or beta-glucosidase; high performance liquid chromatography (HPLC) analysis indicated that the major product of each enzymatic hydrolysis was the 4,5-dihydrodiol (87.2, 69 and 53%, respectively). Eighty-six percent of the conjugates were acid labile following incubation for 2 h in 4 N HCl at 37 degrees C. To our knowledge this is the first demonstration of the metabolism of a polynuclear aromatic hydrocarbon by a freshwater green alga through a dioxygenase pathway and subsequent conjugation and excretion.

Acid Phosphatase↗
PubMed1995

Biotransformation of benzo[a]pyrene and other polycyclic aromatic hydrocarbons and heterocyclic analogs by several green algae and other algal species under gold and white light.

This laboratory has shown that the metabolism of benzo[a]pyrene (BaP), a carcinogenic polycyclic aromatic hydrocarbon (PAH), by a freshwater green alga, Selenastrum capricornutum, under gold light proceeds through a dioxygenase pathway with subsequent conjugation and excretion. This study was undertaken to determine: (1) the effects of different light sources on the enzymatic or photochemical processes involved in the biotransformation of BaP over a dose range of 5-1200 mg/l; (2) the phototoxicity of carcinogenic PAHs and mutagenic quinones to a green alga; (3) the ability of other algal systems to metabolize BaP. Cultures were exposed to different doses of BaP for 2 days at 23 degrees C under gold, white or UV-A fluorescent light on a diurnal cycle of 16 h light, 8 h dark. Under gold light, metabolites of BaP produced by Selenastrum capricornutum were the dihydrodiols of which the 11,12-dihydrodiol was the major metabolite. Under white light, at low doses, the major metabolite was the 9,10-dihydrodiol. With increasing dose, the ratio of dihydrodiols to quinones decreased to less than two. With increasing light energy output, from gold to white to UV-A in the PAH absorbing region, BaP quinone production increased. Of other carcinogenic PAHs studied, only 7H-dibenz[c,g]carbazole was as phototoxic as BaP while 7,12-dimethylbenz[a]anthracene, dibenz[a,j]acridine and non-carcinogenic PAHs, anthracene and pyrene, were not phototoxic. The 3,6-quinone of BaP was found to be highly phototoxic while quinones that included menadione, danthron, phenanthrene-quinone and hydroquinone were not. The data suggest that the phototoxicity of BaP is due to photochemical production of quinones; the 3,6-quinone of BaP is phototoxic and is probably the result of the production of short lived cyclic reactive intermediates by the interaction of light with the quinone. Lastly, only the green algae, Selenastrum capricornutum, Scenedesmus acutus and Ankistrodesmus braunii almost completely metabolized BaP to dihydrodiols. The green alga Chlamydomonas reinhardtii, the yellow alga Ochromonas malhamensis, the blue green algae Anabaena flosaquae and euglenoid Euglena gracilis did not metabolize BaP to any extent. The data indicate that algae are important in their ability to degrade PAHs but the degradation is dependent on the dose of light energy emitted and absorbed, the dose of PAHs to which the algae are exposed, the phototoxicity of PAHs and their metabolite(s) and the species and strain of algae involved. All of these factors will be important in assessing the degradation and detoxification pathways of recalcitrant PAHs by algae.

Anabaena↗
PubMed1984

The phototoxicity of benzo[a]pyrene in the green alga Selenastrum capricornutum.

The effects of selected polycyclic aromatic hydrocarbons (PAHs) on the growth of the green alga Selenastrum capricornutum in three light regimens were examined. In gold fluorescent light, benzo[a]pyrene (BaP) at 12 mg/liter (48 mumole/liter), benz[a]anthracene (BaA) at 40 mg/liter (175 mumole/liter), anthracene (A) at 40 mg/liter (224 mumole/liter), and 13 metabolites of BaP each at 40 micrograms/liter had no effect on algal growth. In cool-white fluorescent light, 30% inhibition of algal growth occurred with 0.1 mumole/liter BaP, 8.0 mumole/liter BaA, and 40 mumole/liter A. BaP at 0.16 mg/liter (0.64 mumole/liter) totally inhibited growth. BaP concentrations an order of magnitude lower inhibited algal growth in fluorescent blacklight. In cool-white light, 5 of 13 metabolites of BaP (each 40 micrograms/liter) inhibited algal growth: 3,6-quinone; 6-hydroxy; 9-hydroxy; 3-hydroxy; and 1,6-quinone. Based on these results, PAHs and metabolites of BaP are selectively phototoxic to S. capricornutum due to the incident light intensity below 550 nm.

Anthracenes↗
PubMed1986

Clustering of cell surface laminin enhances its association with the cytoskeleton.

In order to provide evidence for an association of cell surface laminin with the cytoskeleton, we have examined the detergent extractability of cell surface laminin on murine fibrosarcoma cells. We utilized indirect immunofluorescence with affinity-purified anti-laminin antibodies to determine the distribution, mobility and detergent extractability of laminin bound to the cell surface. We demonstrate that antibody induces clustering of cell surface laminin rendering it resistant to detergent extraction. At low receptor occupancy, approx. 80% of cell surface laminin is detergent-extractable. If cell surface laminin is induced to cluster with anti-laminin antibody, IB4 isolectin from Bandeiraea simplicifolia or by high receptor occupancy, then it is rendered resistant to detergent extraction. This process is temperature-sensitive and inhibited by cytochalasin D (CD). On the basis of these findings, we propose a model in which laminin anchored in the basement membrane in vivo affects the cellular cytoskeleton by facilitating the clustering of cell surface transmembrane laminin receptors which are able to interact with cellular actin.

Animals↗
PubMed1996

Predictive value of proximal femoral bone densitometry in determining local orthogonal material properties.

Models which are based on non-invasive bone measurements may in the future be able to successfully identify individual subjects at an increased risk for hip fracture; thus, we designed a study to determine the usefulness of dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) in predicting the local material properties of human proximal femoral cancellous bone. There has been some disagreement in the scientific literature regarding appropriate predictive models for local material properties of cancellous bone. We sought to confirm that density-mechanical property relationships were consistent from subject to subject, and that three-dimensional QCT measurements were stronger predictors of mechanical properties than two-dimensional DXA results. Linear and power fit relationships between these densitometric measures and material properties were also examined to determine which were more appropriate. Bone cubes from specific regions of highly oriented trabeculae were analyzed separately to determine if cube orientation had an effect on mechanical properties independent of bone density. Ten pairs of ex vivo femurs (five male, five female; age 30-93, mean age 62) were prepared such that specific anatomic planes were visible radiographically. Both QCT and DXA measurements were made on all 20 femurs. Cancellous bone cubes were obtained proceeding along two distinct directions from the proximal end of each femur pair. Unexpectedly, the density-modulus relationships among these ten donors were found to be significantly different at p <0.01 (83 percent of the tests were different at p <0.0001). Density-strength regressions were also significantly different at p <0.01, but this effect was not as consistent nor as statistically significant. In general, the QCT method did not produce predictions of local cancellous bone material properties superior to the DXA method. The linear and power fit models appeared to produce consistent results, with neither being obviously more advantageous. These density measurements explained at best 30-40 percent of the variance in modulus and 50-60 percent of the variance in ultimate stress. The orientation of cancellous cubes in the principal compressive trabeculae region was a significant contributor to mechanical properties (p= 0.0001) independent of bone density. This finding was not as dramatic in the femoral neck cancellous bone region.

Absorptiometry, Photon↗
PubMed1986

Counterimmunoelectrophoresis for detection of human serum antibody to HTLV-III.

We examined the usefulness of a counterimmunoelectrophoresis (CIE) technique for detecting antibodies to HTLV-III using sera that previously had been assessed for antibodies to HTLV-III by the standard enzyme-linked immunosorbent assay (ELISA). We selected a subset of 53 sera from patients with the acquired immune deficiency syndrome (AIDS) or the generalized lymphadenopathy syndrome (GLS) in which 81.1% were initially ELISA-positive, and 96.2% were positive by Western blot technique. In our standard HTLV-III CIE technique, 58.5% were positive and repeat testing increased the yield to 67.9%. Varying several parameters of the standard CIE assay did not improve sensitivity. We also studied 20 ELISA-negative and 10 ELISA-borderline sera from normal controls; all were negative by CIE. These results indicate that CIE may be used for detection of human serum antibodies to HTLV-III, but that the present assay was less sensitive than the HTLV-III ELISA.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Purification and crystallization of Lactobacillus casei folylpolyglutamate synthetase expressed in Escherichia coli.

Folylpolyglutamate synthetase (FPGS) from Lactobacillus casei has been crystallized with polyethylene glycol and acetate buffer at pH 5.0. The enzyme was obtained from Escherichia coli strain SF4 harboring the L. casei FPGS chromosomal gene on a pEMBL vector (pGT3-8.1). Crystals of the enzyme were obtained which diffract to 2.6 A resolution. The crystals are monoclinic, space group P2(1), with unit cell dimensions of a = 54.07 A, b = 45.83 A, c = 84.37 A and beta = 107.92 degrees. A unit cell contains one molecule of the 43,000 Da enzyme per asymmetric unit. A complete X-ray data set on the native crystals has been collected.

Escherichia coli↗
PubMed1992

Protective anti-lipopolysaccharide monoclonal antibodies inhibit tumor necrosis factor production.

Elevated systemic levels of tumor necrosis factor (TNF) have been directly correlated with increased mortality during experimental gram-negative bacterial sepsis. Although monoclonal antibodies (mAbs) directed against gram-negative bacterial lipopolysaccharide (endotoxin, LPS) decrease TNF production in vitro and enhance survival in vivo, the precise relationship between inhibition of TNF secretion and protective capacity has not been defined. We hypothesized that protective anti-LPS mAbs inhibited LPS-stimulated TNF production. To test this hypothesis, we first produced and characterized three anti-LPS mAbs. We then examined the ability of these mAbs to decrease TNF secretion in an in vitro assay using cells from the murine macrophage cell line RAW 264.7. Subsequently, we assessed the protective capacities of these anti-LPS mAbs in a murine mucin peritonitis model of sepsis using live Escherichia coli 0111:B4 bacterial challenge. Our results demonstrated that those anti-LPS mAbs that decreased LPS-stimulated TNF secretion in vitro were protective in vivo. We concluded that inhibition of TNF secretion in vitro reflected protective capacity and that anti-LPS mAbs may confer protection via abrogation of macrophage TNF secretion. Inhibition of TNF production in vitro may provide a valuable test that may facilitate the selection of protective anti-LPS mAbs.

Animals↗
PubMed1994

Characterization of endothelins as chemoattractants for human neutrophils.

The chemotactic response of human neutrophils to endothelins (ET) and ET-derived peptides was examined. ET-1, ET-2, and ET-3 elicited maximum responses at 10(-7), 3.3 x 10(-8) and 10(-7) M, respectively. Relative activities of the peptides at their optimal concentrations were: ET-1, ET-2 > ET-3. The chemotactic activity of ET-1 was localized to its Leu6-Met7-Asp8 segment. Conformation of the disulfide-linked Cys3-Cys11 loop appears to be critical for proper orientation of the chemotactic epitope. In comparison, ET-1 failed to stimulate the neutrophil respiratory burst, degranulation or arachidonic acid metabolism. These results demonstrate the selective chemoattractant activity of endothelins for human neutrophils.

Amino Acid Sequence↗
PubMed1996

In vitro assessment of oral delivery for hexapeptide endothelin antagonists.

Endothelin (ET-1) is a 21-amino acid, vasoconstrictive peptide originally isolated from endothelial cells. It is one member of a class of potent, purportedly paracrine substances that act at receptors in multiple target organs. Antagonists to the receptor subtypes, ETA and ETB, have been designed around the hydrophobic carboxy-terminus of ET-1. The resulting hexapeptides possess low nanomolar receptor affinity, but face formidable challenges to oral delivery, given their peptidic nature. Hence, it was important to discriminate between analogs, as well as to optimize structural features combining binding potency with stability in intestinal fluids and permeability across biological membranes. PD 142893 (Ac-DDip16-Leu-Asp-Ile-Trp21) and PD 145065 (Ac-DBhg16-Leu-Asp-Ile-Ile-Trp21), as well as the N-methyl-isoleucine20 analogs were studies, where DDip = 3,3diphenylalanine and DBhg = 10,11-dihydro-5H-dibenzo[a,d]cycloheptene glycine. Analyses were conducted with specific HPLC methods. Permeabilities across CACO-2 cell monolayers ranged from 2.0x10(-4) to 6.3x10(-4)cm/min. The results suggested that these compounds can be absorbed in vivo, based on comparison of permeabilities with those obtained with reference compounds. Much greater differences were observed between the analogs when stability half-lives were compared after incubation in rat intestinal perfusate. The parent peptides, PD 142893 and PD 145065, were unstable, with half-lives less than 20 min. N-Methylation of Ile20 resulted in large increases in stability half-lives to greater 500 min. Enzyme inhibition studies demonstrated the involvement of carboxypeptidase A in production of the primary metabolite, the des-Trp derivative. Identification of the primary metabolite of the parent peptide was made by differential UV scanning at 214/280 nm and mass spectral analyses.

Animals↗