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PubMed1988

Characterization of trimetrexate transport in human lymphoblastoid cells and development of impaired influx as a mechanism of resistance to lipophilic antifolates.

The purpose of this study was to characterize the transport properties of trimetrexate in WI-L2 human lymphoblastoid cells and determine the mode of resistance that had developed in a subline, WI-L2/TMQ, that was grown in increasing concentrations of trimetrexate. WI-L2/TMQ cells were 62-fold resistant to trimetrexate and 68- and 96-fold cross-resistant to the other lipophilic antifolates metoprine and piritrexim (BW 301U). No cross-resistance was observed with vincristine or doxorubicin, and sensitivity was not increased with 5 micrograms/ml of verapamil, indicating that it was not a typical multidrug resistance phenotype. WI-L2/TMQ exhibited a 2-fold increase in dihydrofolate reductase; however, this did not contribute significantly to the observed resistance, since these cells retained full sensitivity to methotrexate. Nor were there any kinetic alterations in dihydrofolate reductase toward trimetrexate or differences in the levels of thymidylate synthase. The major difference between the sensitive and resistant cell line was a 50% decrease in the influx rate of WI-L2/TMQ cells which produced a corresponding decrease in cellular trimetrexate at the steady state. No difference in efflux rates was detected nor were there any differences in intracellular water or metabolism of trimetrexate. Additional characterization of trimetrexate transport in WI-L2 showed that influx was nonsaturable up to 5 mM extracellular trimetrexate, relatively insensitive to sodium azide, and exhibited a Q10 of 2.7. Influx was, however, inhibited in a dose-dependent manner by concentrations of p-chloromercuribenzylsulfonate above 10 microM. Efflux studies revealed a large nonexchangeable fraction of trimetrexate that was well above the dihydrofolate reductase binding capacity and varied depending on the initial level of cell-associated drug. The intracellular exchangeable trimetrexate concentration at the steady state was always several-fold higher than the extracellular concentration. Retention of trimetrexate appeared to be coupled to some component of energy metabolism, since the presence of sodium azide stimulated this process by 2- to 3-fold. The data suggest that trimetrexate enters cells by passive diffusion but then is distributed and concentrated within the cell through more complex mechanisms which may involve energy coupling, compartmentation, or binding to macromolecules or organelles, although some type of carrier-mediated process cannot be ruled out.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimetabolites, Antineoplastic↗

PubMed2003

Antimutagenic activity of extracts of natural substances in the Salmonella/microsome assay.

Scientific information regarding plants used in folk medicine in the form of teas and their effect on human health or on genetic material has been the subject of many different types of investigation. The antimutagenic activity of two plants Maytenus ilicifolia and Peltastes peltatus, both rich in compounds of the flavonoid and tannin groups and frequently employed in folk medicine, was studied. Antimutagenicity was determined against known mutagenic substances (4-oxide-1-nitroquinoline, sodium azide, 2-nitrofluorene, aflatoxin B(1), 2-aminofluorene and 2-aminoanthracene), using the Salmonella/microsome assay. Infusions of P.peltatus showed high cytotoxicity and a co-mutagenic effect for induction of base pair substitution mutations with 4-oxide-1-nitroquinoline (-S9 mix). Infusions of M.ilicifolia produced similar effects for frameshift and base pair substitution mutations. With the mutagens 2-nitrofluorene (TA98) and sodium azide (TA100) no significant enhancement effects (co-mutagenic effects) were observed and inhibition of mutagenic activity and cytotoxicity were also diminished. In assays evaluating antimutagenic activity in the presence of metabolic activation utilizing S9 mix, high and significant inhibition of aflatoxin B(1)-, 2-aminofluorene- and 2-aminoanthracene-induced mutagenicity was observed in the presence of the infusions using both TA98 and TA100 and employing doses ranging from 25 to 500 mg/plate. Seventy-five percent of the doses tested exhibited a significant or suggestive decrease in induced mutagenicity with the infusion of M.ilicifolia. With the infusion of P.peltatus significant or suggestive antimutagenic responses were observed with 50% of the doses evaluated. Complexity was clearly noted in the responses observed in the interaction of aqueous extracts of M.ilicifolia and P.peltastes with the genetic material and metabolites generated by the S9 mix played an important role in the protection of DNA.

4-Nitroquinoline-1-oxide↗

PubMedDate not supplied

[Utilization of purified myometrium cell plasma membrane Ca2+, Mg2+-ATPase for comparative estimation of the efficiency of energy-dependent Ca2+-transport inhibitors].

With the aim of comparative estimation of efficacy of well-known inhibitors of energy-dependent Ca(2+)-transporting systems their effects were investigated on the activity of purified Ca2+, Mg(2+)-ATPase of the myometrium cell plasma membranes. From the approved inhibitors (eosin Y, o-vanadate, thapsigargin, cyclopiazonic acid, ruthenium red, sodium azide) only eosin Y and o-vanadate are potent inhibitors of myometrium sarcolemma Ca(2+)-pump: the values of Ki equal 0.8 and 4.7 microM, respectively. Thapsigargin and cyclopiazonic acid as well as ruthenium red in concentrations inhibiting, respectively, endo(sarco)plasmic reticulum Ca(2+)-pump and energy-dependent Ca(2+)-transport in mitochondria had no effect on the Ca2+, Mg(2+)-ATPase of the uterus smooth muscle cell plasma membrane. Sodium azide (10 mM) blocking completely Ca(2+)-transport in mitochondria inhibited activity of the plasma membrane Ca(2+)-transporting ATPase by 14%.

Animals↗

PubMed1992

Characterization of an Electron Transport Pathway Associated with Glucose and Fructose Respiration in the Intact Chloroplasts of Chlamydomonas reinhardtii and Spinach.

The role of an electron transport pathway associated with aerobic carbohydrate degradation in isolated, intact chloroplasts was evaluated. This was accomplished by monitoring the evolution of (14)CO(2) from darkened spinach (Spinacia oleracea) and Chlamydomonas reinhardtii chloroplasts externally supplied with [(14)C]fructose and [(14)C]glucose, respectively, in the presence of nitrite, oxaloacetate, and conventional electron transport inhibitors. Addition of nitrite or oxaloacetate increased the release of (14)CO(2), but it was shown that O(2) continued to function as a terminal electron acceptor. (14)CO(2) evolution was inhibited up to 30 and 15% in Chlamydomonas and spinach, respectively, by 50 mum rotenone and by amytal, but at 500- to 1000-fold higher concentrations, indicating the involvement of a reduced nicotinamide adenine dinucleotide phosphate-plastoquinone oxidoreductase. (14)CO(2) release from the spinach chloroplast was inhibited 80% by 25 mum 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone. (14)CO(2) release was sensitive to propylgallate, exhibiting approximately 50% inhibition in Chlamydomonas and in spinach chloroplasts of 100 and 250 mum concentrations, respectively. These concentrations were 20- to 50-fold lower than the concentrations of salicylhydroxamic acid (SHAM) required to produce an equivalent sensitivity. Antimycin A (100 mum) inhibited approximately 80 to 90% of (14)CO(2) release from both types of chloroplast. At 75 mum, sodium azide inhibited (14)CO(2) evolution about 50% in Chlamydomonas and 30% in spinach. Sodium azide (100 mm) combined with antimycin A (100 mum) inhibited (14)CO(2) evolution more than 90%. (14)CO(2) release was unaffected by uncouplers. These results are interpreted as evidence for a respiratory electron transport pathway functioning in the darkened, isolated chloroplast. Chloroplast respiration defined as (14)CO(2) release from externally supplied [1-(14)C]glucose can account for at least 10% of the total respiratory capacity (endogenous release of CO(2)) of the Chlamydomonas reinhardtii cell.

Journal Article↗

PubMed1993

Mechanisms of adherence of Candida albicans to cultured human epidermal keratinocytes.

We established an in vitro adherence model with primarily cultured human keratinocytes as target cells which allows for the investigation of the molecular mechanisms that are responsible for Candida albicans host cell attachment in the initiation of cutaneous candidosis. The extent of C. albicans binding to cultured human keratinocytes was dependent on the yeast inoculum size and the incubation temperature. Heat and paraform-aldehyde treatment of yeasts completely abolished the binding activity of C. albicans. Of the different Candida species tested, C. albicans was by far the most adhesive species. C. albicans adherence was blocked by the acid protease inhibitor pepstatin A and the metabolic inhibitor sodium azide. The latter, however, was much less effective when yeasts were preincubated, suggesting that sodium azide was mainly acting on the keratinocytes. The extracellular matrix protein fibronectin was slightly inhibitory, whereas the fibronectin-derived peptides RGD and RGDS were not able to prevent attachment. PepTite-2000, another RGD-containing synthetic peptide, reduced C. albicans adherence by a margin of 25% (P < 0.005). CDPGYIGSR-NH2, which is a synthetic adhesive peptide derived from the laminin B chain, was much more efficient in its inhibitory activity than the RGD peptides and reduced C. albicans adherence to cultured human keratinocytes up to 76% (P < 0.001). Laminin itself and the synthetic pentapeptide YIGSR were less active. A dose-dependent reduction in adherence was also observed with collagen type III. Additionally, saccharides were tested for their potential to inhibit C. albicans attachment to keratinocytes. The most potent competitive saccharide inhibitors of C. albicans adherence to human keratinocytes were the amino sugars D-(+)-glucosamine and D-(+)-galactosamine with one isolate of C. albicans (4918) and D-(+)-glucosamine and alpha-D-(+)-fucose with another C. albicans isolate (Sp-1). Collectively, our data suggest the existence of multiple molecular mechanisms such as protein-protein, lectin-carbohydrate, and yeast-yeast coaggregational interactions that are responsible for optimal C. albicans attachment to cultured human keratinocytes.

Amino Acid Sequence↗

PubMed2004

[Induction of synthesis of Hsp104 of Saccharomyces cerevisiae in heat shock is controlled by mitochondria].

Heat shock protein Hsp104 of Saccharomyces cerevisiae functions as a protector of cells against heat stress. When yeast are grown in media containing nonfermentable carbon sources, the constitutive level of this protein increases, which suggests an association between the expression of Hsp104 and yeast energy metabolism. In this work, it is shown that distortions in the function of mitochondria appearing as a result of mutation petite or after exposure of cells to the mitochondrial inhibitor sodium azide reduce the induction of Hsp104 synthesis during heat shock. Since the addition of sodium azide suppressed the formation of induced thermotolerance in the parent type and in mutant hsp104, the expression of gene HSP104 and other stress genes during heat shock is apparently regulated by mitochondria.

Heat-Shock Proteins↗

PubMed2000

Increased intracellular generation of reactive oxygen species in mononuclear leukocytes from patients with diabetes mellitus type 2.

Since increased cellular production of reactive oxygen species is a source of oxidative stress and thus may contribute to the development of diabetic complications, the baseline and stimulated concentrations of intracellular reactive oxygen species were measured in 16 patients with diabetes mellitus type 2 and 19 healthy control subjects. Reactive oxygen species and cytosolic calcium were monitored spectrophotometrically using dihydrorhodamine-123 and fura-2, respectively, in a suspension of mononuclear leukocytes. Measurements were made in the presence or absence of superoxide dismutase, sodium azide, genistein, or bisindolylmaleimide 1. Baseline reactive oxygen species concentrations were significantly higher in diabetic patients compared with control (p<0.001). Activation of mononuclear leukocytes by formyl-Met-Leu-Phenylalanine and phytohemagglutinin significantly increased reactive oxygen species in diabetic patients compared with control (p<0.05). The formyl-Met-Leu-Phenylalanine-induced increases were unchanged in the presence of superoxide dismutase, but dropped significantly in the presence of sodium azide by 80% and 73% in diabetic patients and control, respectively (each p<0.01). The formyl-Met-Leu-Phenylalanine-induced responses were significantly inhibited by genistein and bisindolylmaleimide 1 (p<0.01), suggesting the involvement of tyrosine kinase and protein kinase C. Resting calcium (p<0.05) and stimulated calcium were significantly greater in diabetic patients than in control. The results show that patients with diabetes mellitus type 2 generate increased reactive oxygen species under stimulated conditions, suggesting increased risk for oxidative stress and associated complications.

Calcium↗

PubMed1999

Differential dependence of levansucrase and alpha-amylase secretion on SecA (Div) during the exponential phase of growth of Bacillus subtilis.

SecA, the translocation ATPase of the preprotein translocase, accounts for 0.25% of the total protein in a degU32(Hy) Bacillus subtilis strain in logarithmic phase. The SecA level remained constant irrespective of the demand for exoprotein production but dropped about 12-fold during the late stationary phase. Modulation of the level of functional SecA during the exponential phase of growth affected differently the secretion of levansucrase and alpha-amylase overexpressed under the control of the sacB leader region. The level of SecA was reduced in the presence of sodium azide and in the div341 thermosensitive mutant at nonpermissive temperatures. Overproduction of SecA was obtained with a multicopy plasmid bearing secA. The gradual decrease of the SecA level reduced the yield of secreted levansucrase with a concomitant accumulation of unprocessed precursor in the cells, while an increase in the SecA level resulted in an elevation of the production of exocellular levansucrase. In contrast, alpha-amylase secretion was almost unaffected by high concentrations of sodium azide or by very low levels of SecA. Secretion defects were apparent only under conditions of strong SecA deprivation of the cell. These data demonstrate that the alpha-amylase and levansucrase precursors markedly differ in their dependency on SecA for secretion. It is suggested that these precursors differ in their binding affinities for SecA.

Adenosine Triphosphatases↗

PubMed2003

Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity.

Three models are described in rats which attempt to mimic morphological and behavioural pathology of Alzheimer's dementia; intracerebroventricular injection of streptozotocin (STZ), permanent bilateral carotid artery occlusion (2VO) and brain mitochondrial cytochrome oxidase inhibition by sodium azide. Learning and memory are impaired within 4 weeks in all models. This probably involves a reduction in cortical and/or hippocampal cholinergic neurotransmission. STZ causes microglial activation and specific damage to myelinated tracts in the fornix through generation of oxidative stress, thereby disrupting connections between the septum and hippocampus. 2VO results in damage to myelin and CA1 cells in hippocampus and in abnormal processing of APP to beta-amyloid. It is not known if microglial activation and neuronal damage occur after sodium azide administration. Memory and learning can be improved in the STZ and 2VO models by estradiol, melatonin and cholinesterase inhibitors. Antioxidants and neuroprotective agents may also decrease memory deficits by preventing inflammation and neurodegeneration.

Animals↗

PubMed2006

Metabolic regulation of in-vitro-produced bovine embryos. I. Effects of metabolic regulators at different glucose concentrations with embryos produced by semen from different bulls.

The toxic and/or beneficial effects of four metabolic regulators on embryo development were evaluated. In-vitro-produced compact morulae were cultured for 3 days in a chemically defined medium + bovine serum albumin (BSA; CDM-2) plus regulators (4991 total embryos). Phenazine ethosulfate (PES), phloretin (PL), pyrroline-5-carboxylate (P5C), and sodium azide (NaN3) were evaluated at four doses each in factorial combinations with four concentrations of glucose: 0, 0.5, 2, and 8 mm. Phenazine ethosulfate at 0.9 microm resulted in poorer development than lower or no PES. Phloretin was, in general, detrimental for embryo development, but most markedly at the highest dose (270 microm). Pyrroline-5-carboxylate had little effect on post-compaction embryos at the doses studied, 9 to 81 microm. Sodium azide at the concentrations used (3, 9, and 27 microm) had little effect on embryo development compared with controls. Concentrations of glucose had little effect on development of embryos. A fifth metabolic regulator, 2,4-dinitrophenol (DNP), was studied at various doses at pre-morula or morula-blastocyst stages cultured in 2 mm glucose. Embryos (2189 total) cultured in 90 microm DNP developed more slowly and were darker than embryos cultured at lower doses. Embryos cultured in 30 microm DNP had a higher blastocyst rate (48.3%) than controls (34.9%). In the last experiment using G1.2/G2.2 media, DNP (30 microm) resulted in a marked decrease in embryonic development when embryos were exposed at the zygote to 8- to 16-cell stages but had little effect when morulae were exposed for 2 days. The dose-response information for these metabolic regulators is crucial for designing future experiments.

2,4-Dinitrophenol↗

PubMed1995

Modulation of cellular antioxidant defense activities by sodium arsenite in human fibroblasts.

Many studies have shown that oxygen radicals can be produced during arsenic metabolism. We report here that in human fibroblasts (HFW cells) sodium arsenite exposure caused increased formation of fluorescent dichlorofluorescein (DCF) by oxidation of the nonfluorescent form. The enhanced DCF fluorescence was inhibited by a radical scavenger, butylated hydroxytoluene. The effects of sodium arsenite treatment on cellular antioxidant activities were then examined. Treatment of HFW cells with sodium arsenite resulted in a significant increase in heme oxygenase activity and ferritin level. Sodium arsenite-enhanced heme oxygenase synthesis was inhibited by co-treatment of cells with the antioxidants sodium azide and dimethyl sulfoxide. Furthermore, sodium arsenite treatment did not apparently affect glucose-6-phosphate dehydrogenase activity, but resulted in significantly increased glutathione levels and superoxide dismutase activity, slightly decreased glutathione peroxidase activity, and significantly decreased catalase activity. Sodium arsenite toxicity was partly reduced by addition of catalase to the culture medium. These results imply that arsenite can enhance oxidative stress in HFW cells.

Arsenites↗

PubMed2001

The influence of active secretion processes on intestinal absorption of salbutamol in the rat.

Salbutamol was perfused in the small intestine of rat using a standard rat gut "in situ" preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0mM); (2) at a 0.29mM concentration - thought to be close to the allometric dose in man - in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0mM); and (3) at 0.29mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0mM). In free solution, the mixed-order rate constants, k'(a), of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation of enzymatic systems responsible for the secretion of the drug from the enterocyte to the luminal fluid, a process that could explain the poor absorption of salbutamol. In the presence of sodium azide, the k(a) values increased about 1.5-fold, whereas in the presence of verapamil they increased two- to three-fold. These results indicate that salbutamol can act as a substrate of an intestinal secretory transport, which probably includes--at least in part--the enzyme P-glycoprotein, since verapamil has been shown to inhibit this enzyme by dose-dependent competition. This leads to a secretion-limited peroral absorption of salbutamol, which contributes to the poor oral bioavailability of the drug. The possible options for improving salbutamol absorption are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Isolation and characterization of bacteria capable of degrading phenol and reducing nitrate under low-oxygen conditions.

Nitrate-reducing bacteria capable of degrading phenol were isolated from natural and contaminated environments under low-oxygen conditions with nitrate-containing media, using phenol as a sole carbon and energy source. A total of 27 bacteria able to degrade phenol and reduce nitrate under low-oxygen conditions were isolated from all of the inoculum samples, regardless of previous phenol contamination. For all of these bacteria, oxygen was an essential requirement for phenol degradation. Nitrate reduction by 19 of the strains was insensitive to 10 mM sodium azide, and these strains were placed into the alpha- and beta-subclasses of Proteobacteria and two were Gram-positive bacteria. To date, the order of Rhizobiales has hardly been reported to have an ability to degrade aromatic compounds. Interestingly, our study showed that all isolates that were placed into the alpha-subclass of Proteobacteria are in the order of Rhizobiales. Furthermore, the genus Agrobacterium was isolated from most inoculum samples and one genus of Gram-positive bacteria, Staphylococcus, was also isolated. In the case of the remaining eight strains, nitrate reduction was inhibited by 10 mM sodium azide. Of these strains, seven were placed into the gamma-subclass of Proteobacteria.

Alphaproteobacteria↗

PubMed1989

Role of differential drug uptake, efflux, and binding of etoposide in sensitive and resistant human tumor cell lines: implications for the mechanisms of drug resistance.

In order to study the mechanism of etoposide (VP-16) resistance in human tumor cells and to assess the role of P-170 glycoprotein in VP-16 accumulation, we have examined the uptake and efflux of VP-16 in both sensitive and multidrug-resistant MCF-7 human breast and HL60 human promyelocytic leukemia cells. The drug-resistant cells, MCF-7/ADR and HL60/ADR, were selected for resistance to adriamycin and were 200- to 250-fold resistant to VP-16. Whereas MCF-7/ADR cells overexpress the P-170 glycoprotein and show the multidrug-resistant phenotype, HL60/ADR cells do not overexpress the P-170 glycoprotein. Although there was a 2-fold decrease in accumulation of VP-16 in MCF-7/ADR cells, this decrease did not correlate with a 250-fold resistance to the drug. VP-16 efflux was rapid and almost complete from MCF-7 cell lines and it was decreased at 4 degrees. Further, there was a significant increase in VP-16 accumulation in the MCF-7/ADR cells in the presence of glucose-free medium supplemented with sodium azide. However, no change in the pattern of VP-16 efflux was observed. Under these conditions, addition of glucose caused release of VP-16 from MCF-7/ADR cells, suggesting energy-dependent modifications in the drug binding. Coincubation of vincristine with VP-16 also increased the drug accumulation and decreased the rate of efflux of VP-16 in both sensitive and resistant MCF-7 cells, suggesting that vincristine and VP-16 may compete for similar binding and efflux mechanisms in these cell lines. In contrast, daunorubicin increased VP-16 accumulation only in the sensitive MCF-7 cell line, whereas the efflux rate of VP-16 was not significantly changed in either cell line. HL60 sensitive cells accumulated 4- to 5-fold more VP-16 than the resistant subline. Both sensitive and resistant cells showed an important noneffluxable pool of the drug, 3-fold larger for sensitive cells (79 +/- 12 versus 25 +/- 2 pmol of VP-16/mg of protein, for sensitive and resistant cells, respectively). The efflux of VP-16 was temperature dependent only in sensitive cells. VP-16 accumulation in HL60/ADR cells was increased in glucose-free medium supplemented with sodium azide; however, the noneffluxable pool of VP-16 was not significantly changed. In contrast, although these conditions had no effect on the drug accumulation in the parental line, they caused a decrease in the noneffluxable pool of VP-16, suggesting an energy-dependent binding and retention of VP-16.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Unidirectional inversion of ibuprofen in Caco-2 cells: developing a suitable model for presystemic chiral inversion study.

Intestinal chiral inversion of ibuprofen is still lacking direct evidence. In a preliminary experiment, ibuprofen was found to undergo inversion in Caco-2 cells. This investigation was thus conducted to determine the characteristics and influence of some biochemical factors on the chiral inversion of ibuprofen in Caco-2 cells. The effects of substrate concentration (2.5-40 microg/ml), cell density (0.5-2 x 10(6) cells/well), content of serum (0-20%), coexistence of S ibuprofen (corresponding doses), sodium azide (10 mM), exogenous Coenzyme A (CoA) (0.1-0.4 mM), and palmitic acid (5-25 microM) on inversion were examined. A stereoselective HPLC method based on the Chromasil-CHI-TBB column was developed for quantitative analysis of the drug in cell culture medium. The inversion ratio (F(i)) and elimination rate constant were calculated as the indexes of inversion extent. Inversion of ibuprofen in Caco-2 cells was found to be both dose and cell density dependent, indicating saturable characteristics. Addition of serum significantly inhibited the inversion, to an extent of 2.7 fold decrease at 20% content. Preexistence of S enantiomer exerted a significant inhibitory effect (p<0.01 for all tests). Sodium azide decreased the inversion ratio from 0.43 to 0.32 (p<0.01). Exogenous CoA and palmitic acid significantly promoted the inversion at all tested doses (p<0.01 for all tests). This research provided strong evidence to the capacity and capability of intestinal chiral inversion. Although long incubation times up to 120 h were required, Caco-2 cells should be a suitable model for chiral inversion research of 2-APAs considering the human-resourced and well-defined characteristics from the present study.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Angiotensin protects cortical neurons from hypoxic-induced apoptosis via the angiotensin type 2 receptor.

The effects of angiotensin on mouse cortical neuronal cultures exposed to chemical-induced hypoxia was investigated. Cultures exposed to 10 mM sodium azide for 5 min showed a 17% increase in apoptosis when assayed 24 h postinsult. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocked sodium azide-induced cell death suggesting that the NMDA receptor contributes to the mediated cell death. Pretreatment of cultured neurons with angiotensin decreased sodium azide-induced apoptosis by 94%. When the AT(1) receptor was blocked by its receptor antagonist, losartan, angiotensin activation of the AT(2) receptor completely inhibited sodium azide-induced apoptosis. Pretreatment of neurons with the AT(2) receptor antagonist PD123319 resulted in angiotensin reducing sodium azide-induced apoptosis by 48%. These results demonstrate that angiotensin can significantly attenuate sodium azide-induced apoptosis primarily through activation of the AT(2) receptor and suggests that angiotensin may have a protective role in neurons undergoing ischemic injury.

Angiotensin Receptor Antagonists↗

PubMed1998

5'-Substituted thalidomide analogs as modulators of TNF-alpha.

The synthesis of 5'-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF-alpha, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5' of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.

Humans↗

PubMed1993

Chromatographic stability of glucose-silica.

Glucose-silica was prepared and packed into five 100 x 4.6 mm I.D. columns. These columns were tested initially with selected protein mixtures. Each of the columns was stored in one combination of buffer (100 mM sodium sulfate, 20 mM sodium phosphate, pH 6.8), temperature (4 or 20 degrees C), methanol and sodium azide. After a year, we found that storing glucose-silica columns in the buffer containing sodium azide or methanol at 4 degrees C was necessary to prolong stability in storage. However, glucose-silica also exhibited some dynamic instability.

Chromatography, Gel↗