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Biomedical subjects

I Toth

Publications and source records attributed to I Toth.

At least 37 records · Page 2Linked to original sources
PubMed1999

Distribution of a lipidic 2.5 nm diameter dendrimer carrier after oral administration.

The biodistribution of a lipidic peptide dendrimer has been studied after oral administration to female Sprague-Dawley rats (180 g, 9 weeks old). Uptake by gut epithelial tissue of the radiolabelled dendrimer molecule (mol. wt. 6300; diameter 2.5 nm; log P=1.24) was studied in rats after a single oral dose by gavage (14 mg/kg). The maximum levels of dendrimer observed were 3% (blood), 1.5% (liver), 0.1% (spleen), 0.5% (kidneys), 15% (small intestine) and 5% (large intestine). Approximately 6% of a single administered dose (28 mg/kg) was recovered from the entire gastrointestinal tract while 1% was absorbed via the small intestine lymphoid tissue after 3 h; after 12 h, 0.1% was detected. The maximum uptake by the non-lymphoid small intestine was 4% of the dose after 3 h. After 12 h, 0.3 and 4% dendrimer was measured in the lymphoid large intestine and the non-lymphoid large intestine, respectively. The total percentage of the administered dose absorbed through the lymphoid tissue was comparatively greater than through the non-lymphoid tissue of the small intestine with respect to organ weight after 3 and 24 h.

Administration, Oral↗
PubMed1999

Hypoxia alters iron-regulatory protein-1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells.

Ferritin and transferrin receptor expression is post-transcriptionally regulated by a conserved mRNA sequence termed the iron-responsive element (IRE), to which a transacting protein called the iron-regulatory protein (IRP) is bound. Our data demonstrate that hypoxia powerfully enhances IRE/IRP-1 binding in human cell lines. Using the human hepatoma cell line Hep3B as a model, we found that 16 h in a 1% oxygen atmosphere markedly increases IRE/IRP-1 binding as assessed by electromobility shift assay. Hypoxia also decreased cytosolic aconitase activity. The hypoxia-enhanced IRE/IRP-1 binding stabilized the transferrin receptor message, increased the cellular mRNA content by over 10-fold, and doubled surface receptor expression. Simultaneously, hypoxia suppressed ferritin message translation. Hypoxia's effect was most strikingly depicted by the absence of ferritin synthesis in cells challenged with inorganic iron. Our results contrast with previously reported data (Hanson, E. S., and Leibold, E. A. (1998) J. Biol. Chem. 273, 7588-7593) in which a 3% oxygen atmosphere reduced IRE/IRP-1 binding in rat hepatoma cells. We discuss some possible reasons for the differences. In aggregate with other investigations involving responses to hypoxia, iron, or nitric oxide, our data indicate that cellular iron metabolic responses are complex and that IRE/IRP-1 interactions vary between cell lines and perhaps between species.

Animals↗
PubMed1999

The influence of liposome-encapsulated prostaglandin E1 on hydrogen peroxide concentrations in the exhaled breath of patients with the acute respiratory distress syndrome.

UNLABELLED: Hydrogen peroxide (H2O2) levels are increased in the exhaled breath of patients with the acute respiratory distress syndrome (ARDS). Because liposome-encapsulated prostaglandin E1 (PGE1) downregulates the CD11/CD18 receptor of the neutrophil, thereby limiting endothelial adhesion, the use of this drug should decrease the excretion of H2O2 in the expiratory condensate of patients with ARDS. Patients > 11 yr of age with ARDS (diffuse, patchy infiltrates by chest radiograph; Pao2/fraction of inspired oxygen [P/F] ratio < or = 200 mm Hg; pulmonary capillary wedge pressure < or = 18 mm Hg; and the requirement for mechanical ventilation) were randomized to receive placebo (n = 14) or escalating doses (0.15-3.6 micrograms/kg) of liposomal PGE1 (n = 14) every 6 h for up to 7 days. Condensate was collected every morning from the expiratory tubing that was submerged in an ice saltwater bath (-5 degrees C). H2O2 levels were measured by using a horseradish peroxidase assay. Other data collected included white blood cell count and P/F ratios. There was no significant difference in the concentration of H2O2 in the expiratory condensate between the liposomal PGE1 group and the control group either before (0.99 +/- 0.52 vs 0.93 +/- 0.48 mumol/L) or during treatment (1.04 +/- 0.45 vs 0.76 +/- 0.25 mumol/L). Liposomal PGE1 treatment improved the P/F ratio and decreased the white blood cell count over time. Despite its ability to downregulate the CD11/CD18 neutrophil receptor, liposomal PGE1 did not reduce exhaled H2O2 excretion. IMPLICATIONS: White blood cells (WBC) are thought to be part of the cause of the acute respiratory distress syndrome, a lung disease. WBC in the lung produce hydrogen peroxide, which is exhaled. Liposomal PGE1 inhibits WBC function but was found to have no effect in decreasing exhaled hydrogen peroxide in patients with the acute respiratory distress syndrome.

Adult↗
PubMed1998

Lipoamino acid conjugates of methotrexate with antitumor activity.

The synthesis, characterization, and in vitro antitumor activity against a wild and a transport-resistant CCRF-CEM cell line is described for a series of alpha,gamma-bisamide lipoamino acid and oligomer conjugates of methotrexate. The influence of the lipophilicity of the conjugates on the cytotoxicity and the dihydrofolate reductase inhibition was investigated. All compounds were more active than their fatty acid conjugate analogues. Compound le with a 12-carbon atom aliphatic side chain showed the highest in vitro activity.

Amino Acids↗
PubMed1998

Novel liposaccharide conjugates for drug and peptide delivery.

Sugar-lipid conjugates with general structure 1-4 were prepared by coupling amino sugars with N-Boc-protected lipoamino acids and oligomers. Conjugates with general structure 5 were also prepared from glucuronic acid and methyl 2-aminohexadecanoate. The physicochemical properties of the conjugates were modified by varying the nature and number of sugars or the number of lipoamino acids or their alkyl chain length. The ability of the liposaccharides to aggregate was examined. These preliminary experiments have demonstrated the ability of the liposaccharides to form particulate systems per se and also their ability to be incorporated into conventional liposomal systems. The structure of the respective liposaccharides and the molar ratio of liposaccharide to dimyristoyl lecithin and cholesterol were found to have a profound effect on the type of colloidal systems produced.

Amino Acids↗
PubMed1998

Rapid growth mutants of Escherichia coli.

If rapid growth (rap) mutants of Escherichia coli could be obtained, these might prove a valuable contribution to fields as diverse as growth rate control, biotechnology and the regulation of the bacterial cell cycle. To obtain rap mutants, a dnaQ mutator strain was grown for four and a half days continuously in batch culture. At the end of the selection period, there was no significant change in growth rate. The result means that selecting rap mutants may require an alternative strategy and a number of such alternatives are discussed.

Bacteriological Techniques↗
PubMed1998

Synthesis and physicochemical properties of lipophilic polyamide dendrimers.

PURPOSE: To synthesise symmetrical dendritic macromolecules with external lipid surfaces, to investigate their behaviour at the air-water interface and their ability to form supramolecular aggregates, and to gain an understanding of their potential as drug carriers. METHODS: Dendrimeric compounds were synthesised with molecular weights ranging from 737 (1st generation dendrimer) to 25,246 (6th generation dendrimer) with carbon numbers ranging from 40 to 1404. The surface behaviour of these compounds was determined using spread films at the air/water interface on a Langmuir trough, and transmission electron microscopy was used to study the supramolecular aggregates formed by the more hydrophobic members of the series. RESULTS: Dendrimers up to a maximum of 6 generations were synthesised. Surface saturation did not allow the completion of the synthesis of the 7th generation. The limiting surface areas at the air/water interface ranged from 0.4 nm2 to 16.1 nm2 values in good agreement with the areas derived from computer generated molecular models (0.5 nm2 to 14 nm2). CONCLUSIONS: The synthesised dendrimers exhibited a linear relationship between area per molecule and the molecular weight of the compounds. A dendrimer with 16 lipoamino acid branches formed tubular supramolecular aggregates with a helical structure and dimensions in the long axis of 140-200 nm.

Chromatography, High Pressure Liquid↗
PubMed1997

Nitric oxide does not mediate lipopolysaccharide-induced myocardial depression in guinea pigs.

OBJECTIVE: To determine the role of nitric oxide as a mediator of lipopolysaccharide-induced myocardial depression. DESIGN: Prospective, controlled study. SETTING: University research laboratory. SUBJECTS: Male and female Hartley guinea pigs. INTERVENTIONS: Animals (n = 97) received intraperitoneal injections of either saline or Escherichia coli lipopolysaccharide (2 mg/kg). Some (n = 5) animals received two injections of dexamethasone before lipopolysaccharide. Left atria were harvested 6 hrs (n = 20) or 16 hrs (n = 77) later and placed in a tissue bath with Krebs-Henseleit buffer. Contractile tension was measured in the presence or absence of two inhibitors of nitric oxide synthase (NG-nitroarginine [NNA] or aminoguanidine). Atrial and serum nitrite/ nitrate and atrial cyclic guanosine monophosphate (cGMP) concentrations were assayed. MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide caused significant atrial contractile depression at 16 hrs but not 6 hrs compared with control animals. Neither NNA nor aminoguanidine reversed the depression in atrial function. In contrast, exposure of control atria to NNA worsened contractile function. There were no significant differences between control and lipopolysaccharide-treated animals in atrial and serum nitrite/nitrate and atrial cGMP concentrations. CONCLUSIONS: Nitric oxide does not mediate lipopolysaccharide-induced myocardial depression in this animal model. Basal concentrations of nitric oxide may be important since NNA worsened contractile function in control atria.

Animals↗
PubMed1996

Successful treatment of progressive outer retinal necrosis syndrome.

PURPOSE: Progressive outer retinal necrosis is a destructive retinopathy found in patients with acquired immune deficiency syndrome. Treatment of this disorder has been unsuccessful in reported patient series, with the patients experiencing profound bilateral loss of vision. METHODS: We treated six patients with combination antiviral therapy, usually with intravenous foscarnet and either ganciclovir or acyclovir. RESULTS: These six patients retained a visual acuity of 20/100 or better in at least one eye for the remainder of their lives (a period > 4 months for each patient). Retinal detachments developed in four patients, for which vitrectomy and silicone oil tamponade were required. CONCLUSIONS: A combination of intravenous antiviral therapy and aggressive vitrectomy techniques to repair any associated detachments may allow the preservation of useful visual acuity in patients with progressive outer retinal necrosis. This is the first reported series of successful long-term treatment of patients with this disorder.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Ascorbic acid enhances ferritin mRNA translation by an IRP/aconitase switch.

Replenishment of ascorbate in cultured cells, which are almost uniformly vitamin-deficient, increases ferritin mRNA translation in response to iron by 20-fold (Toth, I., Rogers, J. T., McPhee, J. A., Elliott, S. M., Abramson, S. L., and Bridges, K. R. (1995) J. Biol. Chem. 270, 2846-2852). We now demonstrate that ascorbate increases cytosolic aconitase activity. The iron-responsive element-binding protein (IRP-1) exists in three states: bound to mRNA without aconitase activity, free in the cytosol without aconitase activity, and free in the cytosol with aconitase activity. Ascorbate converts free IRP-1 to the enzymatically active form. Enhanced ferritin synthesis with subsequent iron stimulation is due to the altered equilibrium of the free IRP-1. The cellular biology of iron is closely intertwined with that of ascorbate.

Aconitate Hydratase↗
PubMed1995

Ascorbic acid enhances iron-induced ferritin translation in human leukemia and hepatoma cells.

Ascorbate is an important cofactor in many cellular metabolic reactions and is intimately linked to iron homeostasis. Continuously cultured cells are ascorbate deficient due to the lability of the vitamin in solution and to the fact that daily supplementation of media with ascorbate is unusual. We found that ascorbate repletion alone did not alter ferritin synthesis. However, ascorbate-replete human hepatoma cells, Hep3B and HepG2, as well as K562 human leukemia cells achieved a substantially higher cellular ferritin content in response to a challenge with iron than did their ascorbate-deficient counterparts grown under standard culture conditions. Most of the elevation in ferritin content was due to an increase in de novo ferritin synthesis of greater than 50-fold, as shown by in vivo labeling with [35S]methionine and immunoprecipitation. RNA-blot analysis showed only minor changes in steady state levels of ferritin mRNA, suggesting that ascorbate enhances iron-induced ferritin synthesis primarily by post-transcriptional events. Transient gene expression experiments using chloramphenicol acetyltransferase reporter gene constructs showed that the ascorbate effect on ferritin translation is not mediated through the stem-loop near the translational start site that transduces ferritin synthesis in response to cytokines. The data suggest that ascorbate possibly modifies the action of the iron-responsive element on ferritin translation, although more precise structure-function studies are needed to clarify this issue. These data demonstrate a novel role of ascorbate as a signaling molecule in post-transcriptional gene regulation. The mechanism by which ascorbate modulates cellular iron metabolism is complex and requires additional detailed investigation.

Ascorbic Acid↗
PubMed1995

The role of platelet-activating factor in lipopolysaccharide-induced myocardial depression in guinea pigs.

PURPOSE: To determine if platelet-activating factor (PAF) is a key mediator of lipopolysaccharide (LPS)-induced myocardial depression in guinea pigs. METHODS: Hartley guinea pigs of either sex received intraperitoneal (IP) injections of either vehicle (n = 45) or one of three chemically dissimilar PAF receptor antagonists (n = 38) followed 30 to 60 minutes later by IP injections of either saline (0.8 mL, n = 33) or LPS (2 to 4 mg/kg, n = 50). Left atria (LA) were harvested 16 hours later, suspended in Krebs-Henseleit buffer and attached to force-displacement transducers. Starling and force-frequency curves, contractile function in the potentiated and resting states, and inotropic response to either isoproterenol or phenylephrine were measured. RESULTS: LPS caused a significant reduction in LA contractile function. Two of the three PAF receptor antagonists failed to ameliorate LPS-induced alterations in cardiac function. The third antagonist, SR27417, was approximately 50% effective in preventing LA contractile dysfunction. However, this beneficial response appeared to be caused by a primary inotropic effect of SR27417 because LA from animals treated with SR27417 and saline showed significantly higher contractile function compared with LA from animals treated with vehicle and saline. In vitro tests confirmed this. Some LA from LPS-treated animals exhibited reduced contractile responses when in the potentiated state, a sign of impaired calcium release from the sarcoplasmic reticulum (SR). The response of LA from endotoxic animals to isoproterenol was unchanged compared with controls whereas it was markedly impaired to phenylephrine. Use of SR27417 failed to improve this abnormal response. CONCLUSIONS: PAF does not appear to be a primary mediator of LPS-induced myocardial depression in guinea pigs. LPS may impair SR calcium release thereby causing cardiac dysfunction.

Animals↗
PubMed1995

Identification of phosphoproteins in Escherichia coli.

The substrates of ion- and lipid-stimulated protein kinase activity in extracts of Escherichia coli were purified by chromatography. Subsequent N-terminal sequencing suggests that these substrates include the following: a novel 80 kDa protein co-purifying with RNA polymerase but partially homologous to elongation factor G; a protein with an apparent molecular weight of 65 kDa identified as the ribosomal protein S1; and a 32 kDa protein identified as succinyl CoA synthetase, a key enzyme in the tricarboxylic acid cycle. The phosphorylation of these three proteins was markedly stimulated by the addition of manganese, and occurred on threonine, serine or tyrosine residues as indicated by the stability of the phosphoresidues during acid treatment. In addition, a calcium-stimulated protein of 70 kDa was identified as the heat-shock protein DnaK, and a 17 kDa lipid-stimulated phosphoprotein as nucleotide diphosphate kinase.

Adenosine Triphosphate↗
PubMed1994

Circular dichroism, molecular modeling, and serology indicate that the structural basis of antigenic variation in foot-and-mouth disease virus is alpha-helix formation.

Seven antigenic variants obtained from a single field isolate of foot-and-mouth disease virus, serotype A12, differ only at residues 148 and 153 in the immunodominant loop of viral protein VP1. Synthetic peptides corresponding to the region 141-160 are highly immunogenic. UV circular dichroism shows that (i) in aqueous solution the peptides are nearly identical, but in 100% trifluoroethanol they display helix-forming properties which correlate well with their serological crossreactivities for anti-peptide sera, and (ii) these properties are insensitive to substitutions at position 153, except for proline, but are highly sensitive to substitutions at position 148. This pattern can be explained by the effects of these substitutions on the amphiphilic character and positions of helices postulated in the region 146-156. Molecular models indicate that residues 147, 148, 150, 151, 153-155, and 157 are most likely to interact with residues of the antibody paratopes. The data are consistent with the existence of an inverse gamma-turn around Pro-153, and a beta-turn at the cell-attachment site at residues 145-147.

Amino Acid Sequence↗
PubMed1994

Response to inhibition of angiotensin-converting enzyme in human immunodeficiency virus-associated nephropathy: a case report.

The most common chronic nephropathy seen with human immunodeficiency virus (HIV) infection is characterized by heavy proteinuria and rapid deterioration of renal function. We here report the findings in an HIV-seropositive patient with nephrotic-range proteinuria and biopsy-proven HIV-associated nephropathy treated with the angiotensin-converting enzyme (ACE) inhibitor, fosinopril. During treatment periods, the patient demonstrated a significant decrement in 24-hour urinary protein excretion without change in renal function. The patient acted as her own control. After discontinuation of the drug, the 24-hour protein excretion deteriorated to pretreatment levels. ACE inhibition has been reported to decrease proteinuria and to have a beneficial influence on the progression of renal failure in diabetic and nondiabetic renal disease. To date, there is no known therapy for HIV-associated nephropathy. Our preliminary results in this patient suggest the need for long-term studies to assess whether this form of therapy can improve proteinuria over longer periods and, at the same time, ameliorate the progressive form of nephropathy seen in selected HIV-seropositive patients.

AIDS-Associated Nephropathy↗