A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats.
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Many human diseases are associated with the overproduction of oxygen free radicals that inflict cell damage. A manganese(II) complex with a bis(cyclohexylpyridine)-substituted macrocyclic ligand (M40403) was designed to be a functional mimic of the superoxide dismutase (SOD) enzymes that normally remove these radicals. M40403 had high catalytic SOD activity and was chemically and biologically stable in vivo. Injection of M40403 into rat models of inflammation and ischemia-reperfusion injury protected the animals against tissue damage. Such mimics may result in better clinical therapies for diseases mediated by superoxide radicals. (+info)
Nitric oxide synthase expression in the course of lead-induced hypertension.
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We recently showed elevated reactive oxygen species (ROS), reduced urinary excretion of NO metabolites (NOx), and increased NO sequestration as nitrotyrosine in various tissues in rats with lead-induced hypertension. This study was designed to discern whether the reduction in urinary NOx in lead-induced hypertension is, in part, due to depressed NO synthase (NOS) expression. Male Sprague-Dawley rats were randomly assigned to a lead-treated group (given lead acetate, 100 ppm, in drinking water and regular rat chow), a group given lead and vitamin E-fortified chow, or a normal control group given either regular food and water or vitamin E-fortified food for 12 weeks. Tail blood pressure, urinary NOx excretion, plasma malondialdehyde (MDA), and endothelial and inducible NOS (eNOS and iNOS) isotypes in the aorta and kidney were measured. The lead-treated group exhibited a rise in blood pressure and plasma MDA concentration, a fall in urinary NOx excretion, and a paradoxical rise in vascular and renal tissue eNOS and iNOS expression. Vitamin E supplementation ameliorated hypertension, lowered plasma MDA concentration, and raised urinary NOx excretion while significantly lowering vascular, but not renal, tissue eNOS and iNOS expression. Vitamin E supplementation had no effect on either blood pressure, plasma MDA, or NOS expression in the control group. The study also revealed significant inhibition of NOS enzymatic activity by lead in cell-free preparations. In conclusion, lead-induced hypertension in this model was associated with a compensatory upregulation of renal and vascular eNOS and iNOS expression. This is, in part, due to ROS-mediated NO inactivation, lead-associated inhibition of NOS activity, and perhaps stimulatory actions of increased shear stress associated with hypertension. (+info)
Helicobacter treatment with quadruple therapy in primary health care for patients with a history of ulcer disease.
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BACKGROUND: Few patients with a history of peptic ulcer are treated by their GP for H. pylori infection, even though theoretical evidence supports such an approach. OBJECTIVES: We aimed to determine the validity of this recommendation and to test the feasibility of quadruple therapy in primary health care. METHODS: In this prospective, non-randomized intervention study, 51 unselected patients with a history of proven ulcer disease received a 7-day quadruple therapy (lansoprazole, colloidal bismuth subcitrate, tetracycline and metronidazole) from their GP. Main outcome measures were: (i) endoscopically confirmed cure of the infection; (ii) results of serology at entry and at 6 months follow-up; (iii) quality of life at entry, at 6 weeks and at 6 months follow-up; (iv) gastric symptoms at entry, at 6 weeks and at 6 months follow-up; and (v) medication at entry and at 6 months follow-up. RESULTS: Quadruple therapy was well tolerated and there were no drop-outs with this regimen. Intention to treat cure rate was 48/51 (94%, 95% CI 87-100%), per protocol cure rate was 48/49 (98%, 95% CI 94-100%). 45/50 (90%) had positive serology at entry. IgG antibody titres decreased > 40% in 95.2% of patients. Quality of life improved significantly after treatment, gastric symptoms decreased and medication use decreased. CONCLUSIONS: GPs should be encouraged to identify patients with a history of ulcer disease and chronic use of acid suppressants and offer them treatment for H. pylori infection. This approach will cure the infection in almost all patients, it will improve the quality of life and decrease costs. Quadruple therapy does not lose efficacy when employed in primary care. Pre-treatment serological testing is potentially useful for narrowing down the treatment group to those with actual infection, and serology is promising as an easy and cheap follow-up instrument in primary health care. (+info)
Reduction of polysaccharide production in Pseudomonas aeruginosa biofilms by bismuth dimercaprol (BisBAL) treatment.
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Microorganisms in biofilms, cells attached to a surface and embedded in secreted insoluble extracellular polymers, are recalcitrant to chemical biocides and antibiotics. When Pseudomonas aeruginosa ERC1 biofilms were treated continuously with 1 x MIC of bismuth dimercaprol (BisBAL), biofilm density determined by both total cell counts and viable cell counts increased during the first 30 h period then decreased thereafter. After 120 h of treatment there was an approximate 3-log reduction in viable cell areal density compared with the untreated control. Per-cell total polysaccharide production was significantly reduced in biofilms exposed to 12.5 microM BisBAL compared with the untreated control. In biofilm cultures, 1 x MIC of BisBAL did not initially kill attached cells but was enough to reduce polysaccharide production. As treatment proceeded, the normalized polysaccharide content was reduced and those cells attached became susceptible to 1 x MIC of BisBAL. (+info)
Crystal structure of bovine Cu,Zn superoxide dismutase at 3 A resolution: chain tracing and metal ligands.
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An electron density map at 3 angstrom resolution has been calculated for Cu2+, Zn2+ superoxide dismutase from bovine erythrocytes, and the course of the main chain has been traced. The dominant structural feature is an 8-stranded barrel of antiparallel beta-pleated sheet. There is one very short helical section and two long loops of non-repetitive structure. The Cu and Zn are bound between the loops and one side of the beta barrel and are about 6 Angstrom apart, with a common histidine ligand. The Cu has four histidine ligands in a somewhat distorted square plane, and the Zn has three histidines and an aspartate in approximately tetrahedral arrangement. The two coppers of a dimer are about 34 Angstrom apart. The two subunits have essentially the same conformation and have an extensive contact area that mainly involves hydrophobic side chain interactions. The overall folding pattern of the polypeptide chain is very similar to that of an immunoglobulin domain. (+info)
Induction of maturation (meiosis) in Xenopus laevis oocytes by three organomercurials.
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Three organomercurials, p-hydroxymercuribenzoate, p-hydroxymercuriphenylsulfonate, and mersalyl, induce maturation (meiosis) in a large percentage (20-100 percent) of Xenopus laevis oocytes. Maturation takes place even when the follicle cells which surround the oocytes have been withdrawn. Organomercurial- and progesterone-induced maturations have many features in common: they do not occur when the inducer is injected into the oocytes, they require the presence of Ca++ in the medium, they are inhibited by cycloheximide but not by actinomycin D. In both cases, the maturation producing factor and the pseudomaturation inducing factor are produced. Organomercurial-treated oocytes react normally to activating stimuli; their protein synthesis increases, but uptake of amino acids is strongly inhibited. Progesterone and p-hydroxymercuriphenyl-sulfonate act synergically in inducing maturation. The main difference between the two agents is that p-hydroxymercuriphenylsulfonate must act for several hours, whereas, short contact with progesterone is sufficient to induce maturation. (+info)
X-ray absorption spectroscopy using synchrotron radiation for structural investigation of organometallic molecules of biological interest.
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The technique of x-ray absorption spectroscopy using tuneable, very intense x-rays from a high energy electron storage ring has been applied to study of the estended x-ray absorption fine structure for Cu and Ni tetraphenylporphyrin and methemoglobin. Preliminary analysis shows that the spectra may be interpreted as a super-position of modulations arising from the nearest neighbor nitrogen and pyrrole alpha-carbon coordination sheels of the metal atoms. We estimate that with the observed magnitude of noise to modulation amplitude, relative shifts of 0,5% in the metal-nitrogen to metal-carbon bond distances in the prophyrins should be observable using extended x-ray absorption fine structure and that this technique may provide a method of observing these types of structural changes in solution. (+info)
31P magnetic resonance spectroscopy as a predictor of efficacy in photodynamic therapy using differently charged zinc phthalocyanines.
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Photodynamic therapy (PDT) is a developing approach to the treatment of solid tumours which requires the combined action of light and a photosensitizing drug in the presence of adequate levels of molecular oxygen. We have developed a novel series of photosensitizers based on zinc phthalocyanine which are water-soluble and contain neutral (TDEPC), positive (PPC) and negative (TCPC) side-chains. The PDT effects of these sensitizers have been studied in a mouse model bearing the RIF-1 murine fibrosarcoma line studying tumour regrowth delay, phosphate metabolism by magnetic resonance spectroscopy (MRS) and blood flow, using D2O uptake and MRS. The two main aims of the study were to determine if MRS measurements made at the time of PDT treatment could potentially be predictive of ultimate PDT efficacy and to assess the effects of sensitizer charge on PDT in this model. It was clearly demonstrated that there is a relationship between MRS measurements during and immediately following PDT and the ultimate effect on the tumour. For all three drugs, tumour regrowth delay was greater with a 1-h time interval between drug and light administration than with a 24-h interval. In both cases, the order of tumour regrowth delay was PPC > TDEPC = TCPC (though the data at 24 h were not statistically significant). Correspondingly, there were greater effects on phosphate metabolism (measured at the time of PDT or soon after) for the 1-h than for the 24-h time interval. Again effects were greatest with the cationic PPC, with the sequence being PPC > TDEPC > TCPC. A parallel sequence was observed for the blood flow effects, demonstrating that reduction in blood flow is an important factor in PDT with these sensitizers. (+info)