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Biomedical subjects

M M Weber

Publications and source records attributed to M M Weber.

At least 91 records · Page 5Linked to original sources
PubMed1985

Increased atherosclerosis in rabbits immunized with endothelial cells.

Rabbits maintained on normal ration or cholesterol-supplemented diet were immunized with homogenates of endothelial cells grown in cultures that were derived from either bovine or human aorta. Minimal aortic lesions were found in all groups of rabbits fed regular diet; microscopically, differences were seen that manifested as medial lesions in controls and intimal lesions in animals immunized with endothelial cells. Aortic atherosclerosis was significantly increased in the immunized, cholesterol-fed animals over that in controls. This difference was more pronounced in the abdominal aorta where the area with lesions in immunized rabbits was 4-7 times that of controls; atherosclerosis of the thoracic aorta was 2.5-5 times greater in the immunized animals (P less than 0.001 for both segments). Increased atherosclerosis was observed despite a significant reduction in plasma cholesterol in the immunized rabbits (770 +/- 119 mg/dl) compared to controls (1595 +/- 225 mg/dl) (P less than 0.001). Immunization with endothelial cells elicited strong cell-mediated and humoral responses as determined by dermal delayed hypersensitivity and solid-phase immunoradiometric tests, respectively. Cross-reactivity in both assays was found against human and bovine cells. Enhancement of atherosclerosis appears to depend not on induction of immune complexes but on specific antibodies and cell-mediated reactions.

Animals↗
PubMed1984

Comparison of dietary carbohydrates for promotion of DMBA-induced mammary tumorigenesis in rats.

Epidemiologic studies have suggested that sugar consumption is correlated with risk of breast cancer. We tested this possibility using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rat model. Rats were fed diets containing one of three carbohydrates: sucrose, lactose, or corn starch. Tumor yields were similar in the groups fed sucrose and corn starch but significantly lower in the animals fed lactose. Consumption of starch was associated with the most palpable tumors which weighed significantly more than tumors from the other groups. These data indicate significant effects on promotion of mammary tumorigenesis by dietary carbohydrates.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Dietary fat versus caloric content in initiation and promotion of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats.

Enhancement of mammary tumor formation by dietary fat may be mediated via increased caloric intake. Three experiments were performed to study this relationship in 7,12-dimethyl-benz(a)anthracene (DMBA)-treated female Sprague-Dawley rats: (a) high- or low-fat isocaloric diets were fed in a crossover design; (b) low-fat, high-calorie and high-fat, low-calorie diets were fed in a crossover design; (c) pair-fed rats were restricted to 60% of the calories of controls with ad libitum access to food beginning 10 days after DMBA administration. The pair-fed rats received daily 60% of calories, the same level of fiber, and 115% more fat than did rats fed ad libitum. Tumor yield but not tumor incidence was greater in rats fed high-fat rather than low-fat isocaloric diets prior to initiation of tumorigenesis. A low-fat, high-calorie diet led to more tumor incidence and yield than was associated with feeding of a high-fat, low-calorie diet. Caloric restriction (although with concomitant intake of more fat) led to complete inhibition of tumor formation. These results indicate that both high-fat and high-calorie diets exhibit cocarginogenic, not merely promotional, properties. Caloric intake may be a greater determinant than dietary fat of a tumor-enhancing regimen. Finally, restriction of caloric intake during promotion markedly suppresses tumor formation, despite the increased fat content of the restricted diet, suggesting a permissive role for calories in tumor formation. The possibility remains that alterations in levels of other dietary components could also have contributed to the observed effects.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Isoniazid interaction with tyrosine as a possible mode of action of the drug in mycobacteria.

The antitubercular drug isoniazid (INH) was hown by radio-chromatographic studies to react with tyrosine in growth medium. Exogenous tyrosine added to the growth medium interfered with the inhibitory action of INH on Mycobacterium phlei. These observations were confirmed by difference spectra studies which showed that tyrosine would react with INH as long as the tyrosine phenolic hydroxyl group was not blocked. These results led to the hypothesis that INH could exert its influence by interfering with tyrosine residues in mycobacterial proteins. N-acetylimidazole, a tyrosine-acetylating agent, mimicked the action of INH on the reduced nicotinamide adenine dinucleotide oxidase and dehydrogenase activity in electron transport particles from wild-type and INH-resistant M. phlei. Pyrazinamide, a drug structurally related to INH, also mimicked its effect on electron transport particles. To confirm that INH could react with tyrosine in proteins, purified enzymes with known tyrosine positions were tested. Bovine carboxypeptidase A with tyrosine at the active site was inhibited by INH and N-acetylimidazole, whereas the controls, yeast alcohol dehydrogenase and ribonuclease A, were not. It is therefore proposed that tyrosine residues in proteins may serve as the target for INH action in mycobacteria.

Culture Media↗
PubMed1980

Site of action of isoniazid on the electron transport chain and its relationship to nicotinamide adenine dinucleotide regulation in Mycobacterium phlei.

Isoniazid (INH) interacts with nicotinamide adenine dinucleotide (NAD+) in the regulation of reduced NAD (NADH) oxidation in electron transport particles from Mycobacterium phlei. the interaction was shown to be at the level of the NADH dehydrogenase by the use of menadione as an artificial electron acceptor. Binding studies indicated that INH and NAD+ did not compete for a common regulatory site. Unlabeled INH was unable to displace [14C]NAD+ from electron transport particles, and unlabeled NAD+ could not remove [3H]INH from particles. Preincubation of electron transport particles with unlabeled INH did not prevent the subsequent binding of [14C]NAD+, and unlabeled NAD+ did not block the binding of [3H]INH. [14C]NAD+ binding to electron transport particles was specific and reversible. Unlabeled NAD+ could both displace and prevent the binding of labeled nucleotide. Binding of [14C]NAD+ to electron transport particles was proportional to the incubation concentration of label, and NAD+ stimulation of NADH oxidase activity was related to the amount of NAD+ bound to electron transport particles. [3H]INH was irreversibly bound to electron transport particles. INH and NAD+, although operating at the same level of the electron transport chain, did not appear to compete for the same regulatory site.

Binding Sites↗
PubMed1977

Specificity of isoniazid on growth inhibition and competition for an oxidized nicotinamide adenine dinucleotide regulatory site on the electron transport pathway in Mycobacterium phlei.

The mechanism of action of isoniazid (INH) on saprophytic and atypical mycobacteria is thought to be different from that on Mycobacterium tuberculosis because higher concentrations are required to be effective in these species. In this investigation, M. phlei was inhibited by INH at a concentration of 25 mug/ml. Benzoic acid hydrazide (BZH) and nicotinic acid hydrazide (NAH) were inhibitory at levels of 300 and 500 mug/ml, respectively. Inhibition by these compounds was not inoculum dependent. An isolated M. phlei mutant resistant to 100 mug of INH per ml (Inh(r)) was inhibited by INH only at concentrations about equal to those inhibitory for BZH and NAH. When NAH and BZH were below their minimal inhibitory concentrations, INH inhibition was antagonized. Hence, there appears to be a single target site for INH in mycobacteria with different affinities for various hydrazide analogs of INH. The increased inhibitory levels required for the atypical and saprophytic species are due to a decreased affinity of the target site for INH in these species. INH also inhibited both the oxidized nicotinamide adenine dinucleotide (NAD(+)) and adenosine 5'-monophosphate stimulation of reduced NAD (NADH) oxidase activity associated with the M. phlei and M. tuberculosis H(37)R(a) electron transport particles. INH did not reverse the NAD(+) stimulation of oxidase activity in the Inh(r) strain of M. phlei. No direct inhibitory effect of INH on NADH oxidase activity was observed. Incubation of M. phlei electron transport particles at 0 degrees C with INH resulted in a dramatic loss of oxidase activity which could have been prevented if NAD(+) were present. However, INH had no effect upon the NADH oxidase when stored with electron transport particles isolated from the Inh(r) strain. Therefore, INH inhibition of regulation and/or stabilization of the electron transport pathway by NAD(+) or adenosine 5'-monophosphate may account, in part, for the lethal action of the drug on mycobacteria.

Adenosine Monophosphate↗
PubMed1975

Purification and properties of a soluble nicotinamide adenine dinucleotide-linked isocitrate dehydrogenase from Crithidia fasciculata.

A soluble NAD+-linked isocitrate dehydrogenase has been isolated from Crithidia fasciculata. The enzyme was purified 128-fold, almost to homogeneity, and was highly specific for NAD+ as the coenzyme. There is also a cytoplasmic NADP+-linked and a mitochondrial isocitrate dehydrogenase in the organism. Studies of the physical and kinetic properties of the soluble NAD+-isocitrate dehydrogenase from this organism showed that it resembled microbial NADP+-isocitrate dehydrogenases in general, all of which are cytoplasmic enzymes. The enzyme appeared not to be related to other NAD+-isocitrate dehydrogenases, which are found in the mitochondria of eukaryotic cells. The molecular weight of the soluble NAD+-isocitrate dehydrogenase was 105,000 which is within the range of the values for microbial NADP+-isocitrate dehydrogenases. Similar to the NADP+-isocitrate dehydrogenase in this organism, the enzyme was inhibited in a concerted manner by glyoxalate plus oxalacetate. Kinetic analysis revealed that Mn2+ was involved in the binding of isocitrate to the enzyme. Inhibition of the NAD+-linked isocitrate dehydrogenase by p-chloromercuribenzoate could be prevented by prior incubation of the enzyme with both Mn2+ and isocitrate; however, neither ion alone conferred protection. Free isocitrate, free Mn2+, and the Mn2+-isocitrate complex could all bind to the enzyme. Four different mechanisms with respect to the binding of isocitrate to the enzyme were tested. Of these, the formation of the active enzyme-Mn2+-isocitrate complex from (a) the random binding of Mn2+, isocitrate, and the Mn2+-isocitrate complex, or (b) the binding of Mn2+-isocitrate with free Mn2+ and isocitrate acting as dead-end competitors were both in agreement with these data.

Animals↗
PubMed1975

Effect of nicotinamide adenine dinucleotide on the membrane-associated reduced nicotinamide adenine dinucleotide oxidase of Mycobacterium phlei.

NAD+ had a biphasic effect on the NADH oxidase activity in electron transport particles from Mycobacterium phlei. The oxidase was inhibited competitively by NAD+ at concentrations above 0.05 mM. NAD+ in concentrations from 0.02 to 0.05 mM resulted in maximum stimulation of both NADH oxidation and oxygen uptake with concentrations of substrate both above and below the apparent K-M. Oxygen uptake and cyanide sensitivity indicated that the NAD+ stimulatory effect was linked to the terminal respiratory chain. The stimulatory effect was specific for NAD+. NAD+ was also specific in protecting the oxidase during heating at 50 degrees and against inactivation during storage at 0 degrees. NAD+ glycohydrolase did not affect stimulation nor heat protection of the NADH oxidase activity if the particles were previously preincubated with NAD+. Binding studies revealed that the particles bound approximately 3.6 pmol of [14C1NAD+ per mg of electron transport particle protein. Although bound NAD+ represented only a small fraction of the total added NAD+ necessary for maximal stimulation, removal of the apparently unbound NAD+ by Sephadex chromatography revealed that particles retained the stimulated state for at least 48 hours. Further addition of NAD+ to stimulated washed particles resulted in competitive inhibition of oxidase activity. Desensitization of the oxidase to the stimulatory effect of NAD+ was achieved by heating the particles at 50 degrees for 2 min without appreciable loss of enzymatic activity. Kinetic studies indicated that addition of NADH to electron transport particles prior to preincubation with NAD+ inhibited stimulation. In addition, NADH inhibited binding of [14C]NAD+. The utilization of artificial electron acceptors, which act as a shunt of the respiratory chain at or near the flavoprotein component, indicated that NAD+ acts as at the level of the NADH dehydrogenase at a site other than the catalytic one resulting in a conformational change which causes restoration as well as protection of oxidase activity.

Binding Sites↗