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Biomedical subjects

G W Rafter

Publications and source records attributed to G W Rafter.

At least 19 recordsLinked to original sources
PubMed1994

Plasma thiols, copper and rheumatoid arthritis.

A means by which methotrexate diminishes the overproduction of leukotriene B4 by neutrophils from rheumatoid arthritic patients is described. It is postulated that neutrophil intracellular reduced glutathione is decreased by increased cellular copper, which results in leukotriene B4 overproduction. In the arthritic patient it is proposed that there is an inappropriate amount of a copper donor form of ceruloplasmin which contains a reduced copper that was formed during ceruloplasmin's oxidation of plasma cysteine. Oxidation of increased amounts of plasma homocysteine, present during methotrexate administration, restores ceruloplasmin's redox state leading to decreased copper transport into cells.

Animals↗
PubMed1990

Sulfhydryl proteins and the engram.

A scheme, which is selectional not instructional, is described for the molecular basis of the engram. It uses as reactants intermediates formed during the catabolism of neuronal membrane sulfhydryl proteins. It is proposed that these compounds undergoing intermolecular association generate a large number of diverse structures, some of which are selected for further complex formation. The basis of selection is the binding of a particular compound to membrane lipid, which enhances its reaction with another bound compound. Because the composition and configuration of membrane lipids are influenced by environmental factors, the scheme implies that incoming sensory signals are matched with endogenously generated chemical structures.

Brain↗
PubMed1990

Reaction of insulin with reduced glutathione.

An aggregate of insulin, molecular weight about 70,000, was formed when it was incubated with GSH. The aggregate product converted to a low molecular weight product, presumably the insulin A- and B-chains, on addition of urea to mixtures. This conversion requires sulfhydryl-disulfide interchange as a sulfhydryl reagent inhibited it, in part. The aggregate does not form with EDTA in mixtures, but as before, a product of lower molecular weight than insulin was formed. These results support the previously held view that the disulfide bonds formed by insulin are influenced by its structure.

Animals↗
PubMed1988

Interleukin 1 and rheumatoid arthritis.

The erosive changes seen in the joint structures of the rheumatoid arthritic patient can be attributed to the consequences of the action of interleukin 1. Mononuclear leukocytes have been much studied as a source of the interleukin 1, while polymorphonuclear leukocytes have been largely ignored. The hypothesis promulgated here is that polymorphonuclear leukocytes are the source of the interleukin 1 in the joint space in amounts to be arthritogenic in the susceptible patient. It is proposed that the role of the mononuclear leukocytes, which are activated in the systemic circulation, is to induce infiltration of polymorphonuclear leukocytes into the joint space.

Arthritis, Rheumatoid↗
PubMed1987

Reaction of liver pyruvate kinase with sulfhydryl reagents: effect on its activity.

Homogeneous liver pyruvate kinase was reacted with different sulfhydryl reagents, which included o-iodosobenzoate, 5',5'-dithiobis(2-nitrobenzoic acid) and N-ethylmaleimide. Activity determinations of the treated enzyme made with and without Fru(1,6)P2 indicate that the protein contains two sulfhydryl groups per subunit important to its properties, one more accessible than the other. Fru(1,6)P2 added to mixtures prevented loss of activity obtained with o-iodosobenzoate and 5',5'-dithiobis(2-nitrobenzoic acid). It appears that Fru(1,6)P2 does not interfere with the reaction of the reagent with the sulfhydryl group, but prevents an ensuing conformational change, which leads to changes in the enzyme's properties.

Animals↗
PubMed1987

Rheumatoid arthritis: a disturbance in copper homeostasis.

That understanding the mode of action of antirheumatic drugs could help understand the etiology of rheumatoid arthritis is complicated by their apparent different actions on different target cells. The point of view adopted here is that the primary defect in rheumatoid arthritis will be similarly altered by such drugs. The common reactivity of two of the most widely prescribed drugs, D-penicillamine and sodium aurothiomalate, toward albumin-bound copper is proposed as their primary site of action. Elevated serum concentration of this form of copper has previously been suggested to perturb synovial cell metabolism and trigger the disease.

Arthritis, Rheumatoid↗
PubMed1985

Immunoglobulin degradation and D-penicillamine action.

Treatment of human IgG with pancreatic elastase gave a product of higher molecular weight than IgG. Its formation was inhibited by blocking IgG sulfhydryl groups with iodoacetamide. Incubation of the high molecular weight product with either glutathione or D-penicillamine yielded Fab- and Fc-like fragments. Addition of oxidized glutathione to mixtures containing either reduced thiol gave a new product of molecular weight intermediate between the high molecular weight product and Fab- and Fc-like fragments. Oxidized D-penicillamine did not substitute for oxidized glutathione. This new product was formed under conditions that favor protein sulfhydryl-disulfide exchange. The effect of D-penicillamine on its formation was discussed in terms of D-penicillamine's mode of action in rheumatoid arthritis.

Chemical Phenomena↗
PubMed1982

Etiology of rheumatoid arthritis.

The major thesis of the proposed hypothesis is that in the absence of microbial material synovial macrophages in rheumatoid arthritis patients continue to release interleukin 1, which perpetuates the inflammation so characteristic of the disease. Its release is suggested to result from an altered synovial macrophage glutathione metabolism brought about by the action of interleukin 1 on host copper metabolism. Three anti-rheumatic drugs are suggested to act at different points in this pathogenic chain reaction. Alclofenac on interleukin 1, gold thiolates on copper-inhibited macrophage glutathione reductase, and D-penicillamine on IgC catabolism. Drawing upon the hypothesis some suggestions are made for drug design.

Arthritis, Rheumatoid↗
PubMed1979

Disulfide-disulfide interchange catalyzed by a liver supernatant enzyme.

An enzyme widely distributed in rabbit tissues which catalyzes an interchange between N,N-di-dinitrophenyl-L-cystine and oxidized glutathione to form the mixed disulfide is described. D-Penicillamine disulfide can be substituted for oxidized glutathione and the mixed disulfide of cysteine and glutathione can serve as the sole substrate giving as one product of interchange, oxidized glutathione. The enzyme is very labile and only limited purification of it has been achieved. The activity increases with increasing pH above 6.6, the Km for N,N-di-dinitrophenyl-L-cystine is 0.2 mM and for oxidized glutathione 0.8 mM. The enzyme is inhibited by SH reagents with protection against iodoacetamide inactivation provided by N,N-di-dinitrophenyl-L-cystine. Evidence is presented that disulfide-disulfide interchange enzyme is a different activity from the previously described protein disulfide isomerase and thiol transferase.

Animals↗
PubMed1975

Further studies on the activation of microsomal (Na+ + k+)-atpase by a leukocytic product.

Previous studies showed that microsomal (Na+ + K+)ATPase (ATP phosphohydrolase, EC 3.6.1.3) is activated by a proteinaeous material released by polymorphonuclear leukocytes. Investigations on the mode of action of the activator have been conducted by the siolation of 32P-labeled phosphoenzyme intermediates formed in the reaction of ATP and (Na+ + K)-ATPase, which has been postulated to occur through the formation and hydrolysis of acyl phosphate intermediates. The activator caused a concentration-dependent decrease in the recovery of phosphoenzyme intermediates that was not quantitatively altered by the Na+ or K+ concentration of the reaction mixture of by the presence of 1 mM oubain. A decline in phosphoenzyme intermediate recovery was promoted by the addition of the activator to preformed phosphoenzyme intermediates but not by activator that had been pretreated with protease or phenol. In addition, the activator caused a concentration-dependent stimulation of the p-nitrophenyl phosphatase and acetyl phosphatase activities of microsomal (Na+ + K+)-ATPase. It was proposed that the activator stimulates the dephosphorylation step of the (Na+ + K+)-ATPase reaction sequence.

Adenosine Triphosphatases↗
PubMed1975

Activation of rabbit brain microsomal (Na+ plus K+)-dependent ATPase by a leukocytic product.

The properties of a (Na+ plus K+)-dependent ATPase (ATP phosphohydrolase, EC 3.6.1.3) activator contained in leukocytic extracts was investigated. Intact polymorphonuclear leukocytes release the activator in a time- and temperature-dependent process. It is non-dialyzable through cellophane; inactivated by protease, trypsin, or phenol; contains essential sulfhydryl groups; and is heat and acid labile. Treatment of ATPase with the activator and subsequent removable of the activator from mixtures did not reverse the ATPase activation.

Adenosine Triphosphatases↗