Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antirheumatic drug aurothioglucose is an inhibitor of the selenoenzyme GSH peroxidase. During chrysotherapy, the decreased levels of erythrocyte GSH and serum sulfhydryls of rheumatoid arthritis patients are normalized concomitant with clinical efficacy. This investigation examined the in vivo and in vitro effect of gold(I) as aurothioglucose on enzymes related to the GSH redox cycle or metabolism. The enzymes measured were GSH peroxidase, GSSG reductase, gamma-glutamyl transpeptidase, gamma-glutamylcysteine synthetase, GSH S-transferase, GSH thiotransferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and catalase. Rats were injected with 30 mumol aurothioglucose/kg body wt. daily for 7 days by intramuscular injection. GSH levels in aurothioglucose-treated rats were 68% higher in erythrocytes (P less than 0.005) and 45% higher in kidney (P less than 0.001) than in control rats. Treatment with aurothioglucose did not elevate plasma or liver GSH. The enzyme activities that were changed by aurothioglucose treatment were GSH peroxidase in kidney (41% decreased, P = 0.005) and liver (13% decreased, P less than 0.05), gamma-glutamyl transpeptidase in kidney (15% decreased, P less than 0.05), and catalase in kidney (58% decreased, P less than 0.001). Kidney glucose-6-phosphate dehydrogenase activity was increased 50% (P less than 0.005) and GSH S-transferase was increased 72% (P less than 0.001). In vitro the only liver enzymes inhibited more than 50% by concentrations of less than 50 microM aurothioglucose were GSH peroxidase (50% inhibited by 25 microM aurothioglucose) and GSH thiotransferase (50% inhibited by 5 microM aurothioglucose). Studies of in vitro enzyme inhibition by aurothioglucose could not be used to predict decreased enzyme activities in vivo. Although decreased activities of two major enzymes that utilize GSH, GSH peroxidase and gamma-glutamyl transpeptidase, coincided with elevated GSH in kidneys of aurothioglucose-treated rats, a direct cause and effect relationship remains speculative.
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PMID:Effect of aurothioglucose on glutathione and glutathione-metabolizing and related enzymes in rat liver and kidney. 312 Nov 94

Gold(I)-containing compounds have long been used in the treatment of rheumatoid arthritis (RA), but the molecular mechanism of their action has remained largely unknown. In this paper we have demonstrated that gold(I) drugs selectively activate the DNA binding of a heterodimer consisting of the basic-leucine zipper transcription factors Nrf2 and small Maf. Once bound to its recognition DNA sequence termed antioxidant-responsive element or Maf-recognition element, Nrf2/small Maf induces a set of antioxidative stress genes, including heme oxygenase-1 and gamma-glutamylcysteine synthetase, whose products have been demonstrated to contribute to the scavenging of reactive oxygen species and to exhibit anti-inflammatory effects. Our findings suggest that stimulation of antioxidative stress response through activation of Nrf2/small Maf may be a pharmacologically important part of the actions of gold(I) drugs for the treatment of rheumatoid arthritis. Alternatively, activation of Nrf2/small Maf may be a protective response of cells against toxic effects of the drugs.
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PMID:Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(I) compounds. 1142 14

Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL.
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PMID:Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. 2459 28