Effects Of Gold Compounds Research Articles

The effects of phosphanegold(I) thiolates on the biological properties of Acanthamoeba castellanii belonging to the T4 genotype

BackgroundGold compounds have shown promise in the treatment of non-communicable diseases such as rheumatoid arthritis and cancer, and are considered of value as anti-microbial agents against Gram-negative and Gram-positive bacteria, and have anti-parasitic properties against Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, Leishmania infantinum, Giardia lamblia, and Entamoeba histolytica. They are known to affect enzymatic activities that are required for the cellular respiration processes.MethodsAnti-amoebic effects of phosphanegold(I) thiolates were tested against clinical isolate of A. castellanii belonging to the T4 genotype by employing viability assays, growth inhibition assays, encystation assays, excystation assays, and zymographic assays.ResultsThe treatment of A. castellanii with the phosphanegold(I) thiolates tested (i) had no effect on the viability of A. castellanii as determined by Trypan blue exclusion test, (ii) did not affect amoebae growth using PYG growth medium, (iii) did not inhibit cellular differentiation, and (iv) had no effect on the extracellular proteolytic activities of A. castellanii.ConclusionBeing free-living amoeba, A. castellanii is a versatile respirator and possesses respiratory mechanisms that adapt to various aerobic and anaerobic environments to avoid toxic threats and adverse conditions. For the first time, our findings showed that A. castellanii exhibits resistance to the toxic effects of gold compounds and could prove to be an attractive model to study mechanisms of metal resistance in eukaryotic cells.

P2‐373: The anti‐rheumatic gold drug auranofin could be beneficial in Alzheimer's disease by inhibiting astrocyte‐mediated neuroinflammation

Alzheimer's disease (AD) is characterized by chronic inflammation in brain areas affected by the disease process, which may contribute to the neuronal loss characteristic of AD. It is thought that by reducing this inflammation, the neuronal loss observed in AD could be decreased. Astrocytes support neurons by regulating their external chemical environment, but when activated by pathogenic stimuli, these cells can secrete pro-inflammatory and neurotoxic substances that contribute to neuroinflammation and neuronal death. There are currently no effective therapeutic agents directed at astrocyte neurotoxicity or neuroinflammation in general. Auranofin is a potent anti-inflammatory drug which has been used in the treatment of rheumatoid arthritis for many years and has been shown to inhibit several inflammatory pathways such as those involving p38 mitogen activated protein kinases and thioredoxin reductase. However, a potential for auranofin to reduce neuroinflammatory reactions has not been reported. Therefore, the effectiveness of auranofin and several other gold-containing compounds as inhibitors of astrocyte pro-inflammatory functions was investigated. Effects of gold compounds on the following activation parameters of interferon (IFN)-γ stimulated human U373-MG and U118-MG astrocytoma cells as well as primary human astrocytes were studied: i) mRNA expression (RT-qPCR) of several inflammatory markers including interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1 and heme oxygenase (HOX)-1; ii) pro-inflammatory cytokine secretion (ELISA); and iii) toxicity towards SH-SY5Y neuroblastoma cells (MTT and LDH cell viability assays). In the low micromolar range (0.1-5 m M), auranofin inhibited toxicity of stimulated astrocytoma and human primary astrocytes towards SH-SY5Y neuroblastoma cells. Treating SH-SY5Y cells directly with 1 m M auranofin protected neuronal cells from toxicity induced by supernatants from stimulated astrocytes. 1 mM auranofin upregulated expression of HOX-1 in both stimulated and unstimulated astrocytes. It also affected the secretion of pro-inflammatory cytokines. Several other gold-based drugs and a gold salt had no effect in the above assays. Auranofin may decrease toxicity of stimulated astrocytes towards neurons by up-regulating expression of the protective enzyme HOX-1. As an effective inhibitor of neuroinflammatory reactions, auranofin should be tested in animal models and clinically for its potential to slow neurodegeneration observed in AD.

Effects of chrisotherapeutic gold compounds on prostaglandin E2 production.

The mechanism of action of anti-rheumatic gold compounds on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced prostaglandin E(2) (PGE(2)) production in rat peritoneal macrophages were examined. Auranofin (AF) at 3-10 muM inhibited TPA-induced PGE(2) production in a concentration-dependent manner. In the pharmacological experiments, prostaglandin G/H synthase (PGHS)-2-dependent PGE(2) production was inhibited by 10 muM of AF. The enzyme activities of both PGHS-1 and PGHS-2 were not affected by the 10 muM AF. Other gold compounds, aurothioglucose (ATG) and aurothiomalate (ATM) did not inhibit PGE2 production at 10 muM. AF decreased the PGHS-2 protein content, but had no effect on the PGHS-1 protein content. AF at 3-10 muM decreased the PGHS-2 messenger RNA (mRNA) level by RT-PCR determination. Then, the effect of AF on nuclear factor kappa B (NF-kappaB), one of the transcription factors known to regulate transcription of a group of proinflammatory proteins, was determined. AF at 1-10 muM inhibited nuclear translocation of NF-kappaB in a concentration-dependent manner. ATG and ATM at 10 muM did not inhibit NF-kappaB nuclear translocation, but with 20 h preincubation, ATG and ATM inhibited PGE(2) production and NF-kappaB nuclear translocation. AF, ATG, and ATM did not affect the binding of NF-kappaB to its specific DNA. These observations may suggest that the effects of gold compounds on the inhibition of NF-kappaB nuclear translocation plays one of the major role in its anti-inflammatory effects in rat peritoneal macrophages.

Inhibition of Human B Cell Activation by Gold Compounds

The mechanism of action of gold compounds, which are effective in the treatment of rheumatoid arthritis (RA), has not been clearly identified. Although one of the characteristic features of RA is chronic stimulation of B cells, the effects of gold compounds on B cells have not been precisely assessed. We therefore examined the effects of gold sodium thiomalate (GST) on human B cells. IgM production was induced from highly purified B cells obtained from healthy donors by stimulation withStaphylococcus aureusCowan 1 (SA) plus IL-2. T cell proliferation and IFN-γ production were induced from highly purified T cells by stimulation with immobilized mAb to CD3. As little as 0.1 μg/ml (0.25 μM) GST almost completely suppressed B cell IgM production, whereas it did not suppress T cell proliferation or IFN-γ production. The inhibition of IgM production by GST is not due to its thiomalate, but is most likely due to its gold components, since thiomalate alone did not inhibit IgM production. GST was required at the initiation of cultures to exert optimal suppressive effects on IgM production. Moreover, GST suppressed the expression of IL-2R (CD25) and transferrin receptor (CD71) on SA-stimulated B cells. These results indicate that GST preferentially inhibits the function of B cells at concentrations much lower than those which inhibit the function of T cells by interfering with the initial activation of B cells. The direct inhibitory effects of GST on human B cell activation described here may contribute at least in part to its therapeutic effect in RA.

Medicinal chemistry and pharmacology of gold compounds

The only current clinical application for gold drugs is in the treatment of rheumatic diseases, primarily rheumatoid arthritis. Little has changed in this area since the introduction of the orally available gold drug auranofin in 1985. There has been considerable research effort to find alternative therapeutic applications for gold drugs, particularly for the treatment of cancer, but after promising early indications the lead candidate [Au(dppe)2]Cl failed to enter clinical trials due to cardiotoxicity. Despite this setback research in this field has not abated. Recent work in our own laboratory has indicated that stable gold(III) compounds have activity in disease models of human cancer and this may be the way forward in this area. Gold compounds also have potential as antimicrobial agents, particularly against topical infections. The most interesting advances in the pharmacology of gold drugs have come from studies on their mechanism of action. The diverse effects of gold drugs on the immune system have been known for some time but there has been no satisfactory biochemical explanation for these observations. Recent work on the effect of gold compounds on gene transcription provides a new clue to this mechanism. After 60 years of chrysotherapy perhaps an improved understanding of the molecular and biochemical mechanism of gold compounds will provide the impetus for new advances in the medical use of gold drugs.

In vivo effect of gold compounds on thyroxine to triiodothyronine conversion by type I 5'-deiodinase in patients with rheumatoid arthritis.

In vivo effect of gold compounds on thyroxine to triiodothyronine conversion by type I 5'-deiodinase in patients with rheumatoid arthritis.

Helicobacter pylori seroprevalence in patients with rheumatoid arthritis: Effect of nonsteroidal anti-inflammatory drugs and gold compounds

purpose: To investigate the relationship between Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) intolerance and the effect of gold use on the seroprevalence of H. pylori. patients and methods: We examined the frequency of discontinuation of NSAIDs in 132 unselected patients with rheumatoid arthritis attending an outpatient subspecialty clinic, and the effect of gold compound use on the seroprevalence (by IgG enzyme-linked immunosorbent assay) of H. pylori infection in this population. Logistic and multivariate regression analysis was performed adjusting for age, gender, ethnic origin, history of ulcer, and duration of rheumatoid arthritis. results: Fifty-four patients had a positive serology for H. pylori (41%). Twenty-seven of the seropositive patients (50%), versus 45 of the seronegative patients (57.7%), had to discontinue NSAIDs (aspirin and/or nonaspirin) at least once since their diagnosis of rheumatoid arthritis because of gastrointestinal side effects (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.63 to 1.38). Forty-one of the seropositive patients (76%) had received gold compounds as compared with 62 of the seronegative patients (79.5%) (OR: 0.96; 95% CI: 0.61 to 1.50). conclusion: We did not find any relationship between H. pylori seropositivity and NSAID intolerance in patients with rheumatoid arthritis. In addition, our results do not demonstrate a reduction in H. pylori seroprevalence in rheumatoid arthritis patients treated with gold compounds.

Effect of gold compounds on the activity of adenylyl cyclase in human lymphocyte membranes.

To determine the effects of aurothioglucose, aurothiomalate, and auranofin on basal and forskolin-activated adenylyl cyclase activity in human total lymphocyte membranes, and in membranes of T and B lymphocyte subsets. Membranes were isolated from human total lymphocytes and T and B cell subsets. The effects of gold compounds on basal and forskolin-stimulated activity of adenylyl cyclase were measured by radioassay. The gold compounds inhibited adenylyl cyclase activity. This inhibitory effect required the presence of both the sulfhydryl ligands and aurous cation. Regulation of lymphocyte adenylyl cyclase by gold compounds represents a potential mode of action of these drugs in rheumatic diseases.

Effects of gold compounds on the function of phagocytic cells. II. Inhibition of superoxide radical generation by tripeptide-activated polymorphonuclear leukocytes.

The effect of sodium aurothiomalate and triethylphosphine gold on the generation of superoxide radicals by chemotactic tripeptide-activated polymorphonuclear leukocytes has been investigated using a cytochrome C reduction technique. Neither gold compound inhibited the binding of the tripeptide to cells. Sodium aurothiomalate in concentrations ranging from 1 to 100 micrograms/ml produced mild, nonsignificant inhibition of the generation of superoxide radicals. In contrast, triethylphosphine gold at a concentration of 0.25 microgram/ml was associated with a mild enhancement of superoxide radical production, but the enhancement was not statistically significant. At concentrations of 1.25 micrograms/ml and above, there was a profound inhibition of superoxide radical production by these activated cells. Since the products of the respiratory burst, including superoxide, are thought to be inflammatory mediators, it is postulated that the inhibition of superoxide radical generation by gold compounds may be another mechanism by which the compounds modulate their antiinflammatory effects in patients with rheumatoid disease.

The biological chemistry of gold

Interest in the effects of gold compounds on biological systems ranges from their use for anti-inflammatory and anti-bacterial purposes to the study of the method of uptake of gold by micro-organisms. By the application of modern physical techniques new light is being shed on the mechanism of action of gold in these areas.