[Show abstract][Hide abstract] ABSTRACT: Oral iron as a supplement has been associated with adverse health consequences, especially in the context of young children with active malaria. A potential aggravating role of non-transferrin-bound iron (NTBI) has been proposed.
NTBI responses in both a fasting and post-oral iron dosing situation were related to serum iron concentration and ferritin status. Fasting and 1, 2, and 3 h postdose serum samples were obtained in conjunction with oral ferrous sulfate supplementation in aqueous solution of 0, 15, 30, 60, 120 and 240 mg Fe in a cohort of 8 healthy Guatemalan men over a 9-week metabolic protocol. Hemoglobin, serum ferritin, percent transferrin saturation, serum iron and NTBI were all measured.
Circulating levels of serum iron and NTBI increased in a graded fashion in response to oral iron, with the relative increment for NTBI slightly greater than that of iron. Detectable NTBI was occasionally measured in fasting specimens, more frequently in subjects with high ferritin status. Post-iron NTBI responses, by contrast, were higher in normal-ferritin subjects in absolute terms, and rose with increasing postabsorptive serum iron responses.
The appearance and response of circulating NTBI were consistent with recognized principles of iron regulation.
Full-text · Article · Mar 2012 · Annals of Nutrition and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Chronic inflammation has been implemented in the pathogenesis of inflammatory diseases like atherosclerosis. Several pathogens like Chlamydia pneumoniae (Cp) and cytomegalovirus (CMV) result in inflammation and thereby are potentially artherogenic. Those infections could trigger endothelial activation, the starting point of the atherogenic inflammatory cascade. Considering the role of iron in a wide range of infection processes, the presence of iron may complicate infection-mediated endothelial activation.
Endothelial intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial selectin (E-selectin) expression were measured using flow cytometry, as an indication of endothelial activation. Cytotoxicity was monitored using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Immunostaining was applied to measure Cp and CMV infectivity to endothelial cells.
An increased number of infected endothelial cells in a monolayer population leads to a raised expression of adhesion molecules of the whole cell population, suggesting paracrine interactions. Iron additively up-regulated Cp-induced VCAM-1 expression, whereas synergistically potentiated Cp-induced ICAM-1 expression. Together with CMV, iron also enhanced ICAM-1 and VCAM-1 expression. These iron effects were observed without modulation of the initial infectivity of both microorganisms. Moreover, the effects of iron could be reversed by intracellular iron chelation or radical scavenging, conforming modulating effects of iron on endothelial activation after infections.
Endothelial response towards chronic infections depends on intracellular iron levels. Iron status in populations positive for Cp or CMV infections should be considered as a potential determinant for the development of atherosclerosis.
Full-text · Article · Nov 2006 · European Journal of Clinical Investigation
[Show abstract][Hide abstract] ABSTRACT: Alternative targets of attack of the human immunodeficiency virus (HIV) are necessary in light of infection persistence due to onset of resistance after conventional reverse transcriptase and protease inhibitor therapy. We have recently shown that the cancer chemotherapeutic agent bleomycin (BLM) dose-dependently inhibits HIV-1 replication. The mechanism of this viral inhibition in vitro was investigated. Cell-free wild-type virions were affected directly by BLM in the presence of H2O2, as shown by a 38% decrease of viral infectivity. Viral inhibition by BLM did not proceed via NF-κB inhibition. The viral R/U5 DNA product was reduced by 70% without any effect on reverse transcriptase activity. In both a cell-free system as well as two-cell systems the antiviral dependence of BLM on iron and oxidant species was demonstrated. Bleomycin seems to inhibit HIV-1 replication through the same properties that make it a suitable anti-cancer agent. The results presented in this study describe a novel mechanism of HIV-1 inhibition with potential application in viral infections. The anti-HIV effects of BLM in patients receiving this drug in combination with HAART should be carefully monitored in order to evaluate the clinical significance of the findings described in this study.
No preview · Article · May 2004 · Antiviral Research
[Show abstract][Hide abstract] ABSTRACT: Besides the fact that it is a vital element in life, iron may also participate in diverse pathological processes. It has been hypothesised that iron is involved in the development of atherosclerosis and related cardiovascular diseases. Several epidemiological studies as well as in vivo and in vitro experiments are in favour for this iron hypothesis, although some studies have yielded conflicting results. This review describes iron as a risk factor of atherosclerosis, through its involvement in the process of monocyte adhesion to endothelium, a crucial event of atherosclerotic plaque formation. Furthermore, the benefits of iron chelators in preventing this process are reviewed
[Show abstract][Hide abstract] ABSTRACT: BACKGROUNd: The iron chelators deferoxamine (DF) and deferiprone (CP20) have been shown to inhibit human immunodeficiency virus type 1 (HIV-1) replication in human peripheral blood lymphocytes (PBL). The orally active bidentate chelators CP502 and CP511, which also belong to the 3-hydroxypyridin-4-one family, but with higher affinities for iron than CP20, were monitored for their antiviral properties by checking for p24 antigen production and nuclear factor (NF)-kappaB activation, and their ability to induce apoptosis.
Human PBLs were isolated from HIV-1 seronegative donors and subsequently infected with HIV-1(Ba-L) for 2 h. After 5 days' incubation, HIV-1 replication was monitored by p24 antigen production. Cellular proliferation as well as caspase-3 activity were monitored in uninfected cells after a period of 5 days and after 1 day infection, respectively. NF-kappaB activity was also monitored by electromobility shift assays (EMSA) performed on nuclear extracts of Jurkat cells treated with the different chelators for 4 h.
CP502 and CP511 decrease HIV-1 replication by decreasing cellular proliferation in a similar manner to DF and CP20. CP511 seemed to be more potent than either CP502 or CP20. Due to the reduction in cellular proliferation, there was an increase in caspase-3 activity after 24 h incubation. NF-kappaB activity was not affected by any of the chelators.
Iron chelators with high affinities for iron, which are under development for the treatment of iron overload, could contribute to the reduction of HIV-1 replication in infected patients by cellular proliferation inhibition rather than by a direct antiviral action.
Full-text · Article · Apr 2002 · European Journal of Clinical Investigation
[Show abstract][Hide abstract] ABSTRACT: Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators.
The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process.
First some physico-chemical properties of iron concerning solubility, oxidation-reduction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained.
Nuclear factor kappa B (NF-kappaB) activation, regulating proviral transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA.
Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.
Full-text · Article · Mar 2001 · Journal of Clinical Virology
[Show abstract][Hide abstract] ABSTRACT: Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron. Hence, decreasing the availability of
iron may inhibit HIV-1 replication. Deferoxamine and deferiprone, both forming catalytically inactive iron-chelator complexes,
and bleomycin, by use of which iron catalyzes oxidative nucleic acid destruction, were investigated. Expression of p24 antigen
in human monocyte-derived macrophages and peripheral blood lymphocytes (PBL) was reduced by all 3 iron chelators. In PBL,
p24 reduction was mirrored by a decrease in proliferation after incubation with deferoxamine or deferiprone, suggesting that
viral inhibition is closely linked to a decrease in cellular proliferation. In contrast, clinically relevant bleomycin concentrations
reduced p24 levels by ∼50% without affecting proliferation. When deferoxamine and the nucleoside analogue dideoxyinosine were
used in combination, they acted synergistically in inhibiting HIV-1 replication. These observations suggest that iron chelators
with different mechanisms of action could be of additional benefit in antiretroviral combination therapy.
Full-text · Article · Mar 2000 · The Journal of Infectious Diseases