Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Iron mobilization from crocidolite as enhancer of collagen content in rat lung fibroblasts

Asbestos exposure causes pulmonary fibrosis by mechanisms that remain uncertain. There is increasing evidence that iron from asbestos is responsible for many of its effects. In this paper, we investigated the effect of iron mobilized from crocidolite asbestos on collagen content in rat lung fibroblast cultures under serum-free conditions. Crocidolite (2, 4, 6 microg/cm2 well) increased collagen content in a dose-dependent manner (+42 +/- 8, +92 +/- 10, and +129 +/- 13% vs controls). This effect was specific for collagen, since it did not alter total protein content and was inhibited by the iron chelator deferoxamine (DFO). Preincubation of crocidolite with citrate (1 mM) for 48 hr resulted in iron mobilization (51 microM) and increased collagen production (>3-fold) in treated cells. These effects occurred without the intervention of serum factors. The absence of cell damage, proliferation or lipid peroxidation leads to the supposition that iron from crocidolite per se may act as a profibrogenic agent. Although the in vivo participation of other cells and factors cannot be excluded, we conclude that iron released from crocidolite plays a role in collagen increase occurring during asbestosis

Enantioselective Organocatalytic Aryloxylation of beta-Keto Esters

An efficient enantioselective aryloxylation of cyclic β-keto esters with a selection of substituted o-quinones catalyzed by a bifunctional cinchona alkaloid derivative, giving entry to tricyclic dioxin adducts with high enantio- and diastereoselectivity, is described. © Georg Thieme Verlag Stuttgart - New York

Propolis influence on erythrocyte membrane disorder (hereditary spherocytosis): a first approach

Propolis is a resinous substance collected from plants by bees. Its composition depends on the vegetation, the season, and the source area. It usually contains many chemical compounds such as polyphenols, steroids and amino acids. The hereditary spherocytosis (HS) is a type of anaemia characterized by microcytic and hyperchromic red cells, spherical in shape and without central pallor. Clinically, subjects present from asymptomatic conditions to severe haemolytic anaemia. In this study it was evaluated the effect of two propolis extracts in the osmotic fragility of HS patient red blood cell (RBC) membrane. It was found that propolis decreases the erythrocytes membrane fragility, being the effect of Bornes propolis more pronounced than Fundao propolis'. This effect was related with the higher phenolic content of the former propolis. The results obtained in vitro suggest that the membrane fragility increases under oxidative stress conditions for the patient RBC's and the protection effect of propolis is due to its antioxidant properties. These results open doors for future investigations in order to elucidate the mechanisms, identify the main compounds involved in this fragility protection of the erythrocyte membrane. This is the first work reporting an evaluation of the propolis effect in a blood disease. (C) 2010 Elsevier Ltd. All rights reserved

Design, synthesis, and physicochemical and biological characterization of a new iron chelator of the family of hydroxychromenes

Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalized from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, postischaemic reperfusion, xenobiotic intoxications, etc.), In the present work we appropriately modified an iron chelator of the hydroxychromene family in, order to obtain a tridentate chelator that would inactivate the iron redox cycle after its complexation, with a view to using this molecule in human therapy and/or in disease prevention. We synthesized such a chelator for the first time and show, by different physticochemical analysis, its tridentate nature and, importantly, its capacity to chelate iron with enough strength to inhibit both iron-dependent H2O2 generation and lipid peroxidation in in vitro biological systems