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

A large-scale protein-function database

The rate at which data is acquired frequently outstrips the capacity of the human mind to house it. Instead, we mine it. The ability to electronically cull the majority of mankind's knowledge of the functioning of a particular biomolecule at the push of a button would be an acutely effective, efficient research tool. Consider the benefits of crossing such information against single nucleotide polymorphism databases to identify the biochemical lesions associated with disease-linked mutations or associate the functional consequences of mutations with changes in the structures housed in the Protein Data Bank. Additionally, as systems biologists strive to integrate large swaths of metabolism, ready access to initial-rate equilibria and regulatory data will prove immensely useful. Perhaps the greatest value of such a database lies in the myriad ways in which it would integrate into the daily activities of individuals, worldwide. One cannot help but wonder what fraction of the protein-function literature is obscured or even lost to the researcher by imprecise search engines and retrieval strategies