Background
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. Review 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, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles.
Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here.
Conclusions
Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach.
"Iron-mediated oxidative stress is arguably the cause of much of the inflammation typically observed in biological systems, often further mediated via pro-inflammatory cytokines. Another major prediction that comes from the above then is that molecules that are anti-inflammatory, whether widely recognised as such or not, should have beneficial effects in syndromes for which they have not necessarily been tested. An obvious set of candidates in this regard are to be found among the statins,since it is now clear that they have important anti-inflammatory properties (see above). Thus, there are already indications that as well as their established benefits in cardiovascular disease (e.g. [804; 2327]) they may exert benefit in a huge variety of syndromes [838], including sepsis [839; 2060; 2328-2340], heart failure [2341], pain perception [2342], lupus and related diseases [1293; 2343], diabetes [877; 2344], rheumatoid arthritis [866; 869; 890; 2345-2350], kidney disease [2351-2353], inflammatory skin disease [2354], emphysema [2355], ischaemia-reperfusion injury [2356], stroke [864; 872; 2357- 2364], traumatic brain injury [2365-2367], neurodegenerative diseases [860-862; 920; 1294; 2059; 2368-2384], neurotoxicity [2385] and cancer [2386-2400].
There is also a considerable and positive role for nutrients in terms of their chelation of iron. Indeed, polyphenolic compounds, many of which have known health benefits [1804-1813], are widely used as food antioxidants [1814; 1815]. There is of course considerable epidemiological evidence for the benefits of consuming fruit and vegetables that are likely to contain such antioxidants (e.g. [1816-1819]), and – although possibly a minimum – this has been popularised as the ‘five a day’ message (e.g. http://www.fruitsandveggiesmatter.gov/ and http://www.5aday.nhs.uk/). Even though elements of the ‘Mediterranean’ diet that are considered to be beneficial are usually assumed to be so on the basis of their antioxidant capabilities (but cf. [1820]), many of the polyphenolic compounds (e.g. flavones, isoflavones, stilbenes, flavanones, catechins (flavan-3-ols), chalcones, tannins and anthocyanidins) [1821-1828] so implicated may also act to chelate iron as well [1073; 1829-1843]. This is reasonable given that many of these polyphenols and flavonoid compounds [1821; 1844-1853] have groups such as the catechol moiety that are part of the known iron-binding elements of microbial siderophores. Examples include flavones such as quercetin [914; 1813; 1829; 1854-1864], rutin [1829; 1857; 1858; 1865; 1866], baicalin [1860; 1867], curcumin [1813; 1868-1872], kolaviron [1873], flavonol [1874], floranol [1875], xanthones such as mangiferin [1876-1879], morin [1876], catechins [1073; 1807; 1838; 1854; 1880; 1881] and theaflavins [1882], as well as procyanidins [1835; 1883] and melatonin [1628; 1884-1887]. However, the celebrated (trans-)-resveratrol molecule [1888-1902] may act mainly via other pathways.
A considerable number of studies with non-purified dietary constituents containing the above polyphenolic components have also shown promise in inhibiting diseases in which oxidative stress is implicated [1825; 1903-1906]. For instance in stroke and related neuronal aging and stress conditions, preventative activity can be found in blueberries [1907-1913] (and see [1914]), Ginkgo biloba extract (EGb 761) [1910; 1915; 1916], grapes [1917], green tea [1807; 1918-1921], Mangifera indica extract [1879], strawberries [1907], spinach [1907] and Crataegus [922], while combinations of some these components (‘protandim’) have been claimed to reduce ROS levels by stimulating the production of catalase and SOD [1922]. As with pharmaceutical drugs [18; 1923-1925], there are significant problems with bioavailability [1926; 1927], although the necessary measurements are starting to come forward [1804; 1809; 1926-1932]. There is now increasing evidence for the mechanisms with which these dietary components and related natural products and derivatives (often with anti-inflammatory, anti-mutagenic or anti-carcinogenic properties) interact with well recognised cellular signalling pathways."
Full study availabile http://www.biomedcentral.com/content/pdf/1755-8794-2-2.pdf (1.55MB -2469 references)