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

Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

<p>Abstract</p> <p>Background</p> <p>Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells.</p> <p>Results</p> <p>Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted <it>in vitro </it>tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control.</p> <p>Conclusion</p> <p>These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.</p

The Principles of Menu Making (Second Edition)

Determining the distribution of disease prevalence among heterogeneous populations at the national scale is fundamental for epidemiology and public health. Here, we use a combination of methods (spatial scan statistic, topological data analysis, epidemic profile) to study measurable differences in malaria intensity by regions and populations of Colombia. This study explores three main questions: What are the regions of Colombia where malaria is epidemic? What are the regions and populations in Colombia where malaria is endemic? What associations exist between epidemic outbreaks between regions in Colombia? \textit{Plasmodium falciparum} is most prevalent in the Pacific Coast, some regions of the Amazon Basin, and some regions of the Magdalena Basin. \textit{Plasmodium vivax} is the most prevalent parasite in Colombia, particularly in the Northern Amazon Basin, the Caribbean, and municipalities of Sucre, Antioquia and Cordoba. Malaria has been reported to be most common among 15-45 year old men. We find that the age-class suffering high risk of malaria infection ranges from 20 to 30 with an acute peak at 25 years of age. Second, this pattern was not found to be generalizable across Colombian populations, Indigenous and Afrocolombian populations experience endemic malaria (with household transmission). Third, clusters of epidemic malaria for \textit{Plasmodium vivax} were detected across Southern Colombia including the Amazon Basin and the Southern Pacific region. \textit{Plasmodium falciparum}, was is epidemic in 13 of the 1,123 municipalities (1.2\%). Some key locations act as bridges between epidemic and endemic regions. Finally, we generate a regional classification based on intensity and synchrony, dividing the country into epidemic areas and bridge areas