Current observations in the literature suggest that vitamin E may be a suitable candidate for the adjuvant treatment of cancer. Even though historically most research focused on a-tocopherol, more recent evidence suggests that the other isomers of vitamin E (b-, cand d-tocopherols and a-, b-, c-and d-tocotrienols) differ in their proapoptotic potencies. The main focus of this communication is the current understanding of the molecular mechanisms regulated by vitamin E isomers and their analogs during the induction of apoptosis. This review highlights that the mitochondria are the major target for the induction of apoptosis by vitamin E isomers and analogs and that the various signaling pathways regulated by these agents are likely to contribute towards maximizing the intrinsic pathway of apoptosis triggered initially by the mitochondria. Overall, the presentation of recent studies from the literature in this communication allows the drawing of the following important conclusions: (i) no direct link exists between the antioxidant activity of each isomer/derivative and proapoptotic potency, (ii) tocotrienols are more effective proapoptotic agents than tocopherols, (iii) synthetic modifications of the naturally occurring compounds may improve their apoptotic potency and (iv) vitamin E isomers and derivatives regulate caspase-independent pathways of apoptosis. The latter combined with the evidence presented in this review regarding the additive or synergistic anticarcinogenic effects obtained when vitamin E analogs are used in combination with other cancer chemotherapeutic agents, supports further research to design the most promising vitamin E derivatives and clinically test them in adjuvant chemotherapeutic treatments. ' 2008 Wiley-Liss, Inc.Key words: vitamin E; tocopherol; tocotrienol; apoptosis; atocopherol succinate; cancer chemoprevention; chemotherapy Despite great advances in molecular medicine, effective treatment and prevention of cancer has not yet been achieved. Deaths from neoplastic disease in both men and women have exceeded deaths from heart disease. Breast and prostate cancers are the cancers with highest incidence in females and males, respectively, and these cancers are third and second, respectively, to lung cancer in causing death.

Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II without inhibiting topo I. Flavonoids demonstrating potent topo I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3', and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid topo I inhibitory action. A C-2, C-3 double bond was also required, but when the A ring is opened, the requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage complex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavage complex, but prunetin, quercetin, kaempferol, and apigenin stabilized the topo II DNA-complex. Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme. These results are of use for the selection of flavonoids that can inhibit specific topoisomerases at specific stages of the topoisomerization reaction.

No abstract

Emerging infectious diseases of wildlife have been recognized as a major threat to global biodiversity. Endemic species on isolated oceanic islands, such as the Galá pagos, are particularly at risk in the face of introduced pathogens and disease vectors. The black salt-marsh mosquito (Aedes taeniorhynchus) is the only mosquito widely distributed across the Galá pagos Archipelago. Here we show that this mosquito naturally colonized the Galá pagos before the arrival of man, and since then it has evolved to represent a distinct evolutionary unit and has adapted to habitats unusual for its coastal progenitor. We also present evidence that A. taeniorhynchus feeds on reptiles in Galá pagos in addition to previously reported mammal and bird hosts, highlighting the important role this mosquito might play as a bridge-vector in the transmission and spread of extant and newly introduced diseases in the Galá pagos Islands. These findings are particularly pertinent for West Nile virus, which can cause significant morbidity and mortality in mammals (including humans), birds, and reptiles, and which recently has spread from an introductory focus in New York to much of the North and South American mainland and could soon reach the Galá pagos Islands. Unlike Hawaii, there are likely to be no highland refugia free from invading mosquito-borne diseases in Galá pagos, suggesting bleak outcomes to possible future pathogen introduction events.Aedes ͉ disease vector ͉ phylogenetics ͉ West Nile virus

According to receptor theory, the effect of a ligand depends on the amount of agonist–receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G‐protein‐coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G‐protein activation. We developed a complete mathematical model of this step, which suggested the ability to compute fractional occupancy depends on the physical interaction between the inhibitory regulator of G‐protein signaling (RGS), Sst2, and the receptor. Accordingly, replacing Sst2 by the heterologous hsRGS4, incapable of interacting with the receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2 interaction restored robustness. Taken together with other results of our work, we conclude that this GPCR pathway computes fractional occupancy because ligand‐bound GPCR–RGS complexes stimulate signaling while unoccupied complexes actively inhibit it. In eukaryotes, many RGSs bind to specific GPCRs, suggesting these complexes with opposing activities also detect fraction occupancy by a ratiometric measurement. Such complexes operate as push‐pull devices, which we have recently described.