Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria

Impact of Climate Change on Voltinism and Prospective Diapause Induction of a Global Pest Insect – Cydia pomonella (L.)

Global warming will lead to earlier beginnings and prolongation of growing seasons in temperate regions and will have pronounced effects on phenology and life-history adaptation in many species. These changes were not easy to simulate for actual phenologies because of the rudimentary temporal (season) and spatial (regional) resolution of climate model projections. We investigate the effect of climate change on the regional incidence of a pest insect with nearly worldwide distribution and very high potential for adaptation to season length and temperature – the Codling Moth, Cydia pomonella. Seasonal and regional climate change signals were downscaled to the hourly temporal scale of a pest phenology model and the spatial scale of pest habitats using a stochastic weather generator operating at daily scale in combination with a re-sampling approach for simulation of hourly weather data. Under future conditions of increased temperatures (2045–2074), the present risk of below 20% for a pronounced second generation (peak larval emergence) in Switzerland will increase to 70–100%. The risk of an additional third generation will increase from presently 0–2% to 100%. We identified a significant two-week shift to earlier dates in phenological stages, such as overwintering adult flight. The relative extent (magnitude) of first generation pupae and all later stages will significantly increase. The presence of first generation pupae and later stages will be prolonged. A significant decrease in the length of overlap of first and second generation larval emergence was identified. Such shifts in phenology may induce changes in life-history traits regulating the life cycle. An accordingly life-history adaptation in photoperiodic diapause induction to shorter day-length is expected and would thereby even more increase the risk of an additional generation. With respect to Codling Moth management, the shifts in phenology and voltinism projected here will require adaptations of plant protection strategies to maintain their sustainability