Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation

Deceleration of Fusion–Fission Cycles Improves Mitochondrial Quality Control during Aging

Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the ‘mitochondrial infectious damage adaptation’ (MIDA) model according to which a deceleration of fusion–fission cycles reflects a systemic adaptation increasing life span

Comparative phylogeography in the Atlantic forest and Brazilian savannas: pleistocene fluctuations and dispersal shape spatial patterns in two bumblebees

Background: Bombus morio and B. pauloensis are sympatric widespread bumblebee species that occupy two major Brazilian biomes, the Atlantic forest and the savannas of the Cerrado. Differences in dispersion capacity, which is greater in B. morio, likely influence their phylogeographic patterns. This study asks which processes best explain the patterns of genetic variation observed in B. morio and B. pauloensis, shedding light on the phenomena that shaped the range of local populations and the spatial distribution of intra-specific lineages. Results: Results suggest that Pleistocene climatic oscillations directly influenced the population structure of both species. Correlative species distribution models predict that the warmer conditions of the Last Interglacial contributed to population contraction, while demographic expansion happened during the Last Glacial Maximum. These results are consistent with physiological data suggesting that bumblebees are well adapted to colder conditions. Intra-specific mitochondrial genealogies are not congruent between the two species, which may be explained by their documented differences in dispersal ability. Conclusions: While populations of the high-dispersal B. morio are morphologically and genetically homogeneous across the species range, B. pauloensis encompasses multiple (three) mitochondrial lineages, and show clear genetic, geographic, and morphological differences. Because the lineages of B. pauloensis are currently exposed to distinct climatic conditions (and elevations), parapatric diversification may occur within this taxon. The eastern portion of the state of São Paulo, the most urbanized area in Brazil, represents the center of genetic diversity for B. pauloensis

Flower visits, nesting and nest defence behaviour of stingless bees (Apidae: Meliponini): suitability of the bee species for meliponiculture in the Argentinean Chaco region

International audienceFour bionomical features are here described for the seven stingless bees that inhabit a new meliponine beekeeping area: the Argentinean Chaco region. The most commonly visited plants were of herbaceous habits, predominantly had flowers of white/creamy to yellowish colour, with small-sized flowers and were of moderate mass-flowering degree. Lestrimelitta chacoana was the only robber species. The most commonly found nesting substrate was large living tree trunks, and most nests were found at the base of the trunks. Sometimes, nesting substrates and floral resources were provided by the same woody plant. Cryptic small- to medium-sized cerumen tube-like unornamented nest entrances were the most commonly found. Nest defence included aggressive (Scaptotrigona jujuyensis) and docile behaviour; the latter was classified into timid and non-timid. A key to identify the Meliponini fauna of this region is provided. The regional pattern of bionomical features seems to be associated with subtropical climate conditions. The majority of these bee species are suitable for Meliponiculture in the Chaco region