Chemosensory sensitivity reflects reproductive status in the ant Harpegnathos saltator.

Insects communicate with pheromones using sensitive antennal sensilla. Although trace amounts of pheromones can be detected by many insects, context-dependent increased costs of high sensitivity might lead to plasticity in sensillum responsiveness. We have functionally characterized basiconic sensilla of the ant Harpegnathos saltator for responses to general odors in comparison to cuticular hydrocarbons which can act as fertility signals emitted by the principal reproductive(s) of a colony to inhibit reproduction by worker colony members. When released from inhibition workers may become reproductive gamergates. We observed plasticity in olfactory sensitivity after transition to reproductive status with significant reductions in electrophysiological responses to several long-chained cuticular hydrocarbons. Although gamergates lived on average five times longer than non-reproductive workers, the shift to reproductive status rather than age differences matched the pattern of changes in olfactory sensitivity. Decreasing sensillum responsiveness to cuticular hydrocarbons could potentially reduce mutually inhibitory or self-inhibitory effects on gamergate reproduction

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan

Inhibitory Effects of Ethanol on the NLRP3 Inflammasome

Immunosuppression is a major complication of alcoholism and contributes to increased rates of opportunistic infections and sepsis associated with the addiction. The NLRP3 inflammasome is a central intracellular pattern recognition receptor within the innate immune system, which leads to the cleavage and secretion of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Ethanol has been reported to inhibit IL-1β secretion, and here we verify that the alcohol can specifically inhibit activation of the NLRP3 inflammasome resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as ASC secretion in response to several agonists. These results were found to be independent of the activation of GABAA receptors or the inhibition of NMDA receptors. Ethanol was only partially able to prevent IL-1β secretion subsequent to NLRC4 activation and was incapable of preventing NLRP1b dependent IL-1β secretion, which are both largely independent of the adapter protein ASC, and ethanol was shown to prevent the formation of ASC specks. Treatment of cells with ethanol resulted in markedly decreased global tyrosine phosphorylation, while administration of the tyrosine phosphatase inhibitor sodium orthovanadate prior to ethanol restored IL-1β secretion. Multiple alcohol containing organic compounds exerted inhibitory effects on the NLRP3 inflammasome parallel to ethanol; however, isoamyl alcohol’s non-alcohol analog, 2-methylbutane, did not. Together, these results show that ethanol antagonizes the NLRP3 inflammasome at an apical event in its activation potentially through the stimulation of protein tyrosine phosphatases. As other short chain alcohols retain this ability, this effect could be dependent on the hydroxyl group of these compounds

A–C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions

Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A–C estrogens, lacking the B and D estrogen rings. The most potent and selective A–C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC50s of 20–30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound’s ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A–C estrogen is selective, brain penetrant, and facilitates memory consolidation

An in silico approach for modelling T-helper polarizing iNKT cell agonists

Many analogues of the glycolipid alpha-galactosylceramide (α-GalCer) are known to activate iNKT cells through their interaction with CD1d-expressing antigen-presenting cells, inducing the release of Th1 and Th2 cytokines. Because of iNKT cell involvement and associated Th1/Th2 cytokine changes in a broad spectrum of human diseases, the design of iNKT cell ligands with selective Th1 and Th2 properties has been the subject of extensive research. This search for novel iNKT cell ligands requires refined structural insights. Here we will visualize the chemical space of 333 currently known iNKT cell activators, including several newly tested analogues, by more than 3000 chemical descriptors which were calculated for each individual analogue. To evaluate the immunological responses we analyzed five different cytokines in five different test-systems. We linked the chemical space to the immunological space using a system biology computational approach resulting in highly sensitive and specific predictive models. Moreover, these models correspond with the current insights of iNKT cell activation by α-GalCer analogues, explaining the Th1 and Th2 biased responses, downstream of iNKT cell activation. We anticipate that such models will be of great value for the future design of iNKT cell agonists

A label-free diffraction-based sensing displacement immunosensor toquantify low molecular weight organic compounds

[EN] Herein we present a diffractometric immunosensor to quantify low molecular weight organic compounds in a label-free, simple, and sensitive fashion. The approach is based on patterning analyte analogues (haptens) on solid surfaces according to a diffractive structure, and then loading specific antibodies on them to be subsequently displaced by free analytes in solution. This displacement generates a measurable change in the diffractive response that enables to quantify the analyte concentration. In this study we address the fabrication, optimization, and assessment of these diffractive structures of biological probes and their application to the analysis of atrazine, an organic compound extensively used as pesticide. This immunosensor displays well-correlated dose-response curves that reach a detection limit of 1.1¿ng¿mL¿1 of atrazine in label-free conditions. From a general viewpoint, this study also aims to provide insights into exploiting this approach towards prospective in-field analysis and screening strategies to sense multiple low molecular weight compounds in label-free conditions.This work was supported by the Spanish Ministry of Economy and Competitiveness (CTQ2013-45875-R and FIS2011-23175), FEDER, and the Generalitat Valenciana (PROMETEO II/2014/040 and PROMETEO II/2014/072). Special thanks go to Richard A. McAloney and M. Cynthia Goh for hosting M.A.-O. as visiting researcher, sharing their expertise, and offering their valuable support. M.A.-O. also acknowledges the FPI program of the Spanish Ministry of Economy and Competitiveness for a PhD and an EEBB mobility grant.Avella-Oliver, M.; Ferrando Martín, V.; Monsoriu Serra, JA.; Puchades, R.; Maquieira Catala, A. (2018). A label-free diffraction-based sensing displacement immunosensor toquantify low molecular weight organic compounds. Analytica Chimica Acta. 1033:173-179. https://doi.org/10.1016/j.aca.2018.05.060S173179103

Chemosensory sensitivity reflects reproductive status in the ant Harpegnathos saltator

abstract: Insects communicate with pheromones using sensitive antennal sensilla. Although trace amounts of pheromones can be detected by many insects, context-dependent increased costs of high sensitivity might lead to plasticity in sensillum responsiveness. We have functionally characterized basiconic sensilla of the ant Harpegnathos saltator for responses to general odors in comparison to cuticular hydrocarbons which can act as fertility signals emitted by the principal reproductive(s) of a colony to inhibit reproduction by worker colony members. When released from inhibition workers may become reproductive gamergates. We observed plasticity in olfactory sensitivity after transition to reproductive status with significant reductions in electrophysiological responses to several long-chained cuticular hydrocarbons. Although gamergates lived on average five times longer than non-reproductive workers, the shift to reproductive status rather than age differences matched the pattern of changes in olfactory sensitivity. Decreasing sensillum responsiveness to cuticular hydrocarbons could potentially reduce mutually inhibitory or self-inhibitory effects on gamergate reproduction.The final version of this article, as published in Scientific Reports, can be viewed online at: https://www.nature.com/articles/s41598-017-03964-

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro"

The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype