Transcriptomic analysis of insecticide resistance in the lymphatic filariasis vector Culex quinquefasciatus

Culex quinquefasciatus plays an important role in transmission of vector-borne diseases of public health importance, including lymphatic filariasis (LF), as well as many arboviral diseases. Currently, efforts to tackle C. quinquefasciatus vectored diseases are based on either mass drug administration (MDA) for LF, or insecticide-based interventions. Widespread and intensive insecticide usage has resulted in increased resistance in mosquito vectors, including C. quinquefasciatus. Herein, the transcriptome profile of Ugandan bendiocarb-resistant C. quinquefasciatus was explored to identify candidate genes associated with insecticide resistance. High levels of insecticide resistance were observed for five out of six insecticides tested, with the lowest mortality (0.97%) reported to permethrin, while for DDT, lambdacyhalothrin, bendiocarb and deltamethrin the mortality rate ranged from 1.63–3.29%. Resistance to bendiocarb in exposed mosquitoes was marked, with 2.04% mortality following 1 h exposure and 58.02% after 4 h. Genotyping of the G119S Ace-1 target site mutation detected a highly significant association (p 8-fold increase vs unexposed controls). These results provide evidence that bendiocarb resistance in Ugandan C. quinquefasciatus is mediated by both target-site mechanisms and over-expression of detoxification enzymes

Antidepressants’ effects on testosterone and estrogens: What do we know?

Various antidepressants are commonly used to treat depression and anxiety disorders, and sex differences have been identified in their efficacy and side effects. Steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. This review presents published data from preclinical and clinical studies that measure testosterone and estrogen level changes during and/or after acute or chronic administration of different antidepressants. The majority of studies show an interaction between sex hormones and antidepressants on sexual function and behavior, or in depressive symptom alleviation. However, most of the studies omit to investigate antidepressants’ effects on circulating levels of gonadal hormones. From data reviewed herein, it is evident that most antidepressants can influence testosterone and estrogen levels. Still, the evidence is conflicting with some studies showing an increase, others decrease or no effect. Most studies are conducted in male animals or humans, underscoring the importance of considering sex as an important variable in such investigations, especially as depression and anxiety disorders are more common in women than men. Therefore, research is needed to elucidate the extent to which antidepressants can influence both peripheral and brain levels of testosterone and estrogens, in males and females, and whether this impacts the effectiveness or side effects of antidepressants. © 2021 Elsevier B.V

Pharmacology of ketamine and esketamine as rapid-acting antidepressants

The lack of utter efficacy and fast action of commonly used antidepressants that selectively target the monoaminergic neurotransmission has led to the exploration of ketamine's actions. Ketamine's antidepressant effect was firstly described in 1973 and nowadays its therapeutic value as a fast- and long- lasting antidepressant has been extensively established. Ketamine is an antagonist of the N-Methyl-D-aspartate receptor (NMDAR) and its main mechanism of action via NMDAR inhibition expressed in GABAergic (gamma-Aminobutyric acid, GABA) interneurons may be relayed to its antidepressant effects. This review aims to describe the pharmacokinetic and pharmacodynamic profile of ketamine when used for treatment-resistant depression. Moreover, ketamine is a racemic mixture consisting of two enantiomers, R- and S- ketamine. We describe the pharmacology of esketamine, along with the guidelines for effective and safe intranasal administration of esketamine. Lastly, this review presents sex differences in preclinical and clinical studies of ketamine and esketamine administration

Insecticide resistance in the major dengue vectors Aedes albopictus and Aedes aegypti

Aedes mosquitoes are major vectors of human diseases, such as the dengue fever, chikungunya and yellow fever. Their control largely relies on insecticides applied to mosquito larvae habitats, or indoors against adult mosquitoes. However, insecticide resistance has evolved in many Aedes aegypti mosquito populations worldwide and there is evidence that it has compromised the success of control interventions. The levels of resistance in Aedes albopictus is relatively low at present compared to Ae. aegypti, possibly due to the reduced exposure of this more exophilic species to insecticides, particularly those targeting the adult stage. This paper reviews Ae. albopictus susceptibility/resistance status, as well as reports some new bioassay data from European populations (Greece and Italy). The most recent molecular research into Ae. aegypti insecticide resistance mechanisms is also reviewed, with emphasis on neurotoxic insecticides

Insecticide resistance in the major dengue vectors Aedes albopictus and Aedes aegypti

Aedes mosquitoes are major vectors of human diseases, such as the dengue fever, chikungunya and yellow fever. Their control largely relies on insecticides applied to mosquito larvae habitats, or indoors against adult mosquitoes. However, insecticide resistance has evolved in many Aedes aegypti mosquito populations worldwide and there is evidence that it has compromised the success of control interventions. The levels of resistance in Aedes albopictus is relatively low at present compared to Ae. aegypti, possibly due to the reduced exposure of this more exophilic species to insecticides, particularly those targeting the adult stage. This paper reviews Ae. albopictus susceptibility/resistance status, as well as reports some new bioassay data from European populations (Greece and Italy). The most recent molecular research into Ae. aegypti insecticide resistance mechanisms is also reviewed, with emphasis on neurotoxic insecticides

Transgenic expression of the Aedes aegypti CYP9J28 confers pyrethroid resistance in Drosophila melanogaster

The emergence and spread of insecticide resistance in mosquitoes, such as the major vector of dengue and yellow fever Aedes aegypti, is a major public health problem. A number of studies have been conducted to-date aiming to identify specific molecular changes that are associated with the phenotype, in an attempt to use this knowledge to control the development and spread of resistant populations. Several approaches, ranging from classical techniques to high-throughput transcriptomics, have revealed a large number of genes which are associated with the trait. However, the development of functional tools for the validation of the possible role of those genes (if any) in mosquito resistance has not kept similar pace. Here, we report the use of Drosophila melanogaster as a model for establishing the role of A. aegypti cytochrome P450s. We showed that the transgenic expression of the CYP9J28 a gene which is upregulated in pyrethroid resistant A. aegypti mosquitoes and encodes an enzyme capable of metabolizing pyrethroids, in D. melanogaster confers significant levels of pyrethroid resistance. Our study provides solid functional in vivo evidence for the role of the AaegCYP9J28 in pyrethroid resistance and shows for the first time that ectopic expression of mosquito genes in D. melanogaster can be a robust approach for validating candidate resistance genes. Further potential applications of the approach are discussed

Age-related dysregulation of homeostatic control in neuronal microcircuits

Neuronal homeostasis prevents hyperactivity and hypoactivity. Age-related hyperactivity suggests homeostasis may be dysregulated in later life. However, plasticity mechanisms preventing age-related hyperactivity and their efficacy in later life are unclear. We identify the adult cortical plasticity response to elevated activity driven by sensory overstimulation, then test how plasticity changes with age. We use in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduce cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also find overstimulation disrupts cognition in older but not younger animals. We propose that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance