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Alzheimer's disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the elderly. There is no cure against AD. We have recently discovered a novel transient receptor potential canonical 6 (TRPC6)-mediated intracellular signaling pathway that regulates the stability of dendritic spines and plays a role in memory formation. We have previously shown that TRPC6 agonists exert beneficial effects in models of AD and may serve as lead compounds for development of AD therapeutic agents. In the current study, we used the Clarivate Analytics Integrity database to search for additional TRPC6 agonists. We selected four compounds to study as potential neuroprotective agents. We applied bioinformatics analyses to test the basic pharmacological properties of the selected compounds. We performed in vitro screening of these compounds to validate their ability to protect mushroom spines from amyloid toxicity and determined that two of these compounds exert neuroprotective effects in the nanomolar concentration range. We have chosen one of these compounds [piperazine (PPZ)] for further testing. In agreement with previously published data, we have shown that PPZ potentiates TRPC6 channels. We demonstrated that the neuroprotective mechanism of the investigated PPZ is based on activation of neuronal store-operated calcium entry in spines. We have shown that PPZ restores long-term potentiation induction in 6-month-old 5xFAD mouse hippocampal slices. The obtained results suggest that PPZ and its derivatives are potential lead molecules for development of AD therapeutic agents.

The Drosophila Trithorax-like (Trl) gene encodes a GAGA factor which regulates a number of developmentally important genes. In this study, we identify a new function for Drosophila GAGA factor in male germ cell development. Trl mutants carrying strong hypomorphic alleles display loss of primordial germ cells during their migration in embryogenesis and severe disruption in mitochondria structure during early spermatogenesis. The mutation resulted in small testes formation, a deficit of germ cells, abnormal mitochondrial morphogenesis, spermatocyte death through autophagy, and partial or complete male sterility. Pleiotropic mutation effects can be explained by the misexpression of GAGA factor target genes, the products of which are required for germ cell progression into mature sperm.

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The paper focuses on the assessment of the spectrum of biological activities (antineoplastic, anti-inflammatory, antifungal, and antibacterial) with PASS (Prediction of Activity Spectra for Substances) for the major components of three macrophytes widespread in the Holarctic species of freshwater, emergent macrophyte with floating leaves, Nuphar lutea (L.) Sm., and two species of submergent macrophyte groups, Ceratophyllum demersum L. and Potamogeton obtusifolius (Mert. et Koch), for the discovery of their ecological and pharmacological potential. The predicted probability of anti-inflammatory or antineoplastic activities above 0.8 was observed for twenty compounds. The same compounds were also characterized by high probability of antifungal and antibacterial activity. Six metabolites, namely, hexanal, pentadecanal, tetradecanoic acid, dibutyl phthalate, hexadecanoic acid, and manool, were a part of the major components of all three studied plants, indicating their high ecological significance and a certain universalism in their use by various species of water plants for the implementation of ecological and biochemical functions. This report underlines the role of identified compounds not only as important components in regulation of biochemical and metabolic pathways and processes in aquatic ecological systems, but also as potential pharmacological agents in the fight against different diseases.

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Border cell (BC) migration during Drosophila oogenesis is an excellent model for the analysis of the migratory and invasive cell behavior. Most studies on BC migration have exploited a slbo-Gal4 driver to regulate gene expression in these cells or to mark them. Here, we report that the slbo-Gal4 transgene present in the line #6458 from the Bloomington Stock Center is inserted within chickadee (chic), a gene encoding the actin-binding protein Profilin, which promotes actin polymerization and is known to be involved in cell migration. The chic mutation caused by the transgene insertion behaves as a null chic allele and is homozygous lethal. To evaluate possible effects of chic on the assessment of BC behavior, we generated new lines bearing the slbo-Gal4 transgene inserted into different second chromosome loci that do not appear to be involved in cell migration. Using these new lines and the slbo-Gal4-chic line, we defined the functional relationships between the twinfilin (twf) and chic in BC migration. Migration of BCs is substantially reduced by mutations in twf, which encodes an actin-binding protein that inhibits actin filament assembly. The defects caused by twf mutations are significantly suppressed when the slbo-Gal4-chic, but not the new slbo-Gal4 drivers were used. These findings indicate twf and chic interact and function antagonistically during BC migration in Drosophila oogenesis.

Summary Investigation of Drosophila oogenesis provides the opportunity to understand conservative genetic mechanisms underlying fertile female gamete development. In this study, we showed that the Drosophila DNA‐binding protein GAGA factor (GAF) had a multifunctional role in oogenesis and it is involved in the regulation of this process genetic program. We studied the influence on Drosophila oogenesis of a number of mutations in the 5′ region of the Trl gene that encodes GAF. We found that our originally generated Trl mutations lead to a decrease in transcriptional gene activity and levels of GAF expression in both germline and follicular cells. Cytological (fluorescence and electron microscopy) analysis showed that GAF loss resulted in multiple oogenesis defects. Mutations affected the actin cytoskeleton, leading to decrease of cytoplasmic filaments in nurse cells and basal actin in follicular cells. GAF depletion also leads to abnormal follicular cells migration, both border and centripetal. In addition, mutant ovaries demonstrated abnormalities in germ cells, including mitochondria, endoplasmic reticulum, karyosome organization, yolk granule formation and selective transport. Loss of GAF also promoted excessive cell death and egg chamber degradation. In sum, these defects caused very high or full female sterility. Since one of the main GAF activities is regulation of transcription, the complex phenotypes of the Trl mutants might be the consequence of its multiple target genes misexpression.