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Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor - rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 - 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD 50 in male mice 559 mg/kg; LD 50 in female mice 575 mg/kg)., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

To date, the most studied drug in anti-aging research is the mTOR inhibitor - rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation - inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available ( 4, 5, and 7 ) or their synthesis was feasible ( 1, 2, 3, and 6 ) and evaluated in vitro and subsequently in vivo . Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chrienova, Rysanek, Oleksak, Stary, Bajda, Reinis, Mikyskova, Novotny, Andrys, Skarka, Vasicova, Novak, Valis, Kuca, Hodny and Nepovimova.)

Twenty-four novel compounds bearing tetrahydroacridine and N -propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC 50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC 50 = 78 nM) showed the best inhibitory human butyrylcholinesterase ( h BChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [ h AChE]: IC 50 = 0.095 ± 0.001 µM; h BChE: IC 50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7 , 15 , and 25 demonstrated the highest inhibitory potential towards h MAO-B (IC 50 = 163, 40, and 170 nM, respectively). In all, compounds 7 , 15 , 20 , 21 , 23 , and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy- N -(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride ( 15 ) has been identified as a permeable agent that shows a balanced pharmacological profile [IC 50 ( h AChE) = 1.472 ± 0.024 µM; IC 50 ( h BChE) = 0.659 ± 0.077 µM; IC 50 ( h MAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

To clarify the global status and research hotspots of heavy metal pollution phytoremediation, we used Web of Science, Cite Space software, and VOS viewer to analyse 1123 publications from the period of 2000-2020. Literature categories, research hotpots, and the most prolific publications by country, institution, and author were analysed separately. Around 34% of the articles are contributed from five countries: China (29.37%), India (11.00%), Spain (6.29%), Italy (6.20%), and Pakistan (5.67%). The hot research topic keywords were "diversity", "translocation", and "enhanced phytoremediation". Cadmium was the most highly concerned heavy metal in the phytoremediation. Twenty-three articles were highly cited, and they mainly focused on 1) enhancing the remediation ability of plants in heavy metal contaminated soil by microbial and chemical additives; 2) the molecular effect and mechanism of heavy metals on plant growth and development; 3) discovering novel heavy metal hyper-enriched plants which can remediate mixed heavy metal pollution. From the above analysis, we concluded that the future research directions should be 1) strengthening the plant remediation ability by biochemical means; 2) studying the molecular mechanism underlying heavy metal damage to plants; 3) studying the enrichment principle of plants for heavy metals. The present study provides a further understanding of the trends in phytoremediation of heavy metal pollution, and the data analysed can be used as a guide for future research directions., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The ageing population is becoming a significant socio-economic issue. To address the expanding health gap, it is important to deepen our understanding of the mechanisms underlying ageing in various organisms at the single-cell level. The discovery of the antifungal, immunosuppressive, and anticancer drug rapamycin, which possesses the ability to extend the lifespan of several species, has prompted extensive research in the areas of cell metabolic regulation, development, and senescence. At the centre of this research is the mTOR pathway, with key roles in cell growth, proteosynthesis, ribosomal biogenesis, transcriptional regulation, glucose and lipid metabolism, and autophagy. Recently, it has become obvious that mTOR dysregulation is involved in several age-related diseases, such as cancer, neurodegenerative diseases, and type 2 diabetes mellitus. Additionally, mTOR hyperactivation affects the process of ageing per se. In this review, we provide an overview of recent insights into the mTOR signalling pathway, including its regulation and its influence on various hallmarks of ageing at the cellular level.

A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC 50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The ability to adhere via colonization factors to specific receptors located on the intestinal mucosa is a key virulence factor in enterotoxigenic Escherichia coli (ETEC) pathogenesis. Here, the potential glycosphingolipid receptors of the novel human ETEC colonization factor CS30 were examined by binding of CS30-expressing bacteria to glycosphingolipids on thin-layer chromatograms. We thereby found a highly specific binding of CS30-expressing bacteria to a fast-migrating acid glycosphingolipid of human and porcine small intestine, while no binding was obtained with a mutant ETEC strain unable to express CS30 fimbriae. The CS30 binding glycosphingolipid from human small intestine was isolated and characterized by mass spectrometry as sulfatide (SO 3 -3Galβ1Cer). Comparative binding studies using sulfatides with different ceramide compositions gave a preferential binding of CS30 to sulfatide with d18:1-h24:0 ceramide. This ceramide species of sulfatide was also isolated from human small intestine and characterized by mass spectrometry and antibody binding. These studies implicate sulfatide as candidate receptor for mediating attachment of CS30-fimbriated ETEC to human and porcine small intestinal cells. Our findings may be a basis for designing receptor saccharide analogues for inhibition of the intestinal adhesion of CS30-expressing E. coli .

During the last decade, the neurotoxicity of the trichothecenes T-2 toxin and deoxynivalenol (DON) has been a major concern, and many important findings have been reported on this topic. Through a summary of relevant research reports in recent years, we discuss the potential neurotoxic mechanisms of T-2 toxin and DON. In neuronal cells, T-2 toxin induces mitochondrial dysfunction and oxidative stress through a series of signalling pathways, including Nrf2/HO-1 and p53. This toxin crosses the blood-brain barrier (BBB) by altering permeability and induces oxidative stress responses, including ROS generation, lipid peroxidation, and protein carbonyl formation. Cellular metabolites (for example, HT-2 toxin) further promote neurotoxic effects. The type B trichothecene DON induces neuronal cell apoptosis via the MAPK and mitochondrial apoptosis pathways. This molecule induces inflammation of the central nervous system, increasing the expression of proinflammatory molecules. DON directly affects brain neurons and glial cells after passing through the BBB and affects the vitality and function of astrocytes and microglia. Exposure to trichothecenes alters brain dopamine levels, decreases ganglion area, and further induces brain damage. In this review, we mainly discuss the neurotoxicity of T-2 toxin and DON. However, our main goal was to reveal the potential mechanism(s) and offer new topics, including the potential of hypoxia-inducible factors, immune evasion, and exosomes, for future research in this context. This review should help elucidate the neurotoxic mechanism of trichothecenes and provides some potential inspiration for the follow-up study of neurotoxicity of mycotoxins., (Copyright © 2020 Elsevier Ltd. All rights reserved.)