The role of Polypharmacology and Cholinesterase inhibitors

Publisher Copyright: © 2023 NOVA School of Science and Technology. ChemistrySelect published by Wiley-VCH GmbH.Alzheimer's disease (AD) is a devastating syndrome that accounts for 60–70 % of all dementia cases, putting an enormous burden on global healthcare and economy. Unfortunately, there is no cure for AD, and the currently approved drugs are limited in their effects. Given the various pathological mechanisms behind AD, the “one-target, one-drug” paradigm for drug design became obsolete, and a new paradigm, polypharmacology, emerged. Consequently, a greater focus has been put towards multi-target directed ligands (MTDLs), as these can regulate several targets operating in the disease network. Parallel to that, cholinesterase inhibitors have regained popularity after decades of being considered only symptomatic agents with no disease-modifying properties. In this review, the current AD hypotheses and therapeutic targets, the concept of polypharmacology in AD pathology and the importance of cholinesterases in the pathogenesis and biochemical processes of AD are discussed, with a final overview of the current development in cholinesterase-based MTDLs.publishersversionpublishe

Effects of nonthermal atmospheric-pressure plasma on Drosophila development

Nonthermal atmospheric-pressure plasma (NTAPP) is known to induce a wide range of responses at the cellular level. This study is concerned with the effects of NTAPP on a eukaryotic organism as a whole: Drosophila melanogaster. Exposure influenced the larval viability and caused an array of traits that can be classified into three major groups: (1) phenotypic anomalies in larvae (such as melanotic masses, melanized and broken trachea, incomplete shedding of the old cuticle during molting), morphological anomalies of pupae (small size, abnormal form, aberrant development, cryptocephalic forms), and developmental anomalies in adults (abnormal formation of wing, legs, and thorax); (2) larval behavior alteration (nonfeeding of first and second instar larvae, premature wandering, running away from food, immature pupae formation); and (3) excessive fat accumulation and lipid oxidation. The majority of the observed traits can be linked to molting and metamorphosis controlled by the endocrine system, in particular with the steroid hormone ecdysone. Results support the hypothesis that the interaction of NTAPP with the membranes of various organs can have a major role in the interruption of normal ecdysogenesis.info:eu-repo/semantics/publishedVersio

Novel laser-induced luminescence resulting from benzophenone/O-propylated p-tert-butylcalix[4]arene complexes. A diffuse reflectance study

Laser-induced room temperature luminescence of air-equilibrated benzophenone/O-propylated p-tert-butylcalix[ 4] arene solid powdered samples revealed the existence of a novel emission, in contrast with benzophenone/p-tertbutylcalix[ 4] arene complexes, where only benzophenone emits. This novel emission was identified as phosphorescence of 1-phenyl-1,2-propanedione, which is formed as the result of an hydrogen atom abstraction reaction of the triplet excited benzophenone from the propoxy substituents of the calixarene. Room temperature phosphorescence was obtained in air-equilibrated samples in all propylated hosts. The decay times of the benzophenone emission vary greatly with the degree of propylation, the shortest lifetimes being obtained in the tri- and tetrapropylated calixarenes. Triplet - triplet absorption of benzophenone was detected in all cases, and is the predominant absorption in the p-tert-butylcalix[ 4] arene case, where an endo-calix complex is formed. Benzophenone ketyl radical formation occurs with the O-propylated p-tert-butylcalix[ 4] arenes hosts, suggesting a different type of host/guest molecular arrangement. Diffuse reflectance laser. ash photolysis and gas chromatography - mass spectrometry techniques provided complementary information, the former about transient species and the latter regarding the final products formed after light absorption. Product analysis and identification clearly show that the two main degradation photoproducts following laser excitation in the propylated substrates are 1-phenyl-1,2- propanedione and 2- hydroxybenzophenone, although several other minor photodegradation products were identified. A detailed mechanistic analysis is proposed. While the solution photochemistry of benzophenone is dominated by the hydrogen abstraction reaction from suitable hydrogen donors, in these solid powdered samples, the alpha-cleavage reaction also plays an important role. This finding occurs even with one single laser pulse which lasts only a few nanoseconds, and is apparently related to the fact that scattered radiation exists, due to multiple internal reflections possibly trapping light within non-absorbing microcrystals in the sample, and is detected until at least 20 mus after the laser pulse. This could explain how photoproducts thus formed could also be excited with only one laser pulse

Does proteostasis get lost in translation? Implications for protein aggregation across the lifespan

Protein aggregation is a phenomenon of major relevance in neurodegenerative and neuromuscular disorders, cataracts, diabetes and many other diseases. Research has unveiled that proteins also aggregate in multiple tissues during healthy aging yet, the biological and biomedical relevance of this apparently asymptomatic phenomenon remains to be understood. It is known that proteome homeostasis (proteostasis) is maintained by a balanced protein synthesis rate, high protein synthesis accuracy, efficient protein folding and continual tagging of damaged proteins for degradation, suggesting that protein aggregation during healthy aging may be associated with alterations in both protein synthesis and the proteostasis network (PN) pathways. In particular, dysregulation of protein synthesis and alterations in translation fidelity are hypothesized to lead to the production of misfolded proteins which could explain the occurrence of age-related protein aggregation. Nevertheless, some data on this topic is controversial and the biological mechanisms that lead to widespread protein aggregation remain to be elucidated. We review the recent literature about the age-related decline of proteostasis, highlighting the need to build an integrated view of protein synthesis rate, fidelity and quality control pathways in order to better understand the proteome alterations that occur during aging and in age-related diseases.publishe

Unveiling the Influence of Non-Toxic Fluorinated Ionic Liquids Aqueous Solutions in the Encapsulation and Stability of Lysozyme

Proteins are bioactive compounds with high potential to be applied in the biopharmaceutical industry, food science and as biocatalysts. However, protein stability is very difficult to maintain outside of the native environment, which hinders their applications. Fluorinated ionic liquids (FILs) are a promising family of surface-active ionic liquids (SAILs) that have an amphiphilic behavior and the ability to self-aggregate in aqueous solutions by the formation of colloidal systems. In this work, the protein lysozyme was selected to infer on the influence of FILs in its stability and activity. Then, the cytotoxicity of FILs was determined to evaluate their biocompatibility, concluding that the selected compounds have neglected cytotoxicity. Therefore, UV–visible spectroscopy was used to infer the FIL-lysozyme interactions, concluding that the predominant interaction is the encapsulation of the lysozyme by FILs. The encapsulation efficiency was also tested, which highly depends on the concentration and anion of FIL. Finally, the bioactivity and thermal stability of lysozyme were evaluated, and the encapsulated lysozyme keeps its activity and thermal stability, concluding that FILs can be a potential stabilizer to be used in protein-based delivery systems.publishersversionpublishe

ANEURISMA DA AORTA TORÁCICA 29 ANOS APÓS LACERAÇÃO E REPARAÇÃO PRIMÁRIA

A laceração traumática da aorta é uma lesão de elevada mortalidade pré-hospitalar e intra-hospitalar. A sobrevivência a este tipo de lesões é rara e escasseiam dados sobre o prognóstico a longo-prazo destes doentes. Descrevemos um caso clínico de reparação primária de laceração da aorta torácica que se apresentou 29 anos após a repa- ração inicial com aneurisma da aorta torácica na mesma topografia. Foi submetido a reparação endovascular do aneurisma. Discutem-se as técnicas de reparação da laceração da aorta e a evidência existente sobre o prognóstico destes doentes, nomea- damente a incidência de lesões secundárias após a cirurgia inicial, e a necessidade de equacionar um plano de seguimento

Jatrophane and lathyrane diterpenoids from Euphorbia hyberna L

A new diterpene tetraester, from the jatrophane family, and two new diterpene triesters, with a lathyrane skeleton, have been isolated from the chloroform extract of the roots of Euphorbia hyberna L. The structures of these compounds have been established by spectroscopic methods, including 2D NMR experiments.info:eu-repo/semantics/publishedVersio

Chemical constituents of Euphorbia hyberna L. (Euphorbiaceae)

Chemical investigation of the aerial part and the roots of Euphorbia hyberna L. subs. hyberna. resulted in the isolation and identification of four triterpenoids (3�-O-octadecanoyllupeol (1), glut-5-en-3�-ol (2), 24-methylenecicloartan-3�-ol (3) and cicloart-23-ene-3�,25-diol (6)) along with the phenolic compounds ellagic acid (4) and 3,30 -di-O-methylellagic acid (7). Although these are all known compounds, this is the first report of their isolation from this plant. Their structures were elucidated on the basis of spectral methods, including 2D NMR experiences, and confirmed by comparing with the literature data.info:eu-repo/semantics/publishedVersio

Understanding the phase and solvation behavior of fluorinated ionic liquids

the contract of Individual Call to Scientific Employment Stimulus 2021.01432.CEECIND (A.B.P.) Additional partial support has been provided by Khalifa University of Science and Technology through project RC2-2019-007. Publisher Copyright: © 2022 The AuthorsFluorinated ionic liquids (FILs) are defined as molecules having fluorinated tags equal to or longer than 4 carbon atoms in the anion and/or cation structures. They present nanosegregated domains making them 3-in-1 solvents with exceptional properties, including an attractive solubility power. This work is an important contribution towards understanding the current research on the phase behavior of FILs, which may be used as task-specific materials for industrial applications. An overview of the main works published in the last two decades is presented, concerning gas solubility in FILs, the application of membranes to improve the gas absorption in FILs, and the use of modeling approaches to ease the application of FILs in gas capture and separation processes, with emphasis on the relationship between the structural properties and their performance. Contributions concerning the liquid-liquid and solid-liquid equilibria behavior of FILs, including the liquid-liquid equilibria (LLE) of FILs in water and perfluoroalkanes, and the solid-liquid equilibria (SLE) of solid FILs in water and mixtures of FILs are also presented. Regarding the absorption of gases in FILs, a careful analysis of the published works reveals that: (1) an optimal density of fluorine atoms in FILs structure is required to positively impact the absorption of different gases, (2) the functionalization of membranes can be also a useful method to improve the performance in separation processes, and (3) modeling tools can ease the screening of the features that promote the absorption of gases by FILs. The study of FILs LLE showed a rich phase behavior with water and perfluoroalkanes and the enhanced surfactant power of FILs, which is highly dependent on the length of the hydrogenated and fluorinated side chains. Finally, studying the SLE of FILs mixtures allowed the formation of deep eutectic systems that enlarges the applicability of FILs.publishersversionpublishe

New insights into a bacterial metabolic and detoxifying association responsible for the mineralization of the thiocarbamate herbicide molinate

A novel pathway of molinate mineralization promoted by a defined mixed culture composed of five bacteria (named ON1 to ON5) was proposed previously. Evidence was obtained of a metabolic association between Gulosibacter molinativorax ON4T, capable of molinate breakdown, and the remaining bacteria. In the present study, the role of each isolate in that metabolic association was further explored and the possible synergistic effect of all the bacterial isolates for the stability of the mixed culture is discussed. The cleavage of the molinate thioester bond, whether occurring under aerobic or anaerobic conditions, releases ethanethiol (S-ethyl moiety) and an azepane moiety derivative, identified as azepane-1-carboxylic acid. This azepane moiety is degraded, in the presence of oxygen, by Pseudomonas strains ON1 and ON3 and G. molinativorax ON4T. Ethanethiol, which inhibits G. molinativorax ON4T, is consumed by Pseudomonas strain ON1 and Stenotrophomonas maltophilia ON2. Although a two-member mixed culture of G. molinativorax ON4T and Pseudomonas strain ON1 was able to promote the aerobic mineralization of molinate, after 20 successive transfers of the five-member mixed culture in mineral medium with molinate, none of these isolates were lost. The results obtained indicate that the whole mixed culture may have a higher fitness than the two-member culture, even when the basic degradative and cross-protection functions are assured