The α9- and α7-containing nicotinic acetylcholine receptors (nAChRs) mediate numerous physiological and pathological processes by complex mechanisms that are currently the subject of intensive study ...and debate. In this regard, selective ligands serve as invaluable investigative tools and, in many cases, potential therapeutics for the treatment of various CNS disfunctions and diseases, neuropathic pain, inflammation, and cancer. However, the present scenario differs significantly between the two aforementioned nicotinic subtypes. Over the past few decades, a large number of selective α7-nAChR ligands, including full, partial and silent agonists, antagonists, and allosteric modulators, have been described and reviewed. Conversely, reports on selective α9-containing nAChR ligands are relatively scarce, also due to a more recent characterization of this receptor subtype, and hardly any focusing on small molecules. In this review, we focus on the latter, providing a comprehensive overview, while providing only an update over the last five years for α7-nAChR ligands.
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Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR ...protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.
Variations occurring in coffee beans during roasting are ascribable to several chemical-physical phenomena: to quickly track the whole process and to ensure its reproducibility, a process analytical ...technology (PAT) approach is needed.
In this study, a method combining in-line Fourier transform near-infrared (FT-NIR) spectroscopy and chemometric modelling was investigated to get real-time and practical knowledge about the roasting effects on coffee’s chemical-physical composition. In-line spectra were acquired by inserting a NIR probe into a laboratory coffee roaster, running twenty-four roasting experiments, planned spanning different coffee species (Arabica and Robusta), four roasting temperature settings (TS1–TS4) and times (650–1580 s).
Multivariate curve resolution-alternate least squares (MCR-ALS) was used to model the chemical-physical changes occurring during the roasting process, and information about maximum rate, acceleration and deceleration of the process was obtained, also highlighting potential effects due to the different roasting temperatures and coffee varieties.
The proposed approach provides the groundwork for direct real-time implementation of rapid, non-invasive automated monitoring of the roasting process at industrial scale.
A variety of biological active compounds can be classified as 2-substituted 1,4-benzodioxanes bearing one or more substituents at the benzene. The synthesis of these important templates can be ...approached by different strategies. The most straightforward ones generally lead to mixtures of positional isomers, whose identification can be more problematic than separation. Here, we unambiguously elucidate, by HSQC and HMBC NMR analyses, the structure of methyl 8- and 5-bromo-1,4-benzodioxane-2-carboxylate, two versatile synthetic intermediates that are one-step-obtainable from commercial products and easily separable. As conceived, the identification procedure is, in principle, generalizable to any pair of 2-substituted 1,4-benzodioxanes bearing an X substituent at C(8) or C(5).
2-Substituted 1,4-benzodioxanes bearing one or more substituents at benzene are important templates in the design and synthesis of a large variety of biologically active compounds. One of the most ...straightforward synthetic strategies to prepare them in racemic form and with a 2-substituent susceptible to further synthetically useful conversions is the condensation of commercially available methyl 2,3-dibromopropionate with already suitably functionalized catechol. Here, we obtain methyl 8- and 5-nitro-1,4-benzodioxane-2-carboxylate by reaction of methyl 2,3-dibromopropionate with 3-nitrocatechol. After separation, the two positional isomers could be unequivocally identified by HMBC NMR analysis.
In recent years, a number of drugs have been approved for the treatment of cystic fibrosis (CF). Among them, newly released Trikafta, a combination of 3 drugs (VX-661/VX-445/VX-770), holds great ...promise to radically improve the quality of life for a large portion of patients with CF carrying 1 copy of F508del, the most frequent CF transmembrane conductance regulator (CFTR) mutation. Currently available disease-modifying CF drugs work by rescuing the function of the mutated CFTR anion channel. Recent research has shown that membrane lipids, and the cell lipidome in general, play a significant role in the mechanism of CFTR-defective trafficking and, on the other hand, its rescue. In this paper, by using untargeted lipidomics on CFBE41o- cells, we identified distinctive changes in the bronchial epithelial cell lipidome associated with treatment with Trikafta and other CF drugs. Particularly interesting was the reduction of levels of ceramide, a known molecular player in the induction of apoptosis, which appeared to be associated with a decrease in the susceptibility of cells to undergo apoptosis. This evidence could account for additional beneficial roles of the triple combination of drugs on CF phenotypes.
The sale of frozen-thawed fish and fish products, labeled as fresh, is currently one of the most common and insidious commercial food frauds. For this reason, the demand of reliable tools to identify ...the storage conditions is increasing. The present study was performed on two species, commonly sold in large-scale distribution: Cuttlefish (
) and musky octopus (
spp.). Fifty fresh cephalopod specimens were analyzed at refrigeration temperature (2 ± 2 °C), then frozen at -20 °C for 10 days and finally thawed and analyzed again. The performance of three near-infrared (NIR) instruments in identifying storage conditions were compared: The benchtop NIR Multi Purpose Analyzer (MPA) by Bruker, the portable MicroNIR by VIAVI and the handheld NIR SCiO by Consumer Physics. All collected spectra were processed and analyzed with chemometric methods. The SCiO data were also analyzed using the analytical tools available in the online application provided by the manufacturer to evaluate its performance. NIR spectroscopy, coupled with chemometrics, allowed discriminating between fresh and thawed samples with high accuracy: Cuttlefish between 82.3-94.1%, musky octopus between 91.2-97.1%, global model between 86.8-95.6%. Results show how food frauds could be detected directly in the marketplace, through small, ultra-fast and simplified handheld devices, whereas official control laboratories could use benchtop analytical instruments, coupled with chemometric approaches, to develop accurate and validated methods, suitable for regulatory purposes.
Hazelnuts (
L.) are among the most consumed dry fruits all over the world. Their commercial quality is defined, above all, by origin and dimension, as well as by lipid content. Evaluation of this ...parameter is currently performed with chemical methods, which are expensive, time consuming, and complex. In the present work, the near-infrared (NIR) spectroscopy, using both a benchtop research spectrometer and a retail handheld instrument, was evaluated in comparison with the traditional chemical approach. The lipid content of hazelnuts from different growing regions of origin (Italy, Chile, Turkey, Georgia, and Azerbaijan) was determined with two NIR instruments: a benchtop FT-NIR spectrometer (Multi Purpose Analyser-MPA, by Bruker), equipped with an integrating sphere and an optic fibre probe, and the pocket-sized, battery-powered SCiO molecular sensor (by Consumer Physics). The Randall/Soxtec method was used as the reference measurement of total lipid content. The collected NIR spectra were inspected through multivariate data analysis. First, a Principal Component Analysis (PCA) model was built to explore the information contained in the spectral datasets. Then, a Partial Least Square (PLS) regression model was developed to predict the percentage of lipid content. PCA showed samples distributions that could be linked to their total crude fat content determined with the Randall/Soxtec method, confirming that a trend related to the lipid content could be detected in the spectral data, based on their chemical profiles. PLS models performed better with the MPA instrument than SCiO, with the highest R
of prediction (R
= 0.897) achieved by MPA probe, while this parameter for SCiO was much lower (R
= 0.550). Further analyses are necessary to evaluate if more acquisitions may lead to better performances when using the SCiO portable spectrometer.
Fish species substitution is one of the most common forms of fraud all over the world, as fish identification can be very challenging for both consumers and experienced inspectors in the case of fish ...sold as fillets. The difficulties in distinguishing among different species may generate a "grey area" in which mislabelling can occur. Thus, the development of fast and reliable tools able to detect such frauds in the field is of crucial importance. In this study, we focused on the distinction between two flatfish species largely available on the market, namely the Guinean sole (
) and European plaice (
), which are very similar looking. Fifty fillets of each species were analysed using three near-infrared (NIR) instruments: the handheld SCiO (Consumer Physics), the portable MicroNIR (VIAVI), and the benchtop MPA (Bruker). PLS-DA classification models were built using the spectral datasets, and all three instruments provided very good results, showing high accuracy: 94.1% for the SCiO and MicroNIR portable instruments, and 90.1% for the MPA benchtop spectrometer. The good classification results of the approach combining NIR spectroscopy, and simple chemometric classification methods suggest great applicability directly in the context of real-world marketplaces, as well as in official control plans.
The recently reported efficient conversion of cyclic ketones to lactones by Oxone in neutral buffered water is extended to heterocyclic ketones, namely, cyclic N-Boc azaketones and oxoethers with the ...aim of obtaining N-protected azalactones and their analogues with oxygen in place of nitrogen. N-Boc-4-piperidinone and all the cyclic oxoethers were successfully oxidized to lactones, while the azacyclic ketones with nitrogen α-positioned to carbonyl were univocally transformed into N-Boc-ω-amino acids and N-Boc-N-formyl-ω-amino acids operating in alkaline water and DMF, respectively.
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