Magnolol and Luteolin Inhibition of α-Glucosidase Activity: Kinetics and Type of Interaction Detected by In Vitro and In Silico Studies

open7noMagnolol and luteolin are two natural compounds recognized in several medicinal plants widely used in traditional medicine, including type 2 diabetes mellitus. This research aimed to determine the inhibitory activity of magnolol and luteolin on α-glucosidase activity. Their biological profile was studied by multispectroscopic methods along with inhibitory kinetic analysis and computational experiments. Magnolol and luteolin decreased the enzymatic activity in a concentration-dependent manner. With 0.075 µM α-glucosidase, the IC50 values were similar for both compounds (~ 32 µM) and significantly lower than for acarbose (815 μM). Magnolol showed a mixed-type antagonism, while luteolin showed a non-competitive inhibition mechanism. Thermodynamic parameters suggested that the binding of magnolol was predominantly sustained by hydrophobic interactions, while luteolin mainly exploited van der Waals contacts and hydrogen bonds. Synchronous fluorescence revealed that magnolol interacted with the target, influencing the microenvironment around tyrosine residues, and circular dichroism explained a rearrangement of the secondary structure of α-glucosidase from the initial α-helix to the final conformation enriched with β-sheet and random coil. Docking studies provided support for the experimental results. Altogether, the data propose magnolol, for the first time, as a potential α-glucosidase inhibitor and add further evidence to the inhibitory role of luteolin.openDjeujo F.M.; Ragazzi E.; Urettini M.; Sauro B.; Cichero E.; Tonelli M.; Froldi G.Djeujo, F. M.; Ragazzi, E.; Urettini, M.; Sauro, B.; Cichero, E.; Tonelli, M.; Froldi, G

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet\uae model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity

Discovery of Novel Thiazole-Based SIRT2 Inhibitors as Anticancer Agents: Molecular Modeling, Chemical Synthesis and Biological Assays

The search and development of effective sirtuin small molecule inhibitors (SIRTIs) continues to draw great attention due to their wide range of pharmacological applications. Based on SIRTs’ involvement in different biological pathways, their ligands were investigated for many diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases and autoimmune diseases. The elucidation of a substantial number of SIRT2–ligand complexes is steering the identification of novel and more selective modulators. Among them, SIRT2 in the presence of the SirReal2 analog series was the most studied. On this basis, we recently reported structure-based analyses leading to the discovery of thiazole-based compounds acting as SIRT2 inhibitors (T1, SIRT2 IC50 = 17.3 μM). Herein, ligand-based approaches followed by molecular docking simulations allowed us to evaluate in silico a novel small series of thiazoles (3a–3d and 5a, 5d) as putative SIRT2 inhibitors. Results from the computational studies revealed comparable molecular interaction fields (MIFs) and docking positionings of most of these compounds with respect to reference SIRT2Is. Biochemical and biological assays validated this study and pointed to compound 5a (SIRT2 IC50 = 9.0 μM) as the most interesting SIRT2I that was worthy of further development as an anticancer agent

Tricyclic Pyrazoles. Part 8. Synthesis, Biological Evaluation and Modelling of Tricyclic Pyrazole Carboxamides as Potential CB2 Receptor Ligands with Antagonist/Inverse Agonist Properties.

Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1and CB2receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB2receptor affinity (Ki= 4 nM) and remarkable selectivity (KiCB1/KiCB2= 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki= 6 nM), for the bornyl analogue (compound 14: Ki= 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki= 69 nM). Compounds 10 and 14 were also highly selective for the CB2receptor (KiCB1/KiCB2> 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2= 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2receptor-specific in vitro bioassay consisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence and absence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted with the four compounds, which conformed with the structural requirements stated for the binding of antagonist compounds to the human CB2receptor

Are you IDDSI ready?

The International Dysphagia Diet Standardisation Initiative (IDDSI) global framework was launched in November 2015. It was subsequently adopted by the Royal College of Speech and Language Therapists and the British Dietetic Association following expert review and professional membership consultation. In the UK, NHS England established an External IDDSI Reference Group comprising of stakeholders including professional, catering, industry and manufacturing representatives. The IDDSI External reference Group have endorsed a UK Aware, Prepare, Adopt model of implementation and all manufacturers and all healthcare settings are anticipated to be fully IDDSI compliant by April 2019. This requires whole system change with a comprehensive training programme. Those providing and delivering food and drink to individuals with swallowing difficulties need to familiarise themselves with food and drink consistencies and their testing methods. Resources are available to assist local healthcare institutions with implementation of the framework at www.rcslt.org / www.bda.org / www.iddsi.org

Speech Spectrum's Correlation with Speakers' Eysenck Personality Traits

The current study explored the correlation between speakers' Eysenck personality traits and speech spectrum parameters. Forty-six subjects completed the Eysenck Personality Questionnaire. They were instructed to verbally answer the questions shown on a computer screen and their responses were recorded by the computer. Spectrum parameters of /sh/ and /i/ were analyzed by Praat voice software. Formant frequencies of the consonant /sh/ in lying responses were significantly lower than that in truthful responses, whereas no difference existed on the vowel /i/ speech spectrum. The second formant bandwidth of the consonant /sh/ speech spectrum was significantly correlated with the personality traits of Psychoticism, Extraversion, and Neuroticism, and the correlation differed between truthful and lying responses, whereas the first formant frequency of the vowel /i/ speech spectrum was negatively correlated with Neuroticism in both response types. The results suggest that personality characteristics may be conveyed through the human voice, although the extent to which these effects are due to physiological differences in the organs associated with speech or to a general Pygmalion effect is yet unknown

Epidemiology and drug susceptibility of nontuberculous mycobacteria (NTM) in Italy in 2016-2020

Introduction. Nontuberculous mycobacteria (NTM) are environmental mycobacteria which may cause pulmonary and extrapulmonary diseases. These organisms are difficult to treat due to their intrinsic drug-resistance. In Italy, no major nationwide study on NTM epidemiology and drug susceptibility was performed. Methods. Data on the epidemiology of 7,469 NTM clinical isolates identified in Italy in 2016-2020 and on the minimum inhibitory concentrations (MICs) of 1,506 of these strains were analysed. Results. Overall, 63 species were identified in 42 hospital laboratories located in 16 out of 20 regions, with Mycobacterium avium complex (MAC) being the most frequently iso-lated, followed by M. gordonae, M. xenopi, M. abscessus. The MICs of 12 drugs for MAC, M. xenopi, M. kansasii, M. abscessus, M. fortuitum and M. chelonae were interpreted for clinical significance (susceptible, intermediate, resistant) based on the guidelines pub-lished by the Clinical and Laboratory Standards Institute in November 2018. Conclusions. Our data are in line with other nationwide studies and may be of value for further update of microbiological and clinical guidelines

An infant‐led approach to complementary feeding is positively associated with language development

The timing and strategy with which parents first introduce their infants to solid foods may be an important predictor of subsequent developmental outcomes. Recent years have seen a decline in the prevalence of traditional parent‐led feeding of soft, puréed food and a rise in the prevalence of infant‐led complementary feeding. Although there has been some research espousing the benefits of infant‐led complementary feeding for improving food fussiness and self‐regulation, there has been little exploration of this approach that may impact on other developmental outcomes in children. The current study explores whether aspects of the infant‐led approach, specifically the child eating unaided and consuming finger foods and eating with the family, are related to child language outcomes. One hundred thirty one parents of children aged 8–24 months completed questionnaires about their approach to complementary feeding, their current feeding practices, their child's experiences with family foods and child language comprehension/production. The findings suggest that an approach to complementary feeding which promotes infant autonomy in feeding (i.e., eating finger foods rather than puréed foods) and consuming more family foods is related to more advanced child language production and comprehension. Specifically, the prevalence of eating family foods mediated the relationship between eating unaided at the onset of the complementary feeding period and later language outcomes. This study is the first to find a significant relationship between different approaches to introducing solid foods and child language outcomes and these findings highlight the potential for different complementary feeding approaches to influence behaviour beyond mealtimes