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[Display omitted] • Application of a research platform for food geographical authentication. • Multivariate investigation for Allium ampeloprasum L. from Valdichiana (Tuscany). • A. ampeloprasum L. showed a different chemical composition compared to A. sativum. • Glutathione was identified as a potential marker of authentication. • A. ampeloprasum L. extracts displayed interesting vasoactive properties. A research platform for food authentication was set up by combining stable isotope ratio analysis, metabolomics by gas and liquid mass-spectrometry and NMR investigations, chemometric analyses for food excellences. This multi-analytical approach was tested on samples of elephant garlic (Allium ampeloprasum L.), a species belonging to the same genus of common garlic (Allium ampeloprasum L.), mainly produced in southern Tuscany-(Allium ampeloprasum). The isotopic composition allowed the product to be geographically characterized. Flavonoids, like (+)-catechin, cinnamic acids, quercetin glycosides were identified. The samples showed also a significant amount of dipeptides, sulphur-containing metabolites and glutathione, the latter of which could be considered a molecular marker of the analyzed elephant garlic. For nutraceutical profiling to reach quality labels, extracts were investigated in specific biological assays, displaying interesting vasorelaxant properties in rat aorta by mediating nitric oxide release from the endothelium and exhibited positive inotropic and negative chronotropic effects in rat perfused heart. [ABSTRACT FROM AUTHOR]

The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1 , was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2 , was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

• Pecorello and Mantonico pomaces represent a useful source of bioactive compounds. • Calabrian white grape pomaces were firstly investigated for their vasoactive properties. • The effects of extracts were analyzed in in vitro experiments on rat aorta rings. • Pecorello appeared more efficacious than Mantonico as a vasorelaxant extract. The valorisation of agrochemical wastes has become a low cost and sustainable tendency for the development of functional food. In particular, these enriched products seem to be enjoyable tools to treat metabolic disorders. In this field, Calabrian autochthonous white grape pomaces (Mantonico and Pecorello cultivar) were firstly investigated for their vasoactive properties. Skins and seeds were extracted and characterized by NMR spectroscopy, revealig the presence of numerous vasoactive compounds. The effects of extracts were analyzed in in vitro experiments on rat aorta rings (with and without endothelium), contracted by phenylephrine or KCl. Seeds extracts showed, differently from skins, an appreciable endothelium-dependent, eNOS-mediated vasodilation in the range 1–100 µg/mL. From a food market point of view, all the extracts were enclosed into a pectin polymer matrix. In the same experimental conditions, the polymers demonstrated the persistance of vasodilator activity only for Pecorello seed extract, which presented the most rich chemical profile. [ABSTRACT FROM AUTHOR]

Nowadays there is a folk medicine branch called apitherapy that aims to treat diseases with bee products, including honey. Honey has long been known for its medicinal and health promoting properties. It encloses numerous types of phytochemicals with high phenolic and flavonoid content, which contribute to its antioxidant and anti-inflammatory activities. Varieties and variants of polyphenols in honey showed antiproliferative property against several types of cancer. This review focuses on the latest discoveries about the key role of honey in different stages of carcinogenesis, initiation, proliferation and progression, both in vitro and in vivo , as well as on its adjuvant effect in cancer therapy. Although a possible application of honey and its active compounds as drugs against cancer is still far away from clinical practice, scientific results highlight that they could be used as immune booster for patients undergoing chemotherapy. They showed protective effects against the common exasperating and disabling side effects, mostly mucositis. [ABSTRACT FROM AUTHOR]

In this study, we investigate the anti-proliferative activity of a small library of 7-substituted 5 H -pyrrolo[1,2- a ][3,1]benzoxazin-5-one derivatives, against a panel of human cancer cell lines. We reported the synthesis of these compounds in a previous work. 7-Bromo-5 H -benzo[ d ]pyrrolo[2,1- b ][1,3]oxazin-5-one showed a promising anti-proliferative effect. As starting material for Suzuki-Miyaura cross coupling reaction, it was selected for the design and the synthesis of six further derivatives, with the aim to better define structure-activity relationships. The anti-proliferative MTT assay revealed a dose-dependent reduction of cell viability, especially for 7-([1,1′-biphenyl]-4-yl)-5 H -benzo[ d ]pyrrolo[2,1- b ][1,3]oxazin-5-one. Cell cycle and western blotting analysis suggested apoptosis as possible mechanism for its anti-proliferative activity. These preliminary results encourage our interest for further optimizations. [ABSTRACT FROM AUTHOR]

[Display omitted] Ca V 1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca V 1.2 and K Ca 1.1 channels, both in vitro and in silico , as well as on the contractile responses of rat aorta rings. All compounds were effective Ca V 1.2 channel blockers, positioning in the α 1C subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated K Ca 1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K Ca 1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension. [ABSTRACT FROM AUTHOR]

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery. [Display omitted] • Patients with Chronic Lymphocytic Leukemia have apoptosis defects. • The apoptosis defects are caused in part by a reduced expression of p66Shc/STAT4. • HDAC1 inhibition as a strategy for reactivation of STAT4/p66Shc expression. • 6c (chlopynostat) is one of the most potent HDAC1 inhibitors. • 6c induces apoptosis via HDAC1 inhibition, reversing the STAT4/p66Shc defect. [ABSTRACT FROM AUTHOR]

[Display omitted] The progress made so far in the elucidation of the structure of free fatty acid receptor 1 (FFAR1) and its secondary and ternary complexes with partial and full allosteric ligands led to the discovery of various putative binding regions on the FFAR1 surface. Attempts to develop FFAR1 agonists culminated with the identification of TAK-875 (1), whose phase 3 clinical trials were terminated due to potential liver toxicity. In the search of safer agonists, numerous classes of new compounds were designed, synthesized, and tested. Chemical decoration of the scaffolds was rationalized to reach a good balance between lipophilicity, activity, and toxicity. Today, targeting FFAR1 with positive modulators represents an attractive pharmacological tool for the treatment of type 2 diabetes mellitus (T2DM), mainly because of the lack of hypoglycaemic side effects associated with several antidiabetic drugs currently available. Moreover, considering the involvement of FFAR1 in many physio-pathological processes, its agonists are also emerging as possible therapeutic tools for alleviating organ inflammation and fibrosis, as well as for the treatment of CNS disorders, such as Alzheimer's disease and dementia. [ABSTRACT FROM AUTHOR]

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a - t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e , 4g , 4n - o , and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e , 4n , and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e , 4g , 4n , and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation. [Display omitted] • New carbamate-based FAAH inhibitors endowed with improved solubility were developed. • Compounds were characterized as potent, selective, and reversible FAAH inhibitors. • Compounds prevented ROS formation in human astrocytes stressed with TBHP. • Neuroinflammatory damage was induced in hippocampal organotypic explants. • 4e, 4g, 4n, 4s exerted neuroprotection in LPS + IFN-γ-treated hippocampal explants. [ABSTRACT FROM AUTHOR]

The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6. New polypharmacological agents for cancer treatment, based on a dual h HDAC6/ h HDAC8 inhibition profile were developed. The dual inhibitor design investigated the diphenyl-azetidin-2-one scaffold, typified in three different structural families, that, combined to a slender benzyl linker (6c , 6i , and 6j), displays nanomolar inhibition potency against h HDAC6 and h HDAC8 isoforms. Notably, their selective action was also corroborated by measuring their low inhibitory potency towards h HDAC1 and h HDAC10. Selectivity of these compounds was further demonstrated in human cell-based western blots experiments, by testing the acetylation of the non-histone substrates alpha-tubulin and SMC3. Furthermore, the compounds reduced the proliferation of colorectal HCT116 and leukemia U937 cells, after 48 h of treatment. The toxicity of the compounds was evaluated in rat perfused heart and in zebrafish embryos. In this latter model we also validated the efficacy of the dual h HDAC6/ h HDAC8 inhibitors against their common target acetylated-alpha tubulin. Finally, the metabolic stability was verified in rat, mouse, and human liver microsomes. [Display omitted] • Azetidin-2-one has been discovered as a new cap group for HDAC inhibition. • The new compounds showed a dual hHDAC6/HDAC8 inhibition profile. • The dual profile was confirmed by blotting non-histone proteins, such α-tubulin and SMC3. • 6c , 6i and 6j showed a good anti-proliferative effect in HCT116 and U937 cell lines. • Compounds showed no toxicity in rat perfused heart and danio rerio. [ABSTRACT FROM AUTHOR]

Autophagy is a lysosome dependent cell survival mechanism and is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Targeting autophagy in cancer therapy attracted considerable attention in the past as stress-induced autophagy has been demonstrated to contribute to both drug resistance and malignant progression and recently interest in this area has re-emerged. Unlocking the therapeutic potential of autophagy modulation could be a valuable strategy for designing innovative tools for cancer treatment. Microtubule-targeting agents (MTAs) are some of the most successful anti-cancer drugs used in the clinic to date. Scaling up our efforts to develop new anti-cancer agents, we rationally designed multifunctional agents 5a-l with improved potency and safety that combine tubulin depolymerising efficacy with autophagic flux inhibitory activity. Through a combination of computational, biological, biochemical, pharmacokinetic-safety, metabolic studies and SAR analyses we identified the hits 5i,k. These MTAs were characterised as potent pro-apoptotic agents and also demonstrated autophagy inhibition efficacy. To measure their efficacy at inhibiting autophagy, we investigated their effects on basal and starvation-mediated autophagic flux by quantifying the expression of LC3II/LC3I and p62 proteins in oral squamous cell carcinoma and human leukaemia through western blotting and by immunofluorescence study of LC3 and LAMP1 in a cervical carcinoma cell line. Analogues 5i and 5k , endowed with pro-apoptotic activity on a range of hematological cancer cells (including ex-vivo chronic lymphocytic leukaemia (CLL) cells) and several solid tumor cell lines, also behaved as late-stage autophagy inhibitors by impairing autophagosome-lysosome fusion. [Display omitted] • New microtubule targeting agents were synthesized by using a hybridization approach. • Compounds are characterized by potent proapoptotic and autophagy inhibition efficacy. • Autophagic flux inhibition was confirmed by the expression of LC3II/LC3I and p62 proteins. • 5i and 5k are late-stage autophagy inhibitors impairing autophagosome-lysosome fusion. [ABSTRACT FROM AUTHOR]