Design and pharmacological evaluation of Ibuprofen amides derivatives as dual FAAH/COX inhibitors

Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme responsible of the hydrolytic degradation of N-acylethanolamine endocannabinoids, such as the Arachidonoylethanolamide (anandamide, AEA), which it has been shown to alleviate pain and inflammation (1). In particular, the anti-nociceptive and anti-inflammatory effects of AEA could be enhanced by the simultaneous block of FAAH and COX enzymes (2). For this reason, several studies have been carried out in order to develop new FAAH/COX inhibitors (2). In 1997 it was reported that the NSAID ibuprofen inhibited FAAH, although with a modest potency (3), and successively the first dual inibhitor, the amide derivative of ibuprofen with a 2-amino-3-methylpyridine side chain (Ibu-AM5) was reported (4). -5). Benzylamides and piperazinoamides analogs of Ibuprofen have been also designed as less potent FAAH inhibitors than Ibu-AM5 (5). Here, I discuss the computational studies and the structure–activity relationships leading to the design, of novel Ibuprofen amide derivatives with a higher inhibition potency of FAAH and COX, which represent novel powerful anti-nociceptive agents

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor

Avoiding dative overgeneralisation errors: semantics, statistics or both?

Item does not contain fulltextHow do children eventually come to avoid the production of overgeneralisation errors, in particular, those involving the dative (e.g., *I said her "no")? The present study addressed this question by obtaining from adults and children (5-6, 9-10 years) judgements of well-formed and over-general datives with 301 different verbs (44 for children). A significant effect of pre-emption - whereby the use of a verb in the prepositional-object (PO)-dative construction constitutes evidence that double-object (DO)-dative uses are not permitted - was observed for every age group. A significant effect of entrenchment - whereby the use of a verb in any construction constitutes evidence that unattested dative uses are not permitted - was also observed for every age group, with both predictors also accounting for developmental change between ages 5-6 and 9-10 years. Adults demonstrated knowledge of a morphophonological constraint that prohibits Latinate verbs from appearing in the DO-dative construction (e.g., *I suggested her the trip). Verbs' semantic properties (supplied by independent adult raters) explained additional variance for all groups and developmentally, with the relative influence of narrow- vs broad-range semantic properties increasing with age. We conclude by outlining an account of the formation and restriction of argument-structure generalisations designed to accommodate these findings.26 p

Older Worker-Orientated Human Resource Practices, Wellbeing and Leave Intentions: A Conservation of Resources Approach for Ageing Workforces

At a time where there are ageing populations, global shortages of skilled labour, and migration pathways impacted by the COVID-19 pandemic, retaining older workers presents as a vital strategic initiative for organizations globally. This study examines the role of Human Resource Practices (HRPs), which are oriented towards accommodating the needs of an ageing workforce in mitigating psychological distress and turnover intentions. The study collected self-reported survey data from 300 Australian employees over the age of 45, over two time points. Using structural equation modelling, the study analyzed the extent to which Older Worker-oriented Human Resources Practices (OW-HRPs) translate into employee psychological health and retention within organizations, through the mediation of ageism and work–life conflict. The results support our hypothesis that OW-HRPs are associated with lower ageism, better work–life balance; and in combination these reduce psychological distress and help retain older workers in the workforce. We conclude that OW-HRPs can foster work environments conducive to older worker wellbeing, supporting the retention of talent and maintaining effectiveness, in the face of substantial labour supply challenges brought on by the COVID-19 pandemic and an ageing population

Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds

A systematic review of literature on occupational health and safety interventions for older workers.

As the global population ages there is an imperative to enhance labour participation of older workers in ways that support good physical and psychological health. However, there is limited guidance for organisations on how to do this effectively. This systematic review examined literature identified through four databases and a targeted web-search, yielding 39 PRISMA records (32 scholarly, seven grey literature) reporting workplace interventions aimed at improving the injury outcomes of older workers. The review revealed that organisational and composite interventions may be most effective, although an absence of robust research in this area and a scarcity of empirical evidence-based interventions known to improve injury outcomes for older workers was noted. Responding to these shortcomings, this article presents 'A future research agenda for older worker health, safety and well-being interventions.' This systems-based approach has a dual focus on organisational and composite interventions combined with robust research design.Practitioner summary: We conducted a systematic literature review of studies focussed on workplace interventions to improve the physical and psychological safety of older workers. Within the existing literature, evidence for effective interventions and guidance for organisations is weak. We present a future research agenda with a systems approach to address these gaps.fals

Synthesis, characterization, HSA/DNA interactions and antitumor activity of new [Ru(η6-p-cymene)Cl2(L)] complexes

Three new ruthenium(II) complexes were synthesized from different substituted isothiazole ligands 5-(methylamino)-3-pyrrolidine-1-ylisothiazole-4-carbonitrile (1), 5-(methylamino)-3- (4-methylpiperazine-1-yl)isothiazole-4-carbonitrile (2) and 5-(methylamino)-3-morpholine-4- ylisothiazole-4-carbonitrile (3): [Ru(η6-p-cymene)Cl2(L1)]·H2O (4), [Ru(η6 -pcymene)Cl2(L2)] (5) and [Ru(η6-p-cymene)Cl2(L3)] (6). All complexes were characterized by IR, UV-Vis, NMR spectroscopy, and elemental analysis. The molecular structures of all ligands and complexes 4 and 6 were determined by an X-ray. The results of the interactions of CT-DNA (calf thymus deoxyribonucleic acid) and HSA (human serum albumin) with ruthenium (II) complexes reveal that complex 4 binds well to CT-DNA and HSA. Kinetic and thermodynamic parameters for the reaction between complex and HSA confirmed the associative mode of interaction. The results of Quantum mechanics (QM) modelling and docking experiments toward DNA dodecamer and HSA support the strongest binding of the complex 4 to DNA major groove, as well as its binding to IIa domain of HSA with the lowest ΔG energy, which agrees with the solution studies. The modified GOLD docking results are indicative for Ru(p-cymene)LCl··(HSA··GLU292) binding and GOLD/MOPAC(QM) docking/modelling of DNA/Ligand (Ru(II)-N(7)dG7) covalent binding. The cytotoxic activity of compounds was evaluated by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl2H-tetrazolium bromide) assay. Neither of the tested compounds shows activity against a healthy MRC-5 cell line while the MCF-7 cell line is the most sensitive to all. Compounds 3, 4 and 5 were about two times more active than cisplatin, while the antiproliferative activity of 6 was almost the same as with cisplatin. Flow cytometry analysis showed the apoptotic death of the cells with a cell cycle arrest in the subG1 phase

Burkitt lymphoma beyond MYC translocation: N-MYC and DNA methyltransferases dysregulation

Background: The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases. Methods: We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively. Results: We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels. Conclusions: Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer

Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles

Cytotoxic attack particles released by CTLs and NK cells include diverse phospholipid membrane and glycoprotein encapsulated entities that contribute to target cell killing. Supramolecular attack particles (SMAPs) are one type of particle characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a proteinaceous shell including thrombospondin (TSP)-1. TSP-4 was also detected in bulk analysis of SMAPs released by CTLs; however, it has not been investigated whether TSP-4 contributes to distinct SMAP types or the same SMAP type as TSP-1 and, if in the same type of SMAP, whether TSP-4 and TSP-1 cooperate or compete. Here, we observed that TSP-4 expression increased upon CD8+ T cell activation while, surprisingly, TSP-1 was down-regulated. Correlative Light and Electron Microscopy and Stimulated Emission Depletion microscopy localized TSP-4 and TSP-1 in SMAP-containing multicore granules. Superresolution dSTORM revealed that TSP-4 and TSP-1 are usually enriched in the same SMAPs while particles with single-positive shells are rare. Retention Using Selective Hooks assays showed that TSP-4 localizes to the lytic granules faster than TSP-1 and promotes its accumulation therein. TSP-4 contributed to direct CTL-mediated killing, as previously shown for TSP-1. TSP-4 and TSP-1 were both required for latent SMAP-mediated cell killing, in which released SMAPs kill targets after removal of the CTLs. Of note, we found that chronic lymphocytic leukemia (CLL) cell culture supernatants suppressed expression of TSP-4 in CTL and latent SMAP-mediated killing. These results identify TSP-4 as a functionally important component of SMAPs and suggest that SMAPs may be targeted for immune suppression by CLL