A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators

Broad inhibition of plasmodium falciparum cytoadherence by (+)-epigallocatechin gallate

<p>Abstract</p> <p>Background</p> <p>The surface antigen P<it>f</it>EMP-1 is a key virulence factor of the human malaria parasite implicated in the cytoadherence of <it>Plasmodium falciparum </it>infected erythrocytes to a range of receptors on host endothelium. Among these host receptors, binding to ICAM-1 is related to cerebral malaria. The majority of the mortality in children with cerebral malaria is seen within 24 h of hospital admission despite the use of effective anti-parasite drugs, therefore, the development of adjunctive therapies is urgently needed.</p> <p>The polyphenolic compound (+)-epigallocatechin gallate ((+)-EGCG) has been previously evaluated for anti-adhesive properties using a small number of laboratory parasite isolates. Here, this property is further explored using a new panel of ICAM-1-binding patient isolates of <it>P. falciparum </it>to ascertain if (+)-EGCG might be effective as a broad spectrum inhibitor of ICAM-1-based cytoadherence.</p> <p>Methods</p> <p><it>Plasmodium falciparum </it>lines, including A4 and ItG as positive controls and nine new ICAM-1 binding patient isolates, were allowed to bind with ICAM-1-Fc protein under static assay conditions in the presence and absence of 50 μM (+)-EGCG. Adhesion levels of all the parasite strains were quantified by microscopy as the mean number of infected erythrocyte (IE) bound per mm²of surface area and statistical comparisons were made to demonstrate the effect of (+)-EGCG on the binding of various parasite variants to human ICAM-1.</p> <p>Results</p> <p>This study revealed that binding of patient isolates to ICAM-1 was reduced significantly with inhibition levels of 37% in patient isolate BC-12 up to a maximum of 80% in patient isolate 8146 at 50 μM (+)-EGCG.</p> <p>Conclusion</p> <p>Evaluation of the anti-adhesive property of (+)-EGCG against a new panel of ICAM-1-binding patient isolates of <it>P. falciparum </it>showed that this inhibitor, identified as potential mimic of the L43 loop of human ICAM-1, was effective at blocking cytoadherence.</p

Development of Quinazolinone Derivatives as Modulators of Virulence Factors of Pseudomonas aeruginosa Cystic Fibrosis Strains

Pseudomonas aeruginosa (PA), one of the ESKAPE pathogens, is an opportunistic Gram-negative bacterium responsible for nosocomial infections in humans but also for infections in patients affected by AIDS, cancer, or cystic fibrosis (CF). Treatment of PA infections in CF patients is a global healthcare problem due to the ability of PA to gain antibiotic tolerance through biofilm formation. Anti-virulence compounds represent a promising approach as adjuvant therapy, which could reduce or eliminate the pathogenicity of PA without impacting its growth. Pyocyanin is one of the virulence factors whose production is modulated by the Pseudomonas quinolone signal (PQS) through its receptor PqsR. Different PqsR modulators have been synthesized over the years, highlighting this new powerful therapeutic strategy. Based on the promising structure of quinazolin-4(3H)-one, we developed compounds 7a–d, 8a,b, 9, 10, and 11a–f able to reduce biofilm formation and the production of virulence factors (pyocyanin and pyoverdine) at 50 μM in two PA strains responsible for CF acute and chronic infections. The developed compounds did not reduce the cell viability of IB3-1 bronchial CF cells, and computational studies confirmed the potential ability of novel compounds to act as potential Pqs system modulators

Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation

Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f&nbsp;exhibited moderate antioxidant properties as found by in&nbsp;vitro assessment. This compound represents a novel donepezil–hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD

The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity

Synthetic cannabinoids and phytocannabinoids have been shown to suppress seizures both in humans and experimental models of epilepsy. However, they generally have a detrimental effect on memory and memory-related processes. Here we compared the effect of the inhibition of the endocannabinoid (eCB) degradation versus synthetic CB agonist on limbic seizures induced by maximal dentate activation (MDA) acute kindling. Moreover, we investigated the dentate gyrus (DG) granule cell reactivity and synaptic plasticity in naïve and in MDA-kindled anaesthetised rats. We found that both the fatty acid amide hydrolase (FAAH) inhibitor URB597 and the synthetic cannabinoid agonist WIN55,212-2 displayed AM251-sensitive anti-seizure effects. WIN55,212-2, dose-dependently (0.5–2 mg/kg, i.p.) impaired short-term plasticity (STP) and long-term potentiation (LTP) at perforant path-DG synapses in naïve rats. Strikingly, URB597 (1 mg/kg, i.p.) was devoid of any deleterious effects in normal conditions, while it prevented seizure-induced alterations of both STP and LTP. Our evidence indicates that boosting the eCB tone rather than general CB1 activation might represent a potential strategy for the development of a new class of drugs for treatment of both seizures and comorbid memory impairments associated with epilepsy.peer-reviewe

Traceability and authentication in agri-food production: A multivariate approach to the characterization of the Italian food excellence elephant garlic (Allium ampeloprasum L.), a vasoactive nutraceutical

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

Cinnamides Target Leishmania amazonensis Arginase Selectively

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors

In vivo pharmacological evaluations of novel olanzapine analogues in rats: a potential new avenue for the treatment of schizophrenia

Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis