Publications by authors named "Ettore Novellino"

640 Publications

Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase.

J Med Chem 2021 Jun 9. Epub 2021 Jun 9.

Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy.

Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg titration experiments demonstrated that our compounds coordinate the Mg cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00535DOI Listing
June 2021

Vascular Effects of the Polyphenolic Nutraceutical Supplement Taurisolo: Focus on the Protection of the Endothelial Function.

Nutrients 2021 May 2;13(5). Epub 2021 May 2.

Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: = 0.019). In conclusion, Taurisolo preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.
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http://dx.doi.org/10.3390/nu13051540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147644PMC
May 2021

Inhibition studies on carbonic anhydrase isoforms I, II, IV and IX with N-arylsubstituted secondary sulfonamides featuring a bicyclic tetrahydroindazole scaffold.

Eur J Med Chem 2021 Aug 24;220:113490. Epub 2021 Apr 24.

Department of Pharmacy, University of Pisa, Pisa, Italy.

Carbonic Anhydrases (CAs) are pharmaceutically relevant targets for the treatment of several disease conditions. The ubiquitous localization of these enzymes and the high homology shared by the different isoforms represent substantial impediments for the discovery of potential drugs devoid of off-target side effects. As a consequence, substantial efforts are still needed to allow for the full realization of the pharmacological potential of CA modulators. In this contribution, starting from our previous studies, we describe the synthesis of a set of new bicyclic tetrahydroindazoles featuring a secondary sulfonamide. Biological evaluation of the inhibitory activity against the hCA I, II, IV, and IX isoforms allowed drawing a structure-activity relationship profile that was rationalized through theoretical studies. This allowed dissecting the new molecules into the single portions influencing the zinc chelation properties and the selectivity profile thereby offering a new platform for the discovery of new isotype selective CA inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2021.113490DOI Listing
August 2021

Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand.

J Med Chem 2021 05 7;64(10):6972-6984. Epub 2021 May 7.

Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", Via D. Montesano 49, 80131 Naples, Italy.

Over recent years, αvβ6 and αvβ8 Arg-Gly-Asp (RGD) integrins have risen to prominence as interchangeable co-receptors for the cellular entry of herpes simplex virus-1 (HSV-1). In fact, the employment of subtype-specific integrin-neutralizing antibodies or gene-silencing siRNAs has emerged as a valuable strategy for impairing HSV infectivity. Here, we shift the focus to a more affordable pharmaceutical approach based on small RGD-containing cyclic pentapeptides. Starting from our recently developed αvβ6-preferential peptide [RGD-Chg-E]-CONH (), a small library of N-methylated derivatives (-) was indeed synthesized in the attempt to increase its affinity toward αvβ8. Among the novel compounds, [RGD-Chg-(Me)E]-CONH () turned out to be a potent αvβ6/αvβ8 binder and a promising inhibitor of HSV entry through an integrin-dependent mechanism. Furthermore, the renewed selectivity profile of was fully rationalized by a NMR/molecular modeling combined approach, providing novel valuable hints for the design of RGD integrin ligands with the desired specificity profile.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00533DOI Listing
May 2021

A novel β-hairpin peptide derived from the ARC repressor selectively interacts with the major groove of B-DNA.

Bioorg Chem 2021 Jul 22;112:104836. Epub 2021 Mar 22.

Department of Pharmacy, University of Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy. Electronic address:

Transcription factors (TFs) have a remarkable role in the homeostasis of the organisms and there is a growing interest in how they recognize and interact with specific DNA sequences. TFs recognize DNA using a variety of structural motifs. Among those, the ribbon-helix-helix (RHH) proteins, exemplified by the MetJ and ARC repressors, form dimers that insert antiparallel β-sheets into the major groove of DNA. A great chemical challenge consists of using the principles of DNA recognition by TFs to design minimized peptides that maintain the DNA affinity and specificity characteristics of the natural counterparts. In this context, a peptide mimic of an antiparallel β-sheet is very attractive since it can be obtained by a single peptide chain folding in a β-hairpin structure and can be as short as 14 amino acids or less. Herein, we designed eight linear and two cyclic dodeca-peptides endowed with β-hairpins. Their DNA binding properties have been investigated using fluorescence spectroscopy together with the conformational analysis through circular dichroism and solution NMR. We found that one of our peptides, peptide 6, is able to bind DNA, albeit without sequence selectivity. Notably, it shows a topological selectivity for the major groove of the DNA which is the interaction site of ARC and many other DNA-binding proteins. Moreover, we found that a type I' β-hairpin folding pattern is a favorite peptide structure for interaction with the B-DNA major groove. Peptide 6 is a valuable lead compound for the development of novel analogs with sequence selectivity.
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http://dx.doi.org/10.1016/j.bioorg.2021.104836DOI Listing
July 2021

Promelanogenic Effects by an Annurca Apple-Based Natural Formulation in Human Primary Melanocytes.

Clin Cosmet Investig Dermatol 2021 25;14:291-301. Epub 2021 Mar 25.

Department of Pharmacy, School of Medicine and Surgery, University of Naples "Federico II", Naples, 80131, Italy.

Introduction: Melanocytes are engaged in synthesis, transport, and release of pigments at the epidermal-melanin units in response to the finely regulated melanogenic pathway. A multifaceted combination of both intrinsic and extrinsic factors - from endocrine and paracrine dynamics to exogenous stimuli such as sunlight and xenobiotics - modulates expression and activity of proteins involved in pigmentation, including the rate-limiting enzyme tyrosinase. As well as playing critical physiological functions comprising skin photoprotection, melanins define hair and skin pigmentation which in turn have impacted considerably to human social communication since time immemorial. Additionally, numerous skin diseases based on pigmentation alterations can have serious public influence. While several melanogenesis inhibitors are already available, the number of melanin activators and tyrosinase stimulators as drug-like agents is still limited.

Methods: To explore the biological effects of an Annurca Apple-based nutraceutical preparation (AMS) on melanin production, experiments in cellular models of human skin were performed. Both primary cultures and co-cultures of epidermal melanocytes (HEMa) and follicular keratinocytes (HHFK) were used.

Results: We show that AMS, by now branded for its cutaneous beneficial effects, induces in total biocompatibility a significant promelanogenic effect in human primary melanocytes. In line, we found melanin cytosolic accumulation consistent with tyrosinase up-regulation.

Conclusion: Disposal of skin pigmenting agents would be attractive for the treatment of hypopigmentation disorders, to postpone skin photoaging or simply for fashion, so that discovery and development of melanogenesis stimulators, especially from natural sources, is nowadays a dynamic area of research.
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http://dx.doi.org/10.2147/CCID.S299569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008161PMC
March 2021

Novel Peptide-Based PET Probe for Non-invasive Imaging of C-X-C Chemokine Receptor Type 4 (CXCR4) in Tumors.

J Med Chem 2021 03 4;64(6):3449-3461. Epub 2021 Mar 4.

DiSTABiF, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy.

The recently reported CXCR4 antagonist (Ac-Arg-Ala-[DCys-Arg-2Nal-His-Pen]-COH) was investigated as a molecular scaffold for a CXCR4-targeted positron emission tomography (PET) tracer. Toward this end, was functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononanetriacetic acid (NOTA). On the basis of convincing affinity data, both tracers, [Ga]NOTA analogue ([Ga]-) and [Ga]DOTA analogue ([Ga]-), were evaluated for PET imaging in "" models of CHO-hCXCR4 and Daudi lymphoma cells. PET imaging and biodistribution studies revealed higher CXCR4-specific tumor uptake and high tumor/background ratios for the [Ga]NOTA analogue ([Ga]-) than for the [Ga]DOTA analogue ([Ga]-) in both models. Moreover, [Ga]- and [Ga]- displayed rapid clearance and very low levels of accumulation in all nontarget tissues but the kidney. Although the high tumor/background ratios observed in the mouse xenograft model could partially derive from the hCXCR4 selectivity of [Ga]-, our results encourage its translation into a clinical context as a novel peptide-based tracer for imaging of CXCR4-overexpressing tumors.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00066DOI Listing
March 2021

CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme.

Eur J Pharmacol 2021 Apr 10;897:173936. Epub 2021 Feb 10.

Department of Pharmacy, University of Naples "Federico II", 80131, Napoli, Italy. Electronic address:

Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too.
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http://dx.doi.org/10.1016/j.ejphar.2021.173936DOI Listing
April 2021

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds.

Chem Soc Rev 2021 Jan 22;50(2):766-897. Epub 2020 Dec 22.

Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131, Napoli, Italy.

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.
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http://dx.doi.org/10.1039/d0cs00493fDOI Listing
January 2021

Bioactive Compounds for the Management of Hypertriglyceridemia: Evidence From Clinical Trials and Putative Action Targets.

Front Nutr 2020 30;7:586178. Epub 2020 Nov 30.

Department of Pharmacy, University of Naples Federico II, Naples, Italy.

Hypertriglyceridemia refers to the presence of elevated concentrations of triglycerides (TG) in the bloodstream (TG >200 mg/dL). This lipid alteration is known to be associated with an increased risk of atherosclerosis, contributing overall to the onset of atherosclerotic cardiovascular disease (CVD). Guidelines for the management of hypertriglyceridemia are based on both lifestyle intervention and pharmacological treatment, but poor adherence, medication-related costs and side effects can limit the success of these interventions. For this reason, the search for natural alternative approaches to reduce plasma TG levels currently represents a hot research field. This review article summarizes the most relevant clinical trials reporting the TG-reducing effect of different food-derived bioactive compounds. Furthermore, based on the evidence obtained from studies, we provide a description and classification of putative targets of action through which several bioactive compounds can exert a TG-lowering effect. Future research may lead to investigations of the efficacy of novel nutraceutical formulations consisting in a combination of bioactive compounds which contribute to the management of plasma TG levels through different action targets.
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http://dx.doi.org/10.3389/fnut.2020.586178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734325PMC
November 2020

Cardioprotective Effects of Taurisolo® in Cardiomyoblast H9c2 Cells under High-Glucose and Trimethylamine N-Oxide Treatment Sphingolipid Synthesis.

Oxid Med Cell Longev 2020 12;2020:2961406. Epub 2020 Nov 12.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

In addition to high plasma glucose, increased levels of trimethylamine N-oxide (TMAO) have been found in obese subjects, where are considered as a novel risk factor for cardiovascular diseases. The present study aimed to investigate the effect of a novel nutraceutical formulation based on grape polyphenols (registered as Taurisolo®) in counteracting TMAO- and high glucose (HG)-induced cytotoxicity in cardiomyoblast H9c2 cells. Cell damage was induced with HG (HG-H9c2) and HG+TMAO (THG-H9c2); both experimental cell models were, thus, incubated for 72 h in the presence or absence of Taurisolo®. It was observed that Taurisolo® significantly increased the cell viability and reduced lactate dehydrogenase and aspartate transaminase release in both HG- and THG-H9c2 cells. Additionally, through its antioxidant activity, Taurisolo® modulated cell proliferation ERK activation in THG-H9c2. Furthermore, Taurisolo® was able to induce autophagic process increasing the expression of LC3II, a protein marker involved in formation of autophagosome and synthesis of sphingomyelin, ceramides, and their metabolites both in HG- and THG-H9c2 cells. Finally, Taurisolo® reduced hypertrophy and induced differentiation of HG-H9C2 cells into cardiomyocyte-like cells. These data suggest that Taurisolo® counteracts the toxicity induced by TMAO and HG concentrations increasing autophagic process and activating sphingolipid synthesis, resulting in a morphological cell remodeling. In conclusion, our results allow speculating that Taurisolo®, combined with energy restriction, may represent a useful nutraceutical approach for prevention of cardiomyopathy in obese subjects.
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http://dx.doi.org/10.1155/2020/2961406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683148PMC
May 2021

Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals.

J Org Chem 2020 11 19;85(21):14077-14086. Epub 2020 Oct 19.

Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, Italy.

A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species.
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http://dx.doi.org/10.1021/acs.joc.0c01946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015228PMC
November 2020

Genotoxicity Assessment of Three Nutraceuticals Containing Natural Antioxidants Extracted from Agri-Food Waste Biomasses.

Foods 2020 Oct 14;9(10). Epub 2020 Oct 14.

Department of Pharmacy, University of Naples Federico II. Via Montesano 49, 80131 Naples, Italy.

Grapes and apples are the most cultivated fruits in the Mediterranean basin and their agricultural processing is responsible for the production of a large amount of bio-waste. The reuse of this food biomass would increase the volume of recyclable/renewable biomaterial and lower the environmental impact due to the increasing demand for these biological products. To this purpose, agri-food waste from grape and apple processing have become an important source of phytochemicals, and many pharmaceutical industries are using it as starting material to produce dietary supplements, functional foods, and food additives for human consumption. In virtue of the chemical diversity and complexity of agri-food biowaste, developers and producers of nutraceuticals are advised to assess the safety of their final nutraceutical products, in compliance with European Food Safety Authority regulation. Here, we use the Ames test to assess the mutagenicity of three nutraceuticals obtained from agri-food waste biomasses: Taurisolo from grape pomace of L. cv 'Aglianico', AnnurComplex from M. cv 'Annurca' and Limoncella Apple Extract from B. cv 'Limoncella'. The results showed that all three nutraceuticals were non-mutagenic.
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http://dx.doi.org/10.3390/foods9101461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602140PMC
October 2020

Red Propolis and Its Dyslipidemic Regulator Formononetin: Evaluation of Antioxidant Activity and Gastroprotective Effects in Rat Model of Gastric Ulcer.

Nutrients 2020 Sep 26;12(10). Epub 2020 Sep 26.

University of Tiradentes, Av. Murilo Dantas, 300, Aracaju CEP 49032-490, Sergipe, Brazil.

Propolis has various pharmacological properties of clinical interest, and is also considered a functional food. In particular, hydroalcoholic extracts of red propolis (HERP), together with its isoflavonoid formononetin, have recognized antioxidant and anti-inflammatory properties, with known added value against dyslipidemia. In this study, we report the gastroprotective effects of HERP (50-500 mg/kg, p.o.) and formononetin (10 mg/kg, p.o.) in ethanol and non-steroidal anti-inflammatory drug-induced models of rat ulcer. The volume, pH, and total acidity were the evaluated gastric secretion parameters using the pylorus ligature model, together with the assessment of gastric mucus contents. The anti- activities of HERP were evaluated using the agar-well diffusion method. In our experiments, HERP (250 and 500 mg/kg) and formononetin (10 mg/kg) reduced ( < 0.001) total lesion areas in the ethanol-induced rat ulcer model, and reduced ( < 0.05) ulcer indices in the indomethacin-induced rat ulcer model. Administration of HERP and formononetin to pylorus ligature models significantly decreased ( < 0.01) gastric secretion volumes and increased ( < 0.05) mucus production. We have also shown the antioxidant and anti- activities of HERP. The obtained results indicate that HERP and formononetin are gastroprotective in acute ulcer models, suggesting a prominent role of formononetin in the effects of HERP.
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http://dx.doi.org/10.3390/nu12102951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600383PMC
September 2020

Improved Anti-Prion Nucleic Acid Aptamers by Incorporation of Chemical Modifications.

Nucleic Acid Ther 2020 12 29;30(6):414-421. Epub 2020 Sep 29.

Department of Pharmacy, University of Naples Federico II, Naples, Italy.

Nucleic acid aptamers are innovative and promising candidates to block the hallmark event in the prion diseases, that is the conversion of prion protein (PrP) into an abnormal form; however, they need chemical modifications for effective therapeutic activity. This communication reports on the development and biophysical characterization of a small library of chemically modified G-quadruplex-forming aptamers targeting the cellular PrP and the evaluation of their anti-prion activity. The results show the possibility of enhancing anti-prion aptamer properties through straightforward modifications.
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http://dx.doi.org/10.1089/nat.2020.0899DOI Listing
December 2020

Abscisic Acid Treatment in Patients with Prediabetes.

Nutrients 2020 Sep 24;12(10). Epub 2020 Sep 24.

Department of Pharmacy, University of Naples Federico II, 80131 Napoli, Italy.

Aim: to evaluate the effects of abscisic acid (ABA), contained in dwarf peaches, on the regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) conditions.

Materials And Methods: sixty-five patients with IFG or IGT were randomized to take ABA or placebo for 3 months. We evaluated: fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbA), fasting plasma insulin (FPI), homeostatic model assessment of insulin resistance (HOMA-IR), lipid profile and high sensitivity C-reactive protein (Hs-CRP). At baseline, and after 3 months, all patients underwent an oral glucose tolerance test (OGTT), an euglycemic hyperinsulinemic clamp, and a glucagon test.

Results: a significant reduction of HbA, FPG, PPG, FPI and HOMA-IR was observed in the ABA group. After 3 months, 26.7% of patients returned to a normal glycemic status in the ABA group versus zero patients in placebo group; 20.0% were classified as IFG and 53.3% as IGT in the nutraceutical group versus 33.3% and 63.3% in the placebo group. The M value was higher in the ABA group at the end of the treatment. Finally, Hs-CRP was reduced after 3 months of ABA consumption.

Conclusions: abscisic acid can be effective in ameliorating glyco-metabolic compensation and in reducing inflammatory status in patients with IFG or IGT.
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http://dx.doi.org/10.3390/nu12102931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599846PMC
September 2020

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1751-1764

Department of Pharmacy, University of Naples "Federico II", Naples, Italy.

The rapid development of antimicrobial resistance is pushing the search in the discovering of novel antimicrobial molecules to prevent and treat bacterial infections. Self-assembling antimicrobial peptides, as the lipidated peptides, are a novel and promising class of molecules capable of meeting this need. Based on previous work on Temporin L analogs, several new molecules lipidated at the N- or and the C-terminus were synthesised. Our goal is to improve membrane interactions through finely tuning self-assembly to reduce oligomerisation in aqueous solution and enhance self-assembly in bacterial membranes while reducing toxicity against human cells. The results here reported show that the length of the aliphatic moiety is a key factor to control target cell specificity and the oligomeric state of peptides either in aqueous solution or in a membrane-mimicking environment. The results of this study pave the way for the design of novel molecules with enhanced activities.
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http://dx.doi.org/10.1080/14756366.2020.1819258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534258PMC
December 2020

Olive Leaves and Hibiscus Flowers Extracts-Based Preparation Protect Brain from Oxidative Stress-Induced Injury.

Antioxidants (Basel) 2020 Sep 1;9(9). Epub 2020 Sep 1.

Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro, 2, 53100 Siena, Italy.

Oxidative stress (OS) arising from tissue redox imbalance, critically contributes to the development of neurodegenerative disorders. Thus, natural compounds, owing to their antioxidant properties, have promising therapeutic potential. (PRES) is a nutraceutical product composed of leaves- and flowers-extracts of L. and L., respectively, the composition of which has been characterized by HPLC coupled to a UV-Vis and QqQ-Ms detector. As PRES possess antioxidant, antiapoptotic and anti-inflammatory properties, the aim of this study was to assess its neuroprotective effects in human neuroblastoma SH-SY5Y cells and in rat brain slices subjected to OS. PRES (1-50 µg/mL) reverted the decrease in viability as well as the increase in sub-diploid-, DAPI-and annexin V-positive-cells, reduced ROS formation, recovered the mitochondrial potential and caspase-3 and 9 activity changes caused by OS. PRES (50-100 µg/mL) neuroprotective effects occurred also in rat brain slices subjected to HO challenge. Finally, as the neuroprotective potential of PRES is strictly related to its penetration into the brain and a relatively good pharmacokinetic profile, an in-silico prediction of its components drug-like properties was carried out. The present results suggest the possibility of PRES as a nutraceutical, which could help in preventing neurodegenerative diseases.
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http://dx.doi.org/10.3390/antiox9090806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555463PMC
September 2020

Breast Tumor Cell Invasion and Pro-Invasive Activity of Cancer-Associated Fibroblasts Co-Targeted by Novel Urokinase-Derived Decapeptides.

Cancers (Basel) 2020 Aug 24;12(9). Epub 2020 Aug 24.

Institute of Genetics and Biophysics "Adriano Buzzati Traverso", National Research Council, 80131 Naples, Italy.

Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by αv overexpression or abolished by excess vitronectin, anti-αv antibodies or silencing of αv gene, identifying αv-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for αv integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced α-smooth muscle actin (α-SMA) levels. Finally, peptide exposure of αv-expressing primary CAFs led to the downregulation of α-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies.
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http://dx.doi.org/10.3390/cancers12092404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564779PMC
August 2020

Fermentation of Foods and Beverages as a Tool for Increasing Availability of Bioactive Compounds. Focus on Short-Chain Fatty Acids.

Foods 2020 Jul 25;9(8). Epub 2020 Jul 25.

Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.

Emerging evidence suggests that fermentation, historically used for the preservation of perishable foods, may be considered as a useful tool for increasing the nutritional value of fermented products, in terms of increases in bioactive compound content, including short-chain fatty acids (SCFAs), as bacteria end-products, whose beneficial effects on human health are well-established. The purpose of the present manuscript is to summarize studies in this field, providing evidence about this novel potential of fermentation. A limited number of studies directly investigated the increased SCFA levels in fermented foods. All studies, however, agree in confirming that levels of SCFAs in fermented products are higher than in unfermented products, recognizing the key role played by the microorganisms in metabolizing food matrices, producing and releasing bioactive substances. According to the available literature, fermentation might be taken into account by the food industry as a strategy with no environmental impacts to produce functional foods and beverages with a higher nutritional value and health-promoting compounds.
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http://dx.doi.org/10.3390/foods9080999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466228PMC
July 2020

Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells.

Molecules 2020 Jul 8;25(14). Epub 2020 Jul 8.

Dipartimento di Chimica e Tecnologie del Farmaco, 'Sapienza' Università di Roma, 00185 Roma, Italy.

Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis(()-3-bromobenzylidene)piperidin-4-one displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis(()-2-bromobenzylidene) cyclic compounds - to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of - exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (), benzyl (), or acyl (-) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl () and 3-phenylpropyl () decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (-). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.
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http://dx.doi.org/10.3390/molecules25143122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397249PMC
July 2020

Disulfide Bond Replacement with 1,4- and 1,5-Disubstituted [1,2,3]-Triazole on C-X-C Chemokine Receptor Type 4 (CXCR4) Peptide Ligands: Small Changes that Make Big Differences.

Chemistry 2020 Aug 20;26(44):10113-10125. Epub 2020 Jul 20.

DiSTABiF, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100, Caserta, Italy.

Here we investigated the structural and biological effects ensuing from the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4- and 1,5- disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showed high affinity and selectivity against CXCR4. Notably, when assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided a valuable model that highlighted differences in the interactions of the two peptidomimetics with the receptor that could account for their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors.
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http://dx.doi.org/10.1002/chem.202002468DOI Listing
August 2020

May Polyphenols Have a Role Against Coronavirus Infection? An Overview of Evidence.

Front Med (Lausanne) 2020 15;7:240. Epub 2020 May 15.

Department of Pharmacy, University of Naples Federico II, Naples, Italy.

The coronavirus infection is constantly diffusing worldwide and the incidence of death is dramatically increasing, representing one of the greatest disasters in human history. Nowadays, no effective therapeutic approaches have been licensed, despite the rising interest of the scientific research in this specific field, and the daily growing number of publications, while the need to find novel strategies is urgent. Evidence in the literature reported the antiviral activity of polyphenols, the largest class of bioactive compounds in nature. Interestingly, a limited number of studies investigated the efficacy of polyphenols from different raw materials, directly against coronaviruses. The present manuscript aimed to report this evidence and provide a viewpoint on the possibility to use it as a start point for the development of novel natural approaches against this viral infection, eventually designing further appropriate researches.
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http://dx.doi.org/10.3389/fmed.2020.00240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243156PMC
May 2020

MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans.

Sci Transl Med 2020 06;12(548)

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4 T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8 and CD4 responses were induced with up to 30% of CD3CD8 cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.
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http://dx.doi.org/10.1126/scitranslmed.aaz7715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610808PMC
June 2020

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice.

Allergy 2021 01 23;76(1):168-190. Epub 2020 Oct 23.

Dept of Otorhinolaryngology, Chiba University Hospital, Chiba, Japan.

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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http://dx.doi.org/10.1111/all.14422DOI Listing
January 2021

Antimicrobial peptide Temporin-L complexed with anionic cyclodextrins results in a potent and safe agent against sessile bacteria.

Int J Pharm 2020 Jun 21;584:119437. Epub 2020 May 21.

Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy. Electronic address:

Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. Antimicrobial peptides (AMPs) have been proposed as a new class of clinically useful antimicrobials. Special attention has been devoted to frog-skin temporins. In particular, temporin L (TL) is strongly active against Gram-positive, Gram-negative bacteria and yeast strains. With the aim of overcoming some of the main drawbacks preventing the widespread clinical use of this peptide, i.e. toxicity and unfavorable pharmacokinetics profile, we designed new formulations combining TL with different types of cyclodextrins (CDs). TL was associated to a panel of neutral or negatively charged, monomeric and polymeric CDs. The impact of CDs association on TL solubility, as well as the transport through bacterial alginates was assessed. The biocompatibility on human cells together with the antimicrobial and antibiofilm properties of TL/CD systems was explored.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119437DOI Listing
June 2020

HOPPI-NMR: Hot-Peptide-Based Screening Assay for Inhibitors of Protein-Protein Interactions by NMR.

ACS Med Chem Lett 2020 May 20;11(5):1047-1053. Epub 2020 Feb 20.

Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.

Protein-protein interactions (PPIs) contribute to the onset and/or progression of several diseases, especially cancer, and this discovery has paved the way for considering disruption of the PPIs as an attractive anti-tumor strategy. In this regard, simple and efficient biophysical methods for detecting the interaction of the inhibitors with the protein counterpart are still in high demand. Herein, we describe a convenient NMR method for the screening of putative PPI inhibitors based on the use of "hot peptides" (HOPPI-NMR). As a case study, HOPPI-NMR was successful applied to the well-known p53/MDM2 system. Our outcomes highlight the main advantages of the method, including the use of a small amount of unlabeled proteins, the minimization of the risk of protein aggregation, and the ability to identify weak binders. The last leaves open the possibility for application of HOPPI-NMR in tandem with fragment-based drug discovery as a valid strategy for the identification of novel chemotypes acting as PPI inhibitors.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236535PMC
May 2020

From PARP1 to TNKS2 Inhibition: A Structure-Based Approach.

ACS Med Chem Lett 2020 May 3;11(5):862-868. Epub 2020 Feb 3.

Department of Chemistry and Technology of Drugs, ″Sapienza" University of Rome, 00185 Rome, Italy.

Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236224PMC
May 2020

GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis.

ACS Med Chem Lett 2020 May 2;11(5):818-824. Epub 2020 Mar 2.

Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia CH-6900, Italy.

GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn's and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR1 agonists. pharmacological assays showed that compound selectively activates GPBAR1 (EC = 0.3 μM) and reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in THP1 cells. The binding mode of compound in GPBAR1 was elucidated by docking calculations. Moreover, compound protects against TNBS-induced colitis in Gpbar1 rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236273PMC
May 2020

Pyrrolyl Pyrazoles as Non-Diketo Acid Inhibitors of the HIV-1 Ribonuclease H Function of Reverse Transcriptase.

ACS Med Chem Lett 2020 May 5;11(5):798-805. Epub 2020 Mar 5.

Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Roma, Italy.

Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236236PMC
May 2020