Developing novel non-hydroxamate histone deacetylase inhibitors: the chelidamic warhead

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Use of Pinus sylvestris L. (Pinaceae), Origanum vulgare L. (Lamiaceae), and Thymus vulgaris L. (Lamiaceae) essential oils and their main components to enhance itraconazole activity against azole susceptible/not-susceptible Cryptococcus neoformans strains

Abstract Background: Cryptococcal infections, besides being a problem for immunocompromised patients, are occasionally being a problem for immunocompetent patients. In addition, the lower susceptibility of this yeast to azoles is a growing problem in health care. To date, there are very few molecules with any activity towards Cryptococcus neoformans, leading to heightened interest in finding new alternatives or adjuvants to conventional drugs for the treatment of mycosis caused by this yeast. Since the essential oils (EOs) are considered as a potential rich source of bioactive antimicrobial compounds, we evaluated the antifungal activity of Origanum vulgare (oregano), Pinus sylvestris (pine), and Thymus vulgaris (thyme red) EOs, and their components (\u3b1-pinene, carvacrol, thymol) compared with fluconazole, itraconazole, and voriconazole, against C.neoformans clinical strains. Then, we investigated the effect of EOs and components in combination with itraconazole. Methods: EO composition was analysed by Gas chromatography-mass spectrometry (GC-MS). A broth microdilution method was used to evaluate the susceptibility of C.neoformans to azoles, EOs and components. Checkerboard tests, isobolograms and time-kill assays were carried out for combination studies. Results: C.neoformans isolates were susceptible to azoles, while one C.neoformans exhibited a reduced susceptibility to all test edazole drugs. All EOs exerted a good inhibitory activity against all C.neoformans strains. Pine EO was the most effective. Among components, thymol exerted the most remark able activity. By checkerboard testing and isobolographic analysis, combinations of itraconazole with oregano, pine, or thyme EOs, and carvacrol were found to be synergistic (FICI 64 0.5) against azole susceptible C.neoformans. Regarding the azole not susceptible C.neoformans strain, the synergistic effect with itraconazole was observed with thyme EO (chemotype: thymol 26.52%; carvacrol 7.85%), and carvacrol. Time-kill assays confirmed the synergistic effects of itraconazole and oregano or thyme EO against azole susceptible C.neoformans. Binary mixtures of itraconazole/thyme EO or carvacrol yielded additive effects on the azole not susceptible C.neoformans. Conclusions: Our findings highlight the potential effectiveness of thyme, oregano EOs, and carvacrol as natural and cost-effective adjuvants when used in combination with itraconazole. Identification of EOs exerting these effects could be one of the feasible ways to overcome drug resistance, reducing drug concentration and side effects

L'area "Nord-Lucana" ed il sito di Atena Lucana: identità e caratteri di un gruppo indigeno ai margini del Vallo di Diano

Questo studio prende spunto dalla necessità di ricomporre la documentazione materiale rinvenuta nel corso degli anni ad Atena Lucana, proveniente dagli scavi realizzati in tempi e modi differenti, nel tentativo di tracciare un profilo ben delineato del gruppo umano che a partire dalla seconda metà del VII sec. a.C. è insediato in un territorio ai margini del Vallo di Diano. In questa prospettiva, in mancanza di dati sugli abitati, le necropoli analizzate costituiscono un osservatorio sicuramente prezioso per affrontare una lettura più articolata del quadro culturale non solo del Vallo ma anche della Basilicata antica

Indagini archeologiche e territoriali a Pian della Tirena (2012-2013)

L'intervento ha inteso presentare i risultati delle ricerche archeologiche e territoriali condotte a Pian della Tirena, a Nocera Terinese (Cz), un promontorio su cui si sviluppa, in età ellenistica, un abitato brezio, cui segue un insediamento di età romana, forse riconducibile alla colonia di Tempsa, fondata nel 194 a.C. Le indagini hanno documentato, per la prima volta, la presenza di assi stradali disposti ortogonalmente e caratterizzati da una serie di fasi, che vanno dalla fine del IV sec. a.C. al II sec. a.C. La ripresa delle ricognizioni nel territorio, invece, hanno confermato la presenza di una serie di nuclei rurali sparsi, relativi soprattutto alla fase brezia, che occupano le fasce collinari interne. Le ricerche sono maturate nell'ambito del PRIN 2009 "Centri fortificati, insediamenti e processi ambientali nella Calabria tirrenica tra secondo e primo millennio a.C. Un'indagine interdisciplinare"

Protein Recognition by Short Peptide Reversible Inhibitors of the Chromatin-Modifying LSD1/CoREST Lysine Demethylase

The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylaseLSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminaldomain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tailof the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoRESTcan bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively chargedα-helical turn that formsupon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the samebinding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitorsexhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors ofLSD

Pian della Tirena, Torre Galli

Il contributo ha inteso presentare i risultati delle indagini multidisciplinari, condotte in contesti indigeni della Calabria (Pian della Tirena, Torre Galli), tra età protostorica ed ellenistica, attraverso le prospezioni geofisiche e i riscontri stratigrafici

Fluorescent Light Energy (FLE) Generated through Red LED Light and a Natural Photoconverter Gel as a New, Non-Invasive Approach for Facial Age Control: A Pilot Study

This study, for the first time, evaluated the safety and efficacy of a new natural-based topical gel containing a spirulina extract. This photoconverter gel generates fluorescent light energy (FLE) via a red LED light device, which is proven to be effective for age control of facial skin. This was a one-centre, observational, uncontrolled pilot trial. Eight healthy female subjects aged 35 to 65 years old, with Fitzpatrick skin types II–V were recruited. The duration of the study was five treatment sessions of one treatment every seven days, with a final follow-up at one month after the last treatment session. The images and the related data were acquired with the SONY® Mod. DSCRX10M3, the Canfield VISIA Facial Imaging System®, and QUANTIFICARE 3D® analysis. Patient compliance was excellent (100%) and the treatment was described as warm and pleasant by the patients. After 30 days, VISIA parameters such as wrinkles, texture, red areas, and Trueskin Age® had improved. The safety and efficacy of the FLE treatment assessed in this trial were achieved for overall rejuvenation of facial skin, focusing on wrinkles evaluated via the specific VISIA algorithms

Measurement of extended half-life recombinant FVIII molecules: In vitro and ex vivo evidence of relevant assay discrepancies

Background: Extended half-life recombinant FVIII products (EHL-rFVIIIs) have been engineered to improve the pharmacokinetic profile of FVIII, enabling better hemostatic protection with a reduced number of injections in persons with hemophilia. Previous studies showed several discrepancies in FVIII activity (FVIII:C) measurements for EHL-rFVIIIs comparing one-stage clotting assay (OSA) and chromogenic assay (CSA), although a systematic investigation of this phenomenon is still lacking. Objective: Evaluation of the accuracy and precision of measurement of all available EHL-rFVIIIs with 5 different assays both in vitro and ex vivo. Methods: Damoctocog alfa pegol, rurioctocog alfa pegol, turoctocog alfa pegol, and efmoroctocog alfa were tested with 3 OSA types: (1) aPTT-based commercial reagents with colloidal silica (Synthasil, Werfen-IL); (2) ellagic acid, Synthafax (Werfen-IL); and (3) OSA calibrated with each EHL-rFVIII product and colloidal silica. Measurements were also carried out with 2 different commercially available CSA reagents (Coamatic Factor VIII, Chromogenix-Werfen) and Trinichrom FVIII (Tcoag-Stago). A Bland-Altman analysis was performed to compare all assays. Results: The simple OSA showed significant discrepancies between the expected and measured EHL-rFVIII concentrations as CSA methods, whereas the calibrated OSA assay was accurate and precise in determining the activity of all EHL-rFVIIIs in the in vitro setting. Comparable results were found using ex vivo plasma samples. Conclusion: In this study, only OSA with a calibration curve constructed with each EHL-rFVIII product showed acceptable accuracy and precision in EHL-rFVIIIs measurements

The main phenolic compounds responsible for the antioxidant capacity of sweet cherry (Prunus avium L.) pulp

The antioxidant capacity of sweet cherry (Prunus avium L.) pulp extracts is strictly related to the phenolic content, starting from the fact that the higher content of phenolic compounds corresponds to the higher antioxidant indexes. This work aims to assess which compounds characterized three cultivars, namely Ferrovia, Sweetheart, and Lapins grown in Southern Italy and mainly influenced the antioxidant capacity of their extracts. HPLC-MS/ MS analyses were conducted to identify and quantify 17 flavonoids and 25 hydroxicinnamates derivatives. A significant influence of cultivar was revealed from one-way MANOVA (p < 0.05). Furthermore, the extracts were tested for their radical scavenging activity (DPPH and ABTS assays) and reducing power using the Folin-Ciocalteau method. Lapins and Sweetheart extracts, richer in phenolic compounds, returned the highest reducing power and radical scavenging capacity. Finally, a Factorial Analysis was applied to the collected data allowing reliable correlations between phenolics and antioxidant indexes