Curcumin-Based β-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm).Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therap

The Effect of Curcumin on Idiopathic Parkinson Disease: A Clinical and Skin Biopsy Study

There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients

First Results of the “Carbonaceous Aerosol in Rome and Environs (CARE)” Experiment: Beyond Current Standards for PM10

In February 2017 the “Carbonaceous Aerosol in Rome and Environs (CARE)” experiment was carried out in downtown Rome to address the following specific questions: what is the color, size, composition, and toxicity of the carbonaceous aerosol in the Mediterranean urban background area of Rome? The motivation of this experiment is the lack of understanding of what aerosol types are responsible for the severe risks to human health posed by particulate matter (PM) pollution, and how carbonaceous aerosols influence radiative balance. Physicochemical properties of the carbonaceous aerosol were characterised, and relevant toxicological variables assessed. The aerosol characterisation includes: (i) measurements with high time resolution (min to 1–2 h) at a fixed location of black carbon (eBC), elemental carbon (EC), organic carbon (OC), particle number size distribution (0.008–10 μ m), major non refractory PM1 components, elemental composition, wavelength-dependent optical properties, and atmospheric turbulence; (ii) 24-h measurements of PM10 and PM2.5 mass concentration, water soluble OC and brown carbon (BrC), and levoglucosan; (iii) mobile measurements of eBC and size distribution around the study area, with computational fluid dynamics modeling; (iv) characterisation of road dust emissions and their EC and OC content. The toxicological assessment includes: (i) preliminary evaluation of the potential impact of ultrafine particles on lung epithelia cells (cultured at the air liquid interface and directly exposed to particles); (ii) assessment of the oxidative stress induced by carbonaceous aerosols; (iii) assessment of particle size dependent number doses deposited in different regions of the human body; (iv) PAHs biomonitoring (from the participants into the mobile measurements). The first experimental results of the CARE experiment are presented in this paper. The objective here is to provide baseline levels of carbonaceous aerosols for Rome, and to address future research directions. First, we found that BC and EC mass concentration in Rome are larger than those measured in similar urban areas across Europe (the urban background mass concentration of eBC in Rome in winter being on average 2.6 ± 2.5 μ g · m − 3 , mean eBC at the peak level hour being 5.2 (95% CI = 5.0–5.5) μ g · m − 3 ). Then, we discussed significant variations of carbonaceous aerosol properties occurring with time scales of minutes, and questioned on the data averaging period used in current air quality standard for PM 10 (24-h). Third, we showed that the oxidative potential induced by aerosol depends on particle size and composition, the effects of toxicity being higher with lower mass concentrations and smaller particle size. Albeit this is a preliminary analysis, findings reinforce the need for an urgent update of existing air quality standards for PM 10 and PM 2.5 with regard to particle composition and size distribution, and data averaging period. Our results reinforce existing concerns about the toxicity of carbonaceous aerosols, support the existing evidence indicating that particle size distribution and composition may play a role in the generation of this toxicity, and remark the need to consider a shorter averaging period (<1 h) in these new standards

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk

Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells

Dottorato di Ricerca in Medicina Traslazionale. Ciclo XXIXInsulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGFI promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategiesUniversità della Calabri

Esposizione a nanoparticelle di rame in ambienti indoor

L'inquinamento atmosferico è motivo di grande preoccupazione per la salute pubblica e uno dei maggiori fattori di rischio per l'ambiente e la salute umana in tutto il mondo [1]. L'inquinamento dell'aria outdoor è stato riconosciuto come cancerogeno per l'uomo [2]. Tuttavia, l'aria indoor può essere più inquinata di quella outdoor [3]. Recentemente, diversi studi hanno mostrato che l'uso di alcuni elettrodomestici e apparecchi con motori elettrici a spazzola (trapani, aspirapolveri etc.) contribuisce all'inquinamento indoor da particolato atmosferico (PM), aumentando significativamente i livelli di particelle ultrafini e nanoparticelle (NPs) [3]. A causa della scarica dell'arco elettrico durante il funzionamento di tali motori, alcune NPs contengono rame (Cu), un elemento che sembra svolgere un ruolo importante nell’eziopatogenesi della malattia di Alzheimer. Inoltre, si ipotizza che le NPs, a causa delle loro dimensioni, possano traslocare al cervello attraverso il bulbo olfattivo. Il presente studio è stato eseguito per indagare la morfologia e la composizione delle particelle emesse da alcuni elettrodomestici usati quotidianamente in ambienti indoor e monitorare per un lungo periodo la contaminazione da Cu in ambienti indoor a causa di questo tipo di apparecchi. La caratterizzazione morfologica e chimica tramite microscopio elettronico a scansione con sorgente a emissione di campo (HR-FESEM) ha confermato la presenza di NPs, che sono state osservate sia come particelle singole (20-40 nm) che aggregate a formare particelle di dimensioni dell'ordine dei μm [3]. La microanalisi a dispersione di energia con rivelatore a raggi X (XEDS) ha evidenziato la presenza di Cu insieme ad altri elementi [3]. La contaminazione giornaliera negli ambienti indoor dovuta all’uso di apparecchi con motori elettrici a spazzola è stata confermata monitorando per un anno il contenuto di Cu in campioni di PM10 raccolti in abitazioni private. I risultati hanno evidenziato che la popolazione generale può essere cronicamente esposta a NPs di Cu in ambienti indoor e ciò non può essere trascurato visti i possibili effetti avversi per la salute umana determinati dall’esposizione a NPs e del ruolo del Cu nello sviluppo di disturbi neurologici

Reusable Water Bottles: Release of Inorganic Elements, Phthalates, and Bisphenol A in a “Real Use” Simulation Experiment

Reusable water bottles are growing in popularity; thus, possible chemical release from the internal surface into water should be carefully considered to control related health risks. We experimentally evaluated the release into deionized water of 40 elements, six phthalates, and bisphenol‐A for 20 different reusable bottles by simulating the use in real world scenario. The 20 bottles, identified as those most purchased in Italy, were made of various materials (stainless steel, aluminum, plastic, and silicone). The experiment was carried out for four consecutive weeks in duplicate for each type of bottle. Our results showed the release, to various extents, of inorganic elements from all 20 bottles, while the release of phthalates and bisphenol‐A was never found. The elements most frequently released were Al, Sr, Mo, and Cr, while the highest concentrations were for Ca, K, Mg, and Na; the release of toxic elements (such as Pb, Cd, Ni, Sb) also occurred. The comparison of our results with regulatory limits on drinking water quality revealed no exceeding values except for Al. However, these releases represent a further intake, and the related risks cannot be neglected, especially for highly susceptible populations. Thus, it is essential to correctly inform consumers both with dedicated interventions and exhaustive labelling