European waste management regulations and the transition towards circular economy. A shift-and-share analysis.

Environmental legislation in the European Union (EU) aims to bolster the transition towards circular economy. However, a recurring limitation in EU regulations, encompassing not only environmental but also economic, social, and demographic aspects, is the lack of consideration for the unique characteristics of individual Member States when establishing common targets. The present work seeks to investigate the impact of EU waste management regulations on the attainment of circular economy objectives, taking into account national-level socio-economic and demographic characteristics. In order to do so, we employ Shift-and-Share Analysis, using data on 28 EU countries between 1995 and 2018. Our findings indicate that some Member States, namely Estonia, Finland, Hungary, Ireland, Italy, Luxembourg and Slovenia, effectively managed to align their regulatory frameworks with EU directives and create a socio-economic context where citizens and governmental bodies foster the necessary levels of cooperation. Cooperation in turn, with widespread pro-environmental attitudes on part of citizens, efficient waste management on part of specialised firms and proper oversight of waste collection activities on part of institutions, facilitated the achievement of significant circular economy goals.

Dissecting CYP1A2 Activation by Arylalkanoic Acid Prodrugs toward the Development of Anti-Inflammatory Agents.

Arylalkane-derived prodrugs of arylacetic acids are a small group of substances that have long been known for their anti-inflammatory action. Despite their ease of synthesis and good potential for the development of new potent and safe anti-inflammatory agents, this group of substances has not received much attention from researchers so far. Therefore, representative arylalkane derivatives were investigated through molecular docking techniques to verify the possible hepatic activation mode toward active metabolites by CYP1A2. In this regard, arylalkanoic acid prodrugs were docked with a crystallographic structure of human CYP1A2, in which the enzyme is co-crystallized with the selective competitive inhibitor α-naphthoflavone BHF. Of note, all the examined compounds proved capable of interacting with the enzyme active site in a manner similar to Nabumetone, thus confirming that a productive metabolic transformation is feasible. On the basis of these findings, it is possible to argue that subtle differences in the way CYP1A2 accommodates the ligands depend on the fine details of their molecular structures. Overall, these data suggest that compounds simply formed by an aromatic moiety bearing an appropriate alkane-derived chain could lead to innovative anti-inflammatory agents.

Multivariate Curve Resolution Methodology Applied to the ATR-FTIR Data for Adulteration Assessment of Virgin Coconut Oil.

Virgin coconut oil (VCO) is a functional food with important health benefits. Its economic interest encourages fraudsters to deliberately adulterate VCO with cheap and low-quality vegetable oils for financial gain, causing health and safety problems for consumers. In this context, there is an urgent need for rapid, accurate, and precise analytical techniques to detect VCO adulteration. In this study, the use of Fourier transform infrared (FTIR) spectroscopy combined with multivariate curve resolution-alternating least squares (MCR-ALS) methodology was evaluated to verify the purity or adulteration of VCO with reference to low-cost commercial oils such as sunflower (SO), maize (MO) and peanut (PO) oils. A two-step analytical procedure was developed, where an initial control chart approach was designed to assess the purity of oil samples using the MCR-ALS score values calculated on a data set of pure and adulterated oils. The pre-treatment of the spectral data by derivatization with the Savitzky-Golay algorithm allowed to obtain the classification limits able to distinguish the pure samples with 100% of correct classifications in the external validation. In the next step, three calibration models were developed using MCR-ALS with correlation constraints for analysis of adulterated coconut oil samples in order to assess the blend composition. Different data pre-treatment strategies were tested to best extract the information contained in the sample fingerprints. The best results were achieved by derivative and standard normal variate procedures obtaining RMSEP and RE% values in the ranges of 1.79-2.66 and 6.48-8.35%, respectively. The models were optimized using a genetic algorithm (GA) to select the most important variables and the final models in the external validations gave satisfactory results in quantifying adulterants, with absolute errors and RMSEP of less than 4.6% and 1.470, respectively.

Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation.

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.

Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties.

In past decades, anticancer research has led to remarkable results despite many of the approved drugs still being characterized by high systemic toxicity mainly due to the lack of tumor selectivity and present pharmacokinetic drawbacks, including low water solubility, that negatively affect the drug circulation time and bioavailability. The stability studies, performed in mild conditions during their development or under stressing exposure to high temperature, hydrolytic medium or light source, have demonstrated the sensitivity of anticancer drugs to many parameters. For this reason, the formation of degradation products is assessed both in pharmaceutical formulations and in the environment as hospital waste. To date, numerous formulations have been developed for achieving tissue-specific drug targeting and reducing toxic side effects, as well as for improving drug stability. The development of prodrugs represents a promising strategy in targeted cancer therapy for improving the selectivity, efficacy and stability of active compounds. Recent studies show that the incorporation of anticancer drugs into vesicular systems, such as polymeric micelles or cyclodextrins, or the use of nanocarriers containing chemotherapeutics that conjugate to monoclonal antibodies can improve solubility, pharmacokinetics, cellular absorption and stability. In this study, we summarize the latest advances in knowledge regarding the development of effective highly stable anticancer drugs formulated as stable prodrugs or entrapped in nanosystems.

Pediatric nurses in pediatricians' offices: a survey for primary care pediatricians.

BACKGROUND: The role played by nurses in caring for children in pediatricians' officies in the community is crucial to ensure integrated care. In Italy, pediatricians are responsible for the health of children aged 0-14 years living in the community. This study aimed to describe Italian primary care pediatricians' opinions about the usefulness of several nursing activities that pediatric nurses could perform in pediatricians' offices. METHODS: An online survey with pediatricians working in primary care in Italy was conducted between April-December 2018. A 40-item questionnaire was used to assess four types of nursing activities: clinical care, healthcare education, disease prevention, and organizational activities. The answers ranged from 1 (not useful at all) to 6 (very useful). Moreover, three open-ended questions completed the questionnaire. RESULTS: Overall, 707 pediatricians completed the online survey. Participants were mainly female (63%), with a mean age of 57.74 (SD = 6.42). The presence of a pediatric nurse within the pediatrician's office was considered very useful, especially for healthcare education (Mean 4.90; SD 1.12) and disease prevention (Mean 4.82; SD 1.11). Multivariate analysis confirmed that pediatricians 'with less working experience', 'having their office in a small town', and 'collaborating with a secretary and other workers in the office' rated the nurse's activities significantly more useful. CONCLUSIONS: A pediatric nurse in the pediatrician's office can significantly contribute to many activities for children and their families in the community. These activities include clinical care, healthcare education, disease prevention, and the organizational processes of the office. Synergic professional activity between pediatricians and pediatric nurses could ensure higher health care standards in the primary care setting.

Photodegradation of Anti-Inflammatory Drugs: Stability Tests and Lipid Nanocarriers for Their Photoprotection.

The present paper provides an updated overview of the methodologies applied in photodegradation studies of non-steroidal anti-inflammatory drugs. Photostability tests, performed according to international standards, have clearly demonstrated the photolability of many drugs belonging to this class, observed during the preparation of commercial forms, administration or when dispersed in the environment. The photodegradation profile of these drugs is usually monitored by spectrophotometric or chromatographic techniques and in many studies the analytical data are processed by chemometric procedures. The application of multivariate analysis in the resolution of often-complex data sets makes it possible to estimate the pure spectra of the species involved in the degradation process and their concentration profiles. Given the wide use of these drugs, several pharmaceutical formulations have been investigated to improve their photostability in solution or gel, as well as the pharmacokinetic profile. The use of lipid nanocarriers as liposomes, niosomes or solid lipid nanoparticles has demonstrated to both minimize photodegradation and improve the controlled release of the entrapped drugs.

Polyphenols from Citrus Tacle® Extract Endowed with HMGCR Inhibitory Activity: An Antihypercholesterolemia Natural Remedy.

Tacle® is a citrus fruit obtained from the crossbreeding of Clementine and Tarocco cultivars. This fruit retains a promising nutraceutical potential most likely due to a high content in polyphenols, among which the main constituents are the two glycosides naringin and hesperidin. Herein, we evaluated, through an in vitro assay, the capability of Tacle extracts to inhibit the hydroxymethylglutaryl-CoA reductase enzyme, which plays a key role in cholesterol biosynthesis. The results obtained spurred us to investigate whether the anti-enzymatic activity observed may be due to a direct interaction of aglycones naringenin and hesperetin with the enzyme catalytic site. Molecular docking simulations indicated that these two compounds are able to anchor to the protein with binding modes and affinities similar to those found for statins, which represent mainstream medications against hypercholesterolemia. The overall results showed an interesting nutraceutical potential of Tacle, suggesting that its extract could be used for dietary supplementation in the treatment of moderate hypercholesterolemia.

Toward Multitasking Pharmacological COX-Targeting Agents: Non-Steroidal Anti-Inflammatory Prodrugs with Antiproliferative Effects.

The antitumor activity of certain anti-inflammatory drugs is often attributed to an indirect effect based on the inhibition of COX enzymes. In the case of anti-inflammatory prodrugs, this property could be attributed to the parent molecules with mechanism other than COX inhibition, particularly through formulations capable of slowing down their metabolic conversion. In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents.

CCR5/CXCR4 Dual Antagonism for the Improvement of HIV Infection Therapy.

HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy.

Identification by Molecular Docking ofHomoisoflavones from Leopoldia comosa as Ligands of Estrogen Receptors.

The physiological responses to estrogen hormones are mediated within specific tissues by at least two distinct receptors, ER and ER. Several natural and synthetic molecules show activity by interacting with these proteins. In particular, a number of vegetal compounds known as phytoestrogens shows estrogenic or anti-estrogenic activity. The majority of these compounds belongs to the isoflavones family and the most representative one, genistein, shows anti-proliferative effects on various hormone-sensitive cancer cells, including breast, ovarian and prostate cancer. In this work we describe the identification of structurally related homoisoflavones isolated from Leopoldia comosa (L.) Parl. (L. comosa), a perennial bulbous plant, potentially useful as hormonal substitutes or complements in cancer treatments. Two of these compounds have been selected as potential ligands of estrogen receptors (ERs) and the interaction with both isoforms of estrogen receptors have been investigated through molecular docking on their crystallographic structures. The results provide evidence of the binding of these compounds to the target receptors and their interactions with key residues of the active sites of the two proteins, and thus they could represent suitable leads for the development of novel tools for the dissection of ER signaling and the development of new pharmacological treatments in hormone-sensitive cancers.

Selective Nanotrench Filling by One-Pot Electroclick Self-Constructed Nanoparticle Films.

Integration of nanoparticles (NPs) into nanodevices is a challenge for enhanced sensor development. Using NPs as building blocks, a bottom-up approach based on one-pot morphogen-driven electroclick chemistry is reported to self-construct dense and robust conductive Fe3O4 NP films. Deposited covalent NP assemblies establish an electrical connection between two gold electrodes separated by a 100 nm-wide nanotrench.

Multivariate Approaches in Quantitative Structure-Property Relationships Study for the Photostability Assessment of 1,4-Dihydropyridine Derivatives.

1,4-dihydropyridines (1,4-DHPs) are widely recognized as highly effective L-type calcium channel blockers with significant therapeutic benefits in the treatment of cardiovascular disorders. 1,4-DHPs can also target T-type calcium channels, making them promising drug candidates for neurological conditions. When exposed to light, all 1,4-DHPs tend to easily degrade, leading to an oxidation product derived from the aromatization of the dihydropyridine ring. Herein, the elaboration of a quantitative structure-property relationships (QSPR) model was carried out by correlating the light sensitivity of structurally different 1,4-DHPs with theoretical molecular descriptors. Photodegradation experiments were performed by exposing the drugs to a Xenon lamp following the ICH rules. The degradation was monitored by spectrophotometry, and experimental data were elaborated by Multivariate Curve Resolution (MCR) methodologies to assess the kinetic rates. The results were confirmed by the HPLC-DAD method. PaDEL-Descriptor software was used to calculate molecular descriptors and fingerprints related to the chemical structures. Seventeen of the 1875 molecular descriptors were selected and correlated to the photodegradation rate by means of the Ordinary Least Squares (OLS) algorithm. The chemometric model is useful to predict the photosensitivity of other 1,4-DHP derivatives with a very low relative error percentage of 5.03% and represents an effective tool to design new analogs characterized by higher photostability.

Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents.

The biochemical role of the PI3K/PKB/mTOR signalling pathway in cell-cycle regulation is now well known. During the onset and development of different forms of cancer it becomes overactive reducing apoptosis and allowing cell proliferation. Therefore, this pathway has become an important target for the treatment of various forms of malignant tumors, including breast cancer and follicular lymphoma. Recently, several more or less selective inhibitors targeting these proteins have been identified. In general, drugs that act on multiple targets within the entire pathway are more efficient than single targeting inhibitors. Multiple inhibitors exhibit high potency and limited drug resistance, resulting in promising anticancer agents. In this context, the present survey focuses on small molecule drugs capable of modulating the PI3K/PKB/mTOR signalling pathway, thus representing drugs or drug candidates to be used in the pharmacological treatment of different forms of cancer.

Impact of aryloxy-linked quinazolines: a novel series of selective VEGFR-2 receptor tyrosine kinase inhibitors.

Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds have been evaluated for their enzymatic inhibition of VEGFR-2 and EGFR and for their antiproliferative activities on various cancer cell lines. We have studied the impact of the variation in the 4-position substitution of the quinazoline core. Substitution by aryloxy groups led to new compounds which are selective inhibitors of VEGFR-2 enzyme with IC(50) values in the nanomolar range in vitro.

Use of Pluronic Surfactants in Gel Formulations of Photosensitive 1,4-Dihydropyridine Derivatives: A Potential Approach in the Treatment of Neuropathic Pain.

1,4-Dihydropyridines (DHPs) are the most important class of L-type calcium channel blockers that are employed for the treatment of cardiovascular diseases, particularly hypertension. Various modifications on this scaffold lead to the discovery of new DHPs blocking different types of calcium channels. Among them, the T-type calcium channel has recently attracted great interest due to its role in chronic pain conditions. In this study, we selected three newly synthesized DHPs (HM8, HM10 and MD20) with different selectivity profiles to the T-type calcium channel and formulated them in micellar solutions and micellar-in-gel matrices to be tested for potential topical use in the treatment of neuropathic pain. To prevent the well-known sensitivity to light of the DHPs, the studied compounds were entrapped in colloidal aggregates obtained by using edible Pluronic® surfactants and adding α-tocopherol as an antioxidant. All the prepared formulations were exposed to stressing light, according to international rules. Along with the degradation experiments, the concentrations of the parent compounds and by-products were calculated by multivariate curve resolution-alternating least squares (MCR-ALS) applied to the spectral data. The defined formulations proved suitable as light-stable matrices for the DHP compounds, showing an increase in stability for HM8 and MD20 and an almost complete photoprotection for HM10, compared to ethanol solutions and standard gel formulations.

Cateslytin abrogates lipopolysaccharide-induced cardiomyocyte injury by reducing inflammation and oxidative stress through toll like receptor 4 interaction.

Global public health is threatened by new pathogens, antimicrobial resistant microorganisms and a rapid decline of conventional antimicrobials efficacy. Thus, numerous medical procedures become life-threating. Sepsis can lead to tissue damage such as myocardium inflammation, associated with reduction of contractility and diastolic dysfunction, which may cause death. In this perspective, growing interest and attention are paid on host defence peptides considered as new potential antimicrobials. In the present study, we investigated the physiological and biochemical properties of Cateslytin (Ctl), an endogenous antimicrobial chromogranin A-derived peptide, in H9c2 cardiomyocytes exposed to lipopolysaccharide (LPS) infection. We showed that both Ctl (L and D) enantiomers, but not their scrambled counterparts, significantly increased cardiomyocytes viability following LPS, even if L-Ctl was effective at lower concentration (1 nM) compared to D-Ctl (10 nM). L-Ctl mitigated LPS-induced LDH release and oxidative stress, as visible by a reduction of MDA and protein carbonyl groups content, and by an increase of SOD activity. Molecular docking simulations strongly suggested that L-Ctl modulates TLR4 through a direct binding to the partner protein MD-2. Molecular analyses indicated that the protection mediated by L-Ctl against LPS-evoked sepsis targeted the TLR4/ERK/JNK/p38-MAPK pathway, regulating NFkB p65, NFkB p52 and COX2 expression and repressing the mRNA expression levels of the LPS-induced proinflammatory factors IL-1ß, IL-6, TNF-α and NOS2. These findings indicate that Ctl could be considered as a possible candidate for the development of new antimicrobials strategies in the treatment of myocarditis. Interestingly, L-enantiomeric Ctl showed remarkable properties in strengthening the anti-inflammatory and anti-oxidant effects on cardiomyocytes.

Interaction of cationic nickel and manganese porphyrins with the minor groove of DNA.

The capacity of a series of new cationic nickel and manganese metalloporphyrins to bind in the minor groove of DNA was evaluated by binding competition experiments with manganese(III)-bis-aqua-meso-tetrakis(4-N-methylpyridiniumyl)porphyrin, Mn-TMPyP, a powerful artificial nuclease when associated with KHSO(5). The four N-methylpyridiniumyl substituents on this porphyrin macrocycle are responsible for a strong binding affinity for the minor groove of AT-rich DNA. The inhibition of DNA cleavage mediated by Mn-TMPyP/KHSO(5) by the various tested porphyrins correlated with their competitive occupancy of the minor groove site of Mn-TMPyP. Introduction of long and flexible cationic substituents at the periphery of the porphyrin macrocycle precluded the interaction of the porphyrin derivative in the minor groove and resulted in low affinity for DNA. On the other hand, introduction of phenylpyridiniumyl substituents on the porphyrin macrocycle surprisingly conferred the new porphyrin derivative with a tight binding in the minor groove of a six consecutive AT base pairs sequence. These data on structural requirements for minor groove DNA binding will help the rational design of porphyrin derivatives for selective targeting of quadruplex DNA versus double-stranded DNA.

Quinazoline-urea, new protein kinase inhibitors in treatment of prostate cancer.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), two protein tyrosine kinases, are involved in pathological disorders and the progression of different types of carcinomas. Concomitant inhibition of both tyrosine kinase activities appears to be an attractive target for cancer chemotherapy. A series of new quinazoline derivatives substituted by amide, urea, or carbamic acid ester groups have been synthesized. The biological activities of these new compounds have been evaluated for their enzyme inhibition and antiproliferative activities.

Triazolopyrimidinium salts: discovery of a new class of agents for cancer therapy.

Aim: The [1,2,4]triazolo[1,5-a]pyrimidine core is highly privileged in medicinal chemistry due to its versatile pharmacological activity profile. Recently, the search for novel anticancer agents has focused on [1,2,4]triazolo[1,5-a]pyrimidine derivatives. Results: Our hit functionalization has led to the discovery of new [1,2,4]triazolo[1,5-a]pyrimidinium salts with potential anticancer activity. Among a small library of molecules, compound 9 significantly inhibits cancer cell growth in a panel of in vitro models. Molecular docking studies and preliminary binding assay have displayed that 9 could directly bind the Src homology 2 (SH2) domain of STAT3 protein. Conclusion: Compound 9 is a novel promising lead compound that motivates additional evaluation of [1,2,4]triazolo[1,5-a]pyrimidinium salts as novel potential chemotherapeutics.