Serendipitous Identification of Azine Anticancer Agents Using a Privileged Scaffold Morphing Strategy.

The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation.

Asymmetric Reduction of Cyclic Imines by Imine Reductase Enzymes in Non-Conventional Solvents.

The first enantioselective reduction of 2-substituted cyclic imines to the corresponding amines (pyrrolidines, piperidines, and azepines) by imine reductases (IREDs) in non-conventional solvents is reported. The best results were obtained in a glycerol/phosphate buffer 1 : 1 mixture, in which heterocyclic amines were produced with full conversions (>99 %), moderate to good yields (22-84 %) and excellent S-enantioselectivities (up to >99 % ee). Remarkably, the process can be performed at a 100 mM substrate loading, which, for the model compound, means a concentration of 14.5 g L-1 . A fed-batch protocol was also developed for a convenient scale-up transformation, and one millimole of substrate 1 a was readily converted into 120 mg of enantiopure amine (S)-2 a with a remarkable 80 % overall yield. This aspect strongly contributes to making the process potentially attractive for large-scale applications in terms of economic and environmental sustainability for a good number of substrates used to produce enantiopure cyclic amines of high pharmaceutical interest.

Synthesis of Artesunic Acid-Coumarin Hybrids as Potential Antimelanoma Agents.

Current therapy against melanoma relies on surgical treatment or, in alternative, on conventional drug therapy. Often these therapeutic agents are ineffective due to the development of resistance phenomena. For this purpose, chemical hybridization emerged as an effective strategy to overcome the development of drug resistance. In this study, a series of molecular hybrids were synthesized combining the sesquiterpene artesunic acid with a panel of phytochemical coumarins. Cytotoxicity, antimelanoma effect, and cancer selectivity of the novel compounds were evaluated by MTT assay on primary and metastatic cells and on healthy fibroblasts as a reference. The two most active compounds showed lower cytotoxicity and higher activity against metastatic melanoma than paclitaxel and artesunic acid. Further tests, including cellular proliferation, apoptosis, confocal microscopy, and MTT analyses in the presence of an iron chelating agent, were conducted with the aim of tentatively addressing the mode of action and the pharmacokinetic profile of selected compounds.

A Green Blue LED-Driven Two-Liquid-Phase One-Pot Procedure for the Synthesis of Estrogen-Related Quinol Prodrugs.

Quinol derivatives of estrogens are effective pro-drugs in steroid replacement therapy. Here, we report that these compounds can be synthesized in one-pot conditions and high yield by blue LED-driven photo-oxygenation of parent estrogens. The oxidation was performed in buffer and eco-certified 2-methyltetrahydrofuran as the two-liquid-phase reaction solvent, and in the presence of meso-tetraphenyl porphyrin as the photosensitizer. Two steroidal prodrugs 10ß, 17ß-dihydroxyestra-1,4-dien-3-one (DHED) and 10ß-Hydroxyestra-1,4-diene-3,17-dione (HEDD) were obtained with high yield and selectivity.

Unsupervised clustering reveals phenotypes of AKI in ICU COVID-19 patients.

Background: Acute Kidney Injury (AKI) is a very frequent condition, occurring in about one in three patients admitted to an intensive care unit (ICU). AKI is a syndrome defined as a sudden decrease in glomerular filtration rate. However, this unified definition does not reflect the various mechanisms involved in AKI pathophysiology, each with its own characteristics and sensitivity to therapy. In this study, we aimed at developing an innovative machine learning based method able to subphenotype AKI according to its pattern of risk factors. Methods: We adopted a three-step pipeline of analyses. First, we looked for factors associated with AKI using a generalized additive model. Second, we calculated the importance of each identified AKI related factor in the estimated AKI risk to find the main risk factor for AKI, at the single patient level. Lastly, we clusterized AKI patients according to their profile of risk factors and compared the clinical characteristics and outcome of every cluster. We applied this method to a cohort of severe COVID-19 patients hospitalized in the ICU of the Geneva University Hospitals. Results: Among the 248 patients analyzed, we found 7 factors associated with AKI development. Using the individual expression of these factors, we identified three groups of AKI patients, based on the use of Lopinavir/Ritonavir, baseline eGFR, use of dexamethasone and AKI severity. The three clusters expressed distinct characteristics in terms of AKI severity and recovery, metabolic patterns and hospital mortality. Conclusion: We propose here a new method to phenotype AKI patients according to their most important individual risk factors for AKI development. When applied to an ICU cohort of COVID-19 patients, we were able to differentiate three groups of patients. Each expressed specific AKI characteristics and outcomes, which probably reflect a distinct pathophysiology.

Can consumer food choices contribute to reduce environmental impact? The case of cisgenic apples.

In the last decade, cisgenic breeding emerged as a valuable alternative to transgenic genetic modification. Cisgenesis allows to obtain disease-resistant crops, thus reducing the need of chemical pesticides in the fields. This would imply a reduction of the environmental impact deriving from agricultural production. To concretely exploit the potential deriving from such biotechnology application, consumers' willingness to buy and consume such food is an essential matter. In this study we explore consumer choice behavior for cisgenic vs conventional apple alternatives through a hypothetical Choice Experiment, meanwhile examining attribute non-attendance behaviors. The Latent Class Model estimates reveal considerable differences across population segments in terms of choice behavior and preferences. In fact, while some consumers choose based on this attribute, a sizable segment of the population ignores it, suggesting that there may be room on the market for these products with potential implications in terms of environmental and food policy formulation.

Changing attitudes towards healthy food via self-association or nutritional information: What works best?

Individual attitudes, both implicit and explicit, have been identified as one of the multiple drivers of consumer behaviors, including food-related ones. Building on such evidence, in this contribution we seek at increasing implicit and explicit consumer attitudes towards a healthy food, comparing the effectiveness of two different treatments. The former is based on a self-association task, that aims at inducing changes in the evaluation of an object thanks to its positive association with the self. The latter is based on information provision. We test if attitude formation can be moderated by the individual level of nutritional knowledge and health-concern. Additionally, we explored whether the study conditions applied could ultimately affect consumers' preferences for specific product attributes using a Discrete Choice Experiment. The main findings provide insights for future policy strategies aimed at promoting more healthful food consumption. Indeed, the self-association increased implicit attitudes and consumer preferences' towards healthy food, whereas information, that represents the main target of food policy interventions, seems to have no impact on individual attitudes and choice behaviors.

Exploring the Adherence to the Mediterranean Diet and Its Relationship with Individual Lifestyle: The Role of Healthy Behaviors, Pro-Environmental Behaviors, Income, and Education.

The reduction of diet-related diseases and the improvement of environmental sustainability represent two of the major 21st century food policy challenges. Sustainable diets could significantly contribute to achieving both of these goals, improving consumer health and reducing the environmental impact of food production and consumption. The Mediterranean diet (MD) represents an excellent example of sustainable diet, however recent evidence indicates that such a dietary pattern is now progressively disappearing in Mediterranean countries. In such a context, this paper explores how individual lifestyle and habits are related to a high/low adherence to the MD model. The goal is to examine whether there is a relationship between individuals' healthy and pro-environmental behaviors and their level of adherence to the MD. The analysis also explores the role of consumer income and education. The study is based on the Italian population (n = 42,000) and uses a structural equation model approach. The results outline that the MD is part of a sustainability-oriented lifestyle and stress the key role of both income and education in affecting adherence to MD. Future policy aimed at contrasting the gradual disappearance of the MD should emphasize the sustainable dimension of the MD, meanwhile reducing socio-economic disparities among different population segments.

Effects of neuromuscular blockers on transpulmonary pressures in moderate to severe acute respiratory distress syndrome.

PURPOSE: To investigate whether neuromuscular blocking agents (NMBA) exert beneficial effects in acute respiratory distress syndrome (ARDS) by reason of their action on respiratory mechanics, particularly transpulmonary pressures (P L). METHODS: A prospective randomised controlled study in patients with moderate to severe ARDS within 48 h of the onset of ARDS. All patients were monitored by means of an oesophageal catheter and followed up for 48 h. Moderate ARDS patients were randomised into two groups according to whether they were given a 48-h continuous infusion of cisatracurium besylate or not (control group). Severe ARDS patients did not undergo randomisation and all received cisatracurium besylate per protocol. The changes during the 48-h study period in oxygenation and in respiratory mechanics, including inspiratory and expiratory P L and driving pressure, were assessed and compared. Delta P L (∆P L) was defined as inspiratory P L minus expiratory P L. RESULTS: Thirty patients were included, 24 with moderate ARDS and 6 with severe ARDS. NMBA infusion was associated with an improvement in oxygenation in both moderate and severe ARDS, accompanied by a decrease in both plateau pressure and total positive end-expiratory pressure. The mean inspiratory and expiratory P L were higher in the moderate ARDS group receiving NMBA than in the control group. In contrast, there was no change in either driving pressure or ∆P L related to NMBA administration. CONCLUSIONS: NMBA could exert beneficial effects in patients with moderate ARDS, at least in part, by limiting expiratory efforts.

Healthy-unhealthy weight and time preference. Is there an association? An analysis through a consumer survey.

Individual time preference has been recognized as key driver in explaining consumers' probability to have a healthy weight or to incur excess weight problems. The term time preference refers to the rate at which a person is disposed to trade a current satisfaction for a future benefit. This characteristic may affect the extent at which individuals invest in health and may influence diet choices. The purpose of this paper is to analyse which could be the role of time preference (measured in terms of diet-related behaviours) in explaining consumers' healthy or unhealthy body weight. The analysis also considers other drivers predicted to influence BMI, specifically information searching, health-related activities and socio-demographic conditions. The survey was based on face-to-face interviews on a sample of 240 consumers living in Milan. In order to test the hypothesis, we performed a set of seven ORM regressions, all having consumers' BMI as the dependent variable. Each ORM contains a different block of explanatory variables, while time preference is always included among the regressors. The results suggest that the healthy weight condition is associated with a high orientation to the future, with a high interest in nutrition claims, a low attention to health-related claims, and a high level of education. On the opposite, the probability to be overweight or obese increases when consumers are less future-concerned and is associated with a low searching for nutrition claims and to a high interest in health claims.