CORAL: the prediction of biodegradation of organic compounds with optimal SMILES-based descriptors

Abstract CORAL software (http:/www.insilico.eu/coral) has been used to build up quantitative structure-biodegradation relationships (QSPR). The normalized degradation percentage has been used as the measure of biodegradation (for diverse organic compounds, n=445). Six random splits into sub-training, calibration, and test sets were examined. For each split the QSPR one-variable linear regression model based on the SMILES-based optimal descriptors has been built up. The average values of numbers of compounds and the correlation coefficients (r2) between experimental and calculated biodegradability values of these six models for the test sets are n=88.2±11.7 and r2=0.728±0.05. These six models were further tested against a set of chemicals (n=285) for which only categorical values (biodegradable or not) were available. Thus we also evaluated the use of the model as a classifier. The average values of the sensitivity, specificity, and accuracy were 0.811±0.019, 0.795±0.024, and 0.803±0.008, respectively

Human-BasedNewApproachMethodologiesin DevelopmentalToxicityTesting:AStepAheadfromtheState oftheArtwithaFeto–PlacentalOrgan-on-ChipPlatform

Download PDFsettingsOrder Article Reprints Open AccessReview Human-Based New Approach Methodologies in Developmental Toxicity Testing: A Step Ahead from the State of the Art with a Feto–Placental Organ-on-Chip Platform by Michaela Luconi 1,2,†ORCID,Miguel A. Sogorb 3,†ORCID,Udo R. Markert 4ORCID,Emilio Benfenati 5,Tobias May 6,Susanne Wolbank 7ORCID,Alessandra Roncaglioni 5,Astrid Schmidt 4,Marco Straccia 8ORCID andSabrina Tait 9,*ORCID 1 Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy 2 I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Viale Medaglie d’Oro 305, 00136 Rome, Italy 3 Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Avenida de la Universidad s/n, 03202 Elche, Spain 4 Placenta Lab, Department of Obstetrics, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany 5 Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy 6 InSCREENeX GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany 7 Ludwig Boltzmann Institut for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Donaueschingenstrasse 13, 1200 Vienna, Austria 8 FRESCI by Science&Strategy SL, C/Roure Monjo 33, Vacarisses, 08233 Barcelona, Spain 9 Centre for Gender-Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy * Author to whom correspondence should be addressed. † These authors contributed equally to this work. Int. J. Environ. Res. Public Health 2022, 19(23), 15828; https://doi.org/10.3390/ijerph192315828 Submission received: 24 October 2022 / Revised: 20 November 2022 / Accepted: 25 November 2022 / Published: 28 November 2022 (This article belongs to the Section Toxicology and Public Health) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract Developmental toxicity testing urgently requires the implementation of human-relevant new approach methodologies (NAMs) that better recapitulate the peculiar nature of human physiology during pregnancy, especially the placenta and the maternal/fetal interface, which represent a key stage for human lifelong health. Fit-for-purpose NAMs for the placental–fetal interface are desirable to improve the biological knowledge of environmental exposure at the molecular level and to reduce the high cost, time and ethical impact of animal studies. This article reviews the state of the art on the available in vitro (placental, fetal and amniotic cell-based systems) and in silico NAMs of human relevance for developmental toxicity testing purposes; in addition, we considered available Adverse Outcome Pathways related to developmental toxicity. The OECD TG 414 for the identification and assessment of deleterious effects of prenatal exposure to chemicals on developing organisms will be discussed to delineate the regulatory context and to better debate what is missing and needed in the context of the Developmental Origins of Health and Disease hypothesis to significantly improve this sector. Starting from this analysis, the development of a novel human feto–placental organ-on-chip platform will be introduced as an innovative future alternative tool for developmental toxicity testing, considering possible implementation and validation strategies to overcome the limitation of the current animal studies and NAMs available in regulatory toxicology and in the biomedical field

Prediction Of The Neurotoxic Potential Of Chemicals Based On Modelling Of Molecular Initiating Events Upstream Of The Adverse Outcome Pathways Of (Developmental) Neurotoxicity

Developmental and adult/ageing neurotoxicity are an area needing alternative methods for chemical risk assessment. The formulation of a strategy to screen large numbers of chemicals is highly relevant due to potential exposure to compounds that may have long-term adverse health consequences on the nervous system, leading to neurodegeneration. Adverse Outcome Pathways (AOPs) provide information on relevant molecular initiating events (MIEs) and key events (KEs) that could inform the development of computational alternatives for these complex effects. We propose a screening method integrating multiple Quantitative Structure–Activity Relationship (QSAR) models. The MIEs of existing AOP networks of developmental and adult/ageing neurotoxicity were modelled to predict neurotoxicity. Random Forests were used to model each MIE. Predictions re-turned by single models were integrated and evaluated for their capability to predict neurotoxicity. Specifically, MIE predictions were used within various types of classifiers and compared with other reference standards (chemical descriptors and structural fingerprints) to benchmark their predictive capability. Overall, classifiers based on MIE predictions returned predictive performances compa-rable to those based on chemical descriptors and structural fingerprints. The integrated computa-tional approach described here will be beneficial for large-scale screening and prioritisation of chem-icals as a function of their potential to cause long-term neurotoxic effects

CORAL Models for Drug-Induced Nephrotoxicity

Drug-induced nephrotoxicity is a major cause of kidney dysfunction with potentially fatal consequences. The poor prediction of clinical responses based on preclinical research hampers the development of new pharmaceuticals. This emphasises the need for new methods for earlier and more accurate diagnosis to avoid drug-induced kidney injuries. Computational predictions of drug-induced nephrotoxicity are an attractive approach to facilitate such an assessment and such models could serve as robust and reliable replacements for animal testing. To provide the chemical information for computational prediction, we used the convenient and common SMILES format. We examined several versions of so-called optimal SMILES-based descriptors. We obtained the highest statistical values, considering the specificity, sensitivity and accuracy of the prediction, by applying recently suggested atoms pairs proportions vectors and the index of ideality of correlation, which is a special statistical measure of the predictive potential. Implementation of this tool in the drug development process might lead to safer drugs in the future

EFSA's OpenFoodTox: An open source toxicological database on chemicals in food and feed and its future developments

Since its creation in 2002, the European Food Safety Authority (EFSA) has produced risk assessments for over 5000 substances in >2000 Scientific Opinions, Statements and Conclusions through the work of its Scientific Panels, Units and Scientific Committee. OpenFoodTox is an open source toxicological database, available both for download and data visualisation which provides data for all substances evaluated by EFSA including substance characterisation, links to EFSA's outputs, applicable legislations regulations, and a summary of hazard identification and hazard characterisation data for human health, animal health and ecological assessments. The database has been structured using OECD harmonised templates for reporting chemical test summaries (OHTs) to facilitate data sharing with stakeholders with an interest in chemical risk assessment, such as sister agencies, international scientific advisory bodies, and others. This manuscript provides a description of OpenFoodTox including data model, content and tools to download and search the database. Examples of applications of OpenFoodTox in chemical risk assessment are discussed including new quantitative structure–activity relationship (QSAR) models, integration into tools (OECD QSAR Toolbox and AMBIT-2.0), assessment of environmental footprints and testing of threshold of toxicological concern (TTC) values for food related compounds. Finally, future developments for OpenFoodTox 2.0 include the integration of new properties, such as physico-chemical properties, exposure data, toxicokinetic information; and the future integration within in silico modelling platforms such as QSAR models and physiologically-based kinetic models. Such structured in vivo, in vitro and in silico hazard data provide different lines of evidence which can be assembled, weighed and integrated using harmonised Weight of Evidence approaches to support the use of New Approach Methodologies (NAMs) in chemical risk assessment and the reduction of animal testing

Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors

BACKGROUND: Antioxidant supplementation with vitamin E had no effect in the prevention of cardiovascular diseases (CVD) in three recent large, randomized clinical trials. In order to reassess critically the role of vitamin E in CVD prevention, it is important to establish whether these results are related to a lack of antioxidant action. METHODS: We examined the in vivo antioxidant effect of vitamin E (300 mg/day for about three years) in 144 participants in the Primary Prevention Project (females and males, aged ≥ 50 y, with at least one major CV risk factor, but no history of CVD). Urinary 8-epi-PGF(2α) (isoprostane F(2α)-III or 15-F(2t)-isoP), a validated biomarker of lipid peroxidation, was measured by mass spectrometry. RESULTS: Urinary excretion of 8-epi-PGF(2α) [pg/mg creatinine, median (range)] was 141 (67–498) in treated and 148 (76–561) in untreated subjects (p = 0.10). Taking into account possible confounding variables, multiple regression analysis confirmed that vitamin E had no significant effect on this biomarker. Levels of 8-epi-PGF(2α) were in the normal range for most subjects, except smokers and those with uncontrolled blood pressure or hyperglycemia. CONCLUSIONS: Prolonged vitamin E supplementation did not reduce lipid peroxidation in subjects with major cardiovascular risk factors. The observation that the rate of lipid peroxidation was near normal in a large proportion of subjects may help explain why vitamin E was not effective as an antioxidant in the PPP study and was ineffective for CVD prevention in large scale trials

The perception of healthcare quality of elderly in the city of Bari, South Italy

<p>Abstract</p> <p>Background</p> <p>In recent decades in Italy, as in all the industrialized nations, the proportion of elderly subjects in the total population is constantly on the increase. However the increased life expectancy is not always paralleled by a true improvement in the quality of life.</p> <p>In this context, it is essential to analyze elderly real health needs and the responses to these needs, especially in terms of healthcare, that the territorial services are perceived to offer.</p> <p>Methods</p> <p>In the period from June to September 2006 we selected randomly one General Practitioner (GP) for each district of the Bari Municipal Area and, form each GP, we randomly chose 25 patients over 65 years old (YO). We conducted phone interviews using a standard data collection questionnaire and, for each of the recruited subjects, the GP filled a data collection sheet.</p> <p>Results</p> <p>Although the mean age (73.6 years) of the population under study was quite high, the general state of health was judged good both by the G P- and by their elderly patients (>75%).</p> <p>Notably, the great majority of elderly patients considered the healthcare they receive to be satisfactory (>60%): in particular, the GP was the true point of reference for this slice of the population for strictly medical problems as well as for advice. On the contrary, the patients attributed little value to social services, which were poorly known and scarcely used (8.5%). Public hospital facilities played a central role in second level healthcare in more than 30% of cases; private facilities covered by public health insurance were also very important. As possible solutions to the problem of loneliness, 36.6% of the patients declared that they approved of nursing homes.</p> <p>Conclusion</p> <p>Decision makers need to create services supporting the key role played by General Practitioners, who are well aware that their assistance is not sufficient to satisfy the health needs of the elderly.</p

RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population

<p>Abstract</p> <p>Background</p> <p>Several polymorphisms within the renin-angiotensin system cluster of genes have been associated with the advent of coronary artery disease (CAD) or related pathologies. We investigated the distribution of 5 of these polymorphisms in order to find any association with CAD development and distinguish if any of the biochemical and behavioural factors interact with genetic polymorphisms in the advent of the disease.</p> <p>Methods</p> <p><it>ACE </it>I/D (rs4340), <it>ACE </it>A11860G (rs4343), <it>AT1R </it>A1166C (rs5186), <it>AGT </it>T174M (rs4762) and <it>AGT </it>M235T (rs699) gene polymorphisms were PCR-RFLP analysed in 298 CAD patients and 510 controls from Portugal. Several biochemical and behavioural markers were obtained.</p> <p>Results</p> <p><it>ACE </it>I/D DD and <it>ACE</it>11860 GG genotypes are risk factors for CAD in this population. The simultaneous presence of <it>ACE </it>I/D I and <it>ACE</it>11860 A alleles corresponds to a significant trend towards a decrease in CAD incidence. We found several synergistic effects between the studied polymorphisms and classical risk factors such as hypertension, obesity, diabetes and dyslipidaemia: the presence of the DD genotype of <it>ACE </it>I/D (and also <it>ACE</it>11860 GG) increases the odds of developing CAD when associated to each one of these classical risk factors, particularly when considering the male and early onset CAD subgroup analysis; <it>AGT</it>235 TT also increases the CAD risk in the presence of hypertension and dyslipidaemia, and <it>AT1R</it>1166 interacts positively with hypertension, smoking and obesity.</p> <p>Conclusion</p> <p><it>ACE </it>polymorphisms were shown to play a major role in individual susceptibility to develop CAD. There is also a clear interaction between RAS predisposing genes and some biochemical/environmental risk factors in CAD onset, demonstrating a significant enhancement of classical markers particularly by <it>ACE </it>I/D and <it>ACE</it>11860.</p