Rational design, efficient syntheses and biological evaluation of N,N′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (–logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (–logIC50 = 9.04) and the sodium (–logIC50 = 8.54) salts of 4-butyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (–logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (–logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (–logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (–logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (–logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy

In Vitro Toxicological Insights from the Biomedical Applications of Iron Carbide Nanoparticles in Tumor Theranostics:A Systematic Review and Meta-Analysis

(1) Background: Despite the encouraging indications regarding the suitability (biocompatibility) of iron carbide nanoparticles (ICNPs) in various biomedical applications, the published evidence of their biosafety is dispersed and relatively sparse. The present review synthesizes the existing nanotoxicological data from in vitro studies relevant to the diagnosis and treatment of cancer. (2) Methods: A systematic review was performed in electronic databases (PubMed, Scopus, and Wiley Online Library) on December 2023, searching for toxicity assessments of ICNPs of different sizes, coatings, and surface modifications investigated in immortalized human and murine cell lines. The risk of bias in the studies was assessed using the ToxRTool for in vitro studies. (3) Results: Among the selected studies (n = 22), cell viability emerged as the most frequently assessed cellular-level toxicity endpoint. The results of the meta-analysis showed that cell models treated with ICNPs had a reduced cell viability (SMD = −2.531; 95% CI: −2.959 to −2.109) compared to untreated samples. A subgroup analysis was performed due to the high magnitude of heterogeneity (I2 = 77.1%), revealing that ICNP concentration and conjugated ligands are the factors that largely influence toxicity (p &lt; 0.001). (4) Conclusions: A dose-dependent cytotoxicity of ICNP exposure was observed, regardless of the health status of the cell, tested organism, and NP size. Inconsistent reporting of ICNP physicochemical properties was noted, which hinders comparability among the studies. A comprehensive exploration of the available in vivo studies is required in future research to assess the safety of ICNPs’ use in bioimaging and cancer treatment.</p

A nanoinformatics decision support tool for the virtual screening of gold nanoparticle cellular association using protein corona fingerprints

The increasing use of nanoparticles (NPs) in a wide range of consumer and industrial applications has necessitated significant effort to address the challenge of characterizing and quantifying the underlying nanostructure – biological response relationships to ensure that these novel materials can be exploited responsibly and safely. Such efforts demand reliable experimental data not only in terms of the biological dose-response, but also regarding the physicochemical properties of the NPs and their interaction with the biological environment. The latter has not been extensively studied, as a large surface to bind biological macromolecules is a unique feature of NPs that is not relevant for chemicals or pharmaceuticals, and thus only limited data have been reported in the literature quantifying the protein corona formed when NPs interact with a biological medium and linking this with NP cellular association/uptake. In this work we report the development of a predictive model for the assessment of the biological response (cellular association, which can include both internalized NPs and those attached to the cell surface) of surface-modified gold NPs, based on their physicochemical properties and protein corona fingerprints, utilizing a dataset of 105 unique NPs. Cellular association was chosen as the end-point for the original experimental study due to its relevance to inflammatory responses, biodistribution, and toxicity in vivo. The validated predictive model is freely available online through the Enalos Cloud Platform (http://enalos.insilicotox.com/NanoProteinCorona/) to be used as part of a regulatory or NP safe-by-design decision support system. This online tool will allow the virtual screening of NPs, based on a list of the significant NP descriptors, identifying those NPs that would warrant further toxicity testing on the basis of predicted NP cellular association.</p

D10.6 - Final Version of NanoCommons Sustainability Plan

NanoCommons was funded as an infrastructure project for a starting community. This means that it was supposed to build the concepts and foundation on which the community can continue to build solutions and services; in the case of NanoCommons, the infrastructure goal was to address the starting community’s data and nanoinformatics needs. NanoCommons did not start entirely from scratch, as it was building on efforts of the Nanosafety Cluster’s Working Group F on data management, and benefited from a general appreciation of the value of data reuse and computational predictions in the community. The push towards increasing use of chemoinformatics and nanoinformatics approaches was also endorsed by the public, regulatory and funding agencies, including being accelerated by the European ban on animal testing in the cosmetics industry and the European Green Deal. Similarly, industry is increasingly acting as a driver: fostering implementation and adoption of data harmonisation, FAIRness (Findability, Accessibility, Interoperability and Reusability of data) and openness and recognising that these activities require targeted and centralised efforts, which were provided by NanoCommons. However, a starting community is just that: a start upon which the community can build, a coalescence point around which collective efforts can nucleate. Our journey is still at the earliest stages, and much is needed in terms of automation, tooling, and continued training and education to drive the mindset changes within the community to fully embed data management at the start of the data lifecycle. Sustained and continuous support will be needed to achieve sufficient levels of digitalisation, global adoption of reporting standards both in scientific and regulatory settings, and machine-readability and machine-actionable data, all of which will lead to better quality and reproducible research, and more trust in the data and understanding of its applicability and suitability for reuse thus enhancing the value of the data and knowledge generated. This starts with sustaining what we already have, which in our case is the NanoCommons Knowledge Infrastructure, the implemented services from NanoCommons, as well as other associated partners and projects, and the collaboration with other projects established beyond the borders of nanosafety research. The term sustainability can be described as “the ability to be maintained at a certain rate or level”. Applied to NanoCommons, this means that the services/tools/materials that were designed and developed during the project and are already being offered to support the nanosafety community will continue to be maintained and ideally further developed, beyond the end of the funded period of the project, ensuring future accessibility for users and potential customers. Since there will be no direct public funding for these services anymore (pending further applications via Horizon Europe for example), planning for sustainability and creation of a (not necessarily commercial) business model were started very early in the project as a central task of WP10 and possible options were continuously evaluated and adapted based on stakeholder feedback coming from surveys and, more importantly, from users of the starting infrastructure services and expertise who received support in the form of Transnational Access (TA) projects or as part of the Demonstration Cases (see deliverable reports D9.3 and D9.4 for details of the first and second round Demonstration Cases, respectively). Deliverable D10.6 presented here builds on the previous deliverables D10.4 “First Testing and Evaluation Results of NanoCommons Sustainability Plan” and D10.5 “Second Testing and Evaluation Results on the NanoCommons Sustainability Plan”, proposing the first version of the business model and analysing all project activities related to sustainability during the last period, respectively. Together, these three reports outline the considerations and activities undertaken with the aim of ensuring the sustained existence and utilisation of the NanoCommons project outcomes beyond the project lifetime. A major NanoCommons objective has been to achieve a sustainable and open knowledge infrastructure for the whole nanosafety community, and thus a considerable effort was invested in exploring the options and approaches, focussing on those business models consistent with the ethos of openness and accessibility, given the public funding used to develop the services, and the critical importance of access to Environmental Health and Safety (EHS) data globally. In this final deliverable, evaluation of the TAs and Demonstration Cases with respect to their (potential) contributions to the UN Sustainable Development Goals (SDGs) is completed by looking at the results from the third funding period. Additionally, the targeted activities with the strategic partners most of whom were previously identified as significant routes via which to sustain and further develop the NanoCommons tools and services, are summarised. The NanoCommons focus areas for short/long term sustainability are presented, along with the justifications of these choices. All of this information is then condensed into the final NanoCommons sustainability plan

Prospects and challenges for FAIR toxicogenomics data

Peer reviewe

Development of a Robust Read-Across Model for the Prediction of Biological Potency of Novel Peroxisome Proliferator-Activated Receptor Delta Agonists

A robust predictive model was developed using 136 novel peroxisome proliferator-activated receptor delta (PPARδ) agonists, a distinct subtype of lipid-activated transcription factors of the nuclear receptor superfamily that regulate target genes by binding to characteristic sequences of DNA bases. The model employs various structural descriptors and docking calculations and provides predictions of the biological activity of PPARδ agonists, following the criteria of the Organization for Economic Co-operation and Development (OECD) for the development and validation of quantitative structure–activity relationship (QSAR) models. Specifically focused on small molecules, the model facilitates the identification of highly potent and selective PPARδ agonists and offers a read-across concept by providing the chemical neighbours of the compound under study. The model development process was conducted on Isalos Analytics Software (v. 0.1.17) which provides an intuitive environment for machine-learning applications. The final model was released as a user-friendly web tool and can be accessed through the Enalos Cloud platform’s graphical user interface (GUI)

Computational enrichment of physicochemical data for the development of a ζ-potential read-across predictive model with Isalos Analytics Platform

The physicochemical characterisation data from a library of 69 engineered nanomaterials (ENMs) has been exploited in silico following enrichment with a set of molecular descriptors that can be easily acquired or calculated using atomic periodicity and other fundamental atomic parameters. Based on the extended set of twenty descriptors, a robust and validated nanoinformatics model has been proposed to predict the ENM ζ-potential. The five critical parameters selected as the most significant for the model development included the ENM size and coating as well as three molecular descriptors, metal ionic radius (rion), the sum of metal electronegativity divided by the number of oxygen atoms present in a particular metal oxide (Σχ/nO) and the absolute electronegativity (χabs), each of which is thoroughly discussed to interpret their influence on ζ-potential values. The model was developed using the Isalos Analytics Platform and is available to the community as a web service through the Horizon 2020 (H2020) NanoCommons Transnational Access services and the H2020 NanoSoveIT Integrated Approach to Testing and Assessment (IATA).</p

A systematic review on the state-of-the-art and research gaps regarding inorganic and carbon-based multicomponent and high-aspect ratio nanomaterials

This review explores the state-of-the-art with respect to multicomponent nanomaterials (MCNMs) and high aspect ratio nanomaterials (HARNs), with a focus on their physicochemical characterisation, applications, and hazard, fate, and risk assessment. Utilising the PRISMA approach, this study investigates specific MCNMs including cerium-zirconium mixtures (Ce xZr yO 2) and ZnO nanomaterials doped with transition metals and rare earth elements, as well as Titanium Carbide (TiC) nanomaterials contained in Ti-6Al-4V alloy powders. HARNs of interest include graphene, carbon-derived nanotubes (CNTs), and metallic nanowires, specifically Ag-based nanowires. The review reveals a significant shift in research and innovation (R&amp;I) efforts towards these advanced nanomaterials due to their unique properties and functionalities that promise enhanced performance across various applications including photocatalysis, antibacterial and biomedical uses, and advanced manufacturing. Despite the commercial potential of MCNMs and HARNs, the review identifies critical gaps in our understanding of their environmental fate and transformations upon exposure to new environments, and their potential adverse effects on organisms and the environment. The findings underscore the necessity for further research focused on the environmental transformations and toxicological profiles of these nanomaterials to inform Safe and Sustainable by Design (SSbD) strategies. This review contributes to the body of knowledge by cataloguing current research, identifying research gaps, and highlighting future directions for the development of MCNMs and HARNs, facilitating their safe and effective integration into industry. </p

NanoTube Construct:A web tool for the digital construction of nanotubes of single-layer materials and the calculation of their atomistic descriptors powered by Enalos Cloud Platform

NanoTube Construct is a web tool for the digital construction of nanotubes based on real and hypothetical single-layer materials including carbon-based materials such as graphene, graphane, graphyne polymorphs, graphidiyene and non-carbon materials such as silicene, germanene, boron nitride, hexagonal bilayer silica, haeckelite silica, molybdene disulfide and tungsten disulfide. Contrary to other available tools, NanoTube Construct has the following features: a) it is not limited to zero thickness materials with specific symmetry, b) it applies energy minimisation to the geometrically constructed Nanotubes to generate realistic ones, c) it derives atomistic descriptors (e.g., the average potential energy per atom, the average coordination number, etc.), d) it provides the primitive unit cell of the constructed Nanotube which corresponds to the selected rolling vector (i.e., the direction in which the starting nanosheet is rolled to form a tube), e) it calculates whether the Nanotube or its corresponding nanosheet is more energetically stable and f) it allows negative chirality indexes. Application of NanoTube Construct for the construction of energy minimised graphane and molybdenum disulfide nanotubes are presented, showcasing the tool's capability. NanoTube Construct is freely accessible through the Enalos Cloud Platform (https://enaloscloud.novamechanics.com/diagonal/nanotube/)