Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for ...cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.
Abstract With the rapid expansion in the nanotechnology industry, it is essential that the safety of engineered nanomaterials and the factors that influence their associated hazards are understood. A ...vital area governing regulatory health risk assessment is genotoxicology (the study of genetic aberrations following exposure to test agents), as DNA damage may initiate and promote carcinogenesis, or impact fertility. Of late, considerable attention has been given to the toxicity of engineered nanomaterials, but the importance of their genotoxic potential on human health has been largely overlooked. This comprehensive review focuses on the reported abilities of metal nanoparticles, metal-oxide nanoparticles, quantum dots, fullerenes, and fibrous nanomaterials, to damage or interact with DNA, and their ecogenotoxicity is also considered. Many of the engineered nanomaterials assessed were found to cause genotoxic responses, such as chromosomal fragmentation, DNA strand breakages, point mutations, oxidative DNA adducts and alterations in gene expression profiles. However, there are clear inconsistencies in the literature and it is difficult to draw conclusions on the physico-chemical features of nanomaterials that promote genotoxicity, largely due to study design. Hence, areas that require that further attention are highlighted and recommendations to improve our understanding of the genotoxic potential of engineered nanomaterials are addressed.
Inflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident ...macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.
Whilst the liver possesses the ability to repair and restore sections of damaged tissue following acute injury, prolonged exposure to engineered nanomaterials (ENM) may induce repetitive injury ...leading to chronic liver disease. Screening ENM cytotoxicity using 3D liver models has recently been performed, but a significant challenge has been the application of such in vitro models for evaluating ENM associated genotoxicity; a vital component of regulatory human health risk assessment. This review considers the benefits, limitations, and adaptations of specific in vitro approaches to assess DNA damage in the liver, whilst identifying critical advancements required to support a multitude of biochemical endpoints, focusing on nano(geno)toxicology (e.g., secondary genotoxicity, DNA damage, and repair following prolonged or repeated exposures).
A significant challenge facing engineered nanomaterial hazard assessment is the application of physiologically relevant in vitro models for evaluating genotoxicity. This review considers the benefits, limitations, and adaptations of 3D in vitro liver culture systems to assess DNA damage. Important advances that facilitate the evaluation of a range of genotoxicity endpoints are discussed.
Context.
We report the discovery of TOI 263.01 (TIC 120916706), a transiting substellar object (
R
= 0.87
R
Jup
) orbiting a faint M3.5 V dwarf (
V
= 18.97) on a 0.56 d orbit.
Aims.
We setout to ...determine the nature of the Transiting Exoplanet Survey Satellite (TESS) planet candidate TOI 263.01 using ground-based multicolour transit photometry. The host star is faint, which makes radial-velocity confirmation challenging, but the large transit depth makes the candidate suitable for validation through multicolour photometry.
Methods.
Our analysis combines three transits observed simultaneously in
r
′,
i
′, and
z
s
bands usingthe MuSCAT2 multicolour imager, three LCOGT-observed transit light curves in
g
′,
r
′, and
i
′ bands, a TESS light curve from Sector 3, and a low-resolution spectrum for stellar characterisation observed with the ALFOSC spectrograph. We modelled the light curves with P
Y
T
RANSIT
using a transit model that includes a physics-based light contamination component, allowing us to estimate the contamination from unresolved sources from the multicolour photometry. Using this information we were able to derive the true planet–star radius ratio marginalised over the contamination allowed by the photometry.Combining this with the stellar radius, we were able to make a reliable estimate of the absolute radius of the object.
Results.
The ground-based photometry strongly excludes contamination from unresolved sources with a significant colour difference to TOI 263. Furthermore, contamination from sources of the same stellar type as the host is constrained to levels where the true radius ratio posterior has a median of 0.217 and a 99 percentile of0.286. The median and maximum radius ratios correspond to absolute planet radii of 0.87 and 1.41
R
Jup
, respectively,which confirms the substellar nature of the planet candidate. The object is either a giant planetor a brown dwarf (BD) located deep inside the so-called “brown dwarf desert”. Both possibilities offer a challenge to current planet/BD formation models and make TOI 263.01 an object that merits in-depth follow-up studies.
► We consider current in vitro OECD genotoxicity tests for nanomaterials. ► Ames test does not appear to be suitable for nanomaterial assessment. ► In vitro HPRT and micronucleus assays require ...nanomaterial specific protocols. ► We recommend a strategic in vitro genotoxicity testing strategy for nanomaterials.
There is a pressing requirement to define a hazard identification and risk management strategy for nanomaterials due to the rapid growth in the nanotechnology industry and their promise of life-style revolutions through the development of wide-ranging nano-containing consumer products. Consequently, a battery of well defined and appropriate in vitro assays to assess a number of genotoxicity endpoints is required to minimise extensive and costly in vivo testing. However, the validity of the established protocols in current OECD recognised genotoxicity assays for nanomaterials is currently being questioned. In this report, we therefore consider the in vitro OECD genotoxicity test battery including the Ames, micronucleus and HPRT forward mutation assays, and their potential role in the safety assessment of nanomaterial induced DNA damage in vitro.
A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences of chemical exposure on human populations and improve health risk assessments. Currently, linear ...dose-responses are assumed for DNA reactive compounds, ignoring cytoprotective processes that may limit permanent damage. To investigate the biological significance of low-dose exposures, human lymphoblastoid cells were treated with alkylating agents that have different mechanisms of action and DNA targets: methylmethane sulfonate (MMS), methylnitrosourea (MNU), ethylmethane sulfonate (EMS), and ethylnitrosourea (ENU). Chromosomal damage and point mutations were quantified with the micronucleus and hypoxanthine phosphoribosyltransferase forward mutation assays. MNU and ENU showed linear dose-responses, whereas MMS and EMS had nonlinear curves containing a range of nonmutagenic low doses. The lowest observed effect level for induction of chromosomal aberrations was 0.85 microg/mL MMS and 1.40 microg/mL EMS; point mutations required 1.25 microg/mL MMS and 1.40 microg/mL EMS before a mutagenic effect was detected. This nonlinearity could be due to homeostatic maintenance by DNA repair, which is efficient at low doses of compounds that primarily alkylate N(7)-G and rarely attack O atoms. A pragmatic threshold for carcinogenicity may therefore exist for such genotoxins.
We review first-principles calculations relevant to the adsorption of aromatic molecules on metal surfaces. Benzene has been intensively studied on a variety of substrates, providing an opportunity ...to comment upon trends from one metal to another. Meanwhile, calculations elucidating the adsorption of polycyclic aromatic molecules are more sparse, but nevertheless yield important insights into the role of non-covalent interactions. Heterocyclic and substituted aromatic compounds introduce the complicating possibility of electronic and steric effects, whose relative importance can thus far only be gauged on a case-by-case basis. Finally, the coadsorption and/or reaction of aromatic molecules is discussed, highlighting an area where the predictive power of theory is likely to prove decisive in the future.
Human exposure to engineered nanomaterials (ENMs) is inevitable due to the plethora of applications for which they are being manufactured and integrated within. ENMs demonstrate plentiful advantages ...in terms of industrial approaches as well as from a consumer perspective. However, despite such positives, doubts remain over the human health implications of ENM exposure. In light of the increased research focus upon the potential effects of ENM exposure to human health in recent decades, questions still remain regarding the safety of these highly advanced, precision-tuned physical entities. The risk of short-term, high-dose exposure to humans is considered relatively low, although this has formed the direction of the hazard-assessment community since the turn of the 21st century. However, the possibility of humans being exposed repeatedly over a long period of time to a low-dose of ENMs of varying physicochemical characteristics is of significant concern, and thus, industry, government, academic, and consumer agencies are only now beginning to consider this. Notably, when considering the human health implications of such low-dose, long-term, repeated exposure scenarios, the impact of ENMs upon the human immune system is of primary importance. However, there remains a real need to understand the impact of ENMs upon the human immune system, especially the innate immune system, at all stages of life, given exposure to nanosized particles begins before birth, that is, of the fetus. Therefore, the purpose of this perspective is to summarize what is currently known regarding ENM exposure of different components of the innate immune system and identify knowledge gaps that should be addressed if we are to fully deduce the impact of ENM exposure on innate immune function.
Nanomaterials are defined as materials with at least one dimension of 100 nm or less. Their small size confers unique properties that may alter the toxicity profile when compared to larger forms of ...the same material, requiring additional considerations for safety assessment. There has been a rise in the development of nanomaterials for many applications, and although traditional approaches for toxicity testing may address some of the new toxicity concerns, many may not be directly applicable to nanomaterials and new tools or approaches may need to be developed. Since nanomaterials can exist in many different forms, each of which may cause different adverse biological effects, reliance on traditional in vivo models for safety assessment will simply not be feasible or sustainable, given the volume of materials that may need to be tested. It is essential to consider and develop new in vitro methods that can be applied for hazard identification and risk assessment. Many challenges are associated with using alternative approaches to ensure they are as robust and reliable as traditional in vivo approaches, but by overcoming these issues and adopting new testing strategies there are opportunities to improve safety assessments and reduce the reliance on animal‐based toxicity testing strategies.
Nanomaterials have unique properties that may alter the toxicity profile when compared to larger forms of the same material. There are opportunities to integrate in vitro methodologies into the hazard testing and risk assessment process although there are challenges in ensuring they are as robust and reliable as in vivo approaches and ensuring the protection goals are met.
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