Halogenation of common phenolic household and personal care product ingredients enhances their AhR-modulating capacity.

The Aryl Hydrocarbon Receptor (AhR), a ligand-activated transcription factor, orchestrates responses to numerous structurally diverse endogenous and exogenous ligands. In addition to binding various xenobiotics, AhR also recognizes endocrine disruptors, particularly those featuring chlorinated or brominated aromatic structures. There is limited data available on the impact of common household and personal care product ingredients let alone their halogenated transformation products. Herein we bridge this knowledge gap by preparing a library of chlorinated and brominated parabens, bisphenols, UV filters, and nonylphenols. An evaluation of total of 125 compounds for agonistic and antagonistic activity on AhR unveiled a low micromolar agonist, Cl2BPAF with an EC50 of 13 µM. Moreover, our study identified several AhR antagonists, with BrBzP emerging as the most potent with an IC50 of 8.9 µM. To further investigate the functional implications of these compounds, we subjected the most potent agonist and antagonist to a functional assay involving cytokine secretion from peripheral blood mononuclear cells and compared their activity with the commercially available AhR agonist and antagonist. Cl2BPAF exhibited an overall immunosuppressive effect by reducing the secretion of proinflammatory cytokines, including IL-6, IFN-γ, and TNF-α, while BrBzP displayed opposite effects, leading to an increase of those cytokines. Notably, the immunomodulatory effects of Cl2BPAF surpassed those of ITE, a bona fide AhR agonist, while the impact of BrBzP exceeded that of CH223191, a bona fide AhR antagonist. In summary, our study underscores the potential influence of halogenated transformation products on the AhR pathway and, consequently, their role in shaping the immune responses.

In vitro investigation of immunomodulatory activities of selected UV-filters.

Organic UV filters are ubiquitous as they are used in numerous personal care products. Consequently, people constantly come into direct or indirect contact with these chemicals. Albeit studies of the effects of UV filters on human health have been undertaken, their toxicological profiles are not complete. In this work, we investigated the immunomodulatory properties of eight UV filters representing different chemotypes, including benzophenone-1, benzophenone-3, ethylhexyl methoxycinnamate, octyldimethyl-para-aminobenzoic acid, octyl salate, butylmethoxydibenzoylmethane, 3-benzylidenecamphor, and 2,4-di-tert-butyl-6-(5-chlorobenzotriazol-2-yl)phenol. We demonstrated that none of these UV filters were cytotoxic to THP-1 cells at concentrations up to 50 µM. Importantly, our study highlighted the capacity of nontoxic concentrations of avobenzone and 3-benzylidene camphor to increase the secretion of interleukin 8 (IL-8) from both THP-1 cells and THP-1 derived macrophages. Further, they also exhibited a pronounced decrease of IL-6 and IL-10 release from lipopolysaccharide-stimulated peripheral blood mononuclear cells. The observed immune cell alterations suggest that exposure to 3-BC and BMDM could be involved in immune deregulation. Our research thus provided additional insight into UV filter safety profile.

The augmented radiologist: artificial intelligence in the practice of radiology.

In medicine, particularly in radiology, there are great expectations in artificial intelligence (AI), which can "see" more than human radiologists in regard to, for example, tumor size, shape, morphology, texture and kinetics - thus enabling better care by earlier detection or more precise reports. Another point is that AI can handle large data sets in high-dimensional spaces. But it should not be forgotten that AI is only as good as the training samples available, which should ideally be numerous enough to cover all variants. On the other hand, the main feature of human intelligence is content knowledge and the ability to find near-optimal solutions. The purpose of this paper is to review the current complexity of radiology working places, to describe their advantages and shortcomings. Further, we give an AI overview of the different types and features as used so far. We also touch on the differences between AI and human intelligence in problem-solving. We present a new AI type, labeled "explainable AI," which should enable a balance/cooperation between AI and human intelligence - thus bringing both worlds in compliance with legal requirements. For support of (pediatric) radiologists, we propose the creation of an AI assistant that augments radiologists and keeps their brain free for generic tasks.

Genetically designed biomolecular capping system for mesoporous silica nanoparticles enables receptor-mediated cell uptake and controlled drug release.

Effective and controlled drug delivery systems with on-demand release and targeting abilities have received enormous attention for biomedical applications. Here, we describe a novel enzyme-based cap system for mesoporous silica nanoparticles (MSNs) that is directly combined with a targeting ligand via bio-orthogonal click chemistry. The capping system is based on the pH-responsive binding of an aryl-sulfonamide-functionalized MSN and the enzyme carbonic anhydrase (CA). An unnatural amino acid (UAA) containing a norbornene moiety was genetically incorporated into CA. This UAA allowed for the site-specific bio-orthogonal attachment of even very sensitive targeting ligands such as folic acid and anandamide. This leads to specific receptor-mediated cell and stem cell uptake. We demonstrate the successful delivery and release of the chemotherapeutic agent Actinomycin D to KB cells. This novel nanocarrier concept provides a promising platform for the development of precisely controllable and highly modular theranostic systems.

Multifunctional polymer-capped mesoporous silica nanoparticles for pH-responsive targeted drug delivery.

A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The functionality of the system was demonstrated in several cell studies, showing pH-triggered release in the endosome, light-triggered endosomal escape with an on-board photosensitizer, and efficient folic acid-based cell targeting.

Targeted drug delivery in cancer cells with red-light photoactivated mesoporous silica nanoparticles.

Mesoporous nanoparticles for drug delivery would benefit significantly from further improvements in targeting efficiency and endosomal release. We present a system based on colloidal mesoporous silica nanoparticles with targeting-ligands and a red-light photosensitizer. This nanoparticle system provides spatial and temporal control of the release of drugs into the cytosol of cancer cells. Furthermore, the system presents a general platform since it can be loaded with different cargos and adapted for targeting of multiple cell types.