Bioactivity of the ubiquitous tire preservative 6PPD and degradant, 6PPD-quinone in fish and mammalian-based assays.

6PPD-quinone (N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone), a transformation product of the antiozonant 6PPD (N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine) is a likely causative agent of coho salmon (Oncorhynchus kisutch) pre-spawn mortality. Stormwater runoff transports 6PPD-quinone into freshwater streams, rapidly leading to neurobehavioral, respiratory distress, and rapid mortality in laboratory exposed coho salmon, but causing no mortality in many laboratory-tested species. Given this identified hazard, and potential for environmental exposure, we evaluated a set of U.

Burnt Plastic (Pyroplastic) from the M/V Ship Fire and Plastic Spill Contain Compounds That Activate Endocrine and Metabolism-Related Human and Fish Transcription Factors.

In May 2021, the M/V ship fire disaster led to the largest maritime spill of resin pellets (nurdles) and burnt plastic (pyroplastic). Field samples collected from beaches in Sri Lanka nearest to the ship comprised nurdles and pieces of pyroplastic. Three years later, the toxicity of the spilled material remains unresolved.

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells.

Popularized on social media, hand-moldable plastics are formed by consumers into tools, trinkets, and dental prosthetics. Despite the anticipated dermal and oral contact, manufacturers share little information with consumers about these materials, which are typically sold as microplastic-sized resin pellets. Inherent to their function, moldable plastics pose a risk of dermal and oral exposure to unknown leachable substances.

meso-Bromination of cyano- and aquacobalamins facilitates their processing into Co(II)-species by glutathione.

Cyanocobalamin (CNCbl), a medicinal form of vitamin B, is resistant to glutathione (GSH), and undergoes intracellular processing via reductive decyanation producing the Co(II)-form of Cbl (Cbl(II)) mediated by the CblC-protein. Alteration of the CblC-protein structure might inhibit CNCbl processing. Here, we showed that introducing a bromine atom to the C10-position of the CNCbl corrin ring facilitates its reaction with GSH leading to the formation of Cbl(II) and cyanide dissociation.

The Impact of Backbone Fluorination and Side-Chain Position in Thiophene-Benzothiadiazole-Based Hole-Transport Materials on the Performance and Stability of Perovskite Solar Cells.

Perovskite solar cells (PSCs) currently reach high efficiencies, while their insufficient stability remains an obstacle to their technological commercialization. The introduction of hole-transport materials (HTMs) into the device structure is a key approach for enhancing the efficiency and stability of devices. However, currently, the influence of the HTM structure or properties on the characteristics and operational stability of PSCs remains insufficiently studied.

Aquacobalamin Accelerates Orange II Destruction by Peroxymonosulfate via the Transient Formation of Secocorrinoid: A Mechanistic Study.

Besides its use in medicine, vitamin B (cobalamin) and its derivatives have found in numerous applications as catalysts. However, studies related to the activation of oxidants via cobalamin are scant. In this work, we showed how the addition of aquacobalamin (HOCbl) accelerates the destruction of azo-dye Orange II by peroxymonosulfate (HSO) in aqueous solutions.

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease.

Nutritional deficiency and genetic errors that impair the transport, absorption, and utilization of vitamin B (B) lead to hematological and neurological manifestations. The cblC disease (cobalamin complementation type C) is an autosomal recessive disorder caused by mutations and epi-mutations in the gene and the most common inborn error of B metabolism. Pathogenic mutations in disrupt enzymatic processing of B, an indispensable step before micronutrient utilization by the two B-dependent enzymes methionine synthase (MS) and methylmalonyl-CoA mutase (MUT).

Comprehensive assessment of NR ligand polypharmacology by a multiplex reporter NR assay.

Nuclear receptors (NR) are ligand-modulated transcription factors that regulate multiple cell functions and thus represent excellent drug targets. However, due to a considerable NR structural homology, NR ligands often interact with multiple receptors. Here, we describe a multiplex reporter assay (the FACTORIAL NR) that enables parallel assessment of NR ligand activity across all 48 human NRs.

A novel chemo-phenotypic method identifies mixtures of salpn, vitamin D3, and pesticides involved in the development of colorectal and pancreatic cancer.

Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM).

Adduct of Aquacobalamin with Hydrogen Peroxide.

Aquacobalamin binds hydrogen peroxide reversibly to form a cobalt(III) hydroperoxo adduct with a 0.25 mM dissociation constant, as evidenced by UV-vis absorption spectroscopy and corroborated by NMR, Raman spectroscopy, stopped-flow UV-vis measurements, and density functional theory calculations.

Biosynthesis, Quantification and Genetic Diseases of the Smallest Signaling Thiol Metabolite: Hydrogen Sulfide.

Hydrogen sulfide (HS) is a gasotransmitter and the smallest signaling thiol metabolite with important roles in human health. The turnover of HS in humans is mainly governed by enzymes of sulfur amino acid metabolism and also by the microbiome. As is the case with other small signaling molecules, disease-promoting effects of HS largely depend on its concentration and compartmentalization.

Laser spectroscopic and computational insights into unexpected structural behaviours of sandwich complexes upon ionization.

Transition-metal sandwich complexes play key roles in various fields such as fundamental and applied chemistry; many of their unique properties arise from their ability to form stable or reactive ions. The first mass-analyzed threshold ionization (MATI) spectra of mixed sandwich compounds, (Ch)(Cp)Cr and (Cot)(Cp)Ti (Ch = η-CH, Cp = η-CH, Cot = η-CH), presented in this work provide an extremely accurate description of the electron detachment. The ionization energies of the neutrals and stabilization energies of the metal-ligand interactions upon ionization are derived from the MATI data with an accuracy of 0.

Mechanism of cyanocobalamin chlorination by hypochlorous acid.

Hypochlorous acid (HOCl) is a strong oxidant produced by myeloperoxidase. Previous work suggested that HOCl modifies the corrin ring of cobalamins to yield chlorinated species via mechanisms that are incompletely understood. Herein, we report a mechanistic study on the reaction between cyanocobalamin (CNCbl, vitamin B) and HOCl.

Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure.

Per- and polyfluoroalkyl substances (PFAS) are a broad class of hundreds of fluorinated chemicals with environmental health concerns due to their widespread presence and persistence in the environment. Several of these chemicals have been comprehensively studied for experimental toxicity, environmental fate and exposure, and human epidemiology; however, most chemicals have limited or no data available. To inform methods for prioritizing these data-poor chemicals for detailed toxicity studies, we evaluated 142 PFAS using an in vitro screening platform consisting of two multiplexed transactivation assays encompassing 81 diverse transcription factor activities and tested in concentration-response format ranging from 137 nM to 300 μM.

Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC.

Thiolatocobalamins are a class of cobalamins comprised of naturally occurring and synthetic ligands. Glutathionylcobalamin (GSCbl) occurs naturally in mammalian cells, and also as an intermediate in the glutathione-dependent dealkylation of methylcobalamin (MeCbl) to form cob(I)alamin by pure recombinant CblC from C. elegans.

Evaluation of a multiplexed, multispecies nuclear receptor assay for chemical hazard assessment.

Sensitivity to potential endocrine disrupting chemicals in the environment varies across species and is influenced by sequence conservation of their nuclear receptor targets. Here, we evaluated a multiplexed, in vitro assay testing receptors relevant to endocrine and metabolic disruption from five species. The TRANS-FACTORIAL™ system of human nuclear receptors was modified to include additional species: mouse (Mus musculus), frog (Xenopus laevis), zebrafish (Danio rerio), chicken (Gallus gallus), and turtle (Chrysemys picta).

Harmonized Cross-Species Assessment of Endocrine and Metabolic Disruptors by Ecotox FACTORIAL Assay.

Environmental pollution is a threat to humans and wildlife species. Of particular concern are endocrine disrupting chemicals (EDCs). An important target of EDCs is nuclear receptors (NRs) that control endocrine and metabolic responses through transcriptional regulation.

Catalytic effect of riboflavin on electron transfer from NADH to aquacobalamin.

Reduction of cobalamin by non-dedicated cellular reductases has been reported in earlier work, however, the sources of reducing power and the mechanisms are unknown. This study reports results of kinetic and mechanistic investigation of the reaction between aquacobalamin, HOCbl, and reduced β-nicotinamide adenine dinucleotide, NADH. This interaction leads to the formation of one-electron reduced cobalamin, cob(II)alamin, and proceeds via water substitution on aquacobalamin by NADH and further decomposition of NADH-Co(III) complex to cob(II)alamin and NADH.

Reactivity of Small Oxoacids of Sulfur.

Oxidation of sulfide to sulfate is known to consist of several steps. Key intermediates in this process are the so-called small oxoacids of sulfur (SOS)-sulfenic HSOH (hydrogen thioperoxide, oxadisulfane, or sulfur hydride hydroxide) and sulfoxylic S(OH) acids. Sulfur monoxide can be considered as a dehydrated form of sulfoxylic acid.

Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by a RORγt inverse agonist.

Airway neutrophilia occurs in approximately 50% of patients with asthma and is associated with particularly severe disease. Unfortunately, this form of asthma is usually refractory to corticosteroid treatment, and there is an unmet need for new therapies. Pulmonary neutrophilic inflammation is associated with Th17 cells, whose differentiation is controlled by the nuclear receptor, RORγt.

Potential Toxicity of Complex Mixtures in Surface Waters from a Nationwide Survey of United States Streams: Identifying in Vitro Bioactivities and Causative Chemicals.

While chemical analysis of contaminant mixtures remains an essential component of environmental monitoring, bioactivity-based assessments using in vitro systems increasingly are used in the detection of biological effects. Historically, in vitro assessments focused on a few biological pathways, for example, aryl hydrocarbon receptor (AhR) or estrogen receptor (ER) activities. High-throughput screening (HTS) technologies have greatly increased the number of biological targets and processes that can be rapidly assessed.

Evaluating biological activity of compounds by transcription factor activity profiling.

Assessing the biological activity of compounds is an essential objective of biomedical research. We show that one can infer the bioactivity of compounds by assessing the activity of transcription factors (TFs) that regulate gene expression. Using a multiplex reporter system, the FACTORIAL, we characterized cell response to a compound by a quantitative signature, the TF activity profile (TFAP).

Characterization of the complex between native and reduced bovine serum albumin with aquacobalamin and evidence of dual tetrapyrrole binding.

Serum albumin binds to a variety of endogenous ligands and drugs. Human serum albumin (HSA) binds to heme via hydrophobic interactions and axial coordination of the iron center by protein residue Tyr161. Human serum albumin binds to another tetrapyrrole, cobalamin (Cbl), but the structural and functional properties of this complex are poorly understood.

The Identification of Pivotal Transcriptional Factors Mediating Cell Responses to Drugs With Drug-Induced Liver Injury Liabilities.

Drug-induced liver injury (DILI) is a leading cause of drug attrition during drug development and a common reason for drug withdrawal from the market. The poor predictability of conventional animal-based approaches necessitates the development of alternative testing approaches. A body of evidence associates DILI with the induction of stress-response genes in liver cells.

Studies on reaction of glutathionylcobalamin with hypochlorite. Evidence of protective action of glutathionyl-ligand against corrin modification by hypochlorite.

Glutathionylcobalamin (GSCbl), a tight complex of glutathione (GSH) with cobalamin(III), is readily oxidized to aquacobalamin by hypochlorite. Corrin macrocycle remains unmodified in the presence of threefold excess of hypochlorite, whereas aqua- and cyanocobalamins are partially transformed to chlorinated species under the same conditions. The suggested mechanism of reaction between GSCbl and hypochlorite involves subsequent oxidation of thiol and amino groups and dissociation of oxidized glutathione from Co(III)-ion.