Comprehensive metabolic profiling of dioxin-like compounds exposure in laying hens: Implications for toxicity assessment.

The evaluation of toxicity related to polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) is crucial for a comprehensive risk assessment in real-world exposure scenarios. This study employed a controlled feeding experiment to investigate the metabolic effects of dioxin-like compounds (DLCs) on laying hens via feed exposure. Diets enriched with two concentrations (1.17 and 5.13 pg toxic equivalents (TEQ)/g dry weight (dw)) were administered over 14 days, followed by 28 days of clean feed. Metabolomics analyses of blood samples revealed significant metabolic variations between PCDD/Fs and DL-PCBs exposed groups and controls, reflecting the induced metabolic disruption. Distinct changes were observed in sphingosine, palmitoleic acid, linoleate, linolenic acid, taurocholic acid, indole acrylic acid, and dibutyl phthalate levels, implying possible connections between PCDD/Fs and DL-PCBs toxic effects and energy-neuronal imbalances, along with lipid accumulation and anomalous amino acid metabolism, impacting taurine metabolism. Moreover, we identified three differential endogenous metabolites-L-tryptophan, indole-3-acetaldehyde, and indole acrylic acid-as potential ligands for the aryl hydrocarbon receptor (AhR), suggesting their role in mediating PCDD/Fs and DL-PCBs toxicity. This comprehensive investigation provides novel insights into the metabolic alterations induced by PCDD/Fs and DL-PCBs in laying hens, thereby enhancing our ability to assess risks associated with their exposure in human populations.

QSTR Models in Dioxins and Dioxin-like Compounds Provide Insights into Gene Expression Dysregulation.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are a group of organic chemicals containing three-ring structures that can be substituted with one to eight chlorine atoms, leading to 75 dioxin and 135 furan congeners. As endocrine-disrupting chemicals (EDCs), they can alter physiological processes causing a number of disorders. In this study, quantitative structure-toxicity relationship (QSTR) studies were used to determine the correlations between the PCDD/Fs' molecular structures and various toxicity endpoints. Strong QSTR models, with the coefficients of determination (r2) values greater than 0.95 and ANOVA p-values less than 0.0001 were established between molecular descriptors and the endpoints of bioconcentration, fathead minnow LC50, and Daphnia magna LC50. The ability of PCDD/Fs to bind to several nuclear receptors was investigated via molecular docking studies. The results show comparable, and in some instances better, binding affinities of PCDD/Fs toward the receptors relative to their natural agonistic and antagonistic ligands, signifying possible interference with the receptors' natural biological activities. These studies were accompanied by the molecular dynamics simulations of the top-binding PCDD/Fs to show changes in the receptor-ligand complexes during binding and provide insights into these compounds' ability to interfere with transcription and thereby modify gene expression. This introspection of PCDD/Fs at the molecular level provides a deeper understanding of these compounds' toxicity and opens avenues for future studies.

Synthesis and biological profile of substituted hexahydrofuro[3,4-b]furans, a novel class of bicyclic acyl-acyl carrier protein (ACP) thioesterase inhibitors.

BACKGROUND: Weed control is a significant challenge for farmers around the globe. Of the various methods available for combatting weeds, small molecules remain the most effective and versatile technology to date. In the search for novel chemical entities with new modes of action toward herbicide-resistant weeds, we have investigated hexahydrofuro[3,4-b]furan-based acyl-acyl carrier protein (ACP) thioesterase inhibitors inspired by X-ray co-crystal structure-based modeling studies. RESULTS: By exploiting scaffold hopping concepts and molecular modeling studies we were able to identify new hexahydrofuro[3,4-b]furan-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity. CONCLUSION: The present work covers a series of novel herbicidal lead structures that possess a hexahydrofuro[3,4-b]furan scaffold as a structural key feature, carrying ortho-substituted aryloxy side chains. Based on an optimized synthetic approach a broad structure-activity relationship (SAR) study was carried out. The new compounds emerging from our modeling-inspired structural variations show good acyl-ACP thioesterase inhibition in line with promising initial herbicidal activity. Glasshouse trials showed that the hexahydrofuro[3,4-b]furans outlined herein display good control of cold and warm season grass-weed species in pre-emergence application. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors also showed promising efficacy against warm season weeds that are difficult to control. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

A Diels-Alder probe for discovery of natural products containing furan moieties.

Natural products (NPs) are fantastic sources of inspiration for novel pharmaceuticals, oftentimes showing unique bioactivity against interesting targets. Specifically, NPs containing furan moieties show activity against a variety of diseases including fungal infections, and cancers. However, it is challenging to discover and isolate these small molecules from cell supernatant. The work described herein showcases the development of a molecular probe that can covalently modify furan moieties via a [4 + 2] Diels-Alder cycloaddition, making them easily identifiable on liquid chromatography-mass spectrometry (LC-MS). The molecular probe, which undergoes this reaction with a variety of furans, was designed with both a UV-tag and a mass tag to enable easy identification. The probe has been tested with a variety of purified furans, including natural products, methylenomycin furan (MMF) hormones, and MMF derivatives. Moreover, the molecular probe has been tested in crude supernatants of various Streptomyces strains and enables identification of MMFs.

Mechanistic and predictive studies on the oxidation of furans by cytochrome P450: A DFT study.

Furan-containing compounds distribute widely in food, herbal medicines, industrial synthetic products, and environmental media. These compounds can undergo oxidative metabolism catalyzed by cytochrome P450 enzymes (CYP450) within organisms, which may produce reactive products, possibly reacting with biomolecules to induce toxic effects. In this work, we performed DFT calculations to investigate the CYP450-mediated metabolic mechanism of furan-ring oxidation using 2-methylfuran as a model substrate, meanwhile, we studied the regioselective competition of another hydroxylation reaction involving methyl group of 2-methylfuran. As a result, we found the toxicological-relevant cis-enedione product can be produced from O-addition directly via a concerted manner without formation of an epoxide intermediate as traditionally believed. Moreover, our calculations demonstrate the kinetic and thermodynamic feasibility of both furan-ring oxidation and methyl hydroxylation pathways, although the former pathway is a bit more favorable. We then constructed a linear model to predict the rate-limiting activation energies (ΔE*) of O-addition with 11 diverse furan substates based on their adiabatic ionization potentials (AIPs) and condensation Fukui functions (CFFs). The results show a good predictive ability (R2=0.94, Q2CV=0.87). Therefore, AIP and CFF with clear physichem meanings relevant to the mechanism, emerge as pivotal molecular descriptors to enable the fast prediction of furan-ring oxidation reactivities for quick insight into the toxicological risk of furans, using just ground-state calculations.

Effect of support structure of Pt/silicaite-1 catalyst on non-thermal plasma (NTP) assisted chlorobenzene degradation and PCDD/Fs formation.

Development of efficient catalysts for non-thermal plasma (NTP) assisted catalysis to mitigate the formation of harmful by-products is a significant challenge in the degradation of chlorinated volatile organic compounds (Cl-VOCs). In this study, catalytically active Pt nanoparticles supported on non-porous SiO2 and silicalite-1 zeolites (S1) with different pore structure were comparatively investigated for catalytic chlorobenzene degradation under NTP condition. It was shown that the pore structure could significantly impact the metal size and metal dispersion rate. Pt supported on modified S1 hierarchical meso-micro-porous silicalite-1 (Pt/D-S1) exhibited the smallest particle size (∼6.19 nm) and the highest dispersion rate (∼1.87). Additionally, Pt/D-S1 demonstrated superior catalytic performance compared to the other catalysts, achieving the highest chlorobenzene conversion and COx selectivity at about 80% and 75%, respectively. Furthermore, the pore structure also affected the formation of by-products according to the findings from GC-MS analysis. Pt/SiO2 generated a total of 18 different species of organic compounds, whereas only 12 species of organic by-products were identified in the Pt/D-S1 system (e.g. polychlorinated compounds like 3,4 dichlorophenol were exclusively identified in Pt/SiO2). Moreover, dioxin-like polychlorinated biphenyl and other chlorinated organic compounds, which have potential to form highly toxic dioxins, were detected in the catalysts. HRGC-HRMS confirmed and quantified the 17 different dioxin/furans formed on Pt/SiO2 (25,100 ng TEQ kg-1), Pt/S1 (515 ng TEQ kg-1) and Pt/D-S1 (367 ng TEQ kg-1). The correlation between synthesis-structure-performance in this study provides insights into the design of catalysts for deep oxidation of Cl-VOCs in NTP system.

Halogenated aromatic pollutants in routine animal-derived food of south China: Occurrence, sources, and dietary intake risks.

Halogenated aromatic pollutants (HAPs) including polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated dibenzo-p-dioxins/furans (PBDD/Fs), and polybrominated diphenyl ethers (PBDEs) exhibit diverse toxicities and bio-accumulation in animals, thereby imposing risks on human via animal-derived food (ADF) consumption. Here we examined these HAPs in routine ADFs from South China and observed that PBDEs and PCBs showed statistically higher concentrations than PCDD/Fs and PBDD/Fs. PCDD/Fs and PCBs in these ADFs were mainly from the polluted feed and habitat of animals, except PCDD/Fs in egg, which additionally underwent selective biotransformation/progeny transfer after the maternal intake of PCDD/F-polluted stuff. PBDEs and PBDD/Fs were mostly derived from the extensive use of deca-BDE and their polluted environments. Significant interspecific differences were mainly observed for DL-PCBs and partly for PBDD/Fs and PBDEs, which might be caused by their distinct transferability/biodegradability in animals and the different living habit and habitat of animals. The dietary intake doses (DIDs) of these HAPs via ADF consumption were all highest for toddlers, then teenagers and adults. Milk, egg, and fish contributed most to the DIDs and risks for toddlers and teenagers, which results of several cities exceeded the recommended thresholds and illustrated noteworthy risks. Pork, fish, and egg were the top three risk contributors for adults, which carcinogenic and non-carcinogenic risks were both acceptable. Notably, PBDD/Fs showed the lowest concentrations but highest contributions to the total risks of these HAPs, thereby meriting continuous attention.

An efficient one-pot and simple multicomponent approach to the synthesis of highly functionalized furans containing dialkyl phenol.

In this study, arylglyoxals, acetylacetone, and 2,6-dimethyl phenol or 2,6-di-tert-butyl phenol are combined to efficiently synthesize a series of 1-(4-(3,5-dialkylphenyl)-2-methyl-5-phenylfuran-3-yl) ethan-1-one derivatives in excellent yields. These reactions were carried out in acetone at reflux under catalyst-free conditions in the presence of triethylamine as a base for 3 h. NMR, FT-IR, EI-MS, and elemental studies were used to characterize the products' structural characteristics. The present study has also several benefits, such as excellent yields and the ease of workup procedure, making it an appealing, practical, and acceptable one-pot method for producing functionalized derivatives of dialkyl furan.

One-pot Twostep Chemobiocatalytic Synthesis of a Furan Amino Acid from 5-Hydroxymethylfurfural.

Recently, catalytic valorization of biomass-derived furans has received growing interest. 5-Aminomethyl-2-furancarboxylic acid (AMFC), a furan amino acid, holds great promise in the aeras of polymer and pharmaceutical, but its synthesis remains limited. In this work, we report a chemobiocatalytic route toward AMFC by combining laccase-TEMPO system and recombinant Escherichia coli (named E. coli_TAF) harboring ω-transaminase (TA), L-alanine dehydrogenase (L-AlaDH) and formate dehydrogenase (FDH), starting from 5-hydroxymethylfurfural (HMF). In the cascade, HMF is oxidized into 5-formyl-2-furancarboxylic acid (FFCA) by laccase-TEMPO system, and then the resulting intermediate is converted into AMFC by E. coli_TAF via transamination with cheap ammonium formate instead of costly organic amine donors, theoretically generating H2O and CO2 as by-products. The tandem process was run in a one-pot twostep manner, affording AMFC with approximately 81 % yield, together with 10 % 2,5-furandicarboxylic acid (FDCA) as by-product. In addition, the scale-up production of AMFC was demonstrated, with 0.41 g/L h productivity and 8.6 g/L titer. This work may pave the way for green manufacturing of the furan-containing amino acid.

Polychlorinated dibenzodioxins/furans and dioxin-like polychlorinated biphenyls in fish and crustaceans of a recreationally fished estuary, following targeted remediation.

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) are a suite of harmful chemicals (hereafter collectively referred to as 'dioxins'), and their emission into aquatic habitats leads to persistent contamination of sediments, aquatic food-webs, and seafoods. Quantifying contaminant levels in seafood species is important for the ongoing management of exposure risk by fishers, particularly after any remediation actions. We present dioxin concentrations in four seafood species (Yellowfin Bream Acanthopagrus australis, Sea Mullet Mugil cephalus, Eastern School Prawn Metapenaeus macleayi, and Eastern King Prawn Penaeus plebejus) in a recreationally fished estuary, in relation to a contaminated site that has undergone a remediation process, partially removing contaminated sediments (Homebush Bay, Port Jackson, New South Wales, Australia). Dioxin concentrations in these species were measured before (2005/6) and after (2015/16) remediation at a range of locations in and around the remediated site. Dioxin concentrations and congener profiles differed substantially among taxa, and concentrations were frequently higher than Australian screening criteria. The two prawn species showed evidence of a decline in dioxin concentrations after remediation, but the fish species only showed a declining dioxin concentration with distance from the contaminated site (not between periods). There were some minor changes in the congener profile for some species following remediation. While there was evidence for greatly reduced dioxin concentrations in prawn species following remediation, the complex patterns for fish were likely affected by environmental changes, species-specific and temporal changes in lipid content, and animal movement patterns. Future monitoring may aid interpretation of the patterns and modelling of exposure risk associated with seafood consumption into the future.

Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Poly-Substituted Furans from N-Tosylpropargyl Amines with 1,3-Dicarbonyl Compounds.

The treatment of N-tosylpropargyl amines 1 with 1,3-dicarbonyl compounds 2 in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) afforded poly-substituted furans 3 in good-to-high yields via the gold-catalyzed cleavage of the sp3 carbon-nitrogen bond.

Design and validation of a PCR screen for γ-butyrolactone-like regulatory systems in Streptomyces.

γ-butyrolactone and related signalling systems are found in Streptomyces and other actinobacteria where they control the production of secondary or specialized metabolites such as antibiotics. Genetic manipulation of these regulatory systems therefore leads to changes in the secondary metabolite profile of a strain and has been used to activate previously silent secondary metabolite gene clusters. However, there is no easy way to assess the presence of γ-butyrolactone-like systems in Streptomyces strains without whole-genome sequencing. We have therefore developed and tested a PCR screen that is able to detect homologues of the commonly co-located butenolide synthase and γ-butyrolactone receptor genes. This PCR screen could be employed for the screening of strain libraries to detect signalling systems without the necessity for whole-genome sequencing.

Palladium Iodide Catalyzed Multicomponent Carbonylative Synthesis of 2-(4-Acylfuran-2-yl)acetamides.

2-Propargyl-1,3-dicarbonyl compounds have been carbonylated under oxidative conditions and with the catalysis of the PdI2/KI catalytic system to selectively afford previously unreported 2-(4-acylfuran-2-yl)acetamides in fair to good yields (54-81%) over 19 examples. The process takes place under relatively mild conditions and occurs via a mechanistic pathway involving Csp-H activation by oxidative monoamincarbonylation of the terminal triple bond of the substrates with formation of 2-ynamide intermediates, followed by 5-exo-dig O-cyclization (via intramolecular conjugate addition of the in situ formed enolate to the 2-ynamide moiety) and aromative isomerization.

Two new 2-arylbenzo[b]furans from Itea indochinensis and their anti-hepatocellular carcinoma and anti-oxidant effects.

Two new 2-arylbenzo[b]furans (1-2) and ten known compounds (3-12) were identified from the 95% EtOH extract of the branches and leaves of Itea indochinensis for the first time. Their structures were determined mainly based on extensive analyses of UV, IR, 1D/2D NMR and HRMS spectra. The results of MTT assays demonstrated the anti-tumor potential of compound 1 with good selectivity, which displayed moderate inhibitory effects on proliferation of SK-hep-1 cells with IC50 value of 22.3 µM, while weak inhibitory effect on proliferation of HepG2 cells with an inhibition rate of 25% at 20 µM, and no obviously inhibitory effect on proliferation of A549 cells at 20 µM. In addition, compound 1 exhibited its significant scavenging capacity on ABTS·+ free radical with an IC50 value of 0.11 mg/mL, while weak scavenging effects on DPPH and O2·- radicals with scavenging ratios of 32.93% and 21.49% at 1 mg/mL, respectively.

Synthesis and Biological Studies of Benzo[b]furan Derivatives: A Review from 2011 to 2022.

The importance of the benzo[b]furan motif becomes evident in the remarkable results of numerous biological investigations, establishing its potential as a robust therapeutic option. This review presents an overview of the synthesis of and exhaustive biological studies conducted on benzo[b]furan derivatives from 2011 to 2022, accentuating their exceptional promise as anticancer, antibacterial, and antifungal agents. Initially, the discussion focuses on chemical synthesis, molecular docking simulations, and both in vitro and in vivo studies. Additionally, we provide an analysis of the intricate interplay between structure and activity, thereby facilitating comparisons and profoundly emphasizing the applications of the benzo[b]furan motif within the realms of drug discovery and medicinal chemistry.

Comparison of volatile compounds during biological ageing and commercial storage of Cava (Spanish sparkling wine): The role of lees.

Cava is a sparkling wine produced using a traditional method that must be aged in contact with lees for a minimum period of nine months. The contact between wine and lees improves the quality of the final product, and aroma is one of the most important qualitative parameters of a wine. The aim of the work was to study the role of lees in the ageing of Spanish sparkling wine (Cava), by sampling at industrial scale the bottles, from 9 to 30 months of ageing, jointly with the winery and in real time. The volatile profile of Cava during biological ageing and commercial storage, after disgorging, was evaluated by Headspace-Solid Phase Microextraction coupled to gas chromatography-mass spectrometry. More than 60 compounds were identified from several chemical classes including esters, alcohols, terpenes, furans, norisoprenoids, and fatty acids. A reduction in volatile components was observed when the disgorging step took place. When the behaviour of aroma over time was assessed, the principal factor that discriminated between samples was the type of ageing i.e. with or without lees. Evaluation of volatiles over time revealed that furans showed a significant relationship with ageing, indicating that some components of this family could be possible markers of ageing.

Occurrence and carcinogenic potential of airborne PBDD/Fs and PCDD/Fs around a large-scale municipal solid waste incinerator: A long-term passive air sampling study.

Municipal solid waste incinerator (MSWI) not only is deemed one of the uppermost sources of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), but also produces substantial amount of polybrominated dibenzo-p-dioxins/furans (PBDD/Fs) owing to the existence of brominated flame retardants (BFRs) in the waste. So far, however, PBDD/Fs in the vicinal environments of MSWI and their associated risks remain rarely studied. Based on a one-year passive air sampling (PAS) scheme, we investigated airborne PBDD/Fs and PCDD/Fs around a large-scale MSWI that has been operated for multi-years. Both the concentrations of PBDD/Fs and PCDD/Fs showed spatially decreasing trends with the distance away from the MSWI, confirming the influence of the MSWI on the dioxin levels in its ambient air. But its influence on PBDD/Fs was less because PBDD/Fs exhibit lower volatility and therefore lower gaseous concentrations than PCDD/Fs. Compared to the existing global data of airborne PCDD/Fs and PBDD/Fs, our data of the MSWI vicinity were at medium levels, despite PAS samples only represent the concentrations of gaseous dioxins in theory. The seasonal data suggest that meteorological conditions exerted apparent influences over the concentrations and sources of airborne dioxins around the MSWI. As for PCDD/Fs, the MSWI was diagnosed as their uppermost source, followed by local traffic and volatilization/deposition. Whereas the top three PBDD/F sources were related to PBDEs, bromophenol/bromobenzene, and traffic vehicles, respectively. The bioassay-derived TEQs based on the aryl hydrocarbon receptor activation of airborne dioxins around the MSWI were one or two orders of magnitudes higher than their concentration-based TEQs, and the corresponding carcinogenic risks at some MSWI-vicinal sites exceeded the acceptable threshold proposed by the U. S. EPA (10-6 âˆ¼ 10-4) and deserve continuous attention.

A Versatile Route to Acyl (MIDA)Boronates.

A modular approach to highly functional acyl (MIDA)boronates is described. It involves the generation of the hitherto unknown radical derived from acetyl (MIDA)boronate and its capture by various alkenes, including electronically unbiased, unactivated alkenes. In contrast to the anion of acetyl (MIDA)boronate, which has not so far been employed in synthesis, the corresponding radical is well behaved and readily produced from the novel α-xanthyl acetyl (MIDA)boronate. This shelf-stable, easily prepared solid is a convenient acyl (MIDA)boronate transfer agent that provides a direct entry to numerous otherwise inaccessible structures, including latent 1,4-dicarbonyl derivatives that can be transformed into B(MIDA) substituted pyrroles and furans. A competition experiment indicated the acyl (MIDA)boronate substituted radical to be more stable than the all-carbon acetonyl radical but somewhat less reactive in additions to alkenes.

Serum levels of PCDDs, PCDFs and dl-PCBs in general population residing far and near from an urban waste treatment plant under construction in Gipuzkoa, Basque Country (Spain).

This research focused on investigating the basal serum concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in the general population residing in two urban-industrial zones near and far from an energy recovery plant under construction in Gipuzkoa, Basque Country (Spain). The study used a cross-sectional design and included 227 participants who were randomly selected from municipal censuses in both areas. The participants were stratified based on age (ranging from 18 to 70 years) and sex. Serum samples were collected from the participants and analysed following the established protocol to measure the concentrations of PCDD/Fs and dl-PCBs. The study used multiple linear regression models to assess the impact of various sociodemographic variables, lifestyle factors, reproductive history, and diet on the variability of the measured compounds in the participants' serum. The median total toxicity equivalent (TEQ) in serum, was 10.58 pg WHO-TEQ2005 g-1 lipid. Serum PCDD levels were lower in the population residing in the "far" zone than the "near" zone. Age was positively associated with both PCDD/F and dl-PCB levels, indicating that older participants had higher concentrations of these compounds in their serum. This finding might be attributed to cumulative exposure over time. In terms of sex differences, women exhibited lower levels of dl-PCBs compared to men. Among lifestyle factors, smokers showed lower levels of dl-PCBs compared to non-smokers. Furthermore, daily alcohol consumption was significantly associated with higher serum levels of these compounds, with daily drinkers showing higher levels than non-drinkers. Consumption of local poultry was associated with significantly higher serum levels and oil consumption with low levels of PCDD/Fs.

Characterizing the formation of process contaminants during coffee roasting by multivariate statistical analysis.

Coffee is a relevant source of dietary exposure for neoformed furan, alkyl furans and acrylamide. In this study, different statistical methods (hierarchical cluster analysis, correlation analysis, partial least squares regression analysis) were used for characterizing the formation of these process contaminants in green coffee beans roasted under the same standardized conditions. The results displayed a strong correlation between sucrose levels and furans in relation to the other sugars analyzed, while acrylamide formation was strongly related to the free asparagine. The data suggest that a sufficiently large amino acid pool in green coffee favors Maillard-induced acrylamide formation from asparagine, while reactions amongst the carbonyl-containing sugar fragmentation products leading to furan formation are suppressed. If the pool of free amino acids is small, it is depleted faster during roasting, thus favoring the formation of furans by caramelization, basically a sugar degradation process in which reactive carbonyl substances are generated and react together.