In Vitro and in Vivo Study of a Photostable Quinone Compound with Enhanced Therapeutic Efficacy against Chagas Disease.

Chagas disease, a neglected tropical disease caused by the protozoan Trypanosoma cruzi poses a significant health challenge in rural areas of Latin America. The current pharmacological options exhibit notable side effects, demand prolonged administration, and display limited efficacy. Consequently, there is an urgent need to develop drugs that are safe and clinically effective. Previously, we identified a quinone compound (designated as compound 2) with potent antiprotozoal activity, based on the chemical structure of komaroviquinone, a natural product renowned for its antitrypanosomal effects. However, compound 2 was demonstrated considerably unstable to light. In this study, we elucidated the structure of the light-induced degradation products of compound 2 and probed the correlation between the quinone ring's substituents and its susceptibility to light. Our findings led to the discovery of quinones with significantly enhanced light stability, some of which exhibiting antitrypanosomal activity. The most promising compound was evaluated for drug efficacy in a mouse model of Chagas disease, revealing where a notable reduction in blood parasitemia.

Aromatic amine antioxidants (AAs) and p-phenylenediamines-quinones (PPD-Qs) in e-waste recycling industry park: Occupational exposure and liver X receptors (LXRs) disruption potential.

Recently, evidence of aromatic amine antioxidants (AAs) existence in the dust of the electronic waste (e-waste) dismantling area has been exposed. However, there are limited studies investigating occupational exposure and toxicity associated with AAs and their transformation products (p-phenylenediamines-quinones, i.e., PPD-Qs). In this study, 115 dust and 42 hand wipe samples collected from an e-waste recycling industrial park in central China were analyzed for 19 AAs and 6 PPD-Qs. Notably, the median concentration of ∑6PPD-Qs (1,110 ng/g and 1,970 ng/m2) was significantly higher (p < 0.05, Mann-Whitney U test) than that of ∑6PPDs (147 ng/g and 34.0 ng/m2) in dust and hand wipes. Among the detected analytes, 4-phenylaminodiphenylamine quinone (DPPD-Q) (median: 781 ng/g) and 1,4-Bis(2-naphthylamino) benzene quinone (DNPD-Q) (median: 156 ng/g), were particularly prominent, which were first detected in the e-waste dismantling area. Occupational exposure assessments and nuclear receptor interference ability, conducted through estimated daily intake (EDI) and molecular docking analysis, respectively, indicated significant occupational exposure to PPD-Qs and suggested prioritized Liver X receptors (LXRs) disruption potential of PPDs and PPD-Qs. The study provides the first evidence of considerable levels of AAs and PPD-Qs in the e-waste-related hand wipe samples and underscores the importance of assessing occupational exposure and associated toxicity effects.

Comparison of intestinal toxicity in enhancing intestinal permeability and in causing ROS production of six PPD quinones in Caenorhabditis elegans.

As the derivatives of p-phenylenediamines (PPDs), PPD quinones (PPDQs) have received increasing attention due to their possible exposure risk. We compared the intestinal toxicity of six PPDQs (6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ and IPPDQ) in Caenorhabditis elegans. In the range of 0.01-10 µg/L, only 77PDQ (10 µg/L) moderately induced the lethality. All the examined PPDQs at 0.01-10 µg/L did not affect intestinal morphology. Different from this, exposure to 6-PPDQ (1-10 µg/L), 77PDQ (0.1-10 µg/L), CPPDQ (1-10 µg/L), DPPDQ (1-10 µg/L), DTPDQ (1-10 µg/L), and IPPDQ (10 µg/L) enhanced intestinal permeability to different degrees. Meanwhile, exposure to 6-PPDQ (0.1-10 µg/L), 77PDQ (0.01-10 µg/L), CPPDQ (0.1-10 µg/L), DPPDQ (0.1-10 µg/L), DTPDQ (1-10 µg/L), and IPPDQ (1-10 µg/L) resulted in intestinal reactive oxygen species (ROS) production and activation of both SOD-3::GFP and GST-4::GFP. In 6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ, and/or IPPDQ exposed nematodes, the ROS production was strengthened by RNAi of genes (acs-22, erm-1, hmp-2, and pkc-3) governing functional state of intestinal barrier. Additionally, expressions of acs-22, erm-1, hmp-2, and pkc-3 were negatively correlated with intestinal ROS production in nematodes exposed to 6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ, and/or IPPDQ. Therefore, exposure to different PPDQs differentially induced the intestinal toxicity on nematodes. Our data highlighted potential exposure risk of PPDQs at low concentrations to organisms by inducing intestinal toxicity.

Dihydrotanshinone I exhibits antitumor effects via ß-catenin downregulation in papillary thyroid cancer cell lines.

Thyroid cancer is the most common endocrine carcinoma and, among its different subtypes, the papillary subtype (PTC) is the most frequent. Generally, PTCs are well differentiated, but a minor percentage of PTCs are characterized by a worse prognosis and more aggressive behavior. Phytochemicals, naturally found in plant products, represent a heterogeneous group of bioactive compounds that can interfere with cell proliferation and the regulation of the cell cycle, taking part in multiple signaling pathways that are often disrupted in tumor initiation, proliferation, and progression. In this work, we focused on 15,16-dihydrotanshinone I (DHT), a tanshinone isolated from Salvia miltiorrhiza Bunge (Danshen). We first evaluated DHT biological effect on PTC cells regarding cell viability, colony formation ability, and migration capacity. All of these parameters were downregulated by DHT treatment. We then investigated gene expression changes after DHT treatment by performing RNA-seq. The analysis revealed that DHT significantly reduced the Wnt signaling pathway, which plays a role in various diseases, including cancer. Finally, we demonstrate that DHT treatment decreases protein levels of ß-catenin, a final effector of canonical Wnt signaling pathway. Overall, our data suggest a possible use of this nutraceutical as an adjuvant in the treatment of aggressive papillary thyroid carcinoma.

Electrochemical Analysis for Total Alkalinity of Water by the Measurement of Cathodic Prepeak of Quinone Caused by Surplus Acid.

In this study, an electrochemical analysis, coupled with the concept of back neutralization titration and the voltammetric determination of surplus acid, is proposed for determining the total alkalinity of water samples. When linear sweep voltammetry of 3,5-di-tert-butyl-1,2-benzoquinone (DBBQ) with H2SO4 in a water and ethanol (44 : 56, v/v) mixture was carried out using a bare glassy carbon working electrode, a cathodic prepeak of DBBQ caused by H2SO4 was observed on the voltammogram at a more positive potential than when compared with the original cathodic peak of DBBQ. When similar voltammetry was carried out in the presence of Na2CO3 and H2SO4, the cathodic prepeak height of DBBQ was decreased with an increase in the Na2CO3 concentration. The decrease of the cathodic prepeak height of DBBQ was found to be linearly related to the Na2CO3 concentration ranging from 0.025 to 2.5 mM (r2 = 0.998). The total equivalent concentrations of inorganic bases in samples of mineral water and tap water were determined, and then the results were converted to the total alkalinities of the water samples (mg/L CaCO3). The total alkalinities of the water samples determined by the present electrochemical analysis were essentially the same compared with those by the neutralization titration method. From these results, we were able to demonstrate that the present electrochemical analysis with accuracy and precision could be applied to determine the total alkalinity, which is one of the indicators to examine water quality. The present electrochemical analysis would contribute to achieving the sustainable development goals (SDGs) of #6 and #14.

Engineering substrate specificity of quinone-dependent dehydrogenases for efficient oxidation of deoxynivalenol to 3-keto-deoxynivalenol.

The oxidative reaction of Fusarium mycotoxin deoxynivalenol (DON) using the dehydrogenase is a desirable strategy and environmentally friendly to mitigate its toxicity. However, a critical issue for these dehydrogenases shows widespread substrate promiscuity. In this study, we conducted pocket reshaping of Devosia strain A6-243 pyrroloquinoline quinone (PQQ)-dependent dehydrogenase (DADH) on the basis of protein structure and kinetic analysis of substrate libraries to improve preference for particular substrate DON (10a). The variant presented an increased preference for substrate 10a and enhanced catalytic efficiency. A 4.7-fold increase in preference for substrate 10a was observed. Kinetic profiling and molecular dynamics (MD) simulations provided insights into the enhanced substrate specificity and activity. Moreover, the variant exhibited stronger conversion of substrate 10a to 3-keto-DON compared to the wild DADH. Overall, this study provides a feasible protocol for the redesign of PQQ-dependent dehydrogenases with favourable substrate specificity and catalytic activity, which is desperately needed for DON antidote development.

Mixture toxicity of 6PPD-quinone and polystyrene nanoplastics in zebrafish.

Plastic pollution, including micro- and nanoplastics, is a growing concern. Tyre-wear particles (TWPs) are the second largest source of microplastics in the ocean following abrasion of synthetic fibres. In addition to the particles themselves, TWPs contain many harmful chemicals, including 6PPD. This chemical reacts with atmospheric ozone and forms the toxic compound 6PPD-quinone (6PPDq), which poses a danger to aquatic life. There is a knowledge gap in understanding risks associated with the combined toxicity of nanoplastics (NPs) and 6PPDq. The present study aimed to investigate the toxicity of NPs and 6PPDq on adult zebrafish using phenotypic (behaviour, histology) and transcriptomic endpoints. Zebrafish were exposed to four treatments: control (contaminant-free), 50 µg/L 6PPDq, 3 mg/L polystyrene (PS)-NPs, and a combination of 50 µg/L 6PPDq and 3 mg/L PS-NPs. We did not observe locomotory dysregulation in zebrafish exposed to NPs. However, we found significant hyperlocomotion in zebrafish exposed to 6PPDq and this effect was even more substantial after co-exposure with PS-NPs. This study explores the molecular mechanisms behind these effects, identifying genes associated with neurotransmitters and fatty acid metabolism that were dysregulated by the co-exposure. Transcriptomic analysis further showed that both 6PPDq and PS-NPs impacted cellular processes associated with sterol biosynthesis, cholesterol metabolism, and muscle tissue development. The effects on these mechanisms were stronger in co-exposed zebrafish, indicating a heightened risk to cellular integrity and mitochondrial dysfunction. These results highlight the significance of mixture toxicity when studying the effects of NPs and associated chemicals like 6PPDq.

Fragmentation Pattern-Based Screening Strategy Combining Diagnostic Ion and Neutral Loss Uncovered Novel para-Phenylenediamine Quinone Contaminants in the Environment.

Identifying transformed emerging contaminants in complex environmental compartments is a challenging but meaningful task. Substituted para-phenylenediamine quinones (PPD-quinones) are emerging contaminants originating from rubber antioxidants and have been proven to be toxic to the aquatic species, especially salmonids. The emergence of multiple PPD-quinones in various environmental matrices and evidence of their specific hazards underscore the need to understand their environmental occurrences. Here, we introduce a fragmentation pattern-based nontargeted screening strategy combining full MS/All ion fragmentation/neutral loss-ddMS2 scans to identify potential unknown PPD-quinones in different environmental matrices. Using diagnostic fragments of m/z 170.0600, 139.0502, and characteristic neutral losses of 199.0633, 138.0429 Da, six known and three novel PPD-quinones were recognized in air particulates, surface soil, and tire tissue. Their specific structures were confirmed, and their environmental concentration and composition profiles were clarified with self-synthesized standards. N-(1-methylheptyl)-N'-phenyl-1,4-benzenediamine quinone (8PPD-Q) and N,N'-di(1,3-dimethylbutyl)-p-phenylenediamine quinone (66PD-Q) were identified and quantified for the first time, with their median concentrations found to be 0.02-0.21 µg·g-1 in tire tissue, 0.40-2.76 pg·m-3 in air particles, and 0.23-1.02 ng·g-1 in surface soil. This work provides new evidence for the presence of unknown PPD-quinones in the environment, showcasing a potential strategy for screening emerging transformed contaminants in the environment.

Toxicity of substituted p-phenylenediamine antioxidants and their derived novel quinones on aquatic bacterium: Acute effects and mechanistic insights.

Substituted para-phenylenediamines (PPDs) are synthetic chemicals used globally for rubber antioxidation, with their quinone derivatives (PPD-Qs) raising particular environmental concerns due to their severe toxicity to aquatic organisms. Emerging research has identified a variety of novel PPD-Qs ubiquitously detected in the environment, yet experimental proof for the toxicity of PPD-Qs has not been forthcoming due to the unavailability of bulk standards, leaving substantial gaps in the prioritization and mechanistic investigation of such novel pollutants. Here, we use synthesized chemical standards to study the acute toxicity and underlying mechanism of 18 PPD-Qs and PPDs to the aquatic bacterium V. fischeri. Bioluminescence inhibition EC50 of PPD-Qs ranged from 1.76-15.6 mg/L, with several emerging PPD-Qs demonstrating significantly higher toxicity than the well-studied 6PPD-Q. This finding suggests a broad toxicological threat PPD-Qs pose to the aquatic bacterium, other than 6PPD-Q. Biological response assays revealed that PPD-Qs can reduce the esterase activity, cause cell membrane damage and intracellular oxidative stress. Molecular docking unveiled multiple interactions of PPD-Qs with the luciferase in V. fischeri, suggesting their potential functional impacts on proteins through competitive binding. Our results provided crucial toxicity benchmarks for PPD-Qs, prioritized these novel pollutants and shed light on the potential toxicological mechanisms.

A nation-wide study for the occurrence of PPD antioxidants and 6PPD-quinone in road dusts of China.

N,N'-substituted p-phenylenediamines (PPDs) are widely used antioxidants in rubber tires, which could be released and accumulated in road dusts with rubber tires wear. As ozonation product of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), 6PPD-quinone (6PPD-Q) exhibited higher toxicity to coho salmon. However, studies on their environmental behaviors are still limited. Road dust is the major medium PPDs exist, which significantly affects the levels of PPDs in other mediums, especially surface water and particulate matter. In this study, road dust samples were collected in 55 major cities of China to explore the distribution characteristics of PPDs and 6PPD-Q. The concentrations of total PPDs (ΣPPDs) and 6PPD-Q in urban trunk road dust samples were in the ranges of 7.90-727 and 3.00-349 ng/g, with median concentrations of 68 and 49 ng/g, respectively. 6PPD and 6PPD-Q are the dominant components in most road dusts. The functional region-dependent pollution characteristics of PPDs and 6PPD-Q give the first finding that urban tunnel road was the highly polluted region, followed by urban trunk roads. Suburban road dusts had a lower pollution level. Moreover, the estimated daily intake (EDI) of PPDs and 6PPD-Q for children was much higher than adults.

Hydroxy-Safflower Yellow A Mitigates Vascular Remodeling in Rat Pulmonary Arterial Hypertension.

Purpose: The underlying causes of pulmonary arterial hypertension (PAH) often remain obscure. Addressing PAH with effective treatments presents a formidable challenge. Studies have shown that Hydroxysafflor yellow A (HSYA) has a potential role in PAH, While the mechanism underlies its protective role is still unclear. The study was conducted to investigate the potential mechanisms of the protective effects of HSYA. Methods: Using databases such as PharmMapper and GeneCards, we identified active components of HSYA and associated PAH targets, pinpointed intersecting genes, and constructed a protein-protein interaction (PPI) network. Core targets were singled out using Cytoscape for the development of a model illustrating drug-component-target-disease interactions. Intersection targets underwent analysis for Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Selected components were then modeled for target interaction using Autodock and Pymol. In vivo validation in a monocrotaline-induced PAH (MCT-PAH) animal model was utilized to substantiate the predictions made by network pharmacology. Results: We associated HSYA with 113 targets, and PAH with 1737 targets, identifying 34 mutual targets for treatment by HSYA. HSYA predominantly affects 9 core targets. Molecular docking unveiled hydrogen bond interactions between HSYA and several PAH-related proteins such as ANXA5, EGFR, SRC, PPARG, PGR, and ESR1. Conclusion: Utilizing network pharmacology and molecular docking approaches, we investigated potential targets and relevant human disease pathways implicating HSYA in PAH therapy, such as the chemical carcinogenesis receptor activation pathway and the cancer pathway. Our findings were corroborated by the efficacious use of HSYA in an MCT-induced rat PAH model, confirming its therapeutic potential.

High-contrast NIR fluorescent probes for selective detection of NQO1 in breast cancer.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a potential biomarker for breast cancer (BC) diagnosis and prognosis. However, existing fluorescent probes for NQO1 detection have limitations such as short emission wavelength, weak fluorescence response, or large background interference. Here, we developed two novel near-infrared (NIR) fluorescent probes, DCl-Q and DCl2-Q, that selectively detect NQO1 activity in BC cells and tissues. They consist of a trimethyl-locked quinone as the recognition group and a donor-π-acceptor structure with halogen atoms as the reporter group. They exhibit strong fluorescence emission at around 660 nm upon binding to NQO1. We demonstrated that they can distinguish BC cells with different NQO1 expression levels and image endogenous NQO1 in tumor-bearing mice. Our probes provide a convenient and highly sensitive tool for BC diagnosis and prognosis based on NQO1 detection.

Influences of compound age and identity in the effectiveness of insect quinone secretions against the fungus Beauveria bassiana.

Chemical defences against parasites and pathogens can be seen in a wide range of animal taxa, including insect pests such as the red flour beetle Tribolium castaneum. Antimicrobial quinone-based secretions can be used by these beetles to defend against various parasites, particularly the fungal entomopathogen Beauveria bassiana. While quinone secretions can inhibit B. bassiana growth, it is unknown how long they remain effective or how individual secretion compounds contribute to growth inhibition. Here, we tested each individual component of the quinone secretions (methyl-1,4-benzoquinone, ethyl-1,4-benzoquinone, and 1-pentadecene), as well as two mixed solutions that represent the composition range found in natural T. castaneum secretions, after aging for 0, 24, or 72 h. The two quinone compounds equally contributed to B. bassiana inhibition, but their efficacy was significantly reduced after 24 h, with no growth inhibition after 72 h. This indicates that quinones protect insects against B. bassiana for only a limited time, perhaps requiring constant secretion into the environment to effectively defend against this fungal threat. Future investigations may consider the extent to which quinone secretions are effective against other parasites, as well as how their ability to cause parasite damage changes with compound age.

Formation of phenazines, phenoxazines, and benzoxazoles in the browning reactions of o-quinones.

Quinone-induced browning is widely produced in foods and is mostly considered a consequence of quinone/nucleophile reactions. However, even in the absence of amino acids or proteins, o-quinones develop browning. In an attempt to better understand the reaction pathways involved in this browning development, this study describes the reactions of 4-methyl-1,2-benzoquinone with alcohols, ammonia, and short chain aldehydes. These reaction mixtures developed browning at 37 °C and the main produced compounds were isolated by semipreparative HPLC and characterized by NMR and MS as phenazines, phenoxazines, and benzoxazoles. A reaction pathway that explains the formation of all these compounds is proposed. The formation of phenazines is responsible, at least partially, for the produced browning, and the formation of benzoxazoles inhibits such browning. Browning development seems to be a consequence of a competition among the reactions of formation of phenazines, phenoxazines, and benzoxazoles, which appear to be produced from a single intermediate.

Widespread occurrence of two typical N, N'-substituted p-phenylenediamines and their quinones in humans: Association with oxidative stress and liver damage.

While N, N'-substituted p-phenylenediamines (PPDs) and their quinone derivatives (PPDQs) have been widely detected in the environment, there is currently limited data on their occurrence in humans. In this study, we conducted the first serum analysis of two PPDs and PPDQs in the healthy and secondary nonalcoholic fatty liver disease (S-NAFLD) cohorts in South China. The concentrations of four oxidative stress biomarkers (OSBs), namely, 8-iso-prostaglandin F2α (8-PGF2α), 11ß-prostaglandin F2α (11-PGF2α), 15(R)-prostaglandin F2α (15-PGF2α), and 8-hydroxy-2'-deoxyguanosine in serum samples were also measured. Results showed that N-(1,3-dimethybutyl)-N'-phenyl-p-phenylenediamine (6PPD) quinone was the predominant target analytes both in the healthy and S-NAFLD cohorts, with the median concentrations of 0.13 and 0.20 ng/mL, respectively. Significant (p < 0.05) and positive correlations were found between 6PPD concentration and 8-PGF2α, 11-PGF2α, and 15-PGF2α in both the healthy and S-NAFLD cohorts, indicating that 6PPD may be associated with lipid oxidative damage. In addition, concentrations of 6PPD in serum were associated significantly linked with total bilirubin (ß = 0.180 µmol/L, 95%CI: 0.036-0.396) and direct bilirubin (DBIL, ß = 0.321 µmol/L, 95%CI: 0.035-0.677) related to hepatotoxicity. Furthermore, 8-PGF2α, 11-PGF2α, and 15-PGF2α mediated 17.1%, 24.5%, and 16.6% of 6PPD-associated DBIL elevations, respectively. Conclusively, this study provides novel insights into human exposure to and hepatotoxicity assessment of PPDs and PPDQs.

Evaluation of 6-PPD quinone toxicity on lung of male BALB/c mice by quantitative proteomics.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ), a transformation product of tyre-derived 6-PPD, has been frequently detected in different environments. After 6-PPDQ exposure, we here aimed to examine dynamic lung bioaccumulation, lung injury, and the underlying molecular basis in male BALB/c mice. After single injection at concentration of 4 mg/kg, 6-PPDQ remained in lung up to day 28, and higher level of 6-PPDQ bioaccumulation in lung was observed after repeated injection. Severe inflammation was observed in lung after both single and repeated 6-PPDQ injection as indicated by changes of inflammatory cytokines (TNF-α, IL-6 and IL-10). Sirius red staining and hydroxyproline content analysis indicated that repeated rather than single 6-PPDQ injection induced fibrosis in lung. Repeated 6-PPDQ injection also severely impaired lung function in mice by influencing chord compliance (Cchord) and enhanced pause (Penh). Proteomes analysis was further carried out to identify molecular targets of 6-PPDQ after repeated injection, which was confirmed by transcriptional expression analysis and immunohistochemistry staining. Alterations in Ripk1, Fadd, Il-6st, and Il-16 expressions were identified to be associated with inflammation induction of lung after repeated 6-PPDQ injection. Alteration in Smad2 expression was identified to be associated with fibrosis formation in lung of 6-PPDQ exposed mice. Therefore, long-term and repeated 6-PPDQ exposure potentially resulted in inflammation and fibrosis in lung by affecting certain molecular signals in mammals. Our results suggested several aspects of lung injury caused by 6-PPDQ and provide the underlying molecular basis. These observations implied the possible risks of long-term 6-PPDQ exposure to human health.

Transcriptome analysis of the bloom-forming dinoflagellate Prorocentrum donghaiense exposed to Ginkgo biloba leaf extract, with an emphasis on photosynthesis.

Ginkgo biloba leaf extract (GBE) can effectively treat bloom-forming freshwater algae. However, there is limited information about the underlying suppression mechanism of the marine bloom-forming Prorocentrum donghaiense-the most dominant algal bloom species in the East China Sea. We investigated the effect of GBE on P. donghaiense in terms of its response to photosynthesis at the molecular/omic level. In total, 93,743 unigenes were annotated using six functional databases. Furthermore, 67,203 differentially expressed genes (DEGs) were identified in algae treated with 1.8 g∙L-1 GBE. Among these DEGs, we identified the genes involved in photosynthesis. PsbA, PsbB and PsbD in photosystem II, PsaA in photosystem I, and PetB and PetD in the cytochrome b6/f complex were downregulated. Other related genes, such as PsaC, PsaE, and PsaF in photosystem I; PetA in the cytochrome b6/f complex; and atpA, atpD, atpH, atpG, and atpE in the F-type H+-ATPase were upregulated. These results suggest that the structure and activity of the complexes were destroyed by GBE, thereby inhibiting the electron flow between the primary and secondary quinone electron acceptors, primary quinone electron acceptor, and oxygen-evolving complex in the PSII complex, and interrupting the electron flow between PSII and PSI, ultimately leading to a decline in algal cell photosynthesis. These findings provide a basis for understanding the molecular mechanisms underlying P. donghaiense exposure to GBE and a theoretical basis for the prevention and control of harmful algal blooms.

Self-Oxidated Hydrophilic Chitosan Fibrous Mats for Fatal Hemorrhage Control.

Enriching erythrocytes and platelets in seconds and providing a fast seal in bleeding sites is vital to fatal hemorrhage control. Herein, hydrophilic chitosan fibrous mats (CECS-D mats) are fabricated by introducing hydrophilic carboxyethyl groups and subsequent catechol groups onto chitosan fibers. Due to strong hydrophilicity, CECS-D mats exhibit rapid liquid-absorption capacity, especially instantaneous absorptivity to the rabbit blood, which can achieve erythrocyte and platelet aggregations quickly by concentrating blood, thus promoting the formation of blood clots. Furthermore, the mats are self-oxidated to form quinone-amine adducts or quinone multimers by adjusting pH conditions, which not only provides tissue adhesion but also induces erythrocyte aggregation and platelet adhesion, further enhancing the seal and triggering quick closure to achieve fast hemostasis. Therefore, the mats reveal superior hemostatic performance in rabbit liver and spleen models over CECS mats and gauze. Especially in the fatal femoral artery injury model of rabbits, the mats reduce the blood loss by ∼75% and shortened the bleeding time by ∼50% compared with CECS mats, which have been reported to have the same hemostatic effect as commercialized Celox products in a swine femoral artery injury model. Besides, the mats are cytocompatible and degradable as well as antibacterial. This chitosan mat is a promising hemostatic material for fatal hemorrhage control.

Environmentally realistic dose of tire-derived metabolite 6PPD-Q exposure causes intestinal jejunum and ileum damage in mice via cannabinoid receptor-activated inflammation.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is a quinone derivative of a common tire additive 6PPD, whose occurrence has been widely reported both in the environment and human bodies including in adults, pregnant women and children. Yet, knowledge on the potential intestinal toxicity of 6PPD-Q in mammals at environmentally relevant dose remain unknown. In this study, the effects of 6PPD-Q on the intestines of adult ICR mice were evaluated by orally administering environmentally relevant dose or lower levels of 6PPD-Q (0.1, 1, 10, and 100 µg/kg) for 21 days. We found that 6PPD-Q disrupted the integrity of the intestinal barrier, mostly in the jejunum and ileum, but not in the duodenum or colon, in a dose-dependent manner. Moreover, intestinal inflammation manifested with elevated levels of TNF-α, IL-1, and IL-6 mostly observed in doses at 10 and 100 µg/kg. Using reverse target screening technology combining molecular dynamic simulation modeling we identified key cannabinoid receptors including CNR2 activation to be potentially mediating the intestinal inflammation induced by 6PPD-Q. In summary, this study provides novel insights into the toxic effects of emerging contaminant 6PPD-Q on mammalian intestines and that the chemical may be a cannabinoid receptor agonist to modulate inflammation.

Polyethylene nanoparticles at environmentally relevant concentrations enhances neurotoxicity and accumulation of 6-PPD quinone in Caenorhabditis elegans.

The exposure risk of 6-PPD quinone (6-PPDQ) has aroused increasing concern. In the natural environment, 6-PPDQ could interact with other pollutants, posing more severe environmental problems and toxicity to organisms. We here examined the effect of polyethylene nanoplastic (PE-NP) on 6-PPDQ neurotoxicity and the underling mechanisms in Caenorhabditis elegans. In nematodes, PE-NP (1 and 10 µg/L) decreased locomotion behavior, but did not affect development of D-type neurons. Exposure to PE-NP (1 and 10 µg/L) strengthened neurotoxicity of 6-PPDQ (10 µg/L) on the aspect of locomotion and neurodegeneration induction of D-type motor neurons. Exposure to PE-NPs (10 µg/L) caused increase in expressions of mec-4, asp-3, and asp-4 governing neurodegeneration in 10 µg/L 6-PPDQ exposed nematodes. Moreover, exposure to PE-NP (10 µg/L) increased expression of some neuronal genes (daf-7, dbl-1, jnk-1, and mpk-1) in 6-PPDQ exposed nematodes, and RNAi of these genes resulted in susceptibility to neurotoxicity of PE-NP and 6-PPDQ. 6-PPDQ could be adsorbed by PE-NPs, and resuspension of PE-NP and 6-PPDQ after adsorption equilibrium exhibited similar neurotoxicity to co-exposure of PE-NP and 6-PPDQ. In addition, exposure to PE-NP (1 and 10 µg/L) increased 6-PPDQ accumulation in body of nematodes and increased defecation cycle length in 6-PPDQ exposed nematodes. Therefore, 6-PPDQ could be adsorbed on nanoplastics (such as PE-NPs) and enhance both neurotoxicity and accumulation of 6-PPDQ in organisms.