Azoxystrobin is a frequently used fungicide in agriculture. Its toxicological effects on non-target organisms have aroused attention. In the present work, the toxic effects of azoxystrobin on ...zebrafish (Danio rerio) were investigated. Male and female zebrafish were separately exposed to a control solution and three azoxystrobin treatments (1, 10, and 100μg/L) and were sampled on days 7, 14, 21, and 28. Reactive oxygen species (ROS) were accumulated in excess in the zebrafish livers. Superoxide dismutase (SOD) activity was significantly inhibited in the male zebrafish. Moreover, a notable decrease was also observed after day 21 in the female zebrafish. Catalase (CAT) activity was induced by the azoxystrobin treatments with the exception of the 1μg/L treatment. A significant increase in glutathione-S-transferase (GST) activity was observed after day 21. Lipid peroxidation (LPO) was generated, and DNA damage was enhanced in a concentration-dependent manner. In conclusion, azoxystrobin induced oxidative stress and genotoxicity in zebrafish livers.
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•Azoxystrobin induced oxidative stress and genotoxicity in zebrafish livers.•ROS was generated in excess.•SOD was inhibited, CAT and GST were stimulated at most azoxystrobin treatments.•Lipid peroxidation increased as a consequence of oxidative stress.•The excess ROS was one of the causes for the DNA damage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Aryl phosphorus-containing flame retardants (aryl-PFRs) have been frequently detected with increasingly used worldwide as one of alternatives for brominated flame retardants. However, information on ...their adverse effects on human health and ecosystem is insufficient, with limited study on their molecular mode of action in vitro. In this study, the cytotoxicity, DNA damage, mitochondrial impairment and the involved molecular mechanisms of certain frequently detectable aryl-PFRs, including 2-ethylhexyldiphenyl phosphate (EHDPP), methyl diphenyl phosphate (MDPP), bisphenol-A bis (diphenyl phosphate) (BDP), isodecyl diphenyl phosphate (IDPP), cresyl diphenyl phosphate (CDP) and the structurally similar and widely used organophosphorus pesticide chlorpyrifos (CPF), were evaluated in A549 cells using high-content screening (HCS) system. Aryl-PFRs showed different lethal concentration 50 (LC50) values ranging from 97.94 to 546.85 μM in A549 cells using CCK-8 assay. EHDPP, IDPP, CDP, MDPP and CPF demonstrated an ability to induce DNA damage, evidenced by increased DNA content and S phase-reducing cell cycle arrest effect using fluorophore dye cocktail assay. Additionally, the selected aryl-PFRs induced mitochondrial impairment by the increasing mitochondrial mass and decreasing mitochondrial membrane potential. Moreover, BDP, MDPP, and CDP, which contain short alkyl chains showed their potential oxidative stress with intracellular ROS and mitochondrial superoxide overproduction from an initially relatively low concentration. Additionally, based on the promotion of firefly luminescence in p53-transfected A549 cells, p53 activation was found to be involved in aryl-PFRs-induced DNA damage. Further real-time PCR results showed that all selected aryl-PFRs triggered p53/p21/gadd45β-, and p53/p21/mdm2-mediated cell cycle pathways, and the p53/bax mediated apoptosis pathway to induce DNA damage and cytotoxic effects. These results suggest that aryl-PFRs (e.g., BDP, MDPP, CDP) cause oxidative stress-mediated DNA damage and mitochondrial impairment, and p53-dependent pathway was involved in the aryl-PFRs-induced DNA damage and cell cycle arrest. In conclusion, this study improves the understanding of PFRs-induced adverse outcomes and the involved molecular mechanism.
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•The cytotoxicity, DNA damage, and mitochondrial impairment induced by aryl-PFRs were evaluated.•Aryl-PFRs induced oxidative stress-mediated DNA and mitochondrial damage.•EHDP, IDPP, CDP, MDPP and CPF exerted S phase cell ratio-reducing effects.•p53 pathway activation is an underlying mechanism of the induced DNA damage.•Cytotoxicity was evidenced by the upregulation of the p53/bax-mediated apoptosis pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Azoxystrobin has been widely used in recent years. The present study investigated the oxidative stress and DNA damage effects of azoxystrobin on earthworms (Eisenia fetida). Earthworms were exposed ...to different azoxystrobin concentrations in an artificial soil (0, 0.1, 1, and 10mg/kg) and sampled on days 7, 14, 21, and 28. Superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POD), glutathione-S-transferase (GST), reactive oxygen species (ROS), and malondialdehyde (MDA) content were measured by an ultraviolet spectrophotometer to determine the antioxidant responses and lipid peroxidation. Single cell gel electrophoresis (SCGE) was used to detect DNA damage in the coelomocytes. Compared with these in the controls, earthworms exposed to azoxystrobin had excess ROS accumulation and greater SOD, POD, and GST activity while the opposite trend occurred for CAT activity. MDA content increased after 14-day exposure, and DNA damage was enhanced with an increase in the concentration of azoxystrobin. In conclusion, azoxystrobin caused oxidative stress leading to lipid peroxidation and DNA damage in earthworms.
•Azoxystrobin induced oxidative stress and DNA damage in Eisenia fetida.•SOD, POD and GST were all stimulated by azoxystrobin, as opposed to CAT.•Azoxystrobin caused ROS accumulation and lipid peroxidation.•DNA damage increased with increasing azoxystrobin concentration and exposure time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The Open Targets (OT) Platform integrates a wide range of data sources on target-disease associations to facilitate identification of potential therapeutic drug targets to treat human diseases. ...However, due to the complexity that targets are usually functionally pleiotropic and efficacious for multiple indications, challenges in identifying novel target to indication associations remain. Specifically, persistent need exists for new methods for integration of novel target-disease association evidence and biological knowledge bases via advanced computational methods. These offer promise for increasing power for identification of the most promising target-disease pairs for therapeutic development. Here we introduce a novel approach by integrating additional target-disease features with machine learning models to further uncover druggable disease to target indications. We derived novel target-disease associations as supplemental features to OT platform-based associations using three data sources: (1) target tissue specificity from GTEx expression profiles; (2) target semantic similarities based on gene ontology; and (3) functional interactions among targets by embedding them from protein-protein interaction (PPI) networks. Machine learning models were applied to evaluate feature importance and performance benchmarks for predicting targets with known drug indications. The evaluation results show the newly integrated features demonstrate higher importance than current features in OT. In addition, these also show superior performance over association benchmarks and may support discovery of novel therapeutic indications for highly pursued targets. Our newly generated features can be used to represent additional underlying biological relatedness among targets and diseases to further empower improved performance for predicting novel indications for drug targets through advanced machine learning models. The proposed methodology enables a powerful new approach for systematic evaluation of drug targets with novel indications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background The identification of a target-indication pair is regarded as the first step in a traditional drug discovery and development process. Significant investment and attrition occur during ...discovery and development before a molecule is shown to be safe and efficacious for the selected indication and becomes an approved drug. Many drug targets are functionally pleiotropic and might be good targets for multiple indications. Methodologies that leverage years of scientific contributions on drug targets to allow systematic evaluation of other indication opportunities are critical for both patients and drug discovery and development scientists. Methods We introduced a network-based approach to systematically screen and prioritize disease indications for drug targets. The approach fundamentally integrates disease genomics data and protein interaction network. Further, the methodology allows for indication identification by leveraging state-of-art network algorithms to generate and compare the target and disease subnetworks. Results We first evaluated the performance of our method on recovering FDA approved indications for 15 randomly selected drug targets. The results showed superior performance when compared with other state-of-art approaches. Using this approach, we predicted novel indications supported by literature evidence for several highly pursued drug targets such as IL12/IL23 combination. Conclusions Our results demonstrated a potential global approach for indication expansion strategies. The proposed methodology enables rapid and systematic evaluation of both individual and combined drug targets for novel indications. Additionally, this approach provides novel insights on expanding the role of genes and pathways for developing therapeutic intervention strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With the rapid development of electric vehicles (EVs) industry, EV charging service becomes more and more important. Especially, in the case of suddenly drop of air temperature or open holidays that ...large-scale EVs seeking for charging devices (CDs) in a short time. In such scenario, inefficient EV charging scheduling algorithm might lead to a bad service quality, for example, long queueing times for EVs and unreasonable idling time for charging devices. To deal with this issue, this paper propose a Deep-Q-Network (DQN) based two-stage scheduling method for the large-scale EVs charging service. Fine-grained states with two delicate neural networks are proposed to optimize the sequencing of EVs and charging station (CS) arrangement. Two efficient algorithms are presented to obtain the optimal EVs charging scheduling scheme for large-scale EVs charging demand. Three case studies show the superiority of our proposal, in terms of a high service quality (minimized average queuing time of EVs and maximized charging performance at both EV and CS sides) and achieve greater scheduling efficiency. The code and data are available at THE CODE AND DATA. Keywords: charging service, cyber-physical system, deep reinforcement learning, EV charging scheduling algorithm, surge demands.
Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. ...However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.
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•TCEP was less cytotoxic than TCPP in A549 cells.•Both TCEP and TCPP induced oxidative stress and mitochondrial damage.•TCPP resulted in S phase cell decreased, which was greater than that of TCEP.•TCPP induces intact p53/p21/Gadd45β-mediated cell cycle-related signaling pathways.•TCPP activated the p53/Bax-mediated apoptosis pathway with stronger toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Helicobacter pylori (H. pylori), a pathogen inducing peptic disease, is recently found to be binding to the progress of periodontitis. Most previous studies are case-controlled, and they investigate ...the risk of H. pylori infection in disease the development of while few studies evaluate the correlation between H. pylori and periodontal pathogens. Therefore, we investigated the correlation between H. pylori infection with periodontal parameters, periodontal pathogens and inflammation. The results indicated that patients with H. pylori showed significantly higher probing depth and attachment loss than those without (p < 0.05). Among 28 subgingival plaque samples from 14 patients, the frequencies of Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum and Treponema denticola were significantly higher with H. pylori infection than those without H. pylori infection (p < 0.05). However, the frequency of Aggregatibacter actinomycetemcomitans was lower (p < 0.05). Furthermore, after human acute monocytic leukemia cell line (THP-1) was stimulated with cagA-positive standard strains (cagA+ H. pylori 26695), the expression of periodontitis-related molecules Wnt5a, interleukin 8 (IL-8), interleukin 6 (IL-6) and interferon gamma (IFN-γ) significantly increased (p < 0.05). Conversely, the expression of tumor necrosis factor alpha (TNF-α) was almost stable. Meanwhile, cagA+ H. pylori promoted significantly higher expression of IL-8 and Wnt5a than isogenic cagA mutants strains (cagA- H. pylori 26695) did. Taken together, our data suggested that H. pylori might promote the growth of some periodontal pathogens and aggravate the progress of chronic periodontitis.
The water promotion effects, where water can provide a solution-mediated reaction pathway in various heterogeneous chemical catalysis, have been presented and attracted wide attention recently, yet, ...the rational design of catalysts with a certain ability of enhancing water-induced reaction process is full of challenges and difficulties. Here, we show that by incorporating alkali (Na, K) cations as an electronic and/or structural promoter into Pd/rGO-ZnCr2O4 (rGO, reduced graphene oxide), the obtained Pd(Na)/rGO-ZnCr2O4 as a representative example demonstrates an outstanding benzyl alcohol oxidation activity in the Pickering emulsion system in comparison to the alkali-free counterpart. The response experiments of water injection confirm the enhanced activity, and the Na-modified catalyst can further enhance the promotion effects of water on the reaction. The effects of alkali cations for Pd nanoparticles are identified and deciphered by a series of experimental characterizations (XPS, in situ CO-DRIFTS, and CO-TPR coupled with MS), showing that there is abundant −OH on the surface of the catalyst, which is stabilized by the formation of Pd−OHx. The alkali-stabilized Pd−OHx is helpful to enhance the water-induced reaction process. According to the results of in situ Raman as well as UV-vis absorption spectra, the Na-modulated Pd(Na)/rGO-ZnCr2O4 enables the beneficial characteristics for distorting the benzyl alcohol structure and enhancing the adsorption of benzyl alcohol. Further, the mechanism for enhanced water promotion effects is rationally proposed. The strategy of alkali cations-modified catalysts can provide a new direction to effectively enhance the chemical reaction involving small molecule water.
The amplified water-induced effects were discovered over the alkali cations-modified catalysts with high active Pd-OHx for oxidation of benzyl alcohol. This unprecedented finding can provide an avenue to promote and enhance the chemical reactions involved in water-promoted effects. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Electrocatalytic water splitting that is coupled with electrocatalytic chemical oxidation is considered as one of the promising methods for efficiently obtaining hydrogen energy and fine chemicals. ...Herein, we focus on an electrochemical redox activation strategy to rationally manipulate the microstructure and surface valence states of copper foam (CF) and boost the corresponding performance towards electrocatalytic benzyl alcohol oxidation (EBA), accompanied by the efficient hydrogen production. Correspondingly, the Cu(II)‐dominated species are gradually formed on the CF surface with the dissolution and redeposition of copper in the suitable potential range. The new species containing Cu2O, CuO, and Cu(OH)2 during surface reconstruction process of the CF were confirmed by multiple characterization techniques. After 220‐cycled activation (CF‐220), the activated CF achieves an increase of current density for EBA in anode from 9.5 for the original CF to 29.3 mmol/cm2, while the pure hydrogen yield increases threefold than that of the original CF at 1.5 VRHE. The produced new species can endow the CF‐220 with abundant acidity sites, which can enhance the adsorption toward Lewis‐basicity benzyl alcohol, confirmed by NH3‐temperature‐programmed desorption. In situ Raman result further reveals that the as‐produced CuO, Cu(OH)2, and Cu(OH)42− are the main active species toward the EBA process.
An electrochemical redox activation strategy to increase the electrocatalytic activity of copper foam (CF) was presented, achieving the controllable surface reconstruction of CF. The generated yet new copper species triggers an enhanced electrocatalytic benzyl alcohol oxidation reaction (EBA). After 220‐cycled activation, the CF‐220 achieved an increase of current density for EBA in anode from 9.5 to 29.3 mmol/cm2, while the pure hydrogen yield increased three‐fold compared to the original CF at 1.5 VRHE.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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