Hiplot: a comprehensive and easy-to-use web service for boosting publication-ready biomedical data visualization.

Complex biomedical data generated during clinical, omics and mechanism-based experiments have increasingly been exploited through cloud- and visualization-based data mining techniques. However, the scientific community still lacks an easy-to-use web service for the comprehensive visualization of biomedical data, particularly high-quality and publication-ready graphics that allow easy scaling and updatability according to user demands. Therefore, we propose a community-driven modern web service, Hiplot (https://hiplot.org), with concise and top-quality data visualization applications for the life sciences and biomedical fields. This web service permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be conducted by senior bioinformatics or biostatistics researchers. It covers most of the daily demands of biomedical researchers with its equipped 240+ biomedical data visualization functions, involving basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modelling, etc. Moreover, to improve the efficiency in use and development of plugins, we introduced some core advantages on the client-/server-side of the website, such as spreadsheet-based data importing, cross-platform command-line controller (Hctl), multi-user plumber workers, JavaScript Object Notation-based plugin system, easy data/parameters, results and errors reproduction and real-time updates mode. Meanwhile, using demo/real data sets and benchmark tests, we explored statistical parameters, cancer genomic landscapes, disease risk factors and the performance of website based on selected native plugins. The statistics of visits and user numbers could further reflect the potential impact of this web service on relevant fields. Thus, researchers devoted to life and data sciences would benefit from this emerging and free web service.

Heme metabolism mediates the effects of smoking on gut microbiome.

INTRODUCTION: The number of smokers worldwide increased greatly during the past decades and reached 1.14 billion in 2019, becoming a leading risk factor for human health. Tobacco smoking has wide effects on human genetics, epigenetics, transcriptome, and gut microbiome. Although many studies have revealed effects of smoking on host transcriptome, research on the relationship among smoking, host gene expression, and the gut microbiome is limited. METHODS: We first explored transcriptome and metagenome profile differences between smokers and non-smokers. To evaluate the relationship between host gene expression and gut microbiome, we then applied bi-directional mediation analysis to infer causal relationships between smoking, gene expression, and gut microbes. RESULTS: Metagenome and transcriptome analyses revealed 71 differential species and 324 differential expressed genes between smokers and non-smokers. With smoking as an exposure variable, we identified 272 significant causal relationships between gene expression and gut microbes, among which there were 247 genes that mediate the effect of smoking on gut microbes. Pathway-based enrichment analysis showed that these genes were significantly enriched in heme metabolic pathway, which mainly mediated the changes of Bacteroides finegoldii and Lachnospiraceae bacterium 9_1_43BFAA. Additionally, by performing metabolome data analysis in the Integrated Human Microbiome project (iHMP) database, we verified the correlation between the intermediate products of the heme metabolism pathway (porphobilinogen, bilirubin, and biliverdin) and gut microbiome. CONCLUSIONS: By investigating the bi-directional interaction between smoking-related host gene expression and gut microbes, this study provided evidence for the mediation of smoking on gut microbes through co-involvement or interaction of heme metabolism. IMPLICATIONS: By comparing the metagenome and transcriptome sequencing profiles between 34 smokers and 33 age- and gender-matched non-smokers, we are the first to reveal causal relationships among tobacco smoking, host gene expression and gut microbes. These findings offer insight into how smoking affects gut microbes through host gene expression and metabolism, which highlights the importance of heme metabolism in modulating the effects of smoking on gut microbiome.

Catechin from green tea had the potential to decrease the chlorpyrifos induced oxidative stress in larval zebrafish (Danio rerio).

Catechin is a biological compound in green tea (Camellia sinesis), which has anti-oxidant, anti-cancer, anti-apoptotic, anti-inflammatory, and attenuated effects in different experimental models. Chlorpyrifos (CPF), a broad-spectrum organophosphate insecticide, has resulted in oxidative stress, mitochondrial dysfunction, and apoptosis in zebrafish. The goal of this study is to assess whether catechin can alleviate CPF-induced oxidative damage and apoptosis in the early developmental stage of zebrafish. According to the results, we observed that 200 µg/L CPF exposure could induce oxidative stress, ROS production and changing the antioxidant-related enzymes and genes in larval zebrafish. Interestingly, catechin had the potential to reduce the oxidative damage and cell apoptosis caused by CPF exposure in larval zebrafish at different endpoints. Especially, catechin could promote the contents of GSH and activity of GST in zebrafish larvae injured by CPF, suggesting that catechin could repair oxidative damage at a certain degree by regulating the activities and gene transcription of some key enzymes related to GSH pathway in zebrafish. In addition, at transcriptional levels, a high concentration of catechin exposure reduced the expression genes of Mn-SOD, Cat, gst, and GPX induced by CPF in larval zebrafish. These genes mainly reflected the degree of oxidative damage of zebrafish, which was basically consistent with the enzyme activity. Catechin also could reduce the transcription of p53 and bax, which are tightly related to the apoptosis induced by CPF in zebrafish larvae. The expression of genes was consistent with ROS production, which proved that catechin could alleviate the apoptosis induced by CPF. This study discovered that catechin had some antioxidant effects in aquatic animals to reduce the toxicity caused by pesticides and offered the scientific basis for the utilization and development of catechin.

Updated review of research on the gut microbiota and their relation to depression in animals and human beings.

The gut microbiota are being called the human "second brain," as they play a key role in the regulation of the central nervous system (CNS). Recent findings provide strong evidence for the presence of bidirectional communication networks between the gut microbiota and the CNS, and such crosstalk has been correlated with alterations in major depressive disorder (MDD) and other psychiatric disorders. Further, germ-free animal models have been used to investigate the effect of the microbiota on MDD and other psychiatric disorders, which have greatly expanded our knowledge of the role of the microbiota in the etiology of MDD and promoted causality studies of this psychiatric disorder and others as well. In this review, we first introduce the methodological approaches used for microbiota research and then provide an overview of current research progress on the modulatory function and composition of the gut microbiota in MDD and the therapeutic effect of probiotics that has been gained using data from human studies as well as animal experiments. Future research should focus on identification and characterization of specific bacterial strains involved in MDD with the hope of applying these findings in the prevention and treatment of MDD.

Chlorothalonil induces the intestinal epithelial barrier dysfunction in Caco-2 cell-based in vitro monolayer model by activating MAPK pathway.

The widespread use of chlorothalonil (CTL) has caused environmental residues and food contamination. Although the intestinal epithelial barrier (IEB) is directly involved in the metabolism and transportation of various exogenous compounds, there are few studies on the toxic effects of these compounds on the structure and function of IEB. The disassembly of tight junction (TJ) is a major cause of intestinal barrier dysfunction under exogenous compounds intake, but the precise mechanisms are not well understood. Here, we used Caco-2 cell monolayers as an in vitro model of human IEB to evaluate the toxicity of CTL exposure on the structure and function of IEB. Results showed that CTL exposure increased the paracellular permeability of the monolayers and downregulated mRNA levels of the TJ genes (ZO-1, OCLN, and CLDN1), polarity marker gene (SI), and anti-apoptosis gene (BCL-2) but upregulated the mRNA levels of apoptosis-related genes, including BAD, BAX, CASP3, and CASP8. Western blot analysis and immunofluorescence assay results showed the decreased levels and disrupted distribution of TJ protein network, including ZO-1 and CLDN1 in CTL-exposed IEB. In addition, the accumulation of intracellular reactive oxygen species, decreased mitochondrial membrane potential, and increased active CASP3 expression were observed in treated IEB. The result of TUNEL assay further confirmed the occurrence of cell apoptosis after CTL exposure. In addition, the phosphorylation of mitogen-activated protein kinases, including ERK, JNK and p38, was increased in CTL-exposed IEB. In summary, our results demonstrated that CTL exposure induced IEB dysfunction in Caco-2 cell monolayers by activating the mitogen-activated protein kinase pathway.

Sub-chronic exposure to antibiotics doxycycline, oxytetracycline or florfenicol impacts gut barrier and induces gut microbiota dysbiosis in adult zebrafish (Daino rerio).

Antibiotics are widely used in the treatment of bacterial infections and as food additives in the livestock industry. The wide usage of antibiotics causes residues in animal products, like milk, eggs and meat. A number of studies have reported that antibiotic residues exist at high concentrations in watercourses around the world. Doxycycline (DH), oxytetracycline (OTCC) and florfenicol (FF) are the three most commonly used veterinary antibiotics in China. However, studies of the toxic effects of DH, OTCC and FF are limited. In this study, six-moth-old healthy male adult zebrafish were exposed to 0, 10, 30, 100 µg/L DH, OTCC or FF for 21 days. After exposure, some biochemical parameters changed significantly, including total cholesterol (TC), triglyceride (TG), pyruvate and acid phosphatase (ACP). In addition, mucus secretion in the gut decreased and the transcription of related genes also decreased significantly. Moreover, the composition of microbiota in the gut changed significantly. DH, OTCC and FF exposure caused the decrease of diversity of gut microbiota. The relative abundance of Proteobacteria increased significantly after OTCC and FF exposure and Fusobacteria decreased in all antibiotic-treated groups. Further functional prediction analysis also suggested changes in gut microbiota in the OTCC and FF-treated groups, especially those linked to metabolism. To support this idea, we confirmed that some glycolipid related genes also increased significantly in the liver of adult zebrafish after antibiotic exposure. According to these results, DH, OTCC or FF exposure could cause the gut microbiota dysbiosis and dysfunction, and hepatic metabolic disorder in adult male zebrafish.

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice.

Poly(ADP-ribose) polymerase (PARP) is an NAD-consuming enzyme and its specific role in the pathogenesis of alcoholic fatty liver disease (AFLD) remains elusive. In this study, we applied PJ34 [N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride] to inhibit hepatic PARP activity to examine the corresponding pathologic alteration in AFLD in mice and the underlying molecular mechanism. We found that PJ34 decreased the intracellular triglyceride (TG) content in hepatocytes. Moreover, PJ34 suppressed the gene expression of diglyceride acyltransferases DGAT1 and DGAT2 and elevated intracellular NAD+ levels in hepatocytes. These mechanistic observations were validated in alcohol-fed mice injected with PJ34 intraperitoneally. Our results indicate that the PJ34 injection attenuated hepatic TG accumulation in alcohol-fed mice. Furthermore, PJ34 injection lowered the gene expression of hepatic sterol regulatory element binding protein 1c, DGAT1, and DGAT2, whereas PJ34 injection augmented hepatic NAD+ levels in alcohol-fed mice. Finally, nicotinamide riboside supplementation alleviated hepatic TG accumulation in alcohol-fed mice. These data indicate that applying PARP-specific inhibitor PJ34 by intraperitoneal injection attenuated hepatic NAD+ depletion and TG accumulation in alcohol-fed mice and may be a potential candidate for use in AFLD therapy.

Clinical and economic impact of pharmacist interventions on sampled outpatient prescriptions in a Chinese teaching hospital.

BACKGROUND: Limited studies have evaluated the effectiveness of pharmacist interventions on outpatient prescription. The goal of this study was to evaluate the clinical and economic impacts of pharmacist interventions on randomly sampled outpatient prescriptions. METHOD: Outpatient prescriptions of our hospital were sampled automatically and reviewed by pharmacists since 2011. Pharmacists intervened in inappropriate prescriptions (IPs) real-timely, and summarized and analyzed the information monthly. Cost-benefit analysis was performed to estimate the economic benefit of the pharmacist intervention. RESULTS: From 2011 to 2016, pharmacists reviewed 101,271 prescriptions and intervened in 5155 prescriptions. With the interventions of pharmacists, the number of IPs decreased from 1845 to 238, while the inappropriate percentage decreased from 12.60 to 1.22%. The inappropriate rates of different departments and the types decreased annually. IPs were mainly from the Department of Medicine and Department of Surgery and category 1 (Non-indicated medications) in all years. The benefit-to-cost ratios of pharmacist interventions were always more than 1. In the same years, the benefit-to-cost ratios in public payments were higher than those with insurance and self-payment. CONCLUSION: This form of pharmacist intervention constitutes a method that showed positive clinical and economic benefits and is worth expanding in large hospitals. Pharmacists should pay more attention on prescriptions in department of surgery or prescriptions with public payments.

Polyphenylene Oxide Film Sandwiched between SiO2 Layers for High-Temperature Dielectric Energy Storage.

The commercial capacitor using dielectric biaxially oriented polypropylene (BOPP) can work effectively only at low temperatures (less than 105 °C). Polyphenylene oxide (PPO), with better heat resistance and a higher dielectric constant, is promising for capacitors operating at elevated temperatures, but its charge-discharge efficiency (η) degrades greatly under high fields at 125 °C. Here, SiO2 layers are magnetron sputtered on both sides of the PPO film, forming a composite material of SiO2/PPO/SiO2. Due to the wide bandgap and high Young's modulus of SiO2, the breakdown strength (Eb) of this composite material reaches 552 MV/m at 125 °C (PPO: 534 MV/m), and the discharged energy density (Ue) under Eb improves to 3.5 J/cm3 (PPO: 2.5 J/cm3), with a significantly enhanced η of 89% (PPO: 70%). Furthermore, SiO2/PPO/SiO2 can discharge a Ue of 0.45 J/cm3 with an η of 97% at 125 °C under 200 MV/m (working condition in hybrid electric vehicles) for 20,000 cycles, and this value is higher than the energy density (∼0.39 J/cm3 under 200 MV/m) of BOPP at room temperature. Interestingly, the metalized SiO2/PPO/SiO2 film exhibits valuable self-healing behavior. These results make PPO-based dielectrics promising for high-temperature capacitor applications.

γ-Ray Irradiation Significantly Enhances Capacitive Energy Storage Performance of Polymer Dielectric Films.

Polymer dielectric capacitors are fundamental in advanced electronics and power grids but suffer from low energy density, hindering miniaturization of compact electrical systems. It is shown that high-energy and strong penetrating γ-irradiation significantly enhances capacitive energy storage performance of polymer dielectrics. γ-irradiated biaxially oriented polypropylene (BOPP) films exhibit an extraordinarily high energy density of 10.4 J cm-3 at 968 MV m-1 with an efficiency of 97.3%. In particular, an energy density of 4.06 J cm-3 with an ultrahigh efficiency of 98% is reliably maintained through 20 000 charge-discharge cycles under 600 MV m-1. At 125 °C, the γ-irradiated BOPP film still delivers a high discharged energy density of 5.88 J cm-3 with an efficiency of 90% at 770 MV m-1. Substantial improvements are also achieved for γ-irradiated cycloolefin copolymers at a high temperature of 150 °C, verifying the strategy generalizability. Experimental and theoretical analyses reveal that the excellent performance should be related to the γ-irradiation induced polar functional groups with high electron affinity in the molecular chain, which offer deep energy traps to impede charge transport. This work provides a simple and generally applicable strategy for developing high-performance polymer dielectrics.

Ventricular tachyarrhythmias in rats with acute myocardial infarction involves activation of small-conductance Ca2+-activated K+ channels.

In vitro experiments have shown that the upregulation of small-conductance Ca(2+)-activated K(+) (SK) channels in ventricular epicardial myocytes is responsible for spontaneous ventricular fibrillation (VF) in failing ventricles. However, the role of SK channels in regulating VF has not yet been described in in vivo acute myocardial infarction (AMI) animals. The present study determined the role of SK channels in regulating spontaneous sustained ventricular tachycardia (SVT) and VF, the inducibility of ventricular tachyarrhythmias, and the effect of inhibition of SK channels on spontaneous SVT/VF and electrical ventricular instability in AMI rats. AMI was induced by ligation of the left anterior descending coronary artery in anesthetized rats. Spontaneous SVT/VF was analyzed, and programmed electrical stimulation was performed to evaluate the inducibility of ventricular tachyarrhythmias, ventricular effective refractory period (VERP), and VF threshold (VFT). In AMI, the duration and episodes of spontaneous SVT/VF were increased, and the inducibility of ventricular tachyarrhythmias was elevated. Pretreatment in the AMI group with the SK channel blocker apamin or UCL-1684 significantly reduced SVT/VF and inducibility of ventricular tachyarrhythmias (P < 0.05). Various doses of apamin (7.5, 22.5, 37.5, and 75.0 µg/kg iv) inhibited SVT/VF and the inducibility of ventricular tachyarrhythmias in a dose-dependent manner. Notably, no effects were observed in sham-operated controls. Additionally, VERP was shortened in AMI animals. Pretreatment in AMI animals with the SK channel blocker significantly prolonged VERP (P < 0.05). No effects were observed in sham-operated controls. Furthermore, VFT was reduced in AMI animals, and block of SK channels increased VFT in AMI animals, but, again, this was without effect in sham-operated controls. Finally, the monophasic action potential duration at 90% repolarization (MAPD(90)) was examined in the myocardial infarcted (MI) and nonmyocardial infarcted areas (NMI) of the left ventricular epicardium. Electrophysiology recordings showed that MAPD(90) in the MI area was shortened in AMI animals, and pretreatment with SK channel blocker apamin or UCL-1684 significantly prolonged MAPD(90) (P < 0.05) in the MI area but was without effect in the NMI area or in sham-operated controls. We conclude that the activation of SK channels may underlie the mechanisms of spontaneous SVT/VF and susceptibility to ventricular tachyarrhythmias in AMI. Inhibition of SK channels normalized the shortening of MAPD(90) in the MI area, which may contribute to the inhibitory effect on spontaneous SVT/VF and inducibility of ventricular tachyarrhythmias in AMI.

Insights into enhanced toxic effects by the binary mixture of carbendazim and procymidone on hepatic lipid metabolism in mice.

Carbendazim (CBZ) and procymidone (PRO) are two widely used fungicides in agriculture. However, there are still gaps in knowledge regarding about the potential hazards of joint exposure to CBZ and PRO in animals. Here, 6-week-old ICR mice were exposed to CBZ, PRO and CBZ + PRO for 30 days, and metabolomics were performed to discover the mechanism by which the mixture enhanced the effects on lipid metabolism. Co-exposure to CBZ + PRO elevated the body weights, relative liver weights and relative epididymis fat weights, but not in the single exposure groups. Molecular docking analysis suggested that CBZ and PRO combined with peroxisome proliferator-activated receptor (PPARγ) at the same amino acid site as the agonist rosiglitazone. The RT-qPCR and WB results demonstrated that the levels of PPARγ were higher in the co-exposure group than in the single exposure groups. In addition, hundreds of differential metabolites were discovered by metabolomics and enriched in different pathways, such as pentose phosphate pathway and purine metabolism. A unique effect, a decrease in glucose-6-phosphate (G6P) that promoted more NADPH production, was observed in the CBZ + PRO group. These results demonstrated that exposure to CBZ + PRO caused more serious lipid metabolism disorder in the liver than exposure to a single fungicide, which could provide some new insight for the toxic effects after fungicides joint exposure.

Acute chlorothalonil exposure had the potential to influence the intestinal barrier function and micro-environment in mice.

The intestinal barrier maintains intestinal homeostasis and metabolism and protects against harmful pollutants. Some environmental pollutants seriously affect intestinal barrier function. However, it remains unclear whether or how chlorothalonil (CTL) impacts the intestinal barrier function in animals. Herein, 6-week-old male mice were acutely exposed to different CTL concentrations (100 and 300 mg/kg BW) via intragastric administration once a day for 7 days. Histopathological examination revealed obvious inflammation in the mice' colon and ileum. Most notably, CTL exposure increased the intestinal permeability, particularly in the CTL-300 group. CTL exposure reduced the secretion of colonic epithelial mucus and changed the transcription levels of genes bound up with ion transport and ileal antimicrobial peptide (AMP) secretion, indicating intestinal chemical barrier damage. The results of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and Ki67 staining revealed abnormal apoptosis and increased intestinal epithelial cell proliferation, suggesting that CTL exposure led to cytotoxicity and inflammation. The results of 16S rRNA sequencing revealed that CTL exposure altered the intestinal microbiota composition and reduced its diversity and richness in the colon contents. Thus, acute CTL exposure affected the different intestinal barrier- and gut microenvironment-related endpoints in mice.

Significantly enhanced high-temperature capacitive energy storage in cyclic olefin copolymer dielectric films via ultraviolet irradiation.

Polymer dielectrics with high operation temperature (∼150 °C) and excellent capacitive energy storage performance are vital for electric power systems and advanced electronic devices. Here, a very convenient and competitive strategy by preparing ultraviolet-irradiated cyclic olefin copolymer films is demonstrated to be effective in improving the energy storage performance at high temperatures. Compared with the unirradiated film, irradiated films exhibit a higher dielectric constant, higher breakdown strength and stronger mechanical properties as a result of the emergence of the carbonyl group and cross-linking network. Consequently, with a high efficiency above 95%, a superior discharged energy density of ∼3.34 J cm-3 is achieved at 150 °C, surpassing the current dielectric polymers and polymer nanocomposites. In particular, the energy storage performance remains highly reliable over 20 000 cycles under actual operating conditions (200 MV m-1 at 150 °C) in hybrid electric vehicles. This research offers a valuable pathway to build high-energy-density polymer-based capacitor devices working under harsh environments.

Landscapes of gut microbiome and bile acid signatures and their interaction in HBV-associated acute-on-chronic liver failure.

Introduction: Submassive hepatic necrosis (SMHN, defined as necrosis of 15-90% of the entire liver on explant) is a likely characteristic pathological feature of ACLF in patients with hepatitis B cirrhosis. We aimed to comprehensively explore microbiome and bile acids patterns across enterhepatic circulation and build well-performing machine learning models to predict SMHN status. Methods: Based on the presence or absence of SMHN, 17 patients with HBV-related end-stage liver disease who received liver transplantation were eligible for inclusion. Serum, portal venous blood, and stool samples were collected for comparing differences of BA spectra and gut microbiome and their interactions. We adopted the random forest algorithm with recursive feature elimination (RF-RFE) to predict SMHN status. Results: By comparing total BA spectrum between SMHN (-) and SMHN (+) patients, significant changes were detected only in fecal (P = 0.015). Compared with the SMHN (+) group, the SMHN (-) group showed that UDCA, 7-KLCA, 3-DHCA, 7-KDCA, ISOLCA and α-MCA in feces, r-MCA, 7-KLCA and 7-KDCA in serum, γ-MCA and 7-KLCA in portal vein were enriched, and TUDCA in feces was depleted. PCoA analysis showed significantly distinct overall microbial composition in two groups (P = 0.026). Co-abundance analysis showed that bacterial species formed strong and broad relationships with BAs. Among them, Parabacteroides distasonis had the highest node degree. We further identified a combinatorial marker panel with a high AUC of 0.92. Discussion: Our study demonstrated the changes and interactions of intestinal microbiome and BAs during enterohepatic circulation in ACLF patients with SMHN. In addition, we identified a combinatorial marker panel as non-invasive biomarkers to distinguish the SMHN status with high AUC.

Sub-Chronic Difenoconazole Exposure Induced Gut Microbiota Dysbiosis in Mice.

Difenoconazole (DIF) is a widely separated triazole fungicide in many countries. The excessive usage of DIF increases the high volume of residues in agriculture production and water bodies. Some previous studies demonstrated the toxic effects of DIF on non-target animals, however, there were still some gaps in the knowledge of the potential hazards of DIF to mammals and human health. Herein, 7-week-old male mice were exposed to 30 and 100 mg/kg/day DIF for 14 and 56 days. We observed that 56 days of DIF exposure decreased the colonic mucus expression of alcin blue-periodic acid-schiff (AB-PAS) stain and the immunochemical stain of muc2 protein. The transcript levels of mucin protein (muc1, muc2 and muc3) decreased significantly in the gut of mice followed 56 days of 100 mg/kg/day DIF exposure. In addition, the gut microbiota composition was also affected after 14 or 56 days of DIF exposure. Although the mucus expression after 14 days of DIF exposure only decreased slightly, the gut microbiota composition compared with the control group was changed significantly. Moreover, the DIF-30 and DIF-100 caused respectively different changes on the gut microbiota. The relative abundance of Bacteroidetes decreased significantly after 14 days and 56 days of DIF exposure. After 14 days of DIF exposure, there were 35 and 18 differential genera in the DIF-30 and DIF-100 group, respectively. There were 25 and 32 differential genera in the DIF-30 and DIF-100 group after 56 days of exposure, respectively. Meanwhile, the alpha diversity indexes, including observed species, Shannon, Simpson, Chao1 and ACE, in gut microbiota decreased significantly after 56 days of DIF exposure. Interestingly, the relative abundance of Akkermansia increased significantly after 56 days of 100 mg/kg/d DIF exposure. Although Akkermansia was considered as one probiotic, the phenomenon of dramatic Akkermansia increase with the decrease in gut microbiota diversity needed further discussion. These results provided some new insights on how DIF exposure impacts the mucus barrier and induces gut microbiota dysbiosis.

Stereoselective effects of fungicide difenoconazole and its four stereoisomers on gut barrier, microbiota, and glucolipid metabolism in male mice.

Difenoconazole is a commonly used triazole fungicide that consists of four stereoisomers [(2S,4S)-, (2S,4R)-, (2R,4R)-, and (2R,4S)-isomers] with different bioactivity. For example, the toxicity of the (2R,4S)-isomer to fish is approximately seven times higher than that of the (2S,4S)-isomer. However, the stereoselective toxic effects of difenoconazole stereoisomers on mammals have received little attention. In the present study, adult male mice were orally treated with a mixture of the four stereoisomers or each stereoisomer individually (0, 30, or 100 mg/kg/d) by gavage for 28 days. Pathological staining of the liver sections showed that the (2R,4R)-isomer caused lipid droplet accumulation. The mixture or each individual stereoisomers decreased the levels of amino acids and acyl-carnitine in serum. Moreover, the (2S,4R)-, (2R,4R)-, and (2R,4S)-isomers affected intestinal permeability, causing decreases in mucus secretion and tight junction protein expression in colon. Analysis of the gut microbiota composition showed that the stereoisomers caused decreases of OTU numbers and observed species at different levels. Interestingly, difenoconazole and its four stereoisomers reduced the relative abundance of Bacteroidetes at the phylum level and some short-chain fatty acid (SCFA)-producing bacteria. Taking the findings together, 2R-difenoconazole with strong bioactivity against pathogenic fungi also had significant effects in mammals, disrupting hepatic lipid metabolism, intestinal permeability, and gut microbiota. It is concluded that the health risks of the four difenoconazole stereoisomers to mammals should not be overlooked.

The fungicide prothioconazole and its metabolite prothioconazole-desthio disturbed the liver-gut axis in mice.

The triazole fungicide prothioconazole (PTC) can cause adverse effects in animals, and its main metabolite prothioconazole-desthio (PTC-d) is even much more harmful. However, the toxic effects of PTC and PTC-d on the liver-gut axis of mice are still unknown. In the present experiment, we found that oral exposure to PTC and PTC-d increased total bile acids (TBAs) levels in the serum, liver, and feces. Correspondingly, the transcription of genes involved in bile acids (BAs) disposition was significantly influenced by PTC or PTC-d exposure. Furthermore, the BAs composition of serum BAs was analyzed by LC-MS, and the results indicated that PTC and PTC-d exposure changed the BAs composition, lowered the ratio of conjugated/unconjugated BAs, elevated the ratio of CA/b-MCA, and enhanced the hydrophobicity of BAs pool. 16s RNA gene sequencing of the DNA from colonic contents uncovered that PTC and PTC-d exposure altered the relative abundance and constitution of intestinal microbiota, increasing the relative level of Lactobacillus with bile salt hydrolase (BSH) activity. Furthermore, PTC and PTC-d exposure impaired the gut barrier function, causing an increase in mucus secretion. In particular, the effects of PTC-d on some endpoints in the BAs metabolism and gut barrier function had been proven to be more significant than the parent compound PTC. All these findings draw attention to the health risk of PTC and PTC-d exposure in regulating BAs metabolism, which might lead to some metabolic disorders and occur of related diseases in animals.

Bromuconazole exposure induces cardiotoxicity and lipid transport disorder in larval zebrafish.

Bromuconazole (BRO), as one of the typical triazole fungicides, has not been reported on its effects on aquatic organisms. In this study, zebrafish embryos were used as experimental objects to evaluate the toxicity of BRO. In the acute embryo toxicity test, it was observed that the heart rate and growing development were affected by BRO in a concentration-dependent manner, and the half-lethal concentration (LC50) of BRO at 96 h post-fertilization (hpf) was about 11.83 mg/L. Then, low concentrations of BRO (50 ng/L, 0.075 mg/L, 0.3 mg/L, 1.2 mg/L), which were set according to the LC50 and environmental related concentrations, were used to analyze the toxic effects on the different endpoints in larval zebrafish. Interestingly, the transcriptomic analysis found that most different expressed genes (DEGs) could be focused on the pathways of lipid metabolism, myocardial function, glycometabolism, indicating that heart function and lipid metabolism in larval zebrafish were disrupted by BRO. For supporting this idea, we re-exposed the transgenic zebrafish and WT zebrafish embryos, proved that BRO caused damage to heart development and lipid transport on morphological and genetic level, which was consistent with transcriptomic results. In addition, BRO exposure caused oxidative damage in the larvae. Taken together, BRO exposure could affect the myocardial contraction function and lipid transport in larval zebrafish, accompanied by disturbances in the level of oxidative stress, which was of great significance for improving the biotoxicological information of BRO.