Joint toxic mechanism of clothianidin and prochloraz in the earthworm (Eisenia fetida).

Pesticides are typically present as combinations within soil ecosystems and have detrimental effects on untamed surroundings. However, the collective impacts and fundamental mechanisms of pesticides on soil living beings are currently inadequately assessed. In our current work, we evaluated the interactive consequences of clothianidin (CLO) and prochloraz (PRO) on earthworms (Eisenia fetida) using several toxicological tests, such as acute adverse effects, biocatalytic activity, and alterations in transcriptional activity. The findings revealed that CLO (with a 14-day LC50 value of 6.08 mg kg-1) exhibited greater toxicity compared to PRO (with a 14-day LC50 value of 79.41 mg kg-1). Moreover, the combinations of CLO and PRO had synergistic acute effects on E. fetida. Additionally, the activities of POD, CAT, and GST were significantly varied in most instances of single and mixed treatments when compared to the control. Surprisingly, the transcriptional levels of four genes (gst, sod, crt, and ann), related to oxidative load, metabolic detoxification systems, endoplasmic reticulum, and oxytocin neuropeptide, respectively, were also altered in response to single and mixture exposures, as compared to the control. Alterations in enzyme activity and gene transcriptional level could serve as early indicators for detecting co-exposure to pesticides. The findings of this research offered valuable holistic understanding regarding the toxicity of pesticide combinations on earthworms. Further research should be conducted to investigate the persistent effects of pesticide mixtures on terrestrial invertebrates in order to draw definitive conclusions about the associated risks.

Uncovering hidden dangers: The combined toxicity of abamectin and lambda-cyhalothrin on honey bees.

Studying the toxic effects of pesticides on bees has consistently been a prominent area of interest for researchers. Nonetheless, existing research has predominantly concentrated on individual toxicity assessments, leaving a gap in our understanding of mixed toxicity. This study delves into the individual and combined toxic effects of abamectin (ABA) and lambda-cyhalothrin (LCY) on honey bees (Apis mellifera) in laboratory settings. We discovered that ABA (96 h-LC50 value of 0.079 mg/L) exhibited greater acute toxicity to honey bees compared to LCY (96 h-LC50 value of 9.177 mg/L). Moreover, the mixture of ABA and LCY presented an acute antagonistic effect on honey bees. Additionally, our results indicated that exposure to LCY, at medium concentration, led to a reduction in the abundance of gut core bacterium Snodgrassella. However, an increase in the abundance of Bifidobacterium was noted when exposed to a medium concentration of LCY and its mixture with ABA. Transcriptomic analysis revealed significant regulation of certain genes in the medium concentration of all three treatments compared to the control group, primarily enriching in metabolism and immune-related pathways. Following chronic exposure to field-relevant concentrations of ABA, LCY, and their mixture, there were significant alterations in the activities of immunity-related enzyme polyphenol oxidase (PPO) and detoxification enzymes glutathione S-transferase (GST) and carboxylesterase (CarE). Additionally, the expression of four genes (abaecin, cyp9e2, cyp302a1, and GstD1) associated with immune and detoxification metabolism was significantly altered. These findings suggest a potential health risk posed by the insecticides ABA and LCY to honey bees. Despite exhibiting acute antagonistic effect, mixed exposure still induced damage to bees at all levels. This study advances our knowledge of the potential adverse effects of individual or combined exposure to these two pesticides on non-target pollinators and offers crucial guidance for the use of insecticides in agricultural production.

Metabolic perturbations in zebrafish (Danio rerio) larvae exposed to sulfentrazone and imidacloprid.

The intensive and widespread application of pesticides in agroecosystems can lead to the simultaneous exposure of non-target aquatic organisms to insecticides and herbicides. However, the underlying mechanisms through which aquatic organisms undergo metabolic reprogramming to withstand the combined effects of the insecticide imidacloprid (IMI) and herbicide sulfentrazone (SUL) remain poorly elucidated. This study employs metabolomics to investigate the effects of individual and combined exposures to IMI and SUL on zebrafish (Danio rerio), aiming to simulate complex environmental conditions. Metabolomics analysis revealed extensive metabolic reprogramming in larvae induced by the selected agrochemicals. Both individual and combined exposures disrupted nucleotide metabolism, inhibited glycolysis, and led to the accumulation of acetylcholine through the shared modulation of differential metabolites. Notably, individual exposure exhibited a unique mode of action. Larvae exposed to IMI alone showed mitochondrial dysfunction, potentially stemming from interference with the electron transport chain, while SUL-induced disruptions were associated with glycerophospholipid accumulation, marking it as a critical target. Additionally, calculations of the metabolic effect level index indicated antagonistic interactions between SUL and IMI mixtures at an overall metabolic level. The results obtained through investigating the lethal and sub-lethal effects also revealed that the simultaneous application of SUL and IMI may have the potential to diminish acute and developmental toxicity in zebrafish. This study underscores the significance of metabolomics as a valuable and effective strategy for deciphering the toxicity and interactions of agrochemical mixtures.

Relationship between 24 h blood pressure variability and mortality in acute myocardial infarction patients.

BACKGROUND: In recent years, the mortality of patients with AMI has not declined significantly. The relationship between blood pressure variability (BPV) and acute myocardial infarction (AMI) is unclear. We explored the relationship between 24-h BPV and mortality in patients with AMI. HYPOTHESIS: The mortality of patients with AMI is related to BPV. We hope to provide therapeutic ideas for reducing the risk of death in patients with AMI. METHODS: This is a retrospective cohort study. We extracted and analyzed data from the MIMIC-IV 2.0, which was established in 1999 under the auspices of the National Institutes of Health (America). The average real variability (ARV) was calculated for the first 24-h blood pressure measurement after patients with AMI were admitted to the intensive care unit (ICU). Patients were divided into four groups according to ARV quartiles. The outcomes were 30-day, 1-year, and 3-year all-cause mortalities. Data were analyzed using Cox regression, Kaplan-Meier curves, and restricted cubic spline (RCS) curves. RESULTS: We enrolled 1291 patients with AMI, including 475 female. The patients were divided into four groups according to the qualities of diastolic blood pressure (DBP)-ARV. There were significant differences in the 30-day, 1-year and 3-year mortality among the four groups (p = .02, p < .001, p < .001, respectively). After adjustment for confounding factors, systolic blood pressure (SBP)-ARV could not predict AMI patient mortality (p > .05), while the highest DBP-ARV was associated strongly with increased 30-day mortality (HR: 2.291, 95% CI 1.260-4.168), 1-year mortality (HR: 1.933, 95% CI 1.316-2.840) and 3-year mortality (HR: 1.743, 95% CI 1.235-2.461). Kaplan-Meier curves demonstrated that, regardless of SBP or DBP, the long-term survival probabilities of patients in the highest ARV group were significantly lower than that of those in other groups. RCS curves showed that the death risk of patients with AMI first decreased and then increased with the increase in ARV when DBP-ARV < 8.04. The 30-day death risk first increased and then decreased, and the 1-year and 3-year death risks increased and then stabilized with ARV increase when DBP-ARV > 8.04. CONCLUSION: This study showed that patients with AMI may have an increased risk of short- and long-term death if their DBP-ARV is higher or lower during the first 24-h in ICU.

Machine learning-based fracturing parameter optimization for horizontal wells in Panke field shale oil.

In the process of developing tight oil and gas reservoirs, multistage fractured horizontal wells (NFHWs) can greatly increase the production rate, and the optimal design of its fracturing parameters is also an important means to further increase the production rate. Accurate production prediction is essential for the formulation of effective development strategies and development plans before and during project execution. In this study, a novel workflow incorporating machine learning (ML) and particle swarm optimization algorithms (PSO) is proposed to predict the production rate of multi-stage fractured horizontal wells in tight reservoirs and optimize the fracturing parameters. The researchers conducted 10,000 numerical simulation experiments to build a complete training and validation dataset, based on which five machine learning production prediction models were developed. As input variables for yield prediction, eight key factors affecting yield were selected. The results of the study show that among the five models, the random forest (RF) model best establishes the mapping relationship between feature variables and yield. After verifying the validity of the Random Forest-based yield prediction model, the researchers combined it with the particle swarm optimization algorithm to determine the optimal combination of fracturing parameters under the condition of maximizing the net present value. A hybrid model, called ML-PSO, is proposed to overcome the limitations of current production forecasting studies, which are difficult to maximize economic returns and optimize the fracturing scheme based on operator preferences (e.g., target NPV). The designed workflow can not only accurately and efficiently predict the production of multi-stage fractured horizontal wells in real-time, but also be used as a parameter selection tool to optimize the fracture design. This study promotes data-driven decision-making for oil and gas development, and its tight reservoir production forecasts provide the basis for accurate forecasting models for the oil and gas industry.

Influence of continuous nursing on surgical site wound infection and postoperative complication for colorectal cancer patients with stoma: A meta-analysis.

We systematically evaluated the effect of continuous nursing on surgical site wound infections and postoperative complications in colorectal cancer (CRC) patients with stomas. Computerised searches of Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure and Wanfang databases were conducted to collect clinical studies on CRC patients receiving continuous nursing interventions after colorectal stoma surgery; the search period was from the establishment of each database to August 2023. Two researchers independently screened the literature, extracted the data and completed a literature quality assessment. The meta-analysis was performed using Stata 17.0 and included 20 studies with 1759 patients. The meta-analysis showed that continuous nursing significantly lowered the rates of surgical site wound infection (risk ratio [RR] = 0.24, 95% confidence interval [CI]: 0.14-0.43, p < 0.001) and postoperative complications (RR = 0.30, 95% CI: 0.23-0.39, p < 0.001) for CRC stoma patients compared with the control group. Therefore, continuous nursing intervention should be promoted for use in clinical care.

Current-use pesticides monitoring and ecological risk assessment in vegetable soils at the provincial scale.

Pesticides represent one of the largest intentional inputs of potentially hazardous compounds into agricultural soils. However, as an important vegetable producing country, surveys on pesticide residues in soils of vegetable production areas are scarce in China. This study presented the occurrence, spatial distribution, correlation between vegetable types and pesticides, and ecological risk evaluation of 94 current-use pesticides in 184 soil samples from vegetable production areas of Zhejiang province (China). The ecological risks of pesticides to soil biota were evaluated with toxicity exposure ratios (TERs) and risk quotient (RQ). The pesticide concentrations varied largely from below the limit of quantification to 20703.06 µg/kg (chlorpyrifos). The situation of pesticide residues in Jiaxing is more serious than in other cities. Soils in the vegetable areas are highly diverse in pesticide combinations. Eisenia fetida suffered exposure risk from multiple pesticides. The risk posed by chlorpyrifos, which exhibited the highest RQs at all scenarios, was worrisome. Only a few pesticides accounted for the overall risk of a city, while the other pesticides make little or zero contribution. This work will guide the appropriate use of pesticides and manage soil ecological risks, achieving green agricultural production.

Effects of application of the clinical nursing pathway on surgical site wound infection and postoperative complication rates in patients with total knee arthroplasty: A meta-analysis.

This study aimed to systematically evaluate the effects of clinical nursing on surgical site wound infections and postoperative complications in patients after undergoing total knee arthroplasty (TKA). Computerised searches of Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, VIP and Wanfang databases were conducted from inception to August 2023 to collect randomised controlled trials (RCTs) on patients with TKA who received clinical nursing pathway interventions. Literature screening, data extraction and quality assessment of the included studies were performed independently by two researchers. The meta-analysis was performed using Stata 17.0. A total of 14 RCTs with 1174 patients were included, including 587 patients each in the intervention and control groups. The meta-analysis results showed that the application of clinical nursing pathways to patients undergoing TKA significantly reduced surgical site wound infections (risk ratio [RR] = 0.28, 95% confidence interval [CI]: 0.15-0.54, p < 0.001) and postoperative complications (RR = 0.25, 95% CI: 0.17-0.37, p < 0.001). Therefore, clinical nursing pathway interventions in patients undergoing TKA should be promoted in clinical practice as they can effectively reduce the incidence of wound infection and postoperative complications.

Inclusion of frailty improved performance of delirium prediction for elderly patients in the cardiac intensive care unit (D-FRAIL): A prospective derivation and external validation study.

BACKGROUND: The elderly patients admitted to cardiac intensive care unit (CICU) are at relatively high risk for developing delirium. A simple and reliable predictive model can benefit them from early recognition of delirium followed by timely and appropriate preventive strategies. OBJECTIVE: To explore the role of frailty in delirium prediction and develop and validate a delirium predictive model including frailty for elderly patients in CICU. DESIGN: A prospective, observational cohort study. SETTINGS: CICU at China-Japan Friendship Hospital from March 1, 2022 to August 25, 2022 (derivation cohort); CICU at Beijing Anzhen Hospital affiliated to Capital Medical University from March 14, 2023 to May 8, 2023 (external validation cohort). PARTICIPANTS: A total of 236 and 90 participants were enrolled in the derivation and external validation cohorts, respectively. Participants in the derivation cohort were assigned into either the delirium (n = 70) or non-delirium group (n = 166) based on the occurrence of delirium. METHODS: The simplified Chinese version of the Confusion Assessment Method for the Diagnosis of Delirium in the Intensive Care Unit was used to assess delirium twice a day at 8:00-10:00 and 18:00-20:00 until the onset of delirium or discharge from the CICU. Frailty was assessed using the FRAIL scale during the first 24 h in the CICU. Other possible risk factors were collected prospectively through patient interviews and medical records review. After processing missing data via multiple imputations, univariate analysis and bootstrapped forward stepwise logistic regression were performed to select optimal predictors and develop the models. The models were internally validated using bootstrapping and evaluated comprehensively via discrimination, calibration, and clinical utility in both the derivation and external validation cohorts. RESULTS: The study developed D-FRAIL predictive model using FRAIL score, hearing impairment, Acute Physiology and Chronic Health Evaluation-II score, and fibrinogen. The area under the receiver operating characteristic curve (AUC) was 0.937 (95% confidence interval [CI]: 0.907-0.967) and 0.889 (95%CI: 0.840-0.938) even after bootstrapping in the derivation cohort. Inclusion of frailty was demonstrated to improve the model performance greatly with the AUC increased from 0.851 to 0.937 (p < 0.001). In the external validation cohort, the AUC of D-FRAIL model was 0.866 (95%CI: 0.782-0.907). Calibration plots and decision curve analysis suggested good calibration and clinical utility of the D-FRAIL model in both the derivation and external validation cohorts. CONCLUSIONS: For elderly patients in the CICU, FRAIL score is an independent delirium predictor and the D-FRAIL model demonstrates superior performance in predicting delirium.

Spatio-temporal distribution of organochlorine pesticides in agricultural soils of southeast China during 2014-2019.

Organochlorine pesticides (OCPs) are organic pollutants that are persistent and undegradable in the environment. To investigate their residual concentrations, spatial and temporal distributions, and the relationship with the crops planted, 12 individual OCPs in 687 soil samples from Jiangsu, Zhejiang and Jiangxi provinces of southeast China were examined. The detection frequencies of OCPs in the studied areas were 1.89%-64.9%. The concentrations of dichloro-diphenyl-trichloroethanes (DDTs), hexachlorocyclohexanes (HCHs), and endosulfans ranged from 0.01 to 5659 µg/kg, 0.03-3.58 µg/kg, and 0.05-3235 µg/kg, respectively. Jiangsu was mainly contaminated by p,p'-DDT, p,p'-DDD and endosulfan sulfate, Zhejiang was more polluted by OCPs except δ-HCH, and Jiangxi was more vulnerable to the contamination of OCPs except o,p'-DDE. The partial least-squares discrimination analysis (PLS-DA) model with RX2 36.3-36.8% revealed that compounds with similar chemical properties tended to appear in the same year and month. All crop lands were polluted by DDTs and Endosulfans. The highest concentrations of DDTs and Endosulfans were found in citrus and vegetable fields, respectively. This study offers new insight into the layout and partitioning of OCPs in agricultural land and into insecticide management on public health and ecological safety.

Enantioselectivity effects of energy metabolism in honeybees (Apis mellifera) by triticonazole.

The heavy use of agrochemicals is considered a major factor contributing to the decline in wild honeybee populations. Development of low-toxicity enantiomers of chiral fungicides is the key to reducing the potential threats to honeybees. In this study, we evaluated the enantioselective toxic effects of triticonazole (TRZ) on honeybees and its molecular mechanisms. The results showed that after long-term exposure to TRZ, the content of thoracic ATP decreased significantly, by 41 % in R-TRZ treatments and by 46 % in S-TRZ treatments. Furthermore, the transcriptomic results indicated that S-TRZ and R-TRZ significantly altered the expression of 584 genes and 332 genes, respectively. Pathway analysis indicated that R- and S-TRZ could affect different genes expressed in GO terms and metabolic pathways, especially the transport GO terms (GO: 0006810) and pathways of alanine, aspartate and glutamate metabolism, drug metabolism - cytochrome P450, and pentose phosphate. Additionally, S-TRZ had a more pronounced effect on honeybee energy metabolism, disrupting a greater number of genes involved in the TCA cycle and glycolysis/glycogenesis, exerting a stronger effect on energy metabolic pathways, including nitrogen metabolism, sulfur metabolism, and oxidative phosphorylation. In summary, we recommend reducing the proportion of S-TRZ in racemate to minimize the threat to the survival of honeybees and protect the diversity of economic insects.

Prostaglandin Metabolome Profiles in Zebrafish (Danio rerio) Exposed to Acetochlor and Butachlor.

Prostaglandins (PGs) are critically important signaling molecules that play key roles in normal and pathophysiological processes. Many endocrine-disrupting chemicals have been found to suppress PG synthesis; however, studies about the effects of pesticides on PGs are limited. The effects of two known endocrine disrupting herbicides, acetochlor (AC) and butachlor (BC), on PG metabolites in zebrafish (Danio rerio) females and males were studied using widely targeted metabolomics analysis based on ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In total, 40 PG metabolites were detected in 24 zebrafish samples, including female and male samples, with and without exposure to AC or BC at the sub-lethal concentration of 100 µg/L for 96 h. Among them, 19 PGs significantly responded to AC or BC treatment, including 18 PGs that were upregulated. The enzyme-linked immunosorbent assay (ELISA) test in zebrafish showed BC could cause significant upregulation of an isoprostane metabolite, 5-iPF2a-VI, which is positively related to the elevated level of reactive oxygen species (ROS). The present study guides us to conduct a further study to determine whether PG metabolites, including isoprostanes, could be potential biomarkers for chloracetamide herbicides.

Mixture toxicity of pyraclostrobine and metiram to the zebrafish (Danio rerio) and its potential mechanism.

The interplay between pesticides plays a critical role in ecotoxicology since these chemicals rarely emerge as single substances but rather in mixtures with other chemicals. In the present work, we purposed to clarify the combined toxic impacts of pyraclostrobine (PYR) and metiram (MET) on the zebrafish by using numerous indicators. Results exhibited that the 4-day LC50 value of MET to fish embryos was 0.0025 mg a.i. L-1, which was lower compared with PYR (0.019 mg a.i. L-1). Combinations of PYR and MET presented a synergetic impact on fish embryos. Contents of POD, CYP450, and VTG were drastically increased in the plurality of the single and joint treatments relative to the baseline value. Three genes, including vtg1, crh, and il-8, related to the endocrine and immune systems, were also surprisingly up-regulated when fish were challenged by the individual and mixture pesticides compared with the baseline value. These results afforded valuable information on the latent toxicity mechanisms of co-exposure for PYR and MET in the early growth stage of fish. Moreover, our data also revealed that frequent application of these two pesticides might exert a potentially ecotoxicological hazard on aquatic ecosystems. Collectively, the present study provided valuable guidance for the risk evaluation of chemical combinations.

Encapsulation of Imazalil in HKUST-1 with Versatile Antimicrobial Activity.

Based on high surface areas, adjustable porosity and microbicide activity, metal-organic frameworks (MOFs) HKUST-1 are widely used as drug release carriers for their slow degradation characteristics under slightly acidic conditions. In this work, porous HKUST-1 was reacted rapidly by cholinium salt (as the deprotonation agent and template) in an aqueous solution at room temperature. A novel antimicrobial system based on an imazalil encapsulated metal organic framework (imazalil IL-3@HKUST-1) was established. Imazalil IL-3@HKUST-1 could achieve synergism in inhibiting pathogenic fungi and bacteria. Moreover, six days after treatment, the slow and constant release of imazalil from imazalil IL@HKUST-1 exhibited better sustainability and microbicidal activity than imazalil. We believe that the method may provide a new strategy for related plant diseases caused by bacteria or fungi.

Clinical Data and Biocalculation Methods of GABRD Determine the Clinical Characteristics and Immune Relevance of Colorectal Cancer.

Background: The aim of this study was to clarify the expression of gamma-aminobutyric acid type A receptor delta subunit (GABRD) gene in pan-cancer and its correlation with patient prognosis, and to investigate the function and possible mechanism of GABRD in colorectal cancer (CRC). Methods: The Cancer Genome Atlas (TCGA) data were used to analyze the expression differences of GABRD in pan-cancer, and the correlation between GABRD and clinical prognosis of various tumors was analyzed by Cox regression method. According to the expression level of GABRD, Gene Function Annotation (GO) and Kyoto Encyclopedia of Genomes (KEGG) functional enrichment analysis were performed on the differentially expressed genes. Expression of GABRD gene and 44 marker genes of three types of RNA modification (m1A (10), m5C (13), m6A (21)) genes in different tumors was observed. Pearson correlation of GABRD gene and marker genes of five immune pathways was measured. Results: : TCGA data analysis showed that GABRD was significantly upregulated in various tumor tissues, especially COAD and READCOAD. Survival analysis showed that GABRD was a prognostic protective factor in CRC (p < 0.001). The results of survival nomogram showed that GABRD, age, and tumor (T) lymph node (N) distant metastasis (M) stage were independent prognostic factors, and the survival model C-index was 0.724 (0.644-1). Gene enrichment and functional analysis showed that GABRD may be related to protein digestion and absorption, ECM-receptor interaction, extracellular structure organization, extracellular matrix organization, pancreatic secretion, and antimicrobial humoral response. The expression of GABRD was positively correlated in m1A-, m5C-, and m6A-related genes. The GABRD gene was found in B cell, T cell CD4, T cell CD8, neutrophil, macrophage in TCGA-COAD (N = 282), and TCGA-COADREAD (N = 373). The infiltration level and DC was significantly positively correlated (p < 0.05). Also, the Pearson correlation coefficient is the largest. Conclusion: The involvement of GABRD in the occurrence and development of CRC may be related to protein digestion and absorption, ECM-receptor interaction, extracellular structure organization, extracellular matrix organization, pancreatic secretion, and antimicrobial humoral response. GABRD can be used as a molecular marker for the prognosis of CRC.

Guadipyr, a new insecticide, induces microbiota dysbiosis and immune disorders in the midgut of silkworms (Bombyx mori).

Guadipyr, which combines neonicotinoid and semicarbazone functional groups in one molecule, exhibits good activity on several pests and high acute and chronic toxicity to silkworms (Bombyx mori). In this report, the effects of low-dose guadipyr on the midgut microbiota and immune system of silkworms were studied. Results showed that the structure and richness of the midgut microbiota of silkworms were altered after being treated with 5.25 mg/L (1/10 of LC50) of guadipyr. The abundance of Pseudomonas was evidently increased, whereas Curvibacter was substantially reduced, which might be related to the growth and immunity of silkworms. The expression of key genes in the Toll, IMD, and JAK/STAT pathways, which ultimately led to the downregulation of antimicrobial peptide genes (AMPs), such as CecA, Defensin1, Leb, and glv2, was reduced upon guadipyr exposure. Simultaneously, the suppression of steroid hormone 20-hydroxyecdysone receptor and response genes, such as BR-C Z4, was detected in the exposed groups. The decreased expression of these immune regulatory pathway-related and 20-hydroxyecdysone signal pathway-related genes indicated that the immune system of silkworms was affected by low-dose guadipyr. Our results revealed the negative effects of guadipyr on silkworms and highlighted the unneglectable toxicity of low-dose guadipyr to this economic insect. Given the risk, it is necessary to control the application of guadipyr in or around the mulberry fields.

Precise engineering of hybrid molecules-loaded macromolecular nanoparticles shows in vitro and in vivo antitumor efficacy toward the treatment of nasopharyngeal cancer cells.

Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy, and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of gemcitabine (GEM) and cisplatin (PT) exhibits a great anticancer potential, as GEM enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of GEM and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free GEM and PT core and the macromolecular system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside GEM to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-PT NPs). Further, the morphology of GEM NPs, PT NPs, and GEM-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore GEM-PT NPs induced significant apoptosis in human nasopharyngeal carcinoma CNE2 and SUNE1 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In a xenograft model of nasopharyngeal cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a macromolecular hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable of nanotherapy.

Effects of difenoconazole on hepatotoxicity, lipid metabolism and gut microbiota in zebrafish (Danio rerio).

In current study, larvae and adult zebrafish were exposed to difenoconazole to assess its effect on hepatotoxicity, lipid metabolism and gut microbiota. Results demonstrated that difenoconazole could induce hepatotoxicity in zebrafish larvae and adult, 0.400, 1.00, 2.00 mg/L difenoconazole caused yolk retention, yolk sac edema or liver degeneration after embryos exposure for 120 h, hepatocyte vacuolization and neoplasm necrosis were observed in adult liver after 0.400 mg/L difenoconazole exposure for 21 d. RNA sequencing showed that the 41 and 567 differentially expressed genes in zebrafish larvae and liver induced by 0.400 mg/L difenoconazole, were concentrated in pathways related to protein digestion and absorption, pancreatic secretion, steroid biosynthesis, and different metabolic pathways including galactose or sugar metabolism. Difenoconazole exposure caused lipid accumulation in larval yolk sac, and the elevated triglyceride (TG), malondialdehyde (MDA) and reactive oxygen species (ROS) levels in larvae and liver, which further confirmed the lipid metabolism disorders induced by difenoconazole. The results further showed that difenoconazole increased the abundance of gut microbiota such as Firmicutes, Aeromonas, Enterobacteriaceae and Bacteroides, further suggested that gut microbiota might participate in lipid metabolism and hepatotoxicity during zebrafish development. These findings advanced the field of the difenoconazole-induced developmental toxicity in larvae and adult zebrafish, and the imbalance of gut microbiota provided the plausible mode of action for the liver damage and disordered lipid metabolism in zebrafish.

Mitochondrial dysfunction, apoptosis and transcriptomic alterations induced by four strobilurins in zebrafish (Danio rerio) early life stages.

Though the toxicity of strobilurins on non-target aquatic organisms has been characterized, the associated toxic mechanisms have not been fully explored. The present study showed that the larval stage was the most sensitive developmental stage in zebrafish, and pyraclostrobin (PY) had the highest acute toxicity to embryos, larvae, juvenile and adult with 96 h-LC50 at 0.048 mg/L, 0.029 mg/L, 0.039 mg/L, 0.031 mg/L respectively, when compared with the toxicity of trifloxystrobin (TR), kresoxim-methyl (KM) and azoxystrobin (AZ) at corresponding developmental stage. Then we investigated the transcriptomics and developmental toxicity of TR, KM, AZ and PY on zebrafish embryos after 72 h exposure. RNA-seq revealed that the pathways related to cell apoptosis and cancer, and cellular components organelle membrane and mitochondrion, were markedly affected after TR, KM, AZ and PY exposure during zebrafish early life stages. The results were further confirmed by the induction of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) activities, the elevation of H2O2, malondialdehyde (MDA) and reactive oxygen species (ROS) level, as well as the reduction of intracellular calcium ions (Ca2+) and mitochondrial membrane potential (MMP), which indicated that strobilurins could cause mitochondrial dysfunction and cell apoptosis. The present study was performed a systematic analysis of strobilurins to zebrafish at multi-levels, which provided suggestions for further investigation of molecular mechanisms underlying the toxicity induced by strobilurins on aquatic organisms.