Exploring the trophic transfer and effects of microplastics in freshwater ecosystems: A focus on Bellamya aeruginosa to Mylopharyngodon piceus.

Microplastics (MPs) can enter aquatic food webs through direct ingestion from the environment or indirectly via trophic transfer, but their fate and biological effects within local freshwater food chains remain largely unexplored. In this study, we conducted the first investigation on the trophic transfer and impacts of fluorescently labeled polystyrene microplastics (PS-MPs) (100-nm and 10-µm) in a model freshwater food chain consisting of the snail Bellamya aeruginosa and the commercially important fish Mylopharyngodon piceus, both prevalent in Chinese freshwater ecosystems. Quantitative analysis revealed substantial accumulation of MPs in B. aeruginosa, reaching an equilibrium state within 12 h of exposure. While steady-state was not observed, a pronounced time-dependent bioaccumulation of MPs was evident in M. piceus over a five-week period following dietary exposure through the consumption of contaminated B. aeruginosa. Notably, MPs of both sizes underwent translocation from the gastrointestinal tract to the muscle tissue in M. piceus. High-throughput sequencing of the gut microbiota revealed that exposure to 100-nm MPs significantly altered the microbial community composition in M. piceus, and both particle sizes led to increased relative abundance of potentially pathogenic bacterial genera. Our findings provide novel insights into the trophic transfer, tissue accumulation, and biological impacts of MPs in a model freshwater food chain, highlighting the need for further research to assess the ecological and food safety risks associated with microplastic pollution in freshwater environments.

The nematode Caenorhabditis elegans enhances tolerance to landfill leachate stress by increasing trehalose synthesis.

The burgeoning issue of landfill leachate, exacerbated by urbanization, necessitates evaluating its biological impact, traditionally overshadowed by physical and chemical assessments. This study harnesses Caenorhabditis elegans, a model organism, to elucidate the physiological toxicity of landfill leachate subjected to different treatment processes: nanofiltration reverse osmosis tail water (NFRO), membrane bioreactor (MBR), and raw leachate (RAW). Our investigation focuses on the modulation of sugar metabolism, particularly trehalose-a disaccharide serving dual functions as an energy source and an anti-adversity molecule in invertebrates. Upon exposure, C. elegans showcased a 60-70% reduction in glucose and glycogen levels alongside a significant trehalose increase, highlighting an adaptive response to environmental stress by augmenting trehalose synthesis. Notably, trehalose-related genes in the NFRO group were up-regulated, contrasting with the MBR and RAW groups, where trehalose synthesis genes outpaced decomposition genes by 20-30 times. These findings suggest that C. elegans predominantly counters landfill leachate-induced stress through trehalose accumulation. This research not only provides insights into the differential impact of leachate treatment methods on C. elegans but also proposes a molecular framework for assessing the environmental repercussions of landfill leachate, contributing to the development of novel strategies for pollution mitigation and environmental preservation.

Storage, Disposal, and Use of Opioids Among Cancer Patients in Central China: A Multi-Center Cross-Sectional Study.

OBJECTIVE: Unsafe opioid-related practices can lead to abuse, diversion, and accidental overdoses. In this study, we aimed to describe the patterns and beliefs regarding the storage, disposal, and use of opioids among Chinese patients with cancer in their home settings, which remain unclear. METHODS: A multicenter cross-sectional survey was conducted in Hubei Province from October 2022 to June 2023. We collected information on the storage, disposal, and use of opioids among cancer pain inpatients in the oncology department. Logistic regression was used to estimate the factors associated with unsafe disposal and use of opioids. RESULTS: The survey included 221 patients with a median age of 62 years. Only 3.2% stored their opioids under lock and key, and 49.8% were unaware of proper disposal methods. Nearly one-fifth (19.5%) reported having received information on the safe storage (14.0%) and/or disposal (10.0%) of opioids. A total of 44.3% reported unsafe use by sharing (1.8%), losing (4.1%), or taking opioids at a higher dose than prescribed (42.5%). Patients who did not receive information on the safe disposal of opioids (OR = 4.57, P = .0423), had a history of alcohol use (OR = 1.91, P = .0399), and used opioids other than morphine (OR = 2.31, P = .0461) had higher odds of unsafe disposal practices. Individuals with an associate degree/bachelor's degree or above were less likely to dispose of (OR = 0.36, P = .0261) and use (OR = 0.31, P = .0127) opioids unsafely. CONCLUSION: A significant proportion of Chinese patients with cancer exhibit unsafe practices in the storage, disposal, and use of opioids. The study highlights an urgent need for implementing routine education programs and drug "take-back" initiatives to improve opioid-related practices.

Identification of T-cell exhaustion-related genes and prediction of their immunotherapeutic role in lung adenocarcinoma.

Background: Lung adenocarcinoma ranks as the second most widespread form of cancer globally, accompanied by a significant mortality rate. Several studies have shown that T cell exhaustion is associated with immunotherapy of tumours. Consequently, it is essential to comprehend the possible impact of T cell exhaustion on the tumor microenvironment. The purpose of this research was to create a TEX-based model that would use single-cell RNA-seq (scRNA-seq) and bulk-RNA sequencing to explore new possibilities for assessing the prognosis and immunotherapeutic response of LUAD patients. Methods: RNA-seq data from LUAD patients was downloaded from the Cancer Genome Atlas (TCGA) database and the National Center for Biotechnology Information (GEO). 10X scRNA sequencing data, as reported by Bischoff P et al., was utilized for down-sampling clustering and subgroup identification using TSNE. TEX-associated genes were identified through gene set variance analysis (GSVA) and weighted gene correlation network analysis (WGCNA). We utilized LASSO-Cox analysis to establish predicted TEX features. External validation was conducted in GSE31210 and GSE30219 cohorts. Immunotherapeutic response was assessed in IMvigor210, GSE78220, GSE35640 and GSE100797 cohorts. Furthermore, we investigated differences in mutational profiles and immune microenvironment between various risk groups. We then screened TEXRS key regulatory genes using ROC diagnostic curves and KM survival curves. Finally, we verified the differential expression of key regulatory genes through RT-qPCR. Results: Nine TEX genes were identified as highly predictive of LUAD prognosis and strongly correlated with disease outcome. Univariate and multivariate analysis revealed that patients in the low-risk group had significantly better overall survival rates compared with those in the high-risk group, highlighting the model's ability to independently predict LUAD prognosis. Our analysis revealed significant variation in the biological function, mutational landscape, and immune cell infiltration within the tumor microenvironment of both high-risk and low-risk groups. Additionally, immunotherapy was found to have a significant impact on both groups, indicating strong predictive efficacy of the model. Conclusions: The TEX model showed good predictive performance and provided a new perspective for evaluating the efficacy of preimmunization, which provides a new strategy for the future treatment of lung adenocarcinoma.

GSTP alleviates acute lung injury by S-glutathionylation of KEAP1 and subsequent activation of NRF2 pathway.

Oxidative stress plays an important role in the pathogenesis of acute lung injury (ALI). As a typical post-translational modification triggered by oxidative stress, protein S-glutathionylation (PSSG) is regulated by redox signaling pathways and plays diverse roles in oxidative stress conditions. In this study, we found that GSTP downregulation exacerbated LPS-induced injury in human lung epithelial cells and in mice ALI models, confirming the protective effect of GSTP against ALI both in vitro and in vivo. Additionally, a positive correlation was observed between total PSSG level and GSTP expression level in cells and mice lung tissues. Further results demonstrated that GSTP inhibited KEAP1-NRF2 interaction by promoting PSSG process of KEAP1. By the integration of protein mass spectrometry, molecular docking, and site-mutation validation assays, we identified C434 in KEAP1 as the key PSSG site catalyzed by GSTP, which promoted the dissociation of KEAP1-NRF2 complex and activated the subsequent anti-oxidant genes. In vivo experiments with AAV-GSTP mice confirmed that GSTP inhibited LPS-induced lung inflammation by promoting PSSG of KEAP1 and activating the NRF2 downstream antioxidant pathways. Collectively, this study revealed the novel regulatory mechanism of GSTP in the anti-inflammatory function of lungs by modulating PSSG of KEAP1 and the subsequent KEAP1/NRF2 pathway. Targeting at manipulation of GSTP level or activity might be a promising therapeutic strategy for oxidative stress-induced ALI progression.

The Roles of Neutrophil-Derived Myeloperoxidase (MPO) in Diseases: The New Progress.

Myeloperoxidase (MPO) is a heme-containing peroxidase, mainly expressed in neutrophils and, to a lesser extent, in monocytes. MPO is known to have a broad bactericidal ability via catalyzing the reaction of Cl- with H2O2 to produce a strong oxidant, hypochlorous acid (HOCl). However, the overproduction of MPO-derived oxidants has drawn attention to its detrimental role, especially in diseases characterized by acute or chronic inflammation. Broadly speaking, MPO and its derived oxidants are involved in the pathological processes of diseases mainly through the oxidation of biomolecules, which promotes inflammation and oxidative stress. Meanwhile, some researchers found that MPO deficiency or using MPO inhibitors could attenuate inflammation and tissue injuries. Taken together, MPO might be a promising target for both prognostic and therapeutic interventions. Therefore, understanding the role of MPO in the progress of various diseases is of great value. This review provides a comprehensive analysis of the diverse roles of MPO in the progression of several diseases, including cardiovascular diseases (CVDs), neurodegenerative diseases, cancers, renal diseases, and lung diseases (including COVID-19). This information serves as a valuable reference for subsequent mechanistic research and drug development.

Meta Analysis of the Effects of Thalassemia Minor on the Incidence of Amniotic Fluid Abnormalities and the Amount of Bleeding During Delivery.

Objective: To analyze the effects of thalassemia minor on the incidence of amniotic fluid abnormalities and the blood loss of pregnant women during delivery based on the database. Methods: PubMed, EMBASE, EBSCO, Web of Knowledge and Ovid databases were searched for articles on the incidence of amniotic fluid abnormalities and the amount of bleeding during delivery in pregnant women with mild thalassemia; it can also be combined with manual retrieval for literature review. The data retrieval period was from the establishment of the database to June 2022. According to the Newcastle Ottawa scale score, the quality of the six included literature was evaluated, and the Revman processing software was used for meta-analysis. Results: The 6 included articles are all high-quality literature, including 364 cases in the case group and 689 cases in the control group. The publication years of the literature are mainly from 2013 to 2021, and they are all high-quality literature. All literature was blinded, and a total of 4 pregnancy outcomes were extracted from the 6 included literature, including oligohydramnios/oligohydramnios, postpartum hemorrhage, preterm delivery, and cesarean section. Compared to normal pregnant women, the level of postpartum bleeding in thalassemia pregnant women was significantly increased [RR = 2.40, 95% CI (1.63-3.54), P < .05], and the difference was statistically significant. Compared to normal pregnant women, thalassemia pregnant women have a significantly higher risk of developing excessive/insufficient amniotic fluid [RR = 2.71, 95% CI (2.52-2.81), P < .01], and the difference is statistically significant. Compared to normal pregnant women, pregnant women with thalassemia have a significantly higher risk of premature birth [RR = 3.02, 95% CI (1.84~4.96), P < .05], and the difference is statistically significant. Compared to normal pregnant women, the risk of cesarean section in thalassemia pregnant women is significantly increased [RR = 1.68, 95% CI (1.39-2.02), P < .05], and the difference is statistically significant. Conclusion: Thalassemia minor can increase the incidence of amniotic fluid abnormalities and the amount of bleeding during labor. In the future, we should strengthen the health education of pregnant women, improve the understanding of the disease, avoid or reduce the impact of thalassemia on newborns, improve the pregnancy outcome, and provide a more reliable basis for clinical decision-making.However, there are still certain limitations: (1) the literature selected in the study for the past 5 years is relatively small, and they are all single center, retrospective studies, and have a small sample size, resulting in insufficient accuracy of the results of the meta-analysis; (2) Some literature lacks blind methods, which may lead to language bias and implementation bias in the results; (3) The research time is still short, and it has not been clear how different types of thalassemia affect abnormal amniotic fluid volume and postpartum bleeding.

Development and validation of a chiral UPLC-MS/MS method for quantifying S-Oxiracetam and R-Oxiracetam in human plasma, urine and feces: Application to a phase-I clinical pharmacokinetic study.

A chiral UPLC-MS/MS method was developed and validated to determine oxiracetam enantiomers in human plasma, urine, and feces. The R-Oxiracetam and S-Oxiracetam were quantified using a CHIRALPAK ®AD3 column at 25 â„ƒ, and the resolution was greater than 3.2. The S-Oxiracetam is the eutomer that isresponsible for the treatment of various brain damage. Isocratic elution was conducted at a flow rate of 0.9 mL/min for 6 min using the mixture of methanol and acetonitrile (methanol:acetonitrile, 15:85) containing 0.3‰ formic acid. The methods showed linearity at the range of 0.5-100 µg/mL for each oxiracetam enantiomer. A comprehensive validation process was carried out, covering aspects including linearity, selectivity, carryover, accuracy, precision, interferences, matrix effect, recovery, dilution integrity and stability in matrix and solution. The validated methods were successfully applied to quantifying R-Oxiracetam and S-Oxiracetam in human plasma, urine, and feces of 12 healthy subjects treated with either a single dose of 2 g S-Oxiracetam injection or 4 g Oxiracetam injection in a phase-I clinical trial. There was no significant difference for plasma pharmacokinetic parameters of S-Oxiracetam between the two regimens (P＞0.05). The S-Oxiracetam and Oxiracetam were primarily eliminated through urine in their original form, with cumulative excretion rates of 92.16% and 85.92%, respectively, within 24 h after administration. Enantiomers interconversion was not observed in the plasma, urine, or feces. The results of this study suggest that replacing 4 g Oxiracetam injection with 2 g S-Oxiracetam injection could offer clinical benefits by lowering the dosage and mitigating potential risks, based on the pharmacokinetic characteristics.

Diagnostic performance of anti-MAGEA family protein autoantibodies in esophageal squamous cell carcinoma.

MAGEA family proteins are immunogenic and can produce corresponding autoantibodies, and we aim to evaluate the diagnostic value of anti-MAGEA family protein autoantibodies in esophageal squamous cell carcinoma (ESCC). Protein chip was used to detect the expression level of anti-MAGEA autoantibodies (IgG and IgM) in 20 mixed serum samples. Enzyme linked immunosorbent assay was adopted to determine the expression level of autoantibodies in 1019 serum samples (423 ESCC, 423 healthy control (HC), 173 benign esophageal disease (BED)), and stepwise logistic regression analysis was used for developing a diagnostic model. Eight anti-MAGEA autoantibodies were screened out based on the protein chip. The levels of 7 autoantibodies (MAGEA1-IgG, MAGEA3-IgG, MAGEA3-IgM, MAGEA4-IgG, MAGEA6-IgG, MAGEA10-IgG, MAGEA12-IgG) in ESCC were significantly higher than that in HC, and the levels of anti-MAGEA1 IgG, anti-MAGEA3-IgG, anti-MAGEA4-IgG, anti-MAGEA10-IgG and anti-MAGEA12-IgG autoantibodies in ESCC group were significantly higher than those in BED group. The area under curve (AUC), sensitivity and specificity of the logistic regression model (MAGEA1-IgG, MAGEA4-IgG, MAGEA6-IgG, MAGEA12-IgG) in the training set and the validation set were 0.725 and 0.698, 55.2% and 51.8%, 80.4% and 84.5%, respectively, in distinguishing ESCC and HC. The model also could distinguish between ESCC and BED, with the AUC of 0.743, sensitivity of 55.4% and specificity of 89.0%. The positive rate of the model combined with cytokeratin 19 fragment to diagnose ESCC reached 78.0%. The study identified anti-MAGEA autoantibodies with potential diagnostic value for ESCC, which may provide new promising for the detection of the disease.

Identification of novel tumor-associated antigens and evaluation of a panel of autoantibodies in detecting oral cancer.

BACKGROUND: We aimed to identify tumor-associated antigen (TAA) biomarkers through bioinformatic analysis and experimental verification, and to evaluate a panel of autoantibodies against tumor-associated antigens (TAAbs) for the detection of oral cancer (OC). METHODS: GEO and TCGA databases were used to screen significantly up-regulated genes related to OC, and protein-protein interaction (PPI) analysis and Cystoscope software were used to identify key genes. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of autoantibodies in 173 OC patients and 173 normal controls, and binary logistic regression analysis was used to build a diagnostic model. RESULTS: Using bioinformatics, we identified 10 key genes (AURKA, AURKB, CXCL8, CXCL10, COL1A1, FN1, FOXM1, MMP9, SPP1 and UBE2C) that were highly expressed in OC. Three autoantibodies (anti-AURKA, anti-CXCL10, anti-FOXM1) were proven to have diagnostic value for OC in the verification set and the validation set. The combined assessment of these three autoantibodies improved the diagnostic value for OC, with an area under the curve (AUC), sensitivity and specificity of 0.741(95%CI:0.690-0.793),58.4% and 80.4%, respectively. In addition, the combination of these three autoantibodies also had high diagnostic value for oral squamous cell carcinoma (OSCC), with an AUC, sensitivity and specificity of 0.731(95%CI:0.674,0.786), 53.8% and 82.1%, respectively. CONCLUSIONS: Our study revealed that AURKA, CXCL10 and FOXM1 may be potential biomarkers and the panel of three autoantibodies (anti-AURKA, anti-CXCL10 and anti-FOXM1) had good diagnostic value for OC.

Role of miR-21 in the diagnosis of colorectal cancer: Meta-analysis and bioinformatics.

Advanced colorectal cancer (CRC) has a bad prognosis and is challenging to cure. Therefore, there is an urgent need for an effective early diagnosis marker. MicroRNA-21 (miR-21) regulates the expression of multiple cancer target genes. The objective of this study was to assess the diagnostic role of miR-21 in CRC.A meta-analysis of PubMed, Cochrane Library, EMBASE, and Web of Science databases was performed with a carefully designed search strategy to identify records related to the diagnostic role of miR-21 in CRC. TCGA data was used to search for different microRNAs in colorectal cancer samples and surrounding tissues. In addition, potential target genes for miR-21 were predicted and evaluated by functional analysis. We conducted a meta-analysis for 10 studies, including 728 blood samples of patients with CRC and 472 healthy controls. The combined sensitivity and specificity of miR-21 to diagnose colorectal cancer were 0.79 (95% CI: 0.67-0.87) and 0.92 (95% CI: 0.85-0.96), respectively. The combined positive likelihood ratio (PLR) was 10.20 (95% CI: 4.8-21.5), the combined negative likelihood ratio (NLR) was 0.23 (95% CI: 0.14-0.37), the diagnostic odds ratio (DOR) was 45.00 (95% CI:15-132), the area under the summary receiver operating characteristic curve (SROC) for the included studies was 0.93(95%CI: 0.91-0.95). Simultaneously, TCGA data showed that miR-21 was a differential microRNA in colorectal cancer tissues and adjacent tissues, and it was an up-regulated gene. After verification by three databases, 48 target genes of miR-21 were obtained. Through GO enrichment analysis, it was found that the target genes were mainly distributed in the fiber center, the molecular function was mainly focused on cytokine receptor binding, and the biological process was mainly focused on ubiquitin-dependent protein catabolism mediated by the proteasome. KEGG pathway analysis showed that the target genes were mainly distributed in tumor pathways.

Coupling of microplastic contamination in organisms and the environment: Evidence from the tidal flat ecosystem of Hangzhou Bay, China.

Microplastics are a new type of contaminant, widely defined as fragmented plastics with the longest dimension or diameter less than 5 mm, that are widely distributed, difficult to degrade, and easily adsorb other pollutants. Estuaries are key habitats where terrestrial microplastics flow in water runoff and import into the ocean. The ubiquitous use of plastics has resulted in a massive amount of plastic waste that is released and accumulated in bay ecosystems, posing serious ecological impacts. The study of microplastic contamination in Hangzhou Bay, the estuary of the Qiantang River, has important theoretical value in ecology and environmental science. Microplastic contamination in the tidal flats and organisms of Hangzhou Bay is serious and microplastic characteristics (type, size, and polymer type) in organisms were significantly correlated with those in the environmental media. Spatial autocorrelation was found in the abundance of microplastics in marine and tidal flat sediments of Hangzhou Bay, China, but no spatial autocorrelation was found in the sediment environment as a whole. The microplastic abundance in each organism in this study was not statistically correlated by weight or by individual count with its corresponding trophic level (P = 0.239 > 0.05; P = 0.492 > 0.05, respectively). Our study suggests a coupling relationship of microplastic contamination between organisms and the environment and can provide essential data and a scientific foundation for the study of microplastics pollution in Hangzhou Bay, as well as provide important evidence for the ecological and health risk assessment of microplastics.

Mechanistic Study of Icaritin-Induced Inactivation of Cytochrome P450 2C9.

Icaritin (ICT) is a prenylflavonoid derivative that has been approved by National Medical Products Administration for the treatment of hepatocellular carcinoma. This study aims to evaluate the potential inhibitory effect of ICT against cytochrome P450 (CYP) enzymes and to elucidate the inactivation mechanisms. Results showed that ICT inactivated CYP2C9 in a time-, concentration-, and NADPH-dependent manner with Ki = 1.896 µM, Kinact = 0.02298 minutes-1, and Kinact/Ki = 12 minutes-1 mM-1, whereas the activities of other CYP isozymes was minimally affected. Additionally, the presence of CYP2C9 competitive inhibitor, sulfaphenazole, superoxide dismutase/catalase system, and GSH all protected CYP2C9 from ICT-induced activity loss. Moreover, the activity loss was neither recovered by washing the ICT-CYP2C9 preincubation mixture nor the addition of potassium ferricyanide. These results, collectively, implied the underlying inactivation mechanism involved the covalent binding of ICT to the apoprotein and/or the prosthetic heme of CYP2C9. Furthermore, an ICT-quinone methide (QM)-derived GSH adduct was identified, and human glutathione S-transferases (GST) isozymes GSTA1-1, GSTM1-1, and GSTP1-1 were shown to be substantially involved in the detoxification of ICT-QM. Interestingly, our systematic molecular modeling work predicted that ICT-QM was covalently bound to C216, a cysteine residue located in the F-G loop downstream of substrate recognition site (SRS) 2 in CYP2C9. The sequential molecular dynamics simulation confirmed the binding to C216 induced a conformational change in the active catalytic center of CYP2C9. Lastly, the potential risks of clinical drug-drug interactions triggered by ICT as a perpetrator were extrapolated. In summary, this work confirmed that ICT was an inactivator of CYP2C9. SIGNIFICANCE STATEMENT: This study is the first to report the time-dependent inhibition of CYP2C9 by icaritin (ICT) and the intrinsic molecular mechanism behind it. Experimental data indicated that the inactivation was via irreversible covalent binding of ICT-quinone methide to CYP2C9, while molecular modeling analysis provided additional evidence by predicting C216 as the key binding site which influenced the structural confirmation of CYP2C9's catalytic center. These findings suggest the potential of drug-drug interactions when ICT is co-administered with CYP2C9 substrates clinically.

Ubiquitin E3 ligase AtCHYR2 functions in glucose regulation of germination and post-germinative growth in Arabidopsis thaliana.

KEY MESSAGE: Cytoplasm-localized RING ubiquitin E3 ligase AtCHYR2 involved in plant glucose responses during germination and post-germinative growth. CHY ZINC FINGER AND RING PROTEIN (CHYR) containing both a CHY zinc finger and a C3H2C3-type RING domain plays important roles in plant drought tolerance and the abscisic acid (ABA) response; however, their functions in sugar signaling pathways are less studied. Here, we report a glucose (Glc) response gene AtCHYR2, a homolog of RZFP34/CHYR1, which is induced by various abiotic stresses, ABA, and sugar treatments. In vitro, we demonstrated that AtCHYR2 is a cytoplasm-localized RING ubiquitin E3 ligase. Overexpression of AtCHYR2 led to hypersensitivity to Glc and enhanced Glc-mediated inhibition of cotyledon greening and post-germinative growth. Contrastingly, AtCHYR2 loss-of-function plants were insensitive to Glc-regulated seed germination and primary root growth, suggesting that AtCHYR2 is a positively regulator of the plant glucose response. Additionally, physiological analyses showed that overexpression AtCHYR2 increased stomata aperture and photosynthesis under normal condition, and promoted accumulation of endogenous soluble sugar and starch in response to high Glc. Genome-wide RNA sequencing analysis showed that AtCHYR2 affects a major proportion of Glc-responsive genes. Particularly, sugar marker gene expression analysis suggested that AtCHYR2 enhances the Glc response via a signaling pathway dependent on glucose metabolism. Taken together, our findings show that a novel RING ubiquitin E3 ligase, AtCHYR2, plays an important role in glucose responses in Arabidopsis.

The Typical Polybrominated Diphenyl Ethers (PBDEs) and Heavy Metals Distributions in a Formal e-Waste Dismantling Site.

Understanding the release of pollutants from the formal e-waste dismantling site could provide the basic information and potential risk to guide the normative regulation of the process. In this study, the distribution of typical polybrominated diphenyl ethers (PBDEs) and heavy metals in a relocating site of a formal e-waste dismantling company was firstly investigated down to the saturated zone, with a maximum depth of 3.0 m. The mean concentrations of Σ13PBDEs were ranged from 2.815 to 7.178 ng/g, with a peak value of 7.178 ng/g in storage area. BDE-209 was the predominant congener of PBDEs in the soil, with the value ranged from 1.688 to 2.483 ng/g. A higher pollution of PBDEs and HMs was presented in the storage area. The risk assessment of PBDEs mostly posed a low environmental risk (RQ ≤ 0.01) and pentaBDE was found to be the most harmful driver for the potential environmental risk.

Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism.

Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.

Subacute oral toxicology and toxicokinetics of pterostilbene, a novel Top1/Tdp1 inhibiting anti-tumor reagent.

This study evaluated the subacute toxicity and toxicokinetics of a potential anti-cancer drug candidate, pterostilbene, in rats. Animals were orally administered at two repeated doses of 200 and 500 mg/kg for 28 days. No mortality was observed during the 28 days of continuous administration of pterostilbene. Body weight and food consumption in each group increased steadily, while no significant difference was found. Liver weight in the 500 mg/kg female, but not male group increased with mild cytoplasmic vacuoles observed in histopathological study. Toxicokinetics was assessed by measuring plasma concentrations of pterostilbene on the first and 28th day of administration using UPLC-MS/MS. Toxicokinetic parameters showed that AUC0-t significantly increased in all animals, while the increase in females was greater than males. System exposure of pterostilbene appeared to be linear within the administrated dose range. In conclusion, our findings suggested a minimal subacute toxicity profile of pterostilbene, which could strongly support further development of this compound as a novel anti-cancer agent.

Preclinical pharmacokinetics, biodistribution, excretion, and plasma protein binding study of 58Fe-labeled hemin by ICP-MS.

BACKGROUND: Hemin, a stable form of heme iron, is a potential iron supplement for the treatment of iron deficiency. To date, the pharmacokinetics and in vivo ADME properties of hemin are to be elucidated. METHODS: In this study, a rapid, sensitive, and validated inductively coupled plasma mass spectrometry (ICP-MS) method was used in combination with 58Fe stable isotope labeling to systemically investigate the plasma pharmacokinetics, biodistribution, excretion, and plasma binding profiles of hemin in animals. RESULTS: Results showed that the ICP-MS method is accurate and sensitive enough to quantitatively determine the in vivo disposition process of 58Fe derived from 58Fe-labeled hemin. Following intra-gastric administration, 58Fe was rapidly absorbed in gastrointestinal tract, with Cmax of 41.1 ± 23.1 ng/mL, Tmax of 1.38 ± 0.48 h, and bioavailability of 1.12 ± 0.45 % in beagle dogs. Moreover, 58Fe was distributed to various organs including stomach, small intestine, spleen, and liver, within a few hours after intra-gastric administration in rats. Excretion of 58Fe in rats was predominantly via feces (76.3 ± 15.1 % of dosage), whereas minimally via urine (0.14 ± 0.08 % of dosage). Protein binding study revealed majority of 58Fe in plasma was bound to proteins, with average binding rates of 81.0 % and 92.7 % in human and rat plasma, respectively. CONCLUSION: In conclusion, the present study validated the work-flow of preclinical pharmacokinetic studies of iron-containing drug candidates with using ICP-MS and stable (trace) isotope labeling strategy. It also provided useful information to support the further development of hemin as a drug/nutrition supplement candidate.