The effects of Fc fusion protein glucagon-like peptide-1 and glucagon dual receptor agonist with different receptor selectivity in vivo studies.

BACKGROUND: Glucagon-like peptide-1 (GLP-1)/glucagon (GCG) dual receptor agonists with different receptor selectivity are under investigation and have shown significant improvement in both weight loss and glycemic control, but the optimal potency ratio between the two receptors to balance efficacy and safety remains unclear. EXPERIMENTAL APPROACH: We designed and constructed several dual receptor agonists with different receptor potency ratios using Fc fusion protein technology. The long-term effects of the candidates on body weight and metabolic dysfunction-associated steatotic liver disease (MASLD) were evaluated in diet-induced obese (DIO) model mice, high-fat diet (HFD)-ob/ob mice and AMLN diet-induced MASLD mice. Repeat dose toxicity assays were performed to investigate the safety profile of the candidate (HEC-C070) in Sprague Dawley (SD) rats. KEY RESULTS: The high GCG receptor (GCGR) selectivity of HEC-C046 makes it more prominent than other compounds for weight loss and most MASLD parameters but may lead to safety concerns. The weight change of HEC-C052 with the lowest GCG agonism was inferior to that of selective GLP-1 receptor agonist (GLP-1RA) semaglutide in DIO model mice. The GLP-1R selectivity of HEC-C070 with moderate GCG agonism has a significant effect on weight loss and liver function in obese mice, and its lowest observed adverse effect level (LOAEL) was 30 nmol/kg in the repeat dose toxicity study. CONCLUSION: We compared the potential of the Fc fusion protein GLP-1/GCG dual receptor agonists with different receptor selectivity to provide the setting for future GLP-1/GCG dual receptor agonists to treat obesity and MASLD.

Species distribution modeling combined with environmental DNA analysis to explore distribution of invasive alien mosquitofish (Gambusia affinis) in China.

China has become one of the most serious countries suffering from biological invasions in the world. In the context of global climate change, invasive alien species (IAS) are likely to invade a wider area, posing greater ecological and economic threats in China. Western mosquitofish (Gambusia affinis), which is known as one of the 100 most invasive alien species, has distributed widely in southern China and is gradually spreading to the north, causing serious ecological damage and economic losses. However, its distribution in China is still unclear. Hence, there is an urgent need for a more convenient way to detect and monitor the distribution of G. affinis to put forward specific management. Therefore, we detected the distribution of G. affinis in China under current and future climate change by combing Maxent modeling prediction and eDNA verification, which is a more time-saving and reliable method to estimate the distribution of species. The Maxent modeling showed that G. affinis has a broad habitat suitability in China (especially in southern China) and would continue to spread in the future with ongoing climate change. However, eDNA monitoring showed that occurrences can already be detected in regions that Maxent still categorized as unsuitable. Besides temperature, precipitation and human influence were the most important environmental factors affecting the distribution of G. affinis in China. In addition, by environmental DNA analysis, we verified the presence of G. affinis predicted by Maxent in the Qinling Mountains where the presence of G. affinis had not been previously recorded.

The association between metabolic dysfunction-associated steatotic liver disease, cardiovascular and cerebrovascular diseases and the thickness of carotid plaque.

BACKGROUND: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and atherosclerosis has been controversial, which has become a hit of recent research. The study aimed to explore the association between MASLD, cardiovascular and cerebrovascular diseases (CCVD), and the thickness of carotid plaque which was assessed by ultrasound. METHODS: From September 2018 to June 2019, 3543 patients were enrolled. We asked participants to complete questionnaires to obtain information. All patients underwent liver ultrasound and bilateral carotid ultrasound to obtain carotid intima-media thickness (IMT) and maximum carotid plaque thickness (CPT). Hepatic steatosis was quantified during examination according to Hamaguchi's ultrasonographic score, from 0 to 6 points. A score < 2 was defined as without fatty liver, and a score ≥ 2 was defined as fatty liver. Information about blood lipids was collected based on the medical records. RESULTS: We found common risk factors for CCVD events, MASLD, and atherosclerosis. There was a significant correlation between MASLD and carotid plaque, but not with CPT. No association was found between MASLD and CCVD events. CPT and IMT were thicker in CCVD patients than in non-CCVD patients. No significant difference was found between IMT and CPT in MASLD patients and non-MASLD patients. CCVD was independently and consistently associated with higher IMT, and free fatty acid (FFA). CONCLUSIONS: According to our results, we recommend carotid ultrasound examination of the patients when FFA is increased, regardless of the presence of risk factors and MASLD. Due to the distribution of CPT of both CCVD and MASLD patients in the CPT 2-4 mm group, contrast-enhanced ultrasound is necessary to assess the vulnerability of the plaque when CPT ≥ 2 mm. Timely treatment of vulnerable plaques may reduce the incidence of future CCVD events.

Calcitriol reverses age-related hypertension via downregulating renal AP1/AT1R pathway through regulating mitochondrial function.

BACKGROUND: The vitamin D level in the blood is associated with the incidence of hypertension. The present study investigated whether or not calcitriol, an active form of vitamin D, reverses age-related hypertension. METHODS: Young (3-month-old) and aged (12-month-old) C57BL/6 male mice were administered with or without calcitriol at 150 ng/kg per day by oral gavage for 8 weeks. Blood pressure was measured by tail-cuff plethysmography and telemetry, and superoxide production in renal tissue was assessed by fluorescence imaging, and the protein expression of AP1/AT1R signaling pathway was examined by Western blot. RESULTS: We showed that 24-hour renal sodium excretion was impaired and blood pressure was increased in aged mice, which was related to the enhancement of renal AT1R expression and function. In addition, the expression of transcription factor AP1 (a dimer of c-Fos and c-Jun) and the binding of AP1 to the AT1R promoter region was significantly enhanced, accompanied by decreased nuclear translocation of Nrf2, abnormal mitochondrial function including decreased ATP production, NAD+/NADH ratio and mtDNA copy numbers, and increased reactive oxygen species. Calcitriol increased 24-hour urinary sodium excretion and reduced blood pressure in aged mice. Mechanically, calcitriol increased the nuclear translocation of Nrf2, improved mitochondrial function, reduced AP1 binding ability to AT1R promoter, which reversed enhanced AT1R expression and function, and lowered blood pressure in aged mice. CONCLUSIONS: Our findings indicated that calcitriol reversed age-related hypertension via downregulating renal AP1/AT1R pathway through regulating mitochondrial function. Thus, calcitriol may be a valuable therapeutic strategy for age-related hypertension.

m1A Regulatory gene signatures are associated with certain immune cell compositions of the tumor microenvironment and predict survival in kidney renal clear cell carcinoma.

Adenosine N1 methylation (m1A) of RNA, a type of post-transcriptional modification, has been shown to play a significant role in the progression of cancer. The objective of the current research was to analyze the genetic alteration and prognostic significance of m1A regulators in kidney renal clear cell carcinoma (KIRC). Genomic and clinicopathological characteristics were obtained from 558 KIRC patients in the Cancer Genome Atlas (TCGA) and Gene Omnibus Expression (GEO) databases. Alterations in the gene expression of ten m1A-regulators were analyzed and survival analysis was performed using the Cox regression method. We also identified three clusters of patients based on their distinct m1A alteration patterns, using integrated analysis of the ten m1A-related regulators, which were significantly related to overall survival (OS), disease-free survival (DFS) and tumor microenvironment (TME) immune cell infiltration cells in KIRC. Our findings showed that m1A alteration patterns have critical roles in determining TME complexity and its immune cell composition. Furthermore, different m1A expression patterns were significantly associated with DFS and OS rates in KIRC patients. In conclusion, the identified m1A RNA modification patterns offer a potentially effective way to classify KIRC patients based on their TME immune cell infiltration, enabling the development of more personalized and successful treatment strategies for these patients.

The clinical value of carotid plaque score in patients with metabolic syndrome and cardiovascular diseases.

OBJECTIVE: To investigate the relationship between carotid plaque load score (CPS) and metabolic syndrome (MS) and cardiovascular diseases (CVD), in order to provide theoretical basis for the precaution and control of MS and CVD. METHODS: A total of 1962 patients were incorporated into the study and divided into MS group and non-MS group, CVD group and non-CVD group. CPS and CIMT were obtained by carotid artery ultrasound, and the data of each group were statistically analyzed. RESULTS: Age, BMI, basal metabolic rate, body fat rate, gender, and the incidence of central obesity, hypertension, diabetes and dyslipidemia are statistical different between MS group and non-MS group (P < 0.05). CIMT between CVD group and non-CVD group are statistical different (1.040 ± 0.239 VS 0.972 ± 0.297, P < 0.001). CPS was statistically significant between MS group and non-MS group(2.254 ± 2.728 VS 1.548 ± 2.219, P = 0.003) and between CVD group and non-CVD group (2.322 ± 2.760 VS 1.688 ± 2.347, P = 0.004). CONCLUSION: Patients in MS group and CVD group have higher carotid plaque burden than those in non-MS group and non-CVD group. The higher the CPS was, the higher the incidence of MS and CVD was, and the distribution of CPS in MS and CVD population was consistent.

Development of a novel Fc fusion protein dual glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists.

AIM: To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon-like peptide-1 receptor (GLP-1 R) agonist with Fc fusion protein structure. METHODS: We designed and constructed an Fc fusion protein that is a dual agonist (HEC-CG115) with an empirically optimized potency ratio for GLP-1R and GIPR. The long-term effects of HEC-CG115 on body weight and glycaemic control were evaluated in diet-induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC-CG115 in Sprague-Dawley rats. RESULTS: HEC-CG115 displayed high potency for GIPR and relatively low potency for GLP-1R, and we labelled it 'imbalanced'. In animal models, HEC-CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet-induced obese model mice. HEC-CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4-week subcutaneous toxicity study conducted to assess the biosafety of HEC-CG115, the no observed adverse effect level was determined to be 3 mg/kg. CONCLUSION: HEC-CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat-dose toxicity study. Therefore, the use of HEC-CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes.

Antibiotic-Induced Recruitment of Specific Algae-Associated Microbiome Enhances the Adaptability of Chlorella vulgaris to Antibiotic Stress and Incidence of Antibiotic Resistance.

Insights into the symbiotic relation between eukaryotic hosts and their microbiome lift the curtain on the crucial roles of microbes in host fitness, behavior, and ecology. However, it remains unclear whether and how abiotic stress shapes the microbiome and further affects host adaptability. This study first investigated the effect of antibiotic exposure on behavior across varying algae taxa at the community level. Chlorophyta, in particular Chlorella vulgaris, exhibited remarkable adaptability to antibiotic stress, leading to their dominance in phytoplankton communities. Accordingly, we isolated C. vulgaris strains and compared the growth of axenic and nonaxenic ones under antibiotic conditions. The positive roles of antibiotics in algal growth were apparent only in the presence of bacteria. Results of 16S rRNA sequencing further revealed that antibiotic challenges resulted in the recruitment of specific bacterial consortia in the phycosphere, whose functions were tightly linked to the host growth promotion and adaptability enhancement. In addition, the algal phycosphere was characterized with 47-fold higher enrichment capability of antibiotic resistance genes (ARGs) than the surrounding water. Under antibiotic stress, specific ARG profiles were recruited in C. vulgaris phycosphere, presumably driven by the specific assembly of bacterial consortia and mobile genetic elements induced by antibiotics. Moreover, the antibiotics even enhanced the dissemination potential of the bacteria carrying ARGs from the algal phycosphere to broader environmental niches. Overall, this study provides an in-depth understanding into the potential functional significance of antibiotic-mediated recruitment of specific algae-associated bacteria for algae adaptability and ARG proliferation in antibiotic-polluted waters.

A large conserved family of small-molecule carboxyl methyltransferases identified from microorganisms.

Small-molecule carboxyl methyltransferases (CbMTs) constitute a small proportion of the reported methyltransferases, but they have received extensive attention due to their important physiological functions. Most of the small-molecule CbMTs isolated to date originate from plants and are members of the SABATH family. In this study, we identified a type of CbMT (OPCMT) from a group of Mycobacteria, which has a distinct catalytic mechanism from the SABATH methyltransferases. The enzyme contains a large hydrophobic substrate-binding pocket (~400 Å3) and utilizes two conserved residues, Thr20 and Try194, to retain the substrate in a favorable orientation for catalytic transmethylation. The OPCMT_like MTs have a broad substrate scope and can accept diverse carboxylic acids enabling efficient production of methyl esters. They are widely (more than 10,000) distributed in microorganisms, including several well-known pathogens, whereas no related genes are found in humans. In vivo experiments implied that the OPCMT_like MTs was indispensable for M. neoaurum, suggesting that these proteins have important physiological functions.

Field-realistic dose of cefotaxime enhances potential mobility of ß-lactam resistance genes in the gut microbiota of zebrafish (Danio rerio).

With large amounts of cephalosporin end up in natural ecosystems, water has been acknowledged as the large reservoir of ß-lactam resistance over the past decades. However, there is still insufficient knowledge available on the function of the living organisms to the transmission of antibiotic resistance. For this reason, in this study, using adult zebrafish (Danio rerio) as animal model, exposing them to environmentally relevant dose of cefotaxime for 150 days, we asked whether cefotaxime contamination accelerated ß-lactam resistance in gut microbiota as well as its potential transmission. Results showed that some of ß-lactam resistance genes (ßRGs) were intrinsic embedded in intestinal microbiome of zebrafish even without antibiotic stressor. Across cefotaxime treatment, the abundance of most ßRGs in fish gut microbiome decreased apparently in the short term firstly, and then increased with the prolonged exposure, forming distinctly divergent ßRG profiles with antibiotic-untreated zebrafish. Meanwhile, with the rising concentration of cefotaxime, the range of ßRGs' host-taxa expanded and the co-occurrence relationships of mobile genetics elements (MGEs) with ßRGs intensified, indicating the enhancement of ßRGs' mobility in gut microbiome when the fish suffered from cefotaxime contamination. Furthermore, the path of partial least squares path modeling (PLS-PM) gave an integral assessment on the specific causality of cefotaxime treatment to ßRG profiles, showing that cefotaxime-mediated ßRGs variation was most ascribed to the alteration of MGEs under cefotaxime stress, followed by bacterial community, functioning both direct influence as ßRG-hosts and indirect effects via affecting MGEs. Finally, pathogenic bacteria Aeromonas was identified as the critical host for multiple ßRGs in fish guts, and its ß-lactam resistance increased over the duration time of cefotaxime exposure, suggesting the potential spreading risks for the antibiotic-resistant pathogens from environmental ecosystems to clinic. Overall, our finding emphasized cefotaxime contamination in aquatic surroundings could enhance the ß-lactam resistance and its transmission mobility in fish bodies.

Research Progress of Steels for Nuclear Reactor Pressure Vessels.

The nuclear reactor pressure vessel is an important component of a nuclear power plant. It has been used in harsh environments such as high temperature, high pressure, neutron irradiation, thermal aging, corrosion and fatigue for a long time, which puts forward higher standards for the performance requirements for nuclear pressure vessel steel. Based on the characteristics of large size and wall thickness of the nuclear pressure vessel, combined with its performance requirements, this work studies the problems of forging technology, mechanical properties, irradiation damage, corrosion failure, thermal aging behavior and fatigue properties, and summarizes the research progress of nuclear pressure vessel materials. The influencing factors of microstructures evolution and mechanism of mechanical properties change of nuclear pressure vessel steel are analyzed in this work. The mechanical properties before and after irradiation are compared, and the influence mechanisms of irradiation hardening and embrittlement are also summarized. Although the stainless steel will be surfacing on the inner wall of nuclear pressure vessel to prevent corrosion, long-term operation may cause aging or deterioration of stainless steel, resulting in corrosion caused by the contact between the primary circuit water environment and the nuclear pressure vessel steel. Therefore, the corrosion behavior of nuclear pressure vessels materials is also summarized in detail. Meanwhile, the evolution mechanism of the microstructure of nuclear pressure vessel materials under thermal aging conditions is analyzed, and the mechanisms affecting the mechanical properties are also described. In addition, the influence mechanisms of internal and external factors on the fatigue properties, fatigue crack initiation and fatigue crack propagation of nuclear pressure vessel steel are analyzed in detail from different perspectives. Finally, the development direction and further research contents of nuclear pressure vessel materials are prospected in order to improve the service life and ensure safe service in harsh environment.

Increasing salinization of freshwater limits invasiveness of a live-bearing fish: Insights from behavioral and life-history traits.

Biological invasions and continued salinization of freshwater are two global issues with largely serious ecological consequences. Increasing salinity in freshwater systems, as an environmental stressor, may negatively affect normal life activities in fish. It has been documented that salinity limits the invasive success of alien species by mediating physiological and life-history performances, however, there are few studies on how salinity affects its invasive process via altered behaviors. Using wild-caught invasive western mosquitofish (Gambusia affinis) as animal model, in this study, we asked whether gradual increasing salinity affects behaviors (personality and mate choice decision here), life-history traits, as well as the correlation between them by exposing G. affinis to three levels salinity (freshwater, 10 and 20‰). Results showed that, with increased salinity, male tended to be shyer, less active, less sociable, and reduced desire to mate, and female tended to be shyer, less active and lost preferences for the larger male. Furthermore, across salinity treatments, male exhibited reduced body fat content and rising reproduction allocation, however, pregnant female revealed diametrically opposed trends. In addition, the correlation between life-history traits and behaviors was only identified in pregnant female. It seems that either salinity or life-history traits directly affects mosquitofish behaviors. In summary, our results partially emphasize the harmful consequences of salinity on both life-history traits and behavioral performances. These findings provide a novel perspective on how salinity potentially affect fish fitness via altering personalities, mate choice decisions, as well as body condition, and hence supports the idea that salinity could affect the spread of invasive mosquitofish.

Long-term exposure of zebrafish to bisphenol F: Adverse effects on parental reproduction and offspring neurodevelopment.

Bisphenol F (BPF), an alternative to bisphenol A (BPA) has potential endocrine and reproductive toxicity; however, the effects of environmental concentrations of BPF on the reproductive and developmental toxicity of offspring following parental exposure to BPF remain unclear. In the present study, the effects of life-cycle BPF exposure at environmental concentrations on zebrafish reproduction, offspring growth, and development were investigated. The results showed that the life-cycle of BPF exposure significantly elevated oxidative stress levels, increased gonadal apoptosis, and reduced zebrafish (F0) spawning. Notably, through maternal transfer, BPF exposure significantly affected offspring development. Developmental parameters such as hatching rate, spontaneous movements, heart rate, body length, and locomotor behavior decreased in zebrafish larvae (F1). In addition, the expression levels of genes related to oxidative stress, apoptosis, and neurodevelopment were altered in F1 larvae. Therefore, the present study provides evidence that BPF, even at environmental concentrations, can be potentially adverse in terms of reproductive defects and offspring neurodevelopmental disorders. Therefore, BPF, as a substitute for BPA, is worthy of in-depth evaluation.

The potential mechanism of BPF-induced neurotoxicity in adult zebrafish: Correlation between untargeted metabolomics and gut microbiota.

Bisphenol F (BPF) is becoming the main substitute for bisphenol A (BPA) in plastics for food and beverage applications. Previous studies have demonstrated the neurotoxicity of BPF; however, its lifecycle toxicity and the underlying mechanisms remain poorly understood. In the current study, zebrafish were continuously exposed to BPF for four months from the embryo to adult stages in order to assess its neurotoxicity. Locomotor behaviors significantly decreased after BPF exposure, which was accompanied by a decrease in body weight, length, and hatching rate. Additionally, BPF increased the expression of inflammatory genes in the brain and destroyed the zebrafishes' intestinal integrity. Meanwhile, the 16S rRNA gene sequence results showed a significantly decreased microbiota abundance and diversity following BPF treatment. Neurotransmitter metabolites were also altered by BPF. Notably, the correlation analysis between microbiota and neurotransmitter metabolism verified that gut microbiota dysbiosis was closely related to the disturbance of neurotransmitter metabolites. Therefore, the present study evaluated the neurotoxicity of lifecycle exposure to BPF and unraveled a novel mechanism involving disturbance of neurotransmitter metabolism and gut dysbiosis, which may provide potential targets for BPF-mediated neurotoxicity.

A systematic comparison of neurotoxicity of bisphenol A and its derivatives in zebrafish.

As more and more countries have prohibited the manufacture and sale of plastic products with bisphenol A (BPA), a number of bisphenol analogues (BPs), including BPS, BPF and BPAF, have gradually been used as its primary substitutes. Ideally, substitutes used to replace chemicals with environmental risks should be inert, so it makes sense that the risk of the similar chemical substitutes (BPS, BPF, and BPAF) should be assessed before they used. Therefore, in the present study, the neurotoxicity of four BPs at environmentally relevant concentration (200 µg/L) were systematically compared using zebrafish as a model. Our results showed that the four BPs (BPA, BPS, BPF and BPAF) exhibited no obvious effect on the hatchability, survival rate and body length of zebrafish larvae, noteworthily a significant inhibitory effect on spontaneous movement at 24 hpf was observed in the BPA, BPF and BPAF treatment groups. Behavioral tests showed that BPAF, BPF and BPA exposure significantly reduced the locomotor activity of the larvae. Additionally, BPAF treatment adversely affected motor neuron axon length in transgenic lines hb9-GFP zebrafish and decreased central nervous system (CNS) neurogenesis in transgenic lines HuC-GFP zebrafish. Intriguingly, BPAF displayed the strongest effects on the levels and metabolism of neurotransmitters, followed by BPF and BPA, while BPS showed the weakest effects on neurotransmitters. In conclusion, our study deciphered that environmentally relevant concentrations of BPs exposure exhibited differential degrees of neurotoxicity, which ranked as below: BPAF > BPF ≈ BPA > BPS. The possible mechanisms can be partially ascribed to the dramatical changes of multiple neurotransmitters and the inhibitory effects on neuronal development. These results suggest that BPAF and BPF should be carefully considered as alternatives to BPA.

Invasive fish retain plasticity of naturally selected, but diverge in sexually selected traits.

Invasive alien species (IAS) have become a major threat to ecosystems worldwide. From an evolutionary ecological perspective, they allow teasing apart the relative contributions of plasticity and evolutionary divergence in driving rapid phenotypic diversification. When IAS spread across extensive geographic ranges, climatic variation may represent a source of strong natural selection through overwinter mortality and summer heat stress. This could favour local adaptation, i.e., evolutionary divergence of certain traits. IAS, however, are likely to show plasticity in survival-related traits, and environmental fluctuation in their new distribution range could favour the maintenance of this pre-existing phenotypic plasticity. By contrast, sexually selected traits are more likely to undergo evolutionary divergence when components of sexual selection differ geographically. Here, using data from a common-garden rearing experiment of Western mosquitofish (Gambusia affinis Baird and Girard, 1853) from five populations across the species' invasive range in China, we show that invasive mosquitofish have retained plasticity in key physiological (thermal tolerances), morphological and life-history traits even 100 years after their introduction to China, but exhibit heritable population differences in several sexually selected traits, including the shape of the male copulatory organ. Adaptive plasticity of traits linked to immediate survival in different thermal environments-while likely responsible for the species' extraordinary invasion success-could slow down genetic evolution. Several sexually selected traits could diverge geographically and show rapid evolutionary change, e.g., because climate alters selective landscapes arising from mate competition as an indirect consequence of variation in overwinter mortality.

A systematic comparison of the developmental vascular toxicity of bisphenol A and its alternatives in vivo and in vitro.

Due to the potential toxicity of bisphenol A (BPA), several bisphenols (BPs), including bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF), have been gradually used as its main substitutes, and the levels of these alternatives in different environmental media have been constantly increasing. Although some previous studies have shown that bisphenol substitutes have similar or greater acute toxicity and estrogenic effects than BPA, comparative studies on the cardiovascular toxicity of BPs have not been evaluated. In this study, the developmental vascular toxicity of BPA and three predominant substitutes (BPF, BPS and BPAF) were evaluated using zebrafish embryos and human vascular endothelial cells (HUVECs). BP exposure at a sublethal concentration of 1/10 96 h median lethal concentration (96 h-LC50) significantly hindered intersegmental vessel (ISV) growth, delayed common cardinal vein (CCV) remodeling and decreased subintestinal vessels (SIVs) in Tg (fli1:EGFP) zebrafish embryos. Meanwhile, the results of the endothelial tube formation assay showed that in vitro angiogenesis was inhibited by BP exposure. Mechanistically, BP exposure increased oxidative stress characterized by a significant decrease in superoxide dismutase (SOD) and catalase (CAT) activity, accompanied by increased levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in both zebrafish and HUVECs. Therefore, the vascular toxicity and oxidative stress potency of the BPs were compared and evaluated, ranking as follows: BPAF > BPF > BPA > BPS. To the best of our knowledge, the present work, for the first time, systematically provides direct evidence for BPA and its alternatives on developmental vascular toxicity in vitro and in vivo. Therefore, these findings will provide insight into the rational and safe application of BPA substitutes.

Protective Effects of Lignin-Carbohydrate Complexes from Wheat Stalk against Bisphenol a Neurotoxicity in Zebrafish via Oxidative Stress.

Lignin-carbohydrate complexes (LCCs) from different lignocellulosic biomass have shown biological qualities as antioxidant and immunostimulant. By contrast, the application of LCCs as protectant against neurotoxicity caused by different compounds is scarce. In this work, two kinds of LCCs with carbohydrate-rich and lignin-rich fractions were obtained from wheat stalk and used to protect against BPA-neurotoxicity in zebrafish. The results showed that BPA at a concentration of 500 µg/L results in neurotoxicity, including significant behavioral inhibition, and prevents the expression of central nervous system proteins in transgenic zebrafish models (Tg (HuC-GFP)). When the zebrafish was treated by LCCs, the reactive oxygen species of zebrafish decreased significantly with the change of antioxidant enzymes and lipid peroxidation, which was due to the LCCs' ability to suppress the mRNA expression level of key genes related to nerves. This is essential in view of the neurotoxicity of BPA through oxidative stress. In addition, BPA exposure had negative effects on the exercise behavior, the catalase (CAT) and superoxide dismutase (SOD) activity, and the larval development and gene expression of zebrafish larvae, and LCC preparations could recover these negative effects by reducing oxidative stress. In zebrafish treated with BPA, carbohydrate-rich LCCs showed stronger antioxidant activity than lignin-rich LCCs, showing their potential as a neuroprotective agents.

Comparison of seven in silico tools for evaluating of daphnia and fish acute toxicity: case study on Chinese Priority Controlled Chemicals and new chemicals.

BACKGROUND: A number of predictive models for aquatic toxicity are available, however, the accuracy and extent of easy to use of these in silico tools in risk assessment still need further studied. This study evaluated the performance of seven in silico tools to daphnia and fish: ECOSAR, T.E.S.T., Danish QSAR Database, VEGA, KATE, Read Across and Trent Analysis. 37 Priority Controlled Chemicals in China (PCCs) and 92 New Chemicals (NCs) were used as validation dataset. RESULTS: In the quantitative evaluation to PCCs with the criteria of 10-fold difference between experimental value and estimated value, the accuracies of VEGA is the highest among all of the models, both in prediction of daphnia and fish acute toxicity, with accuracies of 100% and 90% after considering AD, respectively. The performance of KATE, ECOSAR and T.E.S.T. is similar, with accuracies are slightly lower than VEGA. The accuracy of Danish Q.D. is the lowest among the above tools with which QSAR is the main mechanism. The performance of Read Across and Trent Analysis is lowest among all of the tested in silico tools. The predictive ability of models to NCs was lower than that of PCCs possibly because never appeared in training set of the models, and ECOSAR perform best than other in silico tools. CONCLUSION: QSAR based in silico tools had the greater prediction accuracy than category approach (Read Across and Trent Analysis) in predicting the acute toxicity of daphnia and fish. Category approach (Read Across and Trent Analysis) requires expert knowledge to be utilized effectively. ECOSAR performs well in both PCCs and NCs, and the application shoud be promoted in both risk assessment and priority activities. We suggest that distribution of multiple data and water solubility should be considered when developing in silico models. Both more intelligent in silico tools and testing are necessary to identify hazards of Chemicals.

Aerobic and Anaerobic Biodegradability of Organophosphates in Activated Sludge Derived From Kitchen Garbage Biomass and Agricultural Residues.

Organophosphates (also known as organophosphate esters, OPEs) have in recent years been found to be significant pollutants in both aerobic and anaerobic activated sludge. Food waste, such as kitchen garbage and agricultural residues, can be used as co-substrates to treat the active sludge in sewage treatment plants (STPs). We investigated the biodegradability of nine OPEs derived from kitchen garbage biomass and agricultural residues under different conditions. Under anaerobic conditions, the rate of removal of triphenyl ester OPEs was significantly higher than that of chloride and alkyl OPEs. The addition of FeCl3 and Fe powder increased the rate of degradation of triphenyl ester OPEs, with a DT50 for triphenyl ester OPEs of 1.7-3.8 d for FeCl3 and 1.3-4.7 d for Fe powder, compared to a DT50 of 4.3-6.9 d for the blank control. Addition of an electron donor and a rhamnolipid increased the rate of removal of chlorinated OPEs, with DT50 values for tris(2-carboxyethyl)phosphine) (TCEP) and tris(1,3-dichloroisopropyl)phosphate (TDCPP) of 18.4 and 10.0 d, respectively, following addition of the electron donor, and 13.7 and 3.0 d, respectively, following addition of the rhamnolipid. However, addition of an electron donor, electron acceptor, surfactant, and Fe powder did not always increase the degradation of different kinds of OPEs, which was closely related to the structure of the OPEs. No treatment increased the removal of alkyl OPEs due to their low anaerobic degradability. Tween 80, a non-ionic surfactant, inhibited anaerobic degradation to some degree for all OPEs. Under aerobic conditions, alkyl OPEs were more easily degraded, chlorinated OPEs needed a long adaptation period to degrade and finally attain a 90% removal rate, while the rates of degradation of triphenyl ester OPEs were significantly affected by the concentration of sludge. Higher sludge concentrations help microorganisms to adapt and remove OPEs. This study provides new insights into methods for eliminating emerging pollutants using activated sludge cultured with kitchen garbage biomass and agricultural residues.