The protective effects of silymarin nanoemulsion on 5-fluorouracil-induced gastrointestinal toxicity in rats

5-Fluorouracil (5FUra) is the third most popular chemotherapeutic component employed to treat solid tumors. In the present study, we aimed to appraise the silymarin (SM) and silymarin nanoemulsion (SMN) effect on 5FUra-induced gastrointestinal toxicity in adult male rats. A total of 30 male Wistar rats were divided into 6 groups including the control (Crl) group, and groups treated with SMN (5 mg.kg⁻¹), SM (5 mg.kg⁻¹), 5FUra + SMN (5 mg.kg⁻¹), and 5FUra + SM (5 mg.kg⁻¹) by IP injection for 14 days. And gastrointestinal toxicity was induced by a single intraperitoneal (IP) injection of 5FUra (100 mg.kg⁻¹) for the last group in the study. Treating rats with SM and SMN diminished elevating malondialdehyde (MDA) levels, and improved total antioxidant capacity (TAC) levels. Also, the intensity of mRNA expression of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) caused by 5FUra in the gastrointestinal tissue tract, and macroscopic oral ulcerations decreased, ass well as weight loss was prevented, particularly in the SMN group. Moreover, in the microscopic scope, there were significant improvements in the levels of hyperemia, hyaline, and inflammatory cell infiltration in the tongue, esophagus, and intestinal tissues in the FUra + SMN and FUra + SM groups compared to 5FUra. Hence, treatment with SM and SMN reduced oxidative stress, histopathological degeneration, and gene expression of inflammatory markers in the gastrointestinal tract. According to the results, treatment with SM and SMN markedly decreases the gastrointestinal toxicity caused by 5FUra.     

Prediction of the joint toxicity of five organophosphorus pesticides to Daphnia magna

The individual toxicities of five organophosphorus pesticides (dichlorvos, parathion, methyl parathion, malathion and dimethoate) to Daphnia magna were investigated in 24-h immobilization experiments. Using these toxicity data, their combined toxicities were measured in pesticide mixtures designed using either ‘equivalent-effect concentration ratios’ or ‘uniform-design concentration ratios’. The toxicities of mixtures of similarly or dissimilarly acting toxicants are often predicted from the individual toxicities of the component compounds, using one of two distinct biometric models: concentration addition (CA) or independent action (IA). The relative accuracies of the CA and IA models were assessed using the model deviation rate (MDR), which represents the difference between the effect predicted from the individual pesticide concentrations and the observed effect. The mean MDR value of CA was 0.93 (range 0.75–1.31) and the mean value obtained by IA was 3.13 (range 2.52–4.37). We conclude that the CA model is better able to predict the joint toxicities of mixtures of organophosphorus pesticides to D. magna.     

Surface response model for prediction of the acute toxicity of Cu(II) and Cr(VI) towardDaphnia magna

A central composite design (CCD) was employed to evaluate the combined effects of pH, hardness and dissolved organic carbon (DOC) on the toxicity of Cu (II) and Cr(VI) towardDaphnia magna. Surface response design (SRD) analysis showed that pH and DOC were found to be most significant for the Cu(II) toxicity (p<0.05), while pH and hardness for the Cr(VI) toxicity. According to the results of chemical speciation using the Visual MINTEQ program, increases in pH and DOC concentration led to decreased toxicity of Cu(II) by reducing the concentration of toxic Cu²⁺ species. For the Cr(VI) toxicity, increases in pH and hardness led to decreased toxicity towardD. magna by reducing the concentrations of toxic HCrO₄ ^? and CrO₄ ^2? species. Based on the SRD analysis, surface response models were developed for prediction of the 24-h and 48-h mortalities ofD. magna in the presence of Cu(II) and Cr(VI) under different pH, hardness and DOC conditions.     

QSAR study using acute toxicity of Daphnia magna and Hyalella azteca through exposure to polycyclic aromatic hydrocarbons (PAHs)

Polycyclic aromatic hydrocarbons are organic chemicals consisting of a small number of benzene rings. PAHs are exposed to the environment by events such as Crude oil spills, even though they are substances present in the environment. Exposure of PAHs to the environment will affect not only the environment, but also the living organisms and the ecosystem as a whole. The effects of PAHs vary widely depending on the type of PAHs and have been studied for a long time. However, there are only 16 kinds of PAHs defined by US EPA, and there are more kinds of PAHs present in the environment. Therefore, it is time- and space-limited to judge the toxicity of all kinds of PAHs by evaluating them. In all cases, the tendency of research is shifting toward predicting toxicity evaluation through modeling rather than the direction of toxicity evaluation. In this study, we constructed a quantitative structure-activity relationship (QSAR) model, one of the molecular structure activation models, and predicted the correlation between the toxicity value and the logKow value of PAHs. Basically, as the logKow value increases, the median effective concentration (EC50) tends to decrease. Compared with the previous studies, Hyalella azteca showed this tendency, but Daphnia magna showed different results when exposed to Naphthalene. The RMSE(Root Mean Square Error) values of Daphnia magna and Hyalella azteca were 6.0049 and 5.9980, respectively, when the QSAR model was constructed using the toxicity data for PAHs. We confirmed the validity of the QSAR model in this study by comparing the results of exposing Daphnia magna to PAHs and the ECOSAR data, one of the existing models. The R² value was found to be 0.9356. This study suggests that it may be helpful to predict the toxicity evaluation and to prepare countermeasures for accidents such as Crude oil spill. It is thought that if more data base is created by using additional types of PAHs and species in the same way as this study in the future, it will help to construct the modeling.

     

Toxicity evaluation of three pesticides on non-target aquatic and soil organisms: commercial formulation versus active ingredient

The Ecological Risk Assessment of pesticides requires data regarding their toxicity to aquatic and terrestrial non-target species. Such requirements concern active ingredient(s), generally not considering the noxious potential of commercial formulations. This work intends to contribute with novel information on the effects of short-term exposures to two herbicides, with different modes of action (Spasor^®, Stam Novel Flo 480^®), and an insecticide (Lannate^®), as well as to corresponding active ingredients (Glyphosate, Propanil and Methomyl, respectively). The microalga Pseudokirchneriella subcapitata (growth inhibition), the cladoceran Daphnia magna (immobilisation), and the earthworm Eisenia andrei (avoidance behaviour) were used as test species. Both herbicides were innocuous to all test organisms at environmentally realistic concentrations, except for Stam and Propanil (highly toxic for Pseudokirchneriella; moderately toxic to Daphnia). Lannate and Methomyl were highly toxic to Daphnia and caused Eisenia to significantly avoid the spiked soil at realistic application rates. The toxicity of formulations either overestimated (e.g. Stam/Propanil for P. subcapitata) or underestimated (e.g. Stam/Propanil for D. magna) that of the active ingredient.     

Ecotoxicity of losartan potassium in aquatic organisms of different trophic levels

The intensive use of the antihypertensive losartan potassium (LOS) has culminated in its high occurrence in aquatic environments. However, insufficient studies had investigated its effects in non-target organisms. In this study, ecotoxicity of LOS was assessed in aquatic organisms from distinct trophic levels (Desmodesmus subspicatus, Daphnia magna, and Astyanax altiparanae). Genotoxicity was assessed by the comet assay in D. magna and A. altiparanae, and biochemical biomarkers for the fish. LOS was more toxic to D. subspicatus (EC_50(72h) = 27.93 mg L⁻¹) than D. magna (EC₅₀ = 303.69 mg L⁻¹). Subsequently, this drug showed to induce more DNA damage in D. magna than A. altiparanae, when exposed to 2.5 mg L⁻¹. No significant stress responses were observed by the fish biomarkers, suggesting that higher trophic levels organisms are more tolerant to LOS toxicity. LOS showed relatively low toxic potential for a short period of exposure, but with different patterns of toxicity for the organisms from distinct trophic levels, contributing to further risk assessment of LOS.     

Comparative Pharmacology and Toxicology of Pharmaceuticals in the Environment: Diphenhydramine Protection of Diazinon Toxicity in Danio rerio but Not Daphnia magna

Pharmaceuticals and other contaminants of emerging concern present unique challenges to environmental risk assessment and management. Fortunately, mammalian pharmacology and toxicology safety data are more readily available for pharmaceuticals than other environmental contaminants. Identifying approaches to read-across such pharmaceutical safety information to non-target species represents a major research need to assess environmental hazards. Here, we tested a biological read-across hypothesis from emergency medicine with common aquatic invertebrate and vertebrate models. In mammals, the antihistamine diphenhydramine (DPH) confers protection from poisoning by acetylcholinesterase inhibition because DPH blocks the acetylcholine receptor. We employed standardized toxicity methods to examine individual and mixture toxicity of DPH and the acetylcholinesterase inhibitor diazinon (DZN) in Daphnia magna (an invertebrate) and Danio rerio (zebrafish, a vertebrate). Though the standardized Fish Embryo Toxicity method evaluates early life stage toxicity of zebrafish (0–3 days post fertilization, dpf), we further evaluated DPH, DZN, and their equipotent mixture during three development stages (0–3, 3–6, 7–10 dpf) in zebrafish embryos. Independent action and concentration addition mixture models and fish plasma modeling were used to assist interpretation of mixture toxicity experiments. Though our primary hypothesis was not confirmed in acute studies with Daphnia magna, DPH conferred a protective effect for acute DZN toxicity to zebrafish when DPH plasma levels were expected to be greater than mammalian therapeutic, but lower than acutely lethal, internal doses. We further observed that timing of developmental exposure influenced the magnitude of DZN and DPH toxicity to zebrafish, which suggests that future zebrafish toxicity studies with pharmaceuticals and pesticides should examine exposure during developmental stages.KEY WORDS: alternative toxicity test methods, biological read-across, comparative pharmacology and toxicology, mixture toxicology, pharmaceuticals in the environment     

Sensitivity of Ethiopian aquatic macroinvertebrates to the pesticides endosulfan and diazinon,compared to literature data

The aims of the present study were to present a methodology for toxicity tests that can be used when analytical resources to verify the test concentrations are limited, and to evaluate whether the sensitivity of a limited number of Ethiopian species to pesticides differs from literature values for, mainly, temperate species. Acute toxicity tests were performed using three Ethiopian aquatic invertebrate species, one crustacean (Diaphanosoma brachyurum) and two insects (Anopheles pharoensis and Culex pipiens) and using the pesticides endosulfan and diazinon. All species–pesticide combinations were tested in duplicate to estimate the consistency, i.e. the intra-laboratory variation, in test results. Daphnia magna was tested as well to allow the test results to be compared directly with values from the literature. Results indicate that the differences between the EC50s obtained for D. magna in this study and those reported in the literature were less than a factor of 2. This indicates that the methodology used is able to provide credible toxicity values. The results of the duplicated tests showed intra-laboratory variation in EC50 values of up to a factor of 3, with one test showing a difference of a factor of 6 at 48 h. Comparison with available literature results for arthropod species using species sensitivity distributions indicated that the test results obtained in this study fit well in the log-normal distribution of the literature values. We conclude that the methodology of performing multiple tests to check for consistency of test results and performing tests with D. magna for comparison with literature values to check for accuracy is able to provide reliable effect threshold levels and that the tested Ethiopian species did not differ in sensitivity from the arthropod species reported on in the literature.     

Hedgehog signalling in allograft vasculopathy: a new therapeutic target?

Allograft vasculopathy (AV) leads to chronic rejection of organ transplants, but its causes are obscure. New research from the Jane-Wit laboratory showed that Sonic Hedgehog (SHH) signalling from damaged graft endothelium drives vasculopathy by promoting proinflammatory cytokine production and NLRP3-inflammasome activation in alloreactive CD4⁺PTCH1^hiPD-1^hiT memory cells, offering new diagnostic and therapeutic strategies.     

Glycine: a long-sought novel ligand for GPR158

G-protein-coupled receptors (GPCRs) are important drug targets with chemically diverse ligands and varying intracellular coupling partners. Recent work by Laboute et al. deorphanized GPR158 as a metabotropic glycine receptor (mGlyR), thereby providing evidence of a novel neuromodulatory system involving this non-canonical Class C receptor with an impact on cognition and affective states.     

Classificatory and quantitative models of the relationship between the structures of chemical compounds and their toxicity for <Emphasis Type="Italic">Daphnia magna</Emphasis>

A structural similarity method was used to construct stable classificatory models for discriminating compounds with mechanisms of general toxicity to Daphnia magna compared with all other compounds with different actions, compounds with the polar narcosis mechanism compared with all others, compounds inhibiting cholinesterase compared with compounds with other mechanisms, and compounds with general toxic actions compared with substances with the polar narcosis mechanism. Simultaneous use of the classificatory and regression models allowed clear identification of substances acting via the general toxicity mechanism, with quantitative assessments of LC₅₀ values and analysis of contributions of steric interactions and hydrogen bonds to toxicity. Our own experimental data on the toxicities (LC₅₀) of 119 chemical compounds with different types of toxic actions to Daphnia magna are presented. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 6, pp. 22–27, June, 2008.     

Joint toxicity of cadmium and SDBS on <Emphasis Type="Italic">Daphnia magna</Emphasis> and <Emphasis Type="Italic">Danio rerio</Emphasis>

Information on joint toxicity is limited. To clarify the joint toxicity and the interactions among toxicants on different aquatic organisms, we investigated the acute toxicity of cadmium and sodium dodecyl benzene sulfonate, two chemicals with high concerns in Chinese waters, on the immobilization of Daphnia magna (D. magna) and the swimming behavior of Danio rerio (D. rerio). Our results illustrated that cadmium and sodium dodecyl benzene sulfonate expressed a synergistic effect on the immobilization of D. magna; and an antagonistic effect on the swimming speed D. rerio, but a synergistic effect on its vertical position in the water column. Based on the observed data, we found the independent action model was more appropriate than the concentration addition model in the prediction of their joint toxicity. Our results gave an example of the joint toxicity investigation, and aided to comprehensive the toxicity action mode of chemical mixtures.     

A deep dive into degrader-induced protein-protein interfaces

Targeted protein degradation (TPD) relies on a comprehensive understanding of interfaces between hijacked E3 ligases and their substrates. In vitro techniques often do not capture the interaction dynamics. Recently, Hanzl et al. introduced deep mutational scanning (DMS) in combination with structural and biochemical approaches to identify residues crucial for degrader activity.     

The critical importance of defined media conditions in Daphnia magna nanotoxicity studies

Due to the widespread use of silver nanoparticles (AgNPs), the likelihood of them entering the environment has increased and they are known to be potentially toxic. Currently, there is little information on the dynamic changes of AgNPs in ecotoxicity exposure media and how this may affect toxicity. Here, the colloidal stability of three different sizes of citrate-stabilized AgNPs was assessed in standard strength OECD ISO exposure media, and in 2-fold (media2) and 10-fold (media10) dilutions by transmission electron microscopy (TEM) and atomic force microscopy (AFM) and these characteristics were related to their toxicity towards Daphnia magna. Aggregation in undiluted media (media1) was rapid, and after diluting the medium by a factor of 2 or 10, aggregation was reduced, with minimal aggregation over 24 h occurring in media10. Acute toxicity measurements were performed using 7 nm diameter particles in media1 and media10. In media10 the EC₅₀ of the 7 nm particles for D. magna neonates was calculated to be 7.46 μg L⁻¹ with upper and lower 95% confidence intervals of 6.84 μg L⁻¹ and 8.13 μg L⁻¹ respectively. For media1, an EC₅₀ could not be calculated, the lowest observed adverse effect concentration (LOAEC) of 11.25 μg L⁻¹ indicating a significant reduction in toxicity compared to that in media10. The data suggest the increased dispersion of nanoparticles leads to enhanced toxicity, emphasising the importance of appropriate media composition to fully assess nanoparticle toxicity in aquatic ecotoxicity tests.     

Emotion regulation difficulties and social control correlates of smoking among pregnant women trying to quit

Approximately 15% of US women currently smoke during pregnancy. An important step toward providing effective smoking cessation interventions during pregnancy is to identify individuals who are more likely to encounter difficulty quitting. Pregnant smokers frequently report smoking in response to intrapersonal factors (e.g., negative emotions), but successful cessation attempts can also be influenced by interpersonal factors (i.e., influence from close others). This study examined the association between emotion regulation difficulties, positive and negative social control (e.g., encouragement, criticism), and smoking cessation-related variables (i.e., smoking quantity, withdrawal symptoms) among pregnant smokers. Data were drawn from the pretreatment wave of a smoking cessation trial enrolling low-income pregnant women who self-reported smoking in response to negative affect (N = 73). Greater emotion regulation difficulties were related to greater smoking urges (b = 0.295, p = .042) and withdrawal symptoms (b = 0.085, p = .003). Additionally, more negative social control from close others was related to fewer smoking days (b = −0.614, p = .042) and higher smoking abstinence self-efficacy (b = 0.017, p = .002). More positive social control from close others interacted with negative affect smoking (b = −0.052, p = .043); the association between negative affect smoking and nicotine dependence (b = 0.812, p < .001) only occurred at low levels of positive social control. Findings suggest that emotion regulation difficulties may contribute to smoking during pregnancy by exacerbating women's negative experiences related to smoking cessation attempts. Negative social control was related to lower smoking frequency and greater confidence in quitting smoking, suggesting that it may assist pregnant smokers' cessation efforts. Positive social control buffered women from the effects of negative affect smoking on nicotine dependence.Trial registrationClinicalTrials.gov, NCT01163864     

Differentiation of the toxicities of silver nanoparticles and silver ions to the Japanese medaka (Oryzias latipes) and the cladoceran Daphnia magna

Abstract

Silver nanoparticles (AgNPs) are increasingly used in various fields. However, little is known about the environmental effects of widespread use of products containing AgNPs. The objective of this study was to determine the ecotoxicity caused by AgNPs. The 48-h effective concentration 50 (EC₅₀) values for Daphnia magna of suspensions of 60 nm and 300 nm AgNPs were 1.0 (95% confidence interval [CI] = 0.1–1.3) and 1.4 (95% CI = 0.3–2.1) μg Ag/l, respectively. The 96 h LC₅₀ values for Oryzias latipes of 60 nm and 300 nm AgNP suspensions were 28 (95% CI = 23–34) and 67 (95% CI = 45–108) μg Ag/l, respectively. To show that toxicity is caused only by Ag⁺ and not by AgNPs, Ag⁺ was adsorbed onto the synthesized sorbents packed in a column and D. magna was exposed to the column-passed-300 nm AgNP suspensions. There was no acute toxicity with the AgNP suspensions not containing Ag⁺.