Large Dataset-Based Regression Model of Chemical Toxicity to Vibrio fischeri.

For the first time, a global regression quantitative structure-toxicity/activity relationship (QSTR/QSAR) model was developed for the toxicity of a large data set including 1236 chemicals towards Vibrio fischeri, by using random forest (RF) regression algorithm. The optimal RF model with RF parameters of mtry = 3, ntree = 150 and nodesize = 5 was based on 13 molecular descriptors. It can achieve accurate prediction for the toxicity of 99.1% of 1236 chemicals, and yield coefficients of determination R2 of 0.893 for 930 log(Mw/IBC50) in the training set, 0.723 for 306 log(Mw/IBC50) in the test se, and 0.865 for 1236 toxicity log(Mw/IBC50) in the total set. The optimal RF global model proposed in this work is comparable to other published local QSTR models on small datasets of the toxicity to Vibrio fischeri.

Application of machine learning to predict the inhibitory activity of organic chemicals on thyroid stimulating hormone receptor.

With the promotion of carbon neutrality, it is also important to synchronously promote the assessment and sustainable management of chemicals so as to protect public health. Humans and animals are possibly exposed to endocrine disruptors that have inhibitory effects on thyroid stimulating hormone receptor (TSHR). As such, it is important to identify chemicals that inhibit TSHR and to develop models to predict their inhibitory activity. In this study, 5952 compounds derived from a cyclic adenosine monophosphate (cAMP) analysis, a key signaling pathway in thyrocytes, were used to establish a binary classification model comparing methods that included random forest (RF), extreme gradient boosting (XGB), and logistic regression (LR). The prediction model based on RF showed the highest identification accuracy for revealing chemicals that may inhibit TSHR. For the RF model, recall was calculated at 0.89, balance accuracy was 0.85, and its receiver operating characteristic (ROC) curve-area under (AUC) was 0.92, indicating that the model had very high predictive capacity. The lowest CDocker energy (CE) and CDocker interaction energy (CIE) for chemicals and TSHR were determined and were subsequently introduced into the predictive model as descriptors. A regression model, extreme gradient boosting-Regression (XGBR), was successfully established yielding an R2 = 0.65 to predict inhibitory activity for active compounds. Parameters that included dissociation characteristics, molecular structure, and binding energy were all key factors in the predictive model. We demonstrate that QSAR models are useful approaches, not only for identifying chemicals that inhibit TSHR, but for predicting inhibitory activity of active compounds.

Prediction of organic compounds adsorbed by polyethylene and chlorinated polyethylene microplastics in freshwater using QSAR.

Microplastics (MPs), a growing class of emerging pollutants in the environment, have attracted widespread attention due to their adsorption properties. Recent research on MPs has mainly concentrated on seawater, and little work has been conducted on freshwater. Investigating and predicting the adsorption behavior of organic pollutants by MPs are necessary in freshwater. In this study, the adsorption behavior of 13 organic chemicals by polyethylene (PE) and chlorinated polyethylene (CPE) MPs was determined under freshwater conditions. Results shows the majority of the organic chemicals exhibit no distinctive differences in their adsorption on two MPs. However, the adsorption of polycyclic aromatic hydrocarbons and chlorobenzene on CPE is obviously stronger than that on PE, and the result is a counter for two pesticides. Quantitative structure activity relationship (QSAR) analysis was performed for the prediction of adsorption capacity. A QSAR model with acceptable performance (R2 = 0.8586) was built to predict the adsorptive affinity (expressed as logKd) of organic compounds on the PE MPs via multivariable linear regression (MLR) on forty-nine determined and collected data. The octanol/water partition coefficient (logKow) and excess molar refractive index (E) play dominant roles in the model. A QSAR model with satisfactory performance (R2 = 0.9302) was also established for logKd values from CPE MPs in freshwater by using 13 adsorption data determined. The logKow and most negative charge on Cl atom (Q-max,cl) play decisive roles in the adsorption. The findings can provide a scientific basis for the risk assessment of waters contaminated by MPs and organic pollutants.

Quantitative source apportionment of heavy metals in cultivated soil and associated model uncertainty.

To estimate spatial distribution, source analysis and uncertainty of heavy metals (Pb, Cd, Cr, Hg, As, Cu, Zn, and Ni) based on geographic information system (GIS), positive matrix factorization model (PMF) and bootstrap (BS) using 382 soil samples collected from cultivated soils in Lanzhou. The mean contents of Cd, Hg, Cu, Zn and Ni were high as 1.7,1.7, 2.1, 1.5 and 1.3 times local background values, mean contents of Pb, Cr and As were lower than local background values. However, the mean contents of eight heavy metals were lower environmental quality risk control standard for soil contamination of agricultural soil. Proportions of four sources were identified: Cr was predominantly contributed by natural sources (29.14%), Cu, Zn and Ni was primarily from industrial sources (25.26%), Hg and As were mainly of agricultural sources (27.49%), Pb and Cd mainly came from traffic source and smelting-related activities (18.09%). Uncertainties analysis contained three aspects: bootstrap runs, factor contributions in the PMF solution, and coefficient of variation (CV) values. By combining the four pollution source factors with bootstrap runs, the accuracy of the four pollution source factors were reliable based on PMF model. The median values in the BS runs was considered the most true factor contribution, and the 5th-95th quartile interval represents the variability of each factor, Factor 4 (traffic source) R2 was 0.70 and lower variability. The highest CV value usually means a significantly deviation degree. In this study, the CV values of Cr in Factor 1, Cu, Zn, and Ni in Factor 2, Hg, and As in Factor 3, Pb, and Cd in Factor 4 were lower, indicates a lower deviation degree. and with the lowest content among heavy metals usually was also with the greatest uncertainties. In this study improves understanding of the reduction of heavy metal pollution in cultivated soil, and also serves as reference for pollution source apportionment in other regions.

Predicting oxidative stress induced by organic chemicals by using quantitative Structure-Activity relationship methods.

Cellular exposure to xenobiotic human-made products will lead to oxidative stress that gives rise to DNA damage, as well as chemical or mechanical damage. Distinguishing the chemicals that will induce oxidative stress and predicting their toxicity is necessary. In the present study, 4270 compounds in the ARE-bla assay were investigated to predict active and inactive compounds by using simple algorithms, namely, recursive partitioning (RP) and binomial logistic regression, and to develop the quantitative structure-activity relationship (QSAR) models of chemicals that activate the ARE pathway to induce oxidative stress and exert toxic effects on cells. A decision tree based on scaffold-based fragments obtained through RP analysis showed the best identification accuracy. However, the overall identification accuracy of this model for active compounds was unsatisfactory due to limited fragments. Furthermore, a binomial logistic regression model was developed from 638 active compounds and 3632 inactive chemicals. The model with a cutoff of 0.15 could predict chemicals that were active or inactive with the prediction accuracy of 69.1%. Its area under the receiver operating characteristic (ROC) curve metric (AUROC) was 0.762, which indicated the acceptable predictive ability of this model. The parameters nBM (number of multiple bonds) and H% (percentage of H atom) played dominant roles in the prediction of the activity (inactive or active) of chemicals. A global QSAR model was developed to predict the toxicity of active chemicals. However, the model displayed an unsatisfactory result with R2 = 0.316 and R2ext = 0.090. Active chemicals were then classified on the basis of structure. A total of 79 compounds with carbon chains could be predicted with acceptable performance by using a QSAR model with six descriptors (R2 = 0.722, R2ext = 0.798, Q2Loo = 0.654, Q2Boot = 0.755, Q2ext = 0.721). The simple models established here contribute to efforts on identification compounds inducing oxidative stress and provide the scientific basis for risk assessment to organisms in the environment.

Ezrin directly interacts with AQP2 and promotes its endocytosis.

The water channel aquaporin-2 (AQP2) is a major regulator of water homeostasis in response to vasopressin (VP). Dynamic trafficking of AQP2 relies on its close interaction with trafficking machinery proteins and the actin cytoskeleton. Here, we report the identification of ezrin, an actin-binding protein from the ezrin/radixin/moesin (ERM) family as an AQP2-interacting protein. Ezrin was first detected in a co-immunoprecipitation (co-IP) complex using an anti-AQP2 antibody in a proteomic analysis. Immunofluorescence staining revealed the co-expression of ezrin and AQP2 in collecting duct principal cells, and VP treatment caused redistribution of both proteins to the apical membrane. The ezrin-AQP2 interaction was confirmed by co-IP experiments with an anti-ezrin antibody, and by pulldown assays using purified full-length and FERM domain-containing recombinant ezrin. By using purified recombinant proteins, we showed that ezrin directly interacts with AQP2 C-terminus through its N-terminal FERM domain. Knocking down ezrin expression with shRNA resulted in increased membrane accumulation of AQP2 and reduced AQP2 endocytosis. Therefore, through direct interaction with AQP2, ezrin facilitates AQP2 endocytosis, thus linking the dynamic actin cytoskeleton network with AQP2 trafficking.

Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Renal Diseases and Clinical Applications.

The mechanisms of kidney diseases, such as acute kidney injury (AKI) and chronic kidney disease (CKD), have been intensively studied. Nonetheless, the morbidity and mortality of AKI and CKD increased in recent years. Recently, natural products have been increasingly recognized as an alternative source for treating renal diseases on account of the conventional experience and the multi-target characteristics. Ganoderma lucidum (G. lucidum, Lingzhi) has been used for centuries as nutraceuticals and alternative medicine to improve health and to treat numerous diseases. Benefiting from various biological activities, such as anti-oxidation, anti-inflammation, anti-tumor growth and metastasis, etc., G. lucidum has been proved to exhibit significant role in preventing and treating various kidney diseases. In this chapter, we review certain researches and provide comprehensive insights into the renoprotective effects of G. lucidum.

Multi-dimensional dynamic fuzzy monitoring model for the effect of water pollution treatment.

The rapid development of the economy in China resulted in increasingly serious water pollution problem. A lot of water pollution treatment projects have been launched to improve the water environment quality. Water pollution treatment is a complex and long-term task. Considering the concept of water pollution with fuzziness and the factors affecting the effect of water pollution treatment (EWPT), this study constructs a multi-dimensional dynamic fuzzy comprehensive monitoring model. The model considers the vague boundaries in the representation of water pollution and various factors affecting the treatment effect, such as monitoring time, monitoring index, and monitoring location. In detail, firstly, existing methods for evaluating the EWPT are analyzed and reviewed. Then a multi-dimensional dynamic model is developed for monitoring the EWPT. Finally, the Yueya Lake of Henan Province in China is taken as an example to demonstrate the effectiveness and practicability of the proposed method. From the analysis of the results, to maintain the cleanliness of the water, efforts should still be made to eliminate and completely block the pollutants on the shore in order to fundamentally solve the problem.

Manganese promotes intracellular accumulation of AQP2 via modulating F-actin polymerization and reduces urinary concentration in mice.

Aquaporin-2 (AQP2) is a water channel protein expressed in principal cells (PCs) of the kidney collecting ducts (CDs) and plays a critical role in mediating water reabsorption and urine concentration. AQP2 undergoes both regulated trafficking mediated by vasopressin (VP) and constitutive recycling, which is independent of VP. For both pathways, actin cytoskeletal dynamics is a key determinant of AQP2 trafficking. We report here that manganese chloride (MnCl2) is a novel and potent regulator of AQP2 trafficking in cultured cells and in the kidney. MnCl2 treatment promoted internalization and intracellular accumulation of AQP2. The effect of MnCl2 on the intracellular accumulation of AQP2 was associated with activation of RhoA and actin polymerization without modification of AQP2 phosphorylation. Although the level of total and phosphorylated AQP2 did not change, MnCl2 treatment impeded VP-induced phosphorylation of AQP2 at its serine-256, -264, and -269 residues and dephosphorylation at serine 261. In addition, MnCl2 significantly promoted F-actin polymerization along with downregulation of RhoA activity and prevented VP-induced membrane accumulation of AQP2. Finally, MnCl2 treatment in mice resulted in significant polyuria and reduced urinary concentration, likely due to intracellular relocation of AQP2 in the PCs of kidney CDs. More importantly, the reduced urinary concentration caused by MnCl2 treatment in animals was not corrected by VP. In summary, our study identified a novel effect of MnCl2 on AQP2 trafficking through modifying RhoA activity and actin polymerization and uncovered its potent impact on water diuresis in vivo.

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice.

BACKGROUND/AIMS: A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. METHODS: Twelve-week-old male C57BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks. Body weight, blood glucose, insulin tolerance, glucose tolerance, pyruvate tolerance and 24-hour urine were measured every 4 weeks. At 24 weeks of age, renal function was evaluated by blood urea nitrogen level, creatinine clearance, urine output, urinary albumin excretion, Periodic Acid-Schiff staining, Masson's trichrome staining and electron microscopy. Changes in insulin signaling and gluconeogenic key regulatory enzymes were detected using Western blot analysis. RESULTS: Dapagliflozin did not alleviate but instead aggravated diabetic nephropathy manifesting as increased levels of microalbuminuria, blood urea nitrogen, and glomerular and tubular damage in db/db mice. Despite adequate glycemic control by dapagliflozin, urinary glucose excretion increased after administration before 24 weeks of age and was likely associated with renal impairment. Increased urinary glucose excretion was mainly derived from the disturbance of glucose homeostasis with elevated hepatic and renal gluconeogenesis induced by dapagliflozin. Although it had no effect on insulin sensitivity and glucose tolerance, dapagliflozin further induced the expression of gluconeogenic key rate-limiting enzymes through increasing the expression levels of FoxO1 in the kidney and liver. CONCLUSION: These experimental results indicate that dapagliflozin aggravates diabetes mellitus-induced kidney injury, mostly through increasing gluconeogenesis.

Aqueous OH Radical Reaction Rate Constants for Organophosphorus Flame Retardants and Plasticizers: Experimental and Modeling Studies.

Aqueous ·OH reaction rate constants ( kOH) for organophosphate esters (OPEs) are essential for assessing their environmental fate and removal potential in advanced oxidation processes (AOPs). Herein experimental and in silico approaches were adopted to obtain kOH values for a variety of OPEs. The determined kOH for 18 OPEs varies from 4.0 × 108 M-1 s-1 to 1.6 × 1010 M-1 s-1. Based on the experimental kOH values, a quantitative structure-activity relationship model that involves molecular structural information on the number of heavy atoms, content index, and the most negative charge of C atoms was developed for predicting kOH of other OPEs. Furthermore, appropriate density functional theory (DFT) and solvation models were selected, which together with transition state theory were employed to predict kOH of three representative OPEs. The deviation between the DFT calculated and the experimental kOH values ( kcal/ kexp) is within 2. Half-lives of the OPEs were estimated to be 0.5-22791.3 days in natural waters and 0.044-19.7 s in AOPs, indicating the OPEs are potentially persistent in natural waters and can be quickly eliminated by AOPs. The determined kOH values and the in silico methods offer a scientific base for assessing OPEs fate in aquatic environments.

Ganoderma triterpenes retard renal cyst development by downregulating Ras/MAPK signaling and promoting cell differentiation.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by the progressive development of renal cysts with further need for effective therapy. Here our aim was to investigate the effect of Ganoderma triterpenes (GT) on the development of kidney cysts. Importantly, GT attenuated cyst development in two mouse models of ADPKD with phenotypes of severe cystic kidney disease. Assays for tubulogenesis showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signaling pathways involved in the pathogenesis of PKD was further investigated by immune blotting. This showed that GT specifically downregulated the activation of the Ras/MAPK signaling pathway both in vitro and in vivo without detectable effect on the mTOR pathway. This mechanism may be involved in GT downregulating intracellular cAMP levels. Screening of 15 monomers purified from GT for their effects on cyst development indicated that CBLZ-7 (ethyl ganoderate C2) had a potent inhibitory effect on cyst development in vitro. Additionally, like GT, CBLZ-7 was able to downregulate forskolin-induced activation of the Ras/MAPK pathway. Thus, GT and its purified monomer CBLZ-7 may be potential therapeutic regents for treating ADPKD.

Aquaporin-3 deletion in mice results in renal collecting duct abnormalities and worsens ischemia-reperfusion injury.

Aquaporin-3 (AQP3), a transporter of water, glycerol and H2O2, is expressed in basolateral membranes of principal cells in kidney collecting duct. Here, we report that AQP3 deletion in mice affects renal function and modulates renal injury. We found collecting duct hyperplasia and cell swelling in kidneys of adult AQP3 null mice. After mild renal ischemia-reperfusion (IR), AQP3 null mice had significantly greater blood urea nitrogen (57mg/dl) and creatinine (136µM) than wild-type mice (35mg/dl and 48µM, respectively), and showed renal morphological changes, including tubular dilatation, erythrocyte diapedesis and collecting duct incompletion. MPO, MDA and SOD following IR in AQP3 null mice were significantly different from that in wild-type mice (1.7U/g vs 0.8U/g, 3.9µM/g vs 2.4µM/g, 6.4U/mg vs 11U/mg, respectively). Following IR, AQP3 deletion inhibited activation of mitogen-activated protein kinase (MAPK) signaling and produced an increase in the ratios of Bax/Bcl-2, cleaved caspase-3/caspase-3 and p-p53/p53. Studies in transfected MDCK cells showed that AQP3 expression attenuated reduced cell viability following hypoxia-reoxygenation, with reduced apoptosis and increased MAPK signaling. Our results support a novel role for AQP3 in modulating renal injury and suggest the mechanisms involved in protection against hypoxic injury.

The Effect of cAMP-PKA Activation on TGF-ß1-Induced Profibrotic Signaling.

BACKGROUND: The cAMP-PKA signaling pathway and TGF-ß1-dependent fibrosis pathways are of particular importance in ADPKD progression, but the cross-talk between these pathways remains unclear. Therefore, we used an MDCK-cell model and embryonic kidney-cyst model to study the regulatory role of cAMP-PKA signaling in the TGF-ß1 induced fibrotic process. METHOD AND RESULTS: Pkd1(flox/flox); Ksp-Cre and Pkd1(+/+); Ksp-Cre mice were used as an in vivo model. Increased kidney volume, renal cysts formation and up-regulation of the fibrosis-related proteins TGF-ß1, connective tissue growth factor (CTGF), and fibronectin (FN) can be observed in Pkd1(flox/flox); Ksp-Cre mice. In an embryonic kidneys-cyst model, TGF-ß1, FN and collagen type I were highly expressed. Western blotting revealed the obviously up-regulation of TGF-ß1, CTGF, FN and collagen type I expression following forskolin treatment in MDCK cells. Selective PKA inhibition with H89 may partially reversed the above effects. Pretreatment with the TGF-ß RI kinase inhibitor VI SB431542 suppressed the increased expression of CTGF, FN and collagen type I caused by forskolin. Our data also indicate that forskolin inhibited TGF-ß-induced ERK1/2 phosphorylation and FN up-regulation. ERK inhibition useing PD98059 significantly inhibited the expression of CTGF, FN and collagen type I caused by TGF-ß1. CONCLUSIONS: The cAMP-PKA signaling pathway can directly promote the production of TGF-ß1 and/or TGF-ß1-dependent fibrogenetic molecules in MDCK cells and embryonic kidney cysts, but when TGF-ß1 and its downstream pathways were highly expressed in MDCK cells, cAMP-PKA had a significantly negative effect on TGF-ß1 induced p-ERK1/2 and FN expression.

MCD-LightGBM System for Intelligent Analyzing Heterogeneous Clinical Drug Therapeutic Effects.

Causal effect estimation of individual heterogeneity is a core issue in the field of causal inference, and its application in medicine poses an active and challenging problem. In high-risk decision-making domain such as healthcare, inappropriate treatments can have serious negative impacts on patients. Recently, machine learning-based methods have been proposed to improve the accuracy of causal effect estimation results. However, many of these methods concentrate on estimating causal effects of continuous outcome variables under binary intervention conditions, and give less consideration to multivariate intervention conditions or discrete outcome variables, thus limiting their scope of application. To tackle this issue, we combine the double machine learning framework with Light Gradient Boosting Machine (LightGBM) and propose a double LightGBM model. This model can estimate binary causal effects more accurately and in less time. Two cyclic structures were added to the model. Data correction method was introduced and improved to transform discrete outcome variables into continuous outcome variables. Multivariate Cyclic Double LightGBM model (MCD-LightGBM) was proposed to intelligently estimate multivariate treatment effects. A visual human-computer interaction system for heterogeneous causal effect estimation was designed, which can be applied to different types of data. This paper reports that the system improved the Logarithm of the Minimum Angle of Resolution (LogMAR) of visual acuity change after Vascular Endothelial Growth Factor (anti-VEGF) treatment in patients with diabetic macular degeneration. The improvement was observed in two clinical problems, from 0.05 to 0.33, and the readmission rate of diabetic patients after cure was reduced from 48.4% to 10.5%. The results above demonstrate the potential of the proposed system in predicting heterogeneous clinical drug treatment effects.

Photolysis of p-phenylenediamine rubber antioxidants in aqueous environment: Kinetics, pathways and their photo-induced toxicity.

The widespread use of rubber antioxidants, especially p-phenylenediamines (PPDs), has raised increasing concerns about their risk assessment. However, there is a notable lack of research on their transformation products (TPs). Photolysis, influenced by active components, plays a significant role in the environmental fates of PPDs. This study investigated four emerging PPDs (N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), N, N'-diphenyl-p-phenylenediamine (DPPD), N-isopropyl-N'-phenyl-p-phenylenediamine (IPPD), and N-cyclohexyl-N'-phenyl-p-phenylenediamine (CPPD)) through a combination of experiments (photolysis kinetics, quenching experiments, acute toxicity test to Vibrio Fischeri (V. fischeri) and identification of photolytic products) and theoretical calculations. The results revealed different pathways for indirect photolysis mediated by the hydroxyl radicals (•OH) and singlet oxygen (1O2) of DPPD and IPPD under simulated sunlight irradiation. The effects of dissolved organic matter (DOM) and fulvic acid (FA) on the rates of photolysis of PPDs highlighted the complex interactions among the molecular structure, light absorption properties, and environmental variables. Quenching for reactive oxygen species (ROS) reduced photo-induced toxicity, whereas the addition of DOM and FA increased it, suggesting the crucial role of ROS in the formation of more toxic photolytic products. The study of photolysis pathways and the evaluation of the health risks provide a comprehensive understanding of the environmental effects of these pollutants.

Notch3 as a novel therapeutic target for the treatment of ADPKD by regulating cell proliferation and renal cyst development.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic kidney disease. Emerging research indicates that the Notch signaling pathway plays an indispensable role in the pathogenesis of numerous kidney diseases, including ADPKD. Herein, we identified that Notch3 but not other Notch receptors was overexpressed in renal tissues from mice with ADPKD and ADPKD patients. Inhibiting Notch3 with γ-secretase inhibitors, which block a proteolytic cleavage required for Notch3 activation, or shRNA knockdown of Notch3 significantly delayed renal cyst growth in vitro and in vivo. Subsequent mechanistic study elucidated that the cleaved intracellular domain of Notch3 (N3ICD) and Hes1 could bind to the PTEN promoter, leading to transcriptional inhibition of PTEN. This further activated the downstream PI3K-AKT-mTOR pathway and promoted renal epithelial cell proliferation. Overall, Notch3 was identified as a novel contributor to renal epithelial cell proliferation and cystogenesis in ADPKD. We envision that Notch3 represents a promising target for ADPKD treatment.

Synthesis and pharmacological evaluation of novel bisindolylalkanes analogues.

In an effort to develop potent anti-cancer chemopreventive agents that act on topoisomerase II, a novel series of bisindolylalkanes analogues such as 3,3'-(thiochroman-4,4-diyl)bis(1H-indole) are synthesized. Structures of all compounds are elucidated by (1)H NMR, (13)C NMR and HRMS. Anti-proliferative activities for all of these compounds are investigated by the method of MTT assay on 7 human cancer lines. Most of them showed antitumor activities in vitro, the half maximal inhibitory concentration (IC50) value is 7.798 µg/mL of 3a against MCF7. Compound 3a showed comparable topoisomerase II inhibitory activity to etoposide (VP-16) at 100 µM concentration. The rest of the compounds also showed varying degree topoisomerase II inhibitory activity.

Photolysis mechanism of eleven insecticides under simulated sunlight irradiation: Kinetics, pathway and QSAR.

Insecticides are widely used in crop protection against insects and frequently detected in aquatic environment. Photolysis kinetics are directly related with exposure assessment and risk assessment. However, the photolysis mechanism of neonicotinoid insecticides with different structures has not been studied and compared systematically in the literature. In this paper, the photolysis rate constants in water were determined for eleven insecticides under irradiation of simulated sunlight. At the same time, the photolysis mechanism and effect of dissolved organic matter (DOM) on their photolysis were studied. The results showed that photolysis rates of eleven insecticides vary in a large range. The photolysis rates of nitro-substituted neonicotinoids and butenolide insecticide are much faster than that of cyanoimino-substituted neonicotinoids and sulfoximine insecticide. The ROS scavenging activity assays reveal that direct photolysis dominates the degradation of seven insecticides and, on the other hand, self-sensitized photolysis dominates four insecticides. The shading-effect from DOM can reduce the direct photolysis rates, on the other hand, ROSs generated by triplet-state DOM (3DOM*) can also accelerate photolysis of insecticides. According to the photolytic products identified from HPLC-MS, these eleven insecticides have different photolysis pathways. Six insecticides are degraded from the removal of nitro group from their parent compounds and four insecticides are degraded through ·OH reaction or singlet oxygen (1O2) reaction. QSAR (quantitative structure-activity relationship) analysis showed that photolysis rate was directly related to the energy gap between the highest occupied molecular orbital to the lowest unfilled molecular orbital (Egap = ELUMO-EHOMO) and dipole moment (δ). These two descriptors reflect the chemical stability and reactivity of insecticides. The pathways developed from identified products and the molecular descriptors of QSAR models can well verify the photolysis mechanisms of eleven insecticides.

Photochemical behavior and photo-induced toxicity of chiral pesticides and their chiral monomers in aqueous environment.

The photochemical behaviors of chiral pollutants in aqueous solutions are rarely studied using chiral monomers, which may hamper their precise risk assessment and lead to suspicious conclusions. In this study, we systematically investigated the phototransformation behavior and toxicity evolution of two widely used chiral pesticides (triadimefon (TF) and triadimenol (TN)) at enantiomer and diastereomer levels, and proposed a calculation method of total photolysis rate constants of chiral mixture. Results show that TF and TN could be photodegraded faster in pure water than in natural waters, and the observed photolysis rate constants (kobs) of TN with two chiral centers exhibit enantioselectivity, i.e., kobs(TN-RS) = kobs(TN-SR) > kobs(TN-RR) = kobs(TN-SS). The photolysis of TF and TN mainly occurs through their excited singlet and triplet states, respectively. Their photodegradation pathways mainly include dechlorination and elimination of triazole ring. TF could also undergo ether bond cleavage. It is also found that, both TF and TN exhibit photo-induced toxicity to V. fischeri, due to the generation of more toxic products than parent compounds. Furthermore, TN exhibits enantioselective photo-induced toxicity after 240-min irradiation, which could be ascribed to the formation of chiral products. These results could benefit the understanding of enantioselective environmental behavior of chiral pollutants.