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The facile and efficient protocol for the synthesis of N-phenyl piperazine based di-thio-carbamates has been reported under neat conditions. A library of novel piperazine based di-thio-carbamates (3a-h) in excellent yields has been prepared. Solvent free, catalyst free and easy work up conditions make this protocol an attractive synthetic protocol to achieve novel biologically active di-thio-carbamates. The synthesized molecules have been characterized by FT-IR, 1 HNMR and 13 CNMR spectroscopic techniques. The pharmacological aspects of these derivatives have been evaluated via hemolysis and thrombolysis. All the target molecules (3a-h) exhibit mild to medium potential as hemolytic and thrombolytic agents. Among the synthesized derivatives, compound 3c showed least cytotoxicity and better thrombolytic potential.

Metam sodium (MS) is a widespread biocide with a broad-spectrum activity. Here, we addressed the behavioral impact of MS by exposing female mice to 50, 100 and 150 mg/kg of MS during both pregnancy and lactation, and evaluated the oxidative stress as a potential mechanism of MS-induced neurotoxicity. The results showed that MS affected fertility and reproduction parameters as well as some aspects of maternal behavior, especially at high doses. In offspring, MS caused a significant delay in the ontogeny of sensorimotor functions. In addition, treated mice exhibited during adulthood an increase of anxiety-like, depression-like behaviors as well as learning and memory impairment. These alterations were accompanied by an increase of the superoxide dismutase activity, and a significant decreased catalase and malondialdehyde activities in specific brain areas. The present work revealed that early exposure to MS induced sensorimotor and behavioral impairments in offspring likely associated with onset of oxidative stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

S-[3-carbamoylsulfanyl-2-(dimethylamino)propyl] carbamothioate (Cartap) (CAS number: 15263-52-2) is a synthetic insecticide of thiocarbamates group that is extensively used in field of agriculture for controlling of several pests like rice stem borer, leaf folder pests in paddy field and diamond back moth, aphids in cabbage and cauliflower crops. Cartap, as a pesticide has not been investigated yet for its effect on vital organs and biochemical stress in vivo and the present study was undertaken to evaluate the same in Swiss albino mice. For this purpose male mice were given three different dose levels of cartap, i.e. 5 mg/kg, 7.5 mg/kg and 15 mg/kg body weight respectively, for 28 days orally. Water was used as vehicle to dissolve cartap. Oral administration of cartap caused significant increase in serum biomarkers, tissue oxidants and decrease in antioxidants along with histopathological findings in liver, kidney and brain tissues. Thus, present study showed that in vivo exposure to cartap induces tissue damage probably via oxidative stress in important vital organs of mice.

Aloe vera has been the most useful medicinal herb in the world since ancient times due to its vast biological effects. The presence of high content of bioactive compounds make Aloe vera a promising complementary and alternative agent in disease prevention. The effectiveness of A. vera -based medicines against pesticide toxicity has never been evaluated. It was therefore envisaged to develop an A. vera -based strategy to protect the non-target animals from adverse effects of the pesticides. This article illustrates the ameliorating effect of aqueous extract (AE) of A. vera leaves against the cartap and malathion toxicity. To evaluate the protective impact of A. vera against cartap (Ctp), malathion (Mtn) and a mixture of both pesticides, the animals were divided in eight groups, each containing six rats: Group 1- C (control), Group 2- AE + C, Group 3- Ctp, Group 4- Mtn, Group 5- Ctp + Mtn, Group 6- AE + Ctp, Group 7- AE + Mtn, Group 8- AE + Ctp + Mtn. Wistar rats exposed to Ctp, Mtn and Ctp + Mtn, displayed significant change in body weight. It was observed that the WBC level increased significantly in Mtn and Ctp + Mtn challenged groups. The contents of TNF-α and IL-6 in serum increased expressively in the Ctp, Mtn and Ctp + Mtn challenged groups. Rats treated with Ctp, Mtn and Ctp + Mtn displayed significant alterations in the levels of antioxidative indices (MDA, GSH, GST, GPx, SOD and CAT). Significant alterations were recorded in the activities of AST, ALT, ACP and ALP in Ctp, Mtn and Ctp + Mtn challenged groups. The histopathological results of liver supported the biochemical data. The pre-treatment of rats with the aqueous extract of A. vera leaves significantly protected them from the toxicity of pesticides. These results suggested that A. vera extract may be used as a promising natural agent for the management of pesticide induced toxicity.

Gastropod mollusks have achieved an eminent importance as biological indicators of environmental quality. In the present study, we applied a multibiomarker approach to evaluate its applicability for the pond snail Lymnaea stagnalis, exposed to common industrial and agricultural pollutants at environmentally relevant concentrations. The snails were exposed to copper (Cu 2+ , 10 µg L -1 ), zinc (Zn 2+ , 130 µg L -1 ), cadmium (Cd 2+ , 15 µg L -1 ), or the thiocarbamate fungicide "Tattoo" (91 µg L -1 ) during 14 days. Metal treatment and exposure to "Tattoo" caused variable patterns of increase or decrease of metal levels in the digestive gland, with a clear accumulation of only Cd and Zn after respective metal exposure. Treatment with Cu and "Tattoo" caused an increase of cytochrome P450-related EROD activity. Glutathione S-transferase was inhibited by exposure to Cu, Zn, and "Tattoo." Treatment with the "Tattoo" led to an inhibition of cholinesterase activity, whereas Cu and Cd increased its activity. Caspase-3 activity was enhanced by up to 3.3 times in all treatments. A nearly uniform inhibitory effect for oxidative stress response parameters was observed in all kinds of exposure, revealing an inhibition of superoxide dismutase (Mn-SOD) activity, a depression of glutathione (GSH and GSSG) and of protein carbonyl levels. Pollutant-specific effects were observed for the catalase activity, superoxide anion production, and lipid peroxidation levels. Due to the high response sensitivity of Lymnaea stagnalis to chemical impacts, we suggest our study as a contribution for biomarker studies with this species under field conditions.

Thiocarbamates are one of the components of pesticides that target weeds by inhibiting adenosine triphosphate (ATP) synthesis. Orbencarb, one of the isomeric thiocarbamates applied to wheat, maize, and soybean, has been found to have toxic effects on mammals and marine ecosystems. Although the toxicity ranges of orbencarb in different organisms are known, specific studies on the environmental contamination and harmful effects of orbencarb on non-target organisms are scarce. In this study, we observed that orbencarb induced embryotoxicity during zebrafish development as well as apoptosis and reactive oxygen species (ROS) production in the intestine. It was further observed that orbencarb decreased the viability of the embryos and simultaneously affected the heart rate and vessel formation. Orbencarb decreased the mRNA levels of ccnd1, ccne1, cdk2, and cdk6 and induced abnormal development of the eyes, brain, yolk sac, and spinal cord in zebrafish embryos. Orbencarb also hampered vasculogenesis in the zebrafish embryos by inhibiting the mRNA expression of flt1, flt4, kdr, and vegfc. Collectively, these results suggested that orbencarb is embryotoxic and disrupts the normal growth of zebrafish embryos by inducing the generation of ROS and hampering vasculogenesis., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present study has investigated developmental neurotoxicity of Metam sodium (MS), from gestational day 6 and throughout the gestation period until delivery. Therefore, mated female mice were orally exposed on a daily basis to 0 (control), 50, 100 or 150 mg of MS/kg of body weight and their standard fertility and reproductive parameters were assessed. The offspring were examined for their sensorimotor development, depression and cognitive performance. Our results showed that MS exposure during pregnancy led to one case of mortality, two cases of abortion and disturbed fertility and reproductive parameters in pregnant dams. In offspring, MS induced an overall delay in innate reflexes and sensorimotor performances. Furthermore, all prenatally treated animals showed an increased level of depression-like behavior as well as a pronounced cognitive impairment in adulthood. These results demonstrated that prenatal exposure to MS causes a long-lasting developmental neurotoxicity and alters a wide range of behavioral functions in mice., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hypochlorous acid (HOCl)/hypochlorite (OCl - ), important reactive oxygen species, play essential roles in many physiological and pathological progresses. Accordingly, we developed a novel dicyanomethylene-4H-pyran (DCM)-based probe DCM-OCl for colorimetric and near-infrared fluorescent turn-on detection of OCl - . The probe exhibited excellent selectivity and sensitivity for OCl - over other bio-related analytes with a detection limit of 80 nM. The excellent selectivity of DCM-OCl for OCl - was ascribed to specific oxidative cleavage of the dimethylthiocarbamate (DMTC) recognition unit by OCl - . Moreover, DCM-OCl exhibited an ultrafast turn-on response (<3 s) to OCl - , potentially allowing real-time detection of OCl - . Furthermore, DCM-OCl was successfully used to image endogenous/exogenous OCl - in living cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Allergic contact dermatitis (ACD) is one of the most common forms of immunotoxicity, and increased understanding of how chemicals trigger these adverse reactions is needed in order to treat or design testing strategies to identify and subsequently avoid exposure to such substances. In this study, we investigated the cellular response induced by rubber chemicals in a dendritic cell (DC) model, focusing on the structurally similar chemicals diethylthiocarbamylbenzothiazole sulfide and dimethylthiocarbamylbenzothiazole sulfide, with regard to regulation of microRNA, and messenger RNA expression. Only a few miRNAs were found to be commonly regulated by both rubber chemicals, among them miR1973, while the overall miRNA expression profiles were diverse. Similarly, out of approximately 500 differentially regulated transcripts for each chemical, about 60% overlapped, while remaining were unique. The pathways predicted to be enriched in the cell model by stimulation with the rubber chemicals were linked to immunological events, relevant in the context of ACD. These results suggest that small structural differences can trigger specific activation of the immune system in response to chemicals. The here presented mechanistic data can be valuable in explaining the immunotoxicological events in DC activation after exposure to skin sensitizing chemicals, and can contribute to understanding, preventing and treating ACD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant antiproliferative activities on human cancer cell lines expressing high levels of FAK at nanomolar concentrations. The compound 14z was identified as the most potent FAK inhibitor among these candidates. 14z has excellent anti-proliferative effect with IC 50 values from 0.001 μM to 0.06 μM on HCT116, PC-3, U87-MG and MCF-7 cell lines and relatively less cytotoxicity to a nonmalignant cell line MCF-10A compared with MCF-7 cells (SI value > 10). 14z also exhibits significant FAK inhibitory activity (IC 50  = 0.07 nM). In addition, compound 14z causes cell cycle arrest at G2/M and prompted apoptosis in both HCT116 and MCF-7 cells in a dose-dependent manner. Further studies show that compound 14z inhibits migration of MCF-7 and has anti-angiogenesis effect on HUVEC cells., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Excessive perfluorooctane sulfonate (PFOS) in natural water ecosystem has the potential to detrimentally affect immune system, but little is known of such effects or underlying mechanisms in fish. In the present study, we evaluated the effects of PFOS on growth performance, organizational microstructure, activities of immune-related enzymes and expressions of immune-related genes in male zebrafish (Danio rerio) exposed to different concentrations of 0, 0.02, 0.04 and 0.08 mg/L of PFOS for 7, 14, and 21 days or cotreatment with PFOS and PDTC to investigate the effects of PFOS on immune system and the potential toxic mechanisms caused by PFOS. The results indicated that PFOS accumulated in livers after exposure, and remarkably elevations were found in three exposure groups compared with the control group at three stages. The growth of the adult zebrafish in the experiments was significantly inhibited, the microstructures of liver were serious damaged. The ROS levels were remarkably increased. The activities of ACP, AKP, and lysozyme were obviously decreased, while the activities of MPO and NF-κB were significantly increased. The expressions of immune-related mRNA were significantly affected. After co-treatment with PFOS and PDTC, the growth inhibition, the morphological damage, the ROS induction, and the expressions of immune-related mRNA were reversed. Taken together, the results indicated that PFOS can significantly inhibit the growth, disturb the immune system by changing the normal structure of liver, the activities of immune-related enzymes, and a series of gene transcriptions involved in immune regulation in liver of male zebrafish. PFOS-induced pro-inflammatory effect of hepatocytes was observed, and the involvement of NF-κB signaling pathway was participated in its action mechanism. These findings provide further evidence that PFOS interferes with the immune regulation of liver of male zebrafish under in vivo conditions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The Amphibian Metamorphosis Assay (AMA) is a screening test for detecting chemicals with thyroid activity. There is little experience in data interpretation and in using AMA data for screening, testing and identifying endocrine disruptors. To investigate the sensitivity of different endpoints of the AMA, the publically available data for 57 thyroid active and inactive chemicals were compiled and analyzed. Endpoints body weight and length appeared as sensitive as apical thyroid responsive endpoints hind limb length (HLL) and developmental stage (DS) for 12 thyroid active chemicals. The sensitivity of body weight, length and HLL was comparable, which is higher than that of DS for 45 thyroid inactive chemicals. The decision logic of the AMA suggests that an advanced development alone indicates thyroid activity. The analysis here showed that advanced development at day 7 could indicate thyroid activity of a chemical. However, advanced development at day 21 may be influenced by thyroid inactive chemicals. Among 39 thyroid inactive chemicals, which affected one or more endpoints, 33% and 77% induced changes in HLL and/or DS at day 7 and 21, respectively; only 10% influenced thyroid histology. These results showed that apical thyroid responsive endpoints HLL and DS are influenced by thyroid active chemicals as well as thyroid inactive chemical. Both endpoints should be combined with thyroid histology for the identification of thyroid active chemicals. The use of the AMA in a testing strategy to identify chemicals with thyroid activity is discussed., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC 50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We investigated toxic effects of the antifouling biocide polycarbamate (PC) on marine fish by conducting acute, early-life stage toxicity (ELS), and embryo toxicity tests. Mummichog (Fundulus heteroclitus) 96-h LC 50 values for hatched larvae (body weight about 2.0 mg) and juveniles (660 ± 36 mg) were about 12 and 630 μg/L, respectively. The ELS test using mummichog embryos yielded a lowest-observed-effect concentration of 3.9 μg/L and a no-observed-effect concentration of 2.1 μg/L with growth as the most sensitive endpoint. The embryo toxicity test for spotted halibut (Verasper variegatus) revealed a 10-d EC 50 of 8.1 μg/L with abnormality as an endpoint. During the ELS and embryo toxicity tests, morphological abnormalities (notochord undulation) were induced in the embryos. Biochemical and gene-expression analysis suggest that PC-induced morphological abnormalities involve disruption of lysyl oxidase-mediated collagen fiber organization, essential for notochord formation, and inhibition of gene expression related to notochord formation ., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The activity of β-lactam antibiotics is compromised by metallo-β-lactamases (MBLs). Herein, a series of dithiocarbamate derivatives were designed and synthesized. Their antibacterial activities were tested in combination with meropenem (MEM) against several MBL (NDM and IMP type)-producing clinical isolates. Clinical isolates harboring NDM-1 and IMP-4 became susceptible to MEM when it was combined with dithiocarbamate compounds 4a, 4b or 4f synthesized in this work. Compounds 4a and 4b increased the effectiveness of MEM by up to 2560 times against strains. In vitro bactericidal dynamics tests showed that bacteria died within 24 h when they were treated with compound 4f + MEM. Compounds 4a, 4b and 4f were non-hemolytic and exhibited low toxicity toward HeLa cells in vitro. These data show that compounds containing dithiocarbamate functional group may be helpful in the development of MBL inhibitors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The present study investigated how principal environmental factors such as temperature and light intensity change the toxicological properties of thiobencarb (TB) herbicide to the green alga, Raphidocelis subcapitata. At first, we investigated the inhibitory effect of TB (0, 15.6, 31.2, 62.4, and 125 μg L -1 ) on growth of R. subcapitata at five temperatures (10, 15, 20, 25, or 30 °C) for 144 h exposure and calculated 72- and 144-h effective concentration values (EC10, 20, and EC50) for growth rate. All EC values significantly decreased with an increasing temperature. The maximum quantum yield of photosystem II in R. subcapitata exposed to 125 μg L -1 of TB was also significantly inhibited with increased temperature. These physiological effects could explain the lower EC values at high temperatures. Then, single and interactive effects of TB, temperature, and light intensity on growth rate were investigated by three-way of analysis of variance. As a result, single and interactive effects were detected in all explanatory variables. These results suggest that temperature and light intensity change the acute toxicity parameter in R. subcapitata exposed to TB and must be considered in evaluating the risk of TB.

Residue data for triazoles (TR) and dithiocarbamates (DT) in 30,786 samples of 30 foods were obtained from mainly two national monitoring programs, and consumption data from a national survey conducted among persons aged 10 years or older. About 16% of the samples contained TR, mainly grape (53.5%), and 16.2% contained DT, mainly apple (59.3%). Flusilazole was the index compound used for the acute effects of TR for women of child-bearing-age (cranium-facial malformation and skeletal variation), cyproconazole for the chronic effects of TR (hepatoxicity), and ethylene-bis-dithitiocarbamates (EBDC) for DT (thyroid toxicity). Exposures were estimated using the Monte Carlo Risk Assessment software. Different models were tested, and a Model-Then-Add approach was found to best estimate the chronic exposures to DT and TR. At the 99.9th percentile (P99.9), the cumulative acute TR intakes accounted for up to 0.5% of the flusilazole ARfD, mainly from beans and rice consumption. The chronic TR and DT intakes accounted for 1 and 6.7% of the respective index compound ADIs, with beans and rice accounting for most of the TR intake (∼70%), and apple for about 51-56% of the DT intake. The estimated risks from the exposure to TR and DT indicate no health concern for the Brazilian population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A new series of thirteen 2-[(4-fluorophenyl)(4-nitrobenzyl)amino]-2-oxoethyl-1-substituted-carbodithioate derivatives (4a-4m) were synthesized and tested for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory potential by an in vitro fluorometric method. Most of the compounds have found to be selective towards MAO-B than MAO-A. Compound 4j that carrying 4-nitrophenyl piperazine moiety, was detected as the most active agent amongst all compounds with the IC 50 value of 0.097 ± 0.003 µM for MAO-B while that of selegiline was 0.040 ± 0.002 µM. The enzyme kinetic study reported that compound 4j is a reversible and non-competitive inhibitor. Interaction modes between the hMAO-B and compound 4j were determined by docking studies. The study also revealed that compound 4j has the highest binding scores. Besides, compound 4j has not cytotoxicity at its effective concentration against hMAO-B., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aims: Our previous study suggested the anti-tumor activity of sepia ink oligopeptide (SIO). Here we sought to investigate the underlying molecular mechanism., Methods: Cell proliferation was evaluated by cell counting kit-8 (CCK-8) assay. Cell apoptosis was determined by Annexin V/Propidium Iodide (PI) staining. The mitochondria pathway was characterized by quantification of Bcl-2, Bax, Caspase-9 and Cyto-C. The death receptor pathway was analyzed by determinement of Fas, Caspase-8 and NIK. The endoplasmic reticulum (ER)-dependent pathway was determined by measurement the expression of CHOP, Caspase-12, GRP78 and Calpain. The associated gene expression was quantified by RT-PCR and protein level was determined by immunoblotting., Results: We demonstrated treatment with structurally modified SIO (CSIO, 5 µM) significantly inhibited cell proliferation and induced apoptosis in lung cancer cell line A549. The mitochondrial pathway, death receptor pathway and ER stress induced apoptosis were stimulated upon CSIO treatment. The administration with respective inhibitors including midiv-1 (50 µM for 2 h), PDTC (20 µM PDTC for 30 min) and ALLN (20 mM ALLN for 5 h) readily reversed the apoptosis inducing effect of CSIO., Conclusion: Our data demonstrates that CSIO is capable of induction apoptosis in lung cancer cell line, which is mediated by all three classical apoptotic pathways. Our results warrant further in vivo investigations of the anti-tumor potential of CSIO., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Organisms in natural environments are often exposed to a broad variety of chemicals, and the multi-chemical mixtures exposure may produce significant toxic effects, even though the individual chemicals are present at concentrations below their no-observed-effect concentrations. This study represents the first attempt that uses the accelerated failure time (AFT) model to quantify the interaction and toxicity of multi-chemical mixtures in environmental toxicology. We firstly conducted the acute immobilization tests with Daphnia magna exposed to mixtures of diazinon (DZN), fenitrothion (MEP); and thiobencarb (TB) in single, binary, and ternary formulations, and then fitted the results to the AFT model. The 48-h EC 50 (concentration required to immobilize 50% of the daphnids at 48h) values for each pesticide obtained from the AFT model are within a factor of 2 of the corresponding values calculated from the single pesticide exposure tests, indicating the methodology is able to provide credible toxicity values. The AFT model revealed either significant synergistic (DZN and MEP; DZN and TB) or antagonistic (MEP and TB) interactions in binary mixtures, while the interaction pattern of ternary mixture depended on both the concentration levels and concentration ratios of pesticides. With a factor of 2, the AFT model accurately estimated the toxicities for 78% of binary mixture formulations that exhibited significant synergistic effects, and the toxicities for all the ternary formulations. Our results showed that the AFT model can provide a simple and efficient way to quantify the interactions between pesticides and to assess the toxicity of their mixtures. This ability may greatly facilitate the ecotoxicological risk assessment of exposure to multi-chemical mixtures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

1,3-Dichloropropene (1,3-D), metam sodium (MS), and dazomet (DZ) are widely used as preplant soil fumigants to solve soilborne problems. To provide a more scientific and accurate evaluation of 1,3-D, MS, and DZ toxicity to the earthworm Eisenia fetida, modified artificial soil test and natural soil test were studied. The suitable soil moisture to maintain over 90% survival of the earthworms after 4 weeks of treatment in an enclosed system for modified artificial soil test and natural soil test were 26.9 to 86.4% of water-holding capacity (WHC) and 66.2 to 84.3% of WHC, respectively. The optimal soil moisture levels for modified artificial soil test and natural soil test (75 and 55% of WHC, respectively) were finally used to evaluate the toxicity of 1,3-D, MS, and DZ on earthworms. Each desiccator with 10 earthworms and natural or artificial soil was stored at 20 ± 1 °C under constant light of 400 to 800 lx for 2 weeks. The modified artificial soil test showed LC 50 values for 1,3-D, MS, and DZ of 3.60, 1.69, and 5.41 mg a.i. kg -1 soil, respectively. The modified natural soil test of the fumigants showed similar LC 50 values of 2.77 and 0.65 mg a.i. kg -1 soil, except for DZ at 0.98 mg a.i. kg -1 soil. The present study confirms that both modified artificial soil test and modified natural soil test offer standard methods for acute toxicity test of 1,3-D, MS, and DZ on the earthworms and scientific evidences for assessing the effects of soil fumigants on non-target organisms in the soils. Graphical Abstract Two novel acute toxicity test methods for soil fumigants on the earthworm Eisenia fetida.

Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (k inact = 1.4 × 10 5 m -1 s -1 ). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys 318 -Cys 326 ), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Nicotinic acetylcholine receptors (nAChRs) of insects play a key role in fast excitatory neurotransmission. Several classes of insecticides target insect nAChRs, which are composed of subunit members of a family of multiple subunit encoding genes. Alternative splicing and RNA A-to-I editing can add further to receptor diversity. Native and recombinant receptors have been explored as sites of insecticide action using radioligands, electrophysiology and site-directed mutagenesis., Methods: We have reviewed the properties of native and recombinant insect nAChRs, the challenges of functional recombinant insect nAChR expression, nAChR interactions with ligands acting at orthosteric and allosteric sites and in particular their interactions with insecticides., Results: Actions on insect nAChRs of cartap, neonicotinoids, spinosyns, sulfoxamines, butenolides and mesoionic insecticides are reviewed and current knowledge of their modes of action are addressed. Mutations that add to our understanding of insecticide action and those leading to resistance are discussed. Co-crystallisation of neonicotinoids with the acetylcholine binding protein (AChBP), a surrogate for the nAChR ligand binding domain, has proved instructive. Toxicity issues relating to insecticides targeting nAChRs are also considered., Conclusion: An overview of insecticide classes targeting insect nAChRs has enhanced our understanding of these important receptors and their insecticide binding sites. However, the subunit composition of native nAChRs remains poorly understood and functional expression still presents difficulties. These topics together with improved understanding of the precise sites of insecticide actions on insect nAChRs will be the subject of future research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Both metam sodium and copper/zinc-containing compounds are widely used as fungicides. They therefore may co-occur in the biosphere. Despite certain studies of individual toxicity for either metam or copper (II)/zinc (II), their synergistic toxicity has not been examined. In this paper, a remarkable synergistic toxicity was observed in HepG2 cells when metam and copper (II)/zinc (II) at non-toxic and sub-toxic levels were combined. Unexpectedly, cell death modes between metam/copper (II) and metam/zinc (II) were different: For metam/copper (II), apoptosis was evident from morphological characteristics including cytoplasm-chromatin condensation, phosphatidylserine (PS) exposure, SubG 0 /G 1 DNA fragmentation, mitochondrial membrane potential decrease, pro/anti-apoptotic protein activation, and cytochrome c release; for metam/zinc (II), necrosis was evident from organelle swelling and uncontrolled collapse. To our knowledge, this work first not only demonstrates the synergistic toxicities of metam and both copper (II)/zinc (II), but also verifies the different modes of apoptosis/necrosis between metam/copper (II) and metam/zinc (II). © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1964-1973, 2016., (© 2015 Wiley Periodicals, Inc.)

A series of novel dithiocarbamate-chalcone derivates were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell lines (EC-109, SK-N-SH and MGC-803). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds II2 and II5 exhibited the excellent growth inhibition against SK-N-SH with IC50 values of 2.03μM and 2.46μM, respectively. Further mechanism studies revealed that compound II2 could obviously inhibit the proliferation of SK-N-SH cells by inducing apoptosis and arresting the cell cycle at G0/G1 phase., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

Thiobencarb and propanil are two of the most extensive used herbicides worldwide in rice cultivation. Especially scanty is the available information regarding the effect of herbicides on fish energy resources. In the present study, the effect of sublethal exposure to these herbicides on the energy reserves of juvenile eel Anguilla anguilla was compared. Eels were exposed to 72 h to the herbicide thiobencarb (0.22 mg L(-1)) or Propanil (0.63 mg L(-1)), and allowed to recover in clean water (144 h). Caloric content was determined in liver and skeletal muscle. Fish exposed to thiobencarb rapidly mobilized energy. Reserves from liver were depleted (21%) compared to control values (2.50 kcal g(-1)) at 2 h, whereas in muscle diminished between 12 and 72 h (35%) (control value 0.89 kcal g(-1)). Energy reserves from liver normalized after 144 h in water while in the skeletal muscle were still depleted (24%). Major harmful effects were induced by propanil. Caloric content in liver diminished from the first hours (depletion of 70% at 48h exposure) and in skeletal muscle a 60% (72 h). At the end of the recovery period, energy reserves in pre-exposed eels represented less than 50% compared to control animals. The study indicated that thiobencarb and propanil would constitute a great risk to animals inhabiting freshwater bodies nearby fields of application. Judging from the results, herbicides resulted toxic enough to mobilize fish energy stores. On the other hand, a period of six days in herbicide-free water was not enough time to allow fish to restore energy budgets., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Application of thiobencarb, pendimethalin and pretilachlor at rates of 7.5, 10.0 and 2.5 kg a.i. ha(-1), respectively, under laboratory conditions, significantly increased microbial biomass C, N and P, resulting in greater availability of C, N and P in soil amended with farm yard manure. Application of thiobencarb highly induced microbial biomass C (46.3 %) and N (40.6 %), while pretilachlor and thiobencarb augmented microbial biomass P to the extent of 14.9 % and 14.1 %, respectively. Application of pendimethalin retained the highest amount of total N (19.9 %), soluble NO3 (-) (56 %) and available P (69.5 %) in soil. A similar trend was recorded with thiobencarb for oxidizable organic C (18.1 %) and with pretilachlor for exchangeable NH4 (+) (65.8 %). At the end of the experiment, the highest stimulation of bacteria was recorded with thiobencarb (29.6 %), while pretilachlor harboured the maximum number of actinomycetes (37.2 %) and fungi (40 %) in soil compared to the untreated control.

In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Dithiocarbamates have emerged as potent carbonic anhydrase (CA) inhibitors in recent years. Given that CAs are important players in cellular metabolism, the objective of this work was to exploit the CA-inhibitory property of dithiocarbamates as a chemotherapeutic weapon against the Leishmania parasite. We report here strong antileishmanial activity of three hitherto unexplored metal dithiocarbamates, maneb, zineb, and propineb. They inhibited CA activity in Leishmania major promastigotes at submicromolar concentrations and resulted in a dose-dependent inhibition of parasite growth. Treatment with maneb, zineb, and propineb caused morphological deformities of the parasite and Leishmania cell death with 50% lethal dose (LD50) values of 0.56 μM, 0.61 μM, and 0.27 μM, respectively. These compounds were even more effective against parasites growing in acidic medium, in which their LD50 values were severalfold lower. Intracellular acidosis leading to apoptotic and necrotic death of L. major promastigotes was found to be the basis of their leishmanicidal activity. Maneb, zineb, and propineb also efficiently reduced the intracellular parasite burden, suggesting that amastigote forms of the parasite are also susceptible to these metal dithiocarbamates. Interestingly, mammalian cells were unaffected by these compounds even at concentrations which are severalfold higher than their antileishmanial LD50s). Our data thus establish maneb, zineb, and propineb as a new class of antileishmanial compounds having broad therapeutic indices., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

In this study, we carried out three bioassays with nine used insecticides in tomato crops to identify their efficiency against tomato leaf miner Tuta absoluta, the physiological selectivity and the activity reduction of insecticides by three rain regimes to predatory wasps Protonectarina sylveirae and Polybia scutellaris. We assessed the mortality caused by the recommended doses of abamectin, beta-cyfluthrin, cartap, chlorfenapyr, etofenprox, methamidophos, permethrin, phenthoate and spinosad to T. absoluta and wasps at the moment of application. In addition, we evaluated the wasp mortality due to the insecticides for 30 days on plants that did not receive rain and on plants that received 4 or 125 mm of rain. Spinosad, cartap, chlorfenapyr, phenthoate, abamectin and methamidophos caused mortality higher than 90% to T. absoluta, whereas the pyrethroids beta-cyfluthrin, etofenprox and permethrin caused mortality between 8.5% and 46.25%. At the moment of application, all the insecticides were highly toxic to the wasps, causing mortality higher than 80%. In the absence of rain, all the insecticides continued to cause high mortality to the wasps for 30 days after the application. The toxicity of spinosad and methamidophos on both wasp species; beta-cyfluthrin on P. sylveirae and chlorfenapyr and abamectin on P. scutellaris, decreased when the plants received 4 mm of rain. In contrast, the other insecticides only showed reduced toxicity on the wasps when the plants received 125 mm of rain.

Introduction: Thiocarbamates are chemicals widely used as pesticides. Occupational exposure is associated with acute intoxication. Populations can be exposed through food and water. Moreover, certain thiocarbamates are used clinically. The widespread use of thiocarbamates raises many issues regarding their toxicological and pharmacological impact., Areas Covered: Thiocarbamates and their metabolites can modify biological macromolecules functions, in particular enzymes, through modification of cysteine residues, chelation of metal ions or modulation of the oxidative stress. Loss of enzyme activity can lead to the disruption of metabolic pathways, and explain, at least in part, the effects of these pesticides. Additionally, their reactivity and ability to easily cross biological barrier confer them a great interest for development of clinical applications., Expert Opinion: Many advances in the study of thiocarbamates metabolism and reactivity have led to a better knowledge of biological effects of these compounds. However, more data are needed on the determination of targets and specificity. Only few data concerning the exposure to a cocktail of pesticides/chemicals are available, raising the need to evaluate the toxic side effects of representative pesticides mixtures. Moreover, the dithiocarbamate Disulfiram has shown great potential in therapeutic applications and leads to the development of pharmacological thiocarbamates derivatives, highly specific to their target and easily distributed.

Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Starting from the available information about the binding of the purine-based htIIα inhibitors in the ATP binding site we designed a virtual screening campaign combining structure-based and ligand-based pharmacophores with a molecular docking calculation searching for compounds that would contain a monocycle mimetic of the purine moiety. We discovered novel 4-amino-6-(phenylamino)-1,3,5-triazines 6, 7 and 11 as monocyclic htIIα inhibitors targeting the ATP binding site. Compound 6 from the 1,3,5-triazine series also displayed cytotoxicity properties in hepatocellular carcinoma (HepG2) cell lines and selectivity against human umbilical vein endothelial (HUVEC) cell lines., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. The stability of compound 9 in simulated vaginal fluid (SVF) was performed via HPLC-PDA method, which supported its utility for vaginal administration., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

An experiment was conducted under laboratory conditions to investigate the effect of two pre-emergence herbicides, viz., thiobencarb (at 1.5 and 4.5 kg active ingredient (a.i.) ha(-1)) and pretilachlor (at 0.5 and 1.5 kg a.i. ha(-1)), on the growth and multiplication of some microorganisms (bacteria, actinomycetes and fungi) in relation to transformations and availability of C and N in the Gangetic alluvial soil (Typic Haplustept) of West Bengal, India. Application of both the herbicides, in general, significantly increased microbial biomass, resulting in greater retention, mineralization and availability of oxidizable organic C and N in soil, and the stimulations were more pronounced when the herbicides were applied at their lower concentrations (recommended field application rates), more so with thiobencarb, as compared to pretilachlor. Compared to untreated control soil, the application of thiobencarb at lower concentration increased the proliferation of total bacteria, actinomycetes and fungi by 57.3, 36.6 and 55.2%, respectively, and released the highest amount (40.2%) of soluble NO₃(-) in soil, while pretilachlor at field application rate induced the growth and multiplication of bacteria and fungi by 58.3 and 17.6%, respectively. Irrespective of the concentrations, the stimulations were at par for both the herbicides towards the retention of oxidizable organic C, total N and exchangeable NH₄(+) in soil.

The present study was aimed to the evaluation of toxicological impact of insecticide cartap hydrochloride on photosynthesis and nitrogen assimilation of a non-heterocystous cyanoprokaryote Leptolyngbya foveolarum isolated from paddy fields of Punjab, India. The microorganism tolerated commercial grade insecticide up to 80 ppm. Lower concentration (20 ppm) of cartap supported good growth with high dry weight of biomass, total protein content, photosynthetic pigments, photosynthesis and respiration compared to untreated control cultures while higher concentrations (40 and 60 ppm) inhibited these parameters in a dose dependent manner. Treatment of the microorganism with 60 ppm cartap lowered the content of photosynthetic pigments with maximum inhibitory effect on phycoerythrin (70% decrease) followed by allophycocyanin (66% decrease). Rates of photosynthesis and respiration were inhibited by 63% and 45%, respectively, while PS-I, II and whole chain activity were decreased by 45%, 67% and 40% respectively, compared to untreated control cultures. Cartap at 60 ppm decreased nitrate and nitrite uptake by 31% and 61%, respectively, whereas uptake of ammonium was slightly increased (18%) in cartap (60 ppm) treated cells. Nitrate and nitrite reductase, and glutamine synthetase activities of the microorganism decreased by 36-50% in 60 ppm cartap. The low levels of growth, photosynthetic pigments and activities of nitrogen assimilating enzymes in cells grown in nitrogen depleted medium supplement with insecticide indicated that insecticide may be used by the organism as a nitrogen source., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The use of pesticides and other chemicals has become a common practice in modern agriculture to enhance and stabilise crop yield, protect the nutritional integrity of food, facilitate food storage to assure year-round supplies, and provide attractive and appealing food products. With the adoption of strict good agricultural practice (GAP), only minimal amounts of pesticide residues should remain on the crops or in connected foods of animal origin up the food chain. To assess their associated health risk to local people, the dietary exposure of Hong Kong adults to residues of four groups of pesticides or their metabolites - organophosphorus pesticides (OPPs), carbamates, pyrethrins and pyrethroids, and dithiocarbamate (DTC) metabolites - is estimated in the first Hong Kong Total Diet Study (TDS). A total of 150 commonly consumed food items were collected and prepared "as consumed". A total of 600 composite food samples were analysed for 85 pesticides or their metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These pesticides were primarily found at low levels (highest mean = 350 μg kg⁻¹) in food samples of plant origin such as vegetables and fruits. Dietary exposures to pesticide residues were estimated based on the analytical results and the food consumption data of the local residents. The estimated dietary exposures of Hong Kong adults to all individual pesticides were well below their respective acceptable daily intakes (ADIs). The percentage contributions of the estimated mean and 95th percentile dietary exposures to the ADIs of individual pesticides were <6% and <24% for the OPPs, <1% for the carbamates and pyrethrins and pyrethroids, and <1% and <4% for the DTC metabolites, respectively. The findings indicate that dietary exposures to all the pesticide residues analysed in this study were unlikely to pose unacceptable health risks to the Hong Kong population.

Turtles frequently oviposit in soils associated with agriculture and, thus, may be exposed to pesticides or fertilizers. The toxicity of a pesticide regime that is used for potato production in Ontario on the survivorship of snapping turtle (Chelydra serpentina) eggs was evaluated. The following treatments were applied to clean soil: 1) a mixture of the pesticides chlorothalonil, S-metolachlor, metribuzin, and chlorpyrifos, and 2) the soil fumigant metam sodium. Turtle eggs were incubated in soil in outdoor plots in which these mixtures were applied at typical and higher field application rates, where the eggs were subject to ambient temperature and weather conditions. The pesticide mixture consisting of chlorothalonil, S-metolachlor, metribuzin, and chlorpyrifos did not affect survivorship, deformities, or body size at applications up to 10 times the typical field application rates. Hatching success ranged between 87% and 100% for these treatments. Metam sodium was applied at 0.1¯ times, 0.3¯ times, 1 times, and 3 times field application rates. Eggs exposed to any application of metam sodium had 100% mortality. At typical field application rates, the chemical regime associated with potato production does not appear to have any detrimental impacts on turtle egg development, except for the use of the soil fumigant metam sodium, which is highly toxic to turtle eggs at the lowest recommended application rate., (© 2013 SETAC.)

Sodium methyldithiocarbamate (SMD) is one of the most abundantly used conventional pesticides in the United States. At dosages relevant to occupational exposure, it causes major effects on the immune system in mice, including a decreased resistance to sepsis. This lab has identified some of the mechanisms of action of this compound and some of the immunological parameters affected, but the global effects have not previously been assessed. The purpose of the present study was to conduct transcriptomic analysis of the effects of SMD on lipopolysaccharide-induced expression of mediators important in innate immunity and inflammation. The results revealed broad effects on expression of transcription factors in both branches of Toll-like receptor 4 (TLR4) signaling (MyD88 and TRIF). However, TLR3 and interferon signaling pathways were decreased to a greater extent, and assessment of the effects of SMD on polyinosinic polycytidylic acid-induced cytokine and chemokine production revealed that these responses mediated by TLR3 were indeed sensitive to the effects of SMD, with inhibition occurring at lower dosages than required to inhibit responses to other immunological stimuli tested in our previous studies. In the downstream signaling pathways of these TLRs, functional analysis also revealed that NF-κB activation was inhibited by SMD, as indicated by gene expression analysis and a reporter construct in mice. A previously unreported effect on luteinizing hormone and follicle-stimulating hormone pathways was also observed.

Epidemiological studies corroborate a correlation between pesticide use and Parkinson's disease (PD). Thiocarbamate and dithiocarbamate pesticides are widely used and produce neurotoxicity in the peripheral nervous system. Recent evidence from rodent studies suggests that these compounds also cause dopaminergic (DAergic) dysfunction and altered protein processing, two hallmarks of PD. However, DAergic neurotoxicity has yet to be documented. We assessed DAergic dysfunction in Caenorhabditis elegans (C. elegans) to investigate the ability of thiocarbamate pesticides to induce DAergic neurodegeneration. Acute treatment with either S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, or a common reactive intermediate of dithiocarbamate and thiocarbamate metabolism, S-methyl-N,N-diethylthiocarbamate (MeDETC), to gradual loss of DAergic cell morphology and structure over the course of 6 days in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. HPLC analysis revealed decreased DA content in the worms immediately following exposure to MeDETC, EPTC, and molinate. In addition, worms treated with the three test compounds showed a drastic loss of DAergic-dependent behavior over a time course similar to changes in DAergic cell morphology. Alterations in the DAergic system were specific, as loss of cell structure and neurotransmitter content was not observed in cholinergic, glutamatergic, or GABAergic systems. Overall, our data suggest that thiocarbamate pesticides promote neurodegeneration and DAergic cell dysfunction in C. elegans, and may be an environmental risk factor for PD., (© 2013 International Society for Neurochemistry.)

An effective synthesis of analogs of the indole phytoalexin cyclobrassinin with NR1R2 group instead of SCH3 was developed starting from indole-3-carboxaldehyde. The target compounds were prepared by spirocyclization of 1-Boc-thioureas with the formation of isolable spiroindoline intermediates, followed by the trifluoroacetic acid-induced cascade reaction consisting of methanol elimination, deprotection and rearrangement of the iminium ion. The structures of novel products were elucided by the (1)H and (13)C NMR spectroscopy, including HMBC, HSQC, COSY, NOESY and DEPT measurements. Several newly synthesized compounds demonstrated significant antiproliferative/cytotoxic activity against human leukemia and solid tumor cell lines, as well as remarkable selectivity of these effects against cancer cells relative to the non-malignant HUVEC cells., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

With thousands of pesticides registered by the United States Environmental Protection Agency, it not feasible to sample for all pesticides applied in agricultural communities. Hazard-ranking pesticides based on use, toxicity, and exposure potential can help prioritize community-specific pesticide hazards. This study applied hazard-ranking schemes for cancer, endocrine disruption, and reproductive/developmental toxicity in Yuma County, Arizona. An existing cancer hazard-ranking scheme was modified, and novel schemes for endocrine disruption and reproductive/developmental toxicity were developed to rank pesticide hazards. The hazard-ranking schemes accounted for pesticide use, toxicity, and exposure potential based on chemical properties of each pesticide. Pesticides were ranked as hazards with respect to each health effect, as well as overall chronic health effects. The highest hazard-ranked pesticides for overall chronic health effects were maneb, metam-sodium, trifluralin, pronamide, and bifenthrin. The relative pesticide rankings were unique for each health effect. The highest hazard-ranked pesticides differed from those most heavily applied, as well as from those previously detected in Yuma homes over a decade ago. The most hazardous pesticides for cancer in Yuma County, Arizona were also different from a previous hazard-ranking applied in California. Hazard-ranking schemes that take into account pesticide use, toxicity, and exposure potential can help prioritize pesticides of greatest health risk in agricultural communities. This study is the first to provide pesticide hazard-rankings for endocrine disruption and reproductive/developmental toxicity based on use, toxicity, and exposure potential. These hazard-ranking schemes can be applied to other agricultural communities for prioritizing community-specific pesticide hazards to target decreasing health risk., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We examined the chronic toxicity of three rice paddy herbicides (simetryn, mefenacet, and thiobencarb) using an amphibian (Silurana tropicalis) metamorphosis assay (a 28-day semistatic test under an individual-separated exposure system). Each herbicide was tested at two concentrations (1/100 and 1/10 of the 96-h LC50 value reported previously) with morphometric, gravimetric, and thyroid-histological endpoints. Simetryn caused significant retardation in growth and development at both test concentrations (0.04 and 0.40mg/L), as indicated by significantly shorter total body lengths and hind limb lengths, smaller wet body masses, and delayed developmental stages compared to those observed in the control tadpoles. However, no clear histopathology was observed in the thyroid glands of the tadpoles exposed to simetryn. These results suggest that simetryn can act as a chemical stressor retarding tadpole growth and development without disrupting thyroid functions, even at 1/100 of the 96-h LC50 value. In addition, scoliosis near the tail base was observed in the tadpoles exposed to 0.40mg/L of simetryn at a significantly high incidence (7/30=23.3%). Therefore, simetryn can also act as a teratogen inducing axial malformations at 1/10 of the 96-h LC50 value. During the 28 days of exposure, neither mefenacet (0.03 and 0.30mg/L) nor thiobencarb (0.008 and 0.080mg/L) induced any abnormalities, although the test concentrations measured immediately before the solution renewals decreased to nearly 50 percent of the nominal concentrations since day 14. Because the concentrations tested for simetryn are likely to occur in paddy water, wild anuran tadpoles in paddy water may therefore be adversely impacted by simetryn., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aim of the present study was the investigation of the effect of in situ exposure history on the responses of freshwater mussels to thiocarbamate fungicide. Male bivalve mollusks Anodonta anatina (Unionidae) from polluted (A) and unpolluted (F) sites were subjected to 14 days of exposure to fungicide Tattoo (mixture of propamocarb and mancozeb, 91 μg L(-1)). When unexposed mussels were compared, chronic effect of toxic environment in site A was confirmed by oxidative stress indices (high levels of superoxide dismutase and catalase activities, lipid peroxidation, protein carbonyls and oxyradical production, low level of total glutathione (GSH)), genotoxicity (high levels of DNA-strand breaks and caspase-3 activity in digestive gland), and cytotoxicity (low lysosomal membrane stability in hemocytes), elevated vitellogenin-like proteins (Vtg-LP) concentration in gonads, high levels of Cu, Zn, Cd, metallothionein (MT)-bound metals (MT-Me) and MT-related thiol (MT-SH), and low ethoxyresorufin-O-deethylase (EROD) activity in digestive gland. The major differences in the responses of the two exposed groups were related to antioxidant defense and MT: in the group A, prominent oxidative stress response with the participation of MT-SH and GSH in the gills, EROD activation, but decrease of MT-Me level was shown, whereas in group F exposure provoked the elevation of MT-Me, caspase-3 and Vtg-LP values. Carbamate did not cause cholinesterase depletion and cytotoxicity. However, genotoxic and pro-oxidant effects (increased levels of hemocytes with micronuclei and nuclear abnormalities, DNA-strand breaks and oxyradical in digestive gland), were common responses for both the exposed groups.

Thiodicarb, a carbamate pesticide widely used on crops, may pose several environmental and health concerns. This study aimed to explore its toxicological profile on male rats using hematological, biochemical, histopathological, and flow cytometry markers. Exposed animals were dosed daily at 10, 20, or 40 mg/kg/body weight (group A, B, and C, respectively) during 30 d. No significant changes were observed in hematological parameters among all groups. After 10 d, a decrease of total cholesterol levels was noted in rats exposed to 40 mg/kg. Aspartate aminotransferase (AST) activity increased (group A at 20 d; groups A and B at 30 d) and alkaline phosphatase (ALP) (group B at 30 d) activity significantly reduced. At 30 d a decrease of some of the other evaluated parameters was observed with total cholesterol and urea levels in group A as well as total protein and creatinine levels in groups A and B. Histological results demonstrated multi-organ dose-related damage in thiodicarb-exposed animals, evidenced as hemorrhagic and diffuse vacuolation in hepatic tissue; renal histology showed disorganized glomeruli and tubular cell degeneration; spleen was ruptured with white pulp and clusters of iron deposits within red pulp; significant cellular loss was noted at the cortex of thymus; and degenerative changes were observed within testis. The histopathologic alterations were most prominent in the high-dose group. Concerning flow cytometry studies, an increase of lymphocyte number, especially T lymphocytes, was seen in blood samples from animals exposed to the highest dose. Taken together, these results indicate marked systemic organ toxicity in rats after subacute exposure to thiodicarb.

Exposure to mercury can lead to several injuries in mammals, including immune system dysfunction, and pyrrolidine dithiocarbamate (PDTC), as a metal chelator and antioxidant, has been indicated to increase the cytotoxic effects of toxic metals. However, the toxicological effects and possible mechanisms of mercury in combination with PDTC are mostly unclear. In this study, we showed that PDTC dramatically increase the cytotoxic effect of HgCl(2) on cultured murine macrophages (RAW 264.7 cells). PDTC augmented HgCl(2)-induced cytotoxic effects by facilitating the entry of mercury into the cells. The Hg(2+)/PDTC complex significantly and rapidly increased the formation of reactive oxygen species (ROS) and decreased intracellular glutathione (GSH) levels in these cells. Flow cytometry analysis showed that the numbers of sub-G1 hypodiploid cells and annexin V-FITC binding cells increased after Hg(2+)/PDTC complex exposure, and several features of mitochondria-dependent apoptosis were also induced, including mitochondrial membrane depolarization, cytosolic cytochrome c release, poly(ADP-ribose) polymerase (PARP) and caspase 3/7 activation, and DNA fragmentation. Moreover, both apoptotic and necrotic cells were detected using acridine orange/ethidium bromide dual staining. Meanwhile, depleted intracellular ATP levels and increased lactate dehydrogenase (LDH) release were observed, suggesting the induction of necrotic cell death processes. These Hg(2+)/PDTC complex-induced cytotoxicity-related signals could be reversed by pretreatment with the antioxidant N-acetylcysteine. In conclusion, these results suggest that Hg(2+)/PDTC complex-induced oxidative stress causes macrophage cell death via both apoptosis and necrosis. These findings imply for the first time that PDTC dramatically increases the uptake and toxicological effects of Hg(2+) instead of detoxification., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

This study was conducted to evaluate the effect of molinate on retinoids homeostasis in rat testis. Molinate was administrated to male Sprague-Dawley rats (200 mg kg(-1) in corn oil, ip). Retinoid measurements were made at 6, 12, 48 and 168 h time points after administration. Testis levels of retinoic acid decreased (32 %) in a statistically significant manner at the 12 and 48 h time points. However, retinol and retinaldehyde were not significantly affected by molinate. These results suggest that molinate affects retinoic acid synthesis in testis and could contribute to understanding the molecular mechanism of molinate involved testicular toxicity.

The immunomodulating properties of functionalized [2-(arylamino)-4,4-dimethyl-6-oxo-cyclohex-1-ene] carbodithioates and 6,6-dimethyl-4-(2-(propan-2-ylidene)hydrazinyl)-6,7-dihydro-2H-indazole-3(5H)-thione compounds have been investigated. Four of them, 13, 18, 19 and 20 inhibited PBMC proliferation induced by phytohemagglutinin (PHA) in a dose dependent manner with an IC(50) of ≤ 20 μM. The Th-1 cytokine, interleukin-2 (IL-2) in PHA/PMA-stimulated peripheral blood mononuclear cells (PBMCs) is significantly inhibited by 13, 19 and 20 with an IC(50) of 8.4 ± 0.4, 5.34 ± 0.15 and 4.9 ± 0.7 μM, respectively. They also inhibited the PMA/lipopolysaccharide-induced proinflammatory cytokines, IL-1β and TNF-α production in human monocytic leukemia cells (THP-1), by 86%, 46% and 59.2% for IL-1β and by 83.8%, 48.2% and 58.7% for TNF-α, respectively. Only 20 showed significant suppressive activity against the phagocyte oxidative burst in a dose dependent manner, with an IC(50) of 23.8 μM. LPS-induced nitrites in mouse macrophages were found to be inhibited by compounds 6, 8, 13-15 and 19 with an IC(50), which range between 7.7 and 63 μM. The cytotoxicity for the active compounds was also studied on Rat Wistar Hepatocyte cell line, CC1 and the Mouse Fibroblast cell line 3T3 NIH in the presence of compounds using a standard MTT assay. Furthermore, structural-activity relationship using automated docking software revealed that active compounds 7, 13 and 19, adapted the same binding mode, however the most active compound 20 is found deeply inserted within the ligand binding site of IL-2, as multiple hydrophobic and hydrophilic key interactions stabilize the compound inside the binding site, thus contributing higher activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Oxidative stress was demonstrated to promote the progression of diabetes mellitus (DM). It has been suggested that copper may play a specific role in the progression and pathogenesis of DM. Pyrrolidine dithiocarbamate (PDTC), a widely apply to the medicine, was known to be capable of enhancing copper accumulation. In this study, we investigated the effect of submicromolar-concentration Cu(2+)/PDTC complex on pancreatic β-cell damage and evaluated the role of oxidative stress in this effect. CuCl(2) (0.01-300μM) did not affect the cell viability in β-cell line RIN-m5F cells. However, combination of CuCl(2) (0.5μM) and PDTC (0.3μM) markedly reduced RIN-m5F cell viability. Cu(2+)/PDTC complex could also increase the LPO and decrease the intracellular reduced GSH levels, and display several features of apoptosis signals including: increase in sub-G1 cell population, annexin-V binding, and caspase-3 activity, mitochondrial dysfunctions, and the activation of PARP and caspase cascades, which accompanied with the marked increase the intracellular Cu(2+) levels. These apoptotic-related responses of Cu(2+)/PDTC complex-induced could be effectively prevented by antioxidant N-acetylcysteine (NAC). Furthermore, Cu(2+)/PDTC complex was capable of increasing the phosphorylations of ERK1/2 and JNK, and its upstream kinase MEK1/2 and MKK4, which could be reversed by NAC. Transfection with ERK2- and JNK-specific si-RNA and specific inhibitors SP600125 and PD98059 could inhibit ERK1/2 and JNK activation and attenuate MMP loss and caspase-3 activity induced by the Cu(2+)/PDTC complex. Taken together, these results are the first report to demonstrate that the Cu(2+)/PDTC complex triggers a mitochondria-regulated apoptosis via an oxidative stress-induced ERK/JNK activation-related pathway in pancreatic β-cells., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)