Superabsorbent hydrogel as a formulation to promote mineralization and accelerate degradation of acetochlor in soils.

The excessive use of herbicides had caused serious environmental pollution and ecological problems. Therefore, it is imperative to explore an effective method to reduce herbicide residues and pollution. In the present study, we used superabsorbent hydrogels coated 14C-acetochlor (SH-ACE) to investigate its behavior in different soils under oxic conditions. After 100 days, the mineralization by SH-ACE was increased by 2.3%, 2.5% and 3.3% in the red clay soils, fluvio-marine yellow loamy soils and coastal saline soils, respectively, compared to the control group. This result indicated that the SH-ACE treatment resulted in more complete degradation and detoxification of acetochlor. In addition, the dissipation rates of acetochlor were significantly faster in the SH-ACE treatment, which reduced the persistence of acetochlor. The probable degradation pathways of acetochlor involved dechlorination, hydroxylation, deethoxymethylation, and the formation of thioacetic acid derivatives in the two treatments, but the contents of transformation products were completely different. These findings suggest that the SH-ACE treatment has a significant effect to accelerate the degradation of acetochlor. When developing green pesticides, we emphasize that superabsorbent hydrogel coating treatment should be considered as a promising method for ecological safety in the environment.

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment.

Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

Effect of the Intramolecular Hydrogen Bond on the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study.

BACKGROUND: Leflunomide (LFM) and its active metabolite, teriflunomide (TFM), have drawn a lot of attention for their anticancer activities, treatment of rheumatoid arthritis and malaria due to their capability to inhibit dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. In this investigation, the strength of intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) was analyzed employing density functional theory (DFT) using B3LYP/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water solution. A detailed electronic structure study was performed using the quantum theory of atoms in molecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of 76-97 kJ/mol, as a medium hydrogen bond. The effect of substitution on the IHB nature was studied by natural bond orbital analysis (NBO). 1H NMR calculations showed an upward trend in the proton chemical shift of the enolic proton in the chelated ring (14.5 to 15.7ppm) by increasing the IHB strength. All the calculations confirmed the strongest IHB in 5-F-ATFM and the weakest IHB in 2-FATFM. Molecular orbital analysis, including the HOMO-LUMO gap and chemical hardness, was performed to compare the reactivity of inhibitors. Finally, molecular docking analysis was carried out to identify the potency of inhibition of these compounds against PfDHODH enzyme. TFM acts as an inhibitor of dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. Leflunomide and its active metabolite teriflunomide have been identified as drugs for treatment of some diseases, such as multiple sclerosis (MS), rheumatoid arthritis (RA), malaria, and cancer. Hydrogen bonds play a key role in the interaction between drugs and enzymes. OBJECTIVES: The aim of the present work is to investigate the effect of the strength of intramolecular hydrogen bonds (IHBs) in the active metabolite analogs of leflunomide or analogs of teriflunomide (ATFMs) and study the interaction of these inhibitors against the PfDHODH enzyme using quantum mechanical methods. METHODS: At first, intramolecular hydrogen bonds in five ATFMs were evaluated by the DFT method, quantum theory of atoms in molecules (QTAIM), nuclear magnetic resonance (NMR), natural bond orbital (NBO), and molecular orbital (MO) analyses. Then, the interaction of these inhibitors against the PfDHODH enzyme were compared using molecular docking study. RESULTS: All the computed results confirm the following trend in the intramolecular hydrogen bond strength in five mono-halo-substituted 2-cyano-3-hydroxy-N-phenylbut-2-enamide (ATFM): 5-FATFM> 4-Br-ATFM ≈ 3-Br-ATFM>3-Cl-ATFM>TFM-Z>2-F-ATFM which is in agreement with QTAIM, NMR, and NBO results. Docking results show that 5-F-ATFM (EHB=97kJ/mol) has the minimum MolDock score due to its considerable IHB strength. CONCLUSION: For strong IHBs (EHB>100kJ/mol), C=O and O-H group are involved in the intramolecular interactions and do not contribute to the external interactions. Also, the docking study revealed maximum binding energy between TFM-Z and PfDHODH enzyme.

Selective Binding of Cyclodextrins with Leflunomide and Its Pharmacologically Active Metabolite Teriflunomide.

The selectivity of encapsulation of leflunomide and teriflunomide by native α-, ß- and γ-cyclodextrins was investigated through 1H NMR and molecular modeling. Thermodynamic analysis revealed the main driving forces involved in the binding. For α-cyclodextrin, the partial encapsulation was obtained while deep penetration was characterized for the other two cyclodextrins, where the remaining polar fragment of the molecule is located outside the macrocyclic cavity. The interactions via hydrogen bonding are responsible for high negative enthalpy and entropy changes accompanying the complexation of cyclodextrins with teriflunomide. These results were in agreement with the molecular modeling calculations, which provide a clearer picture of the involved interactions at the atomic level.

Evaluation of potential miticide toxicity to Varroa destructor and honey bees, Apis mellifera, under laboratory conditions.

The honey bee, Apis mellifera L., is the world's most important managed pollinator of agricultural crops, however, Varroa mite, Varroa destructor Anderson and Trueman, infestation has threatened honey bee survivorship. Low efficacy and development of Varroa mite resistance to currently used Varroacides has increased the demand for innovative, effective treatment tool options that exhibit high efficacy, while minimizing adverse effects on honey bee fitness. In this investigation, the toxicity of 16 active ingredients and 9 formulated products of registered miticides for use on crops from 12 chemical families were evaluated in comparison to amitraz on Varroa mites and honey bees using contact surface and topical exposures. It was found that fenpyroximate (93% mortality), spirotetramat (84% mortality) and spirodiclofen (70% mortality) had greater toxicity to Varroa mites, but high dose rates caused high bee mortality (> 60%). With this in mind, further research is needed to investigate other options to minimize the adverse effect of these compounds on bees. The results also found high toxicity of fenazaquin and etoxazole against Varroa mites causing 92% and 69% mortality, respectively; and were found to be safe on honey bees. Collectively, it is recommended that fenazaquin and etoxazole are candidates for a potential Varroacide and recommended for further testing against Varroa mites at the colony level.

Biological significance of aminophenyl-ß-carboline derivatives formed from co-mutagenic action of ß-carbolines and aniline and o-toluidine and its effect on tumorigenesis in humans: A review.

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of ß-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-ß-carboline derivatives including 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4'- amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)]. Since humans are often simultaneously exposed to ß-carbolines and aniline and o-toluidine, their effects on humans should be clarified. The most potent of these, APNH, induced both point mutations and small deletions in the liver and colon of gpt delta transgenic mice. Major APNH-induced mutations in the liver occurred at a G:C base pair, suggesting that APNH-DNA adducts (dG-C8-APNH) are potentially involved in these mutations. Furthermore, APNH induced hepatic and colon tumors harboring K-ras, ß-catenin, and Apc mutations in F344 rats, with high incidence. Mutations at G:C base pairs were predominant, similar to those in the in vivo mutation assay using gpt delta mice. Moreover, APNH detected in human urine samples obtained from both healthy volunteers on a normal diet and inpatients receiving parenteral alimentation; therefore, APNH can be considered an endogenous carcinogen contributing to tumorigenesis. Exposure levels of these aminophenyl-ß-carboline derivatives may be lower than those of carcinogenic heterocyclic amines (HCAs) including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); however, their health risks in terms of tumorigenesis may be comparable owing to stronger genotoxic effects of APNH rather than HCAs. This review summarized APNH mutagenicity/carcinogenicity, and its in vivo formation. Moreover, the effect on tumorigenesis in humans also discussed.

Tolylfluanid permeates human skin slowly and as dimethylamino sulfotoluidid (DMST).

Tolylfluanid (TF) is a sensitizing biocide used in antifouling products and wood preservatives. Paint application is associated with skin exposure; however, the importance of this exposure route is uncertain as TF skin permeation rates are lacking in the peer-reviewed scientific literature. TF is a lipophilic powder that hydrolyses rapidly in contact with water to dimethylamino sulfotoluidid (DMST). DMST is also a TF metabolite. We characterized TF and DMST skin permeation using an ex vivo flow-through diffusion system with viable and frozen human skin. TF permeated as DMST with a low permeation rate (0.18 ± 0.05 µg/cm2/h) and a moderate time lag (7.1 ± 1.4 h) in viable human skin. Applying DMST gave a 3.5-fold lower permeation rate (0.05 ± 0.01 µg/cm2/h) compared to TF under a similar experimental setting. We simulated paint activities in an exposure chamber to understand a possible skin exposure from airborne TF concentrations. Although, paint can deposit onto the skin during work activities, TF permeation when paint was applied to human skin ex vivo was very low (as TF: 0.004 ± 0.005 µg/cm2/h, and as DMST: 0.02 ± 0.001 µg/cm2/h). Our results show that TF can permeate skin, and consequently, can contribute to sensitization, which support previous reports on sensitization in TF exposed workers.

Rapid screening of amitraz and its metabolite residues in honey using a quick, easy, cheap, effective, rugged, and safe extraction method coupled with UHPLC and Q Exactive.

A method for determining amitraz and 2,4-dimethylaniline in honey was established by using ultra-high-performance liquid chromatoghaphy and Q Exactive after applying quick, easy, cheap, effective, rugged, and safe extracting process. A suitable extraction method was designed to extract the amitraz and 2,4-dimethylaniline after a suitable amount of honey samples was dissolved. A Thermo Syncronis C18 column (100 × 2.1 mm, 1.7 µm) was used for chromatographic separation of the samples. Then the two compounds were quantitatively analyzed via a program of Q Exactive. The linearity of amitraz and 2,4-dimethylaniline was good in the concentration range of 0.5-100 µg/L, and the correlation coefficient R2 was >0.99. The average recovery and relative standard deviation of each component were 81.3-90.0% and 5.1-7.2%. The 24- and 48-h test results showed that the sample needed to be tested within 24 h. The limit of detection was 0.1 µg/kg for amitraz and 2,4-dimethylaniline, whereas for both the limit of quantitation was 0.3 µg/kg.

Evaluation of temperature and pressure effects on retention in supercritical fluid chromatography on polar stationary phases.

Four polar stationary phases (ethylene-bridged hybrid silica, cyanopropyl, 2-ethylpyridine, and zwitterionic sulfobetaine) have been characterized in supercritical fluid chromatography (SFC) by linear free energy relationships (LFER) method with an extended set of Abraham's descriptors. Temperature (25-55 °C) and pressure (110-180 bar) effects on analyte retention, separation selectivity and LFER-coefficients of chromatographic systems have been studied using the 89 test compounds of various chemical classes and carbon dioxide - methanol (9:1 v/v) binary solvent as a mobile phase. It was found that for the selected stationary phases temperature and pressure had only moderate effects on selectivity. The retention times of all analytes decrease, as can be expected, if the pressure rises at the isothermal conditions due to the increase of the fluid density and its eluting power. The effect of temperature on retention is complicated and depends both on the chemical class of analyzed compounds and the stationary phase type. Temperature and pressure variations lead to small changes in the LFER-coefficients, and general trends observed do not depend much on the stationary phase type. It may be difficult to interpret the LFER-analysis results because of the evident, more significant chromatographic phenomena.

Novel pararosaniline based optical sensor for the determination of sulfite in food extracts.

Sulfite, which is a protective agent in various food industries, also is known as an allergen. Therefore, sulfite content in food must be monitored and controlled. In this context, a novel optical sensor is designed for simple, rapid and sensitive determination of the sulfite content in food samples. Acidified pararosaniline (PRA) hydrochloride reagent in cationic form was immobilized on the surface of the Nafion cation exchanger membrane by electrostatic interactions. In formaldehyde medium, the pale purple PRA-Nafion film was converted to rich purple due to the highly conjugated alkyl amino sulfonic acid formation in the presence of sulfite and the absorbance change at 588 nm was recorded. The proposed optical sensor gave a linear response in a wide concentration range for sulfite. The limit of detection (LOD) and the limit of quantification (LOQ) values obtained for sulfite were 0.084 and 0.280 ppm SO2 equivalent, respectively. The proposed optical sensor was validated in terms of linearity, additivity, precision and recovery parameters. The sulfite contents obtained for real food extracts were found to be comparable to the conventional iodometric titration results (with the exception of highly colored samples containing reducing agents, where iodometry was shown to exhibit a systematic error while the proposed sensor could measure the true value). The proposed optical sensor is insensitive to positive interferences from turbidity and colored components of the sample. Sulfite determination in a complex food matrix can be performed using the rapid, simple and sensitive PRA-based sensor without a need for pre-treatment.

Transdermal enhancement strategy of ketoprofen and teriflunomide: The effect of enhanced drug-drug intermolecular interaction by permeation enhancer on drug release of compound transdermal patch.

The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ±â€¯46.8 µg/cm2) and 1.2 times (502.92 ±â€¯24.0 µg/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTg = -17.7 °C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.

Biodegradation of Atrazine by the Novel Klebsiella variicola Strain FH-1.

Bacterial strain FH-1 with high efficiency of degrading Atrazine is separated by means of enrichment culture from the soil applied with Atrazine for many years. FH-1, recognized as Klebsiella variicola based on phylogenetic analysis of 16S rDNA sequences, can grow with Atrazine which is the sole nitrogen source. In fluid inorganic salt medium, the optimal degradation temperature, pH value, and initial concentration of Atrazine are 25°C, 9.0, and 50 mg L-1, respectively, and the degradation rate of Atrazine by strain FH-1 reached 81.5% in 11 d of culture. The degrading process conforms to the kinetics equation of pesticide degradation. Among the metal ions tested, Zn2+ (0.2 mM) has the most significant effect of facilitation on the degradation of Atrazine. In the fluid medium with Zn2+, the degradation rate of Atrazine is increased to 72.5%, while the Cu2+ (0.2 mM) inhibits the degradation of Atrazine. The degradation products of Atrazine by strain FH-1 were identified as HEIT (2-hydroxyl-4-ethylamino-6-isopropylamino-1,3,5-triazine), MEET (2-hydroxyl-4,6-bis(ethylamino)-1,3,5-triazine), and AEEO (4,6-bis(ethylamino)-1,3,5-triazin-2(1H)-one) by HPLC-MS/MS. Three genes (atzC, trzN, and trzD) encoding for Atrazine degrading enzymes were identified by PCR and sequencing in strain FH-1. This study provides additional theoretical support for the application of strain FH-1 in bioremediation of fields polluted by Atrazine.

Development and Evaluation of a Water-in-oil Microemulsion Formulation for the Transdermal Drug Delivery of Teriflunomide (A771726).

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying anti-rheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of anti-inflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.

Novel spectral manipulations for determinations of Tolnaftate along with related toxic compounds: Drug profiling and a comparative study.

A comparative study using novel quadruple divisor and mean centering of ratio spectra spectrophotometric methods was developed for resolution of five- component mixture of Tolnaftate, ß-naphthol (Tolnaftate alkaline degradation product and its toxic impurity), methyl(m-tolyl)carbamic acid (Tolnaftate alkaline degradation product), N-methyl-m-toluidine (Tolnaftate toxic impurity) and methyl paraben (as a preservative). For the novel quadruple divisor method, each component in the quinary mixture was determined by dividing the quinary mixture spectrum by a sum of standard spectrum of equal concentration of the other four components as a quadruple divisor. First derivative of each ratio spectra was then obtained which allowed selective determination of each component without interference from other components in the mixture. The second method was mean centering of ratio spectra that depended on utilizing the mean centered ratio spectra in four successive steps leading to enhancement of the signal to noise ratio. The absorption spectra of the five studied components were recorded in the wavelength range of 210-350 nm. The mean centered fourth ratio spectra amplitudes for each component were used for its determination. The developed methods were successfully applied for determination of laboratory prepared quinary mixtures to ensure method's specificity, then, were further applied on Tinea Cure® cream where no interference from excipients. For the first time, Tolnaftate was determined along with its toxic impurity; ß-naphthol, that could be absorbed by the skin, causing systemic toxic effects, unlike Tolnaftate that poorly absorbed, indicating the significance of this work. The proposed methods were statistically compared with each other and with the reference method. Furthermore, ICH guidelines were followed for their validation.

Assessments of Algal Toxicity and PBT Behaviour of Pesticides with No Eco-toxicological Data: Predictive Ability of QSA/(T)R Models.

In the present study, the effect of eight pesticides with no ecotoxicological data on the growth rate of Chlorella vulgaris was measured. The selected pesticides are acetochlor, acetamiprid, boscalid diphenamid, gibberellic acid, ioxynil, diclofop and 2,4,5-T. The algal toxicity (IC50 ) of boscalid could not be determined within its solubility limit. Acetamiprid, diphenamid and gibberellic acid revealed IC50 values>100 mg/L. Among the others, the order of 96-h IC50 of pesticides was found as acetochlor>ioxynil>diclofop>2,4,5-T. The IC50 values were also predicted by using four Quantitative Structure-Activity/(Toxicity) Relationship (QSA/(T)R) models selected from the literature. The predictions of the models provided by QSARINS-Chem module of QSARINS as well as those obtained in our previous studies were compared with the results of experimental algal toxicity tests that were performed in our laboratory. The QSTR model generated for the toxicity of diverse chemicals to freshwater algae was able to correctly predict the toxicity order of the pesticides tested in the present study, confirming the utility of the QSA/(T)R approach. Additionally, Persistence, Bioaccumulation and Toxicity (PBT) Index model provided via the software QSARINS was employed and boscalid and diclofop were found to be PBT chemicals based on the PBT model. The present study will be very helpful when a more holistic approach applied to understand the fate of these chemicals in the environment.

A robust nanobiocatalyst based on high performance lipase immobilized to novel synthesised poly(o-toluidine) functionalized magnetic nanocomposite: Sterling stability and application.

Herein, as a promising support, a magnetic enzyme nanoformulation have been designed and fabricated by a poly-o-toluidine modification approach. Owing to the magnetic nature and the existence of amine functionalized groups, the as-synthesised poly(o-toluidine) functionalized magnetic nanocomposite (Fe3O4@POT) was employed as potential support for Candida rugosa lipase (CRL) immobilization to explore its application in fruit flavour esters synthesis. The morphology and structure of the Fe3O4@POT NC were examined through various analytical tools. Hydrolytic activity assays disclose that immobilized lipase demonstrated an activity yield of 120%. It is worth mentioning that CRL#Fe3O4@POT showed superior resistance to extremes of temperature and pH and different organic solvents in contrast to free CRL. The magnetic behaviour of the as-synthesised NC was affirmed by alternating gradient magnetometer analysis. It was found to own facile immobilization process, enhanced catalytic performance for the immobilized form which may be stretched to the immobilization of various vital industrial enzymes. Moreover, it retained improved recycling performance. After 10 cycles of repetitive uses, it still possessed around 90% of its initial activity for the hydrolytic reaction, since the enzyme-magnetic nanoconjugate was effortlessly obtained using a magnet from the reaction system. The formulated nanobiocatalyst was selected for the esterification reaction to synthesize the fruit flavour esters, ethyl acetoacetate and ethyl valerate. The immobilized lipase successfully synthesised flavour compounds in aqueous and n-hexane media having significant higher ester yields compared to free enzyme. The present work successfully combines an industrially prominent biocatalyst, CRL, and a novel magnetic nanocarrier, Fe3O4@POT, into an immobilized nanoformulation with upgraded catalytic properties which has excellent potential for practical industrial implications.

Enantioselective thyroid disruption in zebrafish embryo-larvae via exposure to environmental concentrations of the chloroacetamide herbicide acetochlor.

Acetochlor (ACT) is a chiral chloroacetamide pesticide that has been heavily used around the world, resulting in its residues being frequently found in surface waters. It has been reported that ACT is an endocrine disrupting chemical (EDC) with strong thyroid hormone-disrupting activity in aquatic organisms. However, the enantioselectivity underlying thyroid disruption has yet to be understood. In this study, using a zebrafish embryo-larvae model, the enantioselective thyroid disruption of ACT was investigated at a series of environmentally relevant concentrations (1, 2, 10 and 50 µg/L). Our results showed that both racemic ACT and its enantiomers significantly increased the malformation rates of embryos at 72 h postfertilization (hpf). Decreased thyroxine (T4) contents and increased triiodothyronine (T3) contents were found in larvae at 120 hpf, with (+)-S-ACT exhibiting a greater effect than (-)-R-enantiomer. Similarly, (+)-S-ACT also showed a stronger effect on the mRNA expressions of thyroid hormone receptors (TRα and TRß), deiodinase2 (Dio2) and thyroid-stimulating hormone-ß (TSHß) genes. The observed enantioselectivity in TR expressions was consistent with that of in silico binding analysis, which suggested that (+)-S-enantiomer binds more potently to the TRs than (-)-R-enantiomer. In general, ACT enantiomers showed different influences on the secretion of THs, expression of TH-related key genes and binding affinity to TRs. Considering the different toxicity of different enantiomers, our study highlights the importance of enantioselectivity in understanding of thyroid disruption effects of chiral pesticides.

Atmospheric OH oxidation chemistry of trifluralin and acetochlor.

Trifluralin and acetochlor are two nitrogen-containing current use herbicides. While both herbicides have been observed in the atmosphere and have the potential to undergo atmospheric oxidation before deposition to off-target areas, the atmospheric photooxidation chemistry of these species is poorly understood. We use an oxidative flow reactor to expose the two herbicides to increasing concentrations of OH radicals, detecting pesticides and products using an iodide chemical ionization mass spectrometer. We identify new oxidation products and propose photooxidation mechanisms for trifluralin and acetochlor. Both herbicides contain reduced organic nitrogen atoms, and their OH oxidation produces isocyanic acid. While aerosol was observed in the flow reactor only for acetochlor, our results indicate that OH oxidation of neither herbicide would contribute to secondary organic aerosol formation under typical ambient atmospheric conditions. However, high wall losses of both pesticides in the flow reactor suggests that partitioning to pre-existing aerosol may occur and enable subsequent transport in the atmosphere.

Toward 19F magnetic resonance thermometry: spin-lattice and spin-spin-relaxation times and temperature dependence of fluorinated drugs at 9.4 T.

OBJECTIVE: This study examines the influence of the environmental factor temperature on the 19F NMR characteristics of fluorinated compounds in phantom studies and in tissue. MATERIALS AND METHODS: 19F MR mapping and MR spectroscopy techniques were used to characterize the 19F NMR characteristics of perfluoro-crown ether (PFCE), isoflurane, teriflunomide, and flupentixol. T1 and T2 mapping were performed, while temperature in the samples was changed (T = 20-60 °C) and monitored using fiber optic measurements. In tissue, T1 of PFCE nanoparticles was determined at physiological temperatures and compared with the T1-measured at room temperature. RESULTS: Studies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, T1 and T2. T1 of PFCE nanoparticles was higher at physiological body temperatures compared to room temperature. DISCUSSION: The impact of temperature on the 19F NMR parameters of fluorinated compounds demonstrated in this study not only opens a trajectory toward 19F MR-based thermometry, but also indicates the need for adapting MR sequence parameters according to environmental changes such as temperature. This will be an absolute requirement for detecting fluorinated compounds by 19F MR techniques in vivo.

Spatial and molecular changes of mouse brain metabolism in response to immunomodulatory treatment with teriflunomide as visualized by MALDI-MSI.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS). One of the most promising recent medications for MS is teriflunomide. Its primary mechanism of action is linked to effects on the peripheral immune system by inhibiting dihydroorotate dehydrogenase (DHODH)-catalyzed de novo pyrimidine synthesis and reducing the expansion of lymphocytes in the peripheral immune system. Some in vitro studies suggested, however, that it can also have a direct effect on the CNS compartment. This potential alternative mode of action depends on the drug's capacity to traverse the blood-brain barrier (BBB) and to exert an effect on the complex network of brain biochemical pathways. In this paper, we demonstrate the application of high-resolution/high-accuracy matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry for molecular imaging of the mouse brain coronal sections from animals treated with teriflunomide. Specifically, in order to assess the effect of teriflunomide on the mouse CNS compartment, we investigated the feasibility of teriflunomide to traverse the BBB. Secondly, we systematically evaluated the spatial and semi-quantitative brain metabolic profiles of 24 different endogenous compounds after 4-day teriflunomide administration. Even though the drug was not detected in the examined cerebral sections (despite the high detection sensitivity of the developed method), in-depth study of the endogenous metabolic compartment revealed noticeable alterations as a result of teriflunomide administration compared to the control animals. The observed differences, particularly for purine and pyrimidine nucleotides as well as for glutathione and carbohydrate metabolism intermediates, shed some light on the potential impact of teriflunomide on the mouse brain metabolic networks. Graphical Abstract.