Evaluation of the analgesic efficacy of grapiprant compared with robenacoxib in cats undergoing elective ovariohysterectomy in a prospective, randomized, masked, non-inferiority clinical trial.

OBJECTIVES: The main objective of this study was to compare the postoperative analgesic effects of grapiprant with those of robenacoxib in cats undergoing ovariohysterectomy (OVH). METHODS: In total, 37 female cats (age range 4 months-10 years, weighing ⩾2.5 kg) were enrolled in a prospective, randomized, masked, non-inferiority (NI) clinical trial. Cats received oral robenacoxib (1 mg/kg) or grapiprant (2 mg/kg) 2 h before OVH. Analgesia was assessed via the Feline Grimace Scale (FGS), the Glasgow Composite Measure Pain Scale-Feline (CMPS-F), von Frey monofilaments (vFFs) and pressure algometry (ALG) 2 h before treatment administration, at extubation, and 2, 4, 6, 8, 18 and 24 hours after extubation. Hydromorphone (<8 h postoperatively) or buprenorphine (>18 h postoperatively) were administered to cats with scores of ⩾5/20 on CMPS-F and/or ⩾4/10 on FGS. NI margins for CMPS-F and vFFs were set at 3 and -0.2, respectively. A mixed-effect ANOVA was used for FGS scores (P <0.05). Data are reported as mean ± SEM. RESULTS: The data from 33 cats were analyzed. The upper limit of the 95% confidence interval (CI) (0.35) was less than the NI margin of 3 for CMPS-F, and the lower limit of the 95% CI (0.055) was greater than the NI margin of -0.2 for vFFs, indicating NI of grapiprant. The FGS scores were greater than baseline at extubation for both treatments (1.65 ± 0.63; P = 0.001); however, there was no difference between treatments. There was no difference between treatments, nor treatment by time interaction, for vFFs (P <0.001). The CMPS-F scores for both treatments were higher at extubation but returned to baseline after 4 h (P <0.001). For ALG, there was no difference in treatment or treatment by time interaction. The robenacoxib group had lower pressure readings at extubation and 6 h compared with baseline. CONCLUSIONS AND RELEVANCE: These results indicate that grapiprant was non-inferior to robenacoxib for mitigating postsurgical pain in cats after OVH performed via ventral celiotomy. The impact of grapiprant for analgesia in OVH via the flank is unknown.

Design, Synthesis, and Fungicidal Activities of Novel N-(Pyrazol-5-yl)benzamide Derivatives Containing a Diphenylamine Moiety.

To accelerate the development of novel fungicides, a variety of N-(pyrazol-5-yl)benzamide derivatives with a diphenylamine moiety were designed and synthesized using a pharmacophore recombination strategy based on the structure of pyrazol-5-yl-aminophenyl-benzamides. The bioassay results demonstrated that most of the target compounds had excellent in vitro antifungal activities against Sclerotinia sclerotiorum, Valsa mali, and Botrytis cinerea. In particular, compound 5IIIh exhibited remarkable activity against S. sclerotiorum (EC50 = 0.37 mg/L), which was similar to that of fluxapyroxad (EC50 = 0.27 mg/L). In addition, compound 5IIIc (EC50 = 1.32 mg/L) was observed to be more effective against V. mali than fluxapyroxad (EC50 = 12.8 mg/L) and comparable to trifloxystrobin (EC50 = 1.62 mg/L). Furthermore, compound 5IIIh demonstrated remarkable in vivo protective antifungal properties against S. sclerotiorum, with an inhibition rate of 96.8% at 100 mg/L, which was close to that of fluxapyroxad (99.6%). Compounds 5IIIc (66.7%) and 5IIIh (62.9%) exhibited good in vivo antifungal effects against V. mali at 100 mg/L, which were superior to that of fluxapyroxad (11.1%) but lower than that of trifloxystrobin (88.9%). The succinate dehydrogenase (SDH) enzymatic inhibition assay was conducted to confirm the mechanism of action. Molecular docking analysis further revealed that compound 5IIIh has significant hydrogen-bonding, π-π, and p-π conjugation interactions with ARG 43, SER 39, TRP 173, and TYR 58 in the binding site of SDH, and the binding mode was similar to that of the commercial fungicide fluxapyroxad. All of the results suggest that compound 5IIIh could be a potential SDH inhibitor, offering a valuable reference for future studies.

MEK1/2 inhibition decreases pro-inflammatory responses in macrophages from people with cystic fibrosis and mitigates severity of illness in experimental murine methicillin-resistant Staphylococcus aureus infection.

Chronic pulmonary bacterial infections and associated inflammation remain a cause of morbidity and mortality in people with cystic fibrosis (PwCF) despite new modulator therapies. Therapies targeting host factors that dampen detrimental inflammation without suppressing immune responses critical for controlling infections remain limited, while the development of lung infections caused by antimicrobial resistant bacteria is an increasing global problem, and a significant challenge in CF. Pharmacological compounds targeting the mammalian MAPK proteins MEK1 and MEK2, referred to as MEK1/2 inhibitor compounds, have potential combined anti-microbial and anti-inflammatory effects. Here we examined the immunomodulatory properties of MEK1/2 inhibitor compounds PD0325901, trametinib, and CI-1040 on CF innate immune cells. Human CF macrophage and neutrophil phagocytic functions were assessed by quantifying phagocytosis of serum opsonized pHrodo red E. coli, Staphylococcus aureus, and zymosan bioparticles. MEK1/2 inhibitor compounds reduced CF macrophage pro-inflammatory cytokine production without impairing CF macrophage or neutrophil phagocytic abilities. Wild-type C57BL6/J and Cftr tm1kth (F508del homozygous) mice were used to evaluate the in vivo therapeutic potential of PD0325901 compared to vehicle treatment in an intranasal methicillin-resistant Staphylococcus aureus (MRSA) infection with the community-acquired MRSA strain USA300. In both wild-type and CF mice, PD0325901 reduced inflammation associated body mass loss. Wild-type mice treated with PD0325901 had significant reduction in neutrophil-mediated inflammation compared to vehicle treatment groups, with preserved clearance of bacteria in lung, liver, or spleen 1 day after infection in either wild-type or CF mouse models. In summary, this study provides the first data evaluating the therapeutic potential of MEK1/2 inhibitor to modulate CF immune cells and demonstrates that MEK1/2 inhibitors diminish pro-inflammatory responses without impairing host defense mechanisms required for acute pathogen clearance.

A MEK inhibitor arrests the cell cycle of human conjunctival fibroblasts and improves the outcome of glaucoma filtration surgery.

Better agents are needed to improve glaucoma filtration surgery outcomes compared to current ones. The purpose of this study is to determine whether mitogen-activated protein kinase kinase (MEK) inhibitors can effectively arrest the cell cycle of human conjunctival fibroblasts (HCFs) and inhibit the formation of fibrosis and scarring following glaucoma filtration surgery. A cell counting kit­8 assay revealed that the MEK inhibitor PD0325901 exhibited concentration-dependent growth inhibition of HCFs. Quantitative PCR, immunocytochemistry, and western blotting demonstrated decreased expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and increased expression of p27 in HCFs treated with PD0325901. Flow cytometry indicated that PD0325901 arrested the cell cycle of HCFs in the G0/1 phase. The cell-migration assay showed that HCF migration rate was significantly suppressed by PD0325901 exposure. Rabbits were divided into PD0325901-treatment and control groups, and glaucoma filtration surgery was performed. Although intraocular pressure did not differ between PD0325901-treatment and control groups, bleb height was greater in the treatment group. Histopathological evaluation revealed that fibrotic changes were significantly attenuated in the PD0325901-treatment group compared to the control group. In conclusion, the MEK inhibitor impedes HCF proliferation via cell-cycle arrest and may be beneficial for glaucoma filtration surgery by reducing bleb scarring.

Death receptor 5 is required for intestinal stem cell activity during intestinal epithelial renewal at homoeostasis.

Intestinal epithelial renewal, which depends on the proliferation and differentiation of intestinal stem cells (ISCs), is essential for epithelial homoeostasis. Understanding the mechanism controlling ISC activity is important. We found that death receptor 5 (DR5) gene deletion (DR5-/-) mice had impaired epithelial absorption and barrier function, resulting in delayed weight gain, which might be related to the general reduction of differentiated epithelial cells. In DR5-/- mice, the expression of ISC marker genes, the number of Olfm4+ ISCs, and the number of Ki67+ and BrdU+ cells in crypt were reduced. Furthermore, DR5 deletion inhibited the expression of lineage differentiation genes driving ISC differentiation into enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Therefore, DR5 gene loss may inhibit the intestinal epithelial renewal by dampening ISC activity. The ability of crypts from DR5-/- mice to form organoids decreased, and selective DR5 activation by Bioymifi promoted organoid growth and the expression of ISC and intestinal epithelial cell marker genes. Silencing of endogenous DR5 ligand TRAIL in organoids down-regulated the expression of ISC and intestinal epithelial cell marker genes. So, DR5 expressed in intestinal crypts was involved in the regulation of ISC activity. DR5 deletion in vivo or activation in organoids inhibited or enhanced the activity of Wnt, Notch, and BMP signalling through regulating the production of Paneth cell-derived ISC niche factors. DR5 gene deletion caused apoptosis and DNA damage in transit amplifying cells by inhibiting ERK1/2 activity in intestinal crypts. Inhibition of ERK1/2 with PD0325901 dampened the ISC activity and epithelial regeneration. In organoids, when Bioymifi's effect in activating ERK1/2 activity was completely blocked by PD0325901, its role in stimulating ISC activity and promoting epithelial regeneration was also eliminated. In summary, DR5 in intestinal crypts is essential for ISC activity during epithelial renewal under homoeostasis.

Synthesis and In Vitro Evaluation as Potential Anticancer and Antioxidant Agents of Diphenylamine-Pyrrolidin-2-one-Hydrazone Derivatives.

The title compounds were synthesized by the reaction of 5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide with various aldehydes bearing aromatic and heterocyclic moieties and acetophenones, and their cytotoxicity was tested via MTT assay against human triple-negative breast cancer MDA-MB-231, human melanoma IGR39, human pancreatic carcinoma Panc-1, and prostate cancer cell line PPC-1. Furthermore, the selectivity of compounds towards cancer cells compared to fibroblasts was also investigated. Four compounds were identified as the most promising anticancer agents out of a series of pyrrolidinone-hydrazone derivatives bearing a diphenylamine moiety. These compounds were most selective against the prostate cancer cell line PPC-1 and the melanoma cell lines IGR39, with EC50 values in the range of 2.5-20.2 µM against these cell lines. In general, the compounds were less active against triple-negative breast cancer MDA-MB-231 cell line, and none of them showed an inhibitory effect on the migration of these cells. In the 'wound healing' assay, N'-((5-nitrothiophen-2-yl)methylene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide was identified as the most promising derivative that could be further developed as an antimetastatic agent. N'-(5-chloro- and N'-(3,4-dichlorobenzylidene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazides most efficiently reduced the cell viability in IGR39 cell spheroids, while there was no effect of the investigated pyrrolidinone-hydrazone derivatives on PPC-1 3D cell cultures. Antioxidant activity determined via FRAP assay of N'-(1-(4-aminophenyl)ethylidene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide was 1.2 times higher than that of protocatechuic acid.

Assessment and usability of Jatropha biodiesel blend with phenolic antioxidant to control NOx emissions of an unmodified diesel engine.

The excessive utilization of fossil fuels has worsened global warming and exacerbated the levels of air pollution in the environment, forcing us to consider alternative fuels for compression ignition engines. The current research aims to explore the possibilities of renewable fuels outperforming diesel fuel in terms of combustion, performance, and emission characteristics. Biodiesel is an environmentally friendly and renewable alternative fuel. The major drawback of biodiesel is the significant rise in nitrogen oxide (NOx) emissions. The main novelty and objective of this research is to investigate the performance and emission characteristics of variable compression ratio diesel engine using DPA antioxidant additive. For this investigation, diesel, Jatropha biodiesel (B30) and 100 ppm of phenolic antioxidant diphenylamine (DPA) blended with B30 have been used as fuel named B30+DPA100. From experimental outcomes, the inclusion of diphenylamine to B30 blend resulted in brake-specific fuel consumption (BSFC) and exhaust gas temperature (EGT) being reduced by 8.86% and 4.12%, respectively, compared to B30. Simultaneously, there was a 1.11% increase in brake thermal efficiency (BTHE). The B30+DPA100 fuel blend demonstrates effective control over NOx and other emissions. The emissions of NOx, carbon monoxide (CO), hydrocarbon (HC), and smoke from the B30+DPA100 blend have shown a reduction of 6.8%, 5.34%, 7.86%, and 15.67%, respectively, when compared to diesel. However, there has been an increase in carbon dioxide (CO2) by 7.8%. One notable advantage of the B30+DPA100 blend is the significant decrease in NOx emissions. Additionally, the cylinder pressure for B30+DPA100 has been lowered by 4.93% compared to B30. On the other hand, the net heat release rate (NHR) has experienced a 1.72% increase. The particle size of different elements present in the crankcase oil has been calculated by Zetasizer Nano. The analysis revealed varying particle sizes for different elements in the crankcase oil: aluminum (2.724 µm), chromium (2.78 µm), iron (2.423 µm), and lead (2.587 µm).

Designing of fluorine-substituted benzodithiophene-based small molecules with efficient photovoltaic parameters.

In this study, four hole-transporting materials (JY-M1, JY-M2, JY-M3, and JY-M4) are designed by modifying benzothiadiazole-based core with diphenylamine-based carbazole via acceptors through thiophene linkers. The designed molecules exhibited deeper HOMO energy with smaller energy gaps than the reference JY molecule which enhance their hole mobility. The absorption spectra of the JY-M1, JY-M2, JY-M3, and JY-M4 molecules are located at 380 nm to 407 nm in the gaseous phase and 397 nm to 433 nm in the solvent phase, which is red-shifted and higher than the reference molecule, demonstrating that designed molecules possess improved light absorption properties and enhanced effective hole transfer. The dipole moments of the designed molecules (14.74 D to 26.12 D) indicate a greater ability for charge separation, solubility and will be beneficial to produce multilayer films. Moreover, the results of hole reorganization energy (0.38198 eV to 0.45304 eV) and charge transfer integral (0.14315 eV to 0.14665 eV) of designing molecules show improved hole mobility and lower recombination losses compared to the JY molecule. Overall, we suggested that the structural modifications in the designed molecules contributed to their enhanced efficiency in converting light energy into electrical energy and have the potential for utilization in solar devices, paving the way for future advancements in the field of photovoltaics.

Diphenylamine-based hole-transporting materials for excessive-overall performance perovskite solar cells: Insights from DFT calculations.

Density functional theory calculations were employed to identify the ability of some diphenylamine-based hole-transporting materials (HTMs) for use in top-performance perovskite solar cells. The effects of donor/acceptor electron groups and the new π-bridge section in the three-part of structures were investigated thoroughly. The results indicated that adding electron-withdrawing functional groups such as CN in the phenylazo-indol moiety and substituting electron donor groups such as CH3 in the NH2 hydrogen atoms of the diphenylamine section can cause higher power conversion light-harvesting efficiency in new HTMs. Also, the replacement of thieno [3,2-b] benzothiophene as a part of the π bridge with the phenyl group according to the optical and electronic structure properties improves the efficiency of the new phenylazoindole derivatives.

Assessing the occurrence and sources of synthetic additive pollutants in lake sediments using fecal and sewage markers.

Benzotriazole ultraviolet stabilizers (BZT-UVs), substituted diphenylamine antioxidants (S-DPAs), and synthetic phenolic antioxidants (SPAs) are three types of synthetic additive pollutants that are received increasing attention in the recent decade. In this study, a total of twenty-seven target analytes were measured in sediment cores and surface sediments collected from a lake with long sedimentary history. All target analytes were detected in the sediment samples, and mean values of the total ∑BZT-UVs, ∑S-DPAs and ∑SPAs concentrations were 220 ± 552 ng/g dry weight (d.w.), 20.8 ± 27.9 ng/g d. w., and 95.8 ± 146 ng/g d. w., respectively. Based on the dating results of two sediment cores, the total concentrations of BZT-UVs, S-DPA, and SPAs showed a fluctuating but overall increasing trend over time, which intuitively reflects the change of historical emissions. Meanwhile, fecal and sewage markers (i.e., sterols and pharmaceuticals, respectively) were jointly used to trace the probable sources of these pollutants. Results from the correlation and clustering analyses suggest that unregular fecal discharges and point-source domestic sewage need to be considered if pollution in the investigated area is to be controlled. To our knowledge, this study is the initial attempt to reveal the temporal variations of these synthetic additive pollutants in an aquatic environment in China and to demonstrate the feasibility of using markers to trace the sources of emerging pollutant analogues.

Iron overload induced by diphenylamine triggers reactive oxygen species and apoptosis in the spleen of pregnant rats and their fetuses.

Diphenylamine (DPA) is an aniline derivative, used widely as an industrial antioxidant, dye mordant, and agricultural fungicide. DPA was reported as hazardous to mammals both acutely and chronically, however little is known about the toxicity of DPA and its derivatives during pregnancy. This study aimed to evaluate and explain the possible mechanism of toxicity induced by DPA on blood and spleen, as a fundamental hematopoietic target organ, in pregnant rats and their fetuses. Pregnant rats were orally administrated distilled water, corn oil, and/or DPA (400 mg/kg b.wt) from the 5th to 19th day of gestation. DPA-induced spleen toxicity was mirrored by significant upregulation of programmed death-1 (PD-1) protein expression and an increase in the percentage of apoptotic cells and a decrease in their proliferating capacity. These results have been confirmed through marked G0/G1 cell-cycle arrest that was observed by flow cytometric analysis of spleen cells. Moreover, the contents of reactive oxygen species and iron in the spleen tissue were significantly higher than that of the control group. DPA resulted in severe anemia, decreased hemoglobin and hematocrit, thrombocytopenia and leukopenia in addition to significant changes in differential leukocytic count of both mothers and fetuses. Evidently, DPA triggered serious pathological changes in the spleen tissue of both mothers and fetuses and the histochemical examination revealed a significant increase in iron expression. In conclusion, these results implicate the hemato- and splenotoxicity of DPA and the possible role of oxidative stress and apoptosis in DPA-induced toxicity in the spleen of pregnant rats and their fetuses. This in-turn suggests the urgent need to reduce exposure to DPA as possible as it can.

High levels of synthetic antioxidants and ultraviolet filters in children's car seats.

Forty-seven compounds among synthetic phenolic and amino antioxidants and ultraviolet filters, three suites of widely used chemical additives, were measured in eighteen popular children's car seats (fabric, foam, and laminated composites of both layers) marketed in the United States in 2018. Significantly higher levels of target compounds were found in foam and composite samples than in fabric samples. Median total concentrations of phenolic antioxidants and their transformation products ranged from 8.11 µg/g in fabric to 213 µg/g in foam In general, isooctyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate (AO-1135) and 2,4-di-tert-butylphenol (24-DBP) were the most abundant among all target compounds with maximum levels of526 µg/g in composite and 13.7 µg/g, respectively. The total concentrations of amino antioxidants and their transformation products and of ultraviolet filters were at least one order of magnitude lower than those of phenolic antioxidants, with medians of 0.15-37.1 µg/g and 0.29-1.81 µg/g, respectively, in which the predominant congeners were 4-tert-butyl diphenylamine (BDPA), 4,4'-di-tert-butyl diphenylamine (DBDPA), 4-tert-octyl diphenylamine (ODPA), 2,4-dihydroxybenzophenone (BP-1), 2-hydroxy-4-methoxybenzophenone (BP-3), and 2-(2-benzotriazol-2-yl)-4-methylphenol (UV-P). Large variabilities in usage of these chemicals resulted in different compositional patterns among the car seats. These results suggest that these compounds are major polymeric additives in children's car seats as they are present at greater levels than previously measured groups of chemicals like brominated flame retardants and per- and polyfluoroalkyl substances. Given the documented toxic potentials of synthetic antioxidants and ultraviolet filters, their abundances in children products are a cause for concern.

An approach to detecting diphenylamine content and assessing chemical stability of single-base propellants by near-infrared reflectance spectroscopy.

Diphenylamine (DPA) as a stabilizer component plays an important role in maintaining the chemical stability of single-base propellants (SBPs). This work investigated the feasibility of rapidly detecting the content of DPA in SBP by near-infrared reflectance spectroscopy (NIRS). The quantitative NIR model was developed by intervals selection, spectral pretreatment and factor number optimization. The optimal spectral intervals were determined to be 1081 nm âˆ¼ 1280 nm and 1378 nm âˆ¼ 1602 nm based on the characteristic spectral peaks of DPA. By comparing the performance of the developed models with different preprocessing methods, the best preprocessing method was standard normal variate transformation (SNV) + de-trending (Dr) + Smoothing. The optimal number of factors was 6 for DPA model. Partial least squares (PLS) regression was used to establish the calibration models of DPA. For the developed model, the determination coefficients of calibration and prediction (Rc2, Rp2) were 0.9907 and 0.9884, respectively. The root mean square errors of calibration and prediction (RMSEC, RMSEP) were 0.0310 and 0.0342, respectively. The samples in the prediction set were predicted by the developed model, and the average absolute error of the proposed and reference method was only 0.0265. The developed model can be applied in rapid monitor the content of DPA in SBP. In addition, vieille test have demonstrated that the chemical stability of SBP became worse with the decrease of DPA content. The content of DPA contained in the SBP with qualified chemical stability is not less than 0.8753%. Thus, the developed model can be used to judge whether the chemical stability of SBP is qualified or unqualified.

Examination of the pharmacokinetics and differential inhibition of cyclooxygenase isoenzymes in New Zealand white rabbits (Oryctolagus cuniculus) by the Non-Steroidal anti-inflammatory Robenacoxib.

Effective rabbit analgesia is challenging, and there are few studies available on the newer COX-2 selective NSAIDs, such as robenacoxib. This study aimed to establish the pharmacokinetics of oral and subcutaneous robenacoxib, describe its inhibitory actions on COX enzymes, and develop dosing, using six healthy New Zealand white rabbits. Pharmacokinetics were determined from plasma concentrations after oral administration of robenacoxib (0.83-0.96 mg/kg) and also after subcutaneous administration (2 mg/kg). The inhibitory actions of robenacoxib were evaluated by measuring plasma concentrations of thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) as surrogate markers of cyclooxygenase enzyme isoform inhibition. The mean maximum concentration for oral and subcutaneous administration was 0.23 µg/ml and 5.82 µg/ml, respectively. Oral robenacoxib administration did not demonstrate a significant difference between any time point for PGE2 or TBX2 , though subcutaneous administration did for both. There was no significant difference in PGE2 or TBX2 concentrations at any time point when comparing subcutaneous versus oral routes. Although the results support that plasma robenacoxib exceeds the therapeutic levels compared to dogs and cats, there was little significance in the difference in the changes associated with COX-1 and COX-2 inhibition. Further studies are warranted to determine appropriate dosing, safety, and efficacy in rabbits.

Radio-sensitizing effect of MEK inhibition in glioblastoma in vitro and in vivo.

INTRODUCTION: Glioblastoma (GBM) is an incurable cancer type. New therapeutic options are investigated, including targeting the mitogen-activated protein kinase (MAPK) pathway using MEK inhibitors as radio-sensitizers. In this study, we investigated whether MEK inhibition via PD0325901 leads to radio-sensitization in experimental in vitro and in vivo models of GBM. MATERIALS AND METHODS: In vitro, GBM8 multicellular spheroids were irradiated with 3 fractions of 2 Gy, during 5 consecutive days of incubation with either PD0325901 or MEK-162. In vivo, we combined PD0325901 with radiotherapy in the GBM8 orthotopic mouse model, tumor growth was measured weekly by bioluminescence imaging and overall survival and toxicity were assessed. RESULTS: Regrowth and viability of spheroids monitored until day 18, showed that both MEK inhibitors had an in vitro radio-sensitizing effect. In vivo, PD0325901 concentrations were relatively constant throughout multiple brain areas and temporal PD0325901-related adverse events such as dermatitis were observed in 4 out of 14 mice (29%). Mice that were treated with radiation alone or combined with PD0325901 had significantly better survival compared to vehicle (both P < 0.005), however, no significant interaction between PD0325901 MEK inhibition and irradiation was observed. CONCLUSION: The difference between the radiotherapy-enhancing effect of PD0325901 in vitro and in vivo urges further pharmacodynamic/pharmacokinetic investigation of PD0325901 and possibly other candidate MEK inhibitors.

Occurrence, vertical distribution and transport of organic amine pesticides in the seawater from the East China Sea and the South China Sea.

Organic amine pesticides (OAPs) are widely used as insecticides, fungicides and herbicides in agricultural production. China is a large agricultural country, and the sprayed pesticides may impact the fragile marine environment through surface runoff. This study revealed the pollution characteristics of thirty-three OAPs in the East China Sea (ECS) and the South China Sea (SCS) and investigated their vertical variations in water columns. The ∑OAPs ranged from below method detection limits to 3.4 ng/ L, with an average value of 0.93 ng/ L. Diphenylamine and beflubutamid were the two most abundant compounds, contributing 64 % and 14 % of the ∑OAPs, respectively. The ∑OAPs in the ECS were significantly (M-W U test, p < 0.01) higher than that in the SCS, and OAPs exhibited different composition profiles. Diphenylamine was the most abundant compound in the ECS, while beflubutamid was dominant in the SCS, which may be related to industrial production (such as rubber synthesis) and agricultural activities. In the water columns, OAPs concentrations were higher in deep layers compared to that in surface seawater, which may be due to weak light and low temperature reducing the degradation of pesticides, indicating the deep ocean is a sink for OAPs. Under the dilution of seawater, the concentrations of OAPs decreased from the Pearl River Estuary to the open sea, and the South China Sea Warm Current also caused the decrease of OAPs from south to north. A preliminary risk assessment indicated that OAPs in the water pose no significant risk to aquatic organisms.

Water-Dispersible Activatable Nanoprobe for Detecting Cadmium-Ion-Induced Oxidative Stress in Edible Crops via Near-Infrared Second-Window Fluorescence Imaging.

Edible crops are important in terms of food security and sustainable agriculture. Heavy-metal-ion contamination of water/soil has deleterious impacts on the growth of edible crops. Among the heavy metals, cadmium (Cd) is toxic to plants, people, and animals, as it is widely used in industry; it has become the most important metal ion in the soil/water pollution. Once the toxic Cd ion enters edible crops via the water/soil in which the crops grow, it will induce oxidative stress (overproduction of reactive oxygen species with H2O2 being the most abundant) in the crops, and strong oxidative stress leads to the crops' growth depression or inhibition. Hence, it is of great significance to accurately monitor the oxidative stress induced by Cd ions in edible crops, as the monitoring results could be employed for the early warning of Cd-ion pollution in water/soil. Herein, we design an activatable nanoprobe that can detect Cd-ion-induced oxidative stress in edible crops via near-infrared second-window (NIR-II) fluorescence imaging. The molecular probe IXD-B contains the diphenylamine-modified xanthene group acting as the electron-donating unit, bis(methylenemalononitrile)indan as the electron-accepting unit, and the methenephenylboronic acid group as the recognition moiety for H2O2 and the fluorescence quencher. The probe molecules being encapsulated by the amphiphilic DSPE-PEG2000 render the water-dispersible nanoprobe (IXD-B@DSPE-PEG2000). When the nanoprobe enters the edible crops, it can be activated by the overexpressed H2O2 therein and consequently emit strong NIR-II fluorescence signals for visualizing and tracking the oxidative stress in edible crops induced by Cd ions.

A simple and safe approach for simultaneous spectrophotometric determination of nitroglycerin and nitrocellulose in double base solid propellants.

An accurate, simple and safe method was developed for simultaneous determination of nitroglycerine (NG) and nitrocellulose (NC) in double base solid propellants (DB propellants). The proposed method is based on alkaline hydrolysis of NG and NC, and followed by colored reaction of released nitrite ion with p-nitroaniline in the presence of diphenylamine in acidic media and produce azo dye. The absorbance of the azo dye was measured at 534 nm. Two sets of reaction conditions were developed. In the first set, at room temperature, only NG was hydrolyzed and calibration curve obtained. In the second set, at 60 â„ƒ, NG and NC were hydrolyzed simultaneously. Based on obtained amount for the NG at room temperature, and total amount of NG and NC at 60 â„ƒ, the amount of NC was determined by using stoichiometric equations. The calibration curve was linear over the concentration ranges of 0.2-5.0, 0.5-10 µg mL-1 for NG and NC, respectively. The proposed method was successfully applied for the determination of NG and NC in DB propellants with good recoveries ranged from 99 to 101%, and RSD less than 2.0%. The method statistically compared based on t- and F-tests with those obtained in according to military standard method (MIL-STD-286). The results showed that the proposed method offers an accuracy and reliable approach for the determination of these compounds in DB propellants, and can be suggested as a routine method in military quality control laboratories.

A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer.

Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER + breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome.