Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors.

Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment.

HRMS analysis of pesticides in vegetables from Shanghai and risk assessment.

A rapid analytical method for the simultaneous determination of 550 pesticide residues in vegetable samples was developed based on ultra-high performance liquid chromatography-tandem Q/Orbitrap high-resolution mass spectrometry (UPLC-Q/Orbitrap-HRMS). To investigate the risk of exposure to pesticide residues through vegetable consumption, 704 leafy vegetable samples from Shanghai were analysed for multiple residues using this method. A total of 54 pesticide residues were identified in these vegetable samples and 302 samples contained one or more pesticide residue. The levels of the detected pesticides did not pose a health risk in the long term and were acceptable according to the results of the chronic dietary risk assessment. Risk rankings displayed that most of the pesticides were low to medium risk. The findings of this study provide a reference for future pesticide monitoring programmes.

Multi-Residue Screening of Pesticides in Aquatic Products Using High-Performance Liquid Chromatography-Tandem High-Resolution Mass Spectrometry.

Pesticide residues in aquatic products are of great concern due to the risk of environmental transmission and their extensive use in aquaculture. In our work, a quick screening approach was developed for the qualitative and semi-quantitative screening of 87 pesticide residues in aquatic products. The sample preparation was investigated, including extract solvent, extract methods, buffer salts, lipid removal, cleanup materials and filter membranes for aquatic products. Samples were extracted using a modified QuEChERS procedure, and two clean-up procedures were developed for UHPLC-Q/Orbitrap MS analysis based on the fat content of the aquatic products. The screening detection limits for all studied pesticides were distributed between 1 and 500 µg/kg in the three representative matrices. Seventy-one pesticides could be analyzed with a screening limit between 1 and 25 µg/kg in grass carp and crayfish, sixty-one pesticides could be screened for limits between 1 and 50 µg/kg in crab. The accuracy results showed that recoveries ranged from 50 to 120% for 60, 56 and 52 pesticides at medium-level for grass carp, crayfish and crab, respectively. At high spiking levels, 74, 65 and 59 pesticides were recovered within the range of 50-120% for the three matrices, respectively. The relative standard deviations of most compounds in different matrices were less than 20%. With this method, the local farmed aquatic products were tested for pesticide residues. In these samples, ethoxyquinoline, prometryn and phoxim were frequently detected. The majority of these confirmed compounds did not exceed 2.00 µg/kg. A grass carp with trichlorfon at 4.87 µg/kg and two carps with ethoxyquinoline at 200 µg/kg were detected, indicating the potential dietary risk.

Improved LC/MS/MS Quantification Using Dual Deuterated Isomers as the Surrogates: A Case Analysis of Enrofloxacin Residue in Aquatic Products.

Extensive and high residue variations in enrofloxacin (ENR) exist in different aquatic products. A novel quantitative method for measuring ENR using high-performance liquid chromatography-tandem mass spectrometry was developed employing enrofloxacin-d5 (ENR-d5) and enrofloxacin-d3 (ENR-d3) as isotope surrogates. This reduced the deviation of detected values, which results from the overpass of the linear range and/or the large difference in the residue between the isotope standard and ENR, from the actual content. Furthermore, high residue levels of ENR can be directly diluted and re-calibrated by the corresponding curve with the addition of high levels of another internal surrogate without repeated sample preparation, avoiding the overflow of the instrument response. The validation results demonstrated that the method can simultaneously determine ENR residues from MQL (2 µg/kg) to 5000 × MQL (method quantification limit) with recoveries between 97.1 and 106%, and intra-precision of no more than 2.14%. This method realized a wide linear calibration range with dual deuterated isomers, which has not been previously reported in the literature. The developed method was successfully applied to the analysis of ENR in different aquatic products, with ENR residue levels varying from 108 to 4340 µg/kg and an interval of precision in the range of 0.175~6.72%. These results demonstrate that batch samples with a high variation in ENR residues (over the linear range with a single isotope standard) can be detected by the dual isotope surrogates method in a single sample preparation process.

H-beta zeolite-based dispersive solid-phase strategy for the multi-residue determination of pesticides.

In this work, electrostatic interactions, hydrogen bonding and other interactions between a variety of pesticides and H-beta zeolite are discussed based on thermodynamics (Gibbs free energy, enthalpy, and entropy). Combined with the physical properties of the target compounds (octanol-water partition coefficient and molar volume), the characteristics of the physical adsorption on the synthetic zeolite were analyzed, the results of H-beta zeolite adsorption showed that the adsorption rate had a nonlinear relationship with the physical properties, and the adsorption reaction was dominated by the adsorption on the surface and in the pores of the H-beta zeolite. Based on the principle of zeolite adsorption, the parameters of absorbent amount, adsorption time, sample pH, ion strength, sample volume and desorption solvent were optimized, a vortex-assisted dispersive solid-phase extraction procedure coupled with liquid chromatography-tandem mass spectrometry was developed for the analysis of multiple pesticides in surface water. The sample was adjusted by phosphate buffer or hydrochloric acid to pH 4, then adsorbed by 50 mg of zeolite within 10 min, adding 2% (g/v) sodium chloride to the solution. The absorbent was eluted with a mixture of acetonitrile-methanol containing 0.5% formic acid after separation, then filtered prior to analysis. The optimized vortex-assisted dispersive solid-phase extraction method simultaneously achieved a low adsorbent dosage, a high enrichment factor of 25, rapid pre-concentration for 30 min, a low solvent usage of 2 mL and multi-target simultaneous analysis. Method performance in terms of accuracy, precision, limit of detection, and limit of quantitation was performed to validate the reliability of the procedure. The proposed protocol achieved acceptable accuracy (recoveries between 62% and 107%), and precision (relative standard deviation < 20%). The limit of detection of the method was below 0.1 µg/L, and the limit of quantitation was 0.08 µg/L or 0.2 µg/L. The results indicated that zeolite is a promising adsorbent with high adsorption capacity. It has the advantages of being a fast, simple, green and economical method for determining residual pesticides in water.

Pesticides and risk assessment in Shanghai fruit and raw eaten vegetables.

A database of 392 pesticides established by an Ultrahigh performance liquid chromatography-tandem Q/Orbitrap high-resolution mass spectrometer (UPLC-Q/Orbitrap-HRMS) was used to screen multiple residues of pesticides in fruit and raw eaten vegetables from planting farms in Shanghai. Risk assessment was conducted with the screened results of the determined pesticides as to evaluate food safety. In 95% of the samples, one or more pesticides had a content below the maximum residue limits (MRLs) as set in the national Chinese standard. The co-occurrence of multi-residues of pesticides was more severe in peach and muskmelon, when compared with other food. All hazard index values of different groups were in the range of 0.19% to 12.3%, demonstrating that chronic dietary risk of studied fruits and raw eaten vegetables is low and the studied food samples were safe for human consumption in terms of these detected pesticides.

Screening 89 Pesticides in Fishery Drugs by Ultrahigh Performance Liquid Chromatography Tandem Quadrupole-Orbitrap Mass Spectrometer.

Multiclass screening of drugs with high resolution mass spectrometry is of great interest due to its high time-efficiency and excellent accuracy. A high-scale, fast screening method for pesticides in fishery drugs was established based on ultrahigh performance liquid chromatography tandem quadrupole-Orbitrap high-resolution mass spectrometer. The target compounds - were diluted in methanol and extracted by ultrasonic treatment, and the extracts were diluted with MeOH-water (1:1, v/v) and centrifuged to remove impurities. The chromatographic separation was performed on an Accucore aQ-MS column (100 mm × 2.1 mm, 2.6 µm) with gradient elution using 0.1% formic acid in water (containing 5 mmol/L ammonium formate) and 0.1% formic acid in methanol (containing 5 mmol/L ammonium formate) in Full Scan/dd-MS2 (TopN) scan mode. A screening database, including mass spectrometric and chromatographic information, was established for identification of compounds. The screening detection limits of methods ranged between 1-500 mg/kg, the recoveries of real samples spiked with the concentration of 10 mg/kg and 100 mg/kg standard mixture ranged from 70% to 110% for more than sixty compounds, and the relative standard deviations (RSDs) were less than 20%. The application of this method showed that target pesticides were screened out in 10 samples out of 21 practical samples, in which the banned pesticide chlorpyrifos were detected in 3 out of the 10 samples.

The associations of work style and physical exercise with the risk of work-related musculoskeletal disorders in nurses.

OBJECTIVES: This study aimed to investigate the prevalence of work-related musculoskeletal disorders (WMSD) in nurses, and to explore the association of work style and physical exercise with WMSD in this professional group. MATERIAL AND METHODS: In this study, a cross-sectional survey design was applied. A questionnaire survey was conducted on 692 nurses in 5 municipal hospitals, in the period August-October 2015. The survey included personal information, lifestyle, physical exercise and symptoms of WMSD. Chi2 test and logistic regression were used to identify the risk factors of WMSD. RESULTS: The prevalence of WMSD was 84% in all parts of the body in the previous year, with the highest prevalence in the neck (68.2%), followed by waist (67.6%) and shoulder (54.6%). Both univariate and multivariate analyses showed that physical exercise, night shifts and staying up late were associated with WMSD in nurses. The lack of exercise, night shifts and a tendency to stay up significantly increased the risk of WMSD (p < 0.05). CONCLUSIONS: The prevalence of musculoskeletal disorders among the municipal hospital nursing staff is high. An elevated risk of WMSD is observed in nurses who do not do exercises, work shifts and stay up late. Int J Occup Med Environ Health. 2019;32(1):15-24.

Chitosan oligosaccharides alleviate PM2.5-induced lung inflammation in rats.

Air pollution of particulate matter (PM), especially PM2.5, has become a major public health problem in China. Exploration of therapeutic and preventive measures against PM2.5 toxicity is of practical significance. The aim of this study was to examine the inhibitory effects of chitosan oligosaccharides (COS) on PM2.5-induced lung inflammation in rats. Forty SPF (specific pathogen-free) male Wistar rats weighing 200-220 g were randomly divided into four groups: control group, COS group, PM2.5 group, and PM2.5+COS group. COS was pre-administered to rats by gavage at a single dose of 500 mg/kg 2 h before intratracheal instillation of PM2.5 at a single dose of 1.2 mg/kg daily for 3 consecutive days. Normal saline (NS) was used as negative control. Twenty-four hours after the last instillation of PM2.5, rats were sacrificed and subjected to bronchoalveolar lavage (BAL). The BAL fluids (BALF) were collected for measurement of levels of total proteins, lactate dehydrogenase (LDH), interleukin-1 (IL-1ß), IL-8, and tumor necrosis factor-ɑ (TNF-ɑ) using colorimetric or ELISA kits. Levels of total proteins, LDH activities, and pro-inflammatory mediators including IL-1ß, IL-8, and TNF-ɑ in BALF of rats in PM2.5 group significantly increased in comparison with those of the control group. Pre-treatment of rats with COS markedly blocked PM2.5-induced increase in LDH, IL-8, and TNF-ɑ levels in BALF. In conclusion, PM2.5 exposure induces rat lung inflammation, which could be ameliorated by the pre-treatment of COS.

General self-efficacy modifies the effect of stress on burnout in nurses with different personality types.

BACKGROUND: Burnout is a health problem in nurses. Individuals with a certain personality are more susceptible to job-related burnout. General self-efficacy (GSE) is an important predictor of job-related burnout. The relationships between general self-efficacy, job-related burnout and different personality types are still not clear. This study aims to analyze the relationships of job-related burnout, stress, general self-efficacy and personality types, as well as their interactions in job-related burnout. METHOD: A cross-sectional survey of 860 nurses was conducted between June and July 2015 in China. We measured their job-related burnout using the scale of the Maslach Occupational Burnout Scale, and personality, stress, and GSE. Machine learning of generalized linear model were performed. RESULTS: Maslach Burnout Inventory (MBI) professional efficacy was significantly associated with gender, marital status, age, job title and length of service. A machine learning algorithm showed that stress was the most important factor in job-related burnout, followed by GSE, personality type (introvert unstable), and job title. Individuals with low GSE and either introversion or unstable (high neuroticism) personality seemed to have stronger burnout when they faced stress (regardless of stress intensity) compared to others. CONCLUSION: Stress, GSE and introvert unstable personality are the top three factors of job-related burnout. GSE moderates the effect of stress on burnout in nurses with extroversion or neuroticism personality. Reducing stress, increasing GSE, and more social support may alleviate job-related burnout in nurses. Nurses with introvert unstable personality should be given more social support in reducing stress and enhancing their GSE.

Comparative analysis of 3D time-resolved contrast-enhanced magnetic resonance angiography, color Doppler ultrasound and digital subtraction angiography in symptomatic carotid stenosis.

The present study aimed to compare the diagnostic value of contrast-enhanced magnetic resonance angiography (CE MRA) with 3D time-resolved imaging of contrast kinetics, color Doppler ultrasound (CDUS) and digital subtraction angiography (DSA) in extracranial carotid stenosis (CS). A total of 54 patients with symptomatic CS were subjected to CDUS, CE MRA and DSA examination. Results of DSA were defined as the standard, and a total of 216 vessels were examined. In each patient four vessels were examined, namely the bilateral common carotid arteries and the bilateral internal carotid arteries. The sensitivities and specificities of CE MRA and CDUS for various degrees of CS were also determined. It was observed that the sensitivities to mild-level (1-49%), moderate-level (50-69%) and severe-level (70-99%) CS were 85.45, 100 and 100% for CE MRA, and 78.18, 50 and 100% for CDUS, respectively. The corresponding specificities were 95.27, 98.58 and 99.53% for CE MRA, and 79.05, 93.36 and 98.10% for CDUS, respectively. In addition, the carotid sinus plaque detection rate for CDUS was significantly higher than that of DSA and CE MRA (both P<0.001). Detection rates for common carotid artery plaques and internal carotid artery plaques did not significantly differ among the three examination methods (all P>0.05). These data demonstrate that CE MRA has higher sensitivity and specificity than CDUS for the diagnosis of CS, and that CDUS has a higher carotid sinus plaque detection rate than DSA and CE MRA. Therefore, the combination of MRI and CDUS may be a 'gold standard' diagnostic method for the detection of moderate and severe CS.

Effects of Negative Emotions and Life Events on Women's Missed Miscarriage.

BACKGROUND: To investigate the effects of negative emotions and life events on women's missed miscarriage. METHODS: Overall, 214 women diagnosed with a missed miscarriage by prenatal examination from 2016-2017 in Xiamen Maternal and Child Health Care Hospital, Xiamen, China were selected as the observation group compared to 214 women as control group. The general data of the patients were investigated by self-programmed questionnaires. Zung Self-Rating Anxiety Scale, Center Epidemiological Studies Depression Scale; Life Events Scale for Pregnant Women were used conduct the study. General data, anxiety, depression and life events were compared between the two groups of patients, and statistically different factors were included in the multivariate Logistic regression analysis. RESULTS: There were statistically significant differences in the educational level, pre-pregnancy health status, planned pregnancy, pre-pregnancy or gestational gynecological inflammation and the initiative to obtain knowledge of prenatal and postnatal care between the two groups of pregnant women (P<0.01); there were also statistically significant differences in score of life events, score of anxiety and score of depression between them (P<0.01). The high educational level, good health status before pregnancy and the initiative to obtain the knowledge of prenatal and postnatal care were taken as the independent protective factors for the missed miscarriage in pregnant women, while life events, anxiety and depression were independent risk factors for it. CONCLUSION: Negative emotions and life events increase the risk of women's missed miscarriage, and the high educational level, good health status before pregnancy and the initiative to obtain the knowledge of prenatal and postnatal care reduce the risk of women's missed miscarriage.

Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages.

People with type 2 diabetes mellitus (T2DM) have a 25-fold higher risk of limb loss than non-diabetics due in large part to impaired wound healing. Here, we show that the impaired wound healing phenotype found in T2D mice is recapitulated in lethally irradiated wild type recipients, whose hematopoiesis is reconstituted with hematopoietic stem cells (HSCs) from T2D mice, indicating an HSC-autonomous mechanism. This impaired wound healing phenotype of T2D mice is due to a Nox-2-dependent increase in HSC oxidant stress that decreases microRNA let-7d-3p, which, in turn, directly upregulates Dnmt1, leading to the hypermethylation of Notch1, PU.1, and Klf4. This HSC-autonomous mechanism reduces the number of wound macrophages and skews their polarization towards M1 macrophages. These findings reveal a novel inflammatory mechanism by which a metabolic disorder induces an epigenetic mechanism in HSCs, which predetermines the gene expression of terminally differentiated inflammatory cells that controls their number and function.

Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice.

Human exposure to the highly reactive oxidant gas Ozone (O3 ) is associated with inflammatory responses in the airway epithelium. The mechanisms responsible have not been fully elucidated. Epidermal growth factor receptor (EGFR) has previously been shown to play a critical role in the pathogenesis of lung inflammation. To define the role of EGFR in O3 -induced lung inflammation in mice. 40 BALB/c mice were exposed to filtered air (FA) or (0.25, 0.5, 1.00 ppm) O3 for 3 h per day for 7 consecutive days. Levels of reactive oxygen species (ROS), EGF, and transforming growth factor α (TGF-α) in the bronchoalveolar lavage fluid (BALF) of mice were measured using ELISA. BALB/c mice were intratracheally instilled with the EGFR kinase inhibitor PD153035 2 h prior to O3 exposure and every other day thereafter. Phosphorylation of EGFR (Y1068) in lung sections was determined using immunohistochemical staining and western blot 24 h after exposure. Inhalation of O3 induced pronounced lung inflammation in a dose-dependent manner. Levels of ROS, TGF-α, and total proteins and cells in the BALF of mice exposed to 0.5 ppm or 1.0 ppm of O3 were markedly elevated relative to those in the BALF of the mice exposed to FA. In addition, exposure to O3 induced EGFR(Y1068) phosphorylation in the airway epithelium. Administration of PD153035 resulted in a significantly reduced lung inflammation as well as EGFR phosphorylation induced by O3 exposure. Inhalation of O3 leads to inflammatory responses that are dependent on the activation the EGFR in the airway epithelium. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 2016-2027, 2016.

Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice.

BACKGROUND: This study tested the hypothesis that type 2 diabetes restricts multipotency of db/db mesenchymal stem cells (MSCs), promotes their terminal differentiation into adipocytes rather than endothelial cells, thereby promotes adipocytic infiltration into ischemic muscles, and reduces their capacity to participate in postischemic neovascularization. METHODS AND RESULTS: To test this hypothesis, we transplanted MSCs from db/db or wild-type (WT) mice into WT recipients after induction of hind limb ischemia. WT recipients of db/db MSCs demonstrated adipocyte infiltration of ischemic muscle and impaired neovascularization; WT recipients of WT MSCs showed no intramuscular adipocyte infiltration and had significantly enhanced neovascularization (P<0.05; n=6). Confocal microscopy showed that the percentage of MSCs that differentiated into an adipocyte phenotype was greater and into an endothelial cell was less in WT recipients transplanted with db/db MSCs than those transplanted with WT MSCs (P<0.05; n=6). In vitro, db/db MSCs exhibited greater oxidant stress, greater adipocyte differentiation, and less endothelial differentiation than WT MSCs, and these differences were reversed by treatment with N-acetylcysteine or Nox4 siRNA (P<0.05; n=6). Insulin increased Nox4 expression, oxidant stress, and adipocyte differentiation in WT MSCs, and these insulin-induced effects were reversed by Nox4 siRNA (P<0.05; n=6). Reversal of db/db MSC oxidant stress by in vivo pretreatment with Nox4 siRNA before transplantation reversed their impaired capacity to augment postischemic neovascularization. CONCLUSIONS: Type 2 diabetes-induced oxidant stress restricts the multipotency of MSCs and impairs their capacity to increase blood flow recovery after the induction of hind-limb ischemia. Reversal of MSC oxidant stress might permit greater leverage of the therapeutic potential of MSC transplantation in the setting of diabetes.

[Situation and assessment of heavy metal pollution in river and mud in one city in Henan Province].

OBJECTIVE: To study the heavy metal contamination status in river water and mud in the suburb of a city in Henan Province. METHODS: Typical sampling method is used to select a farmland irrigation river of the suburb of a city. Use the atomic absorption spectrophotometry, and measure the heavy metal cadmium (Cd), copper (Cu), lead (Pb) in the river water samples and mud samples by graphite furnace method and flame method, respectively. The results of water were compared with GB 3838-2002, Environmental Quality Standards for Surface Water, and GB 5084-2005, Standards for Irrigation Water Quality. The results of mud were compared with national soil background value. The contents of Cu and Cd in the river samples do not exceed the standard, and that of Pb is 3 to 6 times higher than the standard. According to the single factor pollution index method, the single factor pollution indice of Cu, and Cd in the river are less than 0.2 and are of clean level, while that of Pb reaches 6.84, indicating the Pb pollution in river water is severe. Cu in mud is more than 4 times of the soil background value, and that of Cd is more than 69 times of the soil background value, and that of Pb is more than 2 times of the soil background value. The single item pollution index indicates, in mud, the pollution index of Pb is 2.5, medium level pollution. The pollution indice of Cu and Cd in mud are more than 3, is severe pollution, and the Cd pollution is especially heavy, and the single pollution index reaches 67.76. The comprehensive pollution indice of the river and the mud are 5.346 and 84.115, respectively, indicating that both are at heavy pollution level. The main pollution source of the river originates from Pb, and that of the mud is from Cd and it is required to take measure and control as early as possible.

Child skeletal fluorosis from indoor burning of coal in southwestern China.

OBJECTIVES: We assess the prevalence and pathogenic stage of skeletal fluorosis among children and adolescents residing in a severe coal-burning endemic fluorosis area of southwest China. METHODS: We used a cross-sectional design. A total of 1,616 students aged between 7 and 16 years in Zhijin County, Guizhou, China in late 2004 were selected via a cluster sampling of all 9-year compulsory education schools to complete the study questionnaire. Any student lived in a household that burned coal, used an open-burning stove, or baked foodstuffs over a coal stove was deemed high-risk for skeletal fluorosis. About 23% (370) of students (188 boys, 182 girls) were identified as high-risk and further examined by X-ray. RESULTS: One-third of the 370 high-risk participants were diagnosed with skeletal fluorosis. Overall prevalence of child skeletal fluorosis due to indoor burning of coal was 7.5%. Children aged 12-16 years were significantly more likely to be diagnosed with skeletal fluorosis than children aged 7-11 years (OR = 1.84, 95% CI: 1.17-2.90; P = .0082). Four types of skeletal fluorosis were identified: constrictive (60.7%), raritas (15.6%), mixed (16.4%), and soft (7.4%). Most diagnosed cases (91%) were mild or moderate in severity. In addition, about 97% of 370 high-risk children were identified with dental fluorosis. Dental fluorosis was highly correlated with skeletal fluorosis in this study. CONCLUSIONS: Skeletal fluorosis among children may contribute to poor health and reduced productivity when they reach adulthood. Further efforts to reduce fluoride exposure among children in southwestern of China where coal is burned indoors are desperately needed.