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At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

One two-dimensional heteropolyoxoniobate compound H9[Cu(H4dap)2(H2O)]8{K[Cu(H3dap)2]4}2[VNb12O40(VO)4]3[VNb12O40(VO)4(VO)]·48H2O (1) (H4dap = 1,2-diaminopropane) was obtained by a hydrothermal method.

Introduction: Antibody–drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies.Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis.Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses.Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p Conclusion: Antibody–drug conjugates may increase the risk of sepsis in cancer patients, leading to high mortality. Further studies are warranted to characterize the underlying mechanisms and design preventive measures for ADC-related sepsis.

The present study used soils contaminated with Fusarium oxysporum f. sp. capsici (CCS) and CCS amended with bamboo biochar (CCS + BC) to grow the pepper variety Qujiao No.1 . The physiological performance, and transcriptome and metabolome profiling in leaf (L) and fruit (F) of Qujiao No.1 were conducted. Application of biochar improved soil properties, pepper plant nutrition and increased activities of enzymes related to pest/disease resistance, leading to superior physiological performance and lesser F. wilt disease incidence than plants from CCS. Most of the differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were involved in protein processing in endoplasmic reticulum (fruit), plant pathogen interaction (fruit), photosynthesis (leaf), phenylpropanoid biosynthesis (both tissues) and metabolic pathways (both tissues). Biochar improved plant photosynthesis, enhanced the immune system, energy production and increased stress signaling pathways . Overall, our results provide evidence of a number of pathways induced by biochar in pepper regulating its response to F. wilt disease.

Medicinal plants are complex chemical systems containing thousands of secondary metabolites. The rapid classification and characterization of the components in medicinal plants using mass spectrometry (MS) remains an immense challenge. Herein, a novel strategy is presented for MS through the combination of solid-phase extraction (SPE), multiple mass defect filtering (MMDF) and molecular networking (MN). This strategy enables efficient classification and annotation of natural products. When combined with SPE and MMDF, the improved analytical method of MN can perform the rapid annotation of diverse natural products in Citrus aurantium according to the tandem mass spectrometry (MS/MS) fragments. In MN, MS2LDA can be initially applied to recognize substructures of natural products, according to the common fragmentation patterns and neutral losses in multiple MS/MS spectra. MolNetEnhancer was adopted here to obtain chemical classifications provided by ClassyFire. The results suggest that the integrated SPE-MMDF-MN method was capable of rapidly annotating a greater number of natural products from Citrus aurantium than the classical MN strategy alone. Moreover, SPE and MMDF enhanced the effectiveness of MN for annotating, classifying and distinguishing different types of natural products. Our workflow provides the foundation for the automated, high-throughput structural classification and annotation of secondary metabolites with various chemical structures. The developed approach can be widely applied in the analysis of constituents in natural products.

Four novel three-dimensional interpenetrating frameworks based on {P4Mo6} units, H[C12H14N2]4[TM4(PO4)(H2O)4Na6][TM2(Mo6O12(HPO4)3(PO4)(OH)3)4]·8H2O (1, 2) and H[C14H18N2]4[TM4(PO4)(H2O)4Na6][TM2(M...

Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

Elemicin, an alkenylbenzene constituent of natural oils of several plant species, is widely distributed in food, dietary supplements, and medicinal plants. 1′-Hydroxylation is known to cause metabolic activation of alkenylbenzenes leading to their potential toxicity. The aim of this study was to explore the relationship between elemicin metabolism and its toxicity through comparing the metabolic maps between elemicin and 1′-hydroxyelemicin. Elemicin was transformed into a reactive metabolite of 1′-hydroxyelemicin, which was subsequently conjugated with cysteine (Cys) and N-acetylcysteine (NAC). Administration of NAC could significantly ameliorate the elemicin- and 1′-hydroxyelemicin-induced cytotoxicity of HepG2 cells, while depletion of Cys with diethyl maleate (DEM) increased cytotoxicity. Recombinant human CYP screening and CYP inhibition experiments revealed that multiple CYPs, notably CYP1A1, CYP1A2, and CYP3A4, were responsible for the metabolic activation of elemicin. This study revealed that metabolic activation plays a critical role in elemicin cytotoxicity.

Jiaqin Liu,1,2 Jian Liu,1,2 Xiaoliang Tong,3 Weijun Peng,4 Shanshan Wei,1,2 Taoli Sun,5 Yikun Wang,1,2 Bikui Zhang,1,2 Wenqun Li1,2 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 4Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 5School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of ChinaCorrespondence: Wenqun LiDepartment of Pharmacy, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, People’s Republic of ChinaTel +86-731-85292093Email liwq1204@csu.edu.cnBackground: Huai Hua San (HHS), a famous Traditional Chinese Medicine (TCM) formula, has been widely applied in treating ulcerative colitis (UC). However, the interaction of bioactives from HHS with the targets involved in UC has not been elucidated yet.Aim: A network pharmacology-based approach combined with molecular docking and in vitro validation was performed to determine the bioactives, key targets, and potential pharmacological mechanism of HHS against UC.Materials and Methods: Bioactives and potential targets of HHS, as well as UC-related targets, were retrieved from public databases. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis, including protein–protein interaction (PPI), as well as the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, molecular docking was carried out to predict the combination of active compounds with core targets. Lastly, in vitro experiments were conducted to further verify the findings.Results: A total of 28 bioactive ingredients of HHS and 421 HHS-UC-related targets were screened. Bioinformatics analysis revealed that quercetin, luteolin, and nobiletin may be potential candidate agents. JUN, TP53, and ESR1 could become potential therapeutic targets. PI3K-AKT signaling pathway might play an important role in HHS against UC. Moreover, molecular docking suggested that quercetin, luteolin, and nobiletin combined well with JUN, TP53, and ESR1, respectively. Cell experiments showed that the most important ingredient of HHS, quercetin, could inhibit the levels of inflammatory factors and phosphorylated c-Jun, as well as PI3K-Akt signaling pathway in LPS-induced RAW264.7 cells, which further confirmed the prediction by network pharmacology strategy and molecular docking.Conclusion: Our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HHS against UC. It also provided a promising strategy to uncover the scientific basis and therapeutic mechanism of TCM formulae in treating diseases.Keywords: Huai Hua San, ulcerative colitis, network pharmacology, quercetin, JUN, PI3K/AKT signal pathway

Fructus Aurantii is a traditional medicated diet in East Asia. To determine the underlying chemical markers responsible for the quality and efficacy of Fructus Aurantii, a sensitive metabolomic method was applied to distinguish Fructus Aurantii in Jiangxi Province from other two geographical locations (Hunan Province and Chongqi City) in China. In the present study, multivariate analyses were adopted to compare chemical compositions in 21 batches of Fructus Aurantii samples. Among three geographical origins, 23 differential compounds were structurally identified. Serum pharmacochemistry exhibited that 22 components could be detected in rat serum. Six differential and absorbed components were selected as six potential markers. Statistical analysis of the effects of six potential markers on the quality of Fructus Aurantii revealed that the content of markers varied widely in three origins. Six differential and absorbed components were evaluated further biological activity. Neohesperidin, naringin and meranzin showed inhibitory effect on acetylcholinesterase that regulates gastrointestinal motility in vitro and in silico, suggesting that these three components may be determined as the active biomarkers of Fructus Aurantii. These findings demonstrate the potential of biomarkers for identification and quality control of Fructus Aurantii. This article is protected by copyright. All rights reserved.

Four novel three-dimensional interpenetrating frameworks based on {P

Medicinal plants are complex chemical systems containing thousands of secondary metabolites. The rapid classification and characterization of the components in medicinal plants using mass spectrometry (MS) remains an immense challenge. Herein, a novel strategy is presented for MS through the combination of solid-phase extraction (SPE), multiple mass defect filtering (MMDF) and molecular networking (MN). This strategy enables efficient classification and annotation of natural products. When combined with SPE and MMDF, the improved analytical method of MN can perform the rapid annotation of diverse natural products in Citrus aurantium according to the tandem mass spectrometry (MS/MS) fragments. In MN, MS2LDA can be initially applied to recognize substructures of natural products, according to the common fragmentation patterns and neutral losses in multiple MS/MS spectra. MolNetEnhancer was adopted here to obtain chemical classifications provided by ClassyFire. The results suggest that the integrated SPE-MMDF-MN method was capable of rapidly annotating a greater number of natural products from Citrus aurantium than the classical MN strategy alone. Moreover, SPE and MMDF enhanced the effectiveness of MN for annotating, classifying and distinguishing different types of natural products. Our workflow provides the foundation for the automated, high-throughput structural classification and annotation of secondary metabolites with various chemical structures. The developed approach can be widely applied in the analysis of constituents in natural products.

Coumarins have aroused high interests due to their diverse bioactivities. Understanding of its metabolism contributes to determine the druggability of coumarin in vivo.A sensitive and efficient strategy based on ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) analysis combined with various data-processing techniques including metabolomics and multiple mass defect filter (MMDF) was established for the comprehensive screening and elucidation of potential coumarin metabolites.Total 20 metabolites of scoparone were identified in this study, including 14 undescribed metabolites. The metabolism of two other similar coumarins scopoletin and esculetin also could be determined using this strategy.By the established strategy, this study gives the insights about the major metabolic pathways of scoparone in vivo and in vitro metabolism, including demethylation, hydroxylation, hydration, cysteine conjugation, glucuronide conjugation and sulfate conjugation. Additionally, the metabolic pathways of scopoletin and esculetin were determined as hydroxylation, glucuronidation and sulfation. These results contribute to the understanding of metabolic characterization of coumarins, and demonstrate that the combination of UPLC-MS-based metabolomics and MMDF is a powerful approach to determine the metabolic pathways of coumarin compounds. Coumarins have aroused high interests due to their diverse bioactivities. Understanding of its metabolism contributes to determine the druggability of coumarin in vivo. A sensitive and efficient strategy based on ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) analysis combined with various data-processing techniques including metabolomics and multiple mass defect filter (MMDF) was established for the comprehensive screening and elucidation of potential coumarin metabolites. Total 20 metabolites of scoparone were identified in this study, including 14 undescribed metabolites. The metabolism of two other similar coumarins scopoletin and esculetin also could be determined using this strategy. By the established strategy, this study gives the insights about the major metabolic pathways of scoparone in vivo and in vitro metabolism, including demethylation, hydroxylation, hydration, cysteine conjugation, glucuronide conjugation and sulfate conjugation. Additionally, the metabolic pathways of scopoletin and esculetin were determined as hydroxylation, glucuronidation and sulfation. These results contribute to the understanding of metabolic characterization of coumarins, and demonstrate that the combination of UPLC-MS-based metabolomics and MMDF is a powerful approach to determine the metabolic pathways of coumarin compounds.

1. To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. 2. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. 3. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. 4. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.

A method for rapid on-site determination of cadmium in crayfish by dilute acid extraction and anodic stripping voltammetry (ASV) was established. It was determined to use 3% hydrochloric acid as the extraction solution, 20 min as extraction time, 10% sodium diacetate as the basic solution in performing the anodic stripping voltammetry analysis. In the interval of (0.005–1.0) mg kg−1, the content of cadmium in crayfish had a good linear relationship with the peak current. The method was applied to the crayfish reference material. The limit of detection was 0.005 mg kg−1. The repeatability was 3.8%. The results had no significant difference between ASV and ICP-MS (Inductively Coupled Plasma - Mass Spectrometry) method with T-test statistical method. This method is simple, rapid and sensitive. It has been carried on-site to detect real crawfish sample in food rapid detection vehicle.

Raspberry, the fruit of Rubus Chingii Hu, has been used as a traditional Chinese medicine (TCM) to nourish kidney and strengthen Yang-qi. In order to determine the quality of raspberry, the quality markers (Q-markers) of raspberry that can improve renal function were investigated using UPLC-ESI-QTOF-MS in this study. The results of serum pharmacochemistry indicated that six components rutin, ellagic acid, kaempferol-3-rutinoside, astragalin, tiliroside, and goshonoside F5 in raspberry were absorbed into rat blood. The HEK293 cells treated with cisplatin were used to evaluate the kidney-protecting activity of these absorbed components. All these components could markedly inhibit cell damage induced by cisplatin and restore the levels of malondialdehyde (MDA) and catalase (CAT) in the cells, suggesting that these components may be the Q-markers of raspberry. More importantly, except for ellagic acid, other five Q-markers in raspberries from Dexing of Jiangxi province were higher than those from most of other areas. It is well known that Dexing raspberry is the Dao-di herbs raspberry used in the clinic of Chinese Medicine, demonstrating that these components could be used as Q-markers of raspberry. This study provides a reliable and valuable method for quality evaluation of raspberry.

Three new neolignans, lycocernuasides B-D (1–3), three new serratane triterpenoids, lycernuic ketones D (8) and E (9), and lycernuic A (10), together with six known compounds, were isolated from the 75% aqueous EtOH extract of Palhinhaea cernua. Their structures and absolute configurations were established primarily by NMR, HRESIMS and circular dichroism (CD). All compounds were evaluated the inhibitory activities of xanthine oxidase. Compounds 1–3 displayed moderate inhibitory effects on xanthine oxidase with IC50 values of 30.36 μM, 42.65 μM and 35.33 μM, respectively.

A new biflavone glycoside juglbiflavone A ( 1 ) along with two new lupane-type triterpenes ( 2-3 ) were identified from the roots of Juglans mandshurica Maxim. Their structures and absolute configurations were elucidated by extensive spectroscopic methods including 1D/2D NMR, HRESIMS and CD. Compound 1 is the first example of biflavone glycoside consisted of a flavanol unit and a flavone unit from this genus, which also exhibited moderate cytotoxic activity against SGC-7901 and A549 cell lines in vitro with IC 50 values of 10.08 ± 0.52 μM and 12.44 ± 1.21 μM, respectively.

The mass spectrometry-based metabolomics method was used to systematically investigate the formation of celastrol metabolites,and the effect of celastrol on endogenous metabolites. The mice plasma,urine and feces samples were collected after oral administration of celastrol. Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry( UPLC-QTOF-MS) was applied to analyze the exogenous metabolites of celastrol and its altered endogenous metabolites. Mass defect filtering was adopted to screen for the exogenous metabolites of celastrol. Multivariate statistical analysis was used to identify the endogenous metabolites affected by celastrol. Celastrol and its eight metabolites were detected in urine and feces of mice,and 5 metabolites of them were reported for the first time. The hydroxylated metabolites were observed in the metabolism of both human liver microsomes and mouse liver microsomes. Further recombinant enzyme experiments revealed CYP3 A4 was the major metabolic enzyme involved in the formation of hydroxylated metabolites. Urinary metabolomics revealed that celastrol can affect the excretion of intestinal bacteria-related endogenous metabolites,including hippuric acid,phenylacetylglycine,5-hydroxyindoleacetic acid,urocanic acid,cinnamoylglycine,phenylproplonylglycine and xanthurenic acid. These results are helpful to elucidate the metabolism and disposition of celastrol in vivo,and its mechanism of action.

Elemicin is a constituent of natural aromatic phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

An iodine-mediated one-pot reaction of N-alkyl piperazines is described for the first time. This transformation provides a straightforward and facile pathway to the synthesis of 2-(piperazin-1-yl)pyrazine derivatives with the corresponding N-alkyl piperazines as single material. Based on a series of control experiments, a plausible reaction mechanism has been proposed.

In this work, self-crosslinked sulfonated polyether etherketone membrane (C-SPEEK) was synthesized by Friedel-Crafts alkylation at 130 °C with chloromethylated sulfonated polyether etherketone (SPEEK-Cl). The water uptake (WU) of the C-SPEEK was 47.75% with a 8.69% swelling rate (SR) at 60 °C, compared with the sulfonated polyether etherketone membrane (SPEEK) with WU of 110.60% and SR of 57.99%. The contradiction between dimensional stability and proton conductivity under high sulfonation degree was overcome. The self-crosslinking composite membranes were prepared by doping with carbon nanomaterials (Graphite oxide, GO; reduced graphene oxide, rGO and carbon nanotubes, CNTs) and phosphotungstic acid (HPW). Since HPW and carbon nanomaterials incorporated in membrane facilitate protons conduction via both Grotthuss and Vehicle mechanisms, the hybrid membranes demonstrated the improved conductivities. At 80 °C, C-SPEEK/HPW/GO showed proton conductivity as high as 119.04 mS/cm, which was 2.4 folds higher than that of the C-SPEEK. Furthermore, the superior performance of C-SPEEK/HPW/GO was further validated through H2/O2 single cell test. The C-SPEEK/HPW/GO produced a higher power output of 876.80 mW/cm2, whereas only 776.72 mW/cm2 for C-SPEEK was recorded. Thus, C-SPEEK/HPW/GO and C-SPEEK may be promising membrane materials for potential applications in fuel cells.

A new molybdenum(V) cobalt phosphate, [Co(H2O)6]{[Co(H2O)5]2Co2[(Mo16O32)CO16(HPO4)14(PO4)10(H2O)15]}·38H2O (1), has been prepared under hydrothermal condition, which displays a nonplanar two-dimensional inorganic framework constructed from [(Mo16O32)Co16(HPO4)14(PO4)10(H2O)15]10− wheel clusters and tetrahedral CoO4 linkers. Each wheel forms by the linking of {Co4O16} tetramers and {Mo4O19} tetramers through {PO4} groups in turn, and concurrently has two pendant Co(H2O)5 groups. The susceptibility analysis shows that the d1 electrons in the MoV dimers are spin-paired and the dominant antiferromagnetic behavior is originated from the 21 high-spin CoII ions in 1.

Due to the urgent need for noninvasive detection of skin cholesterol, a portable, intelligent and real-time skin diffuse reflectance spectroscopy measurement system was designed based on a micro-spectrometer. Digitonin-horseradish peroxidase copolymer solution was prepared. According to the properties digitonin binds to the hydroxy of cholesterol molecular specifically and the horseradish peroxidase reacts with TMB color solution (the main component is 3,3’,5,5’-tetramethylbenzidine ) a color change was produced, by which the skin cholesterol was identified and instructed with high sensitivity and high specificity, and the concentration of skin cholesterol was quantified by measuring the degree of color change. In order to validate the feasibility of this method, pig skin which is similar to human skin was taken as the experimental subject, and cholesterol samples of gradient concentration were achieved through the extraction. After that the spectroscopy measurement system was adopted to detect the cholesterol concentration. The experiment result showed that, relative diffuse reflectance can distinguish the cholesterol samples with different concentrations, and the diffuse reflectance intensity factor can quantity the concentrations of cholesterol at characteristic wavelengths (442, 450 and 463 nm) and characteristic wavelength band of 442~500 nm. Linear fitting curves were obtained with the determination coefficient R2 were 0.960, 0.959, 0.958 and 0.958, respectively. The study has shown that, using diffuse reflectance spectroscopy technology can realize noninvasive rapid detection of skin cholesterol, and applying it to the risk assessment of atherosclerotic diseases would contribute to the prevention and control of such diseases significantly.

Tissue intrinsic fluorescence spectrum refers to the fluorescence that is not impaired by tissue absorption and scattering which has the ability to reflect tissue biochemical properties. In order to reduce the influence of tissue absorption and scattering properties on tissue fluorescence spectrum, and then recover tissue intrinsic fluorescence spectrum, a tissue spectrum detection system based on fiber-optic probe was developed for the measurement of tissue fluorescence spectrum and diffusion reflectance spectrum at the same place. On the other hand, diffusion theory was introduced to extract the tissue physiological parameters from the measurement tissue diffusion reflectance spectrum, which included blood volume fraction, oxyhemoglobin saturation, melanin content, reduce scattering coefficient at 500 nm and the ratio of rayleigh scattering and the total scattering. Then tissue optical parameters in visible wavelengths were calculated. According to the tissue optical parameters and measured tissue diffusion spectrum, the intrinsic fluorescence spectrum was recovered from the measured fluorescence. Based on this, clinical trials were conducted to measure human skin fluorescence spectrum and diffusion reflectance spectrum, and then to recover skin intrinsic fluorescence spectrum. Finally, the accumulation of Advanced Glycation End products (AGE) in human skin was evaluated and the probability of diabetes mellitus was predicted. The result shows that the sensitivity and specificity were 69% and 0.75% respectively, when the measured fluorescent was used to screening diabetes mellitus. At the same specificity, the sensitivity was 90% when the recovered intrinsic fluorescence was employed to screening diabetes mellitus.

Soil infiltration, soil physical and chemical properties, root length density and soil fauna diversity were studied in Phyllostachys heterocycla forests with different mulching times in southwest Zhejiang Province, China. Significant differences of soil infiltration capability were found among the forests with different mulching times and among soil layers. Soil infiltration capability generally declined in the deeper soil layers. With mulching management, soil infiltration capability increased under the first mulching, and then declined with the increase of mulching times. The Kostiakov model was suitable for simulating soil infiltration process. With the extending of mulching times (4 to 6 years), soil pH and total/non-capillary porosity decreased, while soil bulk density, soil orga-nic matter and total nitrogen contents increased significantly. Soil initial, steady, and average infiltration rates as well as the cumulative infiltration amount correlated closely with the length density of roots with diameter from 0.5 mm to 5.0 mm, showing a decreasing tendency with the decrease in root length density. Soil fauna density was highest in the forest under the first mulching, and was lowest after third mulching. The decreased numbers of large and meso-arthropods, including Symphyla, Chilopoda, Diplopoda, Hymenoptera and pseudoscorpions, and the micro-arthropods, including Oribatida, Mesostigmata, Onychiuridae, Neanuridae, Cyphoderidae, and Entomobryidae, showed negative effects on soil infiltration. In conclusion, long-term mulching changed soil physical and chemical properties, decreased soil infiltration capability, and suppressed the development of soil fauna, which might cause the decline ofP. heterocycla forests.对浙西南山区4种不同覆盖年限下毛竹林地的土壤入渗、土壤理化性质、土壤根系和土壤动物特征进行了研究.结果表明:不同覆盖年限林地及同一林地不同土壤层次下土壤渗透性能存在较大差异,随着土层加深各林地土壤渗透性能均降低.渗透性能表现为覆盖1次林地＞未覆盖林地＞覆盖2次和3次后的林地.Kostiakov模型适合该研究区域的土壤水分入渗过程模拟.随着林地覆盖年限的增加(4～6年),林地土壤总孔隙度、非毛管孔隙度、pH值显著降低,而土壤容重、有机质和全N含量则显著提高.土壤初渗率、稳渗率、平均渗透率和渗透总量等均随根长密度减少而变小,土壤入渗能力的变化与直径0.5～5.0 mm的根长密度有关.不同覆盖年限毛竹林地土壤动物的平均密度差异显著,覆盖1次的林地最高,而覆盖3次的林地最低.综合纲、唇足纲、倍足纲、膜翅目、伪蝎目等大中型节肢动物,蜱螨目甲螨亚目、中气门亚目,以及弹尾目棘跳科、长角跳科、疣跳科、驼跳科等小型节肢动物数量的减少不利于土壤水分入渗.毛竹林长期覆盖会使土壤理化性状劣变,减弱土壤入渗性能,限制土壤动物活动,进而导致毛竹林退化.

A new cyclic diarylheptanoid (1) and a new flavone glucoside (2), along with seven known compounds, were isolated from the green peel of Juglans mandshurica. Their structures were elucidated based on extensive spectroscopic analyses. Moreover, the cytotoxicity against NCI-H460, A549, and K562 cancer cells of compounds 1-6 was evaluated. The results showed that compound 3 exhibited moderate inhibitory potency against the growth of three cell lines.

Nintedanib is a promising tyrosine kinase inhibitor for clinically treating idiopathic pulmonary fibrosis (IPF). Some clinical cases reported that nintedanib treatment can cause hepatotoxicity and myocardial toxicity. U. S. FDA warns the potential drug-drug interaction when it is co-administrated with other drugs. In order to understand the potential toxicity of nintedanib and avoid drug-drug interaction, the metabolism of nintedanib was systematically investigated in human liver microsomes and mice using metabolomics approach, and the toxicity of metabolites was predicted by ADMET lab. Nineteen metabolites were detected in vivo and in vitro metabolism, and 8 of them were undescribed. Calculated partition coefficients (Clog P) were used to distinguish the isomers of nintedanib metabolites in this study. The major metabolic pathways of nintedanib majorly included hydroxylation, demethylation, glucuronidation, and acetylation reactions. The ADMET prediction indicated that nintedanib was a substrate of the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). And nintedanib and most of its metabolites might possess potential hepatotoxicity and cardiotoxicity. This study provided a global view of nintedanib metabolism, which could be used to understand the mechanism of adverse effects related to nintedanib and its potential drug-drug interaction.

The article analyses the livable environment construction of Shenyang Tiexi old industrial relocation zone. By investigating the conditions of the livable environment construction it sums up the experiences and problems in the process of the construction of the livable environment of Shenyang Tiexi District, and then it puts forward the development strategy of the livable environment construction, which aims at realizing the target of the livable environment construction of the old industrial relocation zone.

Advanced glycation end products (AGEs) are highly associated with hyperglycemia in human skin tissue, and they also have the autofluorescence characteristic. A self-developed optical noninvasive detection device was used to measure the autofluorescence in human skin tissue, and then a neural network pattern recognition model was used to assess the risk of diabetes mellitus of the subject under survey. After the fluorescence spectra were acquired and processed with principal component analysis, four of the leading principal components were chosen to represent a whole spectrum. The established neural network pattern recognition model has 4 input nodes, 6 hidden nodes and 1 output node. A dataset consisting of 487 cases collected in Anhui Provincial Hospital was used to train the model. Seventy percent cases were used as the training set, 15% as the validation set and 15% as the test set. The model can output subject's risk of diabetes mellitus, or a dichotomous judgment. Receiver operating characteristic curve can be drawn with the area under curve of 0. 81, with standard error of 0. 02. When using 0. 5 as the threshold between diabetes mellitus and non-diabetes mellitus, the sensitivity and specificity of this model is 72. 4% and 77. 6% respectively, and the overall accuracy is 74. 9%. The method using human skin autofluorescence spectrum combined with neural network pattern recognition model is proposed for the first time, and the results show that this method has a better screening effect compared with currently used fasting plasma glucose and HbAlc.

A pot experiment was conducted to study the effects of adding different amounts of wheat straw (0 g x kg(-1), N0; 2.08 g x kg(-1), N1) and phosphorus (0 mg x kg(-1), P0; 100 mg x kg(-1), P1; 200 mg x kg(-1), P2; 400 mg x kg(-1), P3) on microorganism community in a soil of low-phosphorus. Adding straw and phosphorus had significant effects on the soil microbial total biomass (MTB), bacterial biomass (MB), fungal biomass (FB), and fungi to bacteria ratio (F/B), which all decreased in order of N1P1N1P0N1P2N1P3N0P1N0P2N0P3. MTB, MB, FB and F/B ratio of the wheat straw addition treatments were all significantly higher than in the non-straw addition treatments under the same level of phosphorus addition. As for the same wheat straw addition, MTB, MB, FB and F/B ratio increased firstly and then decreased with increasing the level of phosphorus addition, and the combinations of P1 level were optimal.

To detect the expression of prostate cancer antigen-1 (PCA-1) in prostate cancer, and to analyze the effects of downregulation of PCA-1 expression on malignant biological behavior of prostate cancer LNCaP cells, and to explore their possible molecular mechanisms.PCA-1-siRNA and control siRNA were transfected into LNCaP cells with lipofectamine 2000. The cell cycle, proliferation and migration were determined by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and Transwell chambers, respectively. Western blotting was used to detect the expression of cyclin E, matrix metallopeptidase 9 (MMP-9) and p21. Immunohistochemistry was used to detect the expression of PCA-1 protein in 126 cases of prostate cancer and 88 cases of benign prostatic hyperplasia (BPH).The positive rate of PCA-1 expression was 77.8% (98/126) in prostate cancer, and 10.2% (9/88) in BPH, and its expression was not significantly related to age, prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) score (P0.05), and was associated with Gleason score, TNM staging and bone metastasis (P0.05). Downregulation of PCA-1 expression inhibited cell proliferation, arrested cell cycle at S phase and decreased cell migration of LNCaP cells. The downregulation of PCA-1 expression decreased the expression of Bcl-xl, cyclin E and MMP-9 proteins, but increased the expression of p21 proteins.PCA-1 may play an important role in the development of prostate cancer. The downregulation of PCA-1 expression can lead to changes in the proliferation, cell cycle and migration of prostate cancer LNCaP cells, and these effects may be associated with the decrease of Bcl-xl, cyclin E and MMP-9 proteins and increase of p21 protein.

Based on the field survey and laboratory analysis, this paper studied the soil aggregate stability and soil organic carbon characteristics in Quercus variabilis and Pinus tabulaeformis plantations in Beijing area. In the two plantations, the contents of soil macro-aggregates decreased with soil depth. In P. tabulaeformis plantation, soil macro-aggregates (0.25 mm) occupied the majority, accounting for 71% -77% of the total; whereas in Q. variabilis plantation, no significant difference was observed in the contents of soil macro-aggregates and micro-aggregates (or =0.25 mm), which accounted for 51% -58% and 42% -49%, respectively. Both the mean mass diameter and the geometrical mean mass diameter of the soil aggregates in P. tabulaeformis plantation were significantly higher than those in Q. variabilis plantation, and the fractal dimension (D) of the soil water-stable aggregates in P. tabulaeformis plantation was lower than that in Q. variabilis plantation, suggesting that P. tabulaeformis plantation was more favorable for the soil aggregate stability than Q. variabilis plantation. Also in the two plantations, the organic carbon content in soil water-stable aggregates decreased with soil depth. The organic carbon content in soil macro-aggregates was significantly higher in P. tabulaeformis plantation (58% -83%) than in Q. variabilis plantation (49% -66% ). It was suggested that in Beijing area, P. tabulaeformis plantation was more beneficial to the soil organic carbon protection, as compared with Q. variabilis plantation.

The necessity to measure advanced glycation endproducts (AGE) was analyzed in the present paper, and the apparatus for measuring skin autofluorescence was also designed making use of the special excitation spectrum and emission spectrum. A portion of tissue at the volar side of the arm of individuals (11 diabetes and 19 control subjects) was illuminated with excitation light, i.e., monochromatic light around 370 nm, and the emission spectrum was detected on the skin of control subjects and diabetic patients respectively. All measurements were performed at room temperature in a semi-dark environment. It can be seen that different sites of an individual could lead to different results, and the color can also affect the results. The technology of fluorescence precorrection was applied in order to get rid of the influence of noise, different site of skin, the color of skin etc. The result indicates that the technology of precorrection is of avail and the repetitiveness is well.