Publications by authors named "Zeyun Li"

21 Publications

  • Page 1 of 1

Comprehensive TCM treatments combined with chemotherapy for advanced non-small cell lung cancer: A randomized, controlled trial.

Medicine (Baltimore) 2021 May;100(18):e25690

Oncology Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine.

Objective: We conducted this study to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in advanced non-small cell lung cancer (NSCLC) patients who underwent chemotherapy.

Design: This was a prospective, open-label, randomized controlled trial. NSCLC patients at stage IIIA, IIIB, or IV were randomly assigned to either TCM plus chemotherapy or chemotherapy alone. The comprehensive TCM treatment consisted of Kang Ai injection, herbal decoction, and Zhenqifuzheng capsules. The primary endpoint was quality of life (QOL) measured by the Functional Assessment of Cancer Therapy-Lung version 4.0. The secondary endpoints were chemotherapy completion rate, tumor response, and adverse events. All assessments were done at baseline, the third week, and the sixth week.

Results: Thirty-nine participants were randomly assigned to the treatment group and 36 to the control group. The QOL scores were significantly improved in the treatment group compared with those of the control group in social well-being (cycle 1, P = .048; cycle 2, P = .015), emotional well-being (cycle 1, P = .047; cycle 2, P = 4.29E-05), and functional well-being (cycle 1, P = .030; cycle 2, P = .003), while the QOL scores in the above 3 domains declined in the control group (P < .05). Both groups had a decline in the physical well-being score (cycle 1, P = .042; cycle 2, P = .017) and lung cancer symptom score (cycle 1, P = .001; cycle 2, P = .001) after 2 courses of intervention. The deterioration in physical well-being and lung cancer symptoms was noticeably smaller in the treatment group (P < .05). There were significant differences between the 2 groups in social well-being, emotional well-being, functional well-being, lung cancer symptom domain, and the total score (P < .05). Patients in the treatment group had a significantly lower incidence of platelet reduction than the control group (P = .028) after 2 cycles of treatment. No significant difference in nonhematological adverse events (AEs) was observed.

Conclusion: This study illustrated that comprehensive TCM treatment could promote the QOL of NSCLC patients, alleviate symptoms, and reduce the AEs caused by chemotherapy, verifying the synergistic and attenuating effects of TCM in NSCLC patients undergoing chemotherapy.

Trial Registration: Chinese Clinical Trial Registry (www.chictr.org.cn): ChiCTR-TRC-13003637.
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http://dx.doi.org/10.1097/MD.0000000000025690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104195PMC
May 2021

Network pharmacology based research into the effect and mechanism of Yinchenhao Decoction against Cholangiocarcinoma.

Chin Med 2021 Jan 21;16(1):13. Epub 2021 Jan 21.

Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Jichang Road, Baiyun District, 510405, Guangzhou, China.

Background: Cholangiocarcinoma refers to an epithelial cell malignancy with poor prognosis. Yinchenhao decoction (YCHD) showed positive effects on cancers, and associations between YCHD and cholangiocarcinoma remain unclear. This study aimed to screen out the effective active components of Yinchenhao decoction (YCHD) using network pharmacology, estimate their potential targets, screen out the pathways, as well as delve into the potential mechanisms on treating cholangiocarcinoma.

Methods: By the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) as well as literature review, the major active components and their corresponding targets were estimated and screened out. Using the software Cytoscape 3.6.0, a visual network was established using the active components of YCHD and the targets of cholangiocarcinoma. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the targets enrichment were performed. The AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The PyMOL software was utilized to visualize the docking results of active compounds and protein targets. In vivo experiment, the IC values and apoptosis rate in PI-A cells were detected using CCK-8 kit and Cell Cycle Detection Kit. The predicted targets were verified by the real-time PCR and western blot methods.

Results: 32 effective active components with anti-tumor effects of YCHD were sifted in total, covering 209 targets, 96 of which were associated with cancer. Quercetin, kaempferol, beta-sitosterol, isorhamnetin, and stigmasterol were identified as the vital active compounds, and AKT1, IL6, MAPK1, TP53 as well as VEGFA were considered as the major targets. The molecular docking revealed that these active compounds and targets showed good binding interactions. These 96 putative targets exerted therapeutic effects on cancer by regulating signaling pathways (e.g., hepatitis B, the MAPK signaling pathway, the PI3K-Akt signaling pathway, and MicroRNAs in cancer). Our in vivo experimental results confirmed that YCHD showed therapeutic effects on cholangiocarcinoma by decreasing IC values, down-regulating apoptosis rate of cholangiocarcinoma cells, and lowering protein expressions.

Conclusions: As predicted by network pharmacology strategy and validated by the experimental results, YCHD exerts anti-tumor effectsthrough multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of cholangiocarcinoma.
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http://dx.doi.org/10.1186/s13020-021-00423-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818939PMC
January 2021

Quantitative H nuclear magnetic resonance (qHNMR) methods for accurate purity determination of glucosinolates isolated from Isatis indigotica roots.

Phytochem Anal 2021 Jan 30;32(1):104-111. Epub 2020 Oct 30.

Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai, China.

Introduction: Glucosinolates (1-5) are important secondary metabolites found in Isatis indigotica roots. Due to their high hydrophilic and ionic nature, purified glucosinolates often contain salt impurities and moisture. Accurate assessment of their purities is important for glucosinolates being utilised as chemical markers.

Objective: To develop and validate quantitative proton ( H) nuclear magnetic resonance (qHNMR) methods for purity assessments of aliphatic and indole glucosinolates (1-5).

Method: Several NMR parameters such as pulse program, relaxation time, and delay time were optimised. Three qHNMR methods were developed using gluconapin (3), neoglucobrassicin (4), and sinigrin (5) for method validation and with maleic acid as internal standard.

Results: The quantification was based on the integrated area ratios of an olefinic proton (H-4 for 1-3; H-6 for 4; and H-3 for 5) of the side chain from glucosinolates relative to the olefinic proton from the internal standard using deuterated water (D O) as the solvent. The qHNMR methods were successfully applied for purity assessments of four aliphatic glucosinolates (1-3 and 5: progoitrin, epiprogoitrin, gluconapin, and sinigrin), and an indole glucosinolate (4: neoglucobrassicin).

Conclusion: The purity of glucosinolates isolated from I. indigotica and commercial sinigrin was accurately assessed using the developed qHNMR method. The qHNMR provides a reliable and superior means to determine the purity of glucosinolates.
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http://dx.doi.org/10.1002/pca.3003DOI Listing
January 2021

A comprehensive analysis of metabolomics and transcriptomics in non-small cell lung cancer.

PLoS One 2020 6;15(5):e0232272. Epub 2020 May 6.

Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, china.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer death globally. More accurate and reliable diagnostic methods/biomarkers are urgently needed. Joint application of metabolomics and transcriptomics technologies possesses the high efficiency of identifying key metabolic pathways and functional genes in lung cancer patients. In this study, we performed an untargeted metabolomics analysis of 142 NSCLC patients and 159 healthy controls; 35 identified metabolites were significantly different between NSCLC patients and healthy controls, of which 6 metabolites (hypoxanthine, inosine, L-tryptophan, indoleacrylic acid, acyl-carnitine C10:1, and lysoPC(18:2)) were chosen as combinational potential biomarkers for NSCLC. The area under the curve (AUC) value, sensitivity (SE), and specificity (SP) of these six biomarkers were 0.99, 0.98, and 0.99, respectively. Potential diagnostic implications of the metabolic characteristics in NSCLC was studied. The metabolomics results were further verified by transcriptomics analysis of 1027 NSCLC patients and 108 adjacent peritumoral tissues from TCGA database. This analysis identified 2202 genes with significantly different expressions in cancer cells compared to normal controls, which in turn defined pathways implicated in the metabolism of the compounds revealed by metabolomics analysis. We built a fully connected network of metabolites and genes, which shows a good correspondence between the transcriptome analysis and the metabolites selected for diagnosis. In conclusion, this work provides evidence that the metabolic biomarkers identified may be used for NSCLC diagnosis and screening. Comprehensive analysis of metabolomics and transcriptomics data offered a validated and comprehensive understanding of metabolism in NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202610PMC
July 2020

Integrated quality evaluation strategy for multi-species resourced herb medicine of Qinjiao by metabolomics analysis and genetic comparation.

Chin Med 2020 11;15:16. Epub 2020 Feb 11.

1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China.

Background: Quality evaluation of multi-species resourced herb medicine (MSRHM) is a main problem for quality control of herb medicine. Current quality evaluation methodology lost consideration of species discrepancy. New quality evaluation strategy for MSRHM is in urgent need. Qinjiao, a representative MSRHM, originated from Pall., Maxim., Duthie ex Burk. or Fisch., has been used as an important herb medicine over 2000 years for expelling wind-dampness and relieving impediment pain. However, quality evaluation among species has never been revealed. The current work proposes an integrated quality evaluation strategy for MSRHM of Qinjiao, which may promote innovation of quality control of MSRHM.

Methods: In this work, 58 batches of Qinjiao covering 4 species were collected. Genetic comparative analysis based on ITS2 sequence was conducted. Metabolomics analysis based on TOF-MS and NMR spectrum were carried out. Compounds underlying species differences were identified and their discrepancies among species were investigated by ANOVA analysis and multivariate analysis.

Results: Four species of Qinjiao can be authenticated by ITS2 sequence comparation. Metabolomics analysis by TOF/MS and NMR revealed chemical discrepancies among species of Qinjiao. Maximum discrepancy was present between Duthie ex Burk. and Fisch. Chemical difference among species were tentative explored. For TOF-MS profiling, 28 constituents were tentative identified, 17 of which were further confirmed by standards. For H-NMR profiling, signals from 5 compounds were assigned. Contents discrepancies were investigated by ANOVA analysis. It seems that (seco)iridoids like loganic acid, gentiopicroside or swertiamarin were richer in specie of Duthie ex Burk., while flavonoid (morroniside) and triterpenoids (roburic aicd, ursolic acid, oleanolic acid, β-sitosterone) were richer in specie of Fisch. The current research demonstrates that metabolite profiling based on both UPLC/Q-TOF MS and H-NMR coupled with ITS2 sequence comparation can be a powerful tool for quality investigation of MSRHM of Qinjiao.

Conclusions: A comprehensive quality evaluation strategy for MSRHM was proposed by integrating UPLC-Q-TOF-MS, NMR based metabolic analysis and ITS2 sequence genetic comparation. The proposed quality evaluation strategy shall promote innovation of quality control of traditional Chinese medicine.
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http://dx.doi.org/10.1186/s13020-020-0292-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014644PMC
February 2020

Allele specific expression of Dof genes responding to hormones and abiotic stresses in sugarcane.

PLoS One 2020 16;15(1):e0227716. Epub 2020 Jan 16.

College of Life Sciences, Center for Genomics and Biotechnology, Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China.

Dof transcription factors plant-specific and associates with growth and development in plants. We conducted comprehensive and systematic analyses of Dof transcription factors in sugarcane, and identified 29 SsDof transcription factors in sugarcane genome. Those SsDof genes were divided into five groups, with similar gene structures and conserved motifs within the same groups. Segmental duplications are predominant in the evolution of Dof in sugarcane. Cis-element analysis suggested that the functions of SsDofs were involved in growth and development, hormones and abiotic stresses responses in sugarcane. Expression patterns indicated that SsDof7, SsDof23 and SsDof24 had a comparatively high expression in all detected tissues, indicating these genes are crucial in sugarcane growth and development. Moreover, we examined the transcription levels of SsDofs under four plant hormone treatments, SsDof7-3 and SsDof7-4 were down-regulated after ABA treatment, while SsDof7-1 and SsDof7-2 were induced after the same treatment, indicating different alleles may play different roles in response to plant hormones. We also analyzed SsDofs' expression profiling under four abiotic stresses, SsDof5 and SsDof28 significantly responded to these four stresses, indicating they are associate with abiotic stresses responses. Collectively, our results yielded allele specific expression of Dof genes responding to hormones and abiotic stresses in sugarcane, and their cis-elements could be crucial for sugarcane improvement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227716PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964845PMC
April 2020

Genome-Wide Analysis of the YABBY Transcription Factor Family in Pineapple and Functional Identification of Involvement in Salt Stress.

Int J Mol Sci 2019 Nov 22;20(23). Epub 2019 Nov 22.

Key Laboratory of Genetics, Breeding and Multiple Utilization of Crops, Ministry of Education, Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology; State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

The plant-specific transcription factor gene family, YABBY, belongs to the subfamily of zinc finger protein superfamily and plays an essential regulatory role in lateral organ development. In this study, nine genes were identified in the pineapple genome. Seven of them were located on seven different chromosomes and the remaining two were located on scaffold 1235. Through protein structure prediction and protein multiple sequence alignment, we found that , lack a C2 structure in their N-terminal C2C2 zinc finger protein structure. Analysis of the -acting element indicated that all the seven pineapple genes contain multiple MYB and MYC elements. Further, the expression patterns analysis using the RNA-seq data of different pineapple tissues indicated that different are preferentially expressed in various tissues. RT-qPCR showed that the expression of , , were highly sensitive to abiotic stresses. Subcellular localization in pineapple protoplasts, tobacco leaves and roots showed that all the seven pineapple YABBY proteins were nucleus localized. Overexpression of in resulted in short root under NaCl treatment, indicating a negative regulatory role of in plant resistance to salt stress. This study provides valuable information for the classification of pineapple genes and established a basis for further research on the functions of AcYABBY proteins in plant development and environmental stress response.
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http://dx.doi.org/10.3390/ijms20235863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929212PMC
November 2019

Studies on genome size estimation, chromosome number, gametophyte development and plant morphology of salt-tolerant halophyte Suaeda salsa.

BMC Plant Biol 2019 Nov 6;19(1):473. Epub 2019 Nov 6.

State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, College of Plant Protection, Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Center for Genomics and Biotechnology, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Background: Soil salinization and alkalization are among the major agricultural threats that affect crop productivity worldwide, which are increasing day by day with an alarming rate. In recent years, several halophytes have been investigated for their utilization in soil remediation and to decipher the mechanism of salt-tolerance in these high salt tolerant genetic repositories. Suaeda salsa is an annual halophytic herb in the family Amaranthaceae, displaying high salt and alkali-resistance and having nutritive value. However, the fundamental biological characteristics of this valuable plant remain to be elucidated until today.

Results: In this study, we observed the morphology and development of Suaeda salsa, including seed morphology, seed germination, plant morphology, and flower development. Using microscopy, we observed the male and female gametophyte developments of Suaeda salsa. Also, chromosome behaviour during the meiosis of male gametophyte was studied. Eventually, the genome size of Suaeda salsa was estimated through flow cytometry using Arabidopsis as reference.

Conclusions: Our findings suggest that the male and female gametophyte developments of Suaeda salsa are similar to those of the model plant Arabidopsis, and the diploid Suaeda salsa contains nine pairs of chromosomes. The findings also indicate that the haploid genome of Suaeda salsa is approximately 437.5 MB. The observations and results discussed in this study will provide an insight into future research on Suaeda salsa.
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http://dx.doi.org/10.1186/s12870-019-2080-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833229PMC
November 2019

Identification of SWI2/SNF2-Related 1 Chromatin Remodeling Complex (SWR1-C) Subunits in Pineapple and the Role of Pineapple SWR1 COMPLEX 6 (AcSWC6) in Biotic and Abiotic Stress Response.

Biomolecules 2019 08 13;9(8). Epub 2019 Aug 13.

Key Laboratory of Genetics, Breeding and Multiple Utilization of Crops, Ministry of Education, Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, College of Crop Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

Chromatin remodeling complex orchestrates numerous aspects of growth and development in eukaryotes. SWI2/SNF2-Related 1 chromatin remodeling complex (SWR1-C) is a member of the SWI/SNF ATPase-containing chromatin remodeling complex responsible for the exchange of H2A for H2A.Z. In plants, SWR1-C plays a crucial role by transcriptionally regulating numerous biological and developmental processes. However, SWR1-C activity remains obscure in pineapple. Here, we aim to identify the SWR1-C subunits in pineapple. By genome-wide identification, we found a total of 11 SWR1-C subunits in the pineapple. The identified SWR1-C subunits were named and classified based on the sequence similarity and phylogenetic analysis. RNA-Seq analysis showed that pineapple SWR1-C subunits are expressed differentially in different organs and at different stages. Additionally, the qRT-PCR of pineapple SWR1-C subunits during abiotic stress exposure showed significant changes in their expression. We further investigated the functions of pineapple SWR1 COMPLEX 6 (AcSWC6) by ectopically expressing it in Arabidopsis. Interestingly, transgenic plants ectopically expressing AcSWC6 showed susceptibility to fungal infection and enhanced resistance to salt and osmotic stress, revealing its involvement in biotic and abiotic stress. Moreover, the complementation of mutant by pineapple SWC6 suggested the conserved function of SWC6 in plants.
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http://dx.doi.org/10.3390/biom9080364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723344PMC
August 2019

Determination of five nucleosides by LC-MS/MS and the application of the method to quantify N -methyladenosine level in liver messenger ribonucleic acid of an acetaminophen-induced hepatotoxicity mouse model.

J Sep Sci 2019 Aug 25;42(16):2668-2678. Epub 2019 Jun 25.

Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China.

Ribonucleic acid N -methyladenosine methylation plays an important role in a variety of biological processes and diseases. Acetaminophen-induced hepatotoxicity is one of the major challenges faced by clinicians. To date, the link between N -methyladenosine and acetaminophen-induced hepatotoxicity has not been studied. In this study, a simple ultra high performance liquid chromatography with tandem mass spectrometry method was developed for the simultaneous determination of five nucleosides (adenosine, uridine, cytidine, guanosine, and N -methyladenosine) in messenger ribonucleic acid. After enzymatic digestion of messenger ribonucleic acid, the nucleosides sample was separated on an Acquity UPLC column with gradient elution using methanol and 0.02% formic acid water, and detected by a Qtrap 4500 mass spectrometer with an electrospray ionization mode. The method was validated over the concentration ranges of 4-800 ng/mL for adenosine, uridine, cytidine, and guanosine and 0.1-20 ng/mL for N -methyladenosine. It was successfully applied to the determination of N -methyladenosine levels in liver messenger ribonucleic acid in an acetaminophen-induced hepatotoxicity mouse model and a control group. This study offers a method for the determination of nucleoside contents in epigenetic studies and constitutes the first step toward the investigation of ribonucleic acid methylation in acetaminophen-induced hepatotoxicity, which will facilitate the elucidation of its mechanism.
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http://dx.doi.org/10.1002/jssc.201900041DOI Listing
August 2019

Characterization of transcriptome profile and clinical features of a novel immunotherapy target CD204 in diffuse glioma.

Cancer Med 2019 07 29;8(8):3811-3821. Epub 2019 May 29.

Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

CD204 is a specific marker of tumor-associated macrophages (TAMs) in glioma. However, the expression levels of CD204 and its involvement in glioma are not fully understood. In this large-scale study, we assessed the expression and function of CD204 in whole-grade glioma molecularly and clinically. In total, 1323 glioma samples, including 301 microarray data and 325 RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) dataset and 697 RNA-seq data from The Cancer Genome Atlas (TCGA) dataset, were utilized. The statistical analysis and graphical work were mainly performed using the R software. Univariate and multivariate Cox analysis demonstrated that CD204 was an independent prognosticator in glioma patients. CD204 expression was positively correlated with the grade of malignancy. CD204 was consistently upregulated in wild-type isocitrate dehydrogenase glioma and highly expressed in mesenchymal glioblastoma. Gene ontology of CD204-related genes showed that CD204 was most enriched in inflammatory response and immune response. It was associated with the stromal and immune populations, especially the monocytic lineage, fibroblasts, and T cells. Circos plots revealed that CD204 was closely associated with many immune checkpoint regulators, especially TIM-3. CD204 expression is consistent with the malignant phenotype of glioma and independently predicts poor outcomes in glioma patients. Additionally, CD204 TAMs, collaborating with other checkpoint members, may contribute to the dysfunction of T cells. These findings suggest that CD204 may be a promising target for glioma immunotherapy.
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http://dx.doi.org/10.1002/cam4.2312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639170PMC
July 2019

In vitro metabolic profiles of motolimod by using liquid chromatography tandem mass spectrometry: Metabolic stability, metabolite characterization and species comparison.

J Pharm Biomed Anal 2019 Apr 7;167:90-99. Epub 2019 Feb 7.

Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address:

Motolimod (VTX-2337) is an agonist of toll-like receptor 8 (TLR8) with potential immune-stimulating and antineoplastic activities. The purpose of this study was to investigate the in vitro metabolic profiles of VTX-2337. The average in vitro T values were 6.93, 8.71, 7.39, 2.85, and 10.58 min in the liver microsomes of mouse, rat, dog, monkey and human respectively, suggesting that VTX-2337 suffered from extensive metabolism. The metabolites were further profiled and identified by using ultra-high performance liquid chromatography coupled with diode array detector and Q-Exactive-Orbitrap tandem mass spectrometer (UHPLC-DAD-Q-Exactive-Orbitrap-MS) operated in positive ion mode. A total of 20 metabolites were detected and their identities were characterized based on their accurate masses, fragment ions and retention times. M13 (depropylation) was the most abundant metabolite in all species. M14 (oxygenation) was also the major metabolite in the liver microsomes of mouse, rat, monkey and human. M1, M5, M10, M15, and M16 were specifically detected in mouse, while M6 and M17 were monkey-specific. All the metabolites present in human could be found in animal species. The metabolic pathways of VTX-2337 referred to oxygenation, hydrolysis, depropylation, and dehydrogenation. Rat had the similar metabolic profiles to humans. The current study provided overall metabolic profiles of VTX-2337, which would be of great help in predicting in vivo pharmacokinetic profiles and in understanding the effectiveness and safety of this drug.
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http://dx.doi.org/10.1016/j.jpba.2019.02.009DOI Listing
April 2019

Identification of metabolites of evobrutinib in rat and human hepatocytes by using ultra-high performance liquid chromatography coupled with diode array detector and Q Exactive Orbitrap tandem mass spectrometry.

Drug Test Anal 2019 Jan 29;11(1):129-139. Epub 2018 Aug 29.

Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Evobrutinib is a highly selective inhibitor of Bruton's tyrosine kinase (BTK) which may be clinically effective in treating certain autoimmune diseases. The purpose of the present study was to investigate the metabolism of evobrutinib in rat and human hepatocytes. Evobrutinib was incubated with rat and human hepatocytes at 37°C for 2 hours after which the samples were analyzed by ultra-high performance liquid chromatography with diode array detection and Q Exactive Orbitrap tandem mass spectrometry (UPLC-DAD-Q Exactive Orbitrap-MS). The acquired data were processed by MetWorks™ software using mass effect filter and background subtraction functions. Under these conditions, 23 metabolites were detected and their identities proposed. Among these metabolites, M13 and M15 were identified by comparison of their retention times, accurate masses, and fragment ions with those of authentic reference standards. The metabolic pathways of evobrutinib were proposed accordingly. Our results demonstrated that evobrutinib was metabolized via hydroxylation, hydrolysis, O-dealkylation, glucuronidation, and GSH conjugation. Species-related metabolic differences between rat and human hepatocytes were observed. M1-M4 were rat-specific metabolites. M13 (hydroxyl-evobrutinib) was the major metabolite whereas M15 (evobrutinib-diol) was a minor metabolite in rat hepatocytes. On the other hand, M6, M11, M16, M17, and M19 were human-specific metabolites. M15 was the most abundant metabolite whereas M13 was the minor metabolite in human hepatocytes. This study provides preliminary information regarding the metabolism of evobrutinib that may be helpful in understanding the pharmacology of evobrutinib.
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http://dx.doi.org/10.1002/dta.2477DOI Listing
January 2019

H-NMR Based Serum Metabolomics Study to Investigate Hepatoprotective Effect of Qin-Jiao on Carbon Tetrachloride-Induced Acute Hepatotoxicity in Rats.

Evid Based Complement Alternat Med 2017 1;2017:6091589. Epub 2017 Nov 1.

Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Gentiana macrophylla Radix, commonly known as Qin-Jiao (QJ), was recorded alone to treat jaundice in Compendium of Materia Medica and has been frequently prescribed for treatment of liver disease in China. However, the underlying mechanism remains unknown. In the present work, QJ of 1,2 g/kg or silybin of 40 mg/kg (positive control) was orally given to rats for 7 days to verify the protective effect on acute liver damage induced by tetrachloride (CCl). Together with serum biochemistry and histopathological examination, H-NMR based metabolomics work was carried out to investigate the efficacy. It turned out that QJ of 2 g/kg exerted comparable protective effect with positive control and partially recovered disturbed metabolism by CCl. Multivariate analysis was conducted and metabolites altered significantly among groups were assigned and discussed, including betaine, glucose, lactate, creatine, and LDL/VLDL. Metabolic regulations involved in QJ or silybin treatment were as follows: tricarboxylic acid (TCA) cycle, synthesis of LDL/VLDL, and gluconeogenesis were enhanced, while betaine metabolism, glycolysis, creatine metabolism, synthesis of ketone bodies, amino acids metabolism, and -oxidation of fatty acids were suppressed. For the first time hepatoprotective effect of QJ on acute liver damage was revealed by H-NMR based metabolomics, prompting understanding of the underlying mechanism.
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http://dx.doi.org/10.1155/2017/6091589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687146PMC
November 2017

Plantago asiatica L. Seed Extract Improves Lipid Accumulation and Hyperglycemia in High-Fat Diet-Induced Obese Mice.

Int J Mol Sci 2017 Jun 30;18(7). Epub 2017 Jun 30.

The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Obesity and its common association with type 2 diabetes, dyslipidemia, and cardiovascular diseases are worldwide epidemics. Currently, to prevent or treat obesity and associated metabolic disorders, herbal dietary supplements or medicines have attracted more and more attention owing to their relative effectiveness with fewer significant side effects. We investigate the therapeutic effects and underlying mechanisms of L. seed extract (PSE) on obesity and associated metabolic disorders in high-fat (HF) diet-induced mice. Our results displayed that PSE did not modify food intake or body weight but decreased abdominal white adipose tissue ratio, white/brown adipocyte size, serum total cholesterol, triglyceride (TG), low density lipoprotein cholesterol, free fatty acid, and hepatic TG concentrations when compared with the HF group. The levels of fasting blood glucose and glucose tolerance were improved in the PSE group when compared with the HF group. Furthermore, PSE upregulated mRNA expressions of peroxisome proliferator activated receptors (PPARs) and target genes related to fatty acid metabolism and energy expenditure in liver and adipose tissue of obese mice when compared with the HF group. PSE treatment effectively improved lipid and glucose metabolism in HF diet-induced obese mice. These effects might be attributed to the upregulation of PPAR signaling.
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http://dx.doi.org/10.3390/ijms18071393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535886PMC
June 2017

Development and validation of a sensitive UHPLC-MS/MS method for quantitation of prucalopride in rat plasma and its application to pharmacokinetics study.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Oct 5;1033-1034:328-333. Epub 2016 Sep 5.

Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, No.1 Jianshe East Road, Henan Province, 450052, PR China. Electronic address:

A rapid, sensitive, selective and accurate ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the quantitation of prucalopride in rat plasma using carbamazepine as an internal standard (IS). Separation was achieved on a Waters ACQUITY UHPLC(®) HSS C18 column (2.1mm×50mm, 1.8μm) column with a gradient mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) as mobile phase at a flow rate of 0.2mL/min. Prucalopride and IS were monitored using positive electrospray triple quadrupole mass spectrometer (Waters Xevo TQD) via multiple reaction monitoring (MRM) mode. The monitored transitions were set at m/z 367.99→195.89 and m/z 236.97→194.04 for prucalopride and IS, respectively. The achieved lower limit of quantitation was 0.1ng/mL. The validated method had an excellent linearity in the range of 0.1-100ng/mL (r>0.996). The intra- and inter-day precisions were both≤7.8% for prucalopride and IS, and the average intra- and inter-day accuracies ranged from -3.0% to 8.5%. Extraction recoveries at three levels QC concentrations were in the range of 90.0-110.0% for prucalopride and 99.6% for IS. Matrix effects were found to be acceptable. The validated assay was successfully applied to a pharmacokinetic study of prucalopride following oral administration of 0.25, 0.5, 1.0mg/kg to female and male rats respectively.
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http://dx.doi.org/10.1016/j.jchromb.2016.09.006DOI Listing
October 2016

Pharmacokinetics, bioavailability, and metabolism of Notoginsenoside Fc in rats by liquid chromatography/electrospray ionization tandem mass spectrometry.

J Pharm Biomed Anal 2015 May 28;109:150-7. Epub 2015 Feb 28.

The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai 201203, China. Electronic address:

Notoginsenoside Fc (NGFc) is a protopanaxadiol-type (PPD-type) saponin from Panax notoginseng, which has perfect anti-platelet aggregatory effect. However, its pharmacokinetics and metabolism in vivo remain unknown. In this study, a simple and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC-MS/MS) method was first developed for the determination of NGFc in rat plasma. After methanol-mediated protein precipitation, separation was achieved on a C18 column with MS detection operated in negative SRM mode at m/z 604.56→m/z 783.90 and m/z 799.93→m/z 637.64 for NGFc and IS, respectively. The assay was linear over the concentration range (r>0.995) with the LLOQ of 0.002μg/ml. The intra- and inter-day precisions (R.S.D.) were 2.45-12.36% and 3.67-14.22%, respectively; whereas accuracy ranged from (R.R.) 93.90% to 99.41%. The extraction recovery, stability, and matrix effect were within the acceptable limits. The validated LC-MS/MS method was successfully applied to the pre-clinical pharmacokinetic studies of NGFc in rat. After oral and intravenous administration, NGFc showed dose-independent pharmacokinetic behaviors with a t1/2 of >22h and its oral bioavailability was 0.10-0.14%. In addition, a total of 10 metabolites were detected and structurally characterized by UPLC-Q/TOF-MS technique, which suggested that deglycosylation was the major metabolic pathway for NGFc in rats.
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http://dx.doi.org/10.1016/j.jpba.2015.02.038DOI Listing
May 2015

A quantitative ¹H nuclear magnetic resonance (qHNMR) method for assessing the purity of iridoids and secoiridoids.

Fitoterapia 2015 Jan 13;100:187-94. Epub 2014 Dec 13.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address:

This paper utilized a quantitative (1)H nuclear magnetic resonance (qHNMR) method for assessing the purity of iridoids and secoiridoids. The method was fully validated, including specificity, linearity, accuracy, precision, reproducibility, and robustness. For optimization of experimental conditions, several experimental parameters were investigated, including relaxation delay (D1), scan numbers (NS) and power length (PL1). The quantification was based on the area ratios of H-3 from analytes relative to aromatic protons from 1,4-dinitrobenzene (internal standard) with methanol-d4 as solvent. Five iridoids and secoiridoids (sweroside, swertiamarin, gentiopicroside, geniposide, genipin) were analyzed. Furthermore, the results were validated by the high performance liquid chromatography coupled with ultraviolet detection (HPLC-UV) method. It can be concluded that the qHNMR method was simple, rapid, and accurate, providing a reliable and superior method for assessing the purity of iridoids and secoiridoids.
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http://dx.doi.org/10.1016/j.fitote.2014.12.001DOI Listing
January 2015

Metabolic profiles of 20(S)-protopanaxadiol in rats after oral administration using ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry.

Rapid Commun Mass Spectrom 2014 Mar;28(6):595-604

The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Pharmacognosy, China Pharmaceutical University, Nanjing, 210038, China.

Rationale: 20(S)-Protopanaxadiol (PPD), a dammarane-type triterpenoid sapogenin, acts as the pharmacophore of ginsenosides which are considered as the principal bioactive components in Chinese ginseng. To fully understand the mechanism of action of PPD, it is important to study its metabolic profiles in vivo.

Methods: Plasma, urine, fece and bile were collected after administration of PPD formulated in 0.5% aqueous Tween-80 to rats (150 mg/kg). Samples were analyzed by using a sensitive and reliable method based on ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS/MS) in both positive and negative ion mode. The chemical structures of metabolites were elucidated by comparing the retention time, accurate molecular mass, and fragmentation patterns of analytes with those of PPD.

Results: In total 29 metabolites, including 10 new metabolites (M20-M29), were tentatively identified and characterized. Among them, two metabolites (M3 and M4) were unambiguously identified by matching their retention times and fragmentation patterns with their standards. Principal metabolites, namely, 20, 24-oxide metabolites (M3 and M4), 26/27-carboxylic acid derivatives (M22 and M23) and a glucuronidated product (M28), were found in the rat plasma.

Conclusions: The results showed that phase I metabolites are monooxygenation, dioxygenation and oxidative dehydrogenation metabolites, and phase II metabolic pathways were demonstrated to be cysteine conjugation and glucuronidation. The newly identified metabolites are useful to understand the mechanism of elimination of PPD and, in turn, its effectiveness and toxicity.
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http://dx.doi.org/10.1002/rcm.6813DOI Listing
March 2014

A combined approach of high-throughput sequencing and degradome analysis reveals tissue specific expression of microRNAs and their targets in cucumber.

PLoS One 2012 30;7(3):e33040. Epub 2012 Mar 30.

Department of Horticulture, Zhejiang University, Hangzhou, China.

MicroRNAs (miRNAs) are endogenous small RNAs playing an important regulatory function in plant development and stress responses. Among them, some are evolutionally conserved in plant and others are only expressed in certain species, tissue or developmental stages. Cucumber is among the most important greenhouse species in the world, but only a limited number of miRNAs from cucumber have been identified and the experimental validation of the related miRNA targets is still lacking. In this study, two independent small RNA libraries from cucumber leaves and roots were constructed, respectively, and sequenced with the high-throughput Illumina Solexa system. Based on sequence similarity and hairpin structure prediction, a total of 29 known miRNA families and 2 novel miRNA families containing a total of 64 miRNA were identified. QRT-PCR analysis revealed that some of the cucumber miRNAs were preferentially expressed in certain tissues. With the recently developed 'high throughput degradome sequencing' approach, 21 target mRNAs of known miRNAs were identified for the first time in cucumber. These targets were associated with development, reactive oxygen species scavenging, signaling transduction and transcriptional regulation. Our study provides an overview of miRNA expression profile and interaction between miRNA and target, which will help further understanding of the important roles of miRNAs in cucumber plants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033040PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316546PMC
August 2012

Characterization and quantification of the triterpenoids in different parts of Xanthoceras sorbifolia by HPLC-ESI-MS.

J Pharm Biomed Anal 2011 May 28;55(2):259-64. Epub 2011 Jan 28.

School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.

Two new triterpenoid glycosides, sorbifoside A (2) and B (3), were isolated from the husks of Xanthoceras sorbifolia along with two known saponins (1, 5). Their structures were established on the basis of 1D and 2D NMR data. A simple and sensitive assay was developed for the simultaneous determination of 6 triterpenoids (1-6, including two triterpenoid aglycones) in X. sorbifolia based on high performance liquid chromatography-mass spectrometry (HPLC-MS) coupled to an electrospray ionization (ESI) interface. The analytes were detected by positive ESI ionization mode and quantified by selected ion monitoring (SIM). All the linear regressions were acquired with r2>0.998. The precisions were evaluated by intra- and inter-day tests, and the relative standard deviation (RSD) values were within the range of 2.0-2.8% and 1.7-2.9%, respectively. The recoveries for the quantified compounds were observed over the range of 95.3-104.7% with RSD values less than 4.6%. The method developed was successfully applied for simultaneous quantification of the six triterpenoids in X. sorbifolia, and our results showed that the contents of triterpenoids in different parts of X. sorbifolia varied significantly.
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http://dx.doi.org/10.1016/j.jpba.2011.01.030DOI Listing
May 2011