Publications by authors named "Hanxue Wang"

16 Publications

  • Page 1 of 1

Foodborne Disease Risk Prediction Using Multigraph Structural Long Short-term Memory Networks: Algorithm Design and Validation Study.

JMIR Med Inform 2021 Aug 2;9(8):e29433. Epub 2021 Aug 2.

Computer Network Information Center, Chinese Academy of Sciences, Beijing, China.

Background: Foodborne disease is a common threat to human health worldwide, leading to millions of deaths every year. Thus, the accurate prediction foodborne disease risk is very urgent and of great importance for public health management.

Objective: We aimed to design a spatial-temporal risk prediction model suitable for predicting foodborne disease risks in various regions, to provide guidance for the prevention and control of foodborne diseases.

Methods: We designed a novel end-to-end framework to predict foodborne disease risk by using a multigraph structural long short-term memory neural network, which can utilize an encoder-decoder to achieve multistep prediction. In particular, to capture multiple spatial correlations, we divided regions by administrative area and constructed adjacent graphs with metrics that included region proximity, historical data similarity, regional function similarity, and exposure food similarity. We also integrated an attention mechanism in both spatial and temporal dimensions, as well as external factors, to refine prediction accuracy. We validated our model with a long-term real-world foodborne disease data set, comprising data from 2015 to 2019 from multiple provinces in China.

Results: Our model can achieve F1 scores of 0.822, 0.679, 0.709, and 0.720 for single-month forecasts for the provinces of Beijing, Zhejiang, Shanxi and Hebei, respectively, and the highest F1 score was 20% higher than the best results of the other models. The experimental results clearly demonstrated that our approach can outperform other state-of-the-art models, with a margin.

Conclusions: The spatial-temporal risk prediction model can take into account the spatial-temporal characteristics of foodborne disease data and accurately determine future disease spatial-temporal risks, thereby providing support for the prevention and risk assessment of foodborne disease.
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http://dx.doi.org/10.2196/29433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369373PMC
August 2021

Simultaneous LC-MS/MS bioanalysis of alkaloids, terpenoids, and flavonoids in rat plasma through salting-out-assisted liquid-liquid extraction after oral administration of extract from Tetradium ruticarpum and Glycyrrhiza uralensis: a sample preparation strategy to broaden analyte coverage of herbal medicines.

Anal Bioanal Chem 2021 Sep 31;413(23):5871-5884. Epub 2021 Jul 31.

Institute of Chinese Materia Medica, The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.

Herbal medicines have historically been practiced in combinatorial way, which achieves therapeutic efficacy by integrative effects of multi-components. Thus, the accurate and precise measurement of multi bioactive components in matrices is inalienable to understanding the metabolism and disposition of herbal medicines. In this study, aiming to provide a strategy that improves analyte coverage, evaluation of six protocols employing sample pretreatment methods- protein precipitation (PPT), liquid-liquid extraction (LLE), sugaring-out-assisted liquid-liquid extraction (SULLE), and salting-out-assisted liquid-liquid extraction (SALLE)- was performed by LC-MS/MS using rat plasma and a mixture of alkaloid (evodiamine, rutaecarpine, dehydroevodiamine), terpenoid (limonin, rutaevin, obacunone), and flavonoid (liquiritin, isoliquiritin, liquiritigenin) standards isolated from Tetradium ruticarpum and Glycyrrhiza uralensis. These protocols were as follows: (1) PPT with methanol, (2) PPT with acetonitrile, (3) LLE with methyl tertiary-butyl ether-dichloromethane, (4) LLE with ethyl acetate-n-butanol, (5) SALLE with ammonium acetate, (6) SULLE with glucose. The results suggested that SALLE produced broader analyte coverage with satisfactory reproducibility, acceptable recovery, and low matrix interference. Then, sample preparation procedure of SALLE, chromatographic conditions, and mass spectrometric parameters were optimized, followed by method validation, showing that good sensitivity (LLOQ ≤ 1 ng mL), linearity (r ≥ 0.9933), precision (RSD ≤ 14.45%), accuracy (89.54~110.87%), and stability could be achieved. Next, the developed method was applied successfully to determine the pharmacokinetic behavior of the nine compounds in rat plasma after intragastric administration with an extract from Tetradium ruticarpum and Glycyrrhiza uralensis (Wuzhuyu-Gancao pair). Based on an extensive review and experiments, a sample preparation procedure that matches with LC-MS/MS technique and can get wider analyte coverage was outlined. The developed SALLE method is rapid, reliable, and suitable for bioanalysis of analytes with diverse polarity, which was expected to be a promising strategy for the pharmacokinetic studies of herbal medicines. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-021-03568-1DOI Listing
September 2021

High-Efficiency Machine Learning Method for Identifying Foodborne Disease Outbreaks and Confounding Factors.

Foodborne Pathog Dis 2021 08 26;18(8):590-598. Epub 2021 Apr 26.

Computer Network Information Center, Chinese Academy of Sciences, Beijing, China.

The China National Center for Food Safety Risk Assessment (CFSA) uses the Foodborne Disease Monitoring and Reporting System (FDMRS) to monitor outbreaks of foodborne diseases across the country. However, there are problems of underreporting or erroneous reporting in FDMRS, which significantly increase the cost of related epidemic investigations. To solve this problem, we designed a model to identify suspected outbreaks from the data generated by the FDMRS of CFSA. In this study, machine learning models were used to fit the data. The recall rate and F1-score were used as evaluation metrics to compare the classification performance of each model. Feature importance and pathogenic factors were identified and analyzed using tree-based and gradient boosting models. Three real foodborne disease outbreaks were then used to evaluate the best performing model. Furthermore, the SHapley Additive exPlanation value was used to identify the effect of features. Among all machine learning classification models, the eXtreme Gradient Boosting (XGBoost) model achieved the best performance, with the highest recall rate and F1-score of 0.9699 and 0.9582, respectively. In terms of model validation, the model provides a correct judgment of real outbreaks. In the feature importance analysis with the XGBoost model, the health status of the other people with the same exposure has the highest weight, reaching 0.65. The machine learning model built in this study exhibits high accuracy in recognizing foodborne disease outbreaks, thus reducing the manual burden for medical staff. The model helped us identify the confounding factors of foodborne disease outbreaks. Attention should be paid not only to the health status of those with the same exposure but also to the similarity of the cases in time and space.
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http://dx.doi.org/10.1089/fpd.2020.2913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390778PMC
August 2021

Machine Learning Prediction of Foodborne Disease Pathogens: Algorithm Development and Validation Study.

JMIR Med Inform 2021 Jan 26;9(1):e24924. Epub 2021 Jan 26.

Computer Network Information Center, Chinese Academy of Sciences, Beijing, China.

Background: Foodborne diseases, as a type of disease with a high global incidence, place a heavy burden on public health and social economy. Foodborne pathogens, as the main factor of foodborne diseases, play an important role in the treatment and prevention of foodborne diseases; however, foodborne diseases caused by different pathogens lack specificity in clinical features, and there is a low proportion of clinically actual pathogen detection in real life.

Objective: We aimed to analyze foodborne disease case data, select appropriate features based on analysis results, and use machine learning methods to classify foodborne disease pathogens to predict foodborne disease pathogens that have not been tested.

Methods: We extracted features such as space, time, and exposed food from foodborne disease case data and analyzed the relationship between these features and the foodborne disease pathogens using a variety of machine learning methods to classify foodborne disease pathogens. We compared the results of 4 models to obtain the pathogen prediction model with the highest accuracy.

Results: The gradient boost decision tree model obtained the highest accuracy, with accuracy approaching 69% in identifying 4 pathogens including Salmonella, Norovirus, Escherichia coli, and Vibrio parahaemolyticus. By evaluating the importance of features such as time of illness, geographical longitude and latitude, and diarrhea frequency, we found that they play important roles in classifying the foodborne disease pathogens.

Conclusions: Data analysis can reflect the distribution of some features of foodborne diseases and the relationship among the features. The classification of pathogens based on the analysis results and machine learning methods can provide beneficial support for clinical auxiliary diagnosis and treatment of foodborne diseases.
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http://dx.doi.org/10.2196/24924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872834PMC
January 2021

Exploration of the effects of altitude change on bacteria and fungi in the rumen of yak (Bos grunniens).

Arch Microbiol 2021 Mar 17;203(2):835-846. Epub 2020 Oct 17.

Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming, People's Republic of China.

The yak (Bos grunniens) is a ruminant animal with strong regional adaptability. However, little is known about the adaptation of the rumen microbial community of yaks at different altitudes and the adaptation mechanism of the host and intestinal microorganisms to the habitat. We investigated the adaptability of the rumen microorganisms of yaks at high and low altitudes. We also compared and analyzed the abundance and diversity of core microorganisms and those that varied between different animals. The aim was to compare the rumen bacterial and fungal communities of grazing yak living at two elevations. Bacteroidetes, Firmicutes, Ascomycota, and Chytridiomycota were the dominant bacteria in the plateau and low-altitude regions. Significant differences between the dominant microorganisms in the rumen of yaks were evident in the two regions. The proportion of fiber-degrading bacteria was significantly different between yaks dwelling at high-altitude and low-altitude regions. The abundance of starch-degrading bacteria was not significantly different with altitude. Species clustering similarity analysis showed that the rumen microorganisms in the two areas were obviously isolated and clustered into branches. Functional prediction showed significant differences in rumen microbial methane metabolism, starch and sucrose metabolism, ion-coupled transporter and bacterial secretion system at different altitudes. Overall, the results of this study improved our understanding of the abundance and composition of microorganisms in the rumen of yak at different altitudes.
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http://dx.doi.org/10.1007/s00203-020-02072-xDOI Listing
March 2021

Potential mechanisms of tremor tolerance induced in rats by the repeated administration of total alkaloid extracts from the seeds of Peganum harmala Linn.

J Ethnopharmacol 2020 Nov 27;262:113183. Epub 2020 Jul 27.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai R&D Centre for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai, 201203, China. Electronic address:

Ethnopharmacological Relevance: The seeds of Peganum harmala Linn have been widely used for the treatment of nervous, cardiovascular, gastrointestinal, respiratory, and endocrine diseases and many other human ailments. However, tremor toxicity occurs after overdose and is tolerated following multiple dosing. Thus far, little is known about the underlying mechanisms of tremors and tremor tolerance.

Aim Of The Study: To investigate the potential mechanisms of tremors and tremor tolerance induced in rats by the repeated administration of total alkaloid extracts from the seeds of P. harmala (TAEP).

Materials And Methods: A tremor model was induced in male Wistar rats by administering TAEP at a dose of 150 mg/kg/day. To evaluate tremor action, behavioral assessment was conducted by using a custom-built tremor acquisition and analysis system. To investigate the relationships between tremors and neurotransmitter levels in the brain, various neurotransmitters were simultaneously quantified by an ultra-performance liquid chromatography combined with electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) system, and the association between these two parameters was analyzed using Pearson correlation coefficients. To further elucidate the potential mechanisms of the alterations of neurotransmitter levels in cortical tissues, the protein expression levels of several important enzymes and transporters that are closely related to neurotransmitter levels were investigated. In addition, neuropathological analysis was conducted to assess the effect of TAEP on neurons in the brain. To further clarify the potential mechanisms of TAEP-induced neurodegeneration in the brain, c-fos was subjected to immunohistochemical analysis, and oxidative stress markers were examined.

Results: Tremors initially occurred in rats after the oral administration of TAEP at a dose of 150 mg/kg/day. However, they were tolerated following repeated dosing. The levels of 5-hydroxytryptamine (5-HT) and glycine (Gly) in cortical tissues were most likely associated with the tremor response. Tremor tolerance also likely resulted from the degeneration of cerebellar Purkinje cells. Furthermore, the alteration of 5-HT levels was mainly attributed to the downregulated expression of monoamine oxidase A (MAO-A). The degeneration of Purkinje neurons might have resulted from the overexpression of c-fos and increased oxidative stress in the cerebellum after the multiple dosing of TAEP.

Conclusion: The tremor response induced by TAEP at high doses is closely related to the concentrations of 5-HT and Gly in cortical tissues. Tremor tolerance may also be attributed to the degeneration of cerebellar Purkinje cells after the repeated dosing of TAEP. Further studies should be conducted to elucidate the interaction of the alkaloids on the neurotransmitter receptors, the expression of related neurotransmitter receptors, the specific signaling pathway involved in regulating MAO-A, and the mechanism of the loss and functional recovery of cerebellar Purkinje neurons.
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http://dx.doi.org/10.1016/j.jep.2020.113183DOI Listing
November 2020

Combined Transplantation With Human Mesenchymal Stem Cells Improves Retinal Rescue Effect of Human Fetal RPE Cells in Retinal Degeneration Mouse Model.

Invest Ophthalmol Vis Sci 2020 07;61(8)

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Purpose: We verified whether fetal RPE (fRPE) cells and mesenchymal stem cells (MSCs) cotransplantation can combine the features of these two cell types and alleviate retinal degeneration in a retinal degenerative disease mouse model.

Methods: Tail vein injection of sodium iodate (NaIO3) was conducted to establish the retinal degenerative disease mouse model. MSCs and fRPE cells were transplanted either separately or combined in the subretinal space of retinal degenerative disease animals. ERG, optical coherence tomography, histologic, and immunofluorescence analyses were performed. Furthermore, the expression level of Crx, rhodopsin, Iba1, F4/80, Caspase 3, nerve growth factor, and brain-derived neurotrophic factor were assessed to investigate the mechanisms involved in cell transplantation effects.

Results: Cotransplantation of fRPE and MSC cells promoted significant improvements in ERG results and in the survival rate of transplanted cells. In addition, MSC and fRPE cell cotransplantation resulted in an increase in the thickness of the total retina, as well as in the outer and inner nuclear layers. Combined transplantation also upregulated the expression level of Crx and rhodopsin and downregulated caspase 3 expression, highlighting its better photoreceptor rescue effect in relation to the single cell type transplantation. Finally, combined transplantation suppressed the expression of Iba1 and F4/80 factors while increasing the endogenous expression of nerve growth factor and brain-derived nerve growth factor neurotrophic factors. These data suggest that MSC and fRPE cell cotransplantation is able to suppress immunoreactions and promote neurotrophic factor excretion.

Conclusions: Combined transplantation of MSCs and fRPE cells results in a better retinal rescue effect than single cell type transplantation in NaIO3-induced retinopathy.
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http://dx.doi.org/10.1167/iovs.61.8.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425709PMC
July 2020

Identification of photodegraded derivatives of usnic acid with improved toxicity profile and UVA/UVB protection in normal human L02 hepatocytes and epidermal melanocytes.

J Photochem Photobiol B 2020 Apr 6;205:111814. Epub 2020 Feb 6.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai R&D Centre for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai 201203, China. Electronic address:

This study focused on the investigation of photodegradation of usnic acid (UA) which is a natural UV absorbing agent in lichens. Despite years of historical use in food supplement, traditional medicine or cosmetic products in many countries, liver toxicity has been found to be one of the severe and life threatening adverse effects in early 2000's. Such severe side effect has limited UA or its synthesized derivatives for further use clinically or commercially. In this study, extracted UA from Usnea longissima in methanol was exposed to natural sunlight for 21 days. Five photodegraded derivatives (1 to 5) with two new and three previously explored compounds were isolated and purified by column chromatography and preparative liquid chromatography. The structures of these derivatives were identified based on the data of nuclear magnetic resonance spectrum, mass spectrum, optical rotation, infrared spectrum, X-ray crystallography and/or electronic circulation dichroism. The cytotoxicity of (+)-UA and 2 to 5 in liver L02 cells and melanocytes were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Experimental results indicated that IC of (+)-UA in liver L02 cells and melanocytes were 24.4 and 6.9 μM respectively, while compound 2 to 5 have lower cytotoxicity with IC of 326.7, 1085.0, 62.7 and 152.4 μM in L02 cells and 87.7, 297.7, 60.2 and 85.0 μM in melanocytes respectively. Besides, (+)-UA and these derivatives were exposed to fix dosed of UVA or UVB. The anti-UVA/UVB activity was determined via Hoechst33342/propidium iodide double staining method, and quantified by computer linked fluorescence microscope equipped with CellsSense Dimension system. Based on analysis, Compound 2 to 5 captured prominent UVA/UVB protection capacity in both hepatocytes and melanocytes (p < .001). In addition, the effects of chemicals on tyrosinase were evaluated via Western Blot analysis. In terms of tyrosinase expression, only 2 showed significant stimulating effect (p < .05). However, the safe use of these derivatives cutaneously should be further studied. In conclusion, the photodegraded derivatives (2 to 5) of extracted UA have lower hepatotoxicity than (+)-UA and captured significant UV protection activities.
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http://dx.doi.org/10.1016/j.jphotobiol.2020.111814DOI Listing
April 2020

Simultaneous determination of polyphenols and triterpenes in pomegranate peel based on high-performance liquid chromatography fingerprint by solvent extraction and ratio blending method in tandem with wavelength switching.

Biomed Chromatogr 2019 Dec 15;33(12):e4690. Epub 2019 Sep 15.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine; The MOE Key Laboratory for Standardization of Chinese Medicines; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.

Traditionally, pomegranate (Punica granatum L.) has been consumed as fresh fruit or as pomegranate juice. Pomegranate peel, the dried husk of P· granatum, is an important herbal medicine for treating diarrhea, hemostasis and insect-induced abdominal pain in China. However, the quality control methods for pomegranate peel remain unsatisfactory. In this work, a new HPLC-based qualitative and quantitative method for quality control of pomegranate peel was developed and validated for the simultaneous determination of polyphenols and triterpenes (including punicalagins A and B, ellagic acid, oleanolic acid and ursolic acid) by solvent extraction and ratio blending method in tandem with wavelength switching. The average recoveries were 98.07-100.61% with relative standard deviation no more than 4.27%. In addition, the fingerprint analysis was conducted to interpret the consistency of the quality test. Thirteen characteristic peaks were selected to evaluate the similarities of 16 batches of pomegranate peel. The similarities of samples were all more than 0.80, indicating that the samples from different areas of China were consistent. The results demonstrated that quantitative analysis and the HPLC fingerprint as a characteristic distinguishing method combining similarity evaluation can be successfully used to assess the quality and to identify the authenticity of pomegranate peel.
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http://dx.doi.org/10.1002/bmc.4690DOI Listing
December 2019

Mechanism-based pharmacokinetics-pharmacodynamics studies of harmine and harmaline on neurotransmitters regulatory effects in healthy rats: Challenge on monoamine oxidase and acetylcholinesterase inhibition.

Phytomedicine 2019 Sep 21;62:152967. Epub 2019 May 21.

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

Background: β-Carboline alkaloid harmine (HAR) and harmaline (HAL) are monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors. However, whether HAR and HAL inhibit MAO or AChE selectively and competitively is unclear.

Purpose: The purpose of this study was to investigate the potential competition inhibition of HAR and HAL on MAO and AChE in brain endothelial cells (RBE4) and in healthy rats to provide a basis for the application of the inhibitors in the treatment of patients with depression and with Parkinson's disease or Alzheimer's disease.

Study Design/methods: The transport properties of HAR and HAL by using blood-brain barrier models constructed with RBE4 were systematically investigated. Then, the modulation effects of HAR and HAL on CNS neurotransmitters (NTs) in healthy rat brains were determined by a microdialysis method coupled with LC-MS/MS. The competition inhibition of HAR and HAL on MAO and AChE was evaluated through real time-PCR, Western blot analysis, and molecular docking experiments.

Results: Results showed that HAL and HAR can be detected in the blood and striatum 300 min after intravenous injection (1 mg/kg). Choline (Ch), gamma-aminobutyric acid (GABA), glutamate (Glu), and phenylalanine (Phe) levels in the striatum decreased in a time-dependent manner after the HAL treatment, with average velocities of 1.41, 0.73, 3.86, and 1.10 (ng/ml)/min, respectively. The Ch and GABA levels in the striatum decreased after the HAR treatment, with average velocities of 1.16 and 0.22 ng/ml/min, respectively. The results of the cocktail experiment using the human liver enzyme indicated that the IC value of HAL on MAO-A was 0.10 ± 0.08 µm and that of HAR was 0.38 ± 0.21 µm. Their IC values on AChE were not obtained. These findings indicated that HAL and HAR selectively acted on MAO in vitro. However, RT-PCR and Western blot analysis results showed that the AChE mRNA and protein expression decreased in a time-dependent manner in RBE4 cells after the HAR and HAL treatments.

Conclusion: NT analysis results showed that HAL and HAR selectively affect AChE in vivo. HAL and HAR may be highly and suitably developed for the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.phymed.2019.152967DOI Listing
September 2019

Subchronic toxicity and concomitant toxicokinetics of long-term oral administration of total alkaloid extracts from seeds of Peganum harmala Linn: A 28-day study in rats.

J Ethnopharmacol 2019 Jun 7;238:111866. Epub 2019 Apr 7.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai R&D Centre for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai, 201203, China. Electronic address:

Ethnopharmacological Relevance: The seeds of Peganum harmala Linn, in which the most abundant active compounds are harmaline and harmine, have been widely used as a traditional medicine in various countries to treat a broad spectrum of diseases including asthma, cough, depression, Parkinson's and Alzheimer's diseases. However, few studies on long-term or subchronic toxicity of seeds of P. harmala were reported after overdose.

Aim Of The Study: To investigate the subchronic toxicity and concomitant toxicokinetics of total alkaloid extracts from seeds of P. harmala (TAEP) after oral administration for four weeks in rats.

Materials And Methods: The subchronic toxicity and concomitant toxicokinetics of TAEP were evaluated after 28-day oral administration in rats at daily dose levels of 15, 45, and 150 mg/kg. The signs of toxicity and mortality were monitored and recorded daily. The body weight and average food consumption were measured weekly. The analyses of hematology, biochemistry, urine, relative organ weights and histopathology were conducted at the termination of treatment and recovery phase. For concomitant toxicokinetics study, the plasma toxicokinetic parameters, tissue distribution, and excretion of predominant ingredients harmaline and harmine in TAEP and metabolites harmalol and harmol were tested.

Results: Following initial repeated exposure to high-dose (150 mg/kg/day) of TAEP excitotoxic reaction, such as tremor, was observed, but tolerated on the fourth day after multiple dosing. The significant alterations in blood glucose and lipid metabolism in liver were observed, but recovered after four weeks of drug withdrawal. The no-observed-adverse-effect level (NOAEL) of TAEP was considered to be 45 mg/kg/day under the present study conditions. There were no significant gender differences in most indexes of subchronic toxicity throughout the experimental period with the exception of food consumption and body weight. In concomitant toxicokinetics study, the alterations of dynamic characteristic for harmaline, harmine and metabolite harmol after multiple oral administration at three doses had been observed. Harmaline, harmine and metabolites harmalol and harmol were widely distributed in organs and there was no accumulation in the tissues examined. The reduction of harmaline and metabolite harmalol in brain after multiple dosing at dose of 150 mg/kg might be closely related to the tremor tolerance. The main excretory pathway for metabolites harmalol and harmol was urinary excretion via kidney.

Conclusions: The results revealed that TAEP at doses of 15 and 45 mg/kg/day in rats might be safe. Excitotoxic reaction such as tremor occurred initially at dose of 150 mg/kg/day, however, the toxicity was tolerant and reversible. In addition, harmaline and harmine in TAEP had a quick absorption into blood and metabolized to harmalol and harmol, and there was no drug accumulation in the detected tissues. Further studies should be investigated to clarify the mechanisms of tremor tolerance and neurotoxicity of TAEP.
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http://dx.doi.org/10.1016/j.jep.2019.111866DOI Listing
June 2019

Stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic pharmacodynamics, and toxic properties of vasicine enantiomers in vitro and in vivo.

Eur J Pharm Sci 2018 Oct 3;123:459-474. Epub 2018 Aug 3.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, 1200 Cailun Road, Shanghai 201203, China; Shanghai R&D Centre for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai 201203, China. Electronic address:

Vasicine (VAS) is a potential natural cholinesterase inhibitor for treatment of Alzheimer's disease. Due to one chiral centre (C-3) presenting in molecule, VAS has two enantiomers, d-vasicine (d-VAS) and l-vasicine (l-VAS). The study was undertaken to investigate the stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic effect and acute toxicity of VAS enantiomers. In results, the glucuronidation metabolic rate of l-VAS was faster than d-VAS in human liver microsomes and isoenzymes tests, and it was proved that the UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B15 were the major metabolic enzymes for glucuronidation of l-VAS, while only UGT1A9 for d-VAS, which take responsibility of the significantly less metabolic affinity of d-VAS than l-VAS in HLM and rhUGT1A9. The plasma exposure of d-VAS in rats was 1.3-fold and 1.6-fold higher than that of l-VAS after intravenous and oral administration of d-VAS and l-VAS, respectively. And the plasma exposure of the major glucuronidation metabolite d-VASG was one of tenth of l-VASG or more less, no matter by intravenous or oral administration. Both d-VAS and l-VAS were exhibited promising acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, and the BChE inhibitory activity of d-VAS with IC of 0.03 ± 0.001 μM was significantly stronger than that of l-VAS with IC of 0.98 ± 0.19 μM. The molecular docking results indicated that d-VAS and l-VAS could bind to the catalytic active site (CAS position) either of human AChE and BChE, and the BChE combing ability of d-VAS (the score of GBI/WAS dG -7.398) was stronger than that of l-VAS (the score of GBI/WAS dG -7.135). Both d-VAS and l-VAS could improving the learning and memory on scopolamine-induced memory deficits in mice. The content of acetylcholine (ACh) after oral administration d-VAS increased more than that of l-VAS in mice cortex, through inhibiting cholinesterase (ChE) and increasing choline acetyltransferase (ChAT). In addition, the LD value of d-VAS (282.51 mg·kg) was slight lower than l-VAS (319.75 mg·kg). These results indicated that VAS enantiomers displayed significantly stereoselective metabolic, pharmacokinetics, anti-amnesic effect and toxic properties in vitro and in vivo. The d-VAS might be the dominant configuration for treating Alzheimer's disease.
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http://dx.doi.org/10.1016/j.ejps.2018.07.058DOI Listing
October 2018

Establishment and application of a new HPLC qualitative and quantitative assay for Gentiana Macrophyllae Radix based on characteristic constituents of anofinic acid and its derivatives.

Biomed Chromatogr 2018 Nov 13;32(11):e4341. Epub 2018 Aug 13.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine; The MOE Key Laboratory for Standardization of Chinese Medicines; Shanghai Key Laboratory of Compound Chinese Medicines; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.

Gentiana Macrophylla Radix (GMR) is officially used as traditional Chinese medicine, but easily confused with Gentianae Radix et Rhizoma (GRR) and adulterants. This study aimed to establish an HPLC method for qualitative and quantitative analysis of GMR based on characteristic components, anofinic acid and its derivatives. HPLC analysis was performed on a C column with gradient elution using acetonitrile and 0.1% phosphoric acid as mobile phase, and detected at 240 nm by conventional methodology validation. For fingerprint analysis, RSDs of relative retention times and relative peak areas of the characteristic peaks were within 0-1.10 and 0-4.08%, respectively. For determination of 2-methoxyanofinic acid, the calibration curve showed good linearity (R  > 0.9999) within the test range. The RSDs of precision, repeatability and stability test did not exceed 2.46, 0.83 and 1.11%, respectively. The average recoveries were between 95.08 and 103.05% with RSDs ≤2.29%. The results showed that there was no significant difference among the four species of GMR, but there were significant differences among GMR, GRR and spurious breeds by principal component analysis and hierarchical cluster analysis. Anofinic acid and its derivatives, as the characteristic markers, could be used for the identification and quality control of GMR.
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http://dx.doi.org/10.1002/bmc.4341DOI Listing
November 2018

Extracts of compound Muniziqi granule suppressed uterus contraction and ameliorated oxytocin-induced primary dysmenorrhea.

J Ethnopharmacol 2018 Sep 19;223:33-40. Epub 2018 May 19.

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine; The MOE Key Laboratory for Standardization of Chinese Medicines; Shanghai Key Laboratory of Compound Chinese Medicines; Shanghai R&D Centre for Standardization of Chinese Medicines, 1200 Cailun Rood, Shanghai 201203, China; The Xinjiang Institute of Materia Medica, Urumqi, Xinjiang 830002, China. Electronic address:

Ethnopharmacological Relevance: Compound Muniziqi granule (CMG) is usually used as a traditional Uighur medicine to treat acne, chloasma, skin inflammation, primary dysmenorrhea (PDM), and menopausal syndrome. However, there are no sufficient data to support the clinic uses of CMG in PDM.

Aim Of The Study: This work aims to examine the effect of CMG as a treatment for PDM and reveal its possible therapeutic mechanism.

Materials And Methods: In vivo and in vitro mouse PDM models were utilized in this study. The mouse uterine contraction was induced by oxytocin after progynova or estradiol benzoate pretreatment. CMG, alkaloid extracts from seeds of Peganum harmala (AEP), and 10% and 95% ethanol extracts from seeds of Nigella glandulifera (EEN10 and EEN95) were given to mice in three doses by gavage. The writhing times within 30 min after oxytocin treatment were recorded to evaluate the analgesic effect, and the glutathione peroxidase (GSH-Px), malondialdehyde (MDA), 6-keto-prostaglandin F (6-k-PGF), prostaglandin F (PGF), thromboxane B2 (TXB), and nitric oxide (NO) levels in uterine tissues and PGF and MDA in serum were determined. The effects (contractile curve) of CMG, AEP, EEN10, and EEN95 on uterus contraction induced by oxytocin in isolated mouse uterus were recorded.

Results: In contrast to the control group, CMG, AEP, N10, and N95 could display analgesic activities dose dependently by reducing the writhing response of the PDM model mice. CMG, AEP, EEN10, and EEN95 could also remarkably decrease the level of PGF, 6-k-PGF, TXB, NO and MDA in uterine tissues and PGF and MDA in serum, whereas the activity of GSH-Px in uterine tissues was increased. Furthermore, CMG, AEP, EEN10, and EEN95 could significantly inhibit the frequency and amplitude of isolated uterus induced by oxytocin in a concentration-dependent manner.

Conclusions: CMG exhibited a significant protective effect on experimental PDM. The mechanisms are probably associated with abating lipid peroxidation and over-inflammatory reaction, and alleviating the contraction of isolated mouse uterus. The seeds of P. harmala and N. glandulifera in the CMG may play an important role in exerting protective effects on PDM. This study provides pre-clinic proof to the use of CMG in clinical practice of PDM.
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http://dx.doi.org/10.1016/j.jep.2018.05.024DOI Listing
September 2018

Simultaneous determination of usnic, diffractaic, evernic and barbatic acids in rat plasma by ultra-high-performance liquid chromatography-quadrupole exactive Orbitrap mass spectrometry and its application to pharmacokinetic studies.

Biomed Chromatogr 2018 Mar 9;32(3). Epub 2017 Nov 9.

The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory for TCM Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Usnea longissima Ach. (Usnea) is used in pharmaceuticals, food and cosmetics. Evernic acid (EA), barbatic acid (BA), diffractaic acid (DA) and usnic acid (UA) are the most typical ingredients in U. longissima and exert a wide variety of biological functions. The study aimed to develop a sensitive method for simultaneous analysis of EA, BA, DA and UA in rat plasma and was applied to pharmacokinetic studies after consumption of UA and ethanol extract from U. longissima (UE). The samples were separated on a BEH C column by gradient elution with 0.5% formic acid in water and in methanol. The relative molecular masses of analytes were obtained in full-scan range from 50.0 to 750.0 m/z under negative ionization mode by UPLC-Q-Exactive Orbitrap MS. All validation parameters, such as lower limit of quantitation, linearity, specificity, precision, accuracy, extraction recovery, matrix effect and stability, were within acceptable ranges and the method was appropriate for biological specimen analysis. The pharmacokinetic results indicated that the absolute bioavailabilities of UA after oral administration of UA and UE reached 69.2 and 146.9%, respectively. Compared with UA in UE, the relative bioavailability of DA, BA and EA reached 103.7, 10.4 and 0.7% after oral administration of UE.
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http://dx.doi.org/10.1002/bmc.4123DOI Listing
March 2018

In in vivo evaluation of the anti-inflammatory and analgesic activities of compound Muniziqi granule in experimental animal models.

BMC Complement Altern Med 2016 Jan 22;16:20. Epub 2016 Jan 22.

Institute of Chinese Materia Medica, The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai,, 201203, China.

Background: Compound Muniziqi granule (MNZQ), a traditional Uighur medicinal preparation, comprises 13 species of medicinal plants. MNZQ is traditionally used for regulating body immunity, modulating inflammation and pain, detoxification, and inhibiting tumor growth. This study aims to scientifically evaluate the anti-inflammatory and analgesic activities of MNZQ, support its clinical use and further research with scientific evidence.

Methods: The analgesic activity of MNZQ was evaluated using hot plate test and acetic acid-induced abdominal writhing test. Acute inflammation was evaluated using xylene-induced ear edema and carrageenan-induced paw edema models, while chronic inflammation was evaluated using cotton pellet-induced granuloma model.

Results: MNZQ exerted analgesic activities with a significant dose-dependent increase in latency in the hot plate test. The percentage inhibition suggested that MNZQ exhibited analgesic activities in the central nervous system. Meanwhile, MNZQ at 0.8, 2.4, and 7.2 g/kg strongly inhibited the acetic acid-induced writhing response by 25.22% (p < 0.01), 44.60% (p < 0.001), and 49.41% (p < 0.001), respectively. MNZQ also exerted analgesic activities in the peripheral nervous system. Moreover, MNZQ was demonstrated a significant anti-inflammatory effect against xylene-induced edema in a dose-dependent manner. The percentage inhibition was 22.24% (p < 0.01) at the highest dosage of 7.2 g/kg. MNZQ at 1.62 and 4.86 g/kg significantly reduced carrageenan-induced rat hind paw edema by 82.43% and 84.32% (p < 0.001), respectively, 1 h after injecting carrageenan, and the inhibitory effect lasted for 5 h. MNZQ also exerted a significant anti-inflammatory effect against cotton pellet-induced granuloma formation. MNZQ at 1.62 and 4.86 g/kg could inhibit granuloma formation by 17.07% and 17.60%, respectively, whereas the percentage inhibition of diclofenac was 33.12%.

Conclusions: The results obtained suggest that MNZQ possesses potential anti-inflammatory and analgesic activities. This study provides a scientific basis for the use of MNZQ in alleviating pain and treating inflammatory disorders.
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http://dx.doi.org/10.1186/s12906-016-0999-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722770PMC
January 2016
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