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Zhang M.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Liu J.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Chen R.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Chen R.,Peking Union Medical College | And 8 more authors.
Organic Letters | Year: 2017

Furanharzianones A and B (2 and 3), two new harziane-type diterpenoids with a tetrahydrofuran and unusual 4/7/5/6/5 ring system, were obtained from the microbial transformation of harzianone (1) by a bacterial strain Bacillus sp. IMM-006. The structures, including the stereochemistry, of the two new compounds were elucidated by extensive spectroscopic analysis. The absolute configuration of 2 was unambiguously determined by single-crystal X-ray diffraction. In addition, a plausible bioconversion pathway was proposed. © 2017 American Chemical Society.


Wang S.-B.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Wang S.-B.,Peking Union Medical College | Pang X.-B.,Peking Union Medical College | Zhao Y.,Peking Union Medical College | And 8 more authors.
Journal of Asian Natural Products Research | Year: 2012

Epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH) have been associated with ischemic stroke. Salvianolic acid A (SAA) is proved to display potent cerebroprotection. However, little information is available about the link between them. This study aimed to investigate whether SAA exhibits its protective effects in rats subjected to middle cerebral artery occlusion (MCAO) through sEH and EETs. The results showed that SAA treatment ameliorated neurological deficits and reduced infarct volume. Notably, the beneficial effects of SAA were attenuated by co-administration of (14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE)), a putative selective EETs antagonist. Furthermore, SAA increased the 14,15-EET levels in the blood and brain of sham and MCAO rats. Assay for hydrolase activity showed that 1 and 3 mg/kg of SAA significantly diminished brain sEH activity of MCAO rats. A fluorescent assay in vitro indicated that SAA could inhibit recombinant human sEH activity in a concentration-dependent manner (IC50 = 1.62 μmol/l). Immunohistochemical analysis showed that SAA at the doses of 1 and 3 mg/kg significantly decreased sEH protein expression in hippocampus CA1 region of MCAO rats. In conclusion, cerebral protection of SAA is mediated, at least in part, via inhibiting sEH to increase EETs levels. © 2012 Copyright Taylor and Francis Group, LLC.


Fang J.-S.,Peking Union Medical College | Liu A.-L.,Peking Union Medical College | Liu A.-L.,Beijing Key Laboratory of Drug Target and Screening Research | Liu A.-L.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | And 3 more authors.
Yaoxue Xuebao | Year: 2014

The emerging of network pharmacology and polypharmacology forces the scientists to recognize and explore new mechanisms of existing drugs. The drug target prediction can play a key significance on the elucidation of the molecular mechanism of drugs and drug reposition. In this paper, we systematically review the existing approaches to the prediction of biological targets of small molecule based on chemoinformatics, including ligand-based prediction, receptor-based prediction and data mining-based prediction. We also depict the strength of these methods as well as their applications, and put forward their developing direction.


Lian W.,Peking Union Medical College | Fang J.,Peking Union Medical College | Li C.,Peking Union Medical College | Pang X.,Peking Union Medical College | And 6 more authors.
Molecular Diversity | Year: 2016

Neuraminidase (NA) is a critical enzyme in the life cycle of influenza virus, which is known as a successful paradigm in the design of anti-influenza agents. However, to date there are no classification models for the virtual screening of NA inhibitors. In this work, we built support vector machine and Naïve Bayesian models of NA inhibitors and non-inhibitors, with different ratios of active-to-inactive compounds in the training set and different molecular descriptors. Four models with sensitivity or Matthews correlation coefficients greater than 0.9 were chosen to predict the NA inhibitory activities of 15,600 compounds in our in-house database. We combined the results of four optimal models and selected 60 representative compounds to assess their NA inhibitory profiles in vitro. Nine NA inhibitors were identified, five of which were oseltamivir derivatives with large C-5 substituents exhibiting potent inhibition against H1N1 NA with (Formula presented.) values in the range of 12.9–185.0 nM, and against H3N2 NA with (Formula presented.) values between 18.9 and 366.1 nM. The other four active compounds belonged to novel scaffolds, with (Formula presented.) values ranging 39.5–63.8  (Formula presented.) M against H1N1 NA and 44.5–114.1  (Formula presented.) M against H3N2 NA. This is the first time that classification models of NA inhibitors and non-inhibitors are built and their prediction results validated experimentally using in vitro assays. © 2015, Springer International Publishing Switzerland.


Wu M.-M.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Yuan Y.-H.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Chen J.,Tianjin University of Traditional Chinese Medicine | Li C.-J.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | And 5 more authors.
Journal of Asian Natural Products Research | Year: 2014

To investigate the protective effect and the underlying mechanism of polygalasaponin F (PS-F) against rotenone-induced PC12 cells, the cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The cell apoptosis rate was analyzed using flow cytometry. The reactive oxygen species was examined using 2′,7′-dichlorofluorescin diacetate, and the adenosine triphosphate depletion was examined using a luciferase-coupled quantification assay. JC-1 staining was used to detect the mitochondrial membrane potential. Western blotting analysis was used to determine cytochrome c, p53, Bax, Bcl-2, and caspase-3. Treatment of PC12 cells with rotenone (1-10 mol/l) significantly reduced the cell viability in a concentration-dependent manner. Treatment with PS-F (0.1, 1, and 10 mol/l) increased the viability of rotenone-induced PC12 cells, decreased rotenone-induced apoptosis, restored rotenone-induced mitochondrial dysfunction, and suppressed rotenone-induced protein expression. PS-F showed a dose-dependent manner in all the treatments. PS-F protects PC12 cells against rotenone-induced apoptosis via ameliorating the mitochondrial dysfunction. Thus, PS-F may be a potential bioactive compound for the treatment of Parkinson's disease. © 2013 Taylor & Francis.


Gao L.,Peking Union Medical College | Zhao G.,Peking Union Medical College | Fang J.-S.,Peking Union Medical College | Yuan T.-Y.,Peking Union Medical College | And 4 more authors.
FEBS Journal | Year: 2014

Based on public gene expression data, we propose a computational approach to optimize gene expression signatures for the use with Connectivity Map (CMap) to reposition drugs or discover lead compounds for Parkinson's disease. This approach integrates genetic information from the Gene Expression Omnibus (GEO) database, the Parkinson's disease gene expression database (ParkDB), the Online Mendelian Inheritance in Man (OMIM) database and the Comparative Toxicogenomics Database (CTD), with the aim of identifying a set of interesting genes for use in computational drug screening via CMap. The results showed that CMap, using the top 20 differentially expressed genes identified by our approach as a gene expression signature, outperformed the same method using all differentially expressed genes (n = 535) as a signature. Utilizing this approach, the candidate compound alvespimycin (17-DMAG) was selected for experimental evaluation in a model of rotenone-induced toxicity in human SH-SY5Y neuroblastoma cells and isolated rat brain mitochondria. The results showed that 17-DMAG significantly attenuated rotenone-induced toxicity, as reflected by the increase of cell viability, the reduction of intracellular reactive oxygen species generation and a reduction in mitochondrial respiratory dysfunction. In conclusion, this computational method provides an effective systematic approach for drug repositioning or lead compound discovery for Parkinson's disease, and the discovery of the neuroprotective effects of 17-DMAG supports the practicability of this method. © 2013 FEBS.


Lu H.-N.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Liu Y.-B.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Qu J.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | Li Y.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines | And 3 more authors.
Journal of Asian Natural Products Research | Year: 2015

Two new sesquiterpenes, oligandrin (1) and oligandric acid (2), together with three analogues, tashironin A (3), tashironin (4), and oplodiol (5), were isolated from the roots of Illicium oligandrum. The structures of new compounds were determined based on 1D and 2D NMR experiments and X-ray diffraction. Compound 1 represents a presumed biosynthetic precursor of seco-prezizaane sesquiterpenes which consists of a novel 6/6/5 tricarbocyclic skeleton. Compound 2 is the first example of chamipinene-type sesquiterpene possessing a 6/4/6 tricyclic system from the genus Illicium. Compounds 1–5 were evaluated in vitro for their activity against coxsackie virus B3 (CVB3), influenza virus A/Hanfang/359/95 (H3N2), and influenza virus A/FM/1/47 (H1N1). Compound 1 showed selective antiviral activity against CVB3 with IC50 value of 11.11 μM. © 2015 Taylor & Francis


Gao L.,Peking Union Medical College | Gao L.,Modern Medicine | Li C.,Peking Union Medical College | Yang R.-Y.,Peking Union Medical College | And 8 more authors.
Pharmacology Biochemistry and Behavior | Year: 2015

Baicalein, a flavonoid from Scutellaria baicalensis Georgi, has been shown to possess neuroprotective properties. The purpose of this study was to explore the effects of baicalein on motor behavioral deficits and gene expression in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease (PD). The behavioral results showed that baicalein significantly improves the abnormal behaviors in MPTP-induced mice model of PD, as manifested by shortening the total time for climbing down the pole, prolonging the latent periods of rotarod, and increasing the vertical movements. Using cDNA microarray and subsequent bioinformatic analyses, it was found that baicalein significantly promotes the biological processes including neurogenesis, neuroblast proliferation, neurotrophin signaling pathway, walking and locomotor behaviors, and inhibits dopamine metabolic process through regulation of gene expressions. Based on analysis of gene co-expression networks, the results indicated that the regulation of genes such as LIMK1, SNCA and GLRA1 by baicalein might play central roles in the network. Our results provide experimental evidence for the potential use of baicalein in the treatment of PD, and revealed gene expression profiles, biological processes and pathways influenced by baicalein in MPTP-treated mice. © 2015 Elsevier Inc. All rights reserved.


Fang J.,Peking Union Medical College | Yang R.,Peking Union Medical College | Gao L.,Peking Union Medical College | Zhou D.,Peking Union Medical College | And 7 more authors.
Journal of Chemical Information and Modeling | Year: 2013

Butyrylcholinesterase (BuChE, EC 3.1.1.8) is an important pharmacological target for Alzheimer's disease (AD) treatment. However, the currently available BuChE inhibitor screening assays are expensive, labor-intensive, and compound-dependent. It is necessary to develop robust in silico methods to predict the activities of BuChE inhibitors for the lead identification. In this investigation, support vector machine (SVM) models and naive Bayesian models were built to discriminate BuChE inhibitors (BuChEIs) from the noninhibitors. Each molecule was initially represented in 1870 structural descriptors (1235 from ADRIANA.Code, 334 from MOE, and 301 from Discovery studio). Correlation analysis and stepwise variable selection method were applied to figure out activity-related descriptors for prediction models. Additionally, structural fingerprint descriptors were added to improve the predictive ability of models, which were measured by cross-validation, a test set validation with 1001 compounds and an external test set validation with 317 diverse chemicals. The best two models gave Matthews correlation coefficient of 0.9551 and 0.9550 for the test set and 0.9132 and 0.9221 for the external test set. To demonstrate the practical applicability of the models in virtual screening, we screened an in-house data set with 3601 compounds, and 30 compounds were selected for further bioactivity assay. The assay results showed that 10 out of 30 compounds exerted significant BuChE inhibitory activities with IC50 values ranging from 0.32 to 22.22 μM, at which three new scaffolds as BuChE inhibitors were identified for the first time. To our best knowledge, this is the first report on BuChE inhibitors using machine learning approaches. The models generated from SVM and naive Bayesian approaches successfully predicted BuChE inhibitors. The study proved the feasibility of a new method for predicting bioactivities of ligands and discovering novel lead compounds. © 2013 American Chemical Society.


PubMed | State Key Laboratory of Bioactive Substance and Function of Natural Medicines
Type: Journal Article | Journal: Journal of Asian natural products research | Year: 2013

Epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH) have been associated with ischemic stroke. Salvianolic acid A (SAA) is proved to display potent cerebroprotection. However, little information is available about the link between them. This study aimed to investigate whether SAA exhibits its protective effects in rats subjected to middle cerebral artery occlusion (MCAO) through sEH and EETs. The results showed that SAA treatment ameliorated neurological deficits and reduced infarct volume. Notably, the beneficial effects of SAA were attenuated by co-administration of (14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE)), a putative selective EETs antagonist. Furthermore, SAA increased the 14,15-EET levels in the blood and brain of sham and MCAO rats. Assay for hydrolase activity showed that 1 and 3mg/kg of SAA significantly diminished brain sEH activity of MCAO rats. A fluorescent assay in vitro indicated that SAA could inhibit recombinant human sEH activity in a concentration-dependent manner (IC(50)=1.62mol/l). Immunohistochemical analysis showed that SAA at the doses of 1 and 3mg/kg significantly decreased sEH protein expression in hippocampus CA1 region of MCAO rats. In conclusion, cerebral protection of SAA is mediated, at least in part, via inhibiting sEH to increase EETs levels.

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