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Sun N.,Shanghai University | Sun N.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | Xie Y.,Shanghai JiaoTong University | Sheng C.,Shanghai University | And 5 more authors.
International Journal of Antimicrobial Agents | Year: 2013

In this study, the distribution of a new triazole drug, iodiconazole, in rat dermal interstitial fluid and blood was investigated by double-site microdialysis following dermal administration. It was demonstrated that well-calibrated microdialysis sampling in rats could be used to assess the percutaneous penetration kinetics of iodiconazole cream. Iodiconazole penetrated rapidly and cleared slowly from the dermis. The ratio of area under the concentration-time curve in dermis (AUCdermis) to that in blood (AUCblood) was close to 20, which meant that the free iodiconazole concentration had a higher distribution in the target tissue. Subsequently, the in vitro antifungal activities of iodiconazole were evaluated and were compared with those of fluconazole, itraconazole, ketoconazole, miconazole and terbinafine. Iodiconazole exhibited broad spectrum and potent activity against 12 kinds of clinically pathogenic fungi. The drug concentration percentage inhibition curves versus time of iodiconazole against the tested fungi elucidated the two-dimensional relationship (concentration-effect) following drug administration, indicating that the percentage inhibition (%) of iodiconazole compared with the drug-free control in dermal dialysate were all >90% in the 900-min sampling time following dermal administration. Moreover, integration of in vivo pharmacokinetic data with the in vitro minimum inhibitory concentration (MIC) provided iodiconazole AUC/MIC ratios in rat dermis and blood of 347.7 h and 18.8 h, respectively, with an iodiconazole cream (2%) dosage of 0.033 g/cm2 (3 cm × 5 cm). These findings show a reservoir effect in the skin following topical application. Iodiconazole topical cream may be a future alternative for treatment of dermatophytosis in humans. © 2012 Elsevier B.V. and the International Society of Chemotherapy.


Tan G.,Shanghai University | Tan G.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | Liao W.,Shanghai University | Liao W.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | And 9 more authors.
PLoS ONE | Year: 2012

Background: In spite of great advances in target-oriented Western medicine for treating myocardial infarction (MI), it is still a leading cause of death in a worldwide epidemic. In contrast to Western medicine, Traditional Chinese medicine (TCM) uses a holistic and synergistic approach to restore the balance of Yin-Yang of body energy so the body's normal function can be restored. Sini decoction (SND) is a well-known formula of TCM which has been used to treat MI for many years. However, its holistic activity evaluation and mechanistic understanding are still lacking due to its complex components. Methodology/Principal Findings: A urinary metabonomic method based on nuclear magnetic resonance and ultra high-performance liquid chromatography coupled to mass spectrometry was developed to characterize MI-related metabolic profiles and delineate the effect of SND on MI. With Elastic Net for classification and selection of biomarkers, nineteen potential biomarkers in rat urine were screened out, primarily related to myocardial energy metabolism, including the glycolysis, citrate cycle, amino acid metabolism, purine metabolism and pyrimidine metabolism. With the altered metabolism pathways as possible drug targets, we systematically analyze the therapeutic effect of SND, which demonstrated that SND administration could provide satisfactory effect on MI through partially regulating the perturbed myocardial energy metabolism. Conclusions/Significance: Our results showed that metabonomic approach offers a useful tool to identify MI-related biomarkers and provides a new methodological cue for systematically dissecting the underlying efficacies and mechanisms of TCM in treating MI. © 2012 Tan et al.


Xu L.-L.,Shanghai University | Li Y.-Y.,Shanghai University | Han T.,Shanghai University | Zhang Q.-Y.,Shanghai University | And 3 more authors.
Applied Microbiology and Biotechnology | Year: 2013

Two strains of endophytic fungi, Penicillium melinii Yuan-25 and Penicillium janthinellum Yuan-27, with strong anti-Pyricularia oryzae activity, were obtained from the roots of Panax ginseng. Based on bioactivity-oriented isolation, a new benzaldehyde derivative, ginsenocin (1), together with six known compounds, methyl 2,4-dihydroxy- 3,5,6-trimethylbenzoate (2), 3,4,5-trimethyl-1,2-benzenediol (3), penicillic acid (4), mannitol (5), ergosterol (6), and ergosterol peroxide (7), were separated from the EtOAc extract of Yuan-25 culture, while brefeldin A (8) was isolated as the major constituent from the EtOAc extract of Yuan-27 culture. The chemical structures were determined based on spectroscopic methods. All the isolated compounds 1-8 were evaluated for their cytotoxicity against six human cancer cell lines. Brefeldin A (8) was the most cytotoxic constituent against all the tested cell lines with IC50 values ≤0.12 μg/ml, while ginsenocin (1) and penicillic acid (4) also exhibited potent cytotoxicity with IC50 values ranging from0.49 to 7.46 μg/ml. Our results suggest that endophytic fungi isolated from P. ginseng are a promising natural source of potential anticancer agents. © Springer-Verlag Berlin Heidelberg 2013.


Tan G.,Shanghai University | Tan G.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | Lou Z.,Shanghai University | Liao W.,Shanghai University | And 8 more authors.
Molecular BioSystems | Year: 2012

An ultra performance liquid chromatography coupled to mass spectrometry-based metabonomic approach, which utilizes both reversed-performance (RP) chromatography and hydrophilic interaction chromatography (HILIC) separations, has been developed to characterize the global serum metabolic profile associated with myocardial infarction (MI). The HILIC was found necessary for a comprehensive serum metabonomic profiling, providing complementary information to RP chromatography. By combining with partial least squares discriminant analysis, 21 potential biomarkers in rat serum were identified. To further elucidate the pathophysiology of MI, related metabolic pathways have been studied. It was found that MI was closely related to disturbed sphingolipid metabolism, phospholipid catabolism, fatty acid transportation and metabolism, tryptophan metabolism, branched-chain amino acids metabolism, phenylalanine metabolism, and arginine and proline metabolism. With the presented metabonomic method, we systematically analyzed the therapeutic effects of Traditional Chinese Medicine Sini decoction (SND). The results demonstrated that SND administration could provide satisfactory effects on MI through partially regulating the perturbed metabolic pathways. © 2012 The Royal Society of Chemistry.


Ming Q.,Shanghai University | Su C.,Shanghai University | Zheng C.,Shanghai University | Jia M.,Shanghai University | And 6 more authors.
Journal of Experimental Botany | Year: 2013

Biotic elicitors can be used to stimulate the production of secondary metabolites in plants. However, limited information is available on the effects of biotic elicitors from endophytic fungi on their host plant. Trichoderma atroviride D16 is an endophytic fungus isolated from the root of Salvia miltiorrhiza and previously reported to produce tanshinone I (T-I) and tanshinone IIA (T-IIA). Here, the effects of extract of mycelium (EM) and the polysaccharide fraction (PSF), produced by T. atroviride D16, on the growth and secondary metabolism of S. miltiorrhiza hairy roots are reported. The results indicated that both EM and PSF promoted hairy root growth and stimulated the biosynthesis of tanshinones in hairy roots. EM slightly suppressed the accumulation of phenolic acids, while PSF had no significant influence on the accumulation of these compounds. When comparing the effects of EM versus PSF, it was concluded that PSF is one of the main active constituents responsible for promoting hairy root growth, as well as stimulating biosynthesis of tanshinones in the hairy root cultures. Moreover, the transcriptional activity of genes involved in the tanshinone biosynthetic pathway increased significantly with PSF treatment. Thus, PSF from endophytic T. atroviride D16 affected the chemical composition of the host plant by influencing the expression of genes related to the secondary metabolite biosynthetic pathway. Furthermore, treatment with PSF can be effectively utilized for large-scale production of tanshinones in the S. miltiorrhiza hairy root culture system. © The Author 2013. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved.


Chen X.,China Pharmaceutical University | Chen X.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | Cao Y.,China Pharmaceutical University | Cao Y.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | And 8 more authors.
Journal of Chromatography A | Year: 2012

Cell membrane chromatography (CMC) is a biological affinity chromatographic method using specific cell membrane as stationary phase. It has been proved to be a practical tool for investigating binding interactions between drugs and membrane receptors. In this study, a novel comprehensive two-dimensional (2D) chromatography approach was established for screening anti-tumor components from herbal medicines (HMs). HepG2/CMC model was first developed and applied as the first dimensional column. Using an automatic ten-port switching valve equipped with two sample loops, the fractions of the first-dimension were introduced in the second-dimension consists of a monolithic column and a time-of-flight mass spectrometry (TOFMS) with high resolving ability. Based on the stability, selectivity and suitability assays of the HepG2/CMC/monolithic column/TOFMS system, berberine (BBR) and tetrahydropalmatine (THP) from Cortex phellodendri amurensis, oxymatrine and matrine from Radix sophorae fl{ligature}avescentis were screened and identified as potential active components. The competitive displacement assay suggested that the four components could act on epidermal growth factor receptor region on the HepG2 cell membrane in similar manner of gefitinib. Furthermore, their inhibiting effects on cell proliferation in vitro were also confirmed and, BBR and THP showed concentration dependently inhibitory ability on HepG2 cell proliferation (p<0.05). The result demonstrated that the proposed comprehensive 2D HepG2/CMC/monolithic column/TOFMS system has the advantages of strong recognition and rapid analysis abilities for the total screening procedure, which will be selectable and practical in drug discovery from complex HM samples and can also be applied to other biochromatography models. © 2012 Elsevier B.V.


Li W.,Shanghai University | Li W.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | Tan G.,Shanghai University | Tan G.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | And 8 more authors.
Analytica Chimica Acta | Year: 2012

Chiral separation of iodiconazole, a new antifungal drug, and 12 new structurally related triadimenol analogues had been developed by capillary electrophoresis (CE) using hydroxypropyl-γ-cyclodextrin (HP-γ-CD) as the chiral selector. The effect of structural features of analytes on Δt and R s was studied under the optimum separation conditions. Using molecular docking technique and binding energy calculations, the inclusion process between HP-γ-CD and enantiomers was investigated and chiral recognition mechanisms were discussed. The results suggest that hydrogen bonding between fluorine at position 4 of the phenyl group beside the chiral carbon and the hydroxyl group on the HP-γ-CD rim and face to face π-π interactions between two phenyl rings highly contributed to the enantiorecognition process between HP-γ-CD and iodiconazole. The N-methyl group beside chiral carbon also played an important role in enantiomeric separation. Additionally, the big difference in binding energy (ΔΔE) highly contributed to good separation in the presence of HP-γ-CD chiral selector, which may be a helpful initial guide for chiral selector selection and predicting the result of enantioseparation. Furthermore, the new mathematical equation established based on the results of molecular mechanics calculations exhibited good capability in predicting chiral separation of these triadimenol analogues using HP-γ-CD mediated CE. © 2012 Elsevier B.V.


Zheng C.-J.,Shanghai University | Zhao X.-X.,Shanghai University | Ai H.-W.,Shanghai University | Lin B.,Shanghai University | And 5 more authors.
Phytomedicine | Year: 2014

The seeds of Vitex negundo L. (Verbenaceae) have been commonly used as a folk remedy for the treatment of rheumatism and joint inflammation in Traditional Chinese Medicine. This study aimed to evaluate the anti-arthritic activity of the extract of V. negundo seeds (EVNS) using Freund's complete adjuvant (CFA) induced arthritis (AA) in rat model. As a result, EVNS, with abundant phenylnaphthalene-type lignans, significantly inhibited the paw edema, decreased the arthritis score and spleen index, and reversed the weight loss of CFA-injected rats. Histopathological studies showed a marked decrease of synovial inflammatory infiltration and synovial lining hyperplasia in the joints of EVNS-treated animals. The remarkable decrement of serum inflammatory factors (TNF-α, IL-1β and IL-6) were observed in EVNS-treated rats, whereas, IL-10, an anti-inflammatory cytokine, was found to be significantly increased by EVNS. The expressions of COX-2 and 5-LOX in PBMC were also inhibited by administration of EVNS. Our results demonstrated that V. negundo seeds possessed potential therapeutic effect on adjuvant induced arthritis in rats by decreasing the levels of TNF-α, IL-1β and IL-6 and increasing that of IL-10 in serum as well as down-regulating the levels of COX-2 and 5-LOX, and therefore may be an effective cure for the treatment of human rheumatoid arthritis. © 2014 Elsevier GmbH.


Zheng C.-J.,Shanghai University | Zhang X.-W.,No 107 Hospital Of Pla | Han T.,Shanghai University | Jiang Y.-P.,Shanghai University | And 4 more authors.
Fitoterapia | Year: 2014

Chemical investigation of Vitex negundo seeds afforded four new lignans, including a phenylindene-type lignan, vitexdoin F (1), and three phenylnaphthalene-type lignans, vitexdoins G, H and I (2-4). Their structures were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. All compounds were evaluated for their anti-inflammatory and anti-osteoporotic activities, employing RAW264.7 macrophages, osteoblast-like UMR106 and osteoclastic cells, respectively. Compound 1 showed significant inhibition on the nitric oxide (NO) production (IC50 4.17 μg/mL) due to its down-regulation of the inducible nitric oxide synthase (iNOS) protein expression in LPS-stimulated RAW264.7 cells, which also exhibited potent stimulatory effects on the proliferation and ALP (alkaline phosphatase) activity of UMR106 cells, and significantly up-regulated the OPG/RANKL protein ratio. © 2013 Elsevier B.V.


Wang C.,China Pharmaceutical University | Wang C.,CAS Dalian Institute of Chemical Physics | Wang C.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research | Wang S.,China Pharmaceutical University | And 4 more authors.
Analytical and Bioanalytical Chemistry | Year: 2010

Formalin-induced pain models were used in rats to evaluate the antinociceptive effect of the total alkaloids of Corydalis yanhusuo (TAC). The results indicated that formalin-evoked spontaneous nociceptive responses (licking behavior) could be inhibited significantly by giving (intragingival) TAC at a single dose of 150 mg/kg. Subsequently, an online comprehensive two-dimensional biochromatography method with a silica-bonded human serum albumin (HSA) column in the first dimension and a monolithic ODS column in the second was developed. The absorbed bioactive components were screened by comparing and contrasting the components detected in the plasma and striatum with those in TAC. More than 100 compounds were separated and detected in the TAC, among which 13 compounds were identified. About 40 compounds (seven compounds identified) were absorbed into the plasma with appropriate concentrations and about 20 compounds (four compounds identified) passed through the blood-brain barrier into the striatum. Of interest, four compounds (protopine, glaucine, tetrahydropalmatine, and corydaline) which were reported to possess profound antinociceptive effects exhibited high concentrations in the striatum. This may result from their synergistic effects in regulating the formalin-induced nociception. The results indicated that the comprehensive two-dimensional biochromatography method developed is capable of screening the bioactive components in Corydalis yanhusuo and providing valuable information for understanding the mechanisms by which Corydalis yanhusuo alleviates nociception. © 2009 Springer-Verlag.

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