Yu Shen

Chinese Academy of Sciences, Peping, Beijing, China

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Publications (24)77.18 Total impact

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    ABSTRACT: Analogues of the natural product (-)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (-)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure-activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.
    ACS Medicinal Chemistry Letters 04/2015; 6(4):386-91. DOI:10.1021/acsmedchemlett.5b00007 · 3.07 Impact Factor
  • RSC Advances 03/2015; 5(34). DOI:10.1039/C5RA01857A · 3.71 Impact Factor
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    ABSTRACT: Five selective 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) competitive inhibitors, hupehenols A-E (1-5), were isolated from Viburnum hupehense. The structure elucidation indicated that compounds 1-5 are new 20,21,22,23,24,25,26,27-octanordammarane triterpenoids. Their structures were established on the basis of NMR spectroscopic and mass spectrometric analysis. Hupehenols A-E (1-5) showed inhibition against human 11β-HSD1, with hupehenols B (2) and E (5) having IC50 values of 15.3 and 34.0 nM, respectively. Moreover, hupehenols C (3) and D (4) are highly selective inhibitors of human 11β-HSD1 when compared to murine 11β-HSD1.
    Journal of Natural Products 01/2015; 78(2). DOI:10.1021/np500896n · 3.95 Impact Factor
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    ABSTRACT: Chemical investigation of the cupules of Lithocarpus polystachyus resulted in the identification of four 3,4-seco-homo-cycloartane and one homo-cycloartane derivatives named lithocarpic acids O-S. Their structures were determined based on extensive 1D/2D NMR, IR, MS spectroscopic analyses and chemical methods. Lithocarpic acid O (1) exhibited inhibitory activities on mouse and human isozymes of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC50 values of 0.49 and 1.1μM, respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Bioorganic & Medicinal Chemistry Letters 10/2014; 24(23). DOI:10.1016/j.bmcl.2014.10.036 · 2.33 Impact Factor
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    ABSTRACT: Fourteen new 3,4-seco-cycloartane-type triterpenes, lithocarpic acids A-N (1-14), together with one known compound, coccinetane E (15), were identified from the cupules of Lithocarpus polystachyus. The structures of 1-14 were determined by spectroscopic data analysis and chemical methods, and the absolute configurations of 1 and 4 were defined unequivocally by X-ray crystallography using Cu Kα radiation. Compounds 1-15 are the first examples of 3,4-seco-cycloartane derivatives isolated from the genus Lithocarpus. Among them, compounds 1 and 2, 9 and 10, and 11 and 12 were found to be three pairs of C-24 epimers, while compounds 7 and 8 represent the first examples of 3,4-seco-norcycloartane-type triterpenes. Compound 1, as the major component of the plant extract, showed potent antibacterial activity against Micrococcus luteus and Bacillus subtilis, with MIC values of 3.1 and 6.3 μg/mL, respectively, as well as inhibitory activity against human and mouse 11β-hydroxysteroid dehydrogenase type 1, with IC50 values of 1.9 and 0.24 μM, respectively.
    Journal of Natural Products 08/2014; 77(8). DOI:10.1021/np500379f · 3.95 Impact Factor
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    ABSTRACT: An exploration for 11β-HSD1 inhibitors from Homonoia riparia returned eight new dammarane-type triterpenoids, horipenoids A-H (), and a known oleanane-type triterpenoid (). Their structures were elucidated on the basis of comprehensive analysis of spectroscopic data, and the absolute configuration of horipenoid E () was established by single crystal X-ray crystallography. Compounds represent a rare class of octanortriterpenoids. Horipenoids C () and E () showed potent inhibition against mouse 11β-HSD1 with IC50 values of 0.810 ± 0.058 and 0.898 ± 0.215 μM, respectively.
    Organic & Biomolecular Chemistry 05/2014; DOI:10.1039/c4ob00807c · 3.49 Impact Factor
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    ABSTRACT: Eighteen new ingol-type diterpenes, euphorantins A-R (1-18), along with four known analogues (19-22), were isolated from the aerial parts of Euphorbia antiquorum. Compounds 1-3 are the first examples of C-17-oxygenated ingol-type diterpenes, and compounds 16-18 represent a rare class of 2,3-di-epimers of ingols. Diterpenes 1, 14, and 22 exhibited inhibitory activities against mouse 11β-HSD1 with IC50 values of 12.0, 6.4, and 0.41 μM, respectively.
    Journal of Natural Products 05/2014; 77(6). DOI:10.1021/np5002237 · 3.95 Impact Factor
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    ABSTRACT: Eleven new guanidine alkaloids, plumbagines A-G (2-8) and plumbagosides A-D (9-12), as well as two known analogues (1, 13), were isolated from the aerial parts of Plumbago zeylanica. Their structures were elucidated by spectroscopic analyses including 1D and 2D NMR, MS, IR, and CD methods. The absolute configuration of 1 was determined by single-crystal X-ray diffraction of its derivative (1a).
    Journal of Natural Products 07/2013; 76(7). DOI:10.1021/np400235s · 3.95 Impact Factor
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    ABSTRACT: A search for inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) from Walsura cochinchinensis yielded 10 new limonoids, cochinchinoids A-J (1-10), and two new triterpenoids, 3-epimesendanin S (11) and cochinchinoid K (12). Their structures were assigned on the basis of spectroscopic data, with the absolute configurations of 1 and 12 being established by X-ray diffraction analysis. Of these compounds, cochinchinoid K (12) displayed inhibitory activity against mouse 11β-HSD1 with an IC50 value of 0.82 μM.
    Journal of Natural Products 06/2013; 76(7). DOI:10.1021/np400260g · 3.95 Impact Factor
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    ABSTRACT: The biological screening of a collection of nature occurring diterpenoids against 11β-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11β-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11β-HSD1) = 9.4 nM and selectivity index (human 11β-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11β-HSD1 were generated using docking simulations. Based on the results, the structural-activity relationships (SARs) of compounds 1b and 2 were also discussed.
    European Journal of Medicinal Chemistry 05/2013; 65C:403-414. DOI:10.1016/j.ejmech.2013.05.010 · 3.43 Impact Factor
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    ABSTRACT: Aberrant nuclear localization of oncogenic transcription factor and coactivator always leads to the development of cancer. We have reported that the oncoprotein hepatitis B virus X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. However, the mechanism of regulating nuclear import of HBXIP remains unclear. In the present study, we found that HBXIP was interacted with c-Fos through their leucine zipper domains in vitro and in vivo. Interestingly, the mutant of leucine zipper of HBXIP (or c-Fos) was unavailable to bind to c-Fos (or HBXIP), resulting in the disappearance of nuclear localization of HBXIP. Moreover, we revealed that the HBXIP nuclear import required for phosphorylation of c-Fos at Thr-232, Thr-325, Thr-331 and Ser-374 by ERK1/2. In addition, the mutant of HBXIP at Ser-108 phosphorylation site failed to import into the nucleus. Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser-108. The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked HBXIP nuclear import. Then, we identified that ATM could bind to HBXIP. Moreover, we validated that the nuclear import of HBXIP contributed to its nuclear function. Therefore, we conclude that the nuclear import of oncoprotein HBXIP requires the interaction with c-Fos through their leucine zipper domains and phosphorylation of both proteins in breast cancer cells. Thus, our finding provides new insights into the mechanism of HBXIP nuclear import. Therapeutically, the block of HBXIP nuclear import is significant in breast cancer.
    Journal of Biological Chemistry 05/2013; DOI:10.1074/jbc.M113.458638 · 4.60 Impact Factor
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    ABSTRACT: We have reported that the oncoprotein hepatitis B virus X-interacting protein (HBXIP) acts as a novel transcriptionalcoactivator to promote proliferation and migration of breast cancer cells. Previously, we showed that HBXIP was able to activate nuclear factor-κB (NF-κB) in breast cancer cells. As an oncogene, the platelet-derived growth factor beta polypeptide (PDGFB) plays crucial roles in carcinogenesis. In the present study, we found that both HBXIP and PDGFB were highly expressed in breast cancer cell lines. Interestingly, HBXIP was able to increase transcriptional activity of NF-κB through PDGFB, suggesting that HBXIP is associated with PDGFB in the cells. Moreover, HBXIP was able to upregulate PDGFB at the levels of mRNA, protein and promoter in the cells. Then, we identified that HBXIP stimulated the promoter of PDGFB through activating transcription factor Sp1. In function, HBXIP enhanced the proliferation of breast cancer cells through PDGFB in vitro. Thus, we conclude that HBXIP upregulates PDGFB via activating transcription factor Sp1 to promote proliferation of breast cancer cells.
    Biochemical and Biophysical Research Communications 03/2013; 434(2). DOI:10.1016/j.bbrc.2013.02.123 · 2.28 Impact Factor
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    ABSTRACT: Five new triterpenoids, caloncobic acids A and B (1 and 2), caloncobalactones A and B (3 and 4), and glaucalactone (5), along with the known compounds 3β,21β-dihydroxy-30-nor-(D:A)-friedo-olean-20(29)-en-27-oic acid (6) and acetyltrichadenic acid B (7), were isolated from the leaves of Caloncoba glauca. The structures of 1-5 were elucidated using spectroscopic methods. Compounds 1-7 were evaluated for their inhibitory activities against two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2). Compounds 1 and 2 exhibited strong inhibitory activities against mouse (EC(50) 132 and 13 nM) and human (EC(50) 105 and 72 nM) 11β-HSD1.
    Journal of Natural Products 02/2012; 75(4):599-604. DOI:10.1021/np200831c · 3.95 Impact Factor
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    ABSTRACT: Three novel triterpenoids, pseudoferic acids A and B (1 and 2) possessed a unique 16,24-cyclo-26-norlanostane skeleton, and pseudoferic acid C (3) featured a cis-fused D/E-ring system, were isolated from the root bark of Pseudolarix kaempferi. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 2 and 3 exhibited weak inhibitory activities against 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1) with IC50 values of 0.44 (mouse 11β-HSD1) and 0.75 μM (human 11β-HSD1), respectively.
    Tetrahedron Letters 02/2012; 53(7):800–803. DOI:10.1016/j.tetlet.2011.12.004 · 2.39 Impact Factor
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    ABSTRACT: Six novel Ia₃-type cyclopeptide alkaloids (1-6) were isolated from stems of Ziziphus apetala. Compound 5 and the known compounds mauritine A (7) and mauritine F (8) were isolated from the roots. Their structures were determined by spectroscopic analyses and chemical methods. The total alkaloids from the roots and the isolated cyclopeptide alkaloids were tested for antidepressant behavior on mice, cytotoxicity, and 11β-hydroxysteroid dehydrogenase (11β-HSD) inhibition in vitro. Only mauritine A (7) showed inhibitory activity on 11β-HSD1, with IC₅₀ values of 52.0 (human) and 31.2 μg/mL (mouse).
    Journal of Natural Products 12/2011; 74(12):2571-5. DOI:10.1021/np200755t · 3.95 Impact Factor
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    ABSTRACT: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11beta-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11beta-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. Emodin is a potent and selective 11beta-HSD1 inhibitor with the IC(50) of 186 and 86 nM for human and mouse 11beta-HSD1, respectively. Single oral administration of emodin inhibited 11beta-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11beta-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. This study demonstrated a new role for emodin as a potent and selective inhibitor of 11beta-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes.
    British Journal of Pharmacology 09/2010; 161(1):113-26. DOI:10.1111/j.1476-5381.2010.00826.x · 4.99 Impact Factor
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    ABSTRACT: Rare merosesquiterpenoids, craterellins A-C (1-3), were isolated from cultures of basidiomycete Craterellus odoratus together with the previously known massarinolin C (4). Structures of 1-3 were elucidated on the basis of extensive spectroscopic analysis. Compounds 1-3 possess a rare, epoxymethylenecyclohexanetriol-bicyclofarnesane sesquiterpene hybrid skeleton. Compounds 1-4 were evaluated for their inhibitory activities against two isozymes of 11beta-hydroxysteroid dehydrogenases (11beta-HSD1 and 11beta-HSD2).
    Phytochemistry 10/2009; 71(1):100-3. DOI:10.1016/j.phytochem.2009.09.020 · 3.35 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 09/2009; 40(39). DOI:10.1002/chin.200939212
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    ABSTRACT: To design and synthese a novel class of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, featuring the (phenylsulfonamido-methyl)pyridine and (phenylsulfonamido-methyl)thiazole framework. Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11beta-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11beta-HSD1. Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations. Structure-activity relationships are also discussed with respect to molecular docking results. This study provides two promising new templates for 11beta-HSD1 inhibitors.
    Acta Pharmacologica Sinica 09/2009; 30(9):1344-50. DOI:10.1038/aps.2009.118 · 2.50 Impact Factor
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    ABSTRACT: PPARgamma and 11beta-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARgamma agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11beta-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of alpha-aryloxy-alpha-methylhydrocinnamic acids as dual functional agents which activate PPARgamma and inhibit 11beta-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARgamma (EC(50)=6.76 microM) and 11beta-HSD1 (IC(50)=0.76 microM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.
    Bioorganic & medicinal chemistry 07/2009; 17(15):5722-32. DOI:10.1016/j.bmc.2009.05.082 · 2.95 Impact Factor

Publication Stats

140 Citations
77.18 Total Impact Points


  • 2009–2015
    • Chinese Academy of Sciences
      • State Key Laboratory of Drug Research
      Peping, Beijing, China
  • 2013
    • Nankai University
      • Department of Biochemistry
      T’ien-ching-shih, Tianjin Shi, China
  • 2005–2006
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China