Yu Shen

Tianjin University, T’ien-ching-shih, Tianjin Shi, China

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Publications (27)89.27 Total impact

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    ABSTRACT: MDM2 and p53 form a negative feedback loop, in which p53 as a transcription factor positively regulates MDM2 and MDM2 negatively regulates tumor suppressor p53 through promoting its degradation. However, the mechanism of the feedback loop is poorly understood in cancers. We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) is a key oncoprotein in the development of cancer. Thus, we supposed that HBXIP might be involved in the event. Here, we observed that the expression levels of HBXIP were positively correlated to those of MDM2 in clinical breast cancer tissues. Interestingly, HBXIP was able to up-regulate MDM2 at the levels of mRNA and protein in MCF-7 breast cancer cells. Mechanically, HBXIP increased the promoter activities of MDM2 through directly binding to p53 in P2 promoter of MDM2. Strikingly, we identified that the acetyltransferase p300 was recruited by HBXIP to p53 in the promoter of MDM2. Moreover, we validated that HBXIP enhanced the p53 degradation mediated by MDM2. Functionally, the knockdown of HBXIP or/and p300 inhibited the proliferation of breast cancer cells in vitro, and the depletion of MDM2 or overexpression of p53 significantly blocked the HBXIP-promoted growth of breast cancer in vitro and in vivo. Thus, we conclude that highly expressed HBXIP accelerates the MDM2-mediated degradation of p53 in breast cancer through modulating the feedback loop of MDM2/p53, resulting in the fast growth of breast cancer cells. Our finding provides new insights into the mechanism of the acceleration of MDM2/p53 feedback loop in the development of cancer. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Jul 2015 · Journal of Biological Chemistry
  • Bin Zhou · Yu Shen · Yan Wu · Ying Leng · Jian-Min Yue
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    ABSTRACT: Thirteen new limonoids, dysoxylumosins A-M (1-13), along with six known analogues (14-19) were isolated from the twigs of Dysoxylum mollissimum. Their structures were established on the basis of spectroscopic data analysis. Compounds 1-6, 8, and 12 exhibited significant inhibitory activities against human and/or mouse 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Dysoxylumosin F (6), the most potent substance isolated, showed an IC50 value of 9.6 ± 0.90 nM against human 11β-HSD1. (Chemical Equation Presented). © 2015 The American Chemical Society and American Society of Pharmacognosy.
    No preview · Article · Jul 2015 · Journal of Natural Products
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    ABSTRACT: Functional TS-1, partially hydrophobilized with organosilanes, was found more active and stable in Pickering emulsion system. In this work, TS-1 behaved simultaneously as a catalyst and solid emulsifier favoring cyclohexanone ammoximation reaction in organic solvent-free condition. The composition, structure, formed emulsion morphology, surface morphology were characterized by Fourier-transform infrared (FT-IR) spectroscopy, conductometer, optical microscope with high speed CCD camera, Brunauer–Emmett–Teller (BET),X-ray diffraction (XRD), scanning electron microscopy (SEM). It indicated that hydrophobilization provided TS-1 a moderate wettability, allowing the formation of stable Pickering emulsion, thus promoting the performence in catalyzing cyclohexanone/H2O2/NH3•H2O reaction system in the absence of organic solvent. What is more, due to alkyl groups grafted to TS-1, the zeolites were comparatively exclusive to aqueous phase and they are more capable to endure severe environment, ie., 200 ºC, under autogenic pressure.
    No preview · Article · Jul 2015 · RSC Advances
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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.
    No preview · Article · Apr 2015 · ACS Medicinal Chemistry Letters
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    ABSTRACT: A search for 11β-HSD1 inhibitors from Ricinodendron heudelotii has afforded seven new tetracyclic triterpenoids ricinodols A–G (1–7), along with three known podocarpane-type diterpenoids (8–10). Ricinodols A (1) and B (2) possess a new carbon skeleton with a novel concurrent rearrangement of Me-19 (10 → 9) and Me-30 (14 → 8). Their structures were elucidated by comprehensive spectroscopic analyses and comparison with reported analogues, while the 24R-configuration of those with a 24-OH group was established by an in situ dimolybdenum CD method. Of these isolates, ricinodol E (5) exhibited the best inhibitory activities against both human and mouse 11β-HSD1 with IC50 values of 0.36 ± 0.26 and 0.84 ± 0.18 μM, respectively.
    Preview · Article · Mar 2015 · RSC Advances
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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.
    No preview · Article · Jan 2015 · Journal of Natural Products
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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.
    No preview · Article · Oct 2014 · Bioorganic & Medicinal Chemistry Letters
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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.
    No preview · Article · Aug 2014 · Journal of Natural Products
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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.
    No preview · Article · May 2014 · Organic & Biomolecular Chemistry
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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. © 2014 The American Chemical Society and American Society of Pharmacognosy.
    No preview · Article · May 2014 · Journal of Natural Products
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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).
    No preview · Article · Jul 2013 · Journal of Natural Products
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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.
    No preview · Article · Jun 2013 · Journal of Natural Products
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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.
    Full-text · Article · May 2013 · European Journal of Medicinal Chemistry
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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.
    Full-text · Article · May 2013 · Journal of Biological Chemistry
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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.
    Full-text · Article · Mar 2013 · Biochemical and Biophysical Research Communications
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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.
    Full-text · Article · Feb 2012 · Journal of Natural Products
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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.
    No preview · Article · Feb 2012 · Tetrahedron Letters
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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).
    Preview · Article · Dec 2011 · Journal of Natural Products
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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.
    Preview · Article · Sep 2010 · British Journal of Pharmacology
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    Ling Zhang · Yu Shen · Fei Wang · Ying Leng · Ji-Kai Liu
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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).
    Preview · Article · Oct 2009 · Phytochemistry

Publication Stats

209 Citations
89.27 Total Impact Points

Institutions

  • 2015
    • Tianjin University
      • School of Chemical Engineering and Technology
      T’ien-ching-shih, Tianjin Shi, China
  • 2013-2015
    • Nankai University
      • • College of Life Sciences
      • • Department of Biochemistry
      T’ien-ching-shih, Tianjin Shi, China
  • 2009-2015
    • Chinese Academy of Sciences
      • • State Key Laboratory of Drug Research
      • • Graduate School
      Peping, Beijing, China
  • 2005-2006
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China