Publications (49)101.12 Total impact
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Article: Effects of CB1 receptor blockade on monosodium glutamate induced hypometabolic and hypothalamic obesity in rats.
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ABSTRACT: Effects of cannabinoid receptor 1 (CB1R) blockade were observed by comparing 9-day and 6-week SR141716 treatments in monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity (HO) in rats for the first time and molecular mechanisms were investigated. Compared with normal rats, the MSG rats display typical symptoms of the metabolic syndrome, i.e., excessive abdominal obesity, hypertriglyceridemia, hyperinsulinemia, insulin resistance, and hepatic steatosis, but with lower food intake. Although both the 9-day and 6-week treatments with the specific CB1R antagonist SR141716 effectively lowered body weight, intraperitoneal adipose tissue mass, serum triglyceride (TG), and insulin level, the effect of chronic treatment is more impressive. Moreover, serum cholesterol, free fatty acids (FFA), fasted and postprandial blood glucose, and insulin insensitivity were more effectively improved by 6-week exposure to SR141716, whereas hypophagia was only effective within the initial 2 weeks. In addition, hepatic steatosis as well as hepatic and adipocyte morphology was improved. Western blot analysis revealed that the markedly increased CB1R expression and decreased insulin receptor (INR) expression in liver and adipose tissues were effectively corrected by SR141716. Consistent with this, deregulated gene expression of lipogenesis and lipolysis as well as glucose metabolic key enzymes were also restored by SR141716. In conclusion, based on present data we found that: (1) alteration of the hypothalamus in MSG rats leads to a lower expression of INR in crucially insulin-targeted tissues and hyperinsulinemia that was reversed by SR141716, (2) the abnormally increased expression of CB1R in liver and adipose tissues plays a vital role in the pathophysiological process of MSG rats, and (3) chronic CB1R blockade leads to a sustained improvement of the metabolic dysfunctions of MSG rats.Archiv für Experimentelle Pathologie und Pharmakologie 04/2013; · 2.65 Impact Factor -
Article: C333H ameliorated insulin resistance through selectively modulating PPARγ in brown adipose tissue of db/db mice.
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ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPAR γ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.Biological & Pharmaceutical Bulletin 04/2013; · 1.66 Impact Factor -
Article: Novel substituted heteroaromatic piperazine and piperidine derivatives as inhibitors of human enterovirus 71 and coxsackievirus a16.
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ABSTRACT: A series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein VP1. The preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against EV71 and Coxsackievirus A16 with low cytotoxicity.Molecules 01/2013; 18(5):5059-71. · 2.39 Impact Factor -
Article: SAR, cardiac myocytes protection activity and 3D-QSAR studies of salubrinal and its potent derivatives.
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ABSTRACT: Salubrinal is a selective inhibitor of endoplasmic reticulum (ER) stress and affords remarkable protection to cardiomyocytes. By studying the structure-activity relationship (SAR) of salubrinal, it was found that modification of the quinoline ring terminus and thiourea unit could confer the compound PP1-24 with markedly enhanced cardioprotective activity (EC50 ≤ 0.3 µM) that is 50-fold more potent than salubrinal. Comparative molecular field analysis (CoMFA) was performed using the obtained biological data and resulted in a statistically significant CoMFA model with high predictive power (q2 = 0.741, r2 = 0.991).Current Medicinal Chemistry 09/2012; · 4.86 Impact Factor -
Article: Salubrinal protects against tunicamycin and hypoxia induced cardiomyocyte apoptosis via the PERK-eIF2α signaling pathway.
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ABSTRACT: This study examined the protective effect of salubrinal and the mechanism underlying this protection against tunicamycin (TM)- and hypoxia-induced apoptosis in rat cardiomyocytes. Neonatal rat cardiomyocytes were cultured from the ventricles of 1-day-old Wistar rats. Cells were exposed to different concentrations of salubrinal (10, 20, and 40 µmol/L) for 30 min followed by TM treatment or hypoxia for 36 h. Apoptosis was measured by a multiparameter HCS (high content screening) apoptosis assay, TUNEL assay and flow cytometry. The phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α) and the expression of cleaved caspase-12 were determined by Western blotting. C/EBP homologous protein (CHOP) was detected by immunocytochemistry. HCS, TUNEL assays and flow cytometry showed that salubrinal protected cardiomyocytes against apoptosis induced by TM or hypoxia. Western blotting showed that salubrinal protected cardiomyocytes against apoptosis by inducing eIF2α phosphorylation and down-regulating the expression of the endoplasmic reticulum stress-mediated apoptotic proteins, CHOP and cleaved caspase-12. Our study suggests that salubrinal protects rat cardiomyocytes against TM- or hypoxia-associated apoptosis via a mechanism involving the inhibition of ER stress-mediated apoptosis.Journal of Geriatric Cardiology 09/2012; 9(3):258-68. -
Article: Methyl-naltrexone bromide methanol monosolvate.
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ABSTRACT: IN THE TITLE COMPOUND [SYSTEMATIC NAME: (4R,4aS,7aR,12bS)-3-cyclo-propyl-meth-yl-4a,9-hy-droxy-7-oxo-2,3,4,4a,5,6,7,7a-octa-hydro-1H-4,12-methano-benzofuro[3,2-e]isoquinolin-3-ium bromide methanol monosolvate], C(21)H(26)NO(4) (+)·Br(-)·CH(3)OH, two of the three six-membered rings adopt chair conformations while the third, which contains a C=C double bond, adopts an approximate half-boat conformation. The 2,3-dihydro-furan ring adopts an envelope conformation. In the crystal, the components are linked by O-H⋯O and O-H⋯Br hydrogen bonds. The absolute stereochemistry was inferred from one of the starting materials.Acta Crystallographica Section E Structure Reports Online 03/2012; 68(Pt 3):o827. · 0.35 Impact Factor -
Article: Synthesis of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents.
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ABSTRACT: Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. Structure-based design and synthesis of 1-(4-carboxybutyl)-4-(4-(substituted benzyloxy)phenyl)-1H-pyrrole-2-carboxylic acid derivatives 7a-h, a subset of eight potential FabH inhibitors, is described in this paper. The Vilsmeier-Haack reaction was employed as a key step. The structures of all the newly synthesized compounds were identified by IR, ¹H-NMR, ¹³C-NMR, ESI-MS and HRMS. The alamarBlue™ microassay was employed to evaluate the compounds 7a-h against Mycobacterium tuberculosis H₃₇Rv. The results demonstrate that the compound 7d possesses good in vitro antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv (Minimum Inhibitory Concentration value [MIC], 12.5 µg/mL).These compounds may prove useful in the discovery and development of new anti-tuberculosis drugs.Molecules 01/2012; 17(5):4770-81. · 2.39 Impact Factor -
Article: Design and synthesis of a series of pyrido[2,3-d]pyrimidine derivatives as CCR4 antagonists.
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ABSTRACT: A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4) antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD₅₀ of compound 6b is 175 mg/kg and the oral LD₅₀ is greater than 2,000 mg/kg.Molecules 01/2012; 17(8):9961-70. · 2.39 Impact Factor -
Article: Novel immunomodulators based on an oxazolin-2-one-4-carboxamide scaffold.
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ABSTRACT: A series of oxazolidin-2-one-4-carboxylic amide compounds (1a-f) were designed and synthesized as the non-phosphate S1P(1) receptor agonists. The single crystal of 1e was prepared and solved to elucidate the structure of 1a-f. EC(50) of 1a-d were about 1.1-3.6 μM in S1P(1) Redistribution® assay, and their cytotoxicity was 8-40-fold lower than FTY720. Though its S1P(1) agonist activities in vitro were about 1000-folds weaker than (S)-FTY720-P, at a dose of 10mg/Kg, the immunosuppressive effects of 1a were comparable to FTY720. So oxazolidin-2-one-4-carboxylic amide derivatives were found as potential immunomodulator, compound 1a could be considered as a lead compound, rational modifications of 1a are anticipated using medicinal chemistry techniques and molecular modeling to obtain analogs with higher affinity and better clinical therapeutic properties.Bioorganic & medicinal chemistry letters 11/2011; 22(1):553-7. · 2.65 Impact Factor -
Article: Novel selective cannabinoid CB(1) receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects.
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ABSTRACT: To characterize the biological profiles of MJ08, a novel selective CB(1) receptor antagonist. Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB(1) and CB(2) receptor redistribution and intracellular Ca(2+) ([Ca(2+)](i)) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice. In radioligand binding assay, MJ08 selectively antagonized CB(1) receptor (IC(50)=99.9 nmol/L). In EGFP-CB(1)_U2OS cells, its IC(50) value against CB(1) receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca(2+)](i) in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB(1) cells. MJ08 (10 nmol/L-10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA(2)=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB(1) cells with an EC(50) value of 78.6 nmol/L, which was lower than the EC(50) value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB(1) receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo. MJ08 is a novel, potent and selective CB(1) receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB(1) receptors.Acta Pharmacologica Sinica 08/2011; 32(9):1148-58. · 1.95 Impact Factor -
Article: Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects
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ABSTRACT: Aim: To characterize the biological profiles of MJ08, a novel selective CB1 receptor antagonist.Acta Pharmacologica Sinica 08/2011; 32(9):1148-1158. · 1.95 Impact Factor -
Article: Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5-halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides.
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ABSTRACT: We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC(50)'s: 0.45-5.08 μM) are more active than Sunitinib (IC(50)'s: 1.35-6.61 μM), and the most active compound 1 h (IC(50): 0.47-3.11 μM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.Bioorganic & medicinal chemistry letters 03/2011; 21(10):3062-5. · 2.65 Impact Factor -
Article: Pharmacophore-based design, synthesis, and biological evaluation of novel chloro-pyridazine piperazines as human rhinovirus (HRV-3) inhibitors.
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ABSTRACT: A series of chloro-pyridazine piperazines were developed based on the structure of human rhinovirus (HRV) capsid-binding inhibitors with proven activity using a pharmacophore model. A preliminary evaluation demonstrated potent activity against HRV-3 with low cytotoxicity. A docking analysis indicated that 8a could fit into, and form tight interactions (e.g., H-bonds, σ-π effect) with the active site in VP1.Bioorganic & medicinal chemistry letters 02/2011; 21(3):1057-9. · 2.65 Impact Factor -
Article: Beclin 1-independent autophagy induced by a Bcl-XL/Bcl-2 targeting compound, Z18.
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ABSTRACT: Inhibitors of Bcl-XL/Bcl-2 can induce autophagy by releasing the autophagic protein Beclin 1 from its complexes with these proteins. Here we report a novel compound targeting the BH3 binding groove of Bcl-XL/Bcl-2, Z18, which efficiently induces autophagy-associated cell death in HeLa cells, without apparent apoptosis. Unexpectedly, the inhibition of Beclin 1 and phosphatidylinositol 3-kinase have no obvious effect on Z18-induced autophagy in HeLa cells, implying that it is a non-canonical Beclin 1-independent autophagy. Meanwhile, the accumulation of autophagosomes is positively correlated with Z18-induced cell death and the full flux of autophagy is not necessary.Autophagy 11/2010; 6(8):1032-41. · 7.45 Impact Factor -
Article: Synthesis of a series of novel 2,4,5-trisubstituted selenazole compounds as potential PLTP inhibitors.
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ABSTRACT: Based on a homology-modeled structure of PLTP and characteristic structural features of reported cholesteryl ester transfer protein (CETP) inhibitors, we designed and synthesized a novel series of 2,4,5-trisubstituted selenazole compounds. Biological evaluation reveals that compounds 12 and 17 exhibit favorable PLTP activity, and their IC(50)s are 8 microM and 10 microM, respectively.Bioorganic & medicinal chemistry letters 09/2010; 20(17):5123-5. · 2.65 Impact Factor -
Article: Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models.
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ABSTRACT: MJ15, a novel cannabinoid CB(1) receptor selective antagonist was discovered. In receptor binding assays, MJ15 displayed a high affinity for rat cannabinoid CB(1) receptor (K(i)=27.2 pM, and IC(50)=118.9 pM), but a much lower affinity for rat cannabinoid CB(2) receptor (only 46% inhibition at 10 microM). At the cellular level, the IC(50) values against activation of cannabinoid CB(1) and CB(2) receptors induced by Win55212-2 in specially designed EGFP-CB(1)_U2OS and EGFP-CB(2)_U2OS cells were 0.11 microM and >10 microM, respectively. In addition, MJ15 dose-dependently blocked Win55212-2 mediated increase of intracellular Ca(2+) levels in hippocampal cells and reversed the inhibitory effects of cannabinoid CB(1) receptor agonist on forskolin-stimulated adenylyl cyclase activity in CHO cells expressing the human cannabinoid CB(1) receptor. In animal experiments, MJ15 demonstrated remarkable effects from 20 to 40 mg/kg, including promoted the small intestine peristalsis in ICR mice and inhibited food intake and body weight increase in diet-induced obesity (DIO) rat and mouse. 40 mg/kg MJ15 significantly reduced food intake at initial 2 weeks of treatment, prevented the increase of body weight and adipose by 46% and 28% respectively in DIO rats, and reduced body weight and adipose gain by 70% and 23% respectively in early onset obesity DIO mice after 4 weeks treatment. Meanwhile, dyslipidemia were ameliorated in both models. Taken together the in vitro and in vivo data, MJ15 is demonstrated to be a potent and selective cannabinoid CB(1) receptor antagonist and holds a prominent potency in obesity and dyslipidemia treatment.European journal of pharmacology 04/2010; 637(1-3):178-85. · 2.59 Impact Factor -
Article: (S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl) propanoic acid compounds: synthesis and biological evaluation of dual PPARalpha/gamma agonists.
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ABSTRACT: A series of novel, potent PPARalpha/gamma dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC(50) value of 0.012+/-0.002 and 0.032+/-0.01 microM, respectively, for hPPARalpha and hPPARgamma in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice.Bioorganic & medicinal chemistry letters 03/2010; 20(8):2605-8. · 2.65 Impact Factor -
Article: (1R*,2R*)-1-(7-Bromo-3-methoxy-naphthalen-2-yl)-4-(dimethyl-amino)-2-(naphthalen-1-yl)-1-phenyl-butan-2-ol.
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ABSTRACT: In the crystal structure of the title compound, C(33)H(32)BrNO(2), the naphthalene ring system and the benzene ring are oriented at dihedral angles of 82.24 (4) and 79.53 (4)°, respectively, to the quinoline ring system. An intra-molecular O-H⋯N hydrogen bond occurs between the hydr-oxy H atom and the amine N atom.Acta Crystallographica Section E Structure Reports Online 01/2010; 66(Pt 3):o636. · 0.35 Impact Factor -
Article: 3-Chloro-6-{4-[3-(4-chloro-phen-oxy)prop-yl]piperazin-1-yl}pyridazine.
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ABSTRACT: In the title compound, C(17)H(20)Cl(2)N(4)O, the piperazine ring adopts a chair conformation and the dihedral angle between the pyridazine ring and the benzene ring is 36.3 (1)°. In the crystal, weak C-H⋯O and C-H⋯(N,N) inter-actions help to establish the packing, which also features short inter-molecular Cl⋯Cl contacts [3.331 (2) Å].Acta Crystallographica Section E Structure Reports Online 01/2010; 66(Pt 3):o716. · 0.35 Impact Factor -
Article: (1R*,2R*)-1-(4-Chloro-phen-yl)-4-dimethyl-amino-1-(3-meth-oxy-2-naphth-yl)-2-(1-naphth-yl)butan-2-ol.
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ABSTRACT: In the title compound, C(33)H(32)ClNO(2), the benzene ring is oriented at dihedral angles of 6.23 (5) and 66.44 (5)° with respect to the two naphthalene ring systems. An intra-molecular O-H⋯N hydrogen bond between the hydr-oxy H atom and the amine N atom generates an S(6) ring.Acta Crystallographica Section E Structure Reports Online 01/2010; 66(Pt 7):o1571. · 0.35 Impact Factor
Top co-authors
Top Journals
Institutions
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2006–2013
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Shenyang Pharmaceutical University
- School of Pharmaceutical Engineering
Shenyang, Liaoning, China -
University of Illinois, Urbana-Champaign
Urbana, IL, USA -
University of Southern California
Los Angeles, CA, USA
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2012
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Beijing Institute of Microbiology and Epidemiology
Beijing, Beijing Shi, China
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2009–2012
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Jilin University
- Department of Pharmacy
Jilin, Jilin Sheng, China
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2009–2010
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Government of the People's Republic of China
Beijing, Beijing Shi, China
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2001–2009
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Academy of Military Medical Sciences
Tianjin, Tianjin Shi, China
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2003
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National ESCA and Surface Analysis Center For Biomedical Problems
Seattle, WA, USA
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