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Hong W.,Fudan University | Hong W.,Shanghai Key Laboratory of Clinical Geriatric Medicine | Xu X.-Y.,Fudan University | Qiu Z.-H.,Fudan University | And 5 more authors.
Acta Pharmacologica Sinica | Year: 2015

Aim: Apolipoprotein E (ApoE) plays an important role in the transport and metabolism of lipids. Recent studies show that bone mass is increased in young apoE-/- mice. In this study we investigated the bone phenotype and metabolism in aged apoE-/- mice. Methods: Femurs and tibias were collected from 18- and 72-week-old apoE-/- mice and their age-matched wild-type (WT) littermates, and examined using micro-CT and histological analysis. Serum levels of total cholesterol, oxidized low-density lipoprotein (ox-LDL) and bone turnover markers were measured. Cultured bone mesenchymal stem cells (BMSCs) from tibias and femurs of 18-week-old apoE-/- mice were used in experiments in vitro. The expression levels of Sirt1 and Runx2 in bone tissue and BMSCs were measured using RT-PCR and Western blot analysis. Results: Compared with age-matched WT littermates, young apoE-/- mice exhibited high bone mass with increased bone formation, accompanied by higher serum levels of bone turnover markers OCN and TRAP5b, and higher expression levels of Sirt1, Runx2, ALP and OCN in bone tissue. In contrast, aged apoE-/- mice showed reduced bone formation and lower bone mass relative to age-matched WT mice, accompanied by lower serum OCN levels, and markedly reduced expression levels of Sirt1, Runx2, ALP and OCN in bone tissue. After BMSCs were exposed to ox-LDL (20 μg/mL), the expression of Sirt1 and Runx2 proteins was significantly increased at 12 h, and then decreased at 72 h. Treatment with the Sirt1 inhibitor EX527 (10 μmol/L) suppressed the expression of Runx2, ALP and OCN in BMSCs. Conclusion: In contrast to young apoE-/- mice, aged apoE-/- mice showe lower bone mass than age-matched WT mice. Long-lasting exposure to ox-LDL decreases the expression of Sirt1 and Runx2 in BMSCs, which may explain the decreased bone formation in aged apoE-/- mice. © 2015 CPS and SIMM All rights reserved.


Wang M.,Fudan University | Hu Y.,Roche Holding AG | Jiang Z.,Fudan University | Shen H.C.,Roche Holding AG | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2016

Convenient methods were developed for copper-mediated oxidative C-H activation of aminoquinoline benzamides. The reaction conditions can be tuned to give either hydroxylation or dimerization compounds as the major products efficiently. Preliminary mechanistic studies suggested that different coordination states of copper may lead to different reaction outcomes. © 2016 The Royal Society of Chemistry.


Tang M.-L.,Fudan University | Zhong C.,Fudan University | Liu Z.-Y.,Fudan University | Peng P.,Fudan University | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2016

To develop novel anti-inflammatory agents with improved pharmaceutical profiles, twenty-eight novel sesquistilbene indanone analogues were synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Among these compounds, compound 11k was found to be one of the most potent analogues in inhibiting NO production in LPS-stimulated RAW264.7 cells. Furthermore, it could also significantly suppress LPS-induced iNOS and COX-2 expression and NO production through TLR4/JNK/NF-κB signaling pathway in a concentration dependent manner. © 2016 Elsevier Masson SAS. All rights reserved.


Tang M.-L.,Fudan University | Zhou L.,Fudan University | Chang J.,Fudan University | Hu Z.-H.,Research Institute for Liver Diseases Shanghai Co. | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2016

3FDT, an analog of docetaxel with a blocked metabolism at its 3′-N-tert-butyloxyl group with three fluorine atoms, exhibits more potent cytotoxicity than docetaxel both with human cancer cell line SK-OV-3 in vitro and with human non-small cell lung cancer A549 xenografts in vivo. To further develop pharmacodynamically and pharmacokinetically favorable fluorinated docetaxel analogs as anticancer agents, we chose 3FDT as the model compound to identify the metabolites of 3FDT in RLMs, rats, and HLMs and the cytochrome P450 enzymes responsible for the metabolism of 3FDT. Our findings indicated that the major metabolic site switched from the C3′ appendage for docetaxel to the taxane ring for 3FDT, and the main metabolizing P450 enzymes switched from CYP3A to CYP3A4 and CYP2E1. © 2016 Elsevier Masson SAS. All rights reserved.


Song J.,Fudan University | Peng P.,Fudan University | Chang J.,Fudan University | Liu M.-M.,Fudan University | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19nM, which is 5 times more potent than that of Ilomastat (IC50 =0.94nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50 =1.58μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t 1/2z was achieved compared with these of the lead compound Ilomastat. © 2016 Elsevier Ltd.


Zhang Q.-W.,Fudan University | Deng X.-X.,Fudan University | Sun X.,Fudan University | Xu J.-X.,Fudan University | And 2 more authors.
PLoS ONE | Year: 2013

Newborn striatal neurons induced by middle cerebral artery occlusion (MCAO) can form functional projections targeting into the substantia nigra, which should be very important for the recovery of motor function. Exercise training post-stroke improves motor recovery in clinic patients and increases striatal neurogenesis in experimental animals. This study aimed to investigate the effects of exercise on axon regeneration of newborn projection neurons in adult rat brains following ischemic stroke. Rats were subjected to a transient MCAO to induce focal cerebral ischemic injury, followed by 30 minutes of exercise training daily from 5 to 28 days after MCAO. Motor function was tested using the rotarod test. We used fluorogold (FG) nigral injection to trace striatonigral and corticonigral projection neurons, and green fluorescent protein (GFP)-targeting retroviral vectors combined with FG double labeling (GFP + -FG+) to detect newborn projection neurons. The results showed that exercise improved the recovery of motor function of rats after MCAO. Meanwhile, exercise also increased the levels of BDNF and VEGF, and reduced Nogo-A in ischemic brain. On this condition, we further found that exercise significantly increased the number of GFP+ -FG+ neurons in the striatum and frontal and parietal cortex ipsilateral to MCAO, suggesting an increase of newborn striatonigral and corticonigral projection neurons by exercise post-stroke. In addition, we found that exercise also increased NeuN+ and FG+ cells in the striatum and frontal and parietal cortex, the ischemic territory, and tyrosine hydroxylase (TH) immunopositive staining cells in the substantia nigra, a region remote from the ischemic territory. Our results provide the first evidence that exercise can effectively enhance the capacity for regeneration of newborn projection neurons in ischemic injured mammalian brains while improving motor function. Our results provide a very important cellular mechanism to illustrate the effectiveness of rehabilitative treatment post-stroke in the clinic. © 2013 Zhang et al.


Wang M.,Fudan University | Liu X.,Fudan University | Zhou L.,Fudan University | Zhu J.,Chinese Academy of Sciences | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2015

An efficient protocol was developed to access 3-fluoro-2-hydroxy-2-substituted benzo[b]furans with Selectfluor™ as the fluorinating reagent in MeCN and water. By utilizing SOCl2/Py as the dehydrating agent, the compounds above were readily converted to 3-fluorinated, 2-substituted benzo[b]furans in high yields. This journal is © The Royal Society of Chemistry 2015.


Dong J.,Fudan University | Xiao L.,Fudan University | Xiao L.,Shanghai Key Laboratory of Clinical Geriatric Medicine | Sheng L.,Fudan University | And 3 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2014

TMPRSS2:ERG gene fusions in prostate cancer have a dominant prevalence of approximately 50.0%, but infomration is limited on differences among ethnic and geographical groups. Some studies focusing on Japanese and Korean patients reported a lower incidence. Investigations concerning Chinese revealed controversial results. We evaluated TMPRSS2:ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions in more than 100 Eastern Chinese prostate cancer patients. Paraffin blocks of needle biopsy and radical prostatectomy were collected from 91 and 18 patients respectively. All patients' clinicopathologic factors were gathered. TMPRSS2:ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions were tested by multi-probe fluorescence in situ hybridization (FISH) assay. TMPRSS2:ERG fusions was present in 14.3% biopsy specimens and 11.1% radical prostatectomy patients. Neither TMPRSS2:ETV1 nor TMPRSS2:ETV4 fusion was found in any case. Altogether, 13 (86.7%) TMPRSS2:ERG fusion positive cases possessed deletion pattern and 7 (46.6%) and insertion pattern. Some 5 cases had both deletion and insertion patterns. While 38.5% (5/13) patients with deletion pattern had distant metastasis, except for one metastatic case harboring both deletion and insertion, there were no patients with insertion pattern accompanied with metastasis. There were no differences between fusion positive and negative cases in the distribution of age, PSA, Gleason score and TNM stage. Eastern Chinese prostate cancer patients have a significantly low incidence of TMPRSS2:ERG fusion. They also lack TMPRSS2:ETV1 and TMPRSS2:ETV4 fusion. There are more deletion pattern than insertion pattern in TMPRSS2:ERG positive cases. Fusion positive and negative patients have no clinicopathologic factor differences.


Tang M.-L.,Fudan University | Peng P.,Fudan University | Liu Z.-Y.,Fudan University | Zhang J.,Fudan University | And 3 more authors.
Chemistry - A European Journal | Year: 2016

The synthesis of enantiomerically pure 3-aryl substituted indanones is developed using an enantioselective sulfoxide-based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para-tolyl sulfoxide-containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)-isopaucifloral F, (+)-quadrangularin A, and (+)-pallidol. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


PubMed | Fudan University and Shanghai Key Laboratory of Clinical Geriatric Medicine
Type: | Journal: Scientific reports | Year: 2016

Nonalcoholic fatty liver disease (NAFLD), a metabolic disorder related to insulin resistance and metabolic syndrome, has become a public health concern. Currently, the principal therapeutic modalities targeting NAFLD are lifestyle interventions. However, the efficacy of long-term lifestyle interventions in managing NAFLD remains largely unexplored. This study aimed to evaluate the efficacy of long-term lifestyle interventions in middle-aged and elderly men with NAFLD. All 280 eligible patients were randomized to the control or test group. Patients in the test group received counseling on diet and exercise from 2 physicians every 3 months via a phone call. Patients in the control group received only counseling in annual checkups without regular intervention. After the 2-year periodic intervention, body weight, abdominal circumference, ALT, TCH, LDL-C and HDL-C decreased in the test group. Specifically, the fatty liver index (FLI) and NAFLD-fibrosis score (NAFLD-FS) reduced markedly in the test group. However, in the control group, there was only a significant decrease in LDL-C, HDL-C and NAFLD-FS (P<0.001). The liver steatosis grade of the test group decreased significantly, while it increased in the control group. In NAFLD, long-term lifestyle interventions exert an anti-obesity effect and attenuate liver dysfunction and steatosis.

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