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Hao X.-D.,Fudan University | Chang J.,Fudan University | Qin B.-Y.,Shanghai Public Health Clinical Center | Zhong C.,Fudan University | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2015

Three series of resveratrol oligomer derivatives were synthesized, including the indenone-type, indene-type and octahydropentalene-type derivatives, among which ten derivatives were novel compounds. Compounds 2, 14f, and 4d were confirmed as ERβ agonists by yeast two-hybrid assay, and compound 2 (isopaucifloral F) was further chosen to evaluate its anti-osteoporosis activity in vivo. Compared with the sham-operated and the positive control groups, isopaucifloral F (10 Î1/4g/kg) showed a notable anti-osteoporosis effect in the ovariectomized (OVX) female rats based on a micro-CT analysis and the following measurements: bone mineral density, bone volume/tissue volume, trabecular thickness, trabecular separation/spacing, and the serum biochemical parameters. LD50 of isopaucifloral F was found to be greater than 5 mg/kg and its effective dose (ED) was found to be about 10 Î1/4g/kg. Therefore, isopaucifloral F may be a promising lead compound for the treatment of postmenopausal osteoporosis. © 2015 Elsevier Masson SAS. Source

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. Source

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. Source

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. Source

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. Source

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