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Central mechanisms mediating the prokinetic effect of erythromycin on the gastric motility in rats

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Central mechanisms mediating the prokinetic effect of erythr...

Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Yong-Hua CHEN~1 Han LIU~2 Ji-Jiang WANG~(1 *) 1 Shanghai Medical College of Fudan University Shanghai 200032 2 Zhongshan Hospital Shanghai 200032

＜正＞Erythromycin and its derivatives are increasingly used as prokinetic agents in the treatment of gastrointestinal motility disorders.Research on the mechanisms underlying the prokinetic actions of erythromycin mainly focused on the nerve endings in the peripheral nervous system and the gastric muscles previously.In recent years,studies have shown that central administered erythromycin increases the activities of gastric neurons and stimulates gastric motility.However, the mechanisms are not known yet.Gastric neurons are mainly located in the dorsal vagal complex of the medulla.Synaptic inputs including GABAergic,glycinergic and glutamatergic components regulate the activities of these neurons.In this study,we identified gastric preganglionic vagal neurons through retrograde fluorescent labeling,and investigated the effect of erythromycin on the synaptic inputs to these neurons using patch-clamp techniques.We found that erythromycin significantly inhibited the glycinergic inhibitory postsynaptic currents in a dose-dependent manner and this inhibition was partially blocked by the motilin receptor antagonist GM-109.In contrast,erythromycin didn’t affect the GABAergic inhibitory postsynaptic currents or glutamatergic excitatory postsynaptic currents.Our findings suggest that erythromycin might affect the gastric motility by the inhibition of glycinergic inputs to the gastric preganglionic vagal neurons via activation of motilin receptors.This might be one of the central mechanisms mediating the prokinetic effect of erythromycin.

关键词： erythromycin synaptic input gastric neuron gastric motility

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Cell Research 2004年第6期14卷 497-506页

作者： Li ZHENG, Jia Qiang REN, Hua LI, Zhao Lu KONG, Hong Guang ZHU Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Institute of Irradiation Medicine, Fudan University, Shanghai, 200032, China Department of Pathology Shanghai Medical College Fudan University Shanghai China Institute of Irradiation Medicine Fudan University Shanghai China

Overexpression and activation of HER-2/neu (also known as c-erbB-2), a proto-oncogene, was found in about 30% of human breast cancers, promoting cancer growth and making cancer cells resistant to chemo- and radio-therapy. Wild-type p53 is crucial in regulating cell growth and apoptosis and is found to be mutated or deleted in 60-70% of human cancers. And some cancers with a wild-type p53 do not have normal p53 function, suggesting that it is implicated in a complex process regulated by many factors. In the present study, we showed that the overexpression of HER-2/neu could decrease the amount of wild-type p53 protein via activating PI3K pathway, as well as inducing MDM2 nuclear translocation in MCF7 human breast cancer cells. Blockage of PI3K pathway with its specific inhibitor LY294002 caused Gl-S phase arrest, decreased cell growth rate and increased chemo- and radio-therapeutic sensitivity in MCF7 cells expressing wild-type p53. However, it did not increase the sensitivity to adriamycin in MDA-MB-453

关键词： HER-2/neu PI3K breast cancer p53 MDM2

Role of Apolipoprotein A-I in Protecting against Endotoxin Toxicity

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Acta Biochimica et Biophysica Sinica 2004年第6期36卷 419-424页

作者： Juan MA, Xue-Ling LIAO, Bin LOU, and Man-Ping WU* Department of Biochemistry, School of Pharmacy, Fudan University, Shanghai 200032, China Department of Biochemistry School of Pharmacy Fudan UniversityShanghai 200032 China

High density lipoprotein (HDL) binds lipopolysaccharide (LPS or endotoxin) and neutralizes its toxicity. We investigated the function of Apolipoprotein A-I (ApoA-I), a major apolipoprotein in HDL, in this process. Mouse macrophages were incubated with LPS, LPS+ApoA-I, LPS+ApoA-I+LFF (lipoprotein-free plasma fraction d>1.210 g/ml), LPS+HDL, LPS+HDL+LFF, respectively. MTT method was used to detect the mortality of L-929 cells which were attacked by the release-out cytokines in LPS-activated macrophages. It was found that ApoA-I significantly decreased L-929 cells mortality caused by LPS treatment (LPS vs. LPS+ApoA-I, P<0.05) and this effect became even more significant when LFF was utilized (LPS vs. LPS+ApoA-I+LFF, P<0.01; LPS vs. LPS+HDL+LFF, P<0.01). There was no significant difference between LPS+ApoA-I+LFF and LPS+HDL+LFF treatment, indicating that ApoA-I was the main factor. We also investigated in vivo effects ofApoA-I on mouse mortality rate and survival time after LPS administration. We found that the mortality in LPS+ApoA-I group (20%) and in LPS+ApoA-I+LFF group (10%) was signifi- cantly lower than that in LPS group (80%) (P<0.05, P<0.01, respectively); the survival time was (43.20 ± 10.13) h in LPS+ApoA-I group and (46.80 ± 3.79) h in LPS+ApoA-I+LFF group, which were significantly longer than that in LPS group (16.25 ± 17.28) h (P<0.01). We also carried out in vitro binding study to investigate the binding capacity of ApoA-I and ApoA-I+LFF to fluorescence labeled LPS (FITC-LPS). It was shown that both ApoA-I and ApoA-I+LFF could bind with FITC-LPS, however, the binding capacity of ApoA-I+LFF to FITC-LPS (64.47 ± 8.06) was significantly higher than that of ApoA-I alone (24.35 ± 3.70) (P<0.01). The results suggest that: (1) ApoA-I has the ability to bind with and protect against LPS; (2) LFF enhances the effect of ApoA-I; (3) ApoA-I is the major contributor for HDL anti-endotoxin function.

关键词： Apolipoprotein-I lipopolysaccharide (LPS) macrophages FITC-lipopolysaccharide (FITC-LPS) L-929 cells

Preventive treatments for recurrence after curative resection of hepatocellular carcinoma-A literature review of randomized control trials

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World Journal of Gastroenterology 2003年第4期9卷 635-640页

作者： Hui-Chuan Sun Zhao-You Tang Liver Cancer Institute and Zhong Shan Hospital,Fudan University,Shanghai 200032,China Associate Professor of Surgery Liver Cancer Institute and Zhong Shan Hospital Fudan University 136 Yi Xue Yuan Road Shanghai 200032 China. sunhc@***

To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications. reporting randomized control trial indexed in PubMed. The treatment approaches presented above included preoperative transcatheter arterial chemoembolization (TACE),post-operative TACE, systemic or locoregional chemotherapy,immunotherapy, Interferons and acyclic retinoic acid Although no standard treatment has been established,several approaches presented promising results, which were both effective and tolerable in post-operative patients. Preoperative TACE was not effective on prolonging survivals,while post-operative TACE was shown with both diseasefree survival and overall survival benefits in some papers,however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant toxicities.Adoptive immunotherapy using LAK cells was proved to be beneficial to patients' survival in a recent paper. Interferon and Interferon β can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multi-centric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities;in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation.

关键词：预防性治疗肝细胞癌肿瘤切除术复发随机对照研究肝动脉化疗栓塞术

Inhibitory Effect of CT120B,an Alternative Splice Variant of CT120A,on Lung Cancer Cell Growth

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Acta Biochimica et Biophysica Sinica 2005年第9期37卷 588-592页

作者： Dong-Ning PAN~(1,2) Jin-Jun LI~(2,3) Lin WEI~2 Ming YAO~(2,3) Da-Fang WAN~(2,3*) Jian-Ren GU~(1,2,3*) 1 Shanghai Medical College,Fudan University,Shanghai 200032,China 2 National Laboratory for Oncogenes and Related Genes,Shanghai Cancer Institute,Shanghai 200032,China 3 Medical School of Shanghai Jiaotong University,Shanghai 200032,China Shanghai Medical College Fudan UniversityShanghai 200032 China National Laboratory for Oncogenes and Related Genes Shanghai Cancer InstituteShanghai 200032 China Medical School of Shanghai Jiaotong UniversityShanghai 200032 China

The expression product of ct120a,a novel gene isolated from human chromosome 17p13.3in our laboratory,was predicted to have seven transmembrane domains and could cause malignanttransformation of mouse NIH3T3 cells.There existed an mRNA splicing variant of ct120a,namely ct120b,which had a 96-nucleotide deletion and produced an in-frame loss of 32 amino acids from codon 136 tocodon 167 of CT120A.The CT120B protein was predicted to have six transmembrane domains.In thisstudy,we observed that the green fluorescent protein-tagged CT120B was localized on plasma membraneand in cytoplasm in SPC-A-1 cells.The expression of CT120B/A in normal lung tissue and in lung cancercells was also examined.Results showed that the stable CT120B overexpression in SPC-A-1 cells resultedin a reduction of cell growth rate,and inhibited tumorigenecity and anchorage-independent growth in nudemice.The functions of CT120A and CT120B for cell growth appeared antagonistic.We suggested that thedelayed G1/S phase transition might contribute to the inhibitory activities of CT120B on cell growth and thatthe deleted 32 amino acids missing in CT120B might be essential for the oncogenetic activities of CT120A.

关键词： CT120B alternative splicing cell growth lung cancer

A New Stilbene Tetramer from Caragana rosea

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Chinese Chemical Letters 2003年第10期14卷 1048-1050页

作者： Guo Xun YANG, Chang Qi HU School of Pharmacy, Fudan University, Shanghai 200032 School of Pharmacy Fudan University Shanghai 200032 China

Cararosinol A, a new stilbene tetramer, was isolated from Caragana rosea. Its structure has been established on the basis of spectroscopic evidence.

关键词： Caragana rosea Leguminase stilbene tetramer.

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Distribution of nimodipine in brain following intranasal administration in rats

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Acta Pharmacologica Sinica 2004年第4期25卷 124-129页

作者： Qi-zhi ZHANG, Xin-guo JIANG2, Chun-hua WU Department of Pharmaceutics, School ofPharmacy, Fudan University, Shanghai 200032, China Department of Pharmaceutics School of Pharmacy Fudan University 上海 200032

AIM: To determine whether nasally applied nimodipine (NM) could improve its systemic bioavailability and be transported directly from the nasal cavity to the brain. METHODS: NM was administered nasally, intravenously (iv), and orally to male Sprague-Dawley rats. At different times post dose, blood, cerebrospinal fluid (CSF), and brain tissue samples were collected, and the concentrations of NM in the samples were analyzed byHPLC. RESULTS: Oral systemic bioavailability of NM in rats was 1.17 %, nasal dosing improved bioavailibility to 67.4 %. Following intranasal administration, NM concentrations in olfactory bulb (OB) within 30 min post dose were found significant higher than in the other brain tissues. However, similar NM levels in different brain regions were observed after iv injection. AUC in CSF and OB from the nasal route was 1.26 and 1.39 fold compared with the iv route, respectively. The brain-to-plasma AUC ratios were significantly higher after nasal administration than after iv administration (P<0.01). CONCLUSION: Nasally administered NM could markedly improve the bioavailability and a fraction of the NM dose could be transported into brain via the olfactory pathway in rats.

关键词： intranasal administration nimodipine olfactory bulb olfactory pathways

Effect of MePEG molecular weight and particle size on in vitro release of tumor necrosis factor-α-loaded nanoparticles

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Acta Pharmacologica Sinica 2005年第2期26卷 242-249页

作者： Chao FANG,Bin SHI,Yuan-ying PEI~2 Department of Pharmaceutics,School of Pharmacy,Fudan University,Shanghai 200032,China Department of Pharmaceutics School of Pharmacy Fudan University Shanghai China

Aim:To study the in vitro release of recombinant human tumor necrosis factor-alpha(rHuTNF-α)encapsulated in poly(methoxypolyethyleneglycol cyanoacry-late-co-n-hexadecyl cyanoacrylate)(PEG-PHDCA)nanoparticles,and investigatethe influence of methoxypolyethyleneglycol(MePEG)molecular weight and par-ticle size.Methods:Three sizes(approximately 80,170,and 240 nm)of PEG-PHDCA nanoparticles loading rHuTNF-α were prepared at different MePEG mo-lecular weights(Mr=2000,5000,and 10000)using the double emulsion method.The in vitro rHuTNF-α release was studied in PBS and rat plasma.Results:Ahigher burst-release and cumulative-release rate were observed for nanoparticleswith higher MePEG molecular weight or smaller particle size.A decreased cu-mulative release of rHuTNF-α following the initial burst effect was found in PBS,while the particle sizes remained constant and MePEG liberated.In contrast,inrat plasma,slowly increased cumulative-release profiles were obtained after theburst effect.During a 5-h incubation in rat plasma,more than 50% of the PEG-PHDCA nanoparticles degraded.Conclusion:The MePEG molecular weightand particle size had an obvious influence on rHuTNF-α release,rHuTNF-αreleased from PEG-PHDCA nanoparticles in a diffusion-based pattern in PBS,but in a diffusion and erosion-controlled manner in rat plasma.

关键词： tumor necrosis factor-alpha stealth nanoparticles polyethylene glycols poly(methoxypolyethyleneglycol cyanoacrylate-con-hexadecyl cyanoacrylate)

Impact of Long-term Exposure to Air Particulate Matter on Life Expectancy and Survival Rate of Shanghai Residents

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Biomedical and Environmental Sciences 2002年第3期15卷 209-214页

作者： KAN HAI-DONG1 AND CHEN BING-HENG Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China Department of Environmental Health School of Public Health Fudan University 上海 200032

Objective To evaluate the impact of long-term air particulate matter exposure on the life expectancy and survival rate of Shanghai residents. Methods Epidemiology - based exposure-response function was used for the calculation of attributable deaths to air particulate matter in Shanghai, and the effect of long-term exposure to particulate matter on life expectancy and survival rate was estimated using the life table of Shanghai residents in 1999. Results It was shown that in 1999, the long-term air particulate matter exposure caused 1.34-1.69 years reduction of life expectancy and a decrease of survival rate for each age group of Shanghai residents. Conclusion The effect of long-term exposure to air particulate matter on life expectancy is substantial in Shanghai.

关键词： Particulate matter Life expectancy Survival rate Shanghai

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