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Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence

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Acta Pharmacologica Sinica 2005年第11期26卷 1290-1296页

作者： Li-ping ZHANG, Li WANG~2.department of Pediatrics, peking {2. first hospital, beijing 100034, china departmentofPediatrics PekingUniversityFirstHospitalBeijing100034China

Aim: Anticonvulsant tolerance and dependence are two obstacles that restrict the clinical use of benzodiazepines (BDZ). In order to explore the mechanism of these two adverse reactions, changes of neuropeptide Y (NPY) and its receptors in the hippocampus of rat models, in relation to flurazepam (FZP, a member of BDZ) tolerance and dependence, were investigated. Methods: The mRNA of preproNPY and its receptors (Y1, Y2. and Y5) in the hippocampus were determined by competitive RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry. Results: A decrease of preproNPY mRNA in the hippocampus was found in tolerant and dependent rats. The level of preproNPY mRNA in the hippocampus was reversely correlated with the degree of tolerance and dependence, measured by the threshold of pentylenetetrazol-induced seizures. Immunohistochemistry indicated a decrease of NPY-immunoreactive material in neurons of the CA1, CA3, and dentate gyrus regions of both tolerant and dependent rats. The mRNA of NPY receptors Y,and Y5decreased in tolerant rats but did not change in dependent rats. The mRNA of NPY receptor Y2.ncreased in tolerant rats but decreased in dependent rats. Conclusion: A decrease of NPY in the hippocampus might be involved in anticonvulsant tolerance and dependence following long-term treatment with FZP. Y,, Y2. and Y5mRNA were also altered in FZP tolerance and dependence.

关键词： benzodiazepines neuropeptide Y flura zepam

Population pharmacokinetic model of valproate and prediction of valproate serum concentrations in children with epilepsy

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Acta Pharmacologica Sinica 2004年第12期25卷 10-17页

作者： De-chun JIANG, Li WANG2.department of Pediatrics, peking {2. first hospital, TherapeuticDrug Monitoring and Clinical Toxicology, Center of peking {2., beijing 100034, china department of Pediatrics Peking University First Hospital Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University 北京 100034

AIM: Using sparse data of valproate (VPA) serum concentrations to build a population pharmacokinetic (PPK) model of VPA in Chinese children with epilepsy and to predict serum concentrations for new patients using a Bayesian approach. METHODS: Two hundred epileptic children, whose VPA serum concentrations were collected, were divided randomly into two groups (A and B, n=100 each). The PPK parameter values of group A were calculated to establish a PPK Model by using the NPEM Program of USC*PACK software. Based on it, VPA serum concentrations of group B were predicted with the Bayesian Fitting Program of the USC*PACK software. To assess the accuracy and precision of prediction, a paired-comparisons t-test was run between predicted and ob- served concentrations, and then the mean prediction error (MPE), mean square prediction error (MSPE), root mean square prediction error (RMSPE), and coincidence rates for different percentages of prediction error were all calculated. RESULTS: Optimum PPK parameters were: Ka, 2.52.±2.743 h-1; Vs, 0.32.±0.496 L/kg; and Kel, 0.0438±0.0384 h-1. For group B, there was no significant difference between predicted and observed concentrations. MPE was -0.43 mg/L, MSPE was 115.40 (mg/L)2. and RMSPE was 5.47 mg/L. The coincidence rates for percent- ages of prediction error, which were less than 5 %, 10 %, 15 %, 2. %, 2. %, and 30 %, were 62.%, 74 %, 82.%, 85 %, 89 %, and 93 %, respectively. CONCLUSION: A PPK model of VPA in epileptic children was successfully established. Based on it, VPA serum concentrations can be predicted accurately with a Bayesian approach.

关键词： pharmacokinetics valproic acid epilepsy Bayes theorem USC*PACK software

A novel endorectal RF coil for high resolution MRI and spectroscopy of the prostate

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Progress in Natural Science:Materials International 2005年第5期15卷 472-476页

作者： ZHANG Hongjie 1,2. SONG Xiaoyu1, WANG Xiaoying3, XU Pingfang1 and BAO Shanglian1*(1. beijing Key Laboratory of Medical Physics & Engineering, peking {2., beijing 100871, china 2. Navy general hospital, beijing 100037, china 3. peking {2. first hospital, beijing 100034, china) beijing Key Laboratory of Medical Physics & Engineering Peking University Beijing 100871 China Navy general hospital Beijing 100037 China peking university {2. hospital Beijing 100034 China

The diagnosis of prostate diseases by magnetic resonance imaging (MRI) in vivo is sometimes difficult for the lower signal to noise ratio (SNR). To increase the SNR of the prostate image, we designed a RF coil that can be inserted into rectum and was named endorectal coil. The properties of RF coil were evaluated using a network analyzer. Moreover the images and spectroscopy of a special phantom were acquired and the results were compared to those of the commercial TORSO coil (G.E. Medical Systems, USA). Our coil gave a significantly higher SNR at the region of interest (ROI). The achieved high local SNR and resulting high spatial resolution would add more anatomic and biochemical information to the diagnosis of prostate diseases.

关键词： MRI RF coil endorectal coil.

Nitric oxide modulates hypoxic pulmonary smooth muscle cell proliferation and apoptosis by regulating carbon monoxide pathway

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Acta Pharmacologica Sinica 2007年第1期28卷 28-35页

作者： Yan-fei WANG~2.Hong TIAN~2.Chao-shu TANG~(3,4) Hong-fang JIN~2.Jun-bao DU~(2.4,5)2.department of Pediatrics,peking {2. first hospital,beijing 100034,china 3 Institute of Cardiovascular Diseases,peking {2. first hospital,beijing 100034,china,4 Key Laboratory of Molecular Cardiovascular Diseases,Ministry of Education,beijing 100034,china departmentofPediatrics PekingUniversityFirstHospitalBeijing100034China InstituteofCardiovascularDiseases PekingUniversityFirstHospitalBeijing100034China KeyLaboratoryofMolecularCardiovascularDiseases MinistryofEduc

Aim:To explore the role of carbon monoxide(CO)in the regulation of hypoxicpulmonary artery smooth muscle cell(PASMC)proliferation and apoptosis bynitric oxide(NO).Methods:PASMC of Wistar rats was cultured in vitro in thepresence of a NO donor,sodium nitroprusside,or an inhibitor of heine oxygenase(HO),zinc protoporphyrin-IX,or under both normoxic and hypoxic *** and carboxyhemoglobin in PASMC medium were detected *** proliferating and apoptotic percentage of PASMC wasmeasured by flow *** expression of HO-1 mRNA in PASMC wasanalyzed by fluorescent real-time quantitative PCR,and the proliferating cell nuclearantigen and caspase-3 were examined by immunocytochemical ***:The results showed that hypoxia suppressed NO generation from PASMC,whichpromoted hypoxic PASMC proliferation and induced ***,hy-poxia induced HO-1 expression in PASMC and promoted CO production fromPASMC,which inhibited PASMC proliferation and regulated PASMC *** upregulated the expression of HO-1 mRNA in hypoxic PASMC;NO also inhib-ited proliferation and promoted apoptosis of hypoxic PASMC,possibly by regu-lating the production of ***:The results indicated that CO couldinhibit proliferation and regulate apoptosis of PASMC,and NO inhibited prolifera-tion and promoted apoptosis of hypoxic PASMC,possibly by regulating the pro-duction of CO.

关键词： hypoxia proliferation apoptosis carbon monoxide nitric oxide

Interaction between hydrogen sulfide/cystathionine γ-lyase and carbon monoxide/heme oxygenase pathways in aortic smooth muscle cells

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Acta Pharmacologica Sinica 2006年第12期27卷 1561-1566页

作者： Hong-fang JIN~2.Jun-bao DU~(2.4)Xiao-hui LI~2.Yan-fei WANG~2.Yin-fang LIANG~2.Chao-shu TANG~3 2.department of Pediatrics,peking {2. first hospital,beijing 100034,china 3 Institute of Cardiovascular Research,peking {2. first hospital,beijing 100034,china department of Pediatrics Peking University First Hospital Beijing 100034 China.

Aim:To investigate the interaction between hydrogen sulfide（H2.）/cystathion-ine γ-lyase（CSE）and carbon monoxide（CO）/heme oxygenase（HO）pathways inaortic smooth muscle cells（ASMC）.Methods:The ASMCs were divided into thefollowing groups:（1）the control group;（2.the zinc protoporphyrin（ZnPP）2.μmol/L group;（3）the propargylglycine（PPG）2.mmol/L,4 mmol/L and 10 mmol/Lgroups;and（4）the sodium hydrosulfide（NariS）1×10-5mol/L,1×10-4mol/L and1×10-3mol/L *** of the groups was further divided into 6h,12.,18hand 2.h *** CO level,represented by carboxyhemoglobin（HbCO）content was measured using a spectrophotometric method and H2. content wasdetected by a sensitive electrode *** and HO-1 expressions were de-tected by Western ***:The H2. content in the medium and CSEexpression by ASMC were markedly increased by ZnPP compared with the con-trol *** content in the medium and HO-1 expression by the ASMCstarted strengthening following 2.h treatment with PPG at 2.mmol/L,but werefurther strengthened following 18h and 2.h treatment with PPG at 4 mmol/Lcompared with the controls（P2. ***,NariS at 1×10-5mol/L and 1×10-4mol/Ldecreased the HbCO level in the medium and HO-1 expression by the ASMC after6h and 12. treatment,while NariS at 1×10-3mol/L decreased them at all timepoints of the ***:The results suggested that endogenousCO/HO and H2./CSE pathways inhibited each other in ASMC under physiologi-cal conditions.

关键词： hydrogen sulfide cystathionine γ-lyase carbon monoxide heme oxygenase

PKB negatively modulates TGF-β responsiveness in prostate carcinoma PC-3 cells through its interaction with Smad3

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Chinese Science Bulletin 2006年第13期51卷 1563-1570页

作者： LI Wei, XIN Dianqi & GUO Yinlu department of Urology, the first hospital of peking university the Urological Research Institute, {2. university, beijing 100034, china department of Urology the First Hospital of Peking University Beijing China he Urological Research Institute Peking University Beijing China

Most prostate cancers are insensitive to growth-inhibitory effect of TGF-β, while PI3K-PKB signaling is highly activated in prostate cancers. We investigated whether the PI3K-PKB signaling con- tributes to TGF-β insensitivity in PTEN-null prostate cancer PC-3 cells. Cell growth analysis showed that inhibition of PI3K-PKB pathway by LY2.4002.en- hanced growth inhibition and cell cycle arrest induced by TGF-β. Furthermore, activation of PI3K-PKB pathway by insulin or overexpression of PKB de- creased the transcriptional activity of TGF-β, as measured by the TGF-β/Smad3-responsive CAGA- luciferase reporter, while inhibition of PI3K-PKB pathway by introducing PTEN, inactive PKB mutant or using LY2.4002.promoted TGF-β-induced expres- sion of CAGA-luciferase. Co-immunoprecipitation studies further demonstrated that Smad3 interacted with PKB through its linker region and MH2.domain. This interaction was facilitated by insulin and disrupted by TGF-β signaling activation. Our results suggest that the PI3K-PKB pathway may play an important role in rendering cell resistance to the antiproliferative effect of TGF-β and regulating cell response to TGF-β.

关键词：前列腺癌蛋白激酶B TGF-β 蛋白质相互作用

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Sodium hydrosulfide alleviated pulmonary vascular structural remodeling induced by high pulmonary blood flow in rats

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Acta Pharmacologica Sinica 2006年第8期27卷 971-980页

作者： Xiao-hui LI~2.Jun-bao DU~(2.6) Ding-fang BU~3 Xiu-ying TANG~4 Chao-shu TANG~5 ~1department of Pediatrics,peking {2. first hospital,Key Laboratory of Molecular Cardiovascular Diseases,Ministry of Education ~3 Laboratory Center ~4Laboratory of Electron Microscopy,peking {2. first hospital,beijing 100034,china ~5department of Physiology,peking {2. Health Science Center,beijing 100083,china department of Pediatrics Peking University First Hospital Key Laboratory of Molecular Cardiovascular Diseases Ministry of Education

Aim:To explore the possible role of endogenous hydrogen sulfide （H2.）,a novelgasotransmitter,in the pathogenesis of pulmonary vascular structural remodeling（PVSR） induced by high pulmonary blood ***:Thirty-two Sprague-Dawley male rats were randomly divided into sham,shunt,sham+NaHS （a H2.donor） and shunt+NaHS *** in shunt and shunt+NaHS groups under-went an abdominal aorta-inferior vena cava shunt,and rats in shunt+NaHS andsham+NaHS groups were intraperitoneally injected with *** was inves-tigated using optical microscope and transmission electron *** H2. was evaluated by sulfide-sensitive *** oxide synthase（NOS）,heme oxygenase （HO-1）,proliferative cell nuclear antigen （PCNA） andextracellular signal-regulated kinase （ERK） activation were analyzed by ***:After 11 weeks of shunting,PVSR developed with a decrease inlung tissue H2. production and an increase in nitric oxide （NO）.However,lungtissue carbon monoxide （CO） did not *** the treatment with NaHS for11 weeks,H2. donor ameliorated PVSR and downregulated PCNA expression andERK activation with an increase in lung tissue CO production and HO-1 proteinexpression but a decrease in NO production,NOS activity and eNOS proteinexpression in shunted ***:H2. exerted a regulatory effect on PVSRinduced by high pulmonary blood ***,H2. down-regulated theERK/MAPK signal pathway,inhibited the NO/NOS pathway and enhanced theCO/HO pathway in rats with high pulmonary blood flow.

关键词： hydrogen sulfide pulmonary hypertension structure remodeling nitric oxide/nitric oxide synthase carbon monoxide/heme oxygenase

Effects of diffusion time and diffusion gradient strength on the mean diffusivity of water molecules in healthy human brain

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Progress in Natural Science:Materials International 2006年第7期16卷 706-711页

作者： GAO Song, WANG Xiaoying and BAO Shanglian ( Laboratory of Medical Physics & Engineering, peking university, {2. 100871, china department of Radiology, The first Affiliated hospital of peking university, beijing 100034, china) peking Univ Lab Med Phys & Engn Beijing 100871 Peoples R China peking Univ Affiliated Hosp 1 Dept Radiol Beijing 100034 Peoples R China

Diffusion time and diffusion gradient strength are two important parameters of pulsed gradient spin echo (PGSE) that is the most commonly used method in diffusion-weighted magnetic resonance imaging. However, the effects of the diffusion time on the mean diffusivity (MD) in previous studies are controversial. In this study, a new experimental protocol was designed to evaluate the effects of the two parameters on the results of PGSE. It was found that MD decreased significantly with the increased diffusion time or increased diffusion gradient strength, which cannot be explained by the previous theories. Through theoretical analysis, we found the flaw in the pulsed gradient spin echo (PGSE) method, which is the explanation for the controversial results of diffusion time obtained by oth- ers.

关键词： diffusion time diffusion gradient strength diffusion-weighted imaging diffusion tensor imaging mean diffusivity.

Peroxisome proliferator-activated receptor γ ligands induce cell cycle arrest and apoptosis in human renal carcinoma cell lines

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Acta Pharmacologica Sinica 2005年第6期26卷 753-761页

作者： Feng-guang YANG~2. Zhi-wen ZHANG~3, Dian-qi XIN~2. Chang-jin SHI~2. Jie-ping WU~2. Ying-lu GUO~(2.4), You-fei GUAN~(3,4) ~2.department of Molecular Biology, Institute of Urology peking {2. first hospital ~3 department of Physiology and Pathophysiology, peking {2. Health Science Center, beijing 100034, china departmentofMolecularBiology InstituteofUrologyPekingUniversityFirstHospitalPekingUniversityHealthscienceCenterBeijing100034China

Aim: To study the effect of peroxisome proliferator-actived receptor y （PPARγ） ligands on cell proliferation and apoptosis in human renal carcinoma cell lines. Methods: The expression of PPARγ was investigated by reverse transcriptase polymerase chain reaction （RT-PCR）, Western blot and immunohistochemistry. The effect of thiazolidinedione （TZD） PPARγ ligands on growth of renal cell carcinoma （RCC） cells was measured by MTT assay and flow cytometric analysis. Cell death ELISA, Hoechst 33342.fluorescent staining and DNA ladder assay were used to observe the effects of PPARγ ligands on apoptosis. Regulatory proteins of cell cycle and apoptosis were detected by Western blot analysis. Results: PPARγ was expressed at much higher levels in renal tumors than in the normal kidney （2.16±0.85 vs 0.90±0.73; P2.μmol/L for pioglitazone, and 5.71 μmol/L and 8.38 μmol/L for troglitazone in 786-0 and A498 cells, respectively. Cell cycle analysis showed a G0/G1arrest in human RCC cells following 2.-h exposure to TZD. Analysis of cell cycle regulatory proteins revealed that TZD decreased the protein levels of proliferating cell nuclear antigen, pRb, cyclin D1, and Cdk4 but increased the levels of p2. and p2. in a time-dependent manner. Furthermore, high doses of TZD induced massive apoptosis in renal cancer cells, with increased Bax expression and decreased Bcl-2.expression. Conclusion: TZD PPARγligands showed potent inhibitory effect on proliferation, and could induce apoptosis in RCC cells. These results suggest that ligands for PPARγ have potential antitumor effects on renal carcinoma cells.

关键词： renal cell carcinoma peroxisome proliferator activated receptor γ cell cycle apoptosis cyclin cdk