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Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line

Acta Pharmacologica Sinica 2007年第11期28卷 1819-1826页

作者： Hong-zhen HU~2,Yue-bo YANG~3,Xiang-dong XU~4,Hong-wei SHEN~5,Yi-min SHU~6,Zi REN~7,Xiao-mao LI~3,Hui-ming SHEN~3,Hai-tao ZENG~(3,8)~2 department of Gynecology and obstetrics,Yijishan hospital,Wannan Medical College,Wuhu 241001,china ~3 department of gynecologyand obstetrics,the third affiliated hospital,sun yat-sen university,guangzhou 510080,china ~4 department of Surgery,the First affiliatedhospital,sun yat-sen university,guangzhou 510080,china ~2 department of Gynecology and obstetrics,the First affiliated hospital,sunyat-sen university,guangzhou 510080.china ~6 department of obstetrics and Gynecology,IVF Program,Stanford university MedicalCenter,Palo Alto,CA 94304,USA ~7 department of Gynecology and obstetrics,Guangdong Provincial People's hospital,guangzhou510080.china department of Gynecology and obstetrics Yijishan Hospital Wannan Medical College Wuhu China department of Gynecology and obstetrics the Third Affiliated Hospital Sun Yat-sen University Guangzhou China department of Surgery the First Affiliated Hospital Sun Yat-sen University Guangzhou China department of Gynecology and obstetrics the First Affiliated Hospital Sun Yat-sen University Guangzhou China department of obstetrics and Gynecology IVF Program Stanford University Medical Center Palo Alto USA department of Gynecology and obstetrics Guangdong Provincial People's Hospital Guangzhou China

Aim:To investigate the apoptosis-inducing effect of oridonin,a diterpenoid iso-lated from Rabdosia rubescens,in the human cervical carcinoma HeLa cell ***:A morphological analysis,nuclear condensation,and fragmentation ofchromatin were monitored using Hoechst 33342 *** viability was as-sessed using the 3-(4,5-dimethylthiazol-(2)-yl)-2,5-diphenyl tetrazolium bromide(MTT) *** apoptosis and the apoptosis-related activation in the HeLa cellline were evaluated by flow cytometry and Western ***:Oridoninsuppressed the proliferation of the HeLa cell line in a dose-and *** treatment downregulated the activation of protein kinase B(Akt),the expression of forkhead box class O (FOXO) transcription factor,andglycogen synthase kinase 3 (GSK3).Oridonin also induced the release of cyto-chrome c accompanied by the activation of caspase-3 and poly-adenosine diphos-phate-ribose polymerase *** addition,Z-D(OMe)-E(OMe)-V-D(OMe)-FMK (z-DEVD-fmk),an inhibitor of caspases,prevented caspase-3 activation andabrogated oridonin-induced cell ***,oridonin treatment of the HeLa cellline downregulated the expression of the inhibitor of the apoptosis ***:Our results showed that oridonin-induced apoptosis involved sev-eral molecular *** may suppress constitutively activated targetsof phosphatidylinositol 3-kinase (Akt,FOXO,and GSK3) in the HeLa cell line,inhibiting the proliferation and induction of caspase-dependent apoptosis.

关键词： cervical carcinoma oridonin apoptosis Akt

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PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression

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Acta Pharmacologica Sinica 2006年第6期27卷 715-723页

作者： Kai sun Qian WANG~2 Xiao-hui HUANG department of Hepatobiliary Surgery,the First affiliated hospital of sun yat-sen university,guangzhou 510080,china department of Hepatobiliary Surgery the First Affiliated Hospital of Sun Yat-Sen University Guangzhou China

Aim:To investigate the effect of peroxisome proliferator-activated receptor gamma(PPARγ)activation on the growth of rat hepatic stellate cells(HSC)and trans-forming growth factor beta(TGF-β)-induced connective tissue growth factor(CTGF)***:After being treated with various amounts of thePPARγ natural ligand 15-deoxy-A 12,14-prostaglandin J2(15-d-PGJ2)or syntheticligand GW7845,the status of HSC proliferation and apoptosis were detected byMTT assay and flow ***,HSC were treated with PPARγ-specific antagonist GW9662 prior to the addition of 15-d-PGJ2or GW7845 andwere subsequently stimulated with TGF-β*** mRNA and protein levels ofCTGF expression were detected by semi-quantitative RT-PCR and Western blot-ting *** changes in the HSC were observed by ***:15-d-PGJ2and GW7845 markedly inhibited HSC prolifera-tion and induced cell apoptosis in a dose-dependent ***,PPARγligands significantly suppressed TGF-β1-induced CTGF expression(at both tran-scriptional and post-transcriptional levels)in HSC,and the inhibitory effect wasdramatically,if not completely,abolished by pretreatment with GW9662,sug-gesting that the inhibition was indeed mediated by PPARγ.Moreover,morpho-logical observation revealed that PPARγ activation caused obvious changes ofHSC from activated to quiescent ***:The PPARγligand hasa potent inhibitory effect on the growth of HSC and TGF-β1-induced CTGFexpression,which makes it a potential antifibrotic candidate for the treatment andprevention of hepatic fibrosis.

关键词： PPAR gamma transforming growth factor beta connective tissue growth factor hepatic stellate cells

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Addition of tanshinone IIA to UW solution decreases skeletal muscle ischemia-reperfusion injury

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Acta Pharmacologica Sinica 2006年第8期27卷 991-999页

作者： Hong-gang WANG Zhi-yong LI Xiao-lin LIU~2 department of Orthopaedics & Microsurgery,the First affiliated hospital of sun yat-sen university,guangzhou 510080,china department of Orthopaedics & Microsurgery the First Affiliated Hospital of Sun Yat-Sen University Guangzhou China

Aim:To investigate whether tanshinone ⅡA could improve the effect of UWsolution for skeletal muscle preservation and to determine the dose range oftanshinone ⅡA providing optimal protection during ischemia and ***:Ischemic rat limbs were perfused with UW solution or UW plus tanshinoneⅡA (UW+T,0.05,0.1,or 0.2 mg/mL) for 0.5h before reperfusion;controls (I/R)received no *** creatine phosphokinase (CPK),aspartate aminotrans-ferase (AST),and lactate dehydrogenase (LDH) were measured pre-ischemia andafter reperfusion (2-h,4-h,and 6-h).Muscle water content,superoxide dismutase(SOD),malondialdehyde (MDA),adenosine triphosphatase (ATPase) were as-sessed pre-reperfusion and after 6-h *** adhesion molecule-1(ICAM-1) and apoptosis were detected after 6-h *** bloodflow was monitored during reperfusion ***:UW and UW+T pre-vented luxury perfusion during reperfusion and inhibited ICAM-1 expression andapoptosis after 6-h *** CPK,AST,and LDH levels in UW ratswere significantly less than those in controls after 2-h reperfusion (no difference,4-h or 6-h reperfusion).After 4-h ischemia,there were significant differences inwater content,MDA,SOD,and ATPase between UW and controls,but no differ-ence after 6-h *** tests with UW+T rats were significantly differentfrom control results at corresponding *** tanshinone doses im-proved ***:UW plus tanshinone ⅡA increased protection againstI/R injury,suggesting that tanshinone ⅡA has clinical value.

关键词： UW solution tanshinone IIA ischemia-reperfusion skeletal muscle

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Microtubule stability and MAP1B upregulation control neuritogenesis in CAD cells

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Acta Pharmacologica Sinica 2006年第9期27卷 1119-1126页

作者： Wen LI~(2,5)Jin-tang XIA~3 Yue FENG~(4,5)2 Laboratory of Surgery,The First affiliated hospital,sun yat-sen university,guangzhou 510080,china 3 department of General Surgery,The First People's hospital of guangzhou,guangzhou 510180,china 4 department of Pharmacology,Emory university School of Medicine,USA Laboratory of Surgery The First Affiliated Hospital Sun Yat-sen University Guangzhou China department of General Surgery The First People's Hospital of Guangzhou Guangzhou China department of Pharmacology Emory University School of Medicine USA

Aim:To study the role of microtubule dynamics and microtubule associated pro-tein 1B(MAP1B)in regulation of the neurite extension in CAD catecholaminergicneuronal cell ***:The neuritogenesis of the CAD cells was abolishedby inhibiting microtubule polymerization with nocodazole and by blocking micro-tubule depolymerization with ***1B and tubulin protein expression wasdetected by Western *** staining of tubulins was observedby fluorescent and confocal ***:Microtubule dynamics wasessential for CAD neurite *** analysis revealed that neurite exten-sion was much more sensitive to nocodazole than to taxol,suggesting a func-tional requirement for highly active microtubule assembly.A remarkableupregulation of MAP IB protein was detected during neurite extension accompa-nied with increased microtubule ***:Upregulation of MAP1Bleads to the stabilization of newly formed microtubules in the developing neurites,which in turn promotes neurite extension.

关键词： microtubule stability microtubule associated protein 1B neuritogenesis

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Activation of PI3-K/Akt pathway for thermal preconditioning to protect cultured cerebellar granule neurons against low potassium-induced apoptosis

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Acta Pharmacologica Sinica 2007年第2期28卷 173-179页

作者： Lin CAO~(2,3) De-xiong CAO~3 Xing-wen SU~2 Li-jun CHEN~2 Ai-lin LIU~2 Wei-jian JIAN~2 Yu-ping WU~2 Peng-xin QIU~2 Guang mei YAN~(2,4)2 department of Pharmacology,Zhongshan Medical School,sun yat-sen university,guangzhou 510080,china 3 department of Anesthesiology The Second affiliated hospital,sun yat-sen university,guangzhou 510120,china department of Pharmacology Zhongshan Medical School Sun Yat-sen University Guangzhou China department of Anesthesiology The Second Affiliated Hospital Sun Yat-sen University Guangzhou China

Aim:This study was designed to investigate whether the activation of thephosphatidylinositol 3-kinase(PI3-K)/Akt pathway is required for thermal pre-conditioning to protect rat cerebellar granule neurons(CGN)against apoptosisinduced by low potassium,and to explore the possibility of a link between theupregulated heat shock protein(HSP)70 expression and Akt activation in theacquisition of neuroprotection induced by thermal ***:CGN cultured for 8 d in vitro were switched to 5K medium for 24 h after thermalpreconditioning(TP;43.5 ℃ for 90 min,then 37 ℃ for 1 h).To study the role of thePI3-K/Akt pathway,a PI3-K inhibitor,LY294002(20 μmol/L)was added into thecultures 1 h before TP.3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bro-mide(MTT)assay and fluorescein diacetate staining were used to determine *** 33258 staining and agar gel electrophoresis were used to testthe morphological and biological characters of *** blot analysis wasemployed to detect the levels of phospho-Akt,phospho-glycogen synthase ki-nase 3β(GSK3β) Akt,GSK3β,and ***:TP protected CGN againstapoptosis induced by low ***294002 inhibited the neuroprotectiveeffect on CGN induced by *** induced a robust activation of Akt and theinactivation of GSK3β via ***,the activation of the PI3-K/Aktpathway by TP persisted for 24 h in the 5K ***294002(20 μmol/L)failedto inhibit the upregulated HSP70 expression induced by ***:Theactivation of the PI3-K/Akt pathway is required for TP to protect CGN againstapoptosis induced by low potassium,but the neuroprotective effect by Akt acti-vation is not mediated through the downstream induction of HSP70 expression.

关键词： thermal preconditioning heat cerebellum neurons apoptosis LY294002 phospho Akt phospho-GSK3β HSP70

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Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis

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Acta Pharmacologica Sinica 2007年第11期28卷 1835-1841页

作者： Xiang-wei YUAN~2,Xiao-feng ZHU~(3,5),Xiu-fang HUANG~4,Pu-yi SHENG~2,Ai-shan HE~2,Zi-bo YANG~2,Rong DENG~3,Gong-kanFENG~3,Wei-ming LIAO~(2,5)~2 department of Orthopedic Surgery,The First affiliated hospital,sun yat-sen university,guangzhou 510080,china ~3 State Key Laboratoryof Oncology in South china,Cancer Center,sun yat-sen university,guangzhou 510060,china ~4 department of Pathology,The affiliatedJiangmen hospital,sun yat-sen university,Jiangmen 529030,china department of Orthopedic Surgery The First Affiliated Hospital Sun Yat-sen University Guangzhou China State Key Laboratory of Oncology in South china Cancer Center Sun Yat-sen University Guangzhou China department of Pathology The Affiliated Jiangmen Hospital Sun Yat-sen University Jiangmen China

Aim:To determine whether interferon-α(IFNα) can enhance doxorubicinsensitivity in osteosarcoma cells and its molecular ***:Cellviability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide *** was studied using Flow cytometry analysis,Hoechst33258 staining,DNA fragmentation assay,as well as the activation ofcaspase-3 and poly (ADP-ribose) *** expression was detectedby Western *** dependence of p53 was determined using ***:IFNα increased doxorubicin-induced cytotoxicity to a muchgreater degree through apoptosis in human osteosarcoma p53-wild U2OS cells,but not p53-mutant MG63 ***α markedly upregulated p53,Bax,Mdm2,andp21,downregulated Bcl-2,and activated caspase-3 and PARP cleavage in re-sponse to doxorubicin in U2OS ***,the siRNA-mediated silencing ofp53 significantly reduced the IFNα/doxorubicin combination-induced cytotoxic-ity and PARP ***:IFNα enhances the sensitivity of humanosteosarcoma U2OS cells to doxorubicin by p53-dependent *** propercombination with IFNα and conventional chemotherapeutic agents may be a ra-tional strategy for improving the treatment of osteosarcoma with functional p53.

关键词： Interferon-α doxorubicin apoptosis p53 osteosarcoma

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PPARγ phosphorylation mediated by JNK MAPK:a potential role in mac-rophage-derived foam cell formation

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Acta Pharmacologica Sinica 2006年第9期27卷 1146-1152页

作者： Ran YIN~2 Yu-gang DONG~(2,4)Hong-liang LI~3 Z department of Cardiology,First affiliated hospital,sun yat-sen university,guangzhou 510080,china 3 Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Beijing 100005,china department of Cardiology First Affiliated Hospital Sun Yat-sen University Guangzhou China Institute of Basic Medical Sciences Chinese Academy of Medical Sciences Beijing China

Aim:To investigate whether oxidized low-density lipoprotein(ox-LDL)modulatesperoxisome proliferator-activated receptorγ(PPARγ)activity through phosphory-lation in macrophages,and the effect of PPARγ phosphorylation on macroph-ages-derived foam cell ***:After exposing the cultured THP-1cells to ox-LDL in the presence or absence of different mitogen-activated proteinkinase(MAPK)inhibitors,PPARγ and phosphorylated PPARγ protein levels weredetected by Western *** activity was analyzed using MAP Kinase As-say *** cholesterol accumulation was assessed by Oil red O stainingand cholesterol oxidase enzymatic *** mRNA level of PPARγtarget genewas determined by reverse transcription-polymerase chain reaction(RT-PCR).Results:ox-LDL evaluated PPARγ phosphorylation status and subsequently de-creased PPARγ target gene expression in a dose-dependent manner,ox-LDL alsoinduced MAPK *** of THP- 1 cells with c-Jun N-terminal kinase-,but not p38- or extracellular signal-regulated kinase-MAPK inhibitor,significantlysuppressed PPARγ phosphorylation induced by ox-LDL,which in turn inhibitedfoam cell ***:In addition to its ligand-dependent activation,ox-LDL modulates PPARγ activity through phosphorylation,which is mediatedby MAPK ***γ phosphorylation mediated by MAPK facilitatesfoam cell formation from macrophages exposed to ox-LDL.

关键词： peroxisome proliferator-activated receptorγ phosphorylation macrophages LDL lipoprotein

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Canal Wall Reconstruction Mastoidectomy

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Journal of Otology 2007年第1期2卷 52-55页

作者： LIU Wei department of Otolaryngology Head and Neck Surgery, third affiliated hospital, sun yat-sen university, guangzhou 510630, china department of Otolaryngology Head and Neck Surgery Third Affiliated Hospital Sun Yat-Sen University Guangzhou 510630 China

Objective To investigate the advantages of canal wall reconstruction(CWR) mastoidectomy, a single-stage technique for cholesteatoma removal and posterior external canal wall reconstruction, over the open and closed procedures in terms of cholesteatoma recurrence. Methods: Between June 2002 and December 2005, 38 patients (40 ears) with cholesteatoma were admited to sun yat-sen Memorial hospital and received surgical treatments. Of these patients, 25 were male with ages ranging between 11 and 60 years(mean = 31.6 years) and 13 were female with ages ranging between 20 and 65 years (mean = 38.8 years). Canal wall reconstruction(CWR)mastoidectomy was performed in 31 ears and canal wall down(CWD) mastoidectomy in 9 ears. Concha cartilage was used for ear canal wall reconstruction in 22 of the 31 CWR procedures and cortical mastoid bone was used in the remaining 9 cases. Results At 0.5 to 4 years follow up, all but one patients remained free of signs of cholesteatoma recurrence, i.e., no retraction pocket or cholesteatoma matrix. One patient, a smoker, needed revision surgery due to cholesteatoma recurrence 1.5 year after the initial operation. The recurrence rate was therefore 3.2% (1/31). Cholesteatoma recurrence was monitored using postoperative CT scans whenever possible. In the case that needed a revision procedure, a retraction pocket was identified by otoendoscopy in the pars flacida area that eventually evolved into a cholesteatoma. A pocket extending to the epitympanum filled with cholesteatoma matrix was confirmed during the revision operation, A decision to perform a modified mastoidectomy was made as the patient refused to quit smoking. The mean air-bone gap in pure tone threshold was 45 dB before surgery and 25 dB after(p < 0.05). There was no difference between using concha cartilage and cortical mastoid bone for the reconstruction regarding air-bone gap improvement, CT findings and otoendoscopic results. Conclusion CWR mastoidectomy can be used for most pati

关键词： Mastoidectomy Ear canal Reconstruction Cholesteatoma

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Clinicopathological features of gastric glomus tumor

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World Journal of Gastroenterology 2010年第36期16卷 4616-4620页

作者： Hui-Qiong Fang,Jing Yang,Fen-Fen Zhang,An-Jia Han,department of Pathology,First affiliated hospital of sun yat-sen university,guangzhou 510080,Guangdong Province,china Hui-Qiong Fang,department of Pathology,Foshan hospital of Traditional Chinese Medicine,Foshan 528000,Guangdong Province,china Jing Yang,department of Pathology,People’s hospital of Zhu-hai City,Zhuhai 519000,Guangdong Province,china Yi Cui,department of Gastroenterology,First affiliated hospital of sun yat-sen university,guangzhou 510080,Guangdong Province,china department of Pathology First Affiliated Hospital of Sun Yat-Sen University Guangzhou 510080 Guangdong Province China.

AIM:To study the clinicopathological features of gastric glomus tumor and review the related Chinese literature published in ***:A case of gastric glomus tumor was *** findings in 56 cases of gastric glomus tumor were ***:Gastric glomus tumor was far more common in women than in men with a female to male ratio of 1.6:*** median age of the patients was 45 years(range 28-79 years).The patients often complained of epigastric pain and bloody *** tumor was located in antrum of the *** greatest diameter of the tumor was ***,the tumor was comprised of nests of glomus cells surrounding the *** cells were small,uniform and ***,smooth muscle actin and actin were expressed in the *** markers,including S-100 protein,CD34,CD117,desmin,CD56,synaptophysin,chromo-granin A,neuron specific enolase and cytokeratin were all ***:Gastric glomus tumor is a rare benign mesenchymal *** diagnosis depends on pathologic *** diagnosis includes gastrointestinal stromal tumor,paraganglioma and carcinoid tumor.

关键词： Stomach Glomus tumor Clinicopathology Immunohistochemistry

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(-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis

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World Journal of Gastroenterology 2007年第8期13卷 1162-1169页

作者： Bao-He Zhu, Wen-Hua Zhan, Zheng-Rong Li, Zhao Wang, Yu-Long He, Jun-Sheng Peng, Shi-Rong Cai, Jin-Ping Ma, Chang-Hua Zhang, department of Gastrointestinal & Pancreatic Surgery, First affiliated hospital, sun yat-sen university Gastric Center of sun yat-sen university, guangzhou 510080, Guangdong Province, china department of Gastrointestinal and Pancreatic Surgery First Affiliated Hospital Sun Yat-Sen University Gastric Center of Sun Yat-Sen University Guangzhou 510080 Guangdong Province China.

AIM： To investigate the effect of （-）-epigallocatechin-3-gallate （EGCG） on growth of gastric cancer and its possible mechanism. METHODS： Heterotopic tumors were induced by subcutaneously injection of SGC-7901 cells in nude mice. Tumor growth was measured by calipers in two dimensions. Tumor angiogenesis was determined with tumor microvessel density （MVD） by immunohistology. Vascular endothelial growth factor （VEGF） protein level and activation of signal transducer and activator of transcription 3 （Star3） were examined by Western blotting. VEGF mRNA expression was determined by RT-PCR and VEGF release in tumor culture medium by ELISA. VEGF-induced cell proliferation was studied by MTT assay, cell migration by gelatin modified Boyden chamber （Transwell） and in vitro angiogenesis by endothelial tube formation in Matrigel. RESULTS： Intraperitoneal injection of EGCG inhibited the growth of gastric cancer by 60.4%. MVD in tumor tissues treated with EGCG was markedly reduced. EGCG treatment reduced VEGF protein level in vitro and in vivo. Secretion and mRNA expression of VEGF in tumor cells were also suppressed by EGCG in a dose-dependent manner. This inhibitory effect was associated with reduced activation of Star3, but EGCG treatment did not change the total Star3 expression. EGCG also inhibited VEGF-induced endothelial cell proliferation, migration and tube formation. CONCLUSION： EGCG inhibits the growth of gastric cancer by reducing VEGF production and angiogenesis, and is a promising candidate for anti-angiogenic treatment of gastric cancer.

关键词： Epigallocatechin-3-gallate Angiogenesis Migration Tube formation Vascular endothelial growth factor Signal transducer and activator of transcription 3 Gastric cancer

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