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Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines

Acta Pharmacologica Sinica 2007年第6期28卷 869-878页

作者： Shu-ping XU~2,Guo-ping SUN~(4,5),Yu-xian SHEN~2,Wan-ren PENG~4,Hua WANG~3,Wei WEI~2~2 institute of clinical pharmacology,anhui medical university,Key Laboratory of Anti-inflammatory and Immunological pharmacology,Key Laboratory of Research and Development of Chinese Medicine,hefei 230032,china ~3 Department of Oncology,Provincial Hospital ofanhui,hefei 230001,china ~4 Department of Oncology,The First Affiliated Hospital of anhui medical university,hefei 23.022,china institute of clinical pharmacology Anhui Medical University Key Laboratory of Anti-inflammatory and Immunological Pharmacology Key Laboratory of Research and Development of Chinese Medicine Hefei China Department of Oncology The First Affiliated Hospital of Anhui Medical University Hefei China Department of Oncology Provincial Hospital of Anhui Hefei China

Aim:To investigate whether paeonol （Pae） has synergistic effects with cisplatin（CDDP） on the growth-inhibition and apoptosis-induction of human hepatomacell lines HepG2and ***:The cytotoxic effect of drugswas measured by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyl-tetrazolium *** coefficient of drug interaction was used to analyze the nature of *** changes were observed by acridine orange fluo-rescence *** cycle and the apoptosis rate were detected by ***-2 and Bax expression were assayed by ***:Pae or CDDP had antiproliferative effect on the 2 cell linesin a dose-dependent manner,with different sensitivities to ***,a synergistic inhibitory effect on the viability of the 2 cell lineswas observed after treatment with a combination of Pae （15.63,31.25,and 62.5mg/L） with various concentrations of *** study showed typical mor-phological changes of apoptosis if the cells were exposed to the two agents for24 *** apoptotic rate of the cells with combination treatment was signifi-cantly higher than that of cells treated with Pae or CDDP *** expressionof Bcl-2 decreased and that of Bax increased in the treated groups,especially inthe combination group,with the ratio of Bcl-2/Bax decreasing ***,a combination of Pae with CDDP resulted in a stronger S phasearrest,compared with Pae or CDDP ***:Pae,in combinationwith CDDP,had a significantly synergistic growth-inhibitory and apoptosis-in-ducing effect on the 2 human hepatoma cell lines,which may be useful inhepatoma treatment.

关键词： paeonol cisplatin drug interaction human hepatoma cell line apoptosis cell cycle

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Melatonin-selenium nanoparticles protects liver against immunological injury induced by bacillus Calmette-Guérin and lipopolysaccharide

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Acta Pharmacologica Sinica 2005年第6期26卷 745-752页

作者： Hua WANG, Wei WEI~3, Sheng-yi ZHANG~2, Yu-xian SHEN, Ni-ping WANG, Li YUE, Shu-yun XU institute of clinical pharmacology, anhui medical university, hefei 230032, china ~2Department of Chemistry, anhui university, hefei 230039, china. institute of clinical pharmacology Anhui Medical University Hefei China Department of Chemistry Anhui University Hefei China

Aim: Melatonin-selenium nanoparticle (MT-Se), a novel complex, was synthesized by preparing selenium nanoparticles in a melatonin medium. The present investigation was designed to determine the protective effects of MT-Se against immunological liver injury in mice induced by bacillus Calmette-Guerin (BCG)/ lipopolysaccharide (LPS). Methods: The model of immunological liver injury in mice was prepared. The levels of alanine aminotransferase, aspartate aminotransferase, nitric oxide (NO) in serum, malondialdehyde content, superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) activities in a liver homo-genate were assayed by spectrophotometry. The content of tumor necrosis fac-tor (TNF) and interleukin-1 (IL-1) were determined by ELISA. The splenocyte proliferation was assayed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetra-zolium bromide (MTT) dye reduction. Meanwhile, a hepatic pathological examination was observed. Results: In the BCG/LPS-induced hepatic injury model, MT-Se administered at doses of 5,10, or 20 mg/kg to the BCG/LPS-treated mice for 10 d significantly reduced the increase in serum aminotransferase, reduced the severe extent of hepatic cell damage and the immigration of inflammatory cells. It also attenuated the increase in the content of thiobarbituric acid-reactive substances and enhanced the decrease in activities of SOD and GSH-px. In contrast, the treatment with MT-Se suppressed the increase in NO level in both the serum and liver tissue. Furthermore, MT-Se significantly lowered an increase in TNF and IL-1 levels in the liver and inhibited the production of TNF and IL-1 by peritoneal macrophages. A downregulation effect of MT-Se on splenocyte proliferation was also observed. Conclusion: MT-Se showed a hepatic protective action on immunological liver injury in mice.

关键词： melatonin selenium liver superoxide dismutase glutathione peroxidase nitric oxide tumor necrosis factor interleukin-1

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Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotype in healthy Chinese subjects

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Acta Pharmacologica Sinica 2005年第3期26卷 384-388页

作者： Yong-mei HU~(2,3) Jian-ming XU~(3,5) Qiao MEI~3 Xin-hua XU~3 Shu-yun XU~42 anhui Geriatric institute 3 Department of Gastroenterology,First Affiliated Hospital of anhui medical university 4 clinical pharmacology institute,anhui medical university,hefei 23.022,china anhui Geriatric institute Hefei 230022 China Department of Gastroenterology First Affiliated Hospital of Anhui Medical University Hefei 230022 China clinical pharmacology institute Anhui Medical University Hefei 230022 China

Aim:To investigate whether the pharmacodynamics and pharmacokinetics ofrabeprazole are dependent on CYP2C19 genotype status in healthy Chinese ***:The CYP2C19 genotype status of healthy Chinese Hart volun-teers was determined using the polymerase chain reaction-restriction fragmentlength polymorphism *** healthy subjects volunteered to participatein the *** were seven homozygous extensive metabolizers （homEM）,sixheterozygous extensive metabolizers （hetEM）,and seven poor metabolizers （PM）.All subjects were Helicobactor pylori-negative,which was determined by sero-logy and13C-urea breath *** （20 mg） was taken orally once daily inthe morning for 8 days,and intragastric pH values were monitored for 24 h byDigitrapper pH after day 1 （single dose） and day 8 （repeated dose）.Meanwhile,blood samples were collected at various time-points for 24 h after *** serum concentrations of rabeprazole were measured using high-performanceliquid ***:The mean area under the curve （AUC） values forrabeprazole differed among the three different genotype groups,with a relativeratio of 1.0,1.3,and 1.8 after a single dose and 1.0,1.1,and 1.7 after repeated dosesin the homEM,hetEM,and PM groups,*** AUC values forrabeprazole after a single dose and after repeated doses were significantly differ-ent between the homEM and PM groups,but not between the homEM and hetEMor hetEM and PM *** significant differences in intragastric pH median,pH>4 total time,and pH>4 time percentage of 24 h,were observed among the threedifferent genotype groups after a single dose or after repeated doses of ***:In healthy Chinese Hart subjects,the pharmacokinetics of rabeprazoleare dependent on a certain degree on CYP2C19 genotype status;however,theacid-inhibitory efficacy of rabeprazole is not influenced significantly by CYP2C 19genetic polymorphism.

关键词： polymorphism(genetics) pharmacokinetics pharmacodynamics rabeprazole

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N-Acetylcysteine attenuates lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice

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Acta Pharmacologica Sinica 2007年第11期28卷 1803-1809页

作者： Hua WANG~2,De-xiang XU~(2,3,4),Jin-wei LU~2,Lei ZHAO~2,Cheng ZHANG~2,Wei WEI~(3,4)~2 Department of Toxieology and ~2 institute of clinical pharmacology anhui medical university,hefei 230032,china Department of Toxicology Anhui Medical University Hefei China institute of clinical pharmacology Anhui Medical University Hefei China

Aim:To investigate the effects of N-acetylcysteine on D-galactosamine (Ga1N)/lipopolysaccharide (LPS)-induced apoptotic liver injury in ***:Whengiven together with a low dose of LPS,Ga1N highly sensitizes animals to produceapoptotic liver injury with severe hepatic congestion,resulting in rapid *** Ga1N/LPS model,TNF-α is the major mediator leading to apoptotic liver *** oxygen species (ROS) are involved in Ga1N-induced sensitization toTNF-α-evoked hepatocyte apoptosis.N-acetylcysteine (NAC) is an antioxidantand a glutathione (GSH) *** this study,we investigated the effects ofNAC on LPS-induced apoptotic liver injury in Ga1N-sensitized ***:Pretreatment with NAC significantly reduced Ga1N/LPS-induced elevation ofserum alanine aminotransferase *** parallel,Ga1N/LPS-induced hepaticnecrosis and congestion were obviously improved by ***,NACpretreatment significantly alleviated Ga1N/LPS-induced hepatic apoptosis,mea-sured by the inhibition of hepatic caspase-3 activity and attenuation of *** pretreatment had no effect on LPS-evoked nitric oxide productionin Ga1N-sensitized *** in serum TNF-α concentration,which wereobserved in Ga1N/LPS-treated mice,were not significantly reduced by *** NAC pretreatment significantly alleviated LPS-induced hepatic GSHdepletion,DL-buthionine-(SR)-sulfoximine,an inhibitor of GSH synthesis,did notinfluence the protective effect of NAC on Ga1N/LPS-induced apoptotic liver ***:NAC attenuates Ga1N/LPS-induced apoptotic liver injury via its strongROS scavenging and anti-apoptotic effects.

关键词： N-acetylcysteine lipopolysaccharide apoptosis liver injury antioxidant

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Interleukin-1 receptor antagonist intervenes in signaling between different types of synoviocytes in rats with adjuvant arthritis

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Acta Pharmacologica Sinica 2006年第1期27卷 111-118页

作者： Yong-qiu ZHENG~2 Wei WEI~(2,3,4) Min DAI~2 Lei ZHU~2 Xiao-yi JIA~2 Yuan WANG1 institute of clinical pharmacology,anhui medical university.hefei 230032,china 3 Key Laboratory of Anti-inflammation and Immunopharmacology in anhui Province,hefei 230032.china institute of clinical pharmacology Anhui Medical University Hefei China Key Laboratory of Anti-inflammation and Immunopharmacology in anhui Province Hefei China

Aim:To investigate the mechanisms of interleukin-1 receptor antagonist （IL-1ra）in the treatment of adjuvant arthritis （AA）.Methods:AA was induced in rats bytreatment with Freund's complete adjuvant （FCA）.Rats were given an intracuta-neous injection of IL-1ra （2.5,10,40mg/kg,3 times per day） from d 14 to d 21 *** proliferation and the activity of IL-1 were determinedby using MTT *** necrosis factor alpha （TNF-α） and prostaglandin E2（PGE2） concentrations were measured by *** ultrastructureof synoviocytes was observed by using a transmission electron *** of c-Jun N-terminal kinase （JNK）,extracellular regulating kinase（ERK） and p38 kinase were detected by Western blot ***:IL-1ra （10and 40 mg/kg,ic,d 14-21） modulated the secondary inflammatory reaction（P40mg/kg,ic,d 14-21） in AA rats significantly decreased the production of IL-1,PGE2and TNF-α by macrophage-like synoviocytes （MLS）（P40 mg/kg,ic.d 14-21）.Conclusion:IL-1ra hasanti-inflammatory effects because it modulates the ultrastructure of synoviocytes,decreases the production of pro-inflammatory mediators by MLS,and inhibits thephosphorylation of MAPK in FLS.

关键词： interleukin-1 receptor experimental arthritis mitogen-activated protein kinase synovial membrane

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Chinese national clinical practice guidelines on the prevention,diagnosis,and treatment of early gastric cancer

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Chinese medical Journal 2024年第8期137卷 887-908页

作者： Peng Li Ziyu Li Enqiang Linghu Jiafu Ji Society of Digestive Endoscopy of the Chinese medical Association Colorectal Surgery Group of the Chinese medical Association Chinese Association of Gastroenterologists&Hepatologists National clinical Research Center for Digestive Diseases Chinese medical Journal clinical Practice Guideline Collaborative Department of Gastroenterology Beijing Friendship HospitalCapital Medical UniversityNational Clinical Research Center for Digestive DiseaseBeijing 100050China Department of Gastrointestinal Surgery Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer Hospital and InstituteBeijing 100142China Department of Gastroenterology and Hepatology the First Medical CenterChinese People’s Liberation Army General HospitalBeijing 100853China 不详

Background:Gastric cancer is one of the most common malignant tumors in the digestive system in *** comprehensive practice guidelines for early gastric cancer in china are currently ***,we created the Chinese national clinical practice guideline for the prevention,diagnosis,and treatment of early gastric ***:This clinical practice guideline(CPG)was developed in accordance with the World Health Organization’s recommended process and with the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)in assessing evidence *** used the Evidence to Decision framework to formulate clinical recommendations to minimize bias and increase transparency in the CPG development *** used the Reporting Items for practice Guidelines in HealThcare(RIGHT)statement and the Appraisal of Guidelines for Research and Evaluation II(AGREE II)as reporting and conduct guidelines to ensure completeness and transparency of the ***:This CPG contains 40 recommendations regarding the prevention,screening,diagnosis,treatment,and follow-up of early gastric cancer based on available clinical studies and *** provide recommendations for the timing of Helicobacter pylori eradication,screening populations for early gastric cancer,indications for endoscopic resection and surgical gastrectomy,follow-up interval after treatment,and other ***:This CPG can lead to optimum care for patients and populations by providing up-to-date medical *** intend this CPG for widespread adoption to increase the standard of prevention,screening,diagnosis,treatment,and follow-up of early gastric cancer;thereby,contributing to improving national health care and patient quality of life.

关键词： Early gastric cancer Prevention Screening Diagnosis Treatment Follow-up

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Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice

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Acta Pharmacologica Sinica 2005年第2期26卷 250-256页

作者： Yong JIN,Jun LI~2,Long-fu RONG,Xiong-wen L(?),Yan HUANG,Shu-yun XUinstitute of clinical pharmacology,School of Pharmacy,anhui medical university,hefei 230032,china institute of clinical pharmacology School of Pharmacy Anhui Medical University Hefei China

Aim:To study the pharmacokinetics and tissue distribution of 5-fluorouracil en-capsulated by galactosylceramide liposomes(5-Fu-GCL)in ***:Theconcentration of 5-fluorouracil(5-Fu)in serum was detected by high performanceliquid chromatography after 5-Fu-GCL(80,40,20 mg/kg)and free 5-Fu(40mg/kg)were injected intravenously into *** tissue distribution of 5-Fu-GCL(40mg/kg)and free 5-Fu(40mg/kg)was investigated,and concentration-timeprofile of the two preparations in the liver were *** were analyzed by3p97 ***:Serum concentration-time curves of 5-Fu-GCL and free5-Fu conformed to one compartment model of first order absorption.5-Fu-GCLat 80,40,and 20 mg/kg had T1/2Keof 25.8±4.2,27.3±4.4,and 28.2±5.6 min;C0of24.9±4.9,17.7±3.6,and 11.5±2.7 mg/L;and AUC of 990.0±45.2,622.5±38.3,and 340.4±25.6 ***.L-1,*** contrast free 5-Fu at 40 kg/mg hadT1/2Keof 15.8±2.2min,C0of 35.8±6.2mg/L,AUC of 639.0±35.9 *** distribution of 5-Fu-GCL in the liver and immune organs was significantlyincreased,while in heart and kidney it was remarkably *** AUC of 5-Fu-GCL in the liver was 3 times higher than that of free ***:Thepharmacokinetics and tissue distribution of 5-Fu-GCL appears to be linear-re-lated and dose-dependent,and exhibits sustained-release and hepatic targetcharacteristics.

关键词： 5-fluorouracil galactosylceramide liposomes pharmacokinetics

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Upregulation of TNF-αand IL-6 mRNA in mouse liver induced by bacille Calmette-Guerin plus lipopolysaccharide

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Acta Pharmacologica Sinica 2006年第4期27卷 460-468页

作者： Dao-fang LIU~(1,2,3) Wei WEI~(1,4) Li-hua SONG~(1,2,3,4) ~1institute of clinical pharmacology,Key Laboratory of Anti-inflammatory and Immunopharmacology in anhui Province.Key Laboratory of Research and Development of Chinese Medicine in anhui Province.anhui medical university,hefei 230032,china:~2Molecular Biology Laboratory,anhui Biology institute,hefei 230088,china ~3Center of Research and Development,anhui Anke Biotechnology Group,hefei 230088.china institute of clinical pharmacology Key Laboratory of Anti-inflammatory and Immunopharmacology in Anhui Province Key Laboratory of Research and Development of Chinese Medicine in Anhui Province Anhui Medical University Hefei China Molecular Biology Laboratory Anhui Biology Institute Hefei China Center of Research and Development Anhui Anke Biotechnology Group Hefei China

Aim:To investigate the mechanism of immunological liver injury induced by bacilleCalmette-Guerin(BCG)plus lipopolysaccharide(LPS).Methods:Mice were in-jected via the tail vein with 125 mg/kg BCG,and 12 d later,the mice were injectedintravenously with different doses of LPS(125,250,or 375 μg/kg).Serum alanineaminotransferase(ALT)activity and liver pathological changes were *** expression of tumor necrosis factor(TNF)-α interleukin(IL)-6,lipopolysac-charide binding protein(LBP)and CD14 mRNA,and NF-κB and IκB-α protein inmouse liver at different time points after BCG and LPS injection were measuredusing RT-PCR,immunohistochemistry and Western blotting analysis,***:The activity of serum ALT in mice treated with BCG and LPS was signifi-cantly *** degrees of liver injury,such as inflammatory cellinfiltration,spotty necrosis,piecemeal necrosis,even bridging necrosis,could beseen in liver sections from mice after BCG and LPS ***,thelevels of TNF-α and IL-6 mRNA in mouse liver were significantly elevated afteradministration of BCG plus LPS(P4 mRNA inmouse liver were markedly upregulated after treatment with BCG and LPS,andtreatment with BCG alone led to an increase in CD14 InRNA in mouse ***,immunoreactivity for NF-κB p65 was predominantly detected in hepatocyte nucleifrom mice treated with BCG plus LPS,compared with the normal *** of IκB-α were strikingly decreased by LPS or BCG plus LPS treatment,compared with the normal group or BCG ***:TNF-α and IL-6mRNA were partially involved in early immunological liver injury induced by chal-lenge with small doses of LPS after BCG *** of TNF-α and IL-6 mRNA might be related to increases in LBP and CD 14 mRNA expression andactivation of NF-κ***,BCG priming in immunological liver injury mayoccur via upregulation of CD 14 mRNA expression in monon uclear cell infiltrationinto t

关键词： liver injury lipopolysaccharide binding protein CD14 tumor necrosis factor-alpha interleukin-6 NF-kappa B

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Inhibitory effect of leflunomide on hepatic fibrosis induced by CCl4 in rats

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Acta Pharmacologica Sinica 2004年第7期25卷 69-74页

作者： Hong-wei YAO2,3, Jun LI3,4, Ji-qiang CHEN2, Shu-yun XU3 2 Zhejiang Respiratory Drugs Research Laboratory of State Drugs Administration of china, School of Medicine, Zhejiang university, Hangzhou 310031 3institute of clinical pharmacology, anhui medical university, hefei 230032, china 浙江大学国家食品药品监督管理局呼吸药物研究实验室 Hangzhou 310031 institute of clinical pharmacology Anhui Medical University Hefei

AIM: To study the effect of leflunomide on CCl4-induced hepatic fibrosis in rats. METHODS: Hepatic fibrosis was induced by subcutaneous injection with 50 % CCl4 in Sprague-Dawley rats. The amount of CCl4 administered was 1 mg/kg. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO) levels in plasma and hydroxyproline (Hyp) contents in liver tissue were assayed by spectrophotometry. The hyaluronic acid (HA) and procollagen III (PC III) were assessed by radioimmunoassay. The transforming growth factor-β1 (TGF-β1) in serum was determined by ELISA. The nuclear factor-kappa B (NF-κB) in liver tissue was examined by immunohistochemistry. Liver samples collected after 12 weeks of CCl4 treatment were stained with hematoxy- lin and eosin. RESULTS: Leflunomide (1, 3, and 9 mg/kg) significantly decreased indices of liver and spleen, the serum transaminase (AST, ALT) activities, HA and PC III levels, and Hyp contents in liver tissue in rats of hepatic fibrosis. Histopathological examination showed leflunomide had inhibitory effect on fibrogenesis and formation of pseudolobulus. Furthermore, leflunomide significantly inhibited NF-κB expression in liver tissue, and reduced elevated serum TGF-β1 and NO levels in rats of hepatic fibrosis. CONCLUSION: Leflunomide showed inhibitory action on hepatic fibrosis induced by CCl4 in rats.

关键词： leflunomide hepatic fibrosis nuclear factor-kappa B transforming growth factor-beta nitric oxide

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Genistein stimulates osteoblastic differentiation via p38 MAPK-Cbfa1 pathway in bone marrow culture

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Acta Pharmacologica Sinica 2007年第10期28卷 1597-1602页

作者： Qing-chuan LIAO~2,Zhou-sheng XIAO~(4,5),Yan-fang QIN~3,Hong-hao ZHOU~4~2 Affiliated Children's Hospital,Nanjing medical university,Nanjing 210008,china,~3 Department of Pathology,School of Medicine,Jinanuniversity,Guangzhou 510632,china ~4 institute of clinical pharmacology,Central South university,Changsha 410078,china Affiliated Children's Hospital Nanjing Medical University Nanjing China institute of clinical pharmacology Central South University Changsha China Department of Pathology School of Medicine Jinan University Guangzhou China

Aim:To test the hypothesis that genistein stimulates the osteoblastic differentia-tion through the p38 mitogen activated protein kinase (MAPK)-core-binding fac-tor 1 (Cbfa1) ***:The activation of p38 MAPK was detected byWestern *** phosphatase (ALP) activity and calcium depositionwere assessed for osteoblastic differentiation of bone marrow-derived mesenchy-mal stem cell (BMSC) *** expression of Cbfa1 was analyzed at both themRNA and protein *** activity of Cbfa1 was detected by electrophoreticmobility shift *** sialoprotein (BSP),ALP,osteocalcin (OC),andosteopontin (OPN) gene transcription were also evaluated by either RT-PCR orNorthern ***:Genistein (0.01-1 μmol/L) dose dependently led tothe rapid and sustained activation of the p38 MAPK pathway in mouse *** with genistein (1 μmol/L) resulted in increased ALP activityand calcium deposition of BMSC cultures as a function of *** alsoenhanced Cbfa1 DNA binding activity and promoted the expressions of Cbfa1itself as well as several Cbfa1-regulated genes,including ALP,BSP,OC,and *** treatment with p38 MAPK inhibitor (SB203580) diminished thegenistein-induced osteoblastic maturation and p38 MAPK-Cbfa1 activation inmouse BMSC ***:These results indicated that genistein couldstimulate the osteoblastic differentiation of BMSC cultures through the p38MAPK-Cbfa1 pathway.

关键词： bone marrow-derived mesenchymal stem cells core-binding factor 1 osteoblastic differentiation genistein mitogen-activated protein kinase

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