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

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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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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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（P<0.01）,ultrastructure of synoviocytes and mitogen-activated protein kinase（MAPK） phosphorylation in AA *** administration of IL-1ra （10 and 40mg/kg,ic,d 14-21） in AA rats significantly decreased the production of IL-1,PGE2and TNF-α by macrophage-like synoviocytes （MLS）（P<0.01）.IL-1ra （2.5 mg/kg）also decreased the production of PGE2（P<0.01） and TNF-α（P<0.05） by MLS inAA *** increased phosphorylation of MAPK and cell proliferation in fibro-blast-like synoviocytes （FLS） stimulated by supernatants of MLS in AA rats wasalso inhibited by IL-1ra （10 and 40 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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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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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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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 230022,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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Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines

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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 230022,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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Therapeutic effects of glucosides of Cheanomeles speciosa on collagen-induced arthritis in mice

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Acta Pharmacologica Sinica 2004年第11期 111-117页

作者： Ling-ling ZHANG, Wei WEI, Shang-xue YAN, Xiang-yang HU, Wu-yi SUNinstitute of clinical pharmacology, anhui medical university, hefei 230032, china

AIM: To investigate the therapeutic effect of the glucosides of Cheanomeles speciosa (GCS) on the collagen-induced arthritis (CIA) in mice. METHODS: Mice were divided randomly into six groups, including normal, CIA, CIA+GCS (60, 120, and 240 mg/kg) and CIA+glucosides of Tripterygium wilfordii (GTW) groups. CIA model was based on mice. The effect of GCS in CIA mice was measured by paw-swelling, arthritis scores, and histo-pathological assessment of synovium. Indices of thymus and spleens were measured. Thymocytes and splenocytes proliferation, activity of interleukin-1 (IL-1), and interleukin-2 (IL-2) were assayed by MTT and [3H]TdR method. The level of anti-collagen type Ⅱ (CII) antibody in serum and prostaglandin E (PGE) in ankle were assayed by ELISA and ultraviolet spectrophotometer method, respectively. RESULTS: The onset of paw-swelling was on d 24 after injection of emulsion. The peak of secondary inflammation appeared on d 36 and then declined after d 40. GCS and GTW significantly reduced paw-swe

关键词： glucosides Cheanomeles speciosa experimental arthritis inflammation immunity

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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(P<0.05).The levels of LBP and CD14 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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Anti-adjuvant arthritis of recombinant human endostatin in rats via inhibition of angiogenesis and proinflarnmatory factors

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Acta Pharmacologica Sinica 2004年第9期 80-83页

作者： Li YUE, Hua WANG, Li-hua LIU, Yu-xian SHEN2, Wei WEIinstitute of clinical pharmacology, anhui medical university, hefei 230032, china

AIM: To investigate the profile of endostatin on adjuvant arthritis (AA) and angiogenesis blockade in synovitis. METHODS: The model of rat AA was induced by injection of intradermal complete Freund’s adjuvant (CFA). Hind paw volume of rat was measured by volume meter and the activities of interleukin-1 (IL-1) and IL-2 were measured by the assay of thymocytes proliferation. IL-1β and tumor necrosis factor-a (TNF-α) produced

关键词： rats experimental arthritis endostatin angiogenesis inhibitors cytokines

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