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oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells

World Journal of Gastroenterology 2012年第31期18卷 4199-4206页

作者： Ning-Li Chai Qiang Fu Hui Shi Chang-Hao Cai Jun Wan Shi-Ping Xu Ben-Yan Wu Department of Gastroenterology South Build-ing of Chinese People's Liberation Army General Hospital Bei-jing 100853 China Department of Gastroenterology Xi'an Children'sHospital Xi'an 710002 Shaanxi Province China

AIM： To investigate the potential mechanism of Arg- Gly-Asp （RGD） peptide-labeled liposome loading oxy- matrine （OM） therapy in CCI4-induced hepatic fibrosis in rats. METHODS： We constructed a rat model of CCh- induced hepatic fibrosis and treated the rats with dif- ferent formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phospha- tase, hepatic histopathology （hematoxylin and eosin stain and Masson staining） and fibrosis-related gene expression of matrix metallopeptidase （MMP）-2, tis- sue inhibitor of metalloproteinase （TIMP）-I as well as type I procollagen via quantitative real-time poly- merase chain reaction. To detect cell viability and apop- tosis of hepatic stellate cells （HSCs）, we performed 3-（4,5）-dimethylthiahiazo（-z-yl）-3,5-diphenytetrazoli- umromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy. RESULTS： OM attenuated CCh-induced hepatic fibro- sis, as defined by reducing serum alkaline phosphatase （344.47± 27.52 U/L vs 550.69 ± 43.78 U/L, P 〈 0.05）, attenuating liver injury and improving collagen deposits （2.36% ± 0.09% vs 7.70% ±0.60%, P 〈 0.05） and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen （P 〈 0.05）. OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and en- hanced the therapeutic effect of OM in terms of serum alkaline phosphatase （272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L, P 〈 0.05）, liver injury, collagen deposits （0.26%± 0.09% vs 2.36% ± 0.09%, P 〈 0.05） and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen （P 〈 0.05）. Moreover, in vitro assay demonstrated that RGD en- hanced the effect of OM on HSC viability and apoptosis. CONCLUSION： OM attenuated hepatic fi

关键词： oxymatrine Arg-Gly-Asp peptide Hepaticstellate cell Hepatic fibrosis Target therapy

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oxymatrine reduces neuroinflammation in rat brain A signaling pathway

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Neural Regeneration Research 2012年第30期7卷 2333-2339页

作者： Jiahui Mao Yae Hu Ailing Zhou Bing Zheng Yi Liu Yueming Du Jia Li Jinyang Lu Pengcheng Zhou Department of Pathophysiology Medical School of Nantong University Nantong 226001 Jiangsu Province China Department of Urology the First People's Hospital of Nantong Nantong 226001 Jiangsu Province China Undergraduate of Medical School of Nantong University Nantong 226001 Jiangsu Province China

Cerebral neuroinflammation models were established by injecting 10μg lipopolysaccharide into the hippocampus of male Sprague-Dawley rats. The rats were treated with an intraperitoneal injection of 120, 90, or 60 mg/kg oxymatrine daily for three days prior to the lipopolysaccharide injection. Twenty-four hours after model induction, the hippocampus was analyzed by real-time quantitative PCR, and the cerebral cortex was analyzed by enzyme-linked immunosorbent assay and western blot assay. The results of the enzyme-linked immunosorbent assay and the real-time quantitative PCR showed that the secretion and mRNA expression of the pro-inflammatory cytokines interleukin-113 and tumor necrosis factor-a were significantly decreased in the hippocampus and cerebral cortex of model rats treated with oxymatrine. Western blot assay and real-time quantitative PCR analysis indicated that toll-like receptor 4 mRNA and protein expression were significantly decreased in the groups receiving different doses of oxymatrine. Additionally, 120 and 90 mg/kg oxymatrine were shown to reduce protein levels of nuclear factor-KB p65 in the nucleus and of phosphorylated IKBa in the cytoplasm of brain cells, as detected by western blot assay. Experimental findings indicate that oxymatrine may inhibit neuroinflammation in rat brain via downregulating the expression of molecules in the toll-like receptor 4/nuclear factor-KB signaling Dathwav.

关键词： oxymatrine neuroinflammation toll-like receptor 4 nuclear factor-KB signaling pathway inflammatory factors lipopolysaccharide hippocampus cerebral cortex neural regeneration

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oxymatrine Inhibits Bocavirus MVC Replication, Reduces Viral Gene Expression and Decreases Apoptosis Induced by Viral Infection

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Virologica Sinica 2019年第1期34卷 78-87页

作者： Yanqin Ding Na Li Jinhan Sun Linran Zhang Jianhui Guo Xueqi Hao Yuning Sun Department of Biochemistry and Molecular Biology Key Laboratory of Fertility Preservation and Maintenance of Ministry of EducationSchool of Basic Medical ScienceNingxia Medical University School of Clinical Medicine Hainan Medical University Department of Respiratory and Critical Care General Hospital of Ningxia Medical UniversityNingxia Medical University

oxymatrine(OMT), as the main active component of Sophoraflavescens, exhibits a variety of pharmacological properties,including anti-oxidative, anti-inflammatory, anti-tumor, and anti-viral activities, and currently is extensively employed to treat viral hepatitis; however, its effects on parvovirus infection have yet to be reported. In the present study, we investigated the effects of OMT on cell viability, virus DNA replication, viral gene expression, cell cycle, and apoptosis in Walter Reed canine cells/3873 D infected with minute virus of canines(MVC). OMT, at concentrations below 4 mmol/L(no cellular toxicity), was found to inhibit MVC DNA replication and reduce viral gene expression at both mRNA and protein levels, which was associated with the inhibition of cell cycle S-phase arrest in early-stage of MVC ***, OMT significantly increased cell viability, decreased MVC-infected cell apoptosis, and reduced the expression of activated caspase 3. Our results suggest that OMT has potential application in combating parvovirus infection.

关键词： oxymatrine (OMT) Minute virus of canines (MVC) Infection Replication Apoptosis

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oxymatrine Improves TNBS-induced Colitis in Rats by Inhibiting the Expression of NF-κB p65

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2008年第4期28卷 415-420页

作者：范恒陈瑞沈霖吕建芳熊鹏程寿折星庄雄 Department of Traditional Chinese Medicine Union Hospital Tongji Medical College Huazhong University of Science and Tech-nology

Inflammatory bowel disease is thought to be regulated by the balance between Th1 and Th2 cytokines secreted by T cells, and NF-κB p65 also plays a predominant role in the intestinal inflammation. We evaluated the potency of oxymatrine, one of active components of Sophora Root, in inhibiting the immune responses and inflammation in 2,4,6-trinitrobenzene sulfonic acid （TNBS）-induced colitis. The inflammation was markedly ameliorated in the oxymatrine-treated rats. The level of IL-2 was increased and that of IL-10 was decreased in colon tissue in the rat model, which was reversed by the treatment of oxymatrine. Moreover, the elevated expression of NF-κB p65 in colon tissue in the model was also improved by oxymatrine treatment. Our results suggest that oxymatrine might be beneficial for the abnormal immune responses and inflammation by regulating the unbalance of Th1 and Th2 cytokines secretion and inhibiting the expression of NF-κB p65 in colon tissue.

关键词： colitis oxymatrine intcrlcukin 2 (IL-2) interleukin 10 (IL-10) nuclear factor-κB p65

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Synergistic effect of oxymatrine and angiogenesis inhibitor NM-3 on modulating apoptosis in human gastric cancer cells

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World Journal of Gastroenterology 2007年第12期13卷 1788-1793页

作者： Ming-Quan Song Jin-Shui Zhu Jin-Lian Chen Long Wang Wei Da Li Zhu Wei-Ping Zhang Department of Gastroenterology The Sixth Affiliated Hospital of Shanghai Jiaotong University Shanghai 200233 China

AIM: To investigate the synergistic effect of oxymatrine(OM) and angiogenesis inhibitor NM-3 on modulatingapoptosis in human gastric cancer cell lines SGC-7901,MKN-45, MKN-74. METHODS: Human gastric cancer lines SGC-7901,MKN-45, MKN-74 were treated with OM in the absenceand presence of NM-3. The inhibitory rates weredetected by MTT assay. Synergistic effect of OM andNM-3 on the growth of survivin, bcl-2, bax and p53 inSGC-7901 cells were examined by semiquantitative RT-PCR and Western blotting, and their growth inhibitoryeffects were also observed on SGC-7901 tumor xenograftin nude ***: OM combined with NM-3 exhibited asynergistic inhibitory effect on the growth of SGC-7901,MKN-45 and MKN-74 cells in a time-dependent ***-four hours after treatment with OM, NM-3 aloneand their combination, mRNA expression of survivin andbcl-2 in SGC-7901 cells decreased, p53 mRNA expressionincreased. OM (4 g/L) combined with NM-3 significantlyincreased the expression of p53 mRNA and decreasedthe expression of survivin and bcl-2 compared witheither agent alone (193% ± 34% vs 129% ± 12%;44% ± 18% vs 92% ± 18%; 36 ± 17% vs 93% ± 23%,P < 0.05). Western blotting showed that the synergisticeffect of OM and NM-3 on protein translation of survivin,bcl-2 and p 53 was in accordance with their ***, OM/NM-3 combination obviously exhibitedantitumor growth effect in xenografted human gastriccancer cells SGC-7901 compared with either agent ***: OM combined with NM-3 has synergisticinhibitory effects on human gastric cancer cells in vitro and can suppress the growth of xenografted human gastric cancer cells SGC-7901 in vivo.

关键词： NM-3 compound oxymatrine Gastric cancer Apoptosis

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Effect of oxymatrine on the replication cycle of hepatitis B virus in vitro

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World Journal of Gastroenterology 2010年第16期16卷 2028-2037页

作者： Xu, Wen-Sheng Zhao, Ke-Kai Miao, Xiao-Hui Ni, Wu Cai, Xiong Zhang, Rui-Qi Wang, Jun-Xue Second Mil Med Univ Changzheng Hosp Dept Infect Dis Shanghai 200003 Peoples R China 404 Hosp Dept Infect Dis Weihai 264200 Shandong Peoples R China

AIM:To determine the antiviral mechanism or target of oxymatrine against hepatitis B virus(HBV).METHODS:HepG2.2.15 cells were incubated with culture medium containing 500 μg/mL of oxymatrine for 2 and 5 *** surface antigen of HBV(HBsAg) and e antigen of HBV(HBeAg) in supernatant were determined by *** DNA in supernatant,and intracellular covalently closed circular DNA(cccDNA),relaxed circular DNA(rcDNA) and pregenomic RNA(pgRNA) were quantif ied by specif ic real-time polymerase chain reaction(PCR) or reverse transcription(RT)-***:Treatment with oxymatrine for 2 d and 5 d reduced the production of HBV by the cell line,as indicated by the decline of HBsAg(22.67%,t = 5.439,P = 0.0322 and 22.39%,t = 5.376,P = 0.0329,respectively),HBeAg(55.34%,t = 9.859,P = 0.0101 and 43.97%,t = 14.080,P = 0.0050) and HBV DNA(40.75%,t = 4.570,P = 0.0447 and 75.32%,t = 14.460,P = 0.0047) in the *** cccDNA was also markedly reduced by 63.98%(t = 6.152,P = 0.0254) and 80.83%(t = 10.270,P = 0.0093),and intracellular rcDNA by 34.35%(t = 4.776,P = 0.0413) and 39.24%(t = 10.050,P = 0.0097).In contrast,intracellular pgRNA increased by 6.90-fold(t = 8.941,P = 0.0123) and 3.18-fold(t = 7.432,P = 0.0176) after 500 μg/mL of oxymatrine treatment for 2 d and 5 d,***:oxymatrine may inhibit the replication of HBV by interfering with the process of packaging pgRNA into the nucleocapsid,or inhibiting the activity of the viral DNA polymerase.

关键词： oxymatrine Hepatitis B virus Replication intermediates Covalently closed circular DNA Pregenomic RNA

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Synthesis of N-Succinyl-chitosan(Suc-Chi) and Preparation of oxymatrine(OM)/N-Succinyl-chitosannanoparticles

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Chemical Research in Chinese Universities 2006年第5期22卷 589-592页

作者： YAN Cheng-yun CHEN Da-wei GU Ji-wei LI Liu-fa School of Pharmacy Shenyang Pharmaceutical University Shenyang 110016 P. R. China College of Chemistry ＆ Pharmacy Jiamusi University Jiamusi 154000 P. R. China

oxymatrine （OM）/N-succinyl-chitosan （Suc-Chi, with a degree of substitution being 0. 32） was synthesized via the ring-opening reaction of succinic anhydride with chitosan in dimethyl sulfoxide. OM-loaded Suc-Chi nanoparticles were prepared by an ionotropic gelation process and OM was quantified via the HPLC method： The influences of the initial OM concentration on the nanoparticle characteristics and OM release behavior were evaluated. The nanoparticles were found to have a mean diameter within a range of 267-392 nm, a positive surface charge, and a zeta potential in the range of 19-27 inV. The formulation with an initial OM concentration of 100μg/mL provided the highest loaded capacity（0. 77% ） and the highest extent of the released OM （68% at 24 h）, suggesting the possibility to achieve a therapeutic dose. According to the data obtained, this Suc-Chi-based nanotechnology will open up new and interesting prospects for the development of new anticancer drugs.

关键词： N-Succinyl-chitosan Synthesis oxymatrine Nanoparticles Characterization

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Treatment of pig serum-induced rat liver fibrosis with Boschniakia rossica, oxymatrine and interferon-α

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World Journal of Gastroenterology 2005年第1期11卷 122-126页

作者： Chun-SongWu Xi-XuPiao Dong-MingPiao Yong-RiJin Cheng-HaoLi DepartmentofGastroenterology theAffiliatedHospitalMedicalCollegeYanbianUniversityYanji133000JilinProvinceChina

AIM: To investigate the effect of Boschniakia rossica (BR),oxymatrine (OM) and interferon-alpha (IFN-α) 1b on the therapy of rat liver fibrosis and its ***: By establishing a rat model of pig serum-induced liver fibrosis, liver/weight index and serum alanine transaminase (ALT) were observed to investigate the therapeutic effect of BR, OM and IFN-α. Radioimmunoassay was utilized to measure procollagen type Ⅲ (PCⅢ) and collagen type Ⅳ (CIV). RT-PCR was used to assay the expression of liver transforming growth factor- beta 1 (TGF-β1) mRNA. Immunohistochemistry of alpha-smooth muscle actin (α-SMA) and pathologic changes of liver tissues were also under ***: Serum PCⅢ and CIV in BR, OM and IFN-α groups were significantly declined compared with those in model group, and their RT-PCR revealed that TGF-β1 mRNA expression was also reduced more than that in model group. Immunohistochemistry demonstrated that α-SMA also declined more than that in model group. Serum ALT in IFN-α, control and model groups was within normal *** ALT in BR group had no significant difference from those of IFN-α, control and model groups. Serum ALT in OM group was significantly higher than those in BR, IFN-α,model, and control ***: BR, OM and IFN-α can prevent pig seruminduced liver rat fibrosis by inhibiting the activation of hepatic stellate cells and synthesizing collagen. OM has hepatotoxicity to rat liver fibrosis induced by pig serum.

关键词： Liver fibrosis Boschniakia rossica oxymatrine Interferon-alpha

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Anti-inflammatory mechanism of oxymatrine in dextran sulfate sodium-induced colitis of rats

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World Journal of Gastroenterology 2005年第31期11卷 4912-4915页

作者： Ping Zheng Feng-Li Niu Wen-Zhong Liu Yao Shi Lun-Gen Lu Shanghai Institute of Digestive Disease Renji Hospital Shanghai Second Medical University Shanghai 200127 China

AIM： To investigate the anti-inflammatory mechanism of oxymatrine in dextran sulfate sodium （DSS）-induced colitis of rats. METHODS： Acute colitis was induced by giving 2% DSS orally in drinking water for 8 d. Twenty-six male rats were randomized into oxymatrine-treated group （group A, 10 rats）, DSS control （group B, 10 rats） and normal control （group C, 6 rats）. The rats in group A were injected muscularly with oxymatrine at the dosage of 63 mg/（kg·d） from d 1 to 11 and drank 2% DSS solution from d 4 to 11. The rats in group B were treated with 0.9% saline in an equal volume as group A and drank 2% DSS solution from d 4 to 11. The rats in group C were treated with 0.9% saline as group B from d 1 to 11 and drank water normally. Diarrhea and bloody stool as well as colonic histology were observed. The levels of serum tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） were determined by ELISA, and nuclear factor-κB （NF-κB） activity and the expression of inter-cellular adhesion molecule-1 （ICAM-1） in colonic mucosa were detected by immunohistochemistry method. RESULTS： Compared with DSS control group, the inflammatory symptoms and histological damages of colonic mucosa in oxymatrine-treated group were significantly improved, the serum levels of TNF-α, IL-6, and the expression of NF-κB, ICAM-1 in colonic mucosa were significantly reduced. CONCLUSION： The fact that oxymatrine can reduce the serum levels of TNF-α, IL-6, and the expression of NF-κB and ICAM-1 in colonic mucosa in DSS-induced colitis of rats indicates that oxymatrine may ameliorate the colonic inflammation and thus alleviate diarrhea and bloody stool.

关键词： oxymatrine Colitis Colonic mucosa

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Effects of oxymatrine on experimental hepatic fibrosis and its mechanism in vivo

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World Journal of Gastroenterology 2005年第2期11卷 268-271页

作者： Guang-FengShi QianLi DepartmentofInfectiousDiseases HuaShanHospitalFuDanUniversityShanghai200040China

AIM: Hepatic fibrogenesis has close relation with hepatic stellate cells (HSC)and tissue inhibitors of metalloproteinase (TIMP). oxymatrine (OM) is a kind of Chinese herb that is found to have some effects on liver fibrosis. We aimed to determine the effects of OM on hepatic fibrosis and explore the possible mechanism. METHODS: Thirty-two rats were randomly divided into four groups; 16 were used to develop hepatic fibrosis by carbon tetrachloride (CCI4) and treated with or without OM, and 16 were used as controls. The expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and α-smooth muscle actin (α-SMA) in the livers of rats was detected by immunohisto-chemical assay. Liver pathology was determined by H&E staining and reticulum staining. RESULTS: In CCl4-injured rats, the normal structure of lobules was destroyed, and pseudolobules were formed. Hyperplasia of fibers was observed surrounding the lobules. While the degree of fibrogenesis in liver tissues was significantly decreased in those rats with OM-treatment compared with those without OM treatment. The pseudolobules were surrounded by strong, multi-layer reticular fibers, which netted into pseudolobules in CCl4-injured rats, however, there was a significant decrease in reticular fibers in OM-treated rats. The expression of TIMP-1 in hepatic cells was weak in control groups, but strong in CCl4-injured groups, however, the expression of TIMP-1 was significantly inhibited by OM (F = 52.93, P0.05). CONCLUSION: OM effectively inhibits CCl4-induced fibrogenesis in rat liver tissues, probably by reducing the expression level of TIMP-1.

关键词： Experimental hepatic fibrosis oxymatrine TIMP-1 α-SMA

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