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GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

Acta Pharmaceutica Sinica B 2024年第3期14卷 1222-1240页

作者： Paipai Guo Ji Jiang Rui Chu Feng He Mingli Ge Ruhong Fang Qiuyun Guan Huijuan Cheng Chunru Jiang Tiantian Su Zhenduo Zhu Hao Liu Wei Wei Shihao Zhang Qingtong Wang Institute of Clinical pharmacology Anhui Medical UniversityKey Laboratory of Anti-inflammatory and Immune MedicineMinistry of EducationCollaborative Innovation Center of Anti-inflammatory and Immune MedicinesHefei 230032China School of Pharmacy Bengbu Medical CollegeBengbu 233030China The Third Affiliated Hospital of anhui Medical University(the First People’s Hospital of Hefei) Hefei 230061China

Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.

关键词： Rheumatoid arthritis Fibroblast-like synoviocytes G protein-coupled receptor kinase 2 Salvador homolog-1 Yes-associated protein

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Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis

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Acta Pharmaceutica Sinica B 2024年第2期14卷 869-880页

作者： Yucheng Zhao Yuedong He Liangliang Han Libo Zhang Yuanzheng Xia Fucheng Yin Xiaobing Wang Deqing Zhao Sheng Xu Fei Qiao Yibei Xiao Lingyi Kong Department of Resources Science of Traditional Chinese Medicines School of Traditional Chinese Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China College of Bioscience and Biotechnology Hunan Agricultural UniversityChangsha 410128China Jiangsu key laboratory of Bioactive Natural Product Research and State key laboratory of Natural Medicines Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China key laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China Ministry of AgricultureTropical Crops Genetic Resources InstituteChinese Academy of Tropical Agricultural SciencesHaikou 517317China Institute of Botany Jiangsu Province and Chinese Academy of SciencesNanjing 210014China Department of pharmacology School of Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Pyran-and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans,respectively,exhibiting diverse physiological and medical bioactivities.However,the biosynthetic mechanisms for their core structures remain poorly understood.Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants.These included three distinct P.praeruptorum prenyltransferases(PpPT1e3)responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors,and two novel CYP450 cyclases(PpDC and PpOC)crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds.Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring.The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis.We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process.This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

关键词： Tetrahydropyrans Tetrahydrofurans Baldwin rules Coumarins CYP450cyclase

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Network pharmacology of Xian-Lian-Jie-Du Decoction in Ameliorating Colorectal Cancer

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World Journal of Traditional Chinese Medicine 2024年第1期10卷 83-92页

作者： Ming-Xia Zhao Cheng-Lin Song Qin-Chang Zhang Hao-Jie Du Shu-Qiong Zhang Yu-Xian Shen Yang Sun Hai-Bo Cheng Wen Lv Department of Pharmacy School of Basic Medical SciencesAnhui Medical UniversityHefeiAnhuiChina Department of Biopharmaceutical Research Institute Anhui Medical UniversityHefeiAnhuiChina Department of Pharmaceutical Analysis State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijingChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor First Clinical CollegeNanjing University of Chinese MedicineNanjingJiangsuChina Deparment of Biotechnology and Pharmaceutical Sciences State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsuChina Deparment of Gynecology Institute of Traditional Chinese Medicine of Zhejiang ProvinceTongde Hospital of Zhejiang ProvinceHangzhouZhejiangChina

Objective:In this study,we screened for therapeutic targets of the Xian-Lian-Jie-Du decoction(XLJDD)for colorectal cancer(CRC)and explored the underlying mechanisms using network pharmacology techniques.Methods:Genes associated with CRC were collected from the Gene Cards database.The names of the active compounds of XLJDD were used as keywords in the“chemical name”in the Traditional Chinese Medicine Systems pharmacology(TCMSP)database to search the targets.The protein-protein interaction(PPI)network was constructed using Cytoscape 3.8.1.Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to identify key target proteins.Results:A total of 234 XLJDD-related targets and 250 cross-targets between XLJDD and CRC were collected based on the TCMSP and HIT 2.0 databases.A PPI network constructed based on the STRING database revealed interactions for all 250 proteins.The network results revealed TP53,MYC,CCND1,AKT1,CASP3,and STAT3 as core potential targets.KEGG pathway analysis of the 250 potential XLJDD targets for CRC in the Metascape database was performed using RStudio software.The top 12 gene ratio aggregated analysis results were visualized in bubble charts.The interleukin(IL)-17 signaling pathway had the highest correlation with the tumor necrosis factor(TNF)signaling pathway.Conclusions:XLJDD may be effective in ameliorating CRC by controlling inflammatory factors related to the IL-17 and TNF pathways and targeting proto-oncogenes and tumor suppressor genes,including MYC,CCND1,CTNNB1,and TP53.

关键词： Colorectal cancer network pharmacology Xian-Lian-Jie-Du decoction

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Uncovering the action mechanism of Shenqi Tiaoshen formula(参芪调肾方) in the treatment of chronic obstructive pulmonary disease through network pharmacology,molecular docking,and experimental verification

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Journal of Traditional Chinese Medicine 2024年第4期 770-783页

作者： YANG Qinjun YIN Dandan WANG Hui GAO Yating WANG Xinheng WU Di TONG Jiabing WANG Chuanbo LI Zegeng School of Chinese Medicine Anhui University of Chinese Medicine anhui province key laboratory of the Application and Transformation of Traditional Chinese Medicine in the Prevention and Treatment of Major Pulmonary Diseases Department of Pharmacy the First Affiliated Hospital of Anhui Medical University Institute of Traditional Chinese Medicine Respiratory Disease Prevention and Control Anhui Academy of Traditional Chinese Medicine Department of Respiratory the First Affiliated Hospital of Anhui University of Chinese Medicine Department of Chinese Medicine the Second Affiliated Hospital of Anhui Medical University

OBJECTIVE: To reveal the potential underlying mechanism of the Shenqi Tiaoshen formula(参芪调肾方, SQTS) in the treatment of chronic obstructive pulmonary disease(COPD) by utilizing network pharmacology, molecular docking, and experimental verification. METHODS: Multiple open-source databases and research related to Traditional Chinese Medicine or compounds were employed to screen active ingredients and corresponding potential targets of the SQTS. The protein-protein interaction network screened hub genes, the relevant molecular mechanism and gene regulation were initially identified through the Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) analysis, and molecular docking was used to confirm further the interaction of the main components bound to the core targets. In vivo experiments on the COPD combined Qi-deficiency syndrome rat model were performed to verify the intervention effects and predicted potential molecular mechanisms of the SQTS. RESULTS: This study selected 156 active compounds and 326 candidate targets for treating COPD. Quercetin, Nobiletin, Kaempferol, Luteolin, Ginsenoside Rh2 and Formononetin were probably the main active compounds of SQTS in COPD treatment as they affected the most COPD-related targets, and interleukin-1(IL-6), signal transducing activator of transcription 3(STAT3), matrix metalloproteinase-9(MMP9), vascular endothelial growth factor A(VEGFA), protein kinase B(AKT1), hypoxiainducible factor-1α(HIF-1α), and forkhead box O3(FoxO3) were identified as the hub genes associated with its therapeutic effect. KEGG analysis was mainly enriched in the signaling pathways closely related to inflammation, immunity and oxidative stress, such as HIF-1, tumor necrosis factor(TNF), phosphatidylinositol 3 kinase(PI3K)-AKT, FoxO, apoptosis, IL-17, and toll-like receptor. Molecular docking confirmed that the main active components shared a good affinity with the hub genes. In vivo experiments, the SQTS was found to improve the body weight, exhaustive swimming time, tailhanging imm

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Cross-talk between MEK1/2-ERK1/2 signaling and G protein-couple signaling in synoviocytes of collagen-induced arthritis rats

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Chinese Medical Journal 2008年第22期121卷 2278-2283页

作者： ZHANG Ling-ling WEI Wei WANG Qing-tong CHEN Jing-yu CHEN Yin Institute of Clinical pharmacology Anhui Medical University key laboratory of anti-inflammatory and immuno-pharmacology in anhui province key laboratory of Research & Development of Chinese Medicine in anhui province Hefei Anhui 230032 China

Background Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in rheumatoid arthritis （RA） pathogenesis. There are co-relations between signaling pathways. The aim of this study was to investigate interactions and cross-talks between MEK1/2-extracellular signal-related kinase （ERK1/2） signaling and G protein-couple signaling in synoviocytes of collagen-induced arthritis （CIA） rats by the stimulation of interleukin-1 （IL-1）, U0126, isoprenaline hydrochloride and aminophyline respectively. Methods Twenty Sprague-Dawley （SD） rats were induced by chicken type II collagen. Synoviocytes of CIA rats were isolated and cultured. The expressions of Gi, phosphorylated MEK1/2 （p-MEK1/2） and phosphorylated ERK1/2 （p-ERK1/2） were detected by Western blotting, cAMP level and protein kinase A （PKA） activity were measured by radioimmunoassay and kinase-glo luminescent kinase assay respectively. Results There was remarkable inflammation in CIA rats accompanied by swelling paws, hyperplastic synovium, pannus and cartilage erosion, cAMP level and PKA activity of synoviocytes decreased. Gi, p-ERK1/2 and p-MEK1/2 increased, rlL-la improved the expression of Gi, p-ERK1/2 and p-MEK1/2, cAMP and PKA increased with stimulation of rlL-1α. U0126 inhibited Gi, cAMP and PKA of synoviocytes stimulated by rlL-la. Isoprenaline hydrochloride enhanced Gi, cAMP and PKA, but had no effects on p-MEK1/2 and p-ERK1/2. Aminophyline increased cAMP and PKA, but inhibited p-MEK1/2 and p-ERK1/2. Conclusions Mitogen-activated protein kinases （MAPKs） and G protein-couple signaling are associated with synovitis. There are cross talks between MAPKs and G protein-couple signaling. The two signaling pathways represent potential therapeutic targets for RA.

关键词： arthritis signaling cross-talk G protein MAP kinases

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Integrated data mining and network pharmacology to discover a novel traditional Chinese medicine prescription against diabetic retinopathy and reveal its mechanism

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TMR Modern Herbal Medicine 2024年第2期7卷 41-55页

作者： Kai-Lun Zhang Xu Wang Xiang-Wei Chang Jun-Fei Gu Bo-Yang Zhu Shi-Bing Wei Bo Wu Can Peng Jiu-Sheng Nie De-Ling Wu College of Pharmacy Anhui University of Chinese MedicineHefei 230012China School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine Nanjing University of Chinese MedicineNanjing 210023China MOE-anhui Joint Collaborative Innovation Center for Quality Improvement of anhui Genuine Chinese Medicinal Materials Anhui University of Chinese MedicineHefei 230012China Institute of Pharmaceutics Anhui Academy of Chinese MedicineHefei 230012China anhui province key laboratory of Pharmaceutical Preparation Technology and Application Anhui University of Chinese MedicineHefei 230012China Engineering Technology Research Center of Modernized Pharmaceutics Anhui Education Department(AUCM)Hefei 230012China The First Clinical Medical College Anhui University of Chinese MedicineHefei 230012China

Background:Diabetic retinopathy(DR)is currently the leading cause of blindness in elderly individuals with diabetes.Traditional Chinese medicine(TCM)prescriptions have shown remarkable effectiveness for treating DR.This study aimed to screen a novel TCM prescription against DR from patents and elucidate its medication rule and molecular mechanism using data mining,network pharmacology,molecular docking and molecular dynamics(MD)simulation.Method:TCM prescriptions for treating DR was collected from patents and a novel TCM prescription was identified using data mining.Subsequently,the mechanism of the novel TCM prescription against DR was explored by constructing a network of core TCMs-core active ingredients-core targets-core pathways.Finally,molecular docking and MD simulation were employed to validate the findings from network pharmacology.Result:The TCMs of the collected prescriptions primarily possessed bitter and cold properties with heat-clearing and supplementing effects,attributed to the liver,lung and kidney channels.Notably,a novel TCM prescription for treating DR was identified,composed of Lycii Fructus,Chrysanthemi Flos,Astragali Radix and Angelicae Sinensis Radix.Twenty core active ingredients and ten core targets of the novel TCM prescription for treating DR were screened.Moreover,the novel TCM prescription played a crucial role for treating DR by inhibiting inflammatory response,oxidative stress,retinal pigment epithelium cell apoptosis and retinal neovascularization through various pathways,such as the AGE-RAGE signaling pathway in diabetic complications and the MAPK signaling pathway.Finally,molecular docking and MD simulation demonstrated that almost all core active ingredients exhibited satisfactory binding energies to core targets.Conclusions:This study identified a novel TCM prescription and unveiled its multi-component,multi-target and multi-pathway characteristics for treating DR.These findings provide a scientific basis and novel insights into the development of drugs for DR prevention and

关键词： TCM prescriptions diabetic retinopathy medication rule molecular mechanism data mining network pharmacology molecular docking

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Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2023年第7期18卷 1512-1520页

作者： Miao Hu Jie Huang Lei Chen Xiao-Rong Sun Zi-Meng Yao Xu-Hui Tong Wen-Jing Jin Yu-Xin Zhang Shu-Ying Dong Department of pharmacology School of PharmacyBengbu Medical CollegeBengbuAnhui ProvinceChina key laboratory of Cardiovascular and Cerebrovascular Diseases Bengbu Medical CollegeBengbuAnhui ProvinceChina anhui Engineering Technology Research Center of Biochemical Pharmaceutical BengbuAnhui ProvinceChina

CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

关键词： cerebral ischemia/reperfusion injury CDGSH iron sulfur domain 2 ferroptosis glutathione peroxidase 4 heme oxygenase 1 HT22 nuclear-factor E2-related factor 2 oxygen-glucose deprivation/reoxygenation injury stroke transferrin receptor 1

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Bufei Huoxue capsule (补肺活血胶囊) alleviates silicosis by inhibiting the activation of nucleotide-like receptor containing pyrin domain 3 inflammasome and macrophages polarization based on network pharmacology

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Journal of Traditional Chinese Medicine 2024年

作者： HANG Wenlu WANG Lin BO Yun ZUO Shurun WANG Songquan LI Haiquan BU Chunlu ZHAO Jie ZHOU Xianmei Department of Respiratory and Critical Care Medicine Second Affiliated Hospital of Xuzhou Medical University Medical College of anhui University of Science and Technology School of Mechatronic Engineering Jiangsu Normal University Department of Respiratory Medicine Jiangsu province Hospital of Chinese Medicine

OBJECTIVE: To predict the targets of Bufei Huoxue capsule （补肺活血胶囊， BFHX） using network pharmacology analysis and to explore its effects and functional targets in a silicotic rat model.METHODS: The drug and disease targets were correlated through network pharmacology analysis to explore the targets and signaling pathways of BFHX affecting silicosis. NR8383 cells were cultured to verify the core genes and pathways. A rat model of silicosis was established to verify whether the mechanism behind SiO2-caused pulmonary fibrosis was alleviated by BFHX （0.82 g/kg） and how it affected key targets and pathways. RESULTS: Overlapping BFHX and silicotic gene targets produced 159 interactive targets， and 55 were screened by network topology analysis. The results of gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses suggested that BFHX could affect silicosis through the nucleotide-like receptor containing pyrin domain 3 （NLRP3） inflammasome. In NR8383 cells， the expression of core genes related to the NLRP3 inflammasome could be inhibited by BFHX treatment. BFHX reduced the degree of alveolitis and collagen deposition， attenuating pulmonary fibrosis in SiO2-induced rat model. Pulmonary macrophage pyroptosis after SiO2exposure was observed under transmission electron microscopy. BFHX alleviated the morphological characteristics of pyroptosis. BFHX also reduced the expression of NLRP3， caspase-1， interleukin-1 beta （IL-1β）， IL-18， IL-6， and tumor necrosis factor-alpha in lung tissues of silicotic rat model. BFHX affected the K ion content in bronchoalveolar lavage fluid when assessed by energy dispersive spectrometer testing. The expression of CD68+and CD206+were also reduced after BFHX intervention. CONCLUSION: NOD-like receptor signaling is vital for BFHX’s effects on silicosis. It exerts anti-pulmonary fibrosis effects by inhibiting pulmonary macrophage pyroptosis and polarization through NLRP3 inflammasome activation.

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CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis

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Acta Pharmacologica Sinica 2019年第8期40卷 1029-1039页

作者： Xiao-yi Jia Yan Chang Fang Wei Xing Dai Yu-jing Wu Xiao-jing Sun Shu Xu Hua-xun Wu Chun Wang Xue-zhi Yang Wei Wei Institute of Clinical pharmacology Anhui Medical University Key Laboratory of Anti-inflammatory and Immune Medicine Ministry of Education Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine School of Pharmacy Anhui University of Chinese Medicine

Paeoniflorin-6’-O-benzene sulfonate(CP-25)is a novel compound derived from paeoniflorin that has been demonstrated to have therapeutic effects in a rat model of rheumatoid arthritis(RA).However,the underlying mechanism has not been elucidated to date.We explored this mechanism in the present study by treating rats with adjuvant arthritis(AA)with CP-25.We found that the membrane EP4 protein level was downregulated;whereas,GRK2 was upregulated,in fibroblast-like synoviocyte(FLS)s of AA rats.Prostaglandin(PGE)2 stimulated FLS proliferation and enhanced the membrane EP4 receptor protein level;the latter was reversed by the administration of an EP4 receptor agonist,whereas the membrane GRK2 protein level gradually increased.The changes in the EP4 receptor and GRK2 expression were enhanced by TNF-α,and the former was accompanied by an alteration in the cyclic(c)AMP level.The EP4 receptor agonist stimulation increased the association between GRK2 and the EP4 receptor.GRK2 knockdown abrogated the abnormalities in FLS proliferation.The CP-25 treatment(100 mg/kg)suppressed joint inflammation with an efficacy that was similar to that of methotrexate.This finding was associated with EP4 upregulation and GRK2 downregulation in FLSs.Thus,GRK2 plays an important role in the abnormal FLS proliferation observed in AA possibly by promoting EP4 receptor desensitization and decreasing the cAMP level.Our results demonstrate that CP-25 has therapeutic potential for the treatment of human RA via GRK2 regulation.

关键词： adjuvant-induced arthritis paeoniflorin-6’-O-benzene sulfonate fibroblast-like synoviocytes G protein-coupled receptor kinase 2 prostaglandin E2

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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 examined.The 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,respectively.Results:The activity of serum ALT in mice treated with BCG and LPS was signifi-cantly increased.Different 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 administration.Furthermore,thelevels of TNF-α and IL-6 mRNA in mouse liver were significantly elevated afteradministration of BCG plus LPS(Pimmunoreactivity for NF-κB p65 was predominantly detected in hepatocyte nucleifrom mice treated with BCG plus LPS,compared with the normal group.Proteinlevels of IκB-α were strikingly decreased by LPS or BCG plus LPS treatment,compared with the normal group or BCG group.Conclusion:TNF-α and IL-6mRNA were partially involved in early immunological liver injury induced by chal-lenge with small doses of LPS after BCG priming.Upregulation of TNF-α and IL-6 mRNA might be related to increases in LBP and CD 14 mRNA expression andactivation of NF-κB.Furthermore,BCG priming in immunological liver injury mayoccur via upregulation of CD 14 mRNA expression in monon uclear cell infiltrationinto the liver.

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

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