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Chinese Journal of Natural Medicines 2024年第7期22卷 582-598页

作者： JIA Kexin MA Zhi ZHANG Yinhao XIE Kaihong LI Jianan WU Jianzhi qu jiaorong LI Fanghong LI Xiaojiaoyang School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China

Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar *** play a central role in the pathogenesis of hepatic fibrosis by reconstructing the immune *** Ⅱ(PIC Ⅱ),extracted from Picrorhizae Rhizoma,has demonstrated therapeutic potential for various liver ***,the mechanisms by which macrophage polarization initiates immune cascades and contributes to the development of liver fibrosis,and whether this process can be influenced by PIC Ⅱ,remain *** the current study,RNA sequencing and multiple molecular approaches were utilized to explore the underlying mechanisms of PIC Ⅱ against liver fibrosis in multidrug-resistance protein 2 knockout(Mdr2^(−/−))*** findings indicate that PIC Ⅱ activates M1-polarized macrophages to recruit natural killer cells(NK cells),potentially via the CXCL16-CXCR6 ***,PIC Ⅱ promotes the apoptosis of activated hepatic stellate cells(aHSCs)and enhances the cytotoxic effects of NK cells,while also reducing the formation of neutrophil extracellular traps(NETs).Notably,the anti-hepatic fibrosis effects associated with PIC Ⅱ were largely reversed by macrophage depletion in Mdr2^(−/−)***,our research suggests that PIC Ⅱ is a potential candidate for halting the progression of liver fibrosis.

关键词： Liver fibrosis PicrosideⅡ M1 macrophage Hepatic stellate cell Natural killer cell Neutrophil

Si-Wu-Tang attenuates liver fibrosis via regulating lncRNA H19-dependent pathways involving cytoskeleton remodeling and ECM deposition

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Chinese Journal of Natural Medicines 2024年第1期22卷 31-46页

作者： qu jiaorong XUE Xiaoyong WANG Zhixing MA Zhi JIA Kexin LI Fanghong ZHANG Yinhao WU Ruiyu ZHOU Fei ZHAO Piwen LI Xiaojiaoyang School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix(ECM).Si-Wu-Tang(SWT),a traditional Chinese medicine(TCM)formula,is known for treating gynecological diseases and liver *** previous studies demonstrated that long non-coding RNA H19(H19)was markedly upregulated in fibrotic livers while its deficiency markedly reversed ***,the mechanisms by which SWT influences H19 remain ***,we established a bile duct ligation(BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the *** results showed that SWT markedly improved ECM deposition and bile duct reactions in the ***,SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling,primarily in hepatic stellate cells(HSCs),and influencing cytoskeleton-related angiogenesis and hepatocellular *** modulation collectively led to reduced ECM *** extensive bioinformatics analyses,we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200,miR-211,and let7b,thereby regulating the above cellular regulatory ***,SWT reversed H19-related miRNAs and signaling pathways,diminishing ECM deposition and liver ***,these protective effects of SWT were diminished with the overexpression of H19 in *** conclusion,our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.

关键词： Liver fibrosis LncRNA H19 Si-Wu-Tang miRNAs Cytoskeleton ECM deposition

Chuanxiong Rhizoma extracts prevent liver fibrosis via targeting CTCF-c-MYC-H19 pathway

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Chinese Herbal Medicines 2024年第1期16卷 82-93页

作者： Yajing Li Fanghong Li Mingning Ding Zhi Ma Shuo Li jiaorong qu Xiaojiaoyang Li School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China

Objective:Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver *** Rhizoma(Chuanxiong in Chinese,CX)is a traditional Chinese herbal product to prevent cerebrovascular,gynecologic and hepatic *** previous study found that CX extracts significantly reduced collagen contraction force of hepatic stellate cells(HSCs).Here,this study aimed to compare the protection of different CX extracts on bile duct ligation(BDL)-induced liver fibrosis and investigate plausible underlying ***:The active compounds of CX extracts were identified by high performance liquid chromatography(HPLC).Network pharmacology was used to determine potential targets of CX against hepatic *** duct hyperplasia and liver fibrosis were evaluated by serologic testing and histopathological *** expression of targets of interest was determined by quantitative real-time PCR(qPCR)and Western ***:Different CX extracts were identified by tetramethylpyrazine,ferulic acid and senkyunolide *** on the network pharmacological analysis,42 overlap targets were obtained via merging the candidates targets of CX and liver *** aqueous,alkaloid and phthalide extracts of CX(CX_(AE),CX_(AL) and CXP_(HL))significantly inhibited diffuse severe bile duct hyperplasia and thus suppressed hepatic fibrosis by decreasing CCCTC binding factor(CTCF)-c-MYC-long non-coding RNA H19(H19)pathway in the BDL-induced mouse ***,CX extracts,especially CX_(AL) and CX_(PHL) also suppressed CTCF-c-MYC-H19 pathway and inhibited ductular reaction in cholangiocytes stimulated with taurocholate acid(TCA),lithocholic acid(LCA)and transforming growth factor beta(TGF-β),as illustrated by decreased bile duct proliferation ***:Our data supported that different CX extracts,especially CX_(AL) and CX_(PHL) significantly alleviated hepatic fibrosis and bile duct hyperplasia via inhibiting CTCF-c-MYC-H19

关键词： Chuanxiong Rhizoma cholangiocytes ductular reaction Ligusticum chuanxiong Hort. liver fibrosis lncRNA H19

Picroside Ⅱ promotes HSC apoptosis and inhibits the cholestatic liver fibrosis in Mdr2-/- mice by polarizing M1 macrophages and balancing immune responses

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Chinese Journal of Natural Medicines 2024年第07期 582-598页

作者： JIA Kexin MA Zhi ZHANG Yinhao XIE Kaihong LI Jianan WU Jianzhi qu jiaorong LI Fanghong LI Xiaojiaoyang School of Life Sciences Beijing University of Chinese Medicine School of Chinese Materia Medica Beijing University of Chinese Medicine

Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar formation. Macrophages play a central role in the pathogenesis of hepatic fibrosis by reconstructing the immune microenvironment. Picroside Ⅱ（PIC Ⅱ）,extracted from Picrorhizae Rhizoma, has demonstrated therapeutic potential for various liver damage. However, the mechanisms by which macrophage polarization initiates immune cascades and contributes to the development of liver fibrosis, and whether this process can be influenced by PIC Ⅱ, remain unclear. In the current study, RNA sequencing and multiple molecular approaches were utilized to explore the underlying mechanisms of PIC Ⅱ against liver fibrosis in multidrug-resistance protein 2 knockout(Mdr2-/-) *** findings indicate that PIC Ⅱ activates M1-polarized macrophages to recruit natural killer cells（NK cells）, potentially via the CXCL16-CXCR6 axis. Additionally, PIC Ⅱ promotes the apoptosis of activated hepatic stellate cells（a HSCs） and enhances the cytotoxic effects of NK cells, while also reducing the formation of neutrophil extracellular traps（NETs）. Notably, the anti-hepatic fibrosis effects associated with PIC Ⅱ were largely reversed by macrophage depletion in Mdr2-/-mice. Collectively, our research suggests that PIC Ⅱ is a potential candidate for halting the progression of liver fibrosis.

关键词：

Si-Wu-Tang attenuates liver fibrosis via regulating lncRNA H19-dependent pathways involving cytoskeleton remodeling and ECM deposition

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Chinese Journal of Natural Medicines 2024年第01期 31-46页

作者： qu jiaorong XUE Xiaoyong WANG Zhixing MA Zhi JIA Kexin LI Fanghong ZHANG Yinhao WU Ruiyu ZHOU Fei ZHAO Piwen LI Xiaojiaoyang School of Life Sciences Beijing University of Chinese Medicine State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and Biochemistry Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical College School of Chinese Materia Medica Beijing University of Chinese Medicine

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix(ECM). Si-Wu-Tang(SWT), a traditional Chinese medicine(TCM) formula, is known for treating gynecological diseases and liver fibrosis. Our previous studies demonstrated that long non-coding RNA H19(H19) was markedly upregulated in fibrotic livers while its deficiency markedly reversed fibrogenesis. However, the mechanisms by which SWT influences H19 remain unclear. Thus, we established a bile duct ligation(BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the liver. Our results showed that SWT markedly improved ECM deposition and bile duct reactions in the liver. Notably, SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling, primarily in hepatic stellate cells(HSCs), and influencing cytoskeleton-related angiogenesis and hepatocellular injury. This modulation collectively led to reduced ECM deposition. Through extensive bioinformatics analyses, we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200, miR-211, and let7b, thereby regulating the above cellular regulatory pathways. Meanwhile, SWT reversed H19-related miRNAs and signaling pathways, diminishing ECM deposition and liver fibrosis. However, these protective effects of SWT were diminished with the overexpression of H19 in vivo. In conclusion, our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.

关键词：

基于网络药理学整合体内实验探究四物汤单味药组分治疗胆汁淤积性肝损伤的作用与机制

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中草药 2024年第5期55卷 1553-1566页

作者：汪乐李佳楠杨洋曲姣蓉李晓骄阳北京中医药大学生命科学学院北京100029 北京中医药大学中药学院北京100029

目的基于网络药理学整合体内实验对比四物汤中4种单味药(川芎Chuanxiong Rhizoma、白芍Paeoniae Radix Alba、当归Angelicae Sinensis Radix、熟地黄Rehmanniae Radix Praeparata)治疗胆汁淤积性肝损伤(cholestatic liver injury,CLI)的药效差异,并探讨各单味药的作用机制。方法利用TCMSP数据库获取川芎、白芍、当归、熟地黄的主要活性成分及作用靶点,通过GeneCards数据库获取CLI靶点,使用Cyctoscape 3.10.1软件分析并构建“单味药-活性成分-作用靶点”网络,借助在线网站获取各单味药与CLI之间的交集靶点,并绘制韦恩图。将靶点基因导入DAVID数据库进行基因富集分析。构建胆总管结扎(bile duct ligation,BDL)动物模型,给予各单味药水提物后,检测血清肝功能相关生化指标,并对肝组织进行病理染色对比药效作用。同时结合qRT-PCR检测CLI相关靶点的基因表达。结果网络药理学结果显示,四物汤中川芎、白芍、当归、熟地黄与CLI之间均存在3个交集靶点[核受体亚家族3C组成员2(nuclear receptor subfamily 3 group C member 2,Nr3c2)、类视黄醇X受体(retinoid X receptor alpha,Rxra)、前列腺素内过氧化物合成酶2(prostaglandin-endoperoxide synthase 2,Ptgs2)]。通过体内验证实验表明白芍、川芎、当归、熟地黄水提物均可显著改善CLI以及相关的肝纤维化情况,且均能下调上述3个共同靶点表达(P<0.05、0.01、0.001)。此外,白芍、川芎的体内抗CLI疗效优于当归、熟地黄提取物。结果还显示白芍与CLI有18个、川芎与CLI有4个与其他单味药不同的独立交集靶点,而当归、熟地黄与CLI之间不存在独立的交集靶点。进一步生信分析发现,白芍作用靶点基因富集于血管生成、肿瘤坏死因子(tumor necrosis factor,TNF)信号通路;川芎作用靶点富集于血管内皮、血管生成、血管生成因子(vascular endothelial growth factor,VEGF)通路。进一步验证结果显示白芍通过下调肝脏中血管细胞黏附分子(vascular cell adhesion molecule 1,Vcam1)、Tnf、有丝分裂原激活蛋白激酶(mitogen-activated protein kinase 8,Mapk8)、AKT丝氨酸/苏氨酸激酶(AKT serine/threonine kinase 1,Akt1)表达改善CLI,川芎通过下调肝脏激酶插入结构域受体(kinase insert domain receptor,Kdr)、Mapk14表达改善CLI。结论四物汤中川芎、白芍、当归、熟地黄均能不同程度地改善胆汁淤积引起的肝损伤及纤维化,它们通过靶向Nr3c2、Rxra、Ptgs2共同改善CLI。白芍、川芎改善CLI疗效优于当归、熟地黄,前者可基于TNF信号通路而后者则是通过调控VEGF信号通路分别特异性改善CLI。

关键词：网络药理学四物汤白芍川芎当归熟地黄胆汁淤积性肝损伤肝纤维化肿瘤坏死因子通路血管生成因子通路氧化芍药苷洋川芎内酯A 阿魏酸 5-羟甲基糠醛

The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

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Signal Transduction and Targeted Therapy 2023年第12期8卷 5904-5918页

作者： jiaorong qu Bojun Qiu Yuxin Zhang Yan Hu Zhixing Wang Zhiang Guan Yiming Qin Tongtong Sui Fan Wu Boyang Li Wei Han Xiaozhong Peng Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China State Key Laboratory of Common Mechanism Research for Major Diseases BeijingChina Department of Molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijing 100070China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingChina State Key Laboratory of Respiratory Health and Multimorbidity BeijingChina National Human Diseases Animal Model Resource Center Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

Glioma is the most prevalent brain tumor,presenting with limited treatment options,while patients with malignant glioma and glioblastoma(GBM)have poor *** physical obstacle to drug delivery imposed by the blood‒brain barrier(BBB)and glioma stem cells(GSCs),which are widely recognized as crucial elements contributing to the unsatisfactory clinical *** this study,we found a small molecule,gambogic amide(GA-amide),exhibited the ability to effectively penetrate the blood-brain barrier(BBB)and displayed a notable enrichment within the tumor ***,GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models,encompassing transgenic and primary patient-derived xenograft(PDX)*** further performed a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)knockout screen to determine the druggable target of *** the combination of the cellular thermal shift assay(CETSA),the drug affinity responsive target stability(DARTS)approach,molecular docking simulation and surface plasmon resonance(SPR)analysis,WD repeat domain 1(WDR1)was identified as the direct binding target of *** direct interaction with WDR1,GA-amide promoted the formation of a complex involving WDR1,MYH9 and Cofilin,which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells(PDCs)and induce PDC apoptosis via the mitochondrial apoptotic *** conclusion,our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.

关键词： glioma invasion homeostasis

外泌体携载阿霉素递送体系构建及体外抗肿瘤活性评价

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药物评价研究 2023年第5期46卷 976-982页

作者：周菲曲姣蓉刘闰平李雅静李晓骄阳北京中医药大学生命科学学院北京100029 北京中医药大学中药学院北京100029

目的制备肝癌细胞Hep1-6外泌体并对化疗药物阿霉素(DOX)进行包载,以期实现对肿瘤细胞更高的靶向活性与杀伤作用。方法采用梯度离心法对肿瘤细胞Hep1-6来源的外泌体进行制备分离;采用透射电镜技术、表面标记蛋白表征以及纳米颗粒追踪分... 详细信息

目的制备肝癌细胞Hep1-6外泌体并对化疗药物阿霉素(DOX)进行包载,以期实现对肿瘤细胞更高的靶向活性与杀伤作用。方法采用梯度离心法对肿瘤细胞Hep1-6来源的外泌体进行制备分离;采用透射电镜技术、表面标记蛋白表征以及纳米颗粒追踪分析技术对外泌体的形态、特征蛋白、粒径分布和浓度进行表征;采用电穿孔方法实现外泌体对DOX的有效包载,制备包载阿霉素外泌体(EXODOX)。采用CCK-8法检测EXODOX与DOX(0.5、1、2、3、5、10μg·mL^(−1))体外对Hep1-6细胞增殖的影响,采用激光共聚焦显微镜观察体外Hep1-6细胞对EXODOX与DOX(1μg·mL^(−1))的靶向摄取作用。结果所制备的外泌体具有形态良好、粒度均一的特性且具备外泌体特征膜蛋白CD63、CD81、肿瘤易感基因101(TSG101)的表达;在电穿孔条件为150 V和75μF下外泌体对DOX具备良好的包载特性;相比于单独给药DOX,在同等质量浓度下EXODOX对Hep1-6细胞增殖抑制作用显著增强(P<0.05、0.01),同时肿瘤细胞对EXODOX的摄取更具靶向性。结论制备的EXODOX较DOX具有更强的体外细胞毒活性,EXODOX表现出对肿瘤细胞更高的靶向特性。

关键词：阿霉素外泌体靶向给药肝癌药物递送细胞增殖摄取

四个山羊品种的角型统计及角型指标与生产性状的相关分析

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黑龙江畜牧兽医 2022年第7期 55-59,128页

作者：刘娇容贾海英刘锦旺袁荣荣杨肖吴仪凡王必琪李媛屈雷宋晓越榆林学院陕西省绒山羊工程技术研究中心陕西榆林719000 佳县通镇区域农牧技术服务中心陕西佳县719200 吴堡县畜牧产业服务中心陕西吴堡718200

为了研究山羊角型是否与生产性状紧密相关,试验采用统计学的方法对共计38545只的阿尔巴斯白绒山羊、“敏盖”内蒙古白绒山羊、陕北白绒山羊、阿拉善白绒山羊的角型进行统计并分析角型分布差异,对角型分布存在显著差异的阿尔巴斯白绒山... 详细信息

为了研究山羊角型是否与生产性状紧密相关,试验采用统计学的方法对共计38545只的阿尔巴斯白绒山羊、“敏盖”内蒙古白绒山羊、陕北白绒山羊、阿拉善白绒山羊的角型进行统计并分析角型分布差异,对角型分布存在显著差异的阿尔巴斯白绒山羊的角型指标(角长、角间距、角基周长)与生产性状(初生重、绒细度、毛长、产绒量、剪绒后体重、额前毛长、角间距和角长)进行相关性分析。结果表明:陕北白绒山羊、“敏盖”内蒙古白绒山羊和阿拉善白绒山羊的优势角型为拧角,所占比例分别为75.31%、94.70%和67.19%;阿尔巴斯白绒山羊公羊的优势角型为螺旋角(63.74%)和拧角(26.41%),母羊的优势角型为螺旋角(38.84%)、弯角(28.14%)和平角(26.60%)。配对样本t检验发现阿尔巴斯白绒山羊公羊和母羊的角型分布存在显著差异(P<0.05)。母羊的角基周长与剪绒后体重显著相关(P<0.05),角长和绒细度显著相关(P<0.05);公羊中未发现角型指标与生产性状的相关性;公母羊的角基周长与角长、角间距均存在显著相关性(P<0.05)。角长、角间距和角基周长这3个角型指标密切相关,角长和角基周长越大、角间距越小,则对应的绒细度越小、剪绒后体重越大。说明山羊的角型与生产性状之间存在相关性。

关键词：山羊角型阿尔巴斯白绒山羊 “敏盖”内蒙古白绒山羊陕北白绒山羊阿拉善白绒山羊绒细度