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Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway

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Journal of Pharmaceutical Analysis 2024年第6期14卷 914-925页

作者： Guiqin Ye Xin Sun Jiuzhou Li Yuanyuan Mai ruilan gao Jianbin Zhang Cancer Center Department of Medical OncologyKey Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhou310014China Clinical Laboratory Yuhuan City HospitalTaizhouZhejiang317600China Hangzhou Medical College Hangzhou311300China Department of Neurosurgery Binzhou People's HospitalBinzhouShandong256600China Institute of Hematology Research The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310060China

Lung cancer ranks the top of malignancies that cause cancer-related deaths *** leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory *** previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf,but their mechanism of action has still not fully *** synthesized Moracin N(MAN)-Probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic *** and its probe exerted similar growth-inhibitory effect on human lung cancer *** proteomic results showed that MAN targeted the programmed death ligand 1(PD-L1)checkpoint pathway and T cell receptor(TCR)signaling pathway,indicating its immune-regulatory ***-free surface plasmon resonance(SPR)results showed the direct interaction of MAN with PD-L1 *** docking analysis demonstrated that MAN bound to E158 residue of PD-L1 *** downregulated the expression levels of PD-L1 in a time-and dose-dependent manner and disrupted the PD-L1/programmed death 1(PD-1)binding,including other secondary metabolites of mulberry leaves Guangsangon E(GSE)and Chalcomoracin(CMR).Human peripheral blood mononuclear cells(PBMCs)co-cultured with MAN-treated A549 cells,resulting in the increase of CD8^(+)GZMB^(+)T cells and the decrease of CD8^(+)PD-1^(+)T *** suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 *** vivo,MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis,indicating their synergistic *** together,secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling,enhance T cell-mediated immunity and inhibit the tumorigenesis of lung *** modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.

关键词： Moracin N Click chemistry PD-L1 T cell Lung cancer

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylationmediated mitophagy

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Acta Pharmaceutica Sinica B 2022年第2期12卷 838-852页

作者： Xin Sun Yuhan Shu Guiqin Ye Caixia Wu Mengting Xu ruilan gao Dongsheng Huang Jianbin Zhang Department of Oncology Cancer Center of Zhejiang Provincial People’s HospitalAffiliated People’s HospitalHangzhou Medical CollegeHangzhou 310014China Clinical Research Institute Zhejiang Provincial People’s HospitalAffiliated People’s HospitalHangzhou Medical CollegeHangzhou 310014China Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province Hangzhou Medical CollegeHangzhou 310014China College of Biomedical Engineering&Instrument Science Zhejiang UniversityHangzhou 310028China Department of Hematology the First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou 310006China

Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for *** evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level,but the underlying mechanism is poorly ***,our study demonstrated that inhibition of histone deacetylase(HDAC)by treatment of HDACis activates mitophagy through mediating Parkin acetylation,leading to inhibition of cervical cancer cell *** analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer,indicating the low acetylation level of *** mass spectrometry,Parkin is identified to interact with two upstream molecules,acetylase acetyl-Co A acetyltransferase 1(ACAT1)and deacetylase *** treatment of suberoylanilide hydroxamic acid(SAHA),Parkin is acetylated at lysine residues 129,220 and 349,located in different domains of Parkin *** in vitro experiments,combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1(PINK1)and the function of Parkin in mitophagy induction and tumor *** tumor xenografts,the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of *** results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis,which offers a new mitophagy modulation strategy for cancer therapy.

关键词： Parkin Mitophagy ACAT1 HDAC2 Acetylation Ubiquitination Tumor suppression Cervical cancer

人参皂甙诱导的造血细胞内信号传递途径的研究

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中华血液学杂志 1999年第6期20卷 292-295页

作者：高瑞兰吴超群浙江中医学院附属医院澳大利亚新南威尔士大学病理系澳大利亚王子威尔士医院

目的探讨人参皂甙（ＧＳ）刺激造血祖细胞增殖有关的细胞内信号传递途径。方法采用Ｎｏｒｔｈｅｒｎ印迹杂交法、电泳带移动阻滞实验、抗体胶结合移动实验和紫外放射交联实验。结果ＮｏｒｔｈｅｒｎＢｌｏｔ显示经ＧＳ诱导的人巨核细胞... 详细信息

目的探讨人参皂甙（ＧＳ）刺激造血祖细胞增殖有关的细胞内信号传递途径。方法采用Ｎｏｒｔｈｅｒｎ印迹杂交法、电泳带移动阻滞实验、抗体胶结合移动实验和紫外放射交联实验。结果ＮｏｒｔｈｅｒｎＢｌｏｔ显示经ＧＳ诱导的人巨核细胞株ＣＨＲＦ２８８、Ｍｅｇ０１和ＭＯ７ｅ细胞的ＧＡＴＡ２ｍＲＮＡ水平增高，分别是未经处理细胞的１．８４，２．４３和１．５２倍。但ＧＡＴＡ１ｍＲＮＡ表达水平低，且ＧＳ处理前后也无明显变化。电泳带移动阻滞实验提示ＧＳ诱导的细胞核内ＧＡＴＡ转录调控蛋白与特定的ＤＮＡ序列结合的活性增高。抗体胶结合移动实验证实与ＤＮＡ结合的主要成分为ＧＡＴＡ２蛋白，紫外放射交联实验确定该复合物的相对分子质量约为５０×１０３，符合ＧＡＴＡ２转录调控蛋白。结论ＧＳ诱导细胞内的信号传递途径与转录因子ＧＡＴＡ２有关，ＧＡＴＡ２有介导ＧＳ刺激造血细胞增殖的作用。

关键词：人参皂甙造血细胞信号传递蛋白类.GATA-2

白藜芦醇抑制K562细胞增殖过程中WT1基因表达及其甲基化水平的变化

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中华血液学杂志 2014年第3期35卷 245-246页

作者：汪丽佩赵燕娜高瑞兰浙江中医药大学基础医学院杭州310058 浙江省中医院血液病研究所

白藜芦醇（resveratr01）可抑制多种肿瘤细胞增殖、诱导凋亡，但确切机制仍不清楚。WT1基因是一种“泛白血病”标志，其表达水平与白血病预后及造血细胞分化程度呈负相关。

关键词： WT1基因表达甲基化水平白藜芦醇 K562细胞增殖过程肿瘤细胞增殖细胞分化程度诱导凋亡

例析机、电、液、PLC在盾构推进系统故障排除中的综合应用

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现代制造技术与装备 2018年第9期54卷 98-101页

作者：高瑞兰济南市技师学院济南250000

结合中铁装备盾构机推进系统出现的故障案例,介绍机械、液压、电气、PLC等在盾构机故障排除中的综合应用,以期为相关行业工作者更高效地开展工作提供参考。

关键词：盾构推进系统故障排除机、电、液、PLC综合应用

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小学数学教学中渗透思想方法的策略研究

科教导刊 2016年第5期 69-70页

作者：高瑞兰福建省龙岩市上杭县实验小学福建龙岩364200

数学教学的精髓是教授并渗透数学思想方法,在数学教学中有着不可忽视的地位和作用,并有着非凡的教育意义。要使学生学好数学,仅仅让他们学习数学知识内容而不教授其精神和方法是万万不行的。我们应该有意识的将一些基本的数学思想方法... 详细信息

数学教学的精髓是教授并渗透数学思想方法,在数学教学中有着不可忽视的地位和作用,并有着非凡的教育意义。要使学生学好数学,仅仅让他们学习数学知识内容而不教授其精神和方法是万万不行的。我们应该有意识的将一些基本的数学思想方法渗透到小学教学中,让学生真正理解并感受数学的价值,在思考解决问题时能运用数学的眼光和数学能力。

关键词：小学数学教学思想方法渗透

数学核心素养导向下小学生自主学习能力的培养

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天津教育 2020年第20期 125-126页

作者：高瑞兰福建省龙岩市上杭县实验小学

本文以核心素养导向下如何培养小学生的自主学习能力为切入点,进一步阐述了自主学习能力的重要性,并就在核心素养导向下学生自主学习能力的培养途径进行初步探索。全文共分为两个部分:第一部分介绍自主学习的重要性;第二部分探讨如何有... 详细信息

本文以核心素养导向下如何培养小学生的自主学习能力为切入点,进一步阐述了自主学习能力的重要性,并就在核心素养导向下学生自主学习能力的培养途径进行初步探索。全文共分为两个部分:第一部分介绍自主学习的重要性;第二部分探讨如何有效地培养小学生的自主学习能力。

关键词：核心素养自主学习能力培养

NF-KB mediates thrombopoitin dependent

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NF-KB mediates thrombopoitin dependent

低极性人参皂苷Rh4对白血病细胞系K562细胞增殖抑制及诱导分化作用的研究

中国细胞生物学学会2005年学术大会、青年学术研讨会

作者： Chaoqun Wu, ruilan gao, Wei Huang School of Life Science, Genetics Institute, Fudan University, Shanghai 200433 Zhejian Hospital of Traditional Chinese Medicine, Hangzhou 310006

Thrombopoietin (Tpo) is regarded as a majof humoral regulator of megakaryopoiesis and thrombocytosis, acts through its receptor c-Mpl to stimulate proliferation and maturation of megakaryocytes and their progenitors. Expression of c-mpl mRNA is not limited to megakaryocytic cells and their precursors. Recent evidence suggests that Tpo also acts on human erythroid, myeloid and multipotential progenitors due to the presence of Tpo receptor on hemopoietic stem cells, megakaryocytic progenitors, and megakaryocytes. Therefore, Tpo has received considerable attention as a therapeutic agent for treating thrombocytopenia or for its use in the ex vivo culture of hematopoietic stem cells. Apart from bone marrow, spleen, and fetal liver, nonhemopoietic tissues such as placenta and brain may express Tpo receptor transcripts. Of major significance is the fact that Tpo receptors are maintained on leukemia cells which are dependent on Tpo for malignant growth and survival. In vitro studies reported that c-Mpl proto-oncogene is expressed on various types of human leukaemia cell lines derived from erythroid progenitors, megakaryocytic progenitors, and stem cells, and also c-Mpl mRNA was detectable on blast cells in about half of acute myeloblastic leukaemia (AML) Here we showed that refeeding with Tpo to the factor deprived megakaryocytic Mo7e cells could induce a peak activity of both DNA binding and transcription of NF-κB proteins followed by its constitutively lower activity, indicating the involvement of NF-κB signaling in survival enhancing role of Tpo. We have investigated the mechanisms underlying NF-κB activation by Tpo, and demonstrated that Tpo triggered PKC-expression is the upstream event of NF-κB activation based on the observation that PKC-suppressor abolishes the Tpo induced NF-κB activation. Western blotting with antiserums against apoptosis suppressors survivin, XIAP, cIAP1 and cIAP2 provides evidence linking the NF-κB activation and the transcriptional regulation o

关键词： PKC NF-KB mediates thrombopoitin dependent

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中华血液学杂志 2015年第4期36卷 347-349页

作者：余潇苓高瑞兰尹利明沃立科浙江中医药大学附属第一医院血液病研究所杭州310006

人参是我国传统中药，其主要药理成分人参皂苷具有抗白血病作用。人参皂苷Rh4是一类仅结合1个糖基的人参三醇型皂苷，属于低极性人参皂苷，具有适中的肠吸收极性，更易进入体内发挥作用，具备较其他多糖基皂苷更高的生物利用度。Rh4具... 详细信息

人参是我国传统中药，其主要药理成分人参皂苷具有抗白血病作用。人参皂苷Rh4是一类仅结合1个糖基的人参三醇型皂苷，属于低极性人参皂苷，具有适中的肠吸收极性，更易进入体内发挥作用，具备较其他多糖基皂苷更高的生物利用度。Rh4具有抗黑色素瘤、抑制黑色素合成的作用，对白血病细胞系P388细胞和L1210细胞具有细胞毒活性。本研究中我们观察人参皂苷Rh4对白血病细胞系株K562细胞增殖及分化的作用，现报道如下。

关键词： K562细胞增殖白血病细胞系诱导分化作用人参皂苷细胞增殖抑制极性 L1210细胞抗白血病作用