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Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

Acta Pharmaceutica Sinica B 2024年第7期14卷 3009-3026页

作者： Saini Setua Shabia Shabir Poornima Shaji Ana Martinez Bulnes Anupam Dhasmana Swathi Holla Nivesh K.Mittal Nirakar Sahoo Tripti Saini Francesco Giorgianni Mohammad Sikander Andrew E.Massey Bilal B.Hafeez Manish K.Tripathi Vincent P.Diego Meena Jaggi Junming Yue Nadeem Zafar Murali M.Yallapu Stephen W.Behrman Sheema Khan Subhash C.Chauhan Department of Pharmaceutical Sciences College of Pharmacyand College of MedicineUniversity of Tennessee Health Science Center(UTHSC)MemphisTN 36163USA Department of Computer Science Islamic University of Science and TechnologyAwantiporaJ&K 192122India Department of Immunology and Microbiology School of MedicineUniversity of Texas Rio Grande ValleyMcAllenTX 78504USA South Texas Center of Excellence in Cancer research School of Medicinethe University of Texas Rio Grande ValleyMcAllenTX 78504USA Himalayan School of Biosciences and Cancer research institute Himalayan Institute of Medical SciencesSwami Rama Himalayan UniversityDehradun 248016India plough Center for Sterile Drug Delivery Solutions UTHSCMemphisTN 38104USA Department of Biology College of SciencesUTRGVMcAllenTX 78539USA National institute of Biomedical Imaging and Bioengineering(NIBIB) National Institutes of HealthBethesdaMD 20892USA South Texas Diabetes and Obesity institute UTRGVMcAllenTX 78504USA Dept.of Laboratory Medicine&Pathology University of WashingtonSeattleWA 98195USA Department of Surgery Baptist Memorial Medical EducationBaptist Memorial HospitalMemphisTN 38120USA Baptist Health Sciences University MemphisTN 38104USA

The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological *** study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ***,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of ***-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model *** found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast ***-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse *** conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer ***,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

关键词： Pancreatic cancer Tumor adjacent normal tissue fibroblasts(NAF) Desmoplasia Extracellular vesicles Exosomes Tumor targeting Ormeloxifene Personalized medicine

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Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E_2 and cytokines

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世界胃肠病学杂志：英文版 2009年第44期15卷 5549-5557页

作者： Mary Ann Cox James Jackson Michaela Stanton Alberto Rojas-Triana Loretta Bober Maureen Laverty Xiaoxin Yang Feng Zhu Jianjun Liu Suke Wang Frederick Monsma Galya Vassileva Maureen Maguire Eric Gustafson Marvin Bayne Chuan-Chu Chou Daniel Lundell Chung-Her Jenh Department of Tumor Biology Schering-Plough Research Institute Kenilworth NJ 07033 United States Department of Cardiovascular and Metabolic Disease research Schering-Plough Research Institute Kenilworth NJ 07033 United States Department of Discovery Technologies Schering-Plough Research Institute Kenilworth NJ 07033 United States Department of Discovery Technologies Schering- Plough Research Institute Kenilworth NJ 07033 United States Department of Inflammation Schering-Plough Research Institute Kenilworth NJ 07033 United States

AIM:To investigate the effect of short-chain fatty ac-ids (SCFAs) on production of prostaglandin E2 (PGE2),cytokines and chemokines in human ***:Human neutrophils and monocytes were isolated from human whole blood by using 1-Step Polymorph and RosetteSep Human Monocyte Enrich-ment Cocktail,respectively. Human GPR41 and GPR43 mRNA expression was examined by quantitative real-time polymerase chain reaction. The calcium flux assay was used to examine the biological activities of SCFAs in human neutrophils and monocytes. The effect ofSCFAs on human monocytes and peripheral blood mononuclear cells (PBMC) was studied by measuring PGE2,cytokines and chemokines in the supernatant. The effect of SCFAs in vivo was examined by intraplantar injection into rat ***:Human GPR43 is highly expressed in human neutrophils and monocytes. SCFAs induce robust calcium flux in human neutrophils,but not in human monocytes. In this study,we show that SCFAs can in-duce human monocyte release of PGE2 and that this effect can be enhanced in the presence of lipopolysac-charide (LPS). In addition,we demonstrate that PGE2 production induced by SCFA was inhibited by pertussis toxin,suggesting the involvement of a receptor-mediated mechanism. Furthermore,SCFAs can specifi cally inhibit constitutive monocyte chemotactic protein-1 (MCP-1) production and LPS-induced interleukin-10 (IL-10) production in human monocytes without affecting the secretion of other cytokines and chemokines examined. Similar activities were observed in human PBMC for the release of PGE2,MCP-1 and IL-10 after SCFA treatment. In addition,SCFAs inhibit LPS-induced production of tumor necrosis factor-α and interferon-γ in human PBMC. Finally,we show that SCFAs and LPS can induce PGE2 production in vivo by intraplantar injection into rat paws (P < 0.01). CONCLUSION:SCFAs can have distinct antiinflammatory activities due to their regulation of PGE2,cytokine and chemokine release from human immune cells.

关键词：前列腺素 PBMC 临床胰腺疾病

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Wiedendiol-A inhibits cholesteryl ester binding to its transfer protein

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中国药理学报 1998年第5期19卷 408-412页

作者：汪苏克 Dept. of CNS/CV Biological research Schering-Plough Research Institute 2015 Galloping Hill Road Kenilworth NJ 07033 United States

Ｅｌｅｖａｔｅｄｈｉｇｈｄｅｎｓｉｔｙｌｉｐｏｐｒｏｔｅｉｎｓ（ＨＤＬ）ａｒｅｐｒｏｔｅｃｔｉｖｅｆｏｒｃｏｒｏｎａｒｙｄｉｓｅａｓｅａｎｄｔｈｅａｃｔｉｖｉｔｉｅｓｏｆｐｌａｓｍａｆａｃｔｏｒｓｔｏｒｅｄｉｓｔｒ... 详细信息

Ｅｌｅｖａｔｅｄｈｉｇｈｄｅｎｓｉｔｙｌｉｐｏｐｒｏｔｅｉｎｓ（ＨＤＬ）ａｒｅｐｒｏｔｅｃｔｉｖｅｆｏｒｃｏｒｏｎａｒｙｄｉｓｅａｓｅａｎｄｔｈｅａｃｔｉｖｉｔｉｅｓｏｆｐｌａｓｍａｆａｃｔｏｒｓｔｏｒｅｄｉｓｔｒｉｂｕｔｅｃｈｏｌｅｓｔｅｒｙｌ...

关键词：维登二醇-A 脂蛋白胆甾醇酯

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用IREFINDER算法在非翻译区搜索人和小鼠的铁反应元件

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Acta Biochimica et Biophysica Sinica 2002年第6期34卷 743-747页

作者：陈新,王鲁泉,黄弋,邱平,MURGOLO Nicholas J.,GREENE Jonathan R.,吴才宏,姜颖北京大学生命科学学院生物信息中心 schering plough研究所北京大学生命科学学院生物信息中心 schering plough研究所 schering plough研究所 schering plough研究所北京大学膜及膜的工程国家重点实验室北京大学生命科学学院生物信息中心北京100871 NJ07033 北京100871 NJ07033 NJ07033 NJ07033 北京100871 北京100871

铁反应元件 (IRE)具有的高度保守的RNA茎环结构 ,是胞质中IRE结合铁调控蛋白 (IRP)的位点。IRP与IRE的结合受细胞内铁含量的调控 ,与铁代谢有着密切的关系。许多与铁代谢有关的基因在 5′UTR或 3′UTR都存在IRE。当铁离子缺乏时 ,IRE与... 详细信息

铁反应元件 (IRE)具有的高度保守的RNA茎环结构 ,是胞质中IRE结合铁调控蛋白 (IRP)的位点。IRP与IRE的结合受细胞内铁含量的调控 ,与铁代谢有着密切的关系。许多与铁代谢有关的基因在 5′UTR或 3′UTR都存在IRE。当铁离子缺乏时 ,IRE与IRP结合 ,使核糖体的翻译进程受阻 ,抑制mRNA的翻译 ;而当铁离子浓度较高时 ,IRP就释放IRE ,促进翻译。因此 ,IRE在 5′UTR调节着翻译的起始[1] 。如果IRE位于 3′UTR ,IRE与IRP的结合可以稳定mRNA并预防其被降解。所有已知的IRE均为C1G5型 ,即环的 1号和 5号碱基位置分别是保守的C和G ;另外还存在一类体外合成的U1A5型IRE ,即环的 1号和 5号碱基位置分别是保守的U和A ,能够在体外有效地结合IRP。由于IRE与铁代谢、氧化性损伤 (oxidativestress)和衰老等过程都有密切的关系 ,因此在临床及新药研制等方面都很受重视。通过改进搜索IRE的算法 ,用计算机程序对人与鼠的mRNA非编码区(UTR)序列数据库进行全面的搜索 ,期望找出可能存在的C1G5或U1A5类型的IRE ,或包含这两种类型IRE的基因。

关键词：铁反应元件铁调控蛋白茎环结构非翻译区

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磷酸二酯酶4作为抗炎药物靶点的研究现状及未来发展方向

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中国药科大学学报 2006年第1期37卷 9-13页

作者：汤慧芳陈季强王鹏浙江大学医学院国家食品药品监督管理局浙江呼吸药物研究实验室杭州310031 Allergy and Immunology Department schering-plough research institute

环腺苷酸(cAMP)-特异性磷酸二酯酶4(PDE4)是目前最热门的药物靶点之一。PDE4抑制剂在临床已表现出对数种炎症性疾病有效,包括哮喘、慢性阻塞性肺病(COPD)、过敏性鼻炎和过敏性皮炎等,在动物模型上对其它多种疾病包括关节炎,败血症等也... 详细信息

环腺苷酸(cAMP)-特异性磷酸二酯酶4(PDE4)是目前最热门的药物靶点之一。PDE4抑制剂在临床已表现出对数种炎症性疾病有效,包括哮喘、慢性阻塞性肺病(COPD)、过敏性鼻炎和过敏性皮炎等,在动物模型上对其它多种疾病包括关节炎,败血症等也有效。由于有恶心及呕吐等不良反应,进入临床研究的第1代PDE4抑制剂如咯利普兰(rolipram),吡拉米特(piclamilast)已中止研究,但是有数个第2代PDE4抑制剂(如西洛司特和罗氟司特)正在研究和开发中。由于,它们仍不能避免恶心呕吐的不良反应,因此,它们的临床使用受到限制。PDE4家族包括4种亚型。目前正在研发中的PDE4抑制剂一般都不能区别PDE4的亚型。最近,已有一些重要的进展使我们能更好的理解各种亚型的不同作用。PDE4亚型的特异性抑制剂有可能降低药物的不良反应并仍保持药物的抗炎活性,因而有可能开发出比目前正在研制的第2代PDE4抑制剂更好的抗炎药物。

关键词：磷酸二酯酶4 药物靶点炎症哮喘慢性阻塞性肺病

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Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype

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World Journal of Gastroenterology 2007年第48期13卷 6529-6537页

作者： Ulrike G Strauch Florian Obermeier Nicole Grunwald Nadja Dunger Heiko C Rath Jürgen Schlmerich A Steinmeyer U Zügel HH Herfarth Department of Internal MedicineⅠ University of Regensburg Medicinal Chemistry Schering AG Berlin Germany research Business Area Dermatology Schering AG Berlin Germany

AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.

关键词：右旋糖苷硫酸钠大肠炎树状细胞

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疫苗诱导对猪肺炎支原体的免疫防卫

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国外畜牧学（猪与禽） 2002年第5期22卷 44-46页

作者：汪秉刚 Robyn Fleck 美国schering-plough动物保健公司猪技术服务部

疾病防制策略包括调整宿主 (猪 )和入侵者 (猪肺炎支原体 )之间的关系。本文介绍的一种策略是利用免疫接种激活猪的免疫系统。对于猪肺炎支原体的免疫应答 (包括体液、粘膜和细胞介导的各个系统 )非常复杂 ,是当前的热门研究课题。

关键词：疫苗诱导猪肺炎支原体免疫防卫

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Soil Insect Diversity and Abundance Following Different Fertilizer Treatments on the Loess Plateau of China

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Journal of Integrative Agriculture 2013年第9期12卷 1644-1651页

作者： LIN Ying-hua LU Ping YANG Xue-yun ZHANG Fu-dao institute of Wetland research Chinese Academy of Forestry Key Laboratory of Forest Protection of State Forestry Administration Research Institute of Ecology Environment and ProtectionChinese Academy of Forestry College of Resources and Environmental Sciences Northwest A&F University institute of Agricultural Resources and Regional Planning Chinese Academy of Agricultural Sciences

The presence of abundant and diverse communities of macro-arthropods is considered an indicator of sustainability in agroecosystems. This study was designed to investigate the effects of different fertilizer treatments on abundance and diversity of insects of arable loess soil on the Loess Plateau of China. These regimes included a control with no fertilizer addition or manure, treatments with application of mineral fertilizers （N, NK, NP, PK, NPK）, treatments with NPK in combination with organic materials such as wheat straw or maize stalk, treatments with two rates of organic manure application; and different crop rotations （Rot. 1： winter wheat summer maize; Rot.2： winter wheat summer maize soybean intercropping; and Rot.3： winter wheat or rapeseed summer maize soybean intercropping）. Soil macro-arthropods were collected from the plough layer （0-20 cm） and sorted by hand after each harvest in June and October 2001 and 2002. A total of 3 132 individuals were collected, from 7 orders and 55 families, dominated by Formicidae （61.72%） and Staphylinidae （14.24%）. The results showed that individuals and groups were significantly influenced by sampling dates, while groups were significantly influenced by the fertilization treatments. Soil insect biodiversity, as determined by the Shannon index, was significantly influenced by fertilization and sampling dates. The abundance of soil insects was positively and significantly correlated with soil moisture content in October 2002. Nitrogen, phosphorus and potassium fertilizers and incorporation of organic materials were favorable factors for abundance and diversity in arable loess soil.

关键词： long-term fertilization soil moisture soil insect loess soil

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抗支原体病免疫接种和母源抗体

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国外畜牧学（猪与禽） 2002年第3期22卷 55-56页

作者：郑嘉清 Vick Rapp-Gabrielson 美国schering-plough动物保健公司生物学研究开发部

由猪肺炎支原体(Mycoplasma hyopneumoniae)引起的猪肺炎一直对全世界养猪业造成着严重的健康问题.猪肺炎支原体感染还为继发性细菌感染创造了条件,因而还是猪呼吸道疾病复合症的重要成员.支原体性肺炎可造成巨大的经济损失,尤其是在猪... 详细信息

由猪肺炎支原体(Mycoplasma hyopneumoniae)引起的猪肺炎一直对全世界养猪业造成着严重的健康问题.猪肺炎支原体感染还为继发性细菌感染创造了条件,因而还是猪呼吸道疾病复合症的重要成员.支原体性肺炎可造成巨大的经济损失,尤其是在猪的生长阶段.

关键词：抗支原体病免疫接种母源抗体猪病肺炎支原体

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Land cover changes and the effects of cultivation on soil properties in Shelihu wetland,Horqin Sandy Land,Northern China

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Journal of Arid Land 2013年第1期5卷 71-79页

作者： Jie LIANI XueYong ZHAO XiaoAn ZUO ShaoKun WANG XinYuan WANG YongQing LUO Naiman Desertification research Station Cold and Arid Regions Environmental and Engineering Research Institute Chinese Academy of Sciences Lanzhou 730000 China University of Chinese Academy of Sciences Beijing 100049 China

Land cover change plays an essential role in the alternation of soils properties. By field investigation and applying satellite images, land cover information in the Shelihu wetland was carried out in an area of 2,819 hm2 in 1985, 1995, 2000, 2005, 2010 and 2011, respectively, in Horqin Sandy Land. A total of 57 soil sampling sites across Shelihu were chosen in wet meadow （CL0）, cropland （CL） and sandy land （SL） according to the spatial characteristics of water body change. Soil texture, organic carbon （SOC）, total nitrogen （TN） and total phosphorus （TP） contents, electrical conductivity （EC） and pH were measured at the soil depths of 0-10, 10-20 and 20-40 cm to examine the influence of agricultural conversion and continuous cultivation on soil properties. The results showed that the study area was covered by water body in 1985, which gradually declined afterwards and then reclaimed rapidly at a mean annual rate of 132.1 hm2/a from wet meadow to cropland since 1995. In 2011, water body was drained and the area was occupied by 10.8% of CL0, 76.9% of CL and 12.3% of SL. Large amounts of SOC, TN and TP were accumulated in the above depths in CL0. Soil in CL0 also had higher EC and silt and clay fractions, lower pH than in SL and CL. Soil in SL was seriously degraded with lower contents of SOC, TN and TP than in CL and CL0. SOC, TN content and EC in CL decreased with the increase of cultivation age, while pH showed a reverse trend with significance at plough horizon. The agricultural conversion in Shelihu was driven by the comprehensive factors of precipitation reduction, economic development and intense competitions for irrigation water. Continuous cultivation in this process is not sustainable because of SOC degradation and nutrient content reduction. The key point is that conventional tillage and removal of residuals induced further land degradation. Wetland reclamation for immediate economic interests led to greater costs in the long-term environmental restoration i

关键词： wetland soil degradation wetland reclamation continuous cultivation Horqin Sandy Land

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