\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"}]},book:{item:{type:"book",id:"3791",leadTitle:null,fullTitle:"Visual Servoing",title:"Visual Servoing",subtitle:null,reviewType:"peer-reviewed",abstract:"The goal of this book is to introduce the visional application by excellent researchers in the world\r\ncurrently and offer the knowledge that can also be applied to another field widely.\r\nThis book collects the main studies about machine vision currently in the world, and has a\r\npowerful persuasion in the applications employed in the machine vision. The contents, which\r\ndemonstrate that the machine vision theory, are realized in different field. For the beginner, it is\r\neasy to understand the development in the vision servoing. For engineer, professor and researcher,\r\nthey can study and learn the chapters, and then employ another application method.",isbn:null,printIsbn:"978-953-307-095-7",pdfIsbn:"978-953-51-5878-3",doi:"10.5772/187",price:119,priceEur:129,priceUsd:155,slug:"visual-servoing",numberOfPages:246,isOpenForSubmission:!1,isInWos:1,hash:"914ef0dc63bd38b6df6d8332f6f28917",bookSignature:"Rong-Fong Fung",publishedDate:"April 1st 2010",coverURL:"https://cdn.intechopen.com/books/images_new/3791.jpg",numberOfDownloads:23953,numberOfWosCitations:11,numberOfCrossrefCitations:6,numberOfDimensionsCitations:18,hasAltmetrics:0,numberOfTotalCitations:35,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 30th 2013",dateEndSecondStepPublish:"August 20th 2013",dateEndThirdStepPublish:"November 24th 2013",dateEndFourthStepPublish:"February 22nd 2014",dateEndFifthStepPublish:"March 24th 2014",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"6571",title:"Prof.",name:"Rong-Fong",middleName:null,surname:"Fung",slug:"rong-fong-fung",fullName:"Rong-Fong Fung",profilePictureURL:"https://mts.intechopen.com/storage/users/6571/images/system/6571.jpg",biography:"Rong-Fong Fung received the M.S. and. Ph.D degrees in Mechanical Engineering\nfrom Chung Yuan University and National Taiwan University, Taiwan, in 1982 and\n1993, respectively. He was a lecturer, associate professor and professor in the\nDepartment of Mechanical Engineering of Chung Yuan University, from 1985 to 2000.\nHe was a visiting scholar of Department of Electrical Engineering of The Ohio State\nUniversity in1997.\nHe is currently, a professor of Department of Mechanical & Automation Engineering\n(from Aug. 2000) and Graduate Institute of Electro-Optical Engineering (from Aug.\n2004), Dean of College of Engineer (from Aug. 2010), and Chairman of Institute of\nEngineering Science and Technology (from Aug. 2010), National Kaohsiung First\nUniversity of Science and Technology (NKFUST), Taiwan. He was Dean of\nAcademic Affairs (Aug. 2004 to July 2007, Aug. 2009 to April 2010, NKFUST) and\nChairman of Graduate Institute of Electro-Optical Engineering (Aug. 2004 to July\n2005, NKFUST).\nProfessor Fung received the Outstanding Research Award (2005, 2010, NKFUST),\nOutstanding Industry-Academia Cooperation Award (2010, NKFUST), Outstanding\nEngineering Professor Award (2006, the Chinese Mechanical Engineering Association,\nTaiwan), and Outstanding Research Award, 2004, NSC, Taiwan).\nHis main research interest includes dynamics and control of opto-mechatronic\nsystems, and equipment development of automated optical inspection (AOI) for LED\nand vehicle lamps.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"524",title:"Sensor Networks",slug:"sensor-networks"}],chapters:[{id:"9768",title:"A Modeling and Simulation Platform for Robot Kinematics Aiming Visual Servo Control",doi:"10.5772/8551",slug:"a-modeling-and-simulation-platform-for-robot-kinematics-aiming-visual-servo-control",totalDownloads:3028,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Lelio R. Soares Jr. and Victor H. Casanova Alcalde",downloadPdfUrl:"/chapter/pdf-download/9768",previewPdfUrl:"/chapter/pdf-preview/9768",authors:[null],corrections:null},{id:"9767",title:"Models and Control Strategies for Visual Servoing",doi:"10.5772/8550",slug:"models-and-control-strategies-for-visual-servoing",totalDownloads:2021,totalCrossrefCites:0,totalDimensionsCites:3,signatures:"Nils T Siebel, Dennis Peters and Gerald Sommer",downloadPdfUrl:"/chapter/pdf-download/9767",previewPdfUrl:"/chapter/pdf-preview/9767",authors:[null],corrections:null},{id:"9766",title:"The Uncalibrated Microscope Visual Servoing for Micromanipulation Robotic System",doi:"10.5772/8549",slug:"the-uncalibrated-microscope-visual-servoing-for-micromanipulation-robotic-system",totalDownloads:1942,totalCrossrefCites:1,totalDimensionsCites:3,signatures:"Xinhan Huang, Xiangjin Zeng and Min Wang",downloadPdfUrl:"/chapter/pdf-download/9766",previewPdfUrl:"/chapter/pdf-preview/9766",authors:[null],corrections:null},{id:"9770",title:"Human-in-the-Loop Control for a Broadcast Camera System",doi:"10.5772/8553",slug:"human-in-the-loop-control-for-a-broadcast-camera-system",totalDownloads:1531,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Rares Stanciu and Paul Oh",downloadPdfUrl:"/chapter/pdf-download/9770",previewPdfUrl:"/chapter/pdf-preview/9770",authors:[null],corrections:null},{id:"9764",title:"Vision-Based Control of the Mechatronic System",doi:"10.5772/8547",slug:"vision-based-control-of-the-mechatronic-system",totalDownloads:3086,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Rong-Fong Fung and Kun-Yung Chen",downloadPdfUrl:"/chapter/pdf-download/9764",previewPdfUrl:"/chapter/pdf-preview/9764",authors:[null],corrections:null},{id:"9763",title:"Online 3-D Trajectory Estimation of a Flying Object from a Monocular Image Sequence for Catching",doi:"10.5772/8546",slug:"online-3-d-trajectory-estimation-of-a-flying-object-from-a-monocular-image-sequence-for-catching",totalDownloads:2335,totalCrossrefCites:0,totalDimensionsCites:2,signatures:"Rafael Herrejon Mendoza, Shingo Kagami and Koichi Hashimoto",downloadPdfUrl:"/chapter/pdf-download/9763",previewPdfUrl:"/chapter/pdf-preview/9763",authors:[null],corrections:null},{id:"9762",title:"Multi-Camera Visual Servoing of a Micro Helicopter Under Occlusions",doi:"10.5772/8545",slug:"multi-camera-visual-servoing-of-a-micro-helicopter-under-occlusions",totalDownloads:1853,totalCrossrefCites:2,totalDimensionsCites:5,signatures:"Yuta Yoshihata, Kei Watanabe, Yasushi Iwatani and Koichi Hashimoto",downloadPdfUrl:"/chapter/pdf-download/9762",previewPdfUrl:"/chapter/pdf-preview/9762",authors:[null],corrections:null},{id:"9761",title:"Model Based Software Production Utilized by Visual Templates",doi:"10.5772/8544",slug:"model-based-software-production-utilized-by-visual-templates",totalDownloads:2594,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Mika Karaila",downloadPdfUrl:"/chapter/pdf-download/9761",previewPdfUrl:"/chapter/pdf-preview/9761",authors:[null],corrections:null},{id:"9765",title:"Visual Servoing for UAVs",doi:"10.5772/8548",slug:"visual-servoing-for-uavs",totalDownloads:2807,totalCrossrefCites:2,totalDimensionsCites:3,signatures:"Pascual Campoy, Ivan F. Mondragon, Miguel A. Olivares-Mendez and Carol Martinez",downloadPdfUrl:"/chapter/pdf-download/9765",previewPdfUrl:"/chapter/pdf-preview/9765",authors:[null],corrections:null},{id:"9769",title:"Video Watermarking Technique using Visual Sensibility and Motion Vector",doi:"10.5772/8552",slug:"video-watermarking-technique-using-visual-sensibility-and-motion-vector",totalDownloads:2772,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Mariko Nakano-Miyatake and Hector Perez-Meana",downloadPdfUrl:"/chapter/pdf-download/9769",previewPdfUrl:"/chapter/pdf-preview/9769",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"66064",slug:"corrigendum-to-textured-bst-thin-film-on-silicon-substrate-preparation-and-its-applications-for-high",title:"Corrigendum to: Textured BST Thin Film on Silicon Substrate: Preparation and Its Applications for High Frequency Tunable Devices",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/66064.pdf",downloadPdfUrl:"/chapter/pdf-download/66064",previewPdfUrl:"/chapter/pdf-preview/66064",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/66064",risUrl:"/chapter/ris/66064",chapter:{id:"62285",slug:"textured-bst-thin-film-on-silicon-substrate-preparation-and-its-applications-for-high-frequency-tuna",signatures:"Congchun Zhang, Jianze Huang, Chunsheng Yang and Guifu Ding",dateSubmitted:"February 7th 2018",dateReviewed:"June 3rd 2018",datePrePublished:"November 5th 2018",datePublished:"January 3rd 2019",book:{id:"7253",title:"Coatings and Thin-Film Technologies",subtitle:null,fullTitle:"Coatings and Thin-Film Technologies",slug:"coatings-and-thin-film-technologies",publishedDate:"January 3rd 2019",bookSignature:"Jaime Andres Perez-Taborda and Alba G. Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"33329",title:"Prof.",name:"guifu",middleName:null,surname:"Ding",fullName:"guifu Ding",slug:"guifu-ding",email:"gfding@sjtu.edu.cn",position:null,institution:{name:"Shanghai Jiao Tong University",institutionURL:null,country:{name:"China"}}},{id:"244624",title:"Associate Prof.",name:"Congchun",middleName:null,surname:"Zhang",fullName:"Congchun Zhang",slug:"congchun-zhang",email:"zhcc@sjtu.edu.cn",position:null,institution:null},{id:"255541",title:"Mr.",name:"Jianze",middleName:null,surname:"Huang",fullName:"Jianze Huang",slug:"jianze-huang",email:"huangjz420@sjtu.edu.cn",position:null,institution:null},{id:"255547",title:"Mr.",name:"Chunsheng",middleName:null,surname:"Yang",fullName:"Chunsheng Yang",slug:"chunsheng-yang",email:"csyang@sjtu.edu.cn",position:null,institution:null}]}},chapter:{id:"62285",slug:"textured-bst-thin-film-on-silicon-substrate-preparation-and-its-applications-for-high-frequency-tuna",signatures:"Congchun Zhang, Jianze Huang, Chunsheng Yang and Guifu Ding",dateSubmitted:"February 7th 2018",dateReviewed:"June 3rd 2018",datePrePublished:"November 5th 2018",datePublished:"January 3rd 2019",book:{id:"7253",title:"Coatings and Thin-Film Technologies",subtitle:null,fullTitle:"Coatings and Thin-Film Technologies",slug:"coatings-and-thin-film-technologies",publishedDate:"January 3rd 2019",bookSignature:"Jaime Andres Perez-Taborda and Alba G. Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"33329",title:"Prof.",name:"guifu",middleName:null,surname:"Ding",fullName:"guifu Ding",slug:"guifu-ding",email:"gfding@sjtu.edu.cn",position:null,institution:{name:"Shanghai Jiao Tong University",institutionURL:null,country:{name:"China"}}},{id:"244624",title:"Associate Prof.",name:"Congchun",middleName:null,surname:"Zhang",fullName:"Congchun Zhang",slug:"congchun-zhang",email:"zhcc@sjtu.edu.cn",position:null,institution:null},{id:"255541",title:"Mr.",name:"Jianze",middleName:null,surname:"Huang",fullName:"Jianze Huang",slug:"jianze-huang",email:"huangjz420@sjtu.edu.cn",position:null,institution:null},{id:"255547",title:"Mr.",name:"Chunsheng",middleName:null,surname:"Yang",fullName:"Chunsheng Yang",slug:"chunsheng-yang",email:"csyang@sjtu.edu.cn",position:null,institution:null}]},book:{id:"7253",title:"Coatings and Thin-Film Technologies",subtitle:null,fullTitle:"Coatings and Thin-Film Technologies",slug:"coatings-and-thin-film-technologies",publishedDate:"January 3rd 2019",bookSignature:"Jaime Andres Perez-Taborda and Alba G. Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"7342",leadTitle:null,title:"Manifolds II",subtitle:"Theory and Applications",reviewType:"peer-reviewed",abstract:"Differential geometry is a very active field of research and has many applications to areas such as physics, in particular gravity. The chapters in this book cover a number of subjects that will be of interest to workers in these areas. It is hoped that these chapters will be able to provide a useful resource for researchers with regard to current fields of research in this important area.",isbn:"978-1-83880-310-0",printIsbn:"978-1-83880-309-4",pdfIsbn:"978-1-83880-716-0",doi:"10.5772/intechopen.75217",price:119,priceEur:129,priceUsd:155,slug:"manifolds-ii-theory-and-applications",numberOfPages:146,isOpenForSubmission:!1,hash:"97f5bd89a6e5006ea10d90df5a6df5a5",bookSignature:"Paul Bracken",publishedDate:"May 22nd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7342.jpg",keywords:null,numberOfDownloads:2797,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:2,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 11th 2018",dateEndSecondStepPublish:"May 2nd 2018",dateEndThirdStepPublish:"July 1st 2018",dateEndFourthStepPublish:"September 19th 2018",dateEndFifthStepPublish:"November 18th 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken",profilePictureURL:"https://mts.intechopen.com/storage/users/92883/images/system/92883.JPG",biography:"Professor Paul Bracken is currently a Professor in the Department of Mathematics, at the University of Texas RGV in Edinburg, TX. He obtained his BSc degree from the University of Toronto and holds a Ph.D. from the University of Waterloo in Canada. His research interests include mathematical problems from the area of quantum mechanics and quantum field theory, differential geometry, a study of partial differential equations as well as their overlap with other problems in physics. He has published more than 160 papers in journals and books and has given many talks at different levels over the years. This is the seventh volume he has worked on with IntechOpen publishers.",institutionString:"The University of Texas Rio Grande Valley",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"9",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"The University of Texas Rio Grande Valley",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"165",title:"Geometry & Topology",slug:"geometry-and-topology"}],chapters:[{id:"65349",title:"The Generalized Weierstrass System in Three-Dimensional Euclidean Space",slug:"the-generalized-weierstrass-system-in-three-dimensional-euclidean-space",totalDownloads:436,totalCrossrefCites:0,authors:[{id:"92883",title:"Prof.",name:"Paul",surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}]},{id:"63626",title:"On Conformal Anti-Invariant Submersions Whose Total Manifolds Are Locally Product Riemannian",slug:"on-conformal-anti-invariant-submersions-whose-total-manifolds-are-locally-product-riemannian",totalDownloads:384,totalCrossrefCites:0,authors:[null]},{id:"62804",title:"Recent Advances of Manifold Regularization",slug:"recent-advances-of-manifold-regularization",totalDownloads:571,totalCrossrefCites:0,authors:[null]},{id:"63130",title:"Manifold Learning in Medical Imaging",slug:"manifold-learning-in-medical-imaging",totalDownloads:547,totalCrossrefCites:0,authors:[null]},{id:"63747",title:"Trajectory Tracking Control of Parallel Manipulator with Integral Manifold and Observer",slug:"trajectory-tracking-control-of-parallel-manipulator-with-integral-manifold-and-observer",totalDownloads:452,totalCrossrefCites:0,authors:[null]},{id:"63611",title:"Manifold-Based Robot Motion Generation",slug:"manifold-based-robot-motion-generation",totalDownloads:415,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"250240",firstName:"Nino",lastName:"Popovic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/250240/images/7088_n.png",email:"nino@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"3513",title:"Advances in Quantum Mechanics",subtitle:null,isOpenForSubmission:!1,hash:"bbea1c081216f267a4480707f4ead9cf",slug:"advances-in-quantum-mechanics",bookSignature:"Paul Bracken",coverURL:"https://cdn.intechopen.com/books/images_new/3513.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5488",title:"Manifolds",subtitle:"Current Research Areas",isOpenForSubmission:!1,hash:"e1193790ca2c8027d4ffc6911dd24365",slug:"manifolds-current-research-areas",bookSignature:"Paul Bracken",coverURL:"https://cdn.intechopen.com/books/images_new/5488.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5213",title:"Research Advances in Quantum Dynamics",subtitle:null,isOpenForSubmission:!1,hash:"15678b0555c714101f8d707a46b4ac60",slug:"research-advances-in-quantum-dynamics",bookSignature:"Paul Bracken",coverURL:"https://cdn.intechopen.com/books/images_new/5213.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10076",title:"Quantum Mechanics",subtitle:null,isOpenForSubmission:!1,hash:"78f2b316d6bb97464dbbf9b683164aff",slug:"quantum-mechanics",bookSignature:"Paul Bracken",coverURL:"https://cdn.intechopen.com/books/images_new/10076.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7776",title:"Research Advances in Chaos Theory",subtitle:null,isOpenForSubmission:!1,hash:"e9646ec4b2bff873ce958ed4d5ad7248",slug:"research-advances-in-chaos-theory",bookSignature:"Paul Bracken",coverURL:"https://cdn.intechopen.com/books/images_new/7776.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"55079",title:"Animal Models of Systemic Sclerosis",doi:"10.5772/intechopen.68551",slug:"animal-models-of-systemic-sclerosis",body:'Systemic sclerosis (SSc) or scleroderma is a rare, chronic connective tissue disease affecting the skin, vessels, musculoskeletal system, and internal organs. The name of this disease is derived from the Greek words “scleros” and “derma” meaning tough skin and was first used by Gintrac in 1847. The first mention of a stiff skin comes from Hippocrates around 400 BC. SSc affects women more often, usually begins in their 40s, and overall survival is shorter (10-year survival of around 70%). Despite advances in pharmacotherapy of organ manifestations and new knowledge about the pathogenesis of SSc, there is still no effective treatment of this serious disease [1]. The etiology of SSc is still unclear, although there are long known associations between some external factors (mainly silicon compounds and organic solvents) and the development of SSc.
The possibility of biopsy sampling of affected tissues in patients with SSc, in particular as a skin biopsy, helped to a large degree to elucidate the pathogenesis of this disease. Histological analysis of biopsy samples of tissues in different stages of the disease has identified three basic pathological processes and their relative time sequence: vasculopathy, inflammation, and fibrosis. The first pathological changes can be detected at the level of microcirculation, in which damage to the endothelium leads to progressive development of inflammation caused by the activation of cells of both the innate and, subsequently, acquired immunity. Activated cells produce pro-fibrotic cytokines, especially transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), and platelet-derived growth factor (PDGF). These cytokines activate resident fibroblasts, which increase production of extracellular matrix (ECM) components that lead to remodeling of a functional tissue to a fibrotic one. The fibrotic phase of the pathogenesis of SSc and its severity and extent determine the morbidity and mortality of this disease [2]. The material from skin biopsies has also enabled the analysis of gene and protein expression, epigenetic modifications, and signaling pathways of different target molecules. The potential importance of these candidate molecules must always be first tested and subsequently confirmed, pending their therapeutic use in SSc. For these purposes, we may use in vitro experiments on tissue or cell cultures isolated from tissues explanted from SSc patients and healthy individuals or in vivo experiments using experimental animal models of SSc [3].
Today, there are numerous animal models of SSc. However, none of the available models mimics the full range of pathologies and clinical manifestations of SSc. Experimental animal models help clarify certain pathological mechanisms and only mimic some aspects of SSc. Each model has its advantages and disadvantages. Selection of an appropriate animal model for the analysis of target genes or candidate molecules for therapy must be carefully considered beforehand [4]. Since the skin fibrosis is a dominant and common feature in most patients with SSc, this pathological process is not only a starting point but also the key aspect for the majority of experimental models. With the progress in scientific knowledge and technologies, new models were developed with other dominant features such as activation of immunity and inflammation, vasculopathy, and specific pathological processes in the involved organs, especially the lungs. However, most of available models provide an overlap of the abovementioned pathological mechanisms and a concurrent involvement of several organs characteristic of SSc.
The aim of this chapter is to introduce traditional, most commonly used experimental animal models of SSc, clarify their basic pathological mechanism, describe the advantages and limitations, and outline their use in preclinical tests of potential therapeutic agents with subsequent clinical trials in patients with SSc.
Tsk1 mice possess an autosomal dominant mutation, tandem duplication in the gene for fibrillin 1, which is an important regulator of the TGF-β signaling and fibrogenesis. In heterozygous mice (labeled Tsk1), this mutation leads to hyperplasia and thickening of the subcutaneous tissue and fascial layers of the skin without striking thickening of the dermis itself (Figure 1). Similarly, hyperplasia of subcutaneous fascia and lipoatrophy can also be detected in the skin of patients with SSc. Tsk1 mice also produce autoantibodies (anti-topoisomerase I, anti-RNA polymerase I, anti-dsDNA) [5–9]. Fibrosis in these mice develops from excessive production of ECM by activated fibroblasts during the activation of TGF-β pathway. The exact mechanism has not yet been elucidated. The progression of fibrosis in Tsk1 mice is mediated by an increased expression of CD19, chronic B-cell activation leading to increased secretion of IL-6, and mast cells. These mechanisms are also applied in the progression of SSc in humans. Tsk1 mice are commonly used as a model mimicking later stages of SSc that are independent of inflammatory infiltrates [10].
Hyperplasia and thickening of the subcutaneous tissue and fascial layers of the skin without striking thickening of the dermis in Tsk1 mice compared to the wild-type littermates (pa/pa). The sections are stained with hematoxylin-eosin (magnification 20-fold; the black vertical bar represents the thickness of the hypodermis).
The advantage of this model is a detailed documentation and endogenous activation of fibroblasts similar to SSc in humans. The limitations to this model include insufficiently elucidated molecular mechanisms, the absence of vascular phenotype, dominant histological changes in the hypodermis, and some other changes, such as emphysema and kyphosis, which are not part of SSc in humans [4].
In 1986, a tight skin 2 (Tsk2) mouse model was first described, which is induced by a chemical compound ethylnitrosourea. This compound induces an autosomal dominant mutation localized on the chromosome 1. Only heterozygous individuals (Tsk2/+) survive [11]. The development of phenotypic features of this model occurs mainly between the third and fourth weeks after birth. The gene responsible for the mutation has not yet been precisely identified [12]. However, using in vivo and in vitro genetic tests, previous studies have demonstrated a significant role of missense mutations in the gene for type III collagen alpha 1 (Col3a1) [13]. The Tsk2/+ mice showed elevated levels of type III collagen and changes in the ECM in the dermis, especially during 10 days after birth, which were still prevalent in seventh to eighth month compared with the wild-type littermates. Furthermore, the Tsk2/+ mice demonstrated the presence of mononuclear inflammatory infiltrates [11]. Cultured fibroblasts isolated from Tsk2 mice showed elevated mRNA expression of Col1a1 and Col3a1 gene and overproduction of collagen fibers [14]. Compared with Tsk1 model, the Tsk2 mice are characterized by abundant mononuclear cells infiltrating the dermis and adipose tissue. These mice have excessive thickening of adventitia of the vessels in the heart and lungs along with changes in the alveolar compartment [14, 15].
These findings indicate a significant use of these models for research of fibrotic processes, such as SSc in humans, as this disease is also characterized by an increased expression and accumulation of collagen in dermal fibroblasts [16, 17]. The Tsk2 mouse model has a large number of very similar clinical manifestations to those seen in SSc patients, including skin thickening, increased production of collagen and ECM, and autoimmune responses [11, 18].
An experimental mouse model for deactivating the TGF-β signaling has been developed, in which the fibroblasts express a non-signaling mutant type II TGF-β receptor that lacks the intracellular kinase domain (TβRIIΔk) [19]. In in vitro experiments, TβRIIΔk was demonstrated to have inhibitory properties on TGF-β signaling and was characterized as a competitive antagonist of TGF-β1 [20]. TGF-β signaling is mediated through type I and type II TGF-β receptors (TβRI and TβRII), which have a serine/threonine kinase activity and trigger subsequent Smad-dependent or Smad-nondependent signaling. Binding of TGF-β1 to TβRII leads to subsequent phosphorylation of TβRI, which then mediates the activation of downstream signaling pathways [21]. Authors of this model hypothesized that only fibroblasts expressing TβRIIΔk would have distorted TGF-β signaling leading to suppression of genes regulated by this pathway and thus achieve reduced pro-fibrotic effects of TGF-β signaling in these fibroblasts. In in vivo experiments, even though fibroblasts cultured from mouse models expressing TβRIIΔk exhibited resistance to exogenous TGF-β, the TβRIIΔk mice paradoxically and surprisingly developed progressive cutaneous, intestinal, and pulmonary fibrosis [19, 22]. The TβRIIΔk model showed phenotypic properties resembling the properties of the activated TGF-β pathway. Fibrosis was demonstrated in both sexes. From the sixth week after birth, TβRIIΔk mice experienced weight loss and developed pathological changes in the lung, in terms of reduced lung capacity and increased presence of connective tissue and ECM components, compared to wild-type littermates [19]. In 10% of these animals, the acquired damage led to death of an adult mouse around the 16th week of age. At week 12, abnormal thickening of the dermis with the loss of subcutaneous adipose tissue can be demonstrated, which can be especially evident in the lower back of these mice. Furthermore, the TβRIIΔk mice are also characterized by elevated levels of collagen.
This model is used not only for understanding the regulatory effects of non-signaling TGF-β receptors and constitutive activation of TGF-β signaling in vivo but also as a model for genetically determined fibrosis [19].
Sirtuin 3 (SIRT3) belongs to the large family of class III histone deacetylases, which alone requires nicotinamide adenine dinucleotide (NAD+) as a cofactor for its proper enzymatic activity [23]. In mammals, there are seven isoforms/classes of sirtuins (SIRT1-7), which differ in specific binding substrates, different biological functions, and various locations in the cell [24]. SIRT3 is found primarily in the mitochondria, and elevated levels were detected during reduced food intake, so-called caloric restriction, and endurance sports [25]. Proper function of SIRT3 in murine models prevents the development of a number of diseases such as cancer, metabolic syndrome, etc. [26, 27]. Experimental mice deficient for SIRT3 (Sirt3-KO) develop cardiac hypertrophy and contractile dysfunction in adulthood [28]. An association between SIRT3 deficiency and aging was analyzed initially on the development of cardiac fibrosis in three age categories of Sirt3-KO mice. Results showed aggravation of fibrotic cardiac impairment depending on higher age of Sirt3-KO mice. Furthermore, formation of tissue fibrosis in a number of other organs again depending on the age was demonstrated in the Sirt3-KO mice. The older the Sirt3-KO mouse, the more affected organs were observed, including the lung, kidney, and liver, in contrast to the corresponding age-matched control group [29]. Mice that lack or have reduced expression of SIRT3 also develop pulmonary arterial hypertension. Nevertheless, malfunction of SIRT3 is not accompanied by the presence of inflammatory infiltrates, even though mitochondrial damage and the presence of oxidative stress have been detected [30]. Studies on SIRT3 also showed that increased expression of SIRT3 prevents the development of experimentally induced organ fibrosis and promotes the essential role of SIRT3 in maintaining cellular homeostasis of tissues during aging [29, 31].
The model of SIRT3-deficient mice allows for deeper examination of cellular mechanisms involved in the development of organ fibrosis and pulmonary arterial hypertension (PAH) in the absence of inflammatory infiltrates, depending on the age of the mouse.
Vinyl chloride is a colorless, toxic gas of sweet fragrance, which is an important component in the production of the polymer polyvinyl chloride (PVC). Some individuals, who are exposed to repeated doses of vinyl chloride, develop cutaneous and pulmonary fibrosis. The development of fibrosis is often preceded by the Raynaud’s phenomenon [32]. Animal models, particularly mice and rats that are exposed to vinyl chloride, develop the same disease as humans. Injections of vinyl chloride to BALB/cJ retired breeder mice lead to the development of cutaneous fibrosis and dermal inflammation with a substantial presence of mononuclear infiltrates similar to SSc in humans [33].
In order to study a variety of genes in in vivo environment with activated TGF-β signaling, which is a central pro-fibrotic cytokine in the pathogenesis of SSc, the TBRICA mouse model was developed with the mutated form of the TGF-β type I receptor (TBRICA) in fibroblasts, which leads to its sustained activation independent of the ligand TGF-β. Specific expression in fibroblasts was achieved using a transcription enhancer of proα2(I) collagen gene, which directs the expression exclusively in fibroblasts [34–36]. The attempt to create transgenic mice despite the specific expression of this mutation only in the fibroblasts was not successful, and the mice died during the gestation. Thus, a postnatally induced sustained activation of TBRI using tamoxifen inducible Cre/loxP system was introduced, which leads to progressive generalized dermal fibrosis with overproduction of type I and type III collagen and adnexal atrophy [35]. This model is also characterized by thickening of the walls of the small arteries of the lungs, kidneys, and adrenal glands, as well as the pulmonary artery. Technical and economic demands of this model led to the introduction of alternative solution, in which local skin fibrosis is achieved by subcutaneous injection with a weakened adenovirus with sustained activation of TBRI, which is no longer limited to fibroblasts [35].
The advantages include a well-described pathological mechanism and a possibility of a detailed in vivo analysis of TGF-β signaling in fibroblasts. The limitations comprise only a minimal representation of inflammation and autoimmunity [4].
This model is a widely used model mimicking the in vivo inflammatory changes present in the early stage of SSc. Bleomycin was originally isolated from
Fibrosis and inflammatory infiltrates in the dermis of mice locally injected with bleomycin compared to control mice injected with saline (NaCl). The sections are stained with hematoxylin-eosin (magnification 100-fold; the black vertical bar represents the thickness of the dermis).
The model of bleomycin-induced dermal fibrosis is very well documented and described, can be applied to numerous strains of mice, and is easy to use. A limitation of this model is that it is artificially induced, it is not associated with significant systemic involvement, and it tends to overestimate anti-fibrotic effect of anti-inflammatory agents [4].
Chronic graft-versus-host disease (GvHD) occurs in 40–60% of long-term survival patients following hematopoietic cell transplantation. Sclerodermatous (SclGvHD) and cytotoxic GvHD types are the two main subtypes of chronic GvHD [41]. SclGvHD is the fibrosing type, and its clinical manifestations are similar to the symptoms of the early inflammatory phase of diffuse cutaneous SSc. Induction of SclGvHD in mice is carried out in (a) a standard manner, when hematopoietic cells are transplanted into sublethally irradiated BALB/c mice or (b) a modified method, when hematopoietic cells are transplanted into immunodeficient recombinase-activating gene-2 (RAG-2) mice [42]. In both cases, SclGvHD is induced by a transplantation of hematopoietic cells of a donor to a recipient with identical major histocompatibility complex (MHC) but with different minor histocompatibility antigens. After reconstitution of hematopoiesis, SclGvHD is induced in the recipient with inflammation and fibrosis of the skin, lung, liver, kidney, gastrointestinal tract, and parotid gland. Besides inflammation and fibrosis, this model is also characterized by production of autoantibodies against nuclear antigens. In the pathogenesis of chronic SclGvHD, alloreactive CD4 T lymphocytes play a key role [43–47].
The advantage of this model is again a good documentation and systemic manifestations. The disadvantage is the need for sophisticated techniques and experience in dealing with problematic immunocompromised mice [4].
For understanding and examining immunological aspects of SSc, a mouse model was developed, based on the murine model of MRL/lpr, which primarily mimics the manifestations of systemic lupus erythematosus (SLE) and other pathological mechanisms of other systemic autoimmune diseases. The MRL/lpr mice are characterized by development of inflammatory involvement of tissues, such as immune complex-mediated vasculitis, arthritis, skin disease, and glomerulonephritis, which are accompanied by the production of autoantibodies [48]. On a molecular level, this model is based on a mutation in the gene encoding the Fas receptor belonging to a tumor necrosis factor (TNF) receptor family [49]. However, to induce symptoms of SSc in this model, a subsequent deletion of the interferon gamma (IFN-γ) receptor was introduced. MRL/lpr mice lacking IFN-γ receptor (MRL/lpγR−/−) are protected from the development of glomerulonephritis, which is often the cause of death of MRL/lpr mice. In fact, previous studies demonstrated the essential role of functional IFN-γ receptor for the development of glomerulonephritis in MRL/lpr mice [50]. In MRL/lpγR−/− mice, there is a number of pathological processes and clinical manifestations characteristic of SSc in humans. This mouse model (MRL/lpγR−/−) promotes the development of proliferative vasculopathy, particularly in the lung, and fibrosis in many organs including the skin, lungs, and kidneys [51]. Furthermore, this model is characterized by the presence of autoantibodies and mononuclear infiltrates in the skin, lungs, liver, and heart, accompanied by increased accumulation of collagen. Increased activation of fibroblasts was also observed in MRL/lpγR−/− mice [51].
This mouse model thus mimics the most typical symptoms for SSc, such as vasculopathy, inflammation, and the presence of autoimmunity.
Fra-2 is a member of a family of transcription factors called activator protein 1 (AP-1). AP-1 is a heterodimer composed of protein subunits belonging to the family of Fos (c-Fos, Fra-1, Fra-2, FosB) and Jun family (c-Jun, JunB, JunD), which regulate cell proliferation, inflammation, and wound healing via binding of AP-1 to the promoters of target genes [52]. Recent studies have reported a significant role of two members of the AP-1 family, Fra-2, and c-Jun on production of TGF-β and on its autocrine signaling in SSc fibroblasts [53, 54]. Overexpression of Fra-2 was also reported in patients with SSc, specifically in myofibroblasts, endothelial cells, and smooth muscle cells, suggesting a potential importance of Fra-2 in the pathogenesis of SSc [54, 55]. Increased expression of Fra-2 in mice leads to the development of systemic inflammation and fibrosis, especially in the skin and lungs. Fra-2 transgenic mice are also characterized by a vascular phenotype with increased apoptosis of endothelial cells of the capillaries, which appear in the ninth week after birth and lead to serious dysfunction of the small arteries of the skin and lungs. Subsequently, at 12 weeks of age, there is a significant development of dermal fibrosis, which correlates with progressive capillary loss [55]. Fra-2 is also highly expressed in the skin tissue of animal models of SSc. High expression of Fra-2 was detected in myofibroblasts in SSc skin lesions, suggesting a specific role of Fra-2 in fibroblast activation and subsequent transdifferentiation into myofibroblasts. Furthermore, it was demonstrated that silencing of Fra-2 gene leads to reduced production of type I collagen and inhibition of apoptosis but also to the development of angiogenesis in human microvascular endothelial cells [54, 55]. Histological changes of proliferative vasculopathy in the lungs of mice resemble pulmonary arterial hypertension in SSc in humans. Lung fibrosis and pulmonary arterial hypertension then lead to pulmonary insufficiency and increased mortality of mice [54, 55]. Pathological processes that are shared between pulmonary vascular involvement in Fra-2 transgenic mice and SSc in humans are further documented by constitutively activated PDGF signaling in murine pulmonary arteries. The key role of this pathway has been demonstrated by the administration of nilotinib, a tyrosine kinase inhibitor of the PDGF receptor, which prevents the development of proliferative vasculopathy and pulmonary fibrosis in Fra-2 transgenic mice [55].
The advantage of this model is the integration of characteristic vascular and fibrotic manifestations and a similar course of the disease as of SSc in humans. The disadvantages of Fra-2 transgenic mice comprise inadequate characterization of the model and the absence of autoimmunity [4].
Urokinase receptor belongs to glycoproteins anchored in the cell membrane via glycosylphosphatidylinositol (GPI) anchor, which is expressed on the surface of fibroblasts, endothelial cells, and lymphohematopoietic cells. The main task of the urokinase-type plasminogen activator receptor (uPAR) is binding the ligand urokinase-type plasminogen activator (uPA) at the interface of cells and matrix. uPA is an important part in the conversion of plasminogen to plasmin and activation of growth factors and matrix metalloproteinases. uPA/uPAR system plays a significant role in fibrinolysis, maintaining cellular homeostasis and angiogenesis. It also participates in many biological processes including differentiation, proliferation, and migration of cells through its interaction with membrane proteins and components of the ECM [56]. Relationship between SSc and uPAR was studied in dermal fibroblasts and endothelial cells obtained from SSc skin lesions, where a decrease in uPAR was detected compared to healthy control cells [57]. Recent studies have demonstrated the effect of inactivation of uPA/uPAR on transdifferentiation of fibroblasts into myofibroblasts and structural and functional changes in vasculature in SSc [58, 59]. uPAR−/− mice mimic fibrotic and vascular manifestations of SSc, which supports a significant role of the uPA/uPAR in the pathogenesis of SSc. In the 12th week, mice with inactivated uPA/uPAR system (uPAR−/−) develop progressive thickening of the skin with increased amount of collagen fibers and the number of activated fibroblasts, as well as the increased presence of perivascular inflammatory infiltrate compared to wild-type littermates. At the same time, fibrosis and perivascular fibrosis in the subcutaneous tissue develop [57]. In the skin of uPAR−/− mice, elevated levels of pro-fibrotic mediators, such as TGF-β and CTGF, were detected. Similar to Fra-2 murine models, uPAR−/− mice have an increased number of apoptotic endothelial cells, reduced number of functional blood vessels, and subsequent development of fibrosis, but do not develop fibroproliferative changes in arteries. During the 24th week, the skin changes stabilize and do not deteriorate [57]. The lung tissue is characterized by interstitial damage, infiltration of inflammatory cells, and excessive deposition of collagen, which is similar to the involvement in SSc patients with interstitial lung disease. Pulmonary involvement is already evident at 12 weeks, with progressive tendencies until the 24th week. This model is also characterized by cardiac involvement, which is also typical for SSc-related cardiomyopathy. This involvement is characterized by damage to cardiomyocytes, differentiation of myofibroblasts, apoptosis of endothelial cells, collagen accumulation, and myocardial fibrosis. However, cardiac involvement occurs later compared to the aforementioned manifestations [57].
Murine models with inactivated uPAR may be used as another preclinical model that mimics vascular changes, fibrosis of tissues similar to those in SSc but again lacks immunological processes typical of this disease [57].
In pulmonary fibrosis, the original functional lung tissue is being replaced by connective tissue which deteriorates the exchange of respiratory gases. The pathogenesis is characterized by damage to epithelial cells and alveolar hyperplasia, accumulation of inflammatory infiltrates, fibroblast hyperplasia, deposition of ECM components, and scarring [60]. Interstitial lung disease in SSc is most commonly characterized by nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) or organizing pneumonia with later development into NSIP [2]. The most frequently used experimental models of pulmonary fibrosis, which mimic some aspects of the human disease, include induction by bleomycin, silica, fluorescein isothiocyanate, and radiation.
To induce pulmonary fibrosis, bleomycin can be administered intratracheally or intranasally directly into the airways but also by subcutaneous, intraperitoneal, or intravenous injection. The principle of action of bleomycin is described in bleomycin-induced skin fibrosis [61]. The main advantage of the use of bleomycin is its availability, ease of administration, and yet the most accurate induction of symptoms of pulmonary fibrosis within 14–28 days (Figure 3). A limitation of this model is the fact that lung fibrosis wanes 28 days after intratracheal administration of bleomycin [61]. Many studies have confirmed that bleomycin-induced experimental pulmonary fibrosis is reversible, unlike pulmonary fibrosis in humans, and after 6 weeks, the animal presents with almost normal lung findings [62].
Fibrotic lung tissue (grey colour) of mice after intratracheal administration of bleomycin compared to control mice after intratracheal instillation of saline (NaCl). The sections are stained with sirius red (magnification 100-fold).
The instillation of silica into the lungs of mice causes the formation of fibrotic nodes and fibrosis, similar to lesions in humans exposed to long-term inhalation of silica dust and aerosol particles. Silica may be administered via an aerosol or intratracheally via oropharyngeal aspiration [60]. Induction of lung fibrosis is based on the activation of macrophages that phagocytose silica particles and begin to produce the pro-fibrotic cytokines PDGF and TGF-β [61]. The fibrotic response is dependent on the particular strain of mice [63]. The main benefit of this model is that the silica particles are not easily removed from the lungs and cause permanent fibrotic stimuli. The disadvantage of this model is that it lacks the characteristic signs of UIP. The experiment is also expensive and time-consuming due to the need for highly specialized equipment for administration of silica via aerosol and due to the development of the disease only during the 12th to 16th week after exposure [61].
Other chemicals used to induce pulmonary fibrosis include fluorescein isothiocyanate (FITC). FITC is administered directly into the respiratory tract, where it acts as a hapten that binds to the protein present in the lungs, resulting in a new persistent antigen and the subsequent formation of antibodies [61]. This association is used in immunofluorescence for localization of pulmonary fibrosis, which correlates closely with the areas of occurrence of the bound FITC. Administration of FITC increases infiltration of mononuclear cells and neutrophils, in particular in the area of the respiratory tract. In terms of pathogenesis, FITC is linked with the occurrence of acute lung injury, the development of edema, inflammation, and the subsequent development of fibrosis [63]. Induction of lung fibrosis by FITC is based on activation of chemokine receptor type 2 (CCR2) signaling [64]. Release of chemokines CCL12, and to a lesser extent CCL2, causes an increase in the number of fibrocytes expressing CCR2 in the affected lung, which leads to pulmonary fibrosis [65, 66]. FITC further induces increased production of pro-fibrotic cytokine IL-13 [67]. The advantage of this model is the visualization of fibrosis using the characteristic green fluorescence. Pulmonary involvement occurs within 14–28 days and persists for at least 6 months. Unfortunately, this model of pulmonary fibrosis has no characteristic findings of UIP [60].
Irradiation of mice also leads to the formation of pulmonary fibrosis, without the use of chemicals. Radiation induces direct cell death of type I and type II pneumocytes and the subsequent accumulation of macrophages at the site of damage. Macrophage activation triggers the production of pro-inflammatory and pro-fibrotic cytokines tumor necrosis factor alpha (TNF-α) and TGF-β, which participate in the formation of fibrosis [61]. Radiation-induced fibrosis has findings consistent with UIP and can only be performed in the C57B1/6 mouse model. The disadvantages of this method are the financial and time demands, since the interval from exposure to the development of the first symptoms is 30 weeks [60].
Pulmonary arterial hypertension (PAH) is a disease of pulmonary arteries caused by contraction and proliferation of smooth muscle cells of the vascular wall, which may occur alone (primary PAH) or accompany interstitial lung disease (secondary PAH) in SSc [2]. The most frequently used experimental models of PAH include a model induced by semaxanib with chronic hypoxia and monocrotaline and a model of athymic rats.
Chronic hypoxia, normally induced by the half fraction of inspired oxygen (i.e., FiO2 10%) for 21 days, leads, unfortunately, only to slight PAH, which is also reversible, unlike PAH in humans, and less pronounced in mice than rats. Furthermore, in mice hypoxia induces perivascular inflammatory infiltrates with the secretion of various pro-inflammatory cytokines and chemokines. Induction of more pronounced and irreversible PAH is achieved by the simultaneous administration of semaxanib (SU5416), a tyrosine kinase inhibitor of the type 1 receptor (Flt) and type 2 receptor (KDR) of vascular endothelial growth factor (VEGF), which was initially developed for cancer treatment [68]. SU5416 is an inhibitor of proliferation and triggers apoptosis of endothelial cells [69]. Paradoxically, however, blocking of VEGFR leads to an expansion of endothelial cells instead of inhibition of their proliferation. This is explained by a compensatory mechanism, when the inhibition of VEGFR is followed by upregulation of other growth factors such as fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) securing the proliferation of endothelial cells [69]. This model is frequently used for a sufficient understanding of the mechanism of hyperproliferation of endothelial cells, which is a characteristic of plexiform lesions of PAH in humans [70].
Monocrotaline (MCTP) is a toxic alkaloid found in the plant
Another commonly used model of PAH is SU5416 treatment of athymic rats. The initial assumption was that the models without T lymphocytes (athymic naked rnu/rnu rats) will exhibit less inflammation with less pronounced PAH. There was, however, paradoxically exactly the opposite, and these models have developed a far higher degree of involvement. Inflammation of the pulmonary artery is induced by activation of macrophages and B cells and the presence of anti-endothelial antibodies. The cause of the development of severe forms of pulmonary hypertension is the absence of anti-inflammatory regulatory T cells, which explains a predisposition for PAH in athymic rats [69].
Chickens of the line UCD-200 were originally isolated from the University of California Leghorn chickens, which had atrophic abnormalities of the comb. This line has systemic manifestations similar to the symptoms of SSc: skin involvement of the comb, neck, and back manifested as edema, Raynaud’s phenomenon-like changes, loss of skin adnexa, and skin thickening leading to necrosis [73]. This involvement develops between the first and second weeks after birth and culminates around the second to fourth week of life. Ischemic finger lesions occur in 20% of chickens, and digital ulcerations develop in later stages. There is also an internal organ involvement, particularly of the esophagus, heart, lung, and kidneys and an increased mortality. At around sixth week of age, the chickens develop glomerulonephritis and pericarditis [73, 74]. Histopathological changes are similar to those in SSc and include massive perivascular mononuclear infiltrates, particularly of T and B lymphocytes and deposition of ECM components by activated fibroblasts, signs of obliterative vasculopathy, and apoptosis of endothelial cells with loss of functional capillaries [73]. Subcutaneous adipose tissue is often replaced by collagen. UCD-200 chickens also produce autoantibodies, especially antinuclear, anti-centromere, and anti-phospholipid antibodies, rheumatoid factor, and antibodies to endothelial cells [74, 75]. UCD-206 chickens are similar to the chickens of the line UCD-200. However, they can develop more serious organ involvement [76].
The advantage of this model is the significant systemic involvement covering almost the complete spectrum of pathological processes and the disease course, which is similar to SSc in humans. While this model of SSc affects both sexes equally, in patients with SSc, women are affected more often. Another difference is the composition of mononuclear infiltrates,which consist, in particular, of monocytes/macrophages and T lymphocytes in humans [77]. The limitations of this model include the avian genetic background, which restricts the molecular studies, and, in particular, a very difficult and costly breeding [4].
One of the first available biological drugs with proven effects in other systemic rheumatic diseases, which were tested in preclinical models of SSc, was the anti-TNF agents. In in vitro experiments, a direct anti-fibrotic effect of TNF-α itself prevailed, while in in vivo experiments, on the contrary, using the TNF inhibitors prevented the development of bleomycin-induced fibrosis, which may be partly explained by the dominant inflammatory component in the model [78, 79]. Results of clinical trials of anti-TNF agents in SSc rather support the anti-fibrotic role of TNF-α itself, judging from progression of fibrosis in anti-TNF-treated SSc patients [80, 81]. Also other clinical trials failed to show significant improvement in skin scores and lung function using etanercept and infliximab, and, thus, the EUSTAR workgroup (EULAR Scleroderma Trials and Research) did not recommend the use of anti-TNF therapy in patients with SSc outside clinical trials [82–84].
The role of B lymphocytes and their depletion has also been studied in experimental models of SSc. Administration of rituximab to 3-day-old Tsk1 mice resulted in a reduction of skin fibrosis, whereas the same application to older, 56-day-old Tsk1 mice did not cause any change [85]. Similar reduction of the skin and pulmonary fibrosis induced by bleomycin was achieved in mice with genetic inactivation of CD19 [86]. Both studies document the effect of depletion of B cells on reduction of fibrosis rather in the early inflammatory phase of experimental SSc. The phase 2 clinical trial and observational study by EUSTAR documented the beneficial effects of rituximab on reduction of skin scores and lung function, but the results will need to be confirmed in a placebo-controlled randomized trial [87–92].
Another, in rheumatology, widely used type of therapy that has been tested in mouse models of SSc was the inhibition of interleukin (IL)-6. Numerous in vitro data demonstrated an increased production of IL-6 by SSc fibroblasts, and its important role as an inducer of activation of fibroblasts and collagen production, and ultimately point to the effective reduction of collagen synthesis through its inhibition [93–95]. In vivo inhibition of IL-6 with antibody against IL-6 receptor reduced the cutaneous fibrosis in a model of bleomycin-induced fibrosis and chronic GvHD, whereas in Tsk1 mice, no improvement was observed, which indicates rather anti-fibrotic effect in the early, inflammatory stage of experimental models of SSc [96–98]. The results of the phase 2/3 double-blind randomized placebo-controlled study faSScinate evaluating efficacy of tocilizumab in 87 patients with an active form of diffuse cutaneous SSc after 48 weeks of treatment showed a trend of reduction in skin scores (p = 0.06) and an encouraging stabilization of FVC (forced lung capacity) compared to placebo (p = 0.09) [99].
Tyrosine kinases such as the PDGF receptor (platelet-derived growth factor) constitute another interesting target of therapy in SSc. Numerous experimental studies demonstrate the anti-fibrotic effects of imatinib mesylate, a multikinase inhibitor (inhibitor of the kinases PDGFR, c-Abl, and c-Kit). In vitro, imatinib reduced the expression of pro-inflammatory and pro-fibrotic genes and collagen production by SSc fibroblasts [100, 101]. In vivo imatinib therapy prevented the development of cutaneous fibrosis induced by bleomycin and in Tsk1 mice and prevented the development of pulmonary, renal, and hepatic fibrosis, as well as reduced established dermal fibrosis [100, 102]. Similar results were obtained in vivo with other PDGFR inhibitors, such as nilotinib and dasatinib [103]. The first promising results from an open clinical trial with imatinib in SSc demonstrated significant improvement in skin scores and FVC after 12 months, however, with numerous side effects, particularly edema. Unfortunately, these findings were not confirmed in two other randomized placebo-controlled clinical trials, one of which was closed for numerous early side effects, and the other failed to show significant improvement in skin scores, and was accompanied by numerous side effects as well [104–106].
Another interesting target of anti-fibrotic therapies investigated in in vitro and in vivo experiments in SSc is a vasoactive small molecule riociguat, a stimulator of soluble guanylate cyclase (sGC). Treatment with riociguat led to a significant improvement in the primary outcome (6-min walking test) after 16 weeks of treatment of pulmonary arterial hypertension in the phase 3 PATENT-1 trial and also met a number of secondary outcomes [107]. In vitro experiments with riociguat resulted in a reduction of collagen synthesis by SSc fibroblasts in a dose-dependent manner. In in vivo experiments, riociguat prevented the development of cutaneous fibrosis induced by bleomycin, in Tsk1 mice, in a TβRI mouse model, and in SclGvHD in which it even reduced the gastrointestinal fibrosis. In the bleomycin-induced skin fibrosis model, riociguat was also shown to reduce the established fibrosis [108–110]. Effectiveness of riociguat in skin and pulmonary involvement is currently being evaluated in an ongoing phase 2 placebo-controlled randomized clinical trial RISE in patients with early diffuse cutaneous SSc.
Currently, there are several well-characterized experimental models through which we can study various pathological processes of SSc. The knowledge gained through animal models of SSc may bring new information and clarify previously unexplained pathogenic mechanisms of SSc. Animal models also serve as a promising tool for developing and testing new candidate molecules for the treatment of SSc. It must be stressed that none of the currently available experimental models includes all aspects of SSc in humans. Most of established models represent several pathologic mechanisms at once. Almost all models, except for a few focused only on vasculopathy, are characterized by severe tissue fibrosis. Conversely, only a few models are acceptable for studying damage to small arteries. It is therefore very important to carefully consider the selection of a suitable model or a combination of several models before commencing specific in vivo experiments. When the aim is to completely analyze the pathogenesis of the disease, it is suitable to prioritize models that mimic a wide spectrum of pathologies of SSc, such as Fra-2 transgenic mice or chicken lines UCD-200/206. For testing a new anti-fibrotic agent, it is preferable to start with a well-characterized model, such as bleomycin-induced fibrosis for inflammation and Tsk1 mice for fibrosis independent of inflammation. Ideally, both abovementioned models should be used for testing, and, subsequently, the efficiency should be checked on a more complex model, such as Fra-2 transgenic mice [4].
Systemic sclerosis represents a great unmet medical need due to its substantial morbidity and mortality and, to date, still missing efficient disease-modifying therapies. Finding novel effective therapeutic approaches requires better and more complex understanding of the pathogenesis of this heterogeneous multisystem disorder. The currently existing animal models of SSc, with their abovementioned limitations, still continue to serve as the basis for the vital preclinical studies of presently available and novel candidate targeted therapies before they can be used in clinical trials in humans. Furthermore, they will be essential for further in-depth analysis of the hallmark pathogenic mechanisms in SSc and for progress in hypothesis-driven and discovery research. In addition, with recent advances in genetic approaches, mapping of the human and murine genome, and novel data from the high-throughput sequencing of the biopsy samples from different subsets of SSc patients and healthy volunteers, there is a new window of opportunity for currently existing animal models to be further explored and used in more suitable and elaborate way and thus lead to vital progress in understanding the pathogenesis of SSc and providing new candidate therapies. Furthermore, the recent use of conditional genetic strategies in murine SSc models, through which particular genes of interest can be turned on/off in determined cell lineages at defined points of time, enables also for assessment of genes, which would have had lethal consequences if manipulated on germ-line level. These approaches also provide novel possibilities to examine modifications to specific cell lineages only and to assess their effect in experimental settings other than prevention (of induction of particular pathology), such as reversal or treatment (of established pathology). Progress in research strategies and new developments in existing animal models will inevitably lead to discovery of novel and more sophisticated animal models of SSc. In the future, a combination of genetic and induction strategies can lead to creation of experimental models which accurately, and to a greater extent, mimic SSc in humans and could lead to substantial clarification of pathological mechanisms and the discovery of a universal causal treatment of SSc. Nevertheless, the existing models have already contributed significantly to preclinical testing of several available biological agents and small molecules, some of which achieved promising results in early clinical studies and could provide better prospects for patients with this incurable disease.
This chapter was supported by grant projects AZV 16-33542A, AZV 16-33574A, SVV 260263, PRVOUK and the Ministry of Health of the Czech Republic [Research Project No. 00023728].
There is much evidence that significant changes in the body and fat weight in men with metabolic disorders, such as severe obesity and type 2 diabetes mellitus (DM2), and with long-term fasting can lead to the alteration in the hypothalamic-pituitary-gonadal (HPG) axis, as illustrated by the changed secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins, the reduced testosterone (T) production by Leydig cells and the impaired spermatogenesis. The alterations in the HPG axis, as a result, lead to infertility [1, 2, 3]. The relationship between the fat content and androgens level has been demonstrated in animals with obesity and DM2, as well as in fasting conditions [4, 5, 6]. All this indicates that adipocyte-produced factors can play an important role in controlling the HPG axis and in regulating the steroidogenesis in Leydig cells. Among these factors, the most interesting are adipokines, such as leptin, adiponectin, resistin and visfatin [3, 7, 8]. It is well known that in metabolic disorders, the plasma levels of these adipokines and the functional activity of adipokines-regulated signaling systems in the target tissues undergo significant changes, which can be considered to be one of the key causes of abnormalities in the HPG axis and androgen deficiency [9, 10, 11].
\nThe regulatory effects of the plasma, pituitary and testicular leptin on the male HPG axis and the testosterone synthesis in the testes in the norm and in the metabolic disorders. Abbreviations: p-Lep and t-Lep, the pituitary and testicular leptin; LepR, leptin receptor; GnRH, gonadotropin-releasing hormone; GnRH-R, receptor of GnRH; LH, luteinizing hormone; T, testosterone; AMPK, AMP-activated protein kinase; CREB, cAMP response element-binding protein; Nur77, c-Jun, c-Fos and Sf1, transcription factors Nur77, c-Jun, c-Fos and Sf1; SREBP1, sterol regulatory element-binding protein-1; cAMP-PDE, cAMP-specific phosphodiesterase; StAR, steroidogenic acute regulatory protein; P450scc and P450c17, cytochromes P450scc (P450 cholesterol side chain cleavage enzyme) and P450c17; 3β-HSD, 3β-hydroxysteroid dehydrogenase; α-MSH, α-melanocyte-stimulating hormone; AgRP, agouti-related peptide; NPY, neuropeptide Y; BBB, blood-brain barrier; BTB, blood-testicular barrier.
The regulatory effects of adiponectin circulating in the blood and adiponectin synthesized in the pituitary and testes on the activity of the male HPG axis and the testosterone production. Abbreviations: AdipoR1 and AdipoR2, adiponectin receptors of the types 1 and 2; ERK1/2, extracellular signal-regulated kinases 1/2; Sp1, transcription factor Sp1. The other abbreviations are the same as in
There is evidence that adipokines affect the different components of the male HPG axis. Transferred to the brain through the blood-brain barrier (BBB), adipokines act on the activity of hypothalamic GnRH-expressing neurons, thus changing the GnRH-stimulated production of luteinizing hormone (LH), the main regulator of T synthesis, by pituitary gonadotrophs [12, 13]. The adipokines can directly affect the gonadotrophs producing LH, and in this regulation both the adipokines circulating in the bloodstream and the adipokines synthesized within the pituitary can be involved [14, 15]. Some adipokines can also directly affect the functions of Leydig cells, as indicated by a high level of adipokines expression in the testes, as well as detection of the main components of the adipokine signaling, including adipokine-specific receptors, in testicular cells, including Leydig cells [16, 17, 18, 19]. The study of the effects of leptin, adiponectin and other adipokines on the male HPG axis and their role in the regulation of steroidogenesis is a major problem of clinical endocrinology and reproductive medicine. The solution of this problem will allow developing the new approaches for restoring the reproductive functions and androgen status in men with endocrine and metabolic disorders, which is based on the normalization of the adipokine signaling in the CNS and at the periphery.
\nThis review presents the comprehensive analysis of the involvement of leptin, adiponectin, resistin and visfatin in the regulation of the male HPG axis and steroidogenesis, as well as of the possible mechanisms of this regulation. The role of adipokines in the dysregulation of the male reproductive system and the impaired steroidogenic activity in the testes in obesity and DM2 are also discussed.
\nLeptin, a 167-amino acid polypeptide hormone encoded by the
The regulatory effects of leptin are realized due to its specific interaction with leptin receptors (Ob-R) that are generated by alternative splicing and include at least six isoforms [26]. The full-length isoform Ob-Rb is active and expressed in the hypothalamus with high intensity [27, 28]. The truncated isoforms, Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf are inactive, but retain the ability to bind to leptin at its excess. It is assumed that they carry out the receptor-mediated transport of leptin through the BBB and, possibly, through other tissue barriers [29, 30]. In the arcuate nuclei (ARC) of hypothalamus, leptin binds to Ob-Rb receptor, which leads to the phosphorylation of JAK2, a non-receptor tyrosine kinase, that phosphorylates the Tyr985, Tyr1077 and Tyr1138 residues located within the intracellular domain of Ob-Rb, each responsible for the activation of certain signaling cascade [23]. It has been shown that the phospho-Tyr985 is responsible for activation of Src Homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) and the mitogen-activated protein kinases (MAPK), such as extracellular signal-related kinases-1/2 (ERK1/2), c-Jun amino-terminal kinases (JNK) and p38-MAPK, which are involved in the regulation of cell growth and differentiation. The targets of MAPK are different transcription factors, including c-Fos, c-Jun and cAMP response element-binding protein (CREB), which control the expression of a large number of genes [3, 31]. The phospho-Tyr1138 is responsible for activation of the transcription factor STAT3 (signal transducer and activator of transcription-3) regulating the expression of genes involved in metabolic and growth processes. In turn, phospho-Tyr1077 induces the activation of the transcription factor STAT5, responsible for the regulation of energy metabolism and endocrine system [23, 32].
\nAnother mechanism of leptin action is the activation of 3-phosphoinositide pathway, which involves phosphatidylinositol-3-kinase (PI3K) and Akt kinase controlling the activity of the multi-component kinase mTOR complex 1. Since Akt-mediated inhibition of this complex in the hypothalamic ARC leads to a decrease in the expression of the
In the recent years, the evidence has been obtained that leptin plays a very important role in the control of male reproductive functions and puberty, which is based on leptin-mediated regulation of the HPG axis [8, 37]. The
A survey of men from Slovenia, Macedonia and Serbia with three different mononucleotide mutations within the
The mutations within the
The effects of leptin on the male HPG axis can be carried out at the level of hypothalamic neurons, pituitary gonadotrophs and testicular cells. It is important to note that the response of the HPG axis to leptin depends on the dose of this adipokine and the duration of treatment, the metabolic and hormonal status, as well as the functional state of the leptin signaling system in the target tissues. This is well illustrated by the data on the influence of leptin on the hypothalamic structures. It is shown that a single i.c.v. administration of leptin to ovariectomized female rats under starvation conditions, when the leptin level was reduced, led to a rapid increase in the plasma LH level, which demonstrates leptin-mediated stimulation of secretory activity of the GnRH-neurons [12, 46]. At the same time, under conditions of prolonged administration of leptin, an increase in LH level [47] or lack of leptin effect on LH secretion [48] were detected, which may be assumed to be due to varying degrees of leptin resistance in the case of long-term action of leptin on hypothalamic neurons. This was supported by the fact that the action of low, nanomolar concentrations of leptin on the ARC and the ventromedial nuclei of the hypothalamus led to an increase in the GnRH secretion, while high, micromolar leptin concentrations did not cause this effect [5, 37]. The i.c.v. administration of leptin to fasting cows led to an increase of both basal and GnRH-stimulated LH secretion, while the administration of leptin to fed animals with the increased leptin level did not induce significant changes in LH level [49, 50]. Thus, the stimulating effect of leptin on the HPG axis at the hypothalamic level was largely dependent on eating behavior, and was the main mechanism that mediates the relationship between the satiety and metabolic status, on the one hand, and the gonadotropins levels and activity of the steroidogenesis system, on the other.
\nThe central effects of leptin on the HPG axis are mediated through its interaction with leptin receptors located on hypothalamic ARC neurons expressing either pro-opiomelanocortin (POMC) or agouti-related peptide (AgRP) and neuropeptide Y (NPY). Due to activation of these neurons by leptin, the positive (POMC-neurons) or negative (AgRP/NPY-neurons) regulation of GnRH-neurons occurs, especially since these neurons themselves do not contain the receptor Ob-Rb and, therefore, can not be target for leptin (Figure 1).
\nLeptin-induced activation of ObRb located on the POMC-neurons leads to an increase in the production of POMC-derived melanocortin peptides, primarily α-melanocyte-stimulating hormone (α-MSH), an agonist of types 3 and 4 melanocortin receptors (MC3R and MC4R) [51]. The α-MSH binds to MC3/4R located on GnRH-neurons, and stimulates the GnRH secretion by them. In favor of this mechanism, there is evidence that the administration of leptin to the preoptic area of the hypothalamus leads simultaneously to an increase in α-MSH level and a stimulation of GnRH secretion [52]. The MC3/4R agonists, such as α-MSH and its analogue melanotan-II are also effective, increasing GnRH release [53, 54]. It should be noted that at least 70% of GnRH-neurons are activated by α-MSH [53]. Both MC3R and MC4R are involved in the effects of melanocortin peptides on GnRH-neurons, since mice lacking only one type of MCR remain capable of reproduction [55, 56].
\nAnother mechanism for leptin regulation of GnRH secretion, in which the melanocortin peptides also participate, is more complex. In accordance with this, in the first stage the melanocortin peptides secreted by POMC-neurons interact with MCR located on the KNDy-neurons. Kisspeptin released from KNDy-neurons binds to the kisspeptin receptors located on GnRH-neurons and stimulates GnRH secretion [57]. In the hypothalamic ARC, the outgrowths of POMC-neurons form the contacts with the bodies of KNDy-neurons, and a release of α-MSH by POMC-neurons causes a rapid depolarization of KNDy-neurons. Pharmacological inhibition of MC3R and MC4R by the antagonist SHU9119 decreases the expression of kisspeptin by 45%. The stimulating effect of melanotan-II on LH production in mice lacking the kisspeptin receptor GPR54 was reduced significantly [57].
\nThe AgRP, the endogenous MC3/4R antagonist, and NPY, both produced by the AgRP/NPY-neurons, mediate the inhibitory effect of leptin on LH production by pituitary gonadotrophs. However, the degradation of AgRP/NPY-neurons and the knockout of the
Leptin can stimulate LH production, acting directly on gonadotrophs (Figure 1). Unlike the hypothalamus, where leptin is mainly transferred from the bloodstream, its source in gonadotrophs can be either the plasma leptin or pituitary leptin synthesized by gonadotrophs [67, 68]. There is a good reason to believe that pituitary leptin functions as a paracrine and autocrine regulator controlling the survival and functional activity of gonadotrophs, since the plasma leptin can not mediate the complex pattern of pituitary hormone secretion [69]. This assumption is supported by the data obtained in mice with tissue-specific knockout of the
The functions of the autonomous leptin system in the pituitary, its participation in gonadotropins production and the relationship between the activity of this system and the physiological state of the HPG axis are supported by the following facts. The
Currently, there is evidence that leptin not only indirectly affects the steroidogenesis in Leydig cells through the regulation of the HPG axis but is also capable of directly affecting the activity of steroidogenesis system [3, 8]. The following facts support this: (1) the transport of leptin circulating in the bloodstream through the blood-testicular barrier (BTB) and the synthesis of leptin in the testicular cells; (2) the expression of leptin receptors and the presence of effector components of the leptin signaling in Leydig cells and (3) the results of the
In 1999, Banks and coauthors showed that leptin circulating in the blood was transported through the BTB, and the permeability was higher than in the case of the BBB [75]. Based on high rate of leptin transport through the BTB and high permeability of this barrier to other proteins, it was concluded that the mechanisms of leptin transport through the BBB and BTB differ significantly. However, taking into account the high density of the truncated isoform Ob-Ra of leptin receptor on the surface of endothelial cells forming the BTB, there is reason to believe that, like the BBB, leptin transport through the BTB is also a receptor-dependent [37]. In this case, one should expect its dependence on the activity of the leptin signaling system at the periphery and its decrease in the conditions of leptin resistance. Another source of intratesticular leptin was its synthesis in the testes of adult men and animals. The highest level of the
The effectors, whose activity is regulated by leptin through the activated forms of Ob-Rb and JAK2, control the activity of the transcription factors regulating the expression of steroidogenesis genes in different ways [3]. Leptin-induced stimulation of Akt-kinase and MAPK results in the phosphorylation and activation of the transcription factor CREB that is also activated by gonadotropins via cAMP-dependent pathways [81]. The activation of p38-MAPK and JNK leads to the stimulation of the transcription factors Nur77 and c-Jun [82, 83]. The main targets for these factors are the genes encoding StAR protein responsible for transport of cholesterol into the mitochondria and P450 cholesterol side chain cleavage enzyme (cytochrome P450scc) converting cholesterol to pregnenolone [84] (Figure 1). Along with this, the activation of MAPK cascade results in an increase in the expression of Sf-1 factor, the coactivator of expression of the gene encoding StAR and the genes
Leptin activation of the STAT3 and STAT5, as well as leptin-induced ERK1/2-dependent activation of the factor c-Fos lead to the opposite effect and suppress steroidogenesis in Leydig cells. An increase in ERK1/2 activity may be due to the prolonged leptin effect on the system Ob-Rb/JAK2 and, as a result, the activation of SHP-2 phosphatase, which affects the activity of MAPK cascade [89]. A decrease in T production by Leydig cells can be the result of AMPK activation, which suppresses the activity of sterol regulatory element-binding protein-1 (SREBP1) [90]. As is well known, SREBP1 positively regulates the
In addition to direct leptin effect on the expression of steroidogenesis genes, this adipokine can modulate the gonadotropin signaling pathways in Leydig cells, inducing an increase in gonadotropin-stimulated T production. It is well known that LH and human chorionic gonadotropin (hCG) specifically bind to LH/hCG receptors located on Leydig cells and stimulate the activity of adenylyl cyclase catalyzing cAMP synthesis, which leads to the activation of protein kinase A and CREB. Further, the level of intracellular cAMP is reduced due to its hydrolysis by cAMP-specific phosphodiesterases (cAMP-PDE), which leads to the attenuation of signal transduction generated by gonadotropins and inhibits their stimulating effect on steroidogenesis. Leptin suppresses the cAMP-PDE activity, maintaining the increased level of intracellular cAMP and thereby potentiates steroidogenic effect of gonadotropins (Figure 1). This is supported by the data that leptin enhances the stimulating effect of hCG on the cAMP level in rat Leydig cells [77].
\nAlong with the regulation of T synthesis in Leydig cells, leptin controls the mass and size of the testes, diameter of the seminiferous tubules and spermatogenesis and affects the survival of Leydig cells and other testicular cells [26, 93]. Leptin also regulates steroidogenesis in the ovaries and adrenal glands, and the mechanisms of its regulatory effect are believed to be similar to those in Leydig cells [37, 94].
\nIn men with obesity, metabolic syndrome and DM2, the activity of the male HPG axis and the T production are decreased, which lead to androgen deficiency [95, 96, 97]. Along with this, in diabetic men the plasma level of estrogens and the ratio of estrogen/T are significantly increased, which due to the increased activity of aromatase and the altered production of sex hormone-binding globulin [98, 99, 100, 101]. The elevated concentrations of reactive oxygen species and inflammatory factors lead to the damage in Leydig cells and reduce their steroidogenic activity [97, 102].
\nIn obesity and DM2, the plasma leptin level is significantly increased [103, 104], which leads to leptin resistance. As a result, the receptor-mediated transport of leptin through the BBB is reduced, which leads to a decrease in the intrahypothalamic leptin level and to a weakening of the regulatory effects of leptin on hypothalamic neurons and GnRH secretion (Figure 1). It is also not possible to exclude the possibility of reducing leptin transport through the BTB, although such data have not yet been obtained.
\nThe detailed study of the relationships between the leptin signaling and androgen deficiency in men with obesity and DM2 are not currently available. In rats with diet-induced obesity, severe hyperleptinemia and leptin resistance was associated with a decrease in the number of Leydig cells by 30%. This can be caused by the reduced intratesticular levels of leptin or the decreased sensitivity of testicular cells to this adipokine that participates in the regulation of survival and proliferation of Leydig cells (Figure 1). Although the plasma T level in obese male rats did not change, in the testes of animals it decreased by 25%, which was associated with a decrease in the expression of the
The deterioration of reproductive functions was found in mice with a knockout of the gene encoding the catalytic p110α-subunit of PI3K in the adipose tissue [106]. In the testes of 30-day knockout mice with severe hyperleptinemia, the expression of the gene encoding leptin was increased, while the expression of the genes encoding StAR and P450scc was reduced. Adult knockout mice had a severe form of hyperleptinemia, obesity, hepatic steatosis and the impaired glucose tolerance, and were infertile. It was quite unexpected that in the testes of knockout animals the expression of the
Polypeptide hormone adiponectin is produced mainly by the adipose tissue [109, 110], but despite this, the plasma adiponectin level is negatively correlated with the body mass index and the reserves of adipose tissue [111]. The plasma level of adiponectin is characterized by gender specificity and significantly lowers in males, which is true for humans and rodents [112]. Adiponectin can be synthesized not only by the adipose tissue but also by the brain, pituitary, testes and others [17, 113]. Adiponectin is consists of a variable N-terminal domain, a large globular C-terminal domain and a collagenous domain located between them, containing 22 collagenous Gly-XY repeats [114, 115, 116]. Using the collagenous repeats, adiponectin molecules interact with each other to form the homotrimeric complexes that aggregate into the hexamers and high-molecular complexes similar to those in the case of tumor necrosis factor-α (TNF-α) [117]. To form the trimeric complex, hydroxylation of the proline and lysine residues in the collagenous repeats is necessary, since the lack of this modification does not allow the formation of such complex and leads to a loss in the adiponectin activity [118, 119]. High-molecular complexes of adiponectin are stabilized by disulfide bonds formed between the trimers [120]. The trimeric, hexameric and high-molecular complexes are present in the bloodstream, while the monomeric forms are found in trace amounts [115, 121, 122, 123]. Post-translational modifications of adiponectin and its oligomerization significantly affect the bioavailability, binding characteristics and pattern of specific activity of adiponectin [115, 120, 123, 124, 125].
\nThe tissues, the targets of adiponectin, express the adiponectin receptors AdipoR1 and AdipoR2, which bind specifically to various forms of adiponectin with different affinity [111, 125, 126, 127]. Despite the fact that both these receptors seven times penetrate the plasma membrane, like classical G protein-coupled receptors, they differ significantly from them in membrane topology, having the extracellular C-terminal domain and the intracellular N-terminal domain. In addition, the adiponectin receptors interact with APPL proteins (adaptor protein, phosphotyrosine interacting with plekstrin-homologous domain and leucine zipper), but not with heterotrimeric G-proteins. The AdipoR1 binds with a high affinity to the truncated globular form of adiponectin and with a low affinity with the oligomeric and high-molecular forms of full-length adiponectin, while AdipoR2 binds with an intermediate affinity to both the full-length and globular forms. The both receptors interact with two isoforms of the APPL proteins, APPL-1 and APPL-2 [128, 129]. The interaction of adiponectin-activated AdipoR1 with APPL-1 leads to the activation of AMPK and the 3-phosphoinositide and MAPK cascades. The APPL-2 forms a complex with APPL-1 and prevents APPL-1-mediated regulations. When adiponectin binds to AdipoR1, the APPL-1/APPL-2 complex dissociates, resulting in the release of APPL-1 to interact with the downstream effector proteins [116, 130].
\nAdiponectin is able to control steroidogenic function in the testes directly, acting on Leydig cells, and indirectly, acting on the HPG axis at the hypothalamic and pituitary levels. To interact with hypothalamic neurons, the main target of adiponectin in the CNS, it is necessary to transport adiponectin into the brain through the BBB. It is suggested that the receptor-mediated transport of adiponectin through the BBB can be carried out through the AdipoR1 and AdipoR2 receptors located on the endothelium of cerebral vessels (Figure 2). In addition, a large number of adiponectin receptors and the components of adiponectin-regulated signaling pathways have been identified in the ARC and paraventricular nuclei of the hypothalamus [131, 132, 133, 134] and in other brain areas [13]. Adiponectin is easily transferred from the bloodstream to the brain and cerebrospinal fluid (CSF), although its concentration in the CSF is low, being only 0.1% of that in the blood [132, 133, 134, 135]. In obesity, which was characterized by the reduced plasma level of adiponectin [134, 136, 137], its concentration in the brain areas was also decreased [134]. It should be noted that, as in the case of circulating adiponectin, a negative correlation was found between the adiponectin level in the CSF and the body mass [133, 134]. Thus, unlike leptin, intracerebral adiponectin deficiency in obesity is caused by a reduced level of this adipokine in the blood. Although there is evidence that adiponectin can be synthesized in the CNS [17, 113], the greatest, if not all, amount of this adipokine comes from the periphery, and the intracerebral level of adiponectin depends on the activity of adiponectin-transporting system of the brain.
\nUpon binding to adiponectin receptors in neurons of the paraventricular nuclei and the periventricular region of the hypothalamus, adiponectin activates AMPK [13, 138], decreases the activity of ERK1/2 [13], causes a weakening of the calcium-dependent signaling pathways and inhibits the hyperpolarization-activated cationic currents responsible for pacemaker activity of GnRH-neurons [139]. It is important to note that the inhibition of ERK1/2 activity is due to an increase in AMPK activity [13]. The main result of adiponectin action on GnRH-neurons is a decrease in the synthesis and secretion of GnRH and, as a consequence, a decreased LH production by gonadotrophs [13, 139] (Figure 2).
\nAdiponectin also interacts with the KNDy-neurons expressing kisspeptin. Adiponectin-induced increase in AMPK activity in these neurons results in the inhibition of AMPK-dependent transport of the transcription factor SP1 into the nucleus, which is illustrated by SP1 accumulation in the cytoplasm. As a result, the expression of the
The inhibitory effect of adiponectin on LH production can be carried out at the pituitary level, since both adiponectin receptors were detected in the LH-expressing gonadotrophs of human and rats [14, 142, 143]. In addition, the expression of the
As noted above, the expression of the
The main regulators of the
The AdipoR2 was located on the surface of Leydig cells, while AdipoR1 was found in the epithelium of the seminiferous tubules. In spermatozoa there are both types of the adiponectin receptors [17, 148, 149]. The
All of the above indicates that adiponectin positively regulates the T synthesis (Figure 2). Indeed, treatment of the MA-10 Leydig cells with adiponectin at the concentrations of 50–5000 ng/mL resulted in an increase in the production of progesterone, a precursor of T, which was associated with cAMP-dependent activation of StAR and cytochrome P450scc [151]. In the earlier studies, it was shown that adiponectin, acting on the testes, suppressed both the basal and hCG-stimulated T production, although the expression of the steroidogenesis enzymes, such as cytochrome P450scc and dehydrogenases 3β-HSD and 17β-HSD3, did not change [17, 148]. The mechanisms of adiponectin action on Leydig cells include the stimulation of PI3K and Akt kinase, which results in the changed expression of Akt-dependent genes, as well as the regulation of ERK1/2, whose activity decreases at low concentrations of adiponectin and increases at its high concentrations [148]. It can be assumed that the dependence of adiponectin effect on ERK1/2 on its concentration, as well as a set of the effector components of MAPK cascade regulated by adiponectin are responsible for the different mode of the regulation of steroidogenesis by this adipokine. The treatment of Leydig cells with adiponectin did not affect the expression of LH receptor, and this indicates the preservation of the sensitivity of these cells to gonadotropins [148].
\nVisfatin produced by the adipose tissue is a multifunctional protein that functions as a signal molecule and as a nicotinamide phosphoribosyltransferase (NAMPT) catalyzing the synthesis of nicotinamide adenine mononucleotide from nicotinamide and 5-phosphoribosyl-1-pyrophosphate [152, 153, 154]. In humans, visfatin includes 491 amino acids and forms a functionally active homodimer complex [10, 155, 156]. Paradoxically, the receptor for visfatin has not yet been found. It is known that the main targets of visfatin, as in the case of most other adipokines, are the MAPK and PI3K/Akt pathway, and the activation of Akt kinase occurs 5 min after treatment of cells with visfatin [156, 157, 158].
\nThe highest concentration of visfatin is detected in the white adipose tissue. In obesity and DM2, the plasma visfatin level is steadily increased, and the degree of this increase varies greatly, due to both the individual characteristics of patients and the various approaches to measure the visfatin concentration [2, 155]. The visfatin level is also increases in women with a polycystic ovary syndrome, for which obesity and insulin resistance are characteristic [155]. Despite an increase in the plasma level of visfatin, its concentration in the CSF decreases, and this is probably due to the impaired transport of visfatin through the BBB. These data suggest that, as in the case of leptin and insulin, the transport of visfatin into the brain can be receptor-mediated, and decreases in the conditions of visfatin resistance.
\nThe data on the involvement of visfatin in regulation of the reproductive system are mainly related to the female HPG axis, folliculogenesis and steroidogenesis in the ovaries [7]. There is a positive correlation between the visfatin level in follicular fluid and the quantity and quality of the follicles [159]. It is assumed that the effect of visfatin on the ovarian steroidogenesis system can be realized via the mechanisms that lead to an increase in the production of insulin-like growth factor-1 (IGF-1), a stimulator of steroidogenesis [138]. In this case, the effects of visfatin are characterized by species specificity. The introduction of recombinant human visfatin into chicken did not stimulate, but, on the contrary, suppressed the basal and IGF-1-stimulated expression of the
In the case of the male reproductive axis, the targets for visfatin may be all of its components. Information on the central mechanisms of action of visfatin is limited to its effect on the hypothalamic neurons responsible for control of glucose homeostasis [160]. However, the fact that visfatin, like leptin, affects the activity of 3-phosphoinositide pathway, supports its possible participation in the regulation of GnRH-neurons activity. The evidences were obtained in favor of the regulation of LH-expressing pituitary gonadotrophs by visfatin. Firstly, the mRNA for visfatin was detected in gonadotrophs, which indicates its synthesis in them and the role of visfatin in the autocrine and paracrine regulation of the anterior pituitary. Secondly, visfatin stimulates the AMPK activity in the cultured murine gonadotroph-like cells LβT2, resulting in a decrease in LH secretion [161].
\nThe ability of visfatin to influence the testicular functions and the T synthesis is supported by the following data. Visfatin is expressed in Leydig cells, spermatocytes and spermatozoa [19], and its level in the seminal fluid is much higher than in the blood [162]. When exposed to Leydig cells, visfatin increases the T production, and the maximal effect of visfatin is achieved at its concentration of 10−6 M [163]. The inhibitor of Raf-1 kinase reduces the stimulating effect of visfatin on steroidogenesis, while the inhibitors of the protein kinases A and C have a little influence on this effect. It is assumed that the effects of visfatin on steroidogenesis may be due to activation of insulin receptors [163], which are widely represented in Leydig cells, especially since previously it has been reported that insulin receptor can interact with visfatin [154, 164]. However, despite the similarity of regulatory effects of insulin and visfatin, in the recent years the ability of visfatin specifically binds to insulin receptor has been questioned [157].
\nResistin is a polypeptide with a molecular mass of 12.5 kDa, which forms a homodimer stabilized by disulfide bonds [138]. Although resistin is mainly secreted by adipocytes of the white and brown adipose tissues and macrophages [165, 166], its expression is also shown in the testes in the Sertoli and Leydig cells, which indicates the participation of resistin in the autocrine and paracrine regulation of testicular cells [16]. The expression of the
The level of resistin in the bloodstream, from which it is able to be transported to the testes, varies greatly depending on the metabolic status, gender and species. Fasting leads to a decrease in the plasma resistin level and the
Using the primary culture of pituitary cells of rhesus monkey it was shown that resistin activates a number of signaling pathways, including cAMP-dependent and 3-phosphoinositide cascades regulating the cell survival and secretory activity. Resistin affects the secretion of growth hormone and adrenocorticotropic hormone, although LH secretion remains unchanged. It should be noted, however, that the treatment of pituitary cells with leptin and adiponectin also did not affect LH secretion, which is probably due to the peculiarities of cultured cells used in the experiment [174].
\nResistin was found in the brain and CSF, and although its concentration was much lower than in the bloodstream, it can be assumed that resistin affects the activity of hypothalamic neurons controlling GnRH secretion [116, 133]. One of the mechanisms of this may be the influence of resistin on the adiponectin signaling in hypothalamic neurons. A prolonged i.c.v. administration of resistin into rats and mice results in a decrease in the expression of both types of adiponectin receptors, AdipoR1 and AdipoR2, and also reduces the functional activity of APPL-1 protein, thereby weakening the APPL-1-mediated adiponectin signaling. There is reason to believe that this effect of resistin is implemented through the receptor TLR4, since the inhibiting effect of resistin on the adiponectin signaling was not detected in mice lacking TLR4 [175].
\nThe
The regulation of the male gonadal axis by adipokines can be carried out both through the changes in the plasma level and bioavailability of adipokines produced (a systemic regulation) and through the changes in the expression and specific activity of adipokines in the target tissues, the components of the HPG axis, such as the hypothalamus, pituitary and testes (an autonomous regulation). In the case of systemic adipokines regulation, the changes in the plasma level of adipokines that are associated with feeding behavior, physiological conditions, and also with an imbalance of adipokines and a resistance to them in obesity, DM2 and other metabolic disorders directly affect the functional activity of the male HPG axis and T production. Of great importance is the activity of the adipokine-transporting system, which transfers the adipokines through the BBB into the brain, where they regulate the GnRH- and KNDy-neurons involved in GnRH secretion, and also through the BTB into the testes, where they control the steroidogenesis system and the synthesis of T, the main effector hormone of the male HPG axis. In the case of autonomous regulation, the adipokines synthesized in the pituitary and testes function as the autocrine and paracrine factors and to a large extent determine functional activity of the components of the HPG axis. On the one hand, they regulate proliferation and survival of gonadotrophs and testicular cells, primarily Leydig cells, and on the other, affect their ability to produce gonadotropins and steroid hormones. It is important to note that between the systemic and autonomous adipokine-mediated regulation of the male HPG axis there are the complex integrative relationships and interactions that are realized at different levels of this axis. As a consequence, the changes in the pattern and levels of adipokines in the bloodstream can be differently associated with activity of the hypothalamic, pituitary and testicular components of the HPG axis, since in this case it is necessary to take into account the functional state of autonomous adipokine systems. The ratio of different adipokines in the blood and in the tissues, the components of the HPG axis, contributes significantly to the resulting effects of adipokines on the reproductive system, since their effects on the male HPG axis, including the testicular steroidogenesis system, may be synergistic or antagonistic.
\nThe study of the role of adipokines in the regulation of the male HPG axis is of great interest, since it will allow in the future to develop the effective approaches for monitoring functional activity of the male reproductive system and correcting the dysfunctions in this system in metabolic and endocrine disorders, including obesity and DM2. The adipokines and their analogues, as well as regulators and modulators of their signaling cascades in the hypothalamic neurons and testes, can be used as potential drugs to improve the reproductive functions and to normalize the steroidogenesis in men. It is also important how the treatment of men with GnRH analogous, gonadotropins with LH-like activity and androgens will affect the systemic and autonomic regulation of the GPH axis by adipokines. This should be taken into account when developing the approaches to improve metabolic status in obese and diabetic patients and in elderly men with an androgen deficiency using the activators of the HPG axis and androgens. The study of the interaction between the male HPG axis and the adipokine system will allow us to decipher the fundamental mechanisms that determine the relationships between the eating behavior, hunger and satiety, on the one hand, and the sexual behavior and aggression, on the other.
\nThis work was supported by the Russian Foundation of Basic Investigations (project No 18-515-45004 IND-a).
\nConflicts of interest are absent.
General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed.
',metaTitle:"Horizon 2020 Compliance",metaDescription:"General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed. ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\\n\\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\\n\\nIn other words, publishing with IntechOpen guarantees compliance.
\\n\\nRead more about Open Access in Horizon 2020 here.
\\n\\nWhich scientific publication to choose?
\\n\\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\\n\\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\\n\\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\n\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\n\nIn other words, publishing with IntechOpen guarantees compliance.
\n\nRead more about Open Access in Horizon 2020 here.
\n\nWhich scientific publication to choose?
\n\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\n\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\n\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5816},{group:"region",caption:"Middle and South America",value:2,count:5281},{group:"region",caption:"Africa",value:3,count:1754},{group:"region",caption:"Asia",value:4,count:10511},{group:"region",caption:"Australia and Oceania",value:5,count:906},{group:"region",caption:"Europe",value:6,count:15913}],offset:12,limit:12,total:119061},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"1175"},books:[],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:26},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:8},{group:"topic",caption:"Business, Management and Economics",value:7,count:3},{group:"topic",caption:"Chemistry",value:8,count:11},{group:"topic",caption:"Computer and Information Science",value:9,count:9},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:9},{group:"topic",caption:"Engineering",value:11,count:25},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:7},{group:"topic",caption:"Mathematics",value:15,count:2},{group:"topic",caption:"Medicine",value:16,count:45},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:4},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:0},popularBooks:{featuredBooks:[{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9629",title:"Electroencephalography",subtitle:"From Basic Research to Clinical Applications",isOpenForSubmission:!1,hash:"8147834b6c6deeeec40f407c71ad60b4",slug:"electroencephalography-from-basic-research-to-clinical-applications",bookSignature:"Hideki Nakano",coverURL:"https://cdn.intechopen.com/books/images_new/9629.jpg",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8445",title:"Dam Engineering",subtitle:"Recent Advances in Design and Analysis",isOpenForSubmission:!1,hash:"a7e4d2ecbc65d78fa7582e0d2e143906",slug:"dam-engineering-recent-advances-in-design-and-analysis",bookSignature:"Zhongzhi Fu and Erich Bauer",coverURL:"https://cdn.intechopen.com/books/images_new/8445.jpg",editors:[{id:"249577",title:"Dr.",name:"Zhongzhi",middleName:null,surname:"Fu",slug:"zhongzhi-fu",fullName:"Zhongzhi Fu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8937",title:"Soil Moisture Importance",subtitle:null,isOpenForSubmission:!1,hash:"3951728ace7f135451d66b72e9908b47",slug:"soil-moisture-importance",bookSignature:"Ram Swaroop Meena and Rahul Datta",coverURL:"https://cdn.intechopen.com/books/images_new/8937.jpg",editors:[{id:"313528",title:"Associate Prof.",name:"Ram Swaroop",middleName:null,surname:"Meena",slug:"ram-swaroop-meena",fullName:"Ram Swaroop Meena"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7031",title:"Liver Pathology",subtitle:null,isOpenForSubmission:!1,hash:"631321b0565459ed0175917f1c8c727f",slug:"liver-pathology",bookSignature:"Vijay Gayam and Omer Engin",coverURL:"https://cdn.intechopen.com/books/images_new/7031.jpg",editors:[{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8158",title:"Veganism",subtitle:"a Fashion Trend or Food as a Medicine",isOpenForSubmission:!1,hash:"d8e51fc25a379e5b92a270addbb4351d",slug:"veganism-a-fashion-trend-or-food-as-a-medicine",bookSignature:"Miljana Z. Jovandaric",coverURL:"https://cdn.intechopen.com/books/images_new/8158.jpg",editors:[{id:"268043",title:"Dr.",name:"Miljana Z.",middleName:"Z",surname:"Jovandaric",slug:"miljana-z.-jovandaric",fullName:"Miljana Z. Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5315},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9629",title:"Electroencephalography",subtitle:"From Basic Research to Clinical Applications",isOpenForSubmission:!1,hash:"8147834b6c6deeeec40f407c71ad60b4",slug:"electroencephalography-from-basic-research-to-clinical-applications",bookSignature:"Hideki Nakano",coverURL:"https://cdn.intechopen.com/books/images_new/9629.jpg",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8445",title:"Dam Engineering",subtitle:"Recent Advances in Design and Analysis",isOpenForSubmission:!1,hash:"a7e4d2ecbc65d78fa7582e0d2e143906",slug:"dam-engineering-recent-advances-in-design-and-analysis",bookSignature:"Zhongzhi Fu and Erich Bauer",coverURL:"https://cdn.intechopen.com/books/images_new/8445.jpg",editors:[{id:"249577",title:"Dr.",name:"Zhongzhi",middleName:null,surname:"Fu",slug:"zhongzhi-fu",fullName:"Zhongzhi Fu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8937",title:"Soil Moisture Importance",subtitle:null,isOpenForSubmission:!1,hash:"3951728ace7f135451d66b72e9908b47",slug:"soil-moisture-importance",bookSignature:"Ram Swaroop Meena and Rahul Datta",coverURL:"https://cdn.intechopen.com/books/images_new/8937.jpg",editors:[{id:"313528",title:"Associate Prof.",name:"Ram Swaroop",middleName:null,surname:"Meena",slug:"ram-swaroop-meena",fullName:"Ram Swaroop Meena"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7031",title:"Liver Pathology",subtitle:null,isOpenForSubmission:!1,hash:"631321b0565459ed0175917f1c8c727f",slug:"liver-pathology",bookSignature:"Vijay Gayam and Omer Engin",coverURL:"https://cdn.intechopen.com/books/images_new/7031.jpg",editors:[{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editedByType:"Edited by",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editedByType:"Edited by",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9536",title:"Education at the Intersection of Globalization and Technology",subtitle:null,isOpenForSubmission:!1,hash:"0cf6891060eb438d975d250e8b127ed6",slug:"education-at-the-intersection-of-globalization-and-technology",bookSignature:"Sharon Waller, Lee Waller, Vongai Mpofu and Mercy Kurebwa",coverURL:"https://cdn.intechopen.com/books/images_new/9536.jpg",editedByType:"Edited by",editors:[{id:"263302",title:"Dr.",name:"Sharon",middleName:null,surname:"Waller",slug:"sharon-waller",fullName:"Sharon Waller"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editedByType:"Edited by",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9629",title:"Electroencephalography",subtitle:"From Basic Research to Clinical Applications",isOpenForSubmission:!1,hash:"8147834b6c6deeeec40f407c71ad60b4",slug:"electroencephalography-from-basic-research-to-clinical-applications",bookSignature:"Hideki Nakano",coverURL:"https://cdn.intechopen.com/books/images_new/9629.jpg",editedByType:"Edited by",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editedByType:"Edited by",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9524",title:"Organ Donation and Transplantation",subtitle:null,isOpenForSubmission:!1,hash:"6ef47e03cd4e6476946fc28ca51de825",slug:"organ-donation-and-transplantation",bookSignature:"Vassil Mihaylov",coverURL:"https://cdn.intechopen.com/books/images_new/9524.jpg",editedByType:"Edited by",editors:[{id:"313113",title:"Associate Prof.",name:"Vassil",middleName:null,surname:"Mihaylov",slug:"vassil-mihaylov",fullName:"Vassil Mihaylov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9280",title:"Underwater Work",subtitle:null,isOpenForSubmission:!1,hash:"647b4270d937deae4a82f5702d1959ec",slug:"underwater-work",bookSignature:"Sérgio António Neves Lousada",coverURL:"https://cdn.intechopen.com/books/images_new/9280.jpg",editedByType:"Edited by",editors:[{id:"248645",title:"Dr.",name:"Sérgio António",middleName:null,surname:"Neves Lousada",slug:"sergio-antonio-neves-lousada",fullName:"Sérgio António Neves Lousada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editedByType:"Edited by",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8158",title:"Veganism",subtitle:"a Fashion Trend or Food as a Medicine",isOpenForSubmission:!1,hash:"d8e51fc25a379e5b92a270addbb4351d",slug:"veganism-a-fashion-trend-or-food-as-a-medicine",bookSignature:"Miljana Z. Jovandaric",coverURL:"https://cdn.intechopen.com/books/images_new/8158.jpg",editedByType:"Edited by",editors:[{id:"268043",title:"Dr.",name:"Miljana Z.",middleName:"Z",surname:"Jovandaric",slug:"miljana-z.-jovandaric",fullName:"Miljana Z. Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1021",title:"Hepatology",slug:"gastroenterology-hepatology",parent:{title:"Gastroenterology",slug:"gastroenterology"},numberOfBooks:56,numberOfAuthorsAndEditors:1687,numberOfWosCitations:492,numberOfCrossrefCitations:385,numberOfDimensionsCitations:921,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"gastroenterology-hepatology",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"7888",title:"Hepatitis A and Other Associated Hepatobiliary Diseases",subtitle:null,isOpenForSubmission:!1,hash:"e027bb08025546d9beb242d55e87c84c",slug:"hepatitis-a-and-other-associated-hepatobiliary-diseases",bookSignature:"Costin Teodor Streba, Cristin Constantin Vere, Ion Rogoveanu, Valeria Tripodi and Silvia Lucangioli",coverURL:"https://cdn.intechopen.com/books/images_new/7888.jpg",editedByType:"Edited by",editors:[{id:"55546",title:"Dr.",name:"Costin Teodor",middleName:"Teodor",surname:"Streba",slug:"costin-teodor-streba",fullName:"Costin Teodor Streba"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7887",title:"Hepatitis B and C",subtitle:null,isOpenForSubmission:!1,hash:"8dd6dab483cf505d83caddaeaf497f2c",slug:"hepatitis-b-and-c",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/7887.jpg",editedByType:"Edited by",editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8330",title:"Nonalcoholic Fatty Liver Disease",subtitle:"An Update",isOpenForSubmission:!1,hash:"d0f8ff2a0673b7be22f7e7c531a2e410",slug:"nonalcoholic-fatty-liver-disease-an-update",bookSignature:"Emad Hamdy Gad",coverURL:"https://cdn.intechopen.com/books/images_new/8330.jpg",editedByType:"Edited by",editors:[{id:"222727",title:"Associate Prof.",name:"Emad Hamdy",middleName:null,surname:"Gad",slug:"emad-hamdy-gad",fullName:"Emad Hamdy Gad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8838",title:"Liver Cirrhosis",subtitle:"Debates and Current Challenges",isOpenForSubmission:!1,hash:"17163eb18a082da0fe70ccc20b7fe69a",slug:"liver-cirrhosis-debates-and-current-challenges",bookSignature:"Georgios Tsoulfas",coverURL:"https://cdn.intechopen.com/books/images_new/8838.jpg",editedByType:"Edited by",editors:[{id:"57412",title:"Prof.",name:"Georgios",middleName:null,surname:"Tsoulfas",slug:"georgios-tsoulfas",fullName:"Georgios Tsoulfas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6718",title:"Hepatitis C",subtitle:"From Infection to Cure",isOpenForSubmission:!1,hash:"7448805e61bfa52ce552c427ad6f16fc",slug:"hepatitis-c-from-infection-to-cure",bookSignature:"Imran Shahid",coverURL:"https://cdn.intechopen.com/books/images_new/6718.jpg",editedByType:"Edited by",editors:[{id:"188219",title:"Prof.",name:"Imran",middleName:null,surname:"Shahid",slug:"imran-shahid",fullName:"Imran Shahid"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6663",title:"Management of Chronic Liver Diseases",subtitle:"Recent Advances",isOpenForSubmission:!1,hash:"833ebcb9a2596f81deff0246ed7c9642",slug:"management-of-chronic-liver-diseases-recent-advances",bookSignature:"Xingshun Qi",coverURL:"https://cdn.intechopen.com/books/images_new/6663.jpg",editedByType:"Edited by",editors:[{id:"197501",title:"Dr.",name:"Xingshun",middleName:null,surname:"Qi",slug:"xingshun-qi",fullName:"Xingshun Qi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6440",title:"Liver Research and Clinical Management",subtitle:null,isOpenForSubmission:!1,hash:"e4bbd66ccead286ab737f23feb053cf8",slug:"liver-research-and-clinical-management",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/6440.jpg",editedByType:"Edited by",editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6073",title:"Non-Alcoholic Fatty Liver Disease",subtitle:"Molecular Bases, Prevention and Treatment",isOpenForSubmission:!1,hash:"6141320881651ddc40a3f35893c209e7",slug:"non-alcoholic-fatty-liver-disease-molecular-bases-prevention-and-treatment",bookSignature:"Rodrigo Valenzuela",coverURL:"https://cdn.intechopen.com/books/images_new/6073.jpg",editedByType:"Edited by",editors:[{id:"72355",title:"Prof.",name:"Rodrigo",middleName:null,surname:"Valenzuela Baez",slug:"rodrigo-valenzuela-baez",fullName:"Rodrigo Valenzuela Baez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5931",title:"Stomach Disorders",subtitle:null,isOpenForSubmission:!1,hash:"489f823dd49e3fa397e477a8101ca4ff",slug:"stomach-disorders",bookSignature:"Jianyuan Chai",coverURL:"https://cdn.intechopen.com/books/images_new/5931.jpg",editedByType:"Edited by",editors:[{id:"28281",title:"Dr.",name:"Jianyuan",middleName:null,surname:"Chai",slug:"jianyuan-chai",fullName:"Jianyuan Chai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5714",title:"Esophageal Abnormalities",subtitle:null,isOpenForSubmission:!1,hash:"132a5e5097b78a76535fde4196596ac9",slug:"esophageal-abnormalities",bookSignature:"Jianyuan Chai",coverURL:"https://cdn.intechopen.com/books/images_new/5714.jpg",editedByType:"Edited by",editors:[{id:"28281",title:"Dr.",name:"Jianyuan",middleName:null,surname:"Chai",slug:"jianyuan-chai",fullName:"Jianyuan Chai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6061",title:"Ascites",subtitle:"Physiopathology, Treatment, Complications and Prognosis",isOpenForSubmission:!1,hash:"ead9b3e5c36413f9ff2c3129fbc57574",slug:"ascites-physiopathology-treatment-complications-and-prognosis",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/6061.jpg",editedByType:"Edited by",editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6014",title:"Update on Hepatitis C",subtitle:null,isOpenForSubmission:!1,hash:"b812442f63938a061f1c84b2338bb187",slug:"update-on-hepatitis-c",bookSignature:"Martina Smolic, Aleksandar Vcev and George Y. Wu",coverURL:"https://cdn.intechopen.com/books/images_new/6014.jpg",editedByType:"Edited by",editors:[{id:"172734",title:"Dr.",name:"Martina",middleName:null,surname:"Smolic",slug:"martina-smolic",fullName:"Martina Smolic"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"3",chapterContentType:"chapter",authoredCaption:"Authored by"}}],booksByTopicTotal:56,mostCitedChapters:[{id:"46479",doi:"10.5772/57353",title:"Floating Drug Delivery Systems for Eradication of Helicobacter pylori in Treatment of Peptic Ulcer Disease",slug:"floating-drug-delivery-systems-for-eradication-of-helicobacter-pylori-in-treatment-of-peptic-ulcer-d",totalDownloads:2046,totalCrossrefCites:85,totalDimensionsCites:196,book:{slug:"trends-in-helicobacter-pylori-infection",title:"Trends in Helicobacter pylori Infection",fullTitle:"Trends in Helicobacter pylori Infection"},signatures:"Yousef Javadzadeh and Sanaz Hamedeyazdan",authors:[{id:"94276",title:"Prof.",name:"Yousef",middleName:null,surname:"Javadzadeh",slug:"yousef-javadzadeh",fullName:"Yousef Javadzadeh"},{id:"98229",title:"Dr.",name:"Sanaz",middleName:null,surname:"Hamedeyazdan",slug:"sanaz-hamedeyazdan",fullName:"Sanaz Hamedeyazdan"}]},{id:"22945",doi:"10.5772/17640",title:"Pathophysiology of Gastric Ulcer Development and Healing: Molecular Mechanisms and Novel Therapeutic Options",slug:"pathophysiology-of-gastric-ulcer-development-and-healing-molecular-mechanisms-and-novel-therapeutic-",totalDownloads:11792,totalCrossrefCites:8,totalDimensionsCites:21,book:{slug:"peptic-ulcer-disease",title:"Peptic Ulcer Disease",fullTitle:"Peptic Ulcer Disease"},signatures:"Matteo Fornai, Luca Antonioli, Rocchina Colucci, Marco Tuccori and Corrado Blandizzi",authors:[{id:"28973",title:"Prof.",name:"Corrado",middleName:null,surname:"Blandizzi",slug:"corrado-blandizzi",fullName:"Corrado Blandizzi"},{id:"44227",title:"Dr.",name:"Matteo",middleName:null,surname:"Fornai",slug:"matteo-fornai",fullName:"Matteo Fornai"},{id:"44229",title:"Dr.",name:"Luca",middleName:null,surname:"Antonioli",slug:"luca-antonioli",fullName:"Luca Antonioli"},{id:"44230",title:"Dr.",name:"Rocchina",middleName:null,surname:"Colucci",slug:"rocchina-colucci",fullName:"Rocchina Colucci"},{id:"44231",title:"Dr.",name:"Marco",middleName:null,surname:"Tuccori",slug:"marco-tuccori",fullName:"Marco Tuccori"}]},{id:"35446",doi:"10.5772/47946",title:"Delivery of Probiotic Microorganisms into Gastrointestinal Tract by Food Products",slug:"delivery-of-probiotic-microorganisms-into-gastrointestinal-tract-by-food-products",totalDownloads:5861,totalCrossrefCites:0,totalDimensionsCites:19,book:{slug:"new-advances-in-the-basic-and-clinical-gastroenterology",title:"New Advances in the Basic and Clinical Gastroenterology",fullTitle:"New Advances in the Basic and Clinical Gastroenterology"},signatures:"Amir Mohammad Mortazavian, Reza Mohammadi and Sara Sohrabvandi",authors:[{id:"97458",title:"Dr.",name:"Amir M.",middleName:null,surname:"Mortazavian",slug:"amir-m.-mortazavian",fullName:"Amir M. Mortazavian"},{id:"99974",title:"Dr.",name:"Sarah",middleName:null,surname:"Sohrabvandi",slug:"sarah-sohrabvandi",fullName:"Sarah Sohrabvandi"}]}],mostDownloadedChaptersLast30Days:[{id:"45493",title:"Biliary Dyspepsia: Functional Gallbladder and Sphincter of Oddi Disorders",slug:"biliary-dyspepsia-functional-gallbladder-and-sphincter-of-oddi-disorders",totalDownloads:5553,totalCrossrefCites:3,totalDimensionsCites:4,book:{slug:"dyspepsia-advances-in-understanding-and-management",title:"Dyspepsia",fullTitle:"Dyspepsia - Advances in Understanding and Management"},signatures:"Meena Mathivanan, Liisa Meddings and Eldon A. Shaffer",authors:[{id:"165693",title:"Dr.",name:"Eldon",middleName:null,surname:"Shaffer",slug:"eldon-shaffer",fullName:"Eldon Shaffer"}]},{id:"56262",title:"Anatomy of Esophagus",slug:"anatomy-of-esophagus",totalDownloads:2872,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"esophageal-abnormalities",title:"Esophageal Abnormalities",fullTitle:"Esophageal Abnormalities"},signatures:"Murat Ferhat Ferhatoglu and Taner Kıvılcım",authors:[{id:"200126",title:"M.D.",name:"Murat Ferhat",middleName:null,surname:"Ferhatoglu",slug:"murat-ferhat-ferhatoglu",fullName:"Murat Ferhat Ferhatoglu"},{id:"206240",title:"Dr.",name:"Taner",middleName:null,surname:"Kivilcim",slug:"taner-kivilcim",fullName:"Taner Kivilcim"}]},{id:"56068",title:"Minimally Invasive Esophagectomy",slug:"minimally-invasive-esophagectomy",totalDownloads:924,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"esophageal-abnormalities",title:"Esophageal Abnormalities",fullTitle:"Esophageal Abnormalities"},signatures:"Rafael Cholvi Calduch, Isabel Mora Oliver, Fernando Lopez Mozos\nand Roberto Martí Obiol",authors:[{id:"203292",title:"Ph.D.",name:"Fernando",middleName:null,surname:"Lopez",slug:"fernando-lopez",fullName:"Fernando Lopez"},{id:"203687",title:"Dr.",name:"Roberto",middleName:null,surname:"Martí",slug:"roberto-marti",fullName:"Roberto Martí"},{id:"204943",title:"Dr.",name:"Rafael",middleName:null,surname:"Cholvi",slug:"rafael-cholvi",fullName:"Rafael Cholvi"},{id:"204944",title:"Dr.",name:"Isabel",middleName:null,surname:"Mora",slug:"isabel-mora",fullName:"Isabel Mora"}]},{id:"21425",title:"Histopathological Diagnosis of Non-Alcoholic and Alcoholic Fatty Liver Disease",slug:"histopathological-diagnosis-of-non-alcoholic-and-alcoholic-fatty-liver-disease",totalDownloads:2948,totalCrossrefCites:2,totalDimensionsCites:2,book:{slug:"liver-biopsy-in-modern-medicine",title:"Liver Biopsy in Modern Medicine",fullTitle:"Liver Biopsy in Modern Medicine"},signatures:"Andrea Tannapfel and Berenike Flott-Rahmel",authors:[{id:"34863",title:"Dr.",name:"Andrea",middleName:null,surname:"Tannapfel",slug:"andrea-tannapfel",fullName:"Andrea Tannapfel"},{id:"53108",title:"Prof.",name:"Berenike",middleName:null,surname:"Flott-Rahmel",slug:"berenike-flott-rahmel",fullName:"Berenike Flott-Rahmel"}]},{id:"55879",title:"Portal Hypertensive Gastropathy (PHG)",slug:"portal-hypertensive-gastropathy-phg-",totalDownloads:1115,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"stomach-disorders",title:"Stomach Disorders",fullTitle:"Stomach Disorders"},signatures:"Samia Ali Gamie",authors:[{id:"204157",title:"Prof.",name:"Samia",middleName:null,surname:"Ali Abdo Gamie",slug:"samia-ali-abdo-gamie",fullName:"Samia Ali Abdo Gamie"}]},{id:"57005",title:"Health-Related Quality of Life in Antiviral-Treated Chronic Hepatitis C Patients",slug:"health-related-quality-of-life-in-antiviral-treated-chronic-hepatitis-c-patients",totalDownloads:988,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"update-on-hepatitis-c",title:"Update on Hepatitis C",fullTitle:"Update on Hepatitis C"},signatures:"Aleksandar Včev, Jelena Jakab, Lucija Kuna and Martina Smolić",authors:[{id:"154595",title:"Prof.",name:"Aleksandar",middleName:null,surname:"Vcev",slug:"aleksandar-vcev",fullName:"Aleksandar Vcev"},{id:"172734",title:"Dr.",name:"Martina",middleName:null,surname:"Smolic",slug:"martina-smolic",fullName:"Martina Smolic"},{id:"204953",title:"Ms.",name:"Lucija",middleName:null,surname:"Kuna",slug:"lucija-kuna",fullName:"Lucija Kuna"},{id:"205159",title:"Dr.",name:"Jelena",middleName:null,surname:"Jakab",slug:"jelena-jakab",fullName:"Jelena Jakab"}]},{id:"55818",title:"Tissue Engineering of Esophagus",slug:"tissue-engineering-of-esophagus",totalDownloads:998,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"esophageal-abnormalities",title:"Esophageal Abnormalities",fullTitle:"Esophageal Abnormalities"},signatures:"Yabin Zhu, Mi Zhou and Ruixia Hou",authors:[{id:"40618",title:"Prof.",name:"Yabin",middleName:null,surname:"Zhu",slug:"yabin-zhu",fullName:"Yabin Zhu"}]},{id:"55045",title:"Hemodynamic Optimization Strategies in Anesthesia Care for Liver Transplantation",slug:"hemodynamic-optimization-strategies-in-anesthesia-care-for-liver-transplantation",totalDownloads:1298,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"liver-cirrhosis-update-and-current-challenges",title:"Liver Cirrhosis",fullTitle:"Liver Cirrhosis - Update and Current Challenges"},signatures:"Alexander A. Vitin, Dana Tomescu and Leonard Azamfirei",authors:[{id:"201176",title:"Associate Prof.",name:"Alexander",middleName:null,surname:"Vitin",slug:"alexander-vitin",fullName:"Alexander Vitin"},{id:"202442",title:"Dr.",name:"Dana",middleName:null,surname:"Tomescu",slug:"dana-tomescu",fullName:"Dana Tomescu"},{id:"202600",title:"Prof.",name:"Leonard",middleName:null,surname:"Azamfirei",slug:"leonard-azamfirei",fullName:"Leonard Azamfirei"}]},{id:"56177",title:"Nutritional Management of Esophageal Cancer Patients",slug:"nutritional-management-of-esophageal-cancer-patients",totalDownloads:1240,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"esophageal-abnormalities",title:"Esophageal Abnormalities",fullTitle:"Esophageal Abnormalities"},signatures:"Dimitrios Schizas, Irene Lidoriki, Demetrios Moris and Theodore\nLiakakos",authors:[{id:"203349",title:"Dr.",name:"Dimitrios",middleName:null,surname:"Schizas",slug:"dimitrios-schizas",fullName:"Dimitrios Schizas"},{id:"204000",title:"MSc.",name:"Irene",middleName:null,surname:"Lidoriki",slug:"irene-lidoriki",fullName:"Irene Lidoriki"},{id:"204001",title:"Dr.",name:"Demetrios",middleName:null,surname:"Moris",slug:"demetrios-moris",fullName:"Demetrios Moris"},{id:"204002",title:"Prof.",name:"Theodore",middleName:null,surname:"Liakakos",slug:"theodore-liakakos",fullName:"Theodore Liakakos"}]},{id:"46479",title:"Floating Drug Delivery Systems for Eradication of Helicobacter pylori in Treatment of Peptic Ulcer Disease",slug:"floating-drug-delivery-systems-for-eradication-of-helicobacter-pylori-in-treatment-of-peptic-ulcer-d",totalDownloads:2046,totalCrossrefCites:86,totalDimensionsCites:196,book:{slug:"trends-in-helicobacter-pylori-infection",title:"Trends in Helicobacter pylori Infection",fullTitle:"Trends in Helicobacter pylori Infection"},signatures:"Yousef Javadzadeh and Sanaz Hamedeyazdan",authors:[{id:"94276",title:"Prof.",name:"Yousef",middleName:null,surname:"Javadzadeh",slug:"yousef-javadzadeh",fullName:"Yousef Javadzadeh"},{id:"98229",title:"Dr.",name:"Sanaz",middleName:null,surname:"Hamedeyazdan",slug:"sanaz-hamedeyazdan",fullName:"Sanaz Hamedeyazdan"}]}],onlineFirstChaptersFilter:{topicSlug:"gastroenterology-hepatology",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/215048/shalom-guy-slutsky",hash:"",query:{},params:{id:"215048",slug:"shalom-guy-slutsky"},fullPath:"/profiles/215048/shalom-guy-slutsky",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()