\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5319",leadTitle:null,fullTitle:"Wetting and Wettability",title:"Wetting and Wettability",subtitle:null,reviewType:"peer-reviewed",abstract:"On the liquid 's surface, the molecules have fewer neighbors in comparison with the bulk volume. As a result, the energy interaction shows itself in the surface tension. Traditionally, the surface tension can be assumed as a force in the unit of the length which can be counted by the unit of Newton on squared meter, or energy on the units of the surface. The surface tension, implies the interface between liquid and vapor, which is an example of the surface tensions. The equilibrium between these surface tensions, decides that a droplet on a solid surface, would have a droplet form or will change to layer form. This book collects new developments in wetting and wettability science.",isbn:null,printIsbn:"978-953-51-2215-9",pdfIsbn:"978-953-51-6647-4",doi:"10.5772/62031",price:139,priceEur:155,priceUsd:179,slug:"wetting-and-wettability",numberOfPages:384,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"49767cc09f266bd5bdf55f4a5c57792b",bookSignature:"Mahmood Aliofkhazraei",publishedDate:"December 16th 2015",coverURL:"https://cdn.intechopen.com/books/images_new/5319.jpg",numberOfDownloads:36280,numberOfWosCitations:134,numberOfCrossrefCitations:69,numberOfCrossrefCitationsByBook:4,numberOfDimensionsCitations:174,numberOfDimensionsCitationsByBook:4,hasAltmetrics:0,numberOfTotalCitations:377,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 20th 2015",dateEndSecondStepPublish:"December 11th 2015",dateEndThirdStepPublish:"March 16th 2016",dateEndFourthStepPublish:"June 14th 2016",dateEndFifthStepPublish:"July 14th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"155413",title:"Dr.",name:"Mahmood",middleName:null,surname:"Aliofkhazraei",slug:"mahmood-aliofkhazraei",fullName:"Mahmood Aliofkhazraei",profilePictureURL:"https://mts.intechopen.com/storage/users/155413/images/3939_n.jpg",biography:"Dr. Mahmood Aliofkhazraei works in the corrosion and surface engineering group at the Tarbiat Modares University. He is the head of Aliofkhazraei research group (www.aliofkhazraei.com). Dr. Aliofkhazraei has received several honors, including the Khwarizmi award and the best young nanotechnologist award of Iran. He is a member of the National Association of Surface Sciences, Iranian Corrosion Association, and National Elite Foundation of Iran. His research focuses on materials science, nanotechnology, and its use in surface and corrosion science.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"13",institution:{name:"Tarbiat Modares University",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"961",title:"Fluid Dynamics",slug:"surface-science-fluid-dynamics"}],chapters:[{id:"48704",title:"Water Vapor Adsorption and Soil Wetting",doi:"10.5772/60953",slug:"water-vapor-adsorption-and-soil-wetting",totalDownloads:2e3,totalCrossrefCites:5,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Soil water management and irrigation practices largely depend on a timely and accurate characterization of temporal and spatial soil moisture dynamics in the root zone. Consequently, measurements and detailed information about soil water sorption, water content, behavior, and potential are required. In that concern, water vapor adsorption is an important phenomenon in arid and semi-arid regions, as well as in dry periods of tropical soils. Therefore, quantifying adsorption is important for agricultural water management, surface energy balance studies, ecological studies, and remote sensing investigations (changes in surface soil moisture content will affect land surface properties such as albedo, emissivity, and thermal inertia). The vapor pressure and isothermal adsorption of water vapor can be used to predict soil moisture adsorption capacity (Wa), specific surface area, and hydro-physical properties of arid soils such as in Egypt and in the tropical soils in Ecuador. Theory of adsorption of water vapor on soil particles is developed among the mono-molecular and poly-molecular adsorption with respect to Brunauer, Emmett, and Teller (BET) theory. Data of soil-water adsorption (W%) at different relative vapor pressures (P/Po) can be obtained for the soils, where the W% values are increased with increasing P/Po in general. The highest values of water adsorption capacity (Wa), specific surface area (S), and other hygro-physical properties such as adsorbed layers and maximum hygroscopic water are observed in the clay depths of soil profiles, while the lowest values can be found in coarse textured soils (sandy and sandy loam soils profiles). Two equations were assumed: (1) to predict P/Po at water adsorption capacity (Wa) and (2) to apply Wa in prediction of soil moisture retention, i.e., ψ (W) function at pF < 4.5.",signatures:"Abdelmonem Mohamed Ahmed Amer",downloadPdfUrl:"/chapter/pdf-download/48704",previewPdfUrl:"/chapter/pdf-preview/48704",authors:[{id:"173965",title:"Dr.",name:"Abdelmonem",surname:"Amer",slug:"abdelmonem-amer",fullName:"Abdelmonem Amer"}],corrections:null},{id:"48806",title:"Wetting Properties at Nanometer Scale",doi:"10.5772/60886",slug:"wetting-properties-at-nanometer-scale",totalDownloads:2169,totalCrossrefCites:4,totalDimensionsCites:10,hasAltmetrics:0,abstract:"The proposed chapter reviews a series of experimental techniques which enable the accurate quantitative study of wetting properties. The introductive part presents some of the many phenomena and processes influenced by wetting, underlining the importance of understanding the fundamental science involved. A few historical considerations about the quantitative study of wetting and related phenomena are given. Next, some of the “classical” techniques employed for studies at the macroscopic scale are presented. The importance of studies of such phenomena at micro- and nanometer level is underlined, as a consequence of the enormous influence that micro- and nanodevices play in our day to day activities, and examples of quantitative studies, involving various measurement techniques, are given from literature. A description of the basic phenomena related to polarization forces in Scanning Polarization Force Microscopy (SPFM) technique is given, followed by experimental details concerning the actual implementation of the technique. Examples of applications of SPFM are given from literature (from the spreading of liquid crystals on solid substrates to studies of corrosion at nanometer level). Particularly, it is emphasized how this versatile technique was successfully used for direct measurements of contact angles for liquid micro- and nano-droplets, enabling the calculation of the dependence of surface potential energy between the surfaces, the spreading coefficient and the disjoining pressure for micro- and nano-droplets.",signatures:"Antoniu Moldovan and Marius Enachescu",downloadPdfUrl:"/chapter/pdf-download/48806",previewPdfUrl:"/chapter/pdf-preview/48806",authors:[{id:"174358",title:"Prof.",name:"Marius",surname:"Enăchescu",slug:"marius-enachescu",fullName:"Marius Enăchescu"},{id:"174363",title:"MSc.",name:"Antoniu",surname:"Moldovan",slug:"antoniu-moldovan",fullName:"Antoniu Moldovan"}],corrections:null},{id:"48768",title:"TiO2 -Based Surfaces with Special Wettability – From Nature to Biomimetic Application",doi:"10.5772/60826",slug:"tio2-based-surfaces-with-special-wettability-from-nature-to-biomimetic-application",totalDownloads:5046,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Super-wetting/antiwetting surfaces with extremely high contrast of surface energy and liquid adhesion have attracted a lot of interest in both fundamental research and industry. Various types of special wetting surfaces can be constructed by adjusting the topographical structure and chemical composition. In this chapter, recent advance of the super-wetting/antiwetting surfaces with special solid/liquid adhesion has been reviewed, with a focus on the biomimetic fabrication and applications of TiO2-based surfaces. Special super-wettability examples include lotus-leaf-inspired surfaces with low adhesion, rose-petal-inspired surfaces with high adhesion, spider silk bio-inspired surfaces with directional adhesion, fish-scale-inspired underwater superoleophobic surface, and artificial surfaces with controllable or stimuli-responsive liquid adhesion. In addition, we will review some potential applications related to artificial antiwetting surface with controllable adhesion, e.g., self-cleaning, antifogging/anti-icing, micro-droplet manipulation, fog/water collection, water/oil separation, anti-bioadhesion, micro-template for patterning, and friction reduction. Finally, the difficulty and prospects of this renascent and rapidly developing field are also briefly proposed and discussed.",signatures:"Jian-Ying Huang and Yue-Kun Lai",downloadPdfUrl:"/chapter/pdf-download/48768",previewPdfUrl:"/chapter/pdf-preview/48768",authors:[{id:"175512",title:"Prof.",name:"Yuekun",surname:"Lai",slug:"yuekun-lai",fullName:"Yuekun Lai"}],corrections:null},{id:"48690",title:"Increased Wettability and Surface Free Energy of Polyurethane by Ultraviolet Ozone Treatment",doi:"10.5772/60798",slug:"increased-wettability-and-surface-free-energy-of-polyurethane-by-ultraviolet-ozone-treatment",totalDownloads:2791,totalCrossrefCites:7,totalDimensionsCites:11,hasAltmetrics:0,abstract:"The wettability of polyurethane (PU) was altered using ultraviolet ozone (UVO) treatment. The effect of UVO treatment on PU surface chemistry was investigated with various experiments. The direct measurement of sessile drops was employed to quantify the static contact angle of different wetting liquids on homogeneous PU films with various UV ozone treatment times. The contact angle of DI water droplets was decreased to 17.2º from 70.04º after 5min UVO treatment. The surface free energy of PU films was 51.46mN/m prior to treatment and was increased to 71.5mN/m after being fully treated. X-ray Photoelectron Spectroscopy (XP) analysis shows a significant amount of polar functional species (C-O and C=O bonding) were formed on the PU surface by UVO treatment. Atomic Force Microscopy (AFM) characterization shows the PU surface morphology was different before and after UVO treatment. The effect of water washing on UVO treated surface was also investigated. An aging effect study indicates the UV ozone modification can sustain the improved wettability with limited hydrophobic recovery, where the DI water contact angle remains constant at around 22º after the UVO treatment.",signatures:"Ping Kuang and Kristen Constant",downloadPdfUrl:"/chapter/pdf-download/48690",previewPdfUrl:"/chapter/pdf-preview/48690",authors:[{id:"57927",title:"Prof.",name:"Kristen",surname:"Constant",slug:"kristen-constant",fullName:"Kristen Constant"},{id:"174381",title:"Dr.",name:"Ping",surname:"Kuang",slug:"ping-kuang",fullName:"Ping Kuang"}],corrections:null},{id:"48976",title:"Wetting and Navier-Stokes Equation — The Manufacture of Composite Materials",doi:"10.5772/61167",slug:"wetting-and-navier-stokes-equation-the-manufacture-of-composite-materials",totalDownloads:1908,totalCrossrefCites:3,totalDimensionsCites:13,hasAltmetrics:0,abstract:"It is well known that there are several processes to manufacture composite materials, a large part of which consist in the infiltration of a liquid (matrix) through a porous medium (reinforcement). To perform these processes, both thermodynamics (wetting) and kinetics (Navier-Stokes) must be considered if a good quality composite material is sought. Although wetting and the laws that govern it have been well known for over 200 years, dating back to the original works of Young and Laplace, this is not the case with the Navier-Stokes equation, which remains so far unsolved. Although the Navier-Stokes equation, which describes the motion of a fluid, has been solved for many particular cases, such as the motion of a fluid through a pipe, which has resulted in the well-known Poiseuille equation, or the motion of a fluid through a porous media, described by the Darcy’s law (empirical law obtained by Darcy), its general solution remains one of the greatest challenges of mathematicians today. Therefore, the objective of this chapter is to present the resolution of the Navier-Stokes equation with the laws of wetting for different cases of interest in the manufacture of composite materials.",signatures:"Mario Caccia, Antonio Camarano, Danilo Sergi, Alberto Ortona and\nJavier Narciso",downloadPdfUrl:"/chapter/pdf-download/48976",previewPdfUrl:"/chapter/pdf-preview/48976",authors:[{id:"173917",title:"Prof.",name:"Javier",surname:"Narciso",slug:"javier-narciso",fullName:"Javier Narciso"}],corrections:null},{id:"48818",title:"Modification of Surface Energy and Wetting of Textile Fibers",doi:"10.5772/60812",slug:"modification-of-surface-energy-and-wetting-of-textile-fibers",totalDownloads:3110,totalCrossrefCites:7,totalDimensionsCites:15,hasAltmetrics:0,abstract:"The modification of the surface energy of textile fibers to improve functional properties such as the wettability was reviewed. This modification can be achieved by physical or chemical methods or by the combination of both. Applications of plasma treatment to improve the wettability of natural and synthetic fibers were considered and some methods of wettability measurement were mentioned. Subsequently the methods aimed to confer water and oil repellency were discussed and the treatment by UV curing of fluorochemicals was explained in detail. Finally the sol-gel techniques useful to modify the surface properties of textiles were introduced and the results of water and oil repellency achievable by sol-gel were presented.",signatures:"Franco Ferrero and Monica Periolatto",downloadPdfUrl:"/chapter/pdf-download/48818",previewPdfUrl:"/chapter/pdf-preview/48818",authors:[{id:"173940",title:"Prof.",name:"Franco",surname:"Ferrero",slug:"franco-ferrero",fullName:"Franco Ferrero"},{id:"174224",title:"Ph.D.",name:"Monica",surname:"Periolatto",slug:"monica-periolatto",fullName:"Monica Periolatto"}],corrections:null},{id:"48911",title:"Surface Energy and Wetting in Island Films",doi:"10.5772/60900",slug:"surface-energy-and-wetting-in-island-films",totalDownloads:2302,totalCrossrefCites:4,totalDimensionsCites:7,hasAltmetrics:0,abstract:"The chapter describes the fundamental aspects of the effects of scale on surface phenomena in condensed films. Experimental and theoretical data for the size and temperature dependencies of the surface energy (including the solid phase); wetting of solid surfaces and free thin films by small metal particles are discussed. Several modern methods of contact angle measurement in small-sized systems based on the optical and electron microscopy methods are described.",signatures:"Sergei Dukarov, Aleksandr Kryshtal and Vladimir Sukhov",downloadPdfUrl:"/chapter/pdf-download/48911",previewPdfUrl:"/chapter/pdf-preview/48911",authors:[{id:"174176",title:"Dr.",name:"Aleksandr",surname:"Kryshtal",slug:"aleksandr-kryshtal",fullName:"Aleksandr Kryshtal"},{id:"174271",title:"Dr.",name:"Sergei",surname:"Dukarov",slug:"sergei-dukarov",fullName:"Sergei Dukarov"},{id:"174272",title:"Dr.",name:"Vladimir",surname:"Sukhov",slug:"vladimir-sukhov",fullName:"Vladimir Sukhov"}],corrections:null},{id:"48822",title:"Wettability of Nanostructured Surfaces",doi:"10.5772/60808",slug:"wettability-of-nanostructured-surfaces",totalDownloads:3129,totalCrossrefCites:11,totalDimensionsCites:32,hasAltmetrics:0,abstract:"There are many studies in literature concerning contact angle measurements on different materials/substrates. It is documented that textiles can be coated with multifunctional materials in form of thin films or nanoparticles to acquire characteristics that can improve the protection and comfort of the wearer. The capacity of oxide nanostructures to inhibit fungal development and neutralize bacteria is a direct consequence of their wetting behavior [1–6]. Moreover, the radical modification of wetting behavior of nanostructures from hydrophilic to hydrophobic when changing the pulsed laser deposition (PLD) ambient will be thoroughly discussed.",signatures:"L. Duta, A.C. Popescu, I. Zgura, N. Preda and I.N. Mihailescu",downloadPdfUrl:"/chapter/pdf-download/48822",previewPdfUrl:"/chapter/pdf-preview/48822",authors:[{id:"17636",title:"Prof.",name:"Ion N.",surname:"Mihailescu",slug:"ion-n.-mihailescu",fullName:"Ion N. Mihailescu"},{id:"23532",title:"Dr.",name:"Andrei",surname:"Popescu",slug:"andrei-popescu",fullName:"Andrei Popescu"},{id:"174343",title:"Dr.",name:"Liviu",surname:"Duta",slug:"liviu-duta",fullName:"Liviu Duta"},{id:"174344",title:"Dr.",name:"Irina",surname:"Zgura",slug:"irina-zgura",fullName:"Irina Zgura"},{id:"174345",title:"Dr.",name:"Ligia",surname:"Frunza",slug:"ligia-frunza",fullName:"Ligia Frunza"}],corrections:null},{id:"48833",title:"Wetting Behavior of Dental Implants",doi:"10.5772/61098",slug:"wetting-behavior-of-dental-implants",totalDownloads:2441,totalCrossrefCites:2,totalDimensionsCites:9,hasAltmetrics:0,abstract:"Titanium (Ti) and titanium alloys are widely used in biomedical devices and components, because of their desirable properties, such as relatively low modulus, good fatigue strength, formability, machinability, corrosion resistance, and biocompatibility. However, Ti and its alloys cannot meet all of the clinical requirements. Therefore, surface modification of Ti has been often performed to improve the biological, chemical, and mechanical properties. Various modifications of surface properties have been investigated to predictably improve the osseointegration of Ti implants. The rate and quality of osseointegration in Ti implants are related to their surface properties. A multiplicity of implant surface forms exist engineered with mechanical features that physically interlock the implant with bone. Various strategies have been utilized to improve bone integration of Ti-based implants. For example, surface grit blasting, acid-etching and anodization methods enhance cell growth, improving implant fixation through increases in interlocking surface area and alterations of oxide thickness. On the other hand, surface composition and hydrophilicity are parameters that may play a role in implant-tissue interaction and osseointegration. Highly hydrophilic surfaces seem more desirable than hydrophobic ones in view of their interactions with biological fluids, cells and tissues. Several recent studies have shown that the surface energy of biomaterials strongly has influence the initial cell attachment and spreading of osteoblastic cells on the biomaterial surfaces. Hallab et al. said that surface energy might be a more important determinant of cell adhesion and proliferation, and might be more useful than surface roughness for generating cell adhesion and cell. It may have the influence on protein adsorption and the structural rearrangement of the proteins on the material. Therefore, understanding the relationship between surface energy and cell adhesion on different biomaterials will facilitate the design of optimized implant material surfaces and subsequently the cell attachment. Surface energy is an important parameter of the material surface. It is affected by several surface characteristics, such as chemical composition, surface charge, and microstructural topography. Many papers reported that surface energy is one of important surface characteristics parameter of modified titanium surfaces. Given the importance of surface wettability of dental implants surfaces in the achievement of osseointegration, the surface free energy values for a given material, obtained by various methods and with use of different measuring liquids, are not consistent. Thus, we provided a review article of the surface modification on titanium surface and the surface wettability. The relationship between CAs and surface preparations was determined in this review.",signatures:"In-Hye Kim, Tae-Yup Kwon and Kyo-Han Kim",downloadPdfUrl:"/chapter/pdf-download/48833",previewPdfUrl:"/chapter/pdf-preview/48833",authors:[{id:"173794",title:"Prof.",name:"Kyo-Han",surname:"Kim",slug:"kyo-han-kim",fullName:"Kyo-Han Kim"},{id:"176743",title:"Ms.",name:"Kim",surname:"In-Hye",slug:"kim-in-hye",fullName:"Kim In-Hye"}],corrections:null},{id:"49177",title:"Influence of Wettability and Reactivity on Refractory Degradation – Interactions of Molten Iron and Slags with Steelmaking Refractories at 1550°C",doi:"10.5772/61271",slug:"influence-of-wettability-and-reactivity-on-refractory-degradation-interactions-of-molten-iron-and-sl",totalDownloads:2068,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Refractories, materials that can withstand high temperatures, play an important role in the iron and steel sector which alone accounts for ~70% of total refractories produced. In this chapter, detailed wettability and interfacial phenomena investigations on alumina-carbon and zirconia-carbon refractories at steelmaking temperatures. The wettability between refractory substrates and molten iron/slags was investigated at 1550°C using the sessile drop approach in a horizontal tube furnace equipped with a CCD camera. Detailed experimental results were obtained on alumina-carbon/molten iron system at high temperatures. Alumina is known to be non-wetting to molten iron while carbon can be easily wetted. Observed contact angles were found to depend strongly on the substrate composition and contact time. While the refractory substrates containing 50 and 60% carbon were found to be non-wetting to molten iron, the substrates containing higher amounts of C (≥ 70%) were found to become increasingly wetting. Molten iron droplets were seen to spread on these substrates.",signatures:"R. Khanna, M. Ikram-ul-Haq and V. Sahajwalla",downloadPdfUrl:"/chapter/pdf-download/49177",previewPdfUrl:"/chapter/pdf-preview/49177",authors:[{id:"19010",title:"Associate Prof.",name:"Rita",surname:"Khanna",slug:"rita-khanna",fullName:"Rita Khanna"}],corrections:null},{id:"49090",title:"The Wetting of Leaf Surfaces and Its Ecological Significances",doi:"10.5772/61205",slug:"the-wetting-of-leaf-surfaces-and-its-ecological-significances",totalDownloads:3521,totalCrossrefCites:13,totalDimensionsCites:25,hasAltmetrics:0,abstract:"Leaf wettability, indicating the affinity for water on leaf surfaces, is a common phenomenon for plants in a wide variety of habitats. The contact angle (θ) of water on leaves measured at the gas, solid and liquid interface is an index of surface wettability. Leaves are termed as “super-hydrophilic” if θ < 40°, “highly wettable” if θ < 90°, and “wettable” if θ < 110°. If θ > 110°, the leaves are classified as being non-wettable, while θ > 130° for highly non-wettable and θ > 150° for super-hydrophobic. Both internal and external factors can influence leaf wettability. The chemical composition and structure of leaf surfaces are internal causes, but the external environment can also influence wettability by affecting the structure and composition of the surface. The main internal factors that affecting leaf wettability include the content and microstructure of the epidermal wax, the number, size and pattern of trichomes, stomatal density, the shape of epidermal cells, and leaf water status. The leaf contact angles increased with the increasing of leaf wax content. However, studies have shown that the contact angles were more dependent on the complexity of wax structure than on the absolute amount. For trichomes, there are three types of interaction between trichomes and water droplets, including (1) low trichomes density: no apparent influence of trichomes on the location of surface moisture, droplet formation and retention ; (2) medium trichomes density: trichomes appear to circle surface moisture into patches; (3) high trichomes density: trichomes appear to hold water droplets above the trichomes. In some cases, a higher stomatal density was accompanied with a higher contact angles. While, it was also observed that there was no significant correlation between contact angle and stomatal density for some species. For the effects of epidermal cells on leaf wettability, it was generally considered that the combination of a dense layer of surface wax and the convex epidermal cells was what created a hydrophobic leaf surface. However, the influence of leaf water content on contact angle of water droplets on different leaf surfaces was complex, e.g., contact angles increased with decreasing of leaf water content, contact angle remained to be constant with different leaf water content.",signatures:"Huixia Wang, Hui Shi and Yanhui Wang",downloadPdfUrl:"/chapter/pdf-download/49090",previewPdfUrl:"/chapter/pdf-preview/49090",authors:[{id:"173921",title:"Dr.",name:"Huixia",surname:"Wang",slug:"huixia-wang",fullName:"Huixia Wang"}],corrections:null},{id:"48816",title:"Wettability and Other Surface Properties of Modified Polymers",doi:"10.5772/60824",slug:"wettability-and-other-surface-properties-of-modified-polymers",totalDownloads:3701,totalCrossrefCites:9,totalDimensionsCites:36,hasAltmetrics:0,abstract:"Surface wettability is one of the crucial characteristics for determining of a material’s use in specific application. Determination of wettability is based on the measurement of the material surface contact angle. Contact angle is the main parameter that characterizes the drop shape on the solid surface and is also one of the directly measurable properties of the phase interface. In this chapter, the wettability and its related properties of pristine and modified polymer foils will be described. The wettability depends on surface roughness and chemical composition. Changes of these parameters can adjust the values of contact angle and, therefore, wettability. In the case of pristine polymer materials, their wettability is unsuitable for a wide range of applications (such as tissue engineering, printing, and coating). Polymer surfaces can easily be modified by, e.g., plasma discharge, whereas the bulk properties remain unchanged. This modification leads to oxidation of the treated layer and creation of new chemical groups that mainly contain oxygen. Immediately after plasma treatment, the values of the contact angles of the modified polymer significantly decrease. In the case of a specific polymer, the strongly hydrophilic surface is created and leads to total spreading of the water drop. Wettability is strongly dependent on time from modification.",signatures:"Nikola Slepickova Kasalkova, Petr Slepicka, Zdenka Kolska and\nVaclav Svorcik",downloadPdfUrl:"/chapter/pdf-download/48816",previewPdfUrl:"/chapter/pdf-preview/48816",authors:[{id:"144929",title:"Prof.",name:"Vaclav",surname:"Svorcik",slug:"vaclav-svorcik",fullName:"Vaclav Svorcik"},{id:"146297",title:"Dr.",name:"Petr",surname:"Slepicka",slug:"petr-slepicka",fullName:"Petr Slepicka"},{id:"147600",title:"Ph.D.",name:"Nikola",surname:"Slepičková Kasálková",slug:"nikola-slepickova-kasalkova",fullName:"Nikola Slepičková Kasálková"},{id:"153983",title:"Dr.",name:"Zdeňka",surname:"Kolská",slug:"zdenka-kolska",fullName:"Zdeňka Kolská"}],corrections:null},{id:"49178",title:"Wettability of Carbonaceous Materials with Molten Iron at 1550°C",doi:"10.5772/61198",slug:"wettability-of-carbonaceous-materials-with-molten-iron-at-1550-c",totalDownloads:2097,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"In the direct iron smelting process, interfacial reactions of carbonaceous materials with molten iron are among some of the key factors that dictate the rate of carbon transfer into molten iron and establish a carbon concentrated melt to reduce iron oxide in the slag phase. Detailed wettability investigations on a range of carbonaceous materials, e.g. synthetic graphite, natural graphite, coke, coal-chars, coke-polymer blends, waste plastics in contact with molten iron at 1550°C were carried out using the sessile drop method. Experimental results on dynamic contact angles are presented in this chapter and are discussed in terms of the basic characteristics of carbons and the changing composition of the interfacial region as a function of time.",signatures:"R. Khanna, I. Mansuri and V. Sahajwalla",downloadPdfUrl:"/chapter/pdf-download/49178",previewPdfUrl:"/chapter/pdf-preview/49178",authors:[{id:"19010",title:"Associate Prof.",name:"Rita",surname:"Khanna",slug:"rita-khanna",fullName:"Rita Khanna"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3817",title:"Developments in Corrosion Protection",subtitle:null,isOpenForSubmission:!1,hash:"8ff86fac7ac8bce142fdc3c0e5a79f30",slug:"developments-in-corrosion-protection",bookSignature:"M. 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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:"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:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],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. 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Disease animals are much show fever, the place such as snout, feet, and breast forms blister and canker. The disease can spread rapidly in many ways. It has broken out many times in the world, causing huge political and economic losses to human beings. The disease was first discovered in 1514 by the Italian monk H. Fracastorius in cattle. In 1897, Loeffler and Frosch demonstrated that a filterable agent caused FMD is the foot-and-mouth disease virus (FMDV) [1]. The causative agent of FMD disease belongs to the family
The FMDV genome is a positive-sense single-stranded RNA virus with a size of about 8.5 kb [2]. FMDV RNA has a 5′ non-coding region on the left, an open reading frame (ORF) in the middle, and a 3′ non-coding region on the right. At the end of the 5′ non-coding region is a viral coding peptide VPg (or 3B), which is covalently bound to the genome. For FMDV, this 5′ untranslated region (UTR) contains S-fragment (short fragment of the genome), poly(C), pseudoknot, cre structures, and internal ribosome entry site (IRES) [3].
The S fragment can form an over 350 bases stem-ring structure, which is isolated from the genome by a variable length homopolymeric cytidylic acid tract (poly(C)), and there are some differences between the S fragments of different serotypes [4]. Carrillo et al. isolated S fragments with a sequence similarity of 80%, indicating that S fragments are highly conservative [5]. The S fragment can protect the successful replication of daughter RNA and will not be degraded by nucleic acid exonuclease, which greatly ensures the replication process of viral RNA. S fragment was involved in mediating the innate immune system. Kloc et al. found that viral RNA could not survive after deletion of more than 163 nt on stem ring of S fragment [6]. In addition, a short fragment of the G320T mutation prevented rescue of viable virus [7].
Different isolates of FMDV have different lengths of poly(C) tract; Harris and Brown found that the length of poly(C) tract may be related to the virulence of FMDV by comparing a virulent and an avirulent strain of foot-and-mouth disease virus [8]. However, other researchers suggest that the differences in virulence may be due to changes elsewhere in the genome of these strains [3].
The poly (C) tract is followed by three to four tandemly repeated pseudoknots (PKs) [9]. In a recent study, researchers compared the virulence and pathogenic mechanism of different FMDV strains in pigs and cattle by constructing PK recombinant FMDV strains and found that the absence of different sizes of PKs resulted in different pathogeny to the host, indicating that the pseudoknot region was the key to determine the viral tropism and virulence of foot-and-mouth disease virus [10].
In some picornavirus genome coding region, there is a known as cis-acting replicative element (cre) of the basic structure of RNA, cre is a conservative AAACA motif of stem loop structure, its function is to add U residues to the protein primer 3B [11]. Furthermore, Mason et al. found that cre plays an important role in genome replication and that this function is independent of its position at the 5′ end of the genome [12].
Eukaryotes generally begin translation by identifying cap structures at the 5′ end of mRNA; however, the initiation of translation can also occur internally, as has been found in picornavirus RNAs, where a functional element called the internal ribosomal entry site (IRES) at the 5′ end of mRNA also performs this function [13]. The FMDV IRES consists of 462 nucleotides with 5 domains [14]. Earlier studies have found that the interaction between IRES and the translation initiation factor eIF4G, which acts as a linker during translation initiation, is the key to in vivo translation [15]. Later, the researchers found an interaction between the IRES of FMD virus and three other translation initiation factors eIF3, eIF4B, and eIF4GII during translation initiation [16]. Furthermore, IRES trans-acting factor (ITAF) (45) promoted IRES-mediated translation in all cells; however, IRES-mediated translation activity was independent of the host range of FMDV, and only the effects of poly-pyrimidine tract binding protein (PTB) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) were observed in FMDV-sensitive cells [17]. In addition, Ras GTPase SH3 domain binding protein 1 (G3BP1) interacts directly with FMDV IRES to negatively regulate translation [18].
The genome of FMDV contains an open reading frame, and ORF encodes four structural proteins (VP1, VP2, VP3, and VP4) and 10 non-structural proteins (L, 2A, 2B, 2C, 3A, 3B1, 3B2, 3B3, 3C, and 3D), whose functions will be detailed in the following sections [19, 20].
The 3′ -terminal region of FMDV consists of two distinct elements, a 90 nt untranslated region (3′-NCR) and a poly(A) tract, which have been found to stimulate IRES-driven translation [21]. Since the IRES are located at the 5′ UTR, it was assumed that there was a connection between the 3′ and 5′ ends of FMDV, and Serrano et al. subsequently demonstrated that different 3′ UTR elements are involved in the interaction between the IRES and the S region, suggesting that the 5′-3′ end of the bridge is in direct RNA-RNA contact and plays a role in RNA replication [22]. The absence of SL1 and SL2, two stem-ring structures in the 3′ non-coding region, affects viral infectivity, and the ΔSL1 mutation has been shown in pigs to be harmless to pigs, but to induce an immune response, which is important for the development of FMDV vaccines [23]. In addition, SL2 is an essential component of virus replication [23, 24].
FMDV is an icosahedral symmetry non-enveloped virus. It consists of four capsid proteins VP1, VP2, VP3, and VP4, among which VP1, VP2, and VP3 are in the outermost layer of the virus, and VP4 is located in the interior of the virus and contacts with RNA [25]. Malik et al. obtained a high-resolution structure (5.2 Å) of the icosahedron of FMDV using cryo-electron microscopy (cryo-EM), notably, the obtained structure did not contain VP4 [26]. FMDV capsids are susceptible to low pH and high temperature and dissociate into pentamers under acidic conditions and release RNA [27].
In 1982, Barteling et al. proposed that FMDV structural protein (VP1) might be involved in early virus-cell interactions [28]. In the second year, Dawe and King found that the early and late viral virulence obtained by infecting BHK21 cells was different, and the researchers found that the point mutations of the VP1 were the cause of mouse virulence and BHK21 cell pathogenicity [29]. Since most of the VP1 protein is exposed on the surface of the virus, which determines the antigenicity of the virus to a large extent, VP1 protein can induce the body to produce specific neutralizing antibodies and induce anti-infection immunity [30, 31, 32, 33, 34]. On the VP1 of FMDV, there is a well-known G-H loop containing a highly conserved Arg-Gly-Asp (RGD) sequence, which is necessary for the virus to adhere to the cell [35, 36]. The researchers used this property of VP1 to make many explorations in the development of a vaccine against FMDV [33, 37, 38, 39, 40, 41, 42]. In addition, studies have shown that VP1 N terminal is related to pH stability of FMD virus particles [43]. A recent study showed that VP1 inhibits the beta interferon signaling pathways by inhibiting IRF3 phosphorylation, dimerization, and nuclear translocation. However, the DnaJ heat shock protein family (Hsp40) member A3 (DNAJA3) can attenuate this effect [44].
For the structural protein VP2, the researchers believe that VP2 is associated with the persistence of FMDV [45]. Amino acid substitutions in the B-C loop of VP2 protein lead to antigenic differences in different types of FMDV, which indicates that VP2 is related to the antigenic diversity of FMDV [46]. In addition, amino acid substitutions in VP2 also affect the replication ability and virulence of the virus [46]. Interestingly, Vazquez-Calvo et al. found that tyrosine replacement of VP2 histidine enhanced the acid resistance of the FMDV capsid [47]. Further studies have shown that VP2 activates the EIF2S1-ATF4 pathway in cells and induces autophagy via the heat shock protein family B [small] member 1 (HSPB1) [48]. In addition, the researchers found applications for VP2 in vaccine development [49, 50] and detection of viral serotypes [51, 52, 53].
VP3 protein is the structural protein of FMDV. An amino acid deficiency of VP3 protein at position 59 of a foot-and-mouth disease virus was found in India, and the presence of this mutant increased the incidence of the epidemic [54, 55, 56]. In addition, the substitution of VP3 H142D for FMD virus can enhance the acid resistance of serotype A [57]. Furthermore, the researchers found that FMDV VP3 inhibited the IFN-beta signaling pathways [58] and the IFN-gamma signal transduction pathways [59]. Interestingly, Qi et al. found that host microRNA miR-1307 promotes the degradation of the viral structural protein VP3 through the proteasome pathway, suggesting that it may be developed for the treatment of foot-and-mouth disease [60].
Regions 20 to 35 of FMDV VP4 may be involved in inducing an immune response in T cells to recognize the T cell epitopes of MHC, a property that could be used to develop peptide vaccines [61, 62].
There are two initiation codes AUG in the ORF of FMDV, which can produce two forms of lead proteases, Lab (synthesized by the first AUG) and Lb (synthesized by the second AUG) [63]. Further studies found that the virus could still be produced in transfected cells when the first AUG was deleted, but not when the second AUG was deleted [64]. FMDV inhibits protein synthesis in host cells after infecting the host, which may be related to the cleavage of eukaryotic translation initiation factor 4GII (eIF4GII) induced by leader protease (L-pro) [65]. Further studies by Moral-Lopez et al. found that L-pro can increase the translation driven by IRES [66]. In addition, phylogenetic analysis of nucleotide sequence in L-pro region of FMD type O serum isolates from India revealed that all amino acid residues at the active cleavage site of L-pro sequence were conserved [67].
The P2 portion of FMDV is eventually processed into three mature peptides, 2A, 2B, and 2C [68]. FMDV 2A protein can cleave the site of 2A/2B, and the researchers applied this property to the field of biotechnology and successfully obtained bioactive proteins by expressing multiple proteins in cells [69, 70, 71, 72, 73, 74, 75, 76]. It has been shown that the 2A polypeptide can cleaving the 2A/2B junction because it has a conserved c-terminal motif [D(V/I)E(S/T)NPGP], where the last P is the first residue of 2B, which is important for protein processing and virus replication [77, 78]. The researchers produced recombinant antigen of FMDV P1-2A3C in plant species, which can induce humoral immunity in guinea pigs [79]. In addition, the development of a genetically engineered vaccine against FMDV 2A may be an effective means of controlling foot-and-mouth disease [80, 81]. The study of 2B by Zhu et al. showed that, in the study of FMDV, 2B expression reduced the expression of retinoic acid-inducible gene I (RIG-I) through the interaction of residues of 2B carboxyl terminal amino acids 105–114 [82]. Further studies have shown that 2B also interacts with MDA5 and negatively regulates RLR-mediated IFN-beta induction [83]. In addition, Zhi et al. demonstrated that 2B activates NLRP3 inflammasome [84]. Further studies revealed that the non-structural protein 2B of FMDV interacts with eEF1G [85] and CypA [86] and plays a role in the process of virus infection and replication. For 2C, it was used to distinguish between infected and vaccinated animals [87, 88, 89, 90]. The researchers identified 2C interacting proteins, including autophagy regulators Beclin1 [91], N-myc, and STAT interactor (Nmi) [92, 93], by yeast two-hybrid system and immunoprecipitation, which are helpful in understanding the mechanism of FMDV.
Similarly, the researchers were able to identify infected and vaccinated animals using non-structural protein 3A [94], which was more specific and sensitive than other non-structural proteins 3B and 3AB [95]. By means of yeast double hybridization, Gladue et al. identified that the interaction between 3A and host protein DCTN3 affected viral virulence [96]. In 2013, a study found that a partial deletion of 3A attenuated the foot-and-mouth disease virus in cattle [97], after 5 years, further research found that the deletion did not prevent subclinical infection [98]. The genome of FMDV contains three copies of the 3B protein (or VPg). In addition, 3A was found to inhibit interferon-beta signaling to evade the host immune system [99]. The study indicates that the 3B copy number is closely related to the virulence of the virus, and the virus containing a single 3B is less virulent, producing only mild disease [100]. By acting on the FMDV capsid precursor, P2-2A, 3C protease cleaved it into VPO, VP3, VP1, and 2A, and these three cleaved independently of each other [101]. Birtley et al. obtained a crystal structure with a resolution of 1.9 Å of 3C protease, which was folded like chymotrypsin and had a cys-his-asp catalytic triad [102]. It has been shown that 3C also attacks the host cytoskeleton during FMDV attack on the host [103]. Further studies showed that 3C protease could inhibit autophagy by degrading the autophagy-related protein ATG5-ATG12 [104]. The last non-structural protein is RNA-dependent RNA polymerase, 3D polymerase. Studies have shown that the synthesis of microRNA targeting 3D polymerase can effectively inhibit the replication of FMD virus in vitro [105, 106]. Therefore, 3D polymerase is one of the effective targets for the development of antiviral drugs targeting FMDV. 5D9, a 3D polymerase inhibitor, can effectively inhibit the replication of FMDV in host cells [107]. There are still many problems to be solved, and the specific function and mechanism of FMD virus non-structural proteins need to be further explored by researchers.
There are seven serotypes of foot-and-mouth disease virus divided into A, O, C, Asia-1, SAT 1, SAT 2, and SAT 3, and there are many subtypes of each serotype. Most of the world has had outbreaks of foot-and-mouth disease, the most common of which is serotype O. Six of the seven serotypes (A, O, C, SAT1, SAT2, and SAT3) have occurred in Africa, while four serotypes (O, A, C, Asia1) in Asia and only three serotypes (O, A, C) in South America [108]. However, there are also SAT 1 and SAT 2 viruses from as well as from Africa entering the Middle East [108]. In addition, the most recent outbreak of foot-and-mouth disease caused by serotype C virus occurred in 2004 and is now probably extinct [109].
The epidemiology of FMDV includes the source of infection and the route of transmission. Foot-and-mouth disease (FMD) has the epidemiological characteristics of rapid epidemic, wide spread, and acute onset. The main source of infection is sick animals and the incubation period of animals, the incubation period 1–7 days, the average 2-4 days. Foot-and-mouth disease mainly affects artiodactyls, mainly cattle, especially calves, followed by pigs, camels, sheep, goats, and wild animals. In addition, the virus was found in blisters, milk, urine, saliva, tears, and feces of sick animals. The transmission route is extensive, which can be transmitted to susceptible animals either by direct contact or by indirect contact (e.g., secretions, feces, animal products, contaminated air, feed, etc.). Foot-and-mouth disease occurs frequently in the spring and fall. Clinical features are blister rash in the oral mucosa, hoof, and breast skin. This disease has broken out in the world several times, causing huge political and economic losses.
Foot-and-mouth disease will reduce the milk production of sick animals; severe cases will cause acute death; animal husbandry production caused a great loss, so many countries in the world to foot-and-mouth disease as the most important animal quarantine object. In the world, the United States and other developed countries have completely eliminated foot-and-mouth disease; however, in the developing countries, foot-and-mouth disease still exists. There are seven serotypes of FMD virus, which cannot be immune to each other due to their different antigens. Vaccination is a reliable and effective method for specific prevention of FMD, and a safe and effective vaccine is a prerequisite for the successful prevention, control, and eventual elimination of FMD. Therefore, in order to effectively prevent and control foot-and-mouth disease, it is necessary to thoroughly study the mechanism of action of the virus and develop more effective prevention and control methods to ensure the healthy development of animal husbandry.
World Health Organization (WHO) defines diabetes mellitus as a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with alterations of carbohydrate absorption, fat and protein metabolism. DM is one of the four major non-communicable diseases along with cardiovascular disease (CVD), cancer and chronic respiratory diseases. Once a disease of affluence, it is now increasingly common among the poor countries [1]. The morbidity and mortality associated with DM arises from minor and macrovascular complications, ischemic heart disease (IHD) and peripheral vascular disease (PVD) [2]. Metformin acts by several mechanisms of action but the major mechanism is inhibiting hepatic gluconeogenesis [3]. The drug may antagonize the action of glucagon, and reduces fasting blood glucose (FBG) [4]. In addition, metformin increases insulin action at target sites, increases peripheral glucose uptake, enhances fatty acid oxidation and reduces glucose absorption from gastrointestinal tract [5]. Diabetes mellitus and statins have a complex association and are the attention of patient and healthcare debate. Statins are widely used as a part of diabetes mellitus care due to that patients with DM have a greater CVD [6]. At the early stage, the heart only showed transcriptional and metabolic altercations, including enhanced inflammation, oxidative stress, depletion of antioxidant proteins, and changes in energy metabolism. Use of statins in diabetes is a controversial when compared with metformin. Although the potential detrimental effects of statin on muscle and liver have been known for a long time, new concerns have emerged regarding the risk of new onset diabetes (NOM). This often leads to discontinuation of statin, non-adherence to therapy, or concerns correlating with initiating statin therapy.
There are several CVD risk factors, including hypertension, dyslipidemia, diabetes mellitus (DM), smoking and obesity, as well as platelet dysfunction. Certain drugs are currently available for treating these risk factors, whereas drug combinations are frequently needed to achieve therapeutic goals especially in hypertension, DM and coronary heart disease (CHD). Based on these considerations our objectives were 1) to assess whether combination therapy shows clinical effectiveness for cognition and functional benefits in a well-characterized prospective cohort of patients with T2DM treated over years with metformin; 2) to determine the magnitude and duration of benefit; 3) to characterize the long-term treatment of patients who receive combination therapy compared to those who were never treated with statins and those who only received metformin as monotherapy; and 4) to use modeling methods to make predictions about the mechanism and clinical course in different treatment groups and dose levels.
Both metformin and statins thus act on glucose—as well as lipid metabolism which is why metformin–statin combination therapy is prescribed to many T2DM patients. Since both drugs act on glucose as well as lipid metabolism, it is important to understand in detail the interactions between metformin and statin mechanism of action on treatment design with different dose level and optimal safety/efficacy profiles. This chapter is therefore designed to provide insight in the mechanism of combined effect of statin/metformin not only on DM and CVD but also with different types of cancer and other diseases. This chapter also explain the interaction of both drugs on preclinical and clinical studies to determine an optimal dosing strategy of both drugs.
Metformin is an oral antidiabetic drug, discovered in 1922, came on the market as late as 1979 [7]. The drug is belongs to the biguanide classification and derivative from guanidine found in
Oral administration of metformin transported into the small intestine across the apical membrane into the enterocytes via several transporter proteins. The main proteins are the plasma monoamine transporter (PMAT; SLC29A4), organic cation transporter 1 (OCT1; SLC22A1) and serotonin transporter protein (SERT; SLC6A4) [11].
Metformin accumulated majorly in the intestine, and in the stomach, liver, kidney and lesser extent in muscle. The accumulation of metformin in intestine and stomach is because of these organs are most exposed to high concentrations of metformin after oral administration. A recent study confirmed the high metformin levels are accumulated in these organs [12]. These concentrations are tenfold higher than metformin concentrations in the liver, indicating that the intestine is probably an important site of action. In fact, the metformin effects in the intestine may be rather different than the effects in the liver. The concentration of metformin in human jejunum has been shown to be 30 to 300 fold greater than in plasma, and earlier studies demonstrating accumulation of metformin in the intestinal mucosa. Metformin navigates to the liver via the portal vein and is taken up predominantly by organic cation transporter (OCT1) as well as by Thiamine transporter (THTR-2). In this chapter, the effects of metformin on the lipid metabolism are highlighted, thereby creating a special focus on the effects on lipids related to the activation of AMPK by metformin (Figure 1) [13].
Schematic diagram of the anti-hyperglycaemic action of metformin on the liver cell.
Metformin is transported into hepatocytes mainly via OCT1, and inhibited the mitochondrial respiratory chain (complex I) through a currently unknown mechanism(s). The deficit in energy production is balanced by reducing gluconeogenesis in the liver. This is mediated in two main ways. First, a decrease in ATP and a concomitantly increase in AMP concentration. Second, increased AMP levels function as a key signaling mediator to (1) allosterically inhibit cAMP–PKA signaling by suppression of adenylatecyclase, (2) allosterically inhibit FBPase, (3) activates AMPK. This leads to inhibition of gluconeogenesis (1 and 2) and lipid/cholesterol synthesis (3).
Metformin is present for over 99% in the mono protonated form in all tissues of the body except in the stomach. The sparse data showed, that metformin is mostly distributed in the cytosolic fraction (~ 70%) of rat hepatic cells compared to mixed membranes (12%), nucleus (~ 5%), and mitochondrial and lysosomal fractions (8%). A low binding affinity of metformin to mitochondrial membranes was seen, and this may be because of the two methyl groups present in metformin structure [14]. Previous study concludes that, the mitochondrial membrane potential may promote entry of metformin (positively charged) [15], which will then concentrate inside the mitochondria (negatively charged) [16]. Molecular modeling of the metformin distribution and validation study confirmed the presence of high concentrations of the drug in the endoplasmic reticulum (ER) and in the mitochondria, based on its membrane potential [17].
The main mechanisms of metformin involved in decreasing the endogenous glucose production and plasma glucose have all been extensively reviewed and critically discussed in earlier studies [18]. Metformin shows beneficial effects on the glucose and lipid metabolism, even though the pathways are not fully understood [19]. In patient studies, the variations of metformin efficacy may be due to the presence of responders and non-responders to the drug treatment [20], racial and ethnic background [21], and personal variation in the adaptation of metformin treatment. Sonne et al., [22] proposed a pathway inducing reduction of LDL cholesterol by the. Inhibition of the intestinal absorption of bile acids is caused by metformin. It causes an increased synthesis of bile acids in the liver, and cholesterol is used for this process [23], thereby causing a decreased amount of cholesterol in the hepatic cells. Upregulation of the LDL-C receptor may increase the uptake of lipoproteins, to restore a sufficient level of cholesterol in the liver. Hence, metformin indirectly decrease the LDL-C concentration and plasma total cholesterol concentrations.
A decreased β cell mass is an important factor in the development of T2DM. High glucose and FFA induce damaging effects on β cells (e.g. decreased insulin secretion and β cell mass) [24]. It is therefore of interest to consider possible beneficial effects of metformin on β cell function. Lipase and amylase are secreted by the pancreas and are often measured to monitor the condition of the pancreas. There were no changes observed in the enzyme levels, and the pancreas volume when metformin (1950 mg/day) was given to T2DM patients for 24 weeks. This works suggesting that metformin does not repair damaged β cells [25].
Statins, block an enzyme called HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) that is involved in the synthesis of mevalonate, a naturally occurring substance that is then used by the body to make cholesterol. By inhibiting this enzyme, LDL-cholesterol and cholesterol production is decreased. Statins also increase the number of LDL receptors on liver cells, which increases the uptake and breakdown of LDL-cholesterol. Most of the effects of statins, including the blocking of the HMG-CoA reductase enzyme occur in the liver. Many research have shown that elevated levels of total cholesterol, LDL-cholesterol, triglycerides, and apolipoprotein B increase a person’s risk of developing heart disease or having a stroke.
Statins are classified based on different criteria, including: 1) how they are obtained, 2) liver metabolism, 3) physicochemical properties, and 4) specific activity. Some of the statins are obtained after fungal fermentation: lovastatin, pravastatin and simvastatin, others by synthesis: fluvastatin, atorvastatin, and cerivastatin. Only five statins are, at this moment, in clinical use: lovastatin, simvastatin, pravastatin, atorvastatin and fluvastatin. Pravastatin is extremely hydrophilic, fluvastatin has intermediate characteristics, lovastatin, simvastatin, atorvastatin and cerivastatin are hydrophobic.
Statins differ in their potency at lowering total cholesterol, triglycerides, LDL-cholesterol, or increasing HDL-cholesterol; their propensity for drug interactions; and their reported safety in people with kidney disease.
Reduce a person’s risk of having a heart attack or stroke or developing angina
Reduce the risk of further heart disease in people with type 2 diabetes or coronary artery disease.
Simvastatin and atorvastatin produce the greatest percentage change in LDL cholesterol levels. Fluvastatin and atorvastatin are also preferred in hypocholesteremic patients with kidney disease.
Pravastatin and fluvastatin have a lower risk of drug interactions because they are not metabolized by cytochrome p450 3A4.
Pitavastatin has a similar effectiveness to atorvastatin but reportedly produces greater increases in HDL-cholesterol that are sustained over the long-term. It is effective at low dosages and has minimal drug interactions.
Statins are a major class of drugs that decrease plasma cholesterol levels and are prescribed as first choice to patients suffering from CVD [26]. Simvastatin and atorvastatin are often given as a first choice to patients with cardiovascular risk factors/cardiovascular disease. In earlier studies reported that low dose (20 mg/day) of atorvastatin given to patients with myocardial infarction showed improved lipid, adipokine, and pro-inflammatory markers and decreased insulin resistance. Higher dose (40 mg/day) of atorvastatin showed hyperglycemia, increased leptin levels and ghrelin deficiency [27, 28] in diabetic patient. It was also discovered that the reduction in LDL-C by statins is an important indicator of increased T2DM risk [29]. Genetic factors and/orange-related factors could as well lead to the development of T2DM during statin treatment.
Several mechanisms possibly involved in the effect of statins on glucose metabolism are summarized in Figure 2. Statin signaling pathway that stimulates endogenous glucose production (EGP) by activation of gluconeogenic genes in human liver cells. Statin activates the pregnaneX receptor (PXR) in the cytoplasm. Many functions are exerts by PXR, such as the stimulation of the expression of proteins involved in regulation of hepatic glucose and removal of xenobiotics, and lipid metabolism [17].
Hypercholesterolemia enhance the entry of LDL particles into sub endothelial space at lesion-prone arterial sites. Monocyte chemotactic protein-1 (MCP-1) and oxidized-LDL act as chemoattractants to direct accumulation of monocytes and their migration to the subendothelial space, where monocytes undergo phenotypic transformation into macrophages. Oxygen free radicals concurrently modify LDL. Oxidatively modified LDL is taken up by nondownregulating macrophage receptors to form lipid-rich foam cells. The foam cells develop into fatty streaks that is the, precursor of atherosclerotic plaques. Statins exhibit pleiotropic effects on many components of atherosclerosis that accompany hypercholesterolemia, abnormal endothelial function and including platelet coagulation abnormalities, and determinants of plaque thrombogenicity such as plaque inflammation and proliferation.
Statin mechanism may contribute to a decreased insulin secretion in the β cell, possibly contributing to the progress of T2DM. The upregulation of LDL-C receptor seen upon inhibition of HMG-CoA reductase are one of the directly affected processes, which results in increased uptake of plasma LDL-C into the β cell [30]. The increased amount of cholesterol within the cell causes interference with translocation of glucokinase, to the mitochondria [31]. A decreased glucose transporter (GLUT2) expression level was observed in simvastatin treated mouse MIN6 cells which resulted in a reduction of ATP levels. This may be the mechanism of inhibition of the KATP channel closure, membrane depolarization and calcium channel opening all leading to reduced insulin secretion [32]. Inhibition of the ATP-dependent potassium channel, depolarization and the decreased influx of intracellular calcium, and calcium concentrations were observed and were related to a decreased insulin secretion. In an ex vivo study, intracellular calcium levels were not affected even though intact with single-islets were treated with simvastatin [33]. Statin treatment may cause inactivation of Ras and Rho molecules, hence the activation and membrane translocalization of GLUT-4 is inhibited. Experiments with atorvastatin treatment in mouse adipocytes confirmed that GLUT-4 located on the plasma membrane moved to the cytosol during treatment and this may result in an increased insulin resistance [34].
Since 1959, evidence from many studies had revealed that there was an association between T2DM and cancer, and patients who had T2DM were more likely to be diagnosed with cancer than patients who had not [35, 36]. A lot of evidence has also shown its beneficial effects in cancers, including prostate, breast, lung, and colorectal cancers [37]. Experimental results in vitro have suggested the effect of statins on growth, migration, apoptosis, and autophagy of cancer cells [38, 39]. The data from in vivo cell culture studies, statins may act as a preventive drug for hepatocellular carcinoma, malignant glioma and bladder cancer [40]. However, the role of statins on the incidence of cancer in patients with T2DM has not been well documented. Fei et al., [41] performed a meta-analysis to evaluate the impact of different types of statins on the risk of cancers with T2DM.The study was systematically searched with the Cochrane Library, PubMed, Embase, and Wanfang databases from January 1999 to March 2017. A pairwise meta-analysis used to estimate the pooled ratios (ORs) and 95% confidence intervals (CIs). NMA was performed to compare different types of statins. In pairwise meta-analysis result showed that, the incidence of cancer in T2DM patients was reduced when simvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, rosuvastatin, and pitavastatin were used. The analyses suggest that rosuvastatin may be more effective than others.
Previous studies on diabetic rats (200–220 g) reported that after 2 weeks of metformin–atorvastatin combination therapy (500 mg metformin and 20 mg atorvastatin per 70 kg body weight), reduced blood glucose, lipid-lowering effects, and reduced in elevated oxidative stress, and positive effects on cardiovascular hypertrophy occurred [42]. The reduction of oxidative stress and liver protection (blood analysis and liver histology studies, e.g. CRP, TNF-α, IL-6, protein carbonyl levels) was also seen in T2DM rats treated with metformin and atorvastatin [43].
Statins consistently showed a protective role in the setting of diabetes cardiomyopathy (DCM) due to their roles of anti-inflammation, anti-oxidation, and antiapoptosis effects [44]. In previous animal experiments, statins could prevent DCM by all evicting left ventricular dysfunction and inhibiting myocardial fibrosis through anti-apoptosis and anti-inflammation pathways. It seems that statins may facilitate the onset of diabetes by impacting peripheral insulin sensitivity and islet b-cell function, while statins can effectively modify the promotive factors and promoting DCM, including inflammation and oxidative stress, thereby protecting the heart against diabetic conditions [45].
An animal study was designed to evaluate the effectiveness safety and mechanism of an atorvastatin/metformin combination therapy in a rabbit atherosclerosis model induced by a high-cholesterol diet. At the end of the experiment, all rabbits were sacrificed by injection of an overdose of sodium pentobarbital solution and the aortas were separated from the surrounding tissues. From the initiation of the aortic arch, 0.5 cm sections were excised for paraffin treatment [46] and the remaining aortas were soaked in 4%paraformaldehyde and then stained with Oil Red O solution, to evaluate the atherosclerotic lesion area of the aorta by image-processing software (ImageJ). One portion stained with hematoxylin and eosin (H&E) before quantification using ImageJ software. In an animal study 12-week high-cholesterol diet induced a significant increase in atherosclerotic lesion area in rabbits in the control (Ctrl) group; after 10 weeks of atorvastatin or metformin treatment, the atherosclerotic lesion area was significantly reduced by 51% and 35%, respectively.
Atorvastatin/metformin combination therapy resulted in an 80% reduction of atherosclerotic plaques compared with the control group. The combination therapy showed which was more effectively than each monotherapy. Compared with control group, the treatment of atorvastatin or metformin significantly reduced the lesion size by 68% and 42%, respectively, while atorvastatin/metformin combination therapy further reduced atherosclerotic lesion size by 86%. It was reported that large HDL is inversely associated with cardiovascular disease [47]. The results suggest that atorvastatin and metformin combination therapy is superior to atorvastatin monotherapy for the treatment of atherosclerosis and the underlying mechanisms might be associated with cholesterol efflux in macrophages. The study results demonstrated that atorvastatin/metformin combination therapy did not show a better lipid-lowering effect than atorvastatin, which is similar with the recent clinical and preclinical data [48]. The CAMERA study revealed that metformin did not affect the lipid profile in statin-treated patients [49]. Forouzandeh
In a clinical study a great number of patients are selected and treated with metformin–atorvastatin combination tablet administered as a single daily dose [52]. There is only a minor chance for toxic drug interactions when treated with metformin and statin together because metformin is not metabolized and is the mechanism for most statins are via the cytochrome P450 system [53]. Since metformin shows beneficial effects on both dyslipidemia and glycemic control and has been shown to reduce CVD risk while statins may have an added beneficial effect on CVD risk. Hence the combined treatment with both drugs seems a good option. Clinical studies on the effects of metformin and statin combination therapy have been carried out but for different diabetic complications [54, 55, 56]. Each of these studies had different objectives and included different patients groups, i.e. either with T2DM, dyslipidemia, treated (different doses), untreated, or newly diagnosed T2DM. This criteria were compared in these studies to arrive at overall results of metformin statin combination therapy. The lowest dose of metformin (500 mg) and atorvastatin (10 mg) once daily resulted in the highest reduction of fasting plasma glucose (−35%). Atorvastatin 20 mg showed to attenuate the glucose and HbA1c-lowering effect in combination with 1000 and 2000 mg metformin.
In another clinical trial, a total of 50 newly diagnosed patients with T2DM with age range of 47.8 ± 7.4 years and prescribed 850 mg/day of metformin (sustained release), with dietary restriction, were enrolled in open-label multi center pilot study. WHO criteria was followed for the selection of newly diagnosed patients [57] and underwent a physical examination and information about their medical history, demographic parameters, and medication history were obtained by questionnaire. The patients received a constant dose regimen of metformin during the 90-day study period. In that study, the use of metformin in newly diagnosed T2DM patients, improves body weight and glycemic control; however, the addition of low-dose atorvastatin did not improve these conditions. Metformin, in a long-term study, reduces the risk of macrovascular disease after a follow-up period of 4 years [58], and this beneficial effect supports to continue metformin treatment with T2DM patients unless contraindicated. The result of this study is consistent with that reported in an experimental animal model, which indicates that the combination of atorvastatin with metformin did not produce a better lipid-lowering effect than atorvastatin [59]. In addition, the study indicated that 10 mg/day did not increase the HbA1c and serum glucose levels, but there was no additional significant improvement in the studied markers when compared with the metformin-treated group.
The effects of metformin on lipid homeostasis discussed earlier in this chapter, indicate that lipid metabolism is positively affected in the intestine and liver leading to decreased plasma triglycerides, LDL-C, and total cholesterol. Metformin effects on lipid metabolism seem to be localized to the intestine. Statins mainly act on plasma cholesterol via activation of the LDL-receptor suggesting that combination therapy should show an additional effect on plasma lipids. Combination therapy with statins and metformin demonstrated beneficial effects in patients with other disease(s)/disorder(s) than T2DM and dyslipidemia [60].
In earlier studies, the effect of metformin alone on the lipid profile was studied, and the result analysis showed that only TG levels and LDL/HDL ratio were significantly improved. Whereas these effects were not significantly different compared with its combination with atorvastatin that improves all lipid profile components. These results indicated that the addition of atorvastatin with metformin did not influence the lipid-lowering effects of monotherapy in newly diagnosed T2DM patients with metformin. In previous studies, although metformin moderately improves the lipid profile, there were inconsistencies in its effects on the lipid parameters [61]. Accordingly, the addition of atorvastatin to metformin treatment in newly diagnosed T2DM patients showed relatively normal lipid profile may be irrational and cost ineffective and the emergence of adverse effects may be highly expected with long-term use.
Diabetic patients receiving metformin have been shown to have a reduced cancer incidence and a decrease in cancer-specific mortality [62]. Statin use was also found to be associated with a reduction in the risk of biochemical recurrence in patients with prostate cancer and a decreased risk of cancer mortality [63, 64]. Based on epidemiologic evidence and the preclinical data for metformin and atorvastatin individually in prostate cancer, the author concluded the beneficial effects of metformin and atorvastatin alone or in combination on SCID mice and cultured prostate cancer cells. Metformin and atorvastatin in combination exhibited potent inhibitory effect on the growth of prostate cancer cells
In T2DM patients with non-alcoholic fatty liver disease (NAFLD) the combination therapy was found to be benefited. Whereas, statin therapy associates negatively with non-alcoholic steatohepatitis and found to be significant fibrosis while a safe use of metformin in patients with T2DM and NAFLD was demonstrated [68]. Combination therapy consisting of metformin and statin treatment is frequently prescribed to women with polycystic ovary syndrome (PCOS). This syndrome increases the risk of T2DM and cardiovascular morbidity as it is associated with abnormal increased lipid levels, insulin resistance, endothelial dysfunction and systemic inflammation [69]. Meta-analysis showed that combined therapy in women with PCOS resulted in improved inflammation and lipid markers but it did not improve insulin sensitivity [70].
Treatments using statins, and combined statins and metformin can effectively improve IR, fasting insulin (F-INS), insulin sensitivity index, hyperandrogenemia, acne, hirsutism, testosterone and decreasing C reactive protein (CRP) [71, 72, 73]. Pre-treatment with atorvastatin for 3 months followed by metformin in patients with PCOS improves insulin and homeostasis model assessment of IR (HOMA-IR) indices and reduces CRP level but does not improve the lipid profile compared with placebo treatment. Hence, atorvastatin pre-treatment enhances the effects of metformin in improving IR, whereas inflammatory markers are not affected by decreased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) after cessation of atorvastatin [74].
The lipid-lowering effect of statins administered with or without metformin in PCOS patients remains ambiguous. This finding is also supported with the meta-analysis performed by Gao et al. [75]. A clinical trial demonstrated that insulin secretion was found to be increased after 6 weeks of statin therapy in women with PCOS [76]. The meta-analysis found that statins fail to improve F-INS and HOMA-IR in single or in combination with metformin. This finding may be due to the following reasons. First, statins may damage endothelial function through loss of the protective anti-proliferative and anti-angiogenic effects of adiponectin, resulting in impaired insulin sensitivity [77]. Second, statins decrease the levels of cholesterol mediated by the farnesoid X receptor (FXR), the deficiency of which is related to IR [78]. The activation of FXR can lower the levels of glucose-6-phosphatase, reduce phosphoenol pyruvate carboxykinase in gluconeogenesis, and increase glycogen synthesis [79]. Hence, induced IR caused by statin therapy may be related to the low expression of FXR [80]. Third, statins (lipophilic) are possibly absorbed by extra-hepatic cells; these statins can deregulate cholesterol metabolism, thus deteriorating IR and attenuating β-cell function [81].
Combination therapy could also be considered for T2DM patients with diabetic retinopathy. Diabetic retinopathy (DR) is a microvascular complication of diabetes caused by hyperglycemia and hyperosmolarity. In T2DM patients and pre-existing DR patients, the use of statin showed a protective effect against development of diabetic macular edema [82]. In T2DM patients receiving statin therapy in combination with increased levels of cholesterol remnants and triglycerides were associated with slight decreased in left ventricular systolic function. Targeting cholesterol remnants might be beneficial for finding cardiac function in T2DM patients receiving statins [83].
A high daily dose of metformin (3000 mg) and simvastatin (40 mg) resulted in an improved insulin resistance, but fasting plasma glucose decreased only by 5%, and observed minor changes on lipid metabolism parameters. This may probably due to the fact that metformin was given on top of simvastatin treatment. The patients involved in these studies had an impaired fasting glucose, dyslipidemia, newly diagnosed T2DM and/or dyslipidemia. However, it could be used for hypothesis-generation rather than making rigid decisions, considering the lack of multiple dose dependent combination studies.
The combination of metformin with insulin may be a better therapeutic option for patients with DM whose hyperglycemia is poorly controlled on insulin treatment. Aviles et al. [84] stated that increased frequency of dosage of insulin causes more improvement in glycemic control and significantly reduce HbA1c which was compared with a combination therapy of insulin and metformin. Furthermore, unchanged FBG and PPBG and HbA1c in patients on metformin and insulin compared to combination of metformin, insulin and simvastatin treated patients. The HbA1c of diabetic patients on simvastatin showed a slight elevation as compared to other groups. Previous studies reported that statin use is associated with a rise of FPG in patients with and without DM [85]. Sattar et al., have identified deterioration in glucose homoeostasis in patients treated with statins and this depends on lipid solubility of statins. Simvastatin can enter easily extra hepatic cells because of its high lipid solubility and may suppress isoprenoid protein synthesis, thus attenuating the action of insulin. The abnormal level of FBG may translate into clinical syndrome of DM with rise in HbA1c is not excluded. The combination of metformin and insulin may be an attractive therapeutic option for patients with DM whose hyperglycemia is poorly controlled on insulin [86].
The mechanism of metformin is a controversial along with the use of statins in diabetes. Although the potential detrimental effects of statin therapy on muscle and liver have been known for a long time, new concerns have emerged regarding the risk of new onset diabetes (NOM) that often leads to discontinuation of statin, concerns correlating with initiating statin therapy or non-adherence to therapy.
Metformin is generally to exert its beneficial effects on glucose metabolism mainly in the liver. In line with recent research articles on the topic we conclude that the drug acts primarily in the intestine. This is due to the at least one order of magnitude higher concentrations of metformin in the intestine than in the liver. The drug present in the liver and its effects may be localized to this organ most probably via its effects on gluconeogenesis. A newly diagnosed patient with T2DM who show inadequate response to metformin may need better treatment approaches to lower atherogenic lipids. Supplementation with niacin or high-dose omega-3 fatty acid could be used in newly diagnosed T2DM patients with borderline values of lipid profile, secondary to lifestyle modifications before using a potent statin such as atorvastatin as the first treatment priority.
The effects of metformin on lipid metabolism as discussed in this chapter indicate that lipid level is positively affected in the intestine and liver leading to decreased LDL-C, plasma triglycerides and total cholesterol. Metformin effects on lipid metabolism seem to be localized to the intestine. Statins mainly act on plasma cholesterol levels via activation of the LDL-receptor suggesting that combination therapy should show an additional effect on plasma lipids. This may influence glucose homeostasis primarily by inhibition of insulin secretion in pancreatic β cells. T2DM patients receiving statin therapy in combination, with increased levels of cholesterol remnants and triglycerides were associated with slight decreased in left ventricular systolic function. Targeting cholesterol remnants in addition to T2DM patients receiving statins might be shown beneficial effect on patient’s cardiac function. To treat T2DM and its secondary complications, the combination therapy of metformin with statins seems well placed and may act as a double-sided sword particularly in the case of statins. Whereas, statins alone increases the risk on T2DM particularly in pre-diabetic subjects, and co-treatment with metformin might reduce this risk.
We have concluded that, previous studies investigated possible sites of interaction of metformin and statins and they act on largely parallel pathways. Many studies suggested that the benefits of statin therapy for diabetes far outweigh any real or perceived risks, not suggested/recommended for discontinuation of statins for diabetic patients. In conclusion, both metformin and atorvastatin can protect DCM via the mechanism of anti-inflammation and anti-apoptosis activities. The combined administration of metformin and atorvastatin resulted in superior protective effects on DCM than a single drug treatment. In this chapter, we have compiled the possible sites of interaction of metformin and statins and conclude that they act on largely parallel pathways.
The authors declare no conflict of interest among themselves.
BA | bile acids |
BMI | body mass index |
CVD | cardiovascular disease |
DCM | Diabetes cardiomyopathy |
DI | disposition indices |
DR | diabetic retinopathy |
DM | Diabetes mellitus |
EGP | endogenous glucose |
FBG | Fasting blood glucose |
FAS | fatty acid synthase |
FFA | free fatty acid |
GLUT | glucose transporter |
HbA1c | glycated hemoglobin |
HDL-C | high-density lipoprotein cholesterol |
HMGCR | 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase |
HMGCS | HMG-CoA synthase |
IFG | impaired fasting glucose |
IHD | Ischemic heart disease |
LDL-C | low-density lipoprotein |
NOM | Non onset diabetes |
OCT | organic cation transporter |
PDX | insulin promoter factor |
PMAT | Plasma monoamine transporter |
PXR | pregnane X receptor |
RCT | Reverse cholesterol transport |
RXR | retinoid X receptor |
SERT | sodium-dependent serotonin transporter |
TNF | Tumor necrosis factor |
T2DM | type 2 diabetes mellitus |
TG | triglycerides |
THTR | thiamine transporter |
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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This chapter explains briefly the fire retardation of wood by using fire retardant coatings.",book:{id:"5827",slug:"new-technologies-in-protective-coatings",title:"New Technologies in Protective Coatings",fullTitle:"New Technologies in Protective Coatings"},signatures:"Thirumal Mariappan",authors:[{id:"198114",title:"Dr.",name:"Thirumal",middleName:null,surname:"Mariappan",slug:"thirumal-mariappan",fullName:"Thirumal Mariappan"}]},{id:"75967",title:"Recent Advances in Ceramic Materials for Dentistry",slug:"recent-advances-in-ceramic-materials-for-dentistry",totalDownloads:729,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Dental ceramics constitute a heterogeneous group of materials with desirable optical and mechanical proprieties combined with chemical stability. They are inorganic non-metallic materials used in several applications. These materials are biocompatible to tissue, highly esthetic, with satisfying resistance to tensile and shear stress. 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Several geological surveys have identified bauxite, iron, gold, diamond, and several metal ores. Because of the diversity and the magnitude of its resources, the country is referred to as a geological scandal. Nowadays the aluminum industry is still at the quarrying stage of bauxite, the main raw material that is converted into alumina and further to aluminum. Approximately 35–40% of the processed bauxite ore goes into the waste as alkaline red mud RM slurry which consists of 15–40% solids. RM and other industrial wastes material such as fly ash FA, rice husk ash RHA, that poses environmental hazards can be mixed to make them apt for usage in engineering applications. Geopolymers GP represent a new class of materials consisting of Al2O3▬SiO2-based material suitable for several engineering application. The present chapter presents the bauxitic potential of Guinea, the subsequent developing alumina industry. It reviews the application of RM for the production of geopolymer materials in the perspective of the valorization of the huge bauxite potential of Guinea.",book:{id:"8612",slug:"geopolymers-and-other-geosynthetics",title:"Geopolymers and Other Geosynthetics",fullTitle:"Geopolymers and Other Geosynthetics"},signatures:"Sékou Traoré, A. Diarra, O. Kourouma and D.L. Traoré",authors:[{id:"266484",title:"Prof.",name:"Sekou",middleName:null,surname:"Traore",slug:"sekou-traore",fullName:"Sekou Traore"},{id:"272379",title:"Dr.",name:"Doussou L.",middleName:null,surname:"Traoré",slug:"doussou-l.-traore",fullName:"Doussou L. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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