Substrates and inhibitors of select renal transporters ([2]; partially reproduced with permission)
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"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:"7582",leadTitle:null,fullTitle:"Nonlinear Optics - Novel Results in Theory and Applications",title:"Nonlinear Optics",subtitle:"Novel Results in Theory and Applications",reviewType:"peer-reviewed",abstract:"Nonlinear optics is a rapidly developing field of modern physics. Nonlinear optical phenomena such as self-focusing, self-phase modulation, soliton formation and propagation, higher harmonic generation, different types of stimulated light scattering, and four-wave mixing have attracted interest from the fundamental point of view of the investigation of light/matter interaction, and as a basis for applications in contemporary optical communications and optical signal processing. Nonlinear Optics - Novel Results in Theory and Applications contains novel results concerning the mathematical methods of nonlinear optical phenomena analysis, soliton formation and propagation in optical fibers, and peculiarities of nonlinear optical phenomena in micro- and nanostructures. The book may be interesting for researchers and engineers interested in nonlinear optics, lasers, and optical communications.",isbn:"978-1-78985-164-9",printIsbn:"978-1-78985-163-2",pdfIsbn:"978-1-83962-009-6",doi:"10.5772/intechopen.77311",price:119,priceEur:129,priceUsd:155,slug:"nonlinear-optics-novel-results-in-theory-and-applications",numberOfPages:154,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"a3ad4a3553a3ec59f7992d4f6495ac07",bookSignature:"Boris I. Lembrikov",publishedDate:"February 6th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7582.jpg",numberOfDownloads:8517,numberOfWosCitations:3,numberOfCrossrefCitations:8,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:11,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:22,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 18th 2018",dateEndSecondStepPublish:"May 9th 2018",dateEndThirdStepPublish:"July 8th 2018",dateEndFourthStepPublish:"September 26th 2018",dateEndFifthStepPublish:"November 25th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"2359",title:"Dr.",name:"Boris I.",middleName:"I.",surname:"Lembrikov",slug:"boris-i.-lembrikov",fullName:"Boris I. Lembrikov",profilePictureURL:"https://mts.intechopen.com/storage/users/2359/images/system/2359.png",biography:"Dr. Boris I. Lembrikov is a senior lecturer at the Holon Institute of Technology (HIT), Israel. He is a co-author of Electrodynamics of Magneto-active Media and author of forty-five papers published in peer-reviewed international scientific journals, sixteen chapters in scientific books, and thirty-eight papers in conference proceedings. He has also edited three books. Dr. Lembrikov’s research interests include nonlinear optics, optical communications, quantum dot lasers, optical amplifiers, and plasmonics.",institutionString:"Holon Institute of Technology (HIT)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"12",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Holon Institute of Technology",institutionURL:null,country:{name:"Israel"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1225",title:"Optical Physics",slug:"optics-and-lasers-optical-physics"}],chapters:[{id:"65062",title:"Introductory Chapter: Nonlinear Optical Phenomena",doi:"10.5772/intechopen.83718",slug:"introductory-chapter-nonlinear-optical-phenomena",totalDownloads:1277,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Boris I. Lembrikov",downloadPdfUrl:"/chapter/pdf-download/65062",previewPdfUrl:"/chapter/pdf-preview/65062",authors:[{id:"2359",title:"Dr.",name:"Boris I.",surname:"Lembrikov",slug:"boris-i.-lembrikov",fullName:"Boris I. Lembrikov"}],corrections:null},{id:"64727",title:"Nonlinear Schrödinger Equation",doi:"10.5772/intechopen.81093",slug:"nonlinear-schr-dinger-equation",totalDownloads:1414,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Firstly, based on the small-signal analysis theory, the nonlinear Schrodinger equation (NLSE) with fiber loss is solved. It is also adapted to the NLSE with the high-order dispersion terms. Furthermore, a general theory on cross-phase modulation (XPM) intensity fluctuation which adapted to all kinds of modulation formats (continuous wave, non-return-to-zero wave, and return-zero pulse wave) is presented. Secondly, by the Green function method, the NLSE is directly solved in the time domain. It does not bring any spurious effect compared with the split-step method in which the step size has to be carefully controlled. Additionally, the fourth-order dispersion coefficient of fibers can be estimated by the Green function solution of NLSE. The fourth-order dispersion coefficient varies with distance slightly and is about 0.002 ps4/km, 0.003 ps4/nm, and 0.00032 ps4/nm for SMF, NZDSF, and DCF, respectively. In the zero-dispersion regime, the higher-order nonlinear effect (higher than self-steepening) has a strong impact on the short pulse shape, but this effect degrades rapidly with the increase of β\n2. Finally, based on the traveling wave solution of NLSE for ASE noise, the probability density function of ASE by solving the Fokker-Planck equation including the dispersion effect is presented.",signatures:"Jing Huang",downloadPdfUrl:"/chapter/pdf-download/64727",previewPdfUrl:"/chapter/pdf-preview/64727",authors:[{id:"198550",title:"Ph.D.",name:"Jing",surname:"Huang",slug:"jing-huang",fullName:"Jing Huang"}],corrections:null},{id:"63615",title:"Three Solutions to the Nonlinear Schrödinger Equation for a Constant Potential",doi:"10.5772/intechopen.80938",slug:"three-solutions-to-the-nonlinear-schr-dinger-equation-for-a-constant-potential",totalDownloads:1118,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"We introduce three sets of solutions to the nonlinear Schrödinger equation for the free particle case. A well-known solution is written in terms of Jacobi elliptic functions, which are the nonlinear versions of the trigonometric functions sin, cos, tan, cot, sec, and csc. The nonlinear versions of the other related functions like the real and complex exponential functions and the linear combinations of them is the subject of this chapter. We also illustrate the use of these functions in Quantum Mechanics as well as in nonlinear optics.",signatures:"Gabino Torres Vega",downloadPdfUrl:"/chapter/pdf-download/63615",previewPdfUrl:"/chapter/pdf-preview/63615",authors:[{id:"93519",title:"Dr.",name:"Gabino",surname:"Torres-Vega",slug:"gabino-torres-vega",fullName:"Gabino Torres-Vega"}],corrections:null},{id:"63619",title:"Hydrodynamic Methods and Exact Solutions in Application to the Electromagnetic Field Theory in Medium",doi:"10.5772/intechopen.80813",slug:"hydrodynamic-methods-and-exact-solutions-in-application-to-the-electromagnetic-field-theory-in-mediu",totalDownloads:706,totalCrossrefCites:6,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The new Vavilov-Cherenkov radiation theory which is based on the relativistic generalization of the Landau theory for superfluid threshold velocity and Abraham theory of the electromagnetic field (EMF) in medium is represented. The new exact solution of the Cauchy problem in unbounded space is obtained for the n-dimensional Euler-Helmholtz (EH) equation in the case of a nonzero-divergence velocity field for an ideal compressible medium. The solution obtained describes the inertial vortex motion and coincides with the exact solution to the n-dimensional Hopf equation which simulates turbulence without pressure. Due to the introduction of a fairly large external friction or by introducing an arbitrary small effective volume viscosity, a new analytic solution of the Cauchy problem for the three-dimensional Navier-Stokes (NS) equation is obtained for compressible flows. This gives the positive solution to the Clay problem (www.clamath.org) generalization on the compressible NS equation. This solution also gives the possibility to obtain a new class of regular solutions to the n-dimensional modification of the Kuramoto-Sivashinsky equation, which is ordinarily used for the description of the nonlinear propagation of fronts in active media. The example for potential application of the new exact solution to the Hopf equation is considered in the connection of nonlinear geometrical optics with weak nonlinear medium at the nonlocality of the small action radii.",signatures:"Sergey G. Chefranov and Artem S. Chefranov",downloadPdfUrl:"/chapter/pdf-download/63619",previewPdfUrl:"/chapter/pdf-preview/63619",authors:[null],corrections:null},{id:"64097",title:"Polarization Properties of the Solitons Generated in the Process of Pulse Breakup in Twisted Fiber Pumped by ns Pulses",doi:"10.5772/intechopen.81574",slug:"polarization-properties-of-the-solitons-generated-in-the-process-of-pulse-breakup-in-twisted-fiber-p",totalDownloads:973,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Common optical fibers are randomly birefringent, and solitons formatting and traveling in them are randomly polarized. However, it is desirable to have solitons with a well-defined polarization. With pump relatively long pulses, the nonlinear effects of modulation instability (MI) and stimulated Raman scattering (SRS) are dominant at the initial stage of the process of supercontinuum (SC) generation; modulation instability results in pulse breakup and formation of short pulses that evolve finally to a bunch of solitons and dispersive waves. We do the research of the polarization of solitons formed by the pulse breakup process by the effect of modulation instability with pump pulses of nanoseconds in standard fiber (SMF-28) with circular birefringence introduced by fiber twist, and the twisted fiber mitigates the random linear birefringence. In this work, we found that polarization ellipticity of solitons is distributed randomly; nevertheless, the average polarization ellipticity is closer to the circular than the polarization ellipticity of the input pulse. In the experimental setup. 200 m of SMF-28 fiber twisted by 6 turns/m was used. We used 1 ns pulse to pump the fiber. The results showed that at circular polarization of the input pulse solitons at the fiber output have polarizations close to the circular, while in the fiber without twist, the soliton polarization was random.",signatures:"Ariel Flores Rosas, Orlando Díaz Hernández, Roberto Arceo,\nGerardo J. Escalera Santos, Sergio Mendoza Vázquez, Elizeth Ramírez Álvarez,\nChristian I. Enriquez Flores and Evgeny Kuzin",downloadPdfUrl:"/chapter/pdf-download/64097",previewPdfUrl:"/chapter/pdf-preview/64097",authors:[null],corrections:null},{id:"63461",title:"Towards Enhancing the Efficiency of Nonlinear Optical Generation",doi:"10.5772/intechopen.80816",slug:"towards-enhancing-the-efficiency-of-nonlinear-optical-generation",totalDownloads:905,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The chapter dwells on two novel approaches towards enhancing the efficiency of nonlinear optical generation. The former is to enable the unabsorbed pump beam to pass through the crystal repeatedly. Integration of an unstable cavity containing the crystal with the stable pump cavity made this possible. The Q of the unstable cavity could be maintained high as the output coupler of the pump laser, itself served as the entrance mirror of this cavity. The unstable nature of the cavity kept the crystal from being exposed to high flux while ensuring longer interaction length. Although this scheme demonstrated in mid-IR region its advantage should persist across UV, visible, and near-IR regions too. The enhancement of conversion efficiency is effected in the second scheme by way of illuminating the crystal with alternate high and low regions of intensity along its length as against the uniform illumination case maintaining the same average intensity as in the conventional operation. The advantage is attributed to the square dependence of the second harmonic on the intensity of the pump. A simple modification of the existing experimental setup involving integration of an additional optical element with the pump cavity allowed exploitation of interference effect to realise such a non-uniform illumination condition.",signatures:"Padma Nilaya J. and Dhruba J. Biswas",downloadPdfUrl:"/chapter/pdf-download/63461",previewPdfUrl:"/chapter/pdf-preview/63461",authors:[null],corrections:null},{id:"63480",title:"Widely Tunable Quantum-Well Laser: OPO Diode Around 2 μm Based on a Coupled Waveguide Heterostructure",doi:"10.5772/intechopen.80517",slug:"widely-tunable-quantum-well-laser-opo-diode-around-2-m-based-on-a-coupled-waveguide-heterostructure",totalDownloads:895,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"We present the design of a widely tunable monolithic source on GaAs/AlGaAs. It consists of a quantum-well distributed feedback (DFB) laser vertically coupled with a waveguide engineered for nonlinear frequency conversion. No regrowth or alignment is necessary, and all the structure stems from a single epitaxy step. Light is emitted by the 0.98 μm DFB laser and transmitted to the underlying waveguide by an adiabatic taper, where it can undergo parametric down-conversion, providing signal and idler beams around 2 μm. Transfer rates and tolerances for transfer and conversion efficiency are calculated to be compatible with the tolerances of current fabrication processes. We estimate that an OPO threshold can be reached in the underlying waveguide for a laser emitted power of 20–100 mW, if high-reflectivity distributed Bragg reflectors (DBRs) are used.",signatures:"Alice Bernard, Jean-Michel Gérard, Ivan Favero and Giuseppe Leo",downloadPdfUrl:"/chapter/pdf-download/63480",previewPdfUrl:"/chapter/pdf-preview/63480",authors:[null],corrections:null},{id:"63398",title:"Stimulated Raman Scattering in Micro- and Nanophotonics",doi:"10.5772/intechopen.80814",slug:"stimulated-raman-scattering-in-micro-and-nanophotonics",totalDownloads:1229,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Micro- and nanophotonics explore behavior of light on the micro-/nanoscale and the interaction of micro-/nanoobjects with light. The driving force for their development is the aim to go beyond the limit of photonics. Because of the diffraction limit, photonics components are not able to confine light to the microscale or nanoscale dimension; therefore, one of the key challenges for micro- and nanophotonics is a reduction in the size of integrated optical devices, while maintaining a high level of performance. As far as light amplifiers and laser sources based on stimulated Raman scattering (SRS) are concerned, important accomplishments have been achieved in the fields of fiber optics amplification and integrated photonics devices. In this chapter, the most interesting investigations in the field of stimulated Raman scattering in micro- and nanophotonics are reviewed. These findings provide promising perspectives for integrated micro-/nano-Raman lasers.",signatures:"Maria Antonietta Ferrara and Luigi Sirleto",downloadPdfUrl:"/chapter/pdf-download/63398",previewPdfUrl:"/chapter/pdf-preview/63398",authors:[{id:"104314",title:"Dr.",name:"Maria Antonietta",surname:"Ferrara",slug:"maria-antonietta-ferrara",fullName:"Maria Antonietta Ferrara"},{id:"247769",title:"Ph.D.",name:"Luigi",surname:"Sirleto",slug:"luigi-sirleto",fullName:"Luigi Sirleto"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3674",title:"Ultra Wideband",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"ultra-wideband",bookSignature:"Boris Lembrikov",coverURL:"https://cdn.intechopen.com/books/images_new/3674.jpg",editedByType:"Edited by",editors:[{id:"2359",title:"Dr.",name:"Boris I.",surname:"Lembrikov",slug:"boris-i.-lembrikov",fullName:"Boris I. 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Clinically, it is characterized by a progressive loss of articular cartilage and remodeling of the underlying bone remodeling due to a combination of an active response of chondrocytes and the inflammatory cells in the surrounding tissues. Recent research place greater emphasis to promotes our understanding of the OA pathophysiology. A variety of risk factors have been identified. These include gender, traumatic injury, obesity, metabolic dysfunction, nutrition, mechanical factors, and environmental and genetic factors. Extensive research over the past 20 years provided a better understanding, diagnosis, and management of OA. The first part of this book deals with the current progress of OA imaging diagnosis and treatments. The second part discusses how exercise could benefit those with OA. The third part explores potential shreds of evidence of medicinal plants in the strategies for disease prevention.
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Understanding the effect of renal transporters on the distribution of drugs, metabolites, and endogenous compounds (e.g., biomarkers for renal toxicity and physiological regulators) are important in safety assessment studies [1]. Drugs (and their metabolites) that preferentially distribute into the kidney may have a greater potential to induce renal toxicity because these compounds may accumulate in the cells surrounding/forming the renal tubules. This disposition may not be deduced by simply sampling plasma; therefore, sampling kidney tissue in addition to plasma is important for measuring concentrations of drugs when renal toxicity is observed in animals. In human safety assessment, sampling of kidney is not generally feasible; therefore, the utility of qualified tissue-, serum- and/or urine-specific biomarkers may help to extrapolate between animal tissue and human exposures.
This chapter will review the role of renal transporters and biomarkers in the safety assessment of drug candidates. Membrane permeability and types of drug transporters will be introduced with focus on specific renal transporters. Examples of cause-effect relationships between renal transporters and toxicity will be discussed. The effect of drugs on the ability of renal transporters to regulate the disposition of endogenous compounds involved in maintaining homeostasis will be discussed. In addition, a case example on the effect of a proprietary drug candidate on a classical biomarker of renal safety will be highlighted where an increase of this biomarker via inhibition of a renal transporter was determined to be benign and not the consequence of renal toxicity. Finally, we will highlight the recent qualification of novel diagnostic renal urinary biomarkers that outperform the traditional renal biomarkers, serum creatinine (sCr) and/or blood urea nitrogen (BUN) in monitoring renal injury in preclinical (rat) studies. We will also highlight use of selected novel renal biomarkers in rat and dog studies with the paradigm renal toxicant, cisplatin.
Molecules cross cellular barriers by three main pathways: (1) passive diffusion across the cell membranes; (2) passive diffusion between adjacent cells; and (3) carrier-mediated transport (Fig. 1). Lipophilic molecules cross the cells membrane by transcellular diffusion. By contrast, hydrophilic molecules that are not recognized by a carrier cannot partition into the hydrophobic membrane and thus traverse the epithelial barrier via the paracellular pathway. Hormones and certain immune system molecules can utilize membrane invaginations for transport across the cell (e.g. via caveolae). All other compounds must interact with carrier proteins, either in a facilitated manner (down the concentration gradient) or via “active” transport, potentially against a concentration gradient. The driving force to allow active transport may include the use of ATP hydrolysis, pH gradients, or electrogenic properties of the cell. [2]
Routes of translocation through cellular barriers. ① Lipid soluble compounds can permeate through the epithelium by simple passive diffusion (transcellular route).
Transporters depicted in Pathway
Transporters depicted in Pathway
For pharmaceutical compounds, members of the Solute Carrier (SLC) superfamily of membrane transport proteins (depicted in Pathway
The kidney is responsible for clearance of many drugs including polar hydrophilic compounds such as ß-lactam antibiotics and non-steroidal anti-inflammatory drugs [9]. Polar compounds may be actively taken up by the proximal tubule cells through a variety of transporters including OCT2, OAT1 and 3 (Fig. 2, Table 1). Once taken up into the proximal tubule cells, compounds generally must efflux out of the cells into the urine by a different set of transporters including MRP2, P-gp, and MRP4 (i.e., facilitation of tubular secretion). In the human kidney, the order of transporter mRNA expression (highest to lowest) is OAT1, OAT3, P-gp, MRP2, and OCT2 [10].
Recently, the importance of renal transporters called multidrug and toxin extrusion proteins (MATE), which are expressed in the apical (luminal) membrane of proximal tubule epithelial cells, have been highlighted [11]. Functionally, MATEs act as efflux transporters, thereby mediating the excretion of metabolic waste products and xenobiotics. Two isoforms, MATE1 and 2, have been identified, and, so far, only a limited number of substrates, including clinically used drugs such as metformin and cimetidine, are known [12].
Compounds may be reabsorbed from the tubular fluid back into the tubule cells or cleared from the body. The interplay between various transporters located on the basolateral (blood) or apical (luminal) side dictates the overall renal clearance of a compound. As with the liver, renal transporters can therefore be a site of potential drug-drug interactions (DDI). Inhibition of the basolateral transporters (by the primary compound, metabolites, or a co-administered compound) can lead to increased exposure of the drug and longer half-lives in the systemic circulation. Inhibition of renal uptake of some drugs may actually induce toxicity by inhibiting their renal excretion. For example, severe methotrexate toxicity due to an increase in serum concentrations was observed in patients after co-administration with probenecid which inhibited OAT1 and MRP, and consequently the tubular secretion of methotrexate [13, 14]. Inhibition of the luminal efflux transporters, again by either the compound itself or a co-administered drug, can also cause an increase in systemic exposure if the basolateral transporters are able to transport the compound back into the systemic circulation. Alternatively, inhibition of the luminal efflux transporters can cause a compound to be “trapped” in the cell which may lead to renal toxicity [2].
Select drug transporters located in the kidney predicted to play a role in drug distribution and elimination. Influx transporters located on the basolateral or blood side of the kidney tubule cells include the organic anion transporters OAT1 and 3, and the organic cation transporter OCT2. Efflux transporters located on the basolateral side include multiple members of the multidrug resistance protein family such as MRP1 and MRP6. Efflux transporters located on the apical or luminal side of the tubule membrane which pump drugs from the interior of the tubule cell into the tubular fluid include P-gp, MRP2 and MRP4 ([
OCT2/SLC22A2 | \n\t\t\tcimetidine, metformin, MPP+, quinine TEA | \n\t\t\tcimetidine, clonidine, procainamide, quinine | \n\t\t\t[15, 16] | \n\t\t
OAT1/SLC22A6 | \n\t\t\tadefovir, para-aminohippurate, furosemide | \n\t\t\tfurosemide, indomethacin, probenecid, urate | \n\t\t\t[17, 18] | \n\t\t
OAT3/SLC22A8 | \n\t\t\tbenzylpenicillin, furosemide, methotrexate, pravastatin | \n\t\t\tgemfibrozil, indomethacin, probenecid, salicylate | \n\t\t\t[17, 19] | \n\t\t
P-gp/ABCB1 | \n\t\t\tdigoxin, daunorubicin, doxorubicin, fexofenadine, irinotecan, paclitaxel, quinidine, saquinavir, verapamil | \n\t\t\tcyclosporine A, elacridar, quinidine, valspodar, verapamil | \n\t\t\t[4, 5, 20, 21] | \n\t\t
MRP1/ABCC1 | \n\t\t\tdaunorubicin, etoposide, methotrexate, glutathione, glucuronide and sulfate conjugates, vincristine | \n\t\t\tdelavirdine, efavirenz, MK571, probenecid | \n\t\t\t[6, 20] | \n\t\t
MRP2/ABCC2 | \n\t\t\tSimilar to MRP1, cisplatin, methotrexate | \n\t\t\tdelavirdine, efavirenz, MK571, probenecid | \n\t\t\t[20, 22, 23] | \n\t\t
MRP4/ABCC4 | \n\t\t\tadefovir, azidothymidine monophosphate, prostaglandins, methotrexate | \n\t\t\tindomethacin, ketoprofen | \n\t\t\t[24, 25] | \n\t\t
Substrates and inhibitors of select renal transporters ([2]; partially reproduced with permission)
Compound-induced toxicities can be better extrapolated from animals to humans when these comparisons are based on toxicokinetics instead of dose alone [26]. For example, the safety margin that is based on the ratio of the animal exposure at the no observed adverse effect level (NOAEL) to human exposure at the efficacious dose is a key predictor of human safety risk. To calculate this safety margin, the animal and human exposure is determined by analyzing drug and metabolite(s) concentrations in plasma, which is the most practical and widely accepted way of assessing this risk. However, most safety issues are not due to drug plasma concentration but due to concentration of drug in various organs/tissues.
Sampling plasma and extrapolating this exposure to organs or tissues assumes that 1) concentration of drug in plasma is in equilibrium with concentrations in tissues, 2) changes in plasma drug concentrations reflect changes in tissue drug concentrations over time, and 3) distribution of drug and its metabolites are not affected by cells (e.g., drug transporters and enzymes) that protect many of these tissues [27]. Drug transport into tissues may not be a passive process and may depend on drug transporters, and thus these assumptions may result in an inaccurate assessment of target organ exposure to drug and/or metabolites. Even without a drug being a substrate for a drug transporter, lysosomal trapping of weak bases (e.g., liver and lung) or accumulation in membranes (e.g., muscle) can occur that can subsequently give rise to preferential distribution of the drug and its metabolites. For more details, refer to http://www.intechopen.com/books/toxicity-and-drug-testing/toxicokinetics-and-organ-specific-toxicity [27].
If the compound enters tubular cells via uptake transporters (e.g. OCT2, OAT1, OAT3), but not effluxed (into luminal fluid or urine), very high compound concentrations can occur in the renal cells/tissue. A convincing cause-effect relationship exists between uptake of renal toxicants via transporters and associated renal toxicity where co-administration of probenecid (inhibits renal uptake of organic anions) or either cimetidine or imatinib (inhibits renal uptake of organic cations) may reduce renal toxicity (by limiting uptake). For example, co-administration of cisplatin with imatinib prevents cisplatin-induced renal toxicity by inhibiting influx via OCT2 [28]. Another example is co-administration of cephaloridine with probenecid lowers the potential risk of cephaloridine-induced renal toxicity by inhibiting the OAT1-mediated transport of cephaloridine into the proximal tubule cell [29].
Influx transporter OAT1 (minor contribution by OAT3) is involved in the renal safety of acyclic nucleotide phosphonates (adefovir, cidofovir, and tenofovir), which are eliminated predominantly into the urine [30-32]. The dose-limiting toxicity for acyclic nucleotide phosphonates is renal failure, particularly for adefovir and cidofovir which may accumulate in the kidney [33, 34]. Patients treated with tenofovir exhibit a lower incidence of renal dysfunction at doses used to treat HIV compared to adefovir and cidofovir [35, 36]. In vitro studies showed that cells expressing human OAT1 showed enhanced toxicity to adefovir and cidofovir [500-fold) compared to cells that do not express OAT1 [37]. Unlike adefovir and cidofovir, tenofovir is less nephrotoxic to OAT1-expressing cells [38]. Additional in vitro studies demonstrated that OAT1 inhibitors such as nonsteroidal anti-inflammatory drugs, protect OAT1-expressing cells from adefovir- and cidofovir-induced cytotoxicity by preventing their cellular accumulation [39].
Efflux transporters in the kidney also play a potential role in the safety of a drug by pumping the drug out of the tubule cell and into the blood or urine (tubular fluid) and preventing the accumulation of the drug in the tubule cell. For example, the efflux transporters, MRPs, may be another crucial factor in the renal accumulation of acyclic nucleotide analogs (in addition to the uptake) and subsequent nephrotoxicity. Interestingly, renal toxicity in patients is observed with tenofovir when co-administered with an inhibitor of MRP2, ritonavir [40]. However, tenofovir is also a substrate for MRP4 that may not be inhibited by ritonavir [41, 42]. Other members of the MRP family (MRP5 and 8) may also be involved in the transport of acyclic nucleotide analogs [43]. Transport of adefovir and cidofovir was not observed in the membrane vesicles expressing human MRP2 and BCRP; furthermore, transport of adefovir and tenofovir but not cidofovir was observed only in the membrane vesicles expressing MRP4 [41]. To support these in vitro observations, the kidney accumulation of adefovir and tenofovir was significantly greater in Mrp4 knockout mice; however, there was no change in the kinetic parameters of cidofovir in these mice [41].
Another example of the relationship between efflux transporters and renal safety is MATE and platinum drugs. MATE can effectively mediate the transport of oxaliplatin, but not that of cisplatin [44]. Interestingly, oxaliplatin is effectively transported into renal proximal tubular cells by OCT2 but does not accumulate due to MATE-mediated renal extrusion, which may be the reason that oxaliplatin is much less nephrotoxic than cisplatin. Therefore, the interplay between renal OCTs and MATEs may influence the pharmacokinetics of platinum compounds and may critically determine the severity of platinum-associated adverse events [45].
This idea of reducing tubule exposure or even renal tissue half-life and consequently increasing the safety of drugs is also emphasized by studies investigating differences in renal safety of bisphophonates. In a rat model, zoledronic acid, but not ibandronate, induces progressive renal toxicity [46]. Ibandronate has a terminal renal tissue half-life of 24 days [47], whereas the renal tissue half-life of zoledronic acid (150–200 days) does not allow enough time for repair of renal damage [48]. Renal excretion is the only route of elimination of bisphosphonates. Interestingly, studies in rats demonstrated that alendronate is actively secreted by an uncharacterized renal transport system, and not by the anionic or cationic renal transport systems [49].
Understanding the tissue distribution and the substrate specificity for drug transporters can significantly aid safety assessment. In addition, this increased understanding can support the development of drugs with improved safety [1, 27] and/or a different route of administration that avoids distribution to the organ(s) where the compound-induced toxicity occurs. For example, an aerosolized form of [14C]-cidofovir (dose-limiting toxicity is nephrotoxicity) administered to mice (via inhalation) results in the prolonged retention of radiolabeled drug in the lungs (site of initial viral replication) at levels exceeding those in the kidneys [34]. In contrast, subcutaneous injection produces much higher concentrations of [14C]-cidofovir in the kidneys compared to the lungs [34]. Possibly in the future, the disposition of drug candidates may be directed by targeting specific drug transporters in organs like the kidney to significantly improve the renal safety of the drug candidate.
Renal transporters regulate disposition of endogenous compounds that control homeostasis of a physiological system. Therefore, alteration in the activity of renal transporters by drugs may be a method to treat disease but also unexpected changes to the activity of these transporters may induce adverse effects. For example, Na+-dependent dicarboxylate transporters and OATs are involved in the disposition of dicarboxylates which are important regulators of the renovascular system; therefore, these renal transporters may play an important role in the maintenance of blood pressure [50]. Another example is the role of renal transporters in the regulation of serum uric acid levels where renal transporters of uric acid like GLUT9 (SLC2A9) may be a target for treatment of gout [51].
Recently, renal glucose transport has become a very active target for drug development. The kidney reabsorbs 99% of the glucose that filters through the renal glomeruli [52]. Approximately 90% of the glucose is reabsorbed by the low affinity, high capacity sodium-dependent glucose cotransporter (SGLT) 2 in the proximal tubules. The remaining glucose is reabsorbed by the high affinity, low capacity transporter, SGLT1 (expressed in the segment 3 of the proximal tubule). Co-transport with sodium enables movement of glucose by SGLTs against a concentration gradient, with the sodium gradient maintained by the Na+/K+ ATPase pump. Individuals with SGLT2 mutations (e.g., familial renal glucosuria or FRG) have persistent yet benign renal glucosuria [53]. Similar to the effect observed with FRG, novel drugs are being developed to reduce glucose reabsorption by inhibiting SGLT2. One such example, dapagliflozin is a selective SGLT2 inhibitor that is being developed for the treatment of type 2 diabetes mellitus, a disorder characterized by elevated blood glucose [54]. In diabetic rat models, dapagliflozin has been shown to decrease serum glucose concomitant with glycosuria. Similar effects have been observed in clinical trials with decreased hemoglobin A1c, fasting plasma glucose, postprandial glucose, and body weight in patients with type 2 diabetes.
Creatinine is a breakdown product of creatine phosphate in muscle that is cleared by glomerular filtration and tubular secretion, and is routinely used as a diagnostic biomarker of renal function. For example, sCr can be used to estimate creatinine clearance which is then used to calculate glomerular filtration rate (GFR). Generally, a doubling of sCr suggests a 50% reduction in GFR.
Yet, sCr measurement as an indicator of compound-induced renal toxicity is often unreliable as sCr levels can be altered by changes in the levels of muscle mass and/or dietary protein. For example, sCr levels are often less reliable for detecting impaired GFR in the elderly, females, those with chronic illness associated with muscle wasting, African Americans, amputees, and vegans; various equations can be used to adjust for some of these factors to obtain a more reliable estimation of GFR [55, 56].
Creatinine is actively secreted by organic cation transporters including OCT2 and MATE which results in an overestimation of GFR by up to 40% [57-60]. For example, a drug that inhibits OCT2 can cause an increase in sCr levels independent of renal impairment [61]. Increased sCr levels in such cases typically stabilize over time and are not considered clinically relevant.
sCr increases due to OCT2 and MATE inhibition show a characteristic temporal pattern. When a drug is administered over several days, creatinine levels increase quickly, reach a plateau, and return to baseline levels shortly after drug discontinuation. This pattern is illustrated in the following case example from a clinical study with Compound A (Fig. 3). Subjects were administered placebo or one of three dose levels of Compound A daily for 2 weeks. sCr levels were unchanged for the placebo group, but mild, dose-dependent increases were observed for subjects receiving Compound A. Increases were observed at the first post-treatment time point, and increased levels were maintained during the 2-week treatment period. sCr levels decreased once treatment was discontinued. In nonclinical studies (rat and monkey) with Compound A, there was no evidence of renal injury associated with sCr increases even when elevated sCr levels were maintained for durations as long as 9 months. The time course and magnitude of the sCr changes observed with Compound A are consistent with transporter inhibition and have been observed for marketed drugs, such as cimetidine and trimethoprim. For cimetidine, maximum inhibition of sCr secretion occurs within 24 hours after administration and sCr levels return to baseline several days after discontinuation of dosing [62].
Temporal pattern of sCr changes in human subjects following 14 days oral administration of Compound A.
A proposed strategy for investigating increased sCr levels when inhibition of renal transporter(s) is suspected is provided in Fig. 4. First, GFR should be determined with an alternative method (e.g., measurement of serum levels of cystatin C) to rule out renal impairment as a cause for the creatinine increase. Serum cystatin C is a more accurate biomarker for GFR estimation because it is filtered in the glomeruli, but not secreted by renal transporters [55]. Other methods such as inulin [63] or radioisotopes also are available, but are impractical clinically as these methods can be costly and time-consuming and may delay clinical intervention. If the GFR measured with an alternative method remains suppressed, potential renal injury can be investigated with various biomarkers (see Section 7). If GFR is not affected, then OCT2 or MATE inhibition can be explored with an in vitro study. An IC50 in the range of clinically relevant concentrations would support inhibition of renal transporters as the mechanism for the sCr increase. Other mechanisms such as changes in sCr production (e.g., diet, disease status) would need to be explored if the sCr increase is not explained by inhibition of renal transporters.
Strategy to investigate involvement of renal transporters in sCr changes.
Inhibition of metformin uptake into CHO cells expressing OCT2 by Compound A. With CHO cells, stably transfected with cDNA encoding for OCT2, transport of a prototypical substrate of OCT2, metformin (10 µM, 1 min) was determined in the presence and absence of various concentrations of Compound A.
Compound A was investigated with the described strategy (Fig. 4). Although sCr was increased, GFR was not affected when calculated with serum cystatin C. Compound A was then tested for OCT2 inhibition and shown to inhibit metformin uptake into CHO cells expressing OCT2 in a concentration-dependent manner (Fig. 5). Concentrations of Compound A were similar between the in vitro inhibition profile and human plasma concentrations where sCr increases were observed. Based on these data, Compound A was considered to increase sCr levels by inhibiting tubular secretion of creatinine via OCT2.
Similar to OCT2, elevation of sCr by a drug can also occur with the inhibition of MATE transporters. For example, pyrimethamine, a potent inhibitor of MATE transporters and a weak inhibitor of OCT2 [64], increased sCr within 28 h from 81 +/- 14 to 102 +/- 16 µM (P = 0.002) in the healthy volunteers [65]. Therefore, inhibition of MATE transporters should also be considered to be a potential mechanism when increased levels of sCr are clinically-associated with drug administration.
While the aforementioned examples in this chapter show that concentrations of drug and/or metabolites in tissues provide greater predictivity for toxicity compared to plasma, routine tissue sampling is not generally feasible in clinical safety assessments. Biomarkers are important tools in renal safety assessment because they can provide early and non-invasive indication of compound-induced toxicities. Regulatory agencies (i.e., United States Food & Drug Administration, FDA; European Medicines Agency, EMA and/or Japanese Pharmaceuticals & Medical Devices Agency, PMDA) have recognized the need for novel, qualified, translational renal biomarkers [66-68]. Traditional renal biomarkers, sCr and BUN, used in both preclinical and clinical settings lack both specificity and sensitivity. For example, increases in sCr and BUN levels may reflect alteration in GFR that can occur with or without renal tubular pathology and increases in sCr and BUN are measureable 2-3 days after significant loss of renal function because the kidney has a huge functional reserve [69, 70]. Increased sCr may be predictive of kidney injury only when nearly half of the functional nephron capacity has been lost and the kidneys are unable to regulate fluid and electrolyte homeostasis [71]. sCr may also be elevated due to physiologic states unrelated to compound-induced nephrotoxicity such as dehydration and muscle damage [68, 72].
To date, eight urinary rat renal biomarkers have been qualified by the Critical Path Institute’s Predictive Safety Testing Consortium (PSTC), Nephrotoxicity Working Group [66, 67] and the International Life Sciences Institute-Health and Environmental Safety Institute (ILSI-HESI), Biomarkers of Nephrotoxicity Project Group [68] for monitoring compound-induced, progressive renal injury in rats. The qualified rat renal biomarkers include urinary markers: kidney injury molecule-1 (KIM-1), albumin, total protein, ß2-microalbumin, cystatin C, clusterin, trefoil factor-3 (TFF-3) and renal papillary antigen-1 (RPA-1). These novel biomarkers are highly sensitive, specific (show differential expression patterns within nephron segments), and add to the diagnostic values of sCr and BUN.
The utility of these qualified rat urinary renal biomarkers include monitoring renal function, tissue injury response and tissue leakage [72]. Functional renal biomarkers are used for monitoring changes in renal physiology, GFR and/or tubular reabsorption and include urinary total protein [73-77], albumin [75, 78, 79], ß2-microalbumin [80], and cystatin C. High levels of proteins in urine (proteinuria) indicate progressive loss of renal function and alterations of the glomerular filtration barrier such as damage to the glomerular podocytes or leakage of plasma proteins into the filtrate. Urinary albumin is synthesized in the liver, circulates in systemic blood vessels, and is a major high molecular weight serum protein larger than the pores of the glomerular filter. Albumin is normally filtered and absorbed by proximal tubule epithelium, degraded, and reutilized or excreted into the urine; therefore, the appearance of albumin in urine represents injury to the glomerular basement membrane [72]. Glomerular injury with subsequent impairment of tubular reabsorption may be detected by urinary levels of ß2-microalbumin and cystatin C; which appear to be more reliable than traditional renal biomarkers, sCr and BUN [67]. The gene for cystatin C is expressed in all nucleated cells and bears the characteristics of a housekeeping gene; therefore, cystatin C production rate is assumed to remain constant, a characteristic which lends to its utility in the clinic as an endogenous marker of GFR [80]. ß2-microalbumin is produced by mononulear cells which limits use as a GFR marker.
Urinary total protein, urinary albumin, urinary ß2-microalbumin and urinary cystatin C are qualified for use in GLP rat studies to assess potential glomerular changes and/or impaired tubular reabsorption [67]. When compound-induced tubular injury or glomerular alterations have been identified in rat studies, urinary total protein, urinary albumin, urinary β2-microglobulin and urinary cystatin C can be used as bridging biomarkers to monitor kidney safety in clinical settings.
Renal tissue injury response biomarkers that have been qualified for monitoring compound-induced renal injury in the rat include urinary KIM-1, urinary clusterin, urinary RPA-1 and urinary TFF-3. Urinary KIM-1, also referred to as T-cell immunoglobulin mucin-1 (TIM-1) or hepatitis A virus cellular receptor-1 (HAVCR-1) is expressed primarily but not exclusively in proximal tubular epithelial cells and lymphocytes [81, 82]. KIM-1 mRNA and subsequently KIM-1 protein is expressed during de-differentiation of proximal tubular epithelial cells. KIM-1 has been reported to function as a receptor in the phagocytosis of apoptotic tubule epithelial cells [82]. When KIM-1 protein is cleaved, the ectodomain is shed into the urine and is stable at room temperature for several hours. KIM-1 has specificity and sensitivity for use as a urinary biomarker to monitor compound-induced proximal tubular injury in rats. Similar KIM-1 characteristics observed in the rat have been demonstrated in humans; and the cleaved ectodomain of KIM-1 can be detected in the urine of patients with acute tubular necrosis; therefore, urinary KIM-1 is also considered qualified as a clinical bridging biomarker to monitor kidney safety in clinical studies on a “case-by-case” basis following the identification of tubular injury in rats [82].
Early detection and sensitivity of urinary KIM-1 as a biomarker of renal tubular injury were demonstrated with a model of cisplatin-induced acute kidney injury (AKI) in male Sprague Dawley rats treated for 1, 3, 5, 7, or 14 days at 1 mg/kg/day [83]. As early as 1 day after cisplatin treatment, positive KIM-1 immunostaining, observed in the outer medulla of the kidney, indicated the onset of proximal tubular injury in the absence of functional changes. After 3 days of treatment, KIM-1 protein levels in urine increased more than 20-fold concurrently with tubular basophilia. After 5 days, sCr and BUN levels were elevated concurrently with tubular degeneration. Cisplatin-induced increases in urinary and renal KIM-1 protein levels were detected prior to changes in BUN, demonstrating the sensitivity of KIM-1 as a diagnostic tool for detection of compound-induced proximal tubular injury in rats.
In another study in male Beagle dogs, KIM-1 was identified as a renal tissue injury response marker (author’s unpublished data). Animals were intravenously administered cisplatin [0.75 mg/kg/day for up to 5 days) and humanely euthanized when sCr levels were ≥1.9 mg/dL, indicating significant loss of GFR. AKI was histologically characterized by tubule dilatation, vacuolization, degeneration, regeneration, and interstitial inflammation. Increased sCr was not observed until approximately day 16 (Fig. 6], while increased urinary KIM-1 mRNA levels were detected as early as Day 2 and were highly predictive of cisplatin-induced renal tissue injury. KIM-1 protein expression was detected in the injured proximal tubular epithelial cells (degenerated, vacuolized and dilated tubules) or regenerated proximal tubular epithelial cells (tubular basophilia), primarily in the S2 segment correlated with histomorphologic changes (Fig. 7). Neither urinary KIM-1 mRNA by quantitative polymerase chain reaction analysis nor renal KIM-1 protein expression with immunostaining in canines with compound-induced AKI has been previously reported.
sCr and urinary KIM-1 (uKIM-1] mRNA measurements in dogs with cisplatin-induced AKI. (A) sCr increased significantly in one dog on day 16. (B) Relative quantification of uKIM-1 mRNA levels in dogs with cisplatin-induced AKI. Data are means ± SEM; a indicates P<0.001, b indicates P<0.01, and c and * indicate P<0.05 relative to predose (Pre) values.
Representative hematoxylin and eosin-staining in a cisplatin-treated dog indicating tubular degeneration in proximal tubules (c); representative cytoplasmic renal KIM-1 immunostaining in S2 segment proximal tubular epithelial cells (a, b and d).
Another renal injury biomarker, clusterin, exists as a secreted isoform or a nuclear isoform, although only the 80 kDa glycosylated secreted isoform is constitutively expressed during early stages of renal development and later in response to injury to proximal and distal tubules, papillae, glomeruli, and collecting ducts [72, 81, 84, 85]. Secreted clusterin is believed to be anti-apoptotic, and involved in lipid recycling, cell aggregation and cell attachment. Urinary clusterin levels correlate with the severity of tubular damage [84]. In male Wistar rats, clusterin mRNA was markedly induced and immunostaining demonstrated clusterin primarily in tubules in the cortex and medulla following administration of puromycin aminonucleoside (15 mg/100 g body weight, subcutaneously). Clusterin may differentiate between glomerular and tubular injuries [84]. In a model of cisplatin-induced AKI in male Sprague Dawley rats, urinary clusterin measurements were detected prior to changes in BUN [83]. Positive clusterin immunostaining accurately correlated with the histopathologic findings. Urinary clusterin has not been approved for clinical use [82].
Induction of RPA-1 expression correlates with immunoreactivity of inducible nitric oxide synthase (iNOS) and nitrotyrosine. Thus, RPA-1 is believed to be increased in the cytoplasm of intact cells of the collecting duct epithelium and proximal tubule epithelium following compound-induced injury to nephron segments as a result of iNOS-dependent signal transduction pathways [72, 86]. Rat renal RPA-1 is highly expressed in the epithelial cells in medullary (papilla) and cortical collecting ducts and in the medullary loop of Henle. In the rat, urinary RPA-1 is the qualified diagnostic marker of choice for monitoring compound-induced progressive renal papillary necrosis [50] and recovery [72]. TFF-3 is expressed in tubules of the outer stripe of the outer medulla; urinary TFF3 protein levels are markedly reduced in response to renal tubular injury [79]; however, TFF-3 may not outperform BUN and/or sCr to detect kidney injury in rats [79]. Neither urinary RPA-1 nor urinary TFF-3 [79] has been qualified for clinical use to date.
Tissue leakage markers: glutathione-S-transferase alpha (α-GST), glutathione-S-transferase-mu (mu-GST/GSTYb1), and N-acetyl-β-D-glucosaminidase (NAG) are released from cells upon structural damage to proximal tubular epithelium (rat α-GST) and distal tubular epithelium (rat mu-GST) and reflect primarily tubular cell necrosis in various animal models [83, 87, 88] and humans [89] where compound induced kidney injury was evident. Yet, α-GST, mu-GST, and NAG have not been qualified; and their translational characteristics have not been well defined to date.
In conclusion, the importance of biomarkers in renal safety assessment have been described with emphasis on those biomarkers that have been qualified in rats and on a case-by-case basis in the clinical setting [67]. Other potentially translational biomarkers of kidney injury have been reported and are under consideration for qualification [90-92]. In addition, biomarkers specific to a condition or disease are available. For example, erythropoietin (EPO) which is produced primarily by fibroblast-like cortical interstitial cells in the kidney and functions to prevent apoptosis of early erythroid precursor cells can be used as a biomarker for various conditions of anemia [93], secondary forms of polycythemia [94], and abuse of erythropoiesis-stimulating agents by athletes [95]. Another example is ferritin, a ubiquitous intracellular protein that functions to store iron in a non-toxic form [96]. Serum ferritin levels correlate with total body iron stores and is often used along with other iron tests as a biomarker for determination of endogenous iron stores to aid diagnosis of disease including but not limited to iron deficiency anemia and acute renal failure [97] in patients with nephrohotic proteinuria likely due to non-specific hepatic protein synthesis to compensate for loss of iron-binding transferrin [98].
Increased understanding of the effect of renal transporters on the distribution of a drug will enhance safety assessment. Limiting the accumulation and/or distribution of a compound to the kidney through selective interaction with renal transporters will potentially identify safer drugs. Renal transporters also can be exploited as potential targets for therapeutic agents by affecting the disposition of endogenous substrates. In the case of sCr, potential inhibition of renal transporters can limit its utility as a safety biomarker. Whereas data are available for the relationship between 8 qualified biomarkers that outperform sCr and/or BUN in monitoring compound-induced renal injury in rats, the translation from rats to humans is limited by the availability of qualified human biomarkers. Efforts are in progress to further assess the translatability of urinary biomarkers in higher species including canines, non-human primates and humans.
CF is a multi-organ disease that also affects the exocrine and endocrine pancreas [1]. CFRD is a discrete entity of type 3 Diabetes mellitus, displaying aspects from both type 1 Diabetes mellitus and type 2 Diabetes mellitus. It is the most frequent comorbidity in CF involving around 31% of CF patients older than 18 years [2] and up to more than 40% in those older than 30 years [3]. It results from involvement of the endocrine pancreatic function and is the end stage of early onset impaired glucose homeostasis [4]. Today, additional CFRD is still a risk factor for decreased pulmonary function but no longer for increased mortality [3]. In the past, an increased mortality, in part depending on sex and severe CFTR mutation, was observed [5]. Several aspects of the disease’s pathophysiology are not yet completely understood [6], but some new insights might help to understand the process [7]. Clinically, there is a need for screening since earlier prospective studies regarding CFRD showed that most CF patients exhibited no clinical signs of hyperglycemia at the time they were diagnosed with CFRD by oral glucose tolerance tests (OGTTs) [8]. The advantages and disadvantages of different screening approaches will be discussed. Even after diagnosis, there is some discussion on how to treat patients with CFRD diagnosed by screening. Guidelines recommended insulin treatment [9] but registry data from the US [2] and Europe [10] showed that a relevant proportion of CF patients with CFRD are not treated with daily insulin. Alternative treatment options might be needed, and a recent study demonstrated that oral antidiabetic drugs are not inferior to insulin regarding HbA1c over 2 years after CFRD was diagnosed by annual OGTT screening [11]. Upcoming CFTR modulator treatment is an interesting area regarding glucose homeostasis and CFRD. The results of two small case studies [12, 13] on CF patients treated with ivacaftor imply that there is a possibility that CFTR modulation might also influence insulin secretion. Additionally, a registry study showed a trend to a reduced prevalence of CFRD in those treated with ivacaftor for a longer time [14]. In another case study with five patients (F508 del homozygous) treated with lumacaftor/ivacaftor, no consistent effect on glucose tolerance or insulin secretion was observed [15]. Overall, there are a number of important aspects of CFRD, from its pathophysiology to screening, diagnosis, treatment, best methods of follow-up, and new perspectives with CFTR modulator treatment options.
In 1994, a first study reporting the prevalence of CFRD was published [16]. Prevalence was 14.7% in all Danish CF patients. More recent data from the CFF patient registry showed an age-dependent prevalence from around 2% in those younger than 10 years up to around 40–50% in adults [2]. The prevalence is in the same range as reported from Germany (Table 1) [17] as a European country. The prevalence varies between different European countries based on a recent report of the ECFS patient registry [18]. While diabetes prevalence has risen, incidence has fallen significantly: from 4 cases per 100 patient-years during the 1998–2002 interval to 2.7 cases per 100 patient-years between 2003 and 2008, representing a 40% decrease in the number of diabetes diagnoses in the US [3]. In a longitudinal study from the UK, the incidence was 3.5% (observation period 1996–2005) [19].
Severe genotype, pancreatic insufficiency, and female gender remain considerable intrinsic risk factors for early acquisition of CFRD [18]. In a large prospective study with 1093 patients, impaired fasting glucose, impaired glucose tolerance, and indeterminate glucose tolerance were all predictors of future CFRD [20] .
Diabetes in CF | 0–5 years | 6–11 yeas | 12–17 years | 18–29 years | 30–39 years | >40 years |
---|---|---|---|---|---|---|
Diabetes | 0.1 | 1.2 | 11.1 | 21.6 | 32.0 | 46.6 |
Of these CFRD | 0.0 | 100 | 86.7 | 96.5 | 94.5 | 94.3 |
Of these not CFRD | 0.1 | 0.0 | 13.3 | 3.6 | 5.5 | 5.7 |
Frequency in % of CF patients with diabetes in 2018.
Adapted from table 17 and table 18 [17].
An increased mortality used to be described mainly for female CF patients with CFRD [21]. Mortality rate decreased from 1992–1997 to 2003–2008 in females from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There was no longer a sex difference in mortality [3]. A follow-up study (2008–2012) from the same CF center reported that there still was a sex difference in adults, but only in severe genotypes with higher prevalence of CFRD, resulting in an increased mortality in females [22]. Consequently, there is still a discussion about the gender influence on CFRD and survival.
Since the CF gene was detected, there has been the question of a CFTR mutation/mutation class-related risk for CFRD or whether there are other mutations outside of the CFTR gene that may modify the risk of developing CFRD.
In a longitudinal study from the UK, CFTR mutation classes I and II were shown to increase the risk of CFRD independently of other known risk factors [19]. A more recent study reported the risk for CFRD and mortality in adults studied in the years 2008–2012 [22]. CFRD was associated with increased mortality independently of mutation category (mild or severe) [22].
A study looking for CFRD frequency in different age groups and the influence of mutation classes of the CFTR gene found that the prevalence of CFRD increased with age from 2.6% in patients <18 years to 22.1% in patients 18 years or older in those homozygous for group II (including del phen 508, the most frequent CFTR mutation) mutations. It was only 1.5% in patients 18 years or older in group IV/any CFTR mutations [23]. In general, group IV mutations are less severe than class II mutations and this results also in a low risk for CFRD. If CFRD as a complication of CF has developed, there is still an increased mortality risk even in mild mutation classes (e.g., CFTR mutation class IV), but the risk for developing CFRD is higher in severe CFTR mutation classes (e.g., CFTR mutation class I or II).
The frequency of HLA types related to type 1 or type 2 diabetes were in the same range in CF patients with or without diabetes. There was also no difference in frequency compared to normal population [23]. As for other comorbidities, there are also modifiers for CFRD. Susceptibility to CFRD is at least in part determined by variants at SLC26A9 and at four loci associated with type 2 diabetes in the general population [24]. In a very recent study, a wide overlap with genetic modifiers of type 2 diabetes was described [25]. This might allow for a stratification of CFRD screening. Those with less risk depending on CFTR mutation classes and modifier genes might be screened starting at an older age and less frequently than those with a high risk for CFRD.
The mechanism of how diabetes develops in CF is not yet completely understood. Difficult access to animal models and human pancreatic tissue may contribute to this situation. Two recent reviews focused on the pathogenesis of CFRD [26, 27]. Insulin secretion is reduced even with normal OGTT and this is observed even in kids [28]. Insulin sensitivity is not or only minimally impaired apart from severe infections or systemic glucocorticoid treatment [29]. An often-discussed question concerned the possible existence of a direct influence of CFTR on α or β-cells. In an elegant study, murine models of β-cell CFTR deletion and human pancreas and islets from controls and CF patients were used [7]. There were some important results: (1) In the murine cell model, CFTR did not affect β-cell function. (2) In human islets, nearly no expression of CFTR mRNA was detected. (3) Additionally, there was no CFTR protein or electrical activity. (4) The secretion of islet hormones (insulin and glucagon) was in the normal range and only minimal changes in important islet-regulatory transcripts were detected. (5) As a consequence of inflammation, only 35% of β-cell area was conserved and the other part of the islet was compounded by immune infiltration. Overall, CFRD seems to be a consequence of beta-cell loss, accompanied by inflammation of the islets. There is no reason to think that CFTR mutations directly cause islet dysfunction [7].
As there are usually no typical diabetes-related symptoms [8], there is a need to screen for CFRD. Guidelines recommended a regular oral glucose tolerance test (OGTT) for screening [9]. Annual screening should start at the age of 10 years, as recommended in the US and by the ECFS, or at 12 years, as recommended in the UK. Because OGTT is time-consuming for patients and CF center staff, there is some interest in more comfortable alternative methods. The screening rate with OGTT in CF is nowhere near the recommendations in guidelines. In median, only 61.3% of CF patients aged 10–17 years and only 32.8% of adults were screened by OGTT in the US [2]. Nevertheless, it is possible to increase the rate of screening by OGTT, as shown from a program in a pediatric CF center that increased its annual screening rate for outpatients from 45% to 71% [30].
In a registry study, it has recently been reported that CF centers that screen more frequently for CFRD detected CFRD earlier and that those that screened less often had a faster decrease in pulmonary function [31]. This supports the view that screening for CFRD is an important tool to optimize CF care.
HbA1c is quickly collected and simple to measure, which makes it a comfortable test for both patients and CF center staff. To reduce the need for OGTT, the question was whether HbA1c was able to identify those patients at risk for CFRD. However, because of low sensitivity to detect CFRD, HbA1c has not been recommended as a screening tool for CFRD [32] for many years. This has recently become controversial. If a low HbA1c (<5.5%) as threshold was used to identify CF patients with CFRD, the sensitivity covered a wide range from 93% [33] to only 78% [34]. As of now, there is not enough evidence that HbA1c is a reliable tool to screen for CFRD.
To make OGTT more comfortable for patients and staff, different modifications of the OGTT procedure were investigated. A shorter sample time (1 h) [35, 36] was discussed, as well as a lower glucose load (50 g) [37]. Both approaches need evaluation in a larger cohort. So far, standard (WHO) OGTT is still recommended.
Another way to uncover impaired glucose homeostasis and CFRD even earlier than using OGTT is CGM. OGTTs were compared with 6 days of CGM in detecting glucose disturbance in 30 CF patients (age: 10–18 years). CGM identified glucose changes that had been missed by OGTT. This might help to initiate treatment of glucose disturbance before CFRD is diagnosed [38]. However, since even OGTT is only rarely used in many CF centers there is no reason to expect that the more sophisticated CGM will be used more frequently.
OGTT: Glucose 1.75 g/kg body weight in 250–300 ml water max 75 g glucose drinking in 5 min
Performed after >8 h of fasting in the morning.
No physical activity during the test.
Often the OGTT is done during the annual assessment. No other investigations during the OGTT (such as an ultrasound) are allowed.
Blood glucose is measured before (0 min) and 60 min and 120 min after drinking the glucose load.
Disturbance of glucose homeostasis starts early in life, CFRD being the end stage [4]. This opens the discussion on the best time to start treatment even before CFRD is diagnosed by OGTT. Insulin is the only recommended treatment. This should be accompanied by an education program and dietary advice. Despite recommendations, insulin is used only in around 75% of all CFRD patients all over the world [2, 17, 40].
Insulin is the recommended treatment for CFRD. There are two problems with this recommendation. (1) A relevant percentage of CFRD patients do not use insulin (see Table 2). This is the case in the US [2], the UK [41], and Germany [17] at least, as the national registers documented. All these are registries sponsored by CF organizations. Data from a German/Austrian general diabetes registry [42] that collects data from both CFRD patients and type 1 and 2 diabetes patients have shown that only 77% of CFRD patients were on insulin [40]. There might be several reasons for this. First of all, most patients do not realize symptoms of hyperglycemia early in the course of CFRD [8]. Secondly, CF treatment is an enormous burden for adult CF patients and families [43] as well as for children with CF. They spent 74 min a day with treatment, compared to type 1 diabetes with 56 min and asthma with 6 min [44]. Perhaps they like to avoid this additional burden of insulin treatment. (2) The optimal insulin regime is not defined and different regimes are in use. This includes long-term once-daily insulin, intensified insulin treatment several times a day, or an insulin pump with continuous insulin and pushes with meals. The more intensive insulin treatment with a pump is less in use, at least in adolescents and young adults, compared to type 1 diabetes patients in the same age range [45]. In adult CFRD patients treated with insulin, the mean daily dose was not different to matched type 1 or type 2 diabetes patients [46].
Blood glucose mmol/l (mg/dl) | |||
---|---|---|---|
Start | 60 min | 120 min | |
Normal glucose tolerance (NGT) | <5·6 (100) | <11·1 (200) | <7·8 (140) |
Fasting hyperglycemia (FH) | >5·6 (100) and <7·0 (126) | <11·1 (200) | <7·8 (140) |
Impaired glucose tolerance (IGT) | <7·0 (126) | <11·1 (200) | >7·8 (140) <11·1 (200) |
Indeterminate glycemia (INDET) | <7·0 (126 ) | >11·1 (200) | <7·8 (140) |
Diabetes (CFRD) without FH | <7·0 (126) | – | >11·1 (200) |
CFRD with FH | ≥7·0 (126) | – | >11·1 (200) |
One single optimal insulin regime for all CFRD patients does not exist, since individual adjustment to medical needs and patients’ options is required. The treatment of CFRD is a team approach including dieticians, diabetologists, psychologists, and the CF physician.
Oral antidiabetic drugs have been used in CFRD for many years [47]. The group of sulfonylurea (glibenclamide) had some disadvantages. They showed inhibitions of CFTR Cl channels in vitro [48, 49, 50]. The non-sulfonylurea hypoglycemic agent repaglinide showed only a weak inhibition of CFTR Cl channels [51]. In 2001, a study was published that showed postprandial effects of premeal insulin lispro and premeal repaglinide on postprandial glucose levels in humans. Glucose decreased (peak, 2 h and 5 h AUC) with insulin lispro, and glucose decreased with repaglinide only 5 h AUC. Insulin secretion (5 h AUC) increased only with insulin lispro [52]. In the latest Cochrane review regarding the use of oral antidiabetic drugs in CFRD, published in 2016, it was concluded that controlled prospective studies are needed [53]. There are two prospective randomized controlled trials comparing the effects of insulin versus repaglinide in patients with newly diagnosed CFRD [11, 54]. In a 12-month trial, there was a significant increase in BMI only in the insulin group. Comparing the insulin to the repaglinide group, there was no significant difference in BMI, HbA1c, or pulmonary function changes over the study period [54]. In the other study over 24 months, there was no difference between the groups (insulin and repaglinide) regarding HbA1c, BMI, and pulmonary function. It was concluded from that study that at least a subgroup of patients with newly diagnosed CFRD can be treated initially with oral antidiabetic drugs [11]. This might be an option for those who refuse insulin due to the additional treatment burden (Table 3).
Indication therapy in case of CFRD | 0–5 years | 6–11 yeas | 12–17 years | 18–29 years | 30–39 years | >40 years |
---|---|---|---|---|---|---|
Insulin | 100 | 72.7 | 64.0 | 67.6 | 76.9 | 75.7 |
Oral antidiabetics | 0 | 9.1 | 11.0 | 9.3 | 9.3 | 8.8 |
Dietary measures | 0 | 27.3 | 39.0 | 21 | 25 | 23.3 |
Frequency in % of CF patients with indication therapies related to diabetes in 2018.
Adapted from table 22 and table 23 [17].
The well-known diet restrictions and advice for type 1 or type 2 diabetes are not transferable to CFRD. In CFRD, the patients need a high-caloric nutrition, in contrast to what is recommended in other types of diabetes. Therefore, a dietician trained in CFRD is needed to support the patient with detailed information regarding nutrition in the special situation of CFRD [55].
HbA1c is not recommended to diagnose CFRD (see Section 4.1.1.). The situation is different for monitoring CFRD. HbA1c is used to monitor glycemic control in CFRD. In CFRD, the target value for HbA1c should be lower than in type 1 diabetes, because in CFRD mean plasma glucose does not correlate with HbA1c [56]. This is, for example, incorporated in the Australian Standards of Care for CFRD [57]. Adults with CFRD have a significantly lower HbA1c value compared to type 1 diabetes adults (6.8% vs. 7.9%) [58]. How low HbA1c values should be to prevent long-term diabetic comorbidities like microangiopathies (see also Section 6.1) is unknown.
A more strict control of glucose homeostasis with insulin treatment is achievable with CGM and is accompanied by an improved clinical outcome [59]. This requires the cooperation of the entire CFRD team and particularly the support by a diabetologist.
In general, adherence to diabetes care guidelines (ADA/CFF) is suboptimal [40] and improvement is urgently needed.
With decreased mortality, CF patients spend more years living with CFRD. Today, CF patients tend to develop microvascular complications, much like patients with type 1 or type 2 diabetes [60]. In long-standing CFRD (>10 years) with fasting hyperglycemia, 14% of patients had microalbuminuria and 16% had retinopathy [61]. The percentage of patients with hypertension was lower in adult CFRD patients while the percentage of patients suffering from nephropathy was higher compared to type 1 and 2 diabetes [58]. These data underline the need for routine screening for CFRD complications.
More sophisticated eye investigations demonstrated changes at the retina level.
Screening for this kind of complication should be also mandatory [62]. Percentage of patients with retinopathy did not differ between adults with CFRD and type 1 or type 2 diabetes [58].
Macrovascular complications have not been described so far. However, with increasing duration of CFRD in older CF patients, this kind of complication has to be expected. Even microvascular complications develop later in CFRD than in other types of diabetes.
The risk for acute severe hyperglycemia exists but the condition is very rare [63]. Most CFRD patients do not develop a ketoacidosis. This might be related to residual insulin secretion and glucagon counter regulation. Hyperglycemia measured by HbA1c is a risk factor for mortality. In a prospective observational study, a HbA1c ≥ 6.5% was associated with a threefold increased risk of death [64]. Measuring HbA1c is mandatory and it should be kept in mind that the target value is lower than in type 1 or type 2 diabetes (see also Section 5.2.1).
The detected frequency of hypoglycemia is higher with CGM than with OGTT [65]. There is no prognostic relevance of hypoglycemia during OGT for later development of CFRD [66]. In general, it seems that the risk of hypoglycemia is not different from other types of diabetes and instruction on how to handle CFRD in daily life should address this risk.
With improved clinical course of CF and improved life expectancy, more female CF patients want to become pregnant. According to the UK guidelines [55], there are four groups.
CFRD and IGT: optimized diabetes control and needs to be referred to a specialized diabetes team.
NGT (tested in the last 3 months): OGT in first trimester and the next between week 24 and week 28.
Unknown glycemic status: OGT before becoming pregnant, if possible.
With better clinical conditions, physical activities in all age groups of CF patients increased. Patients with CFRD should exercise and be educated about the risk of hypoglycemia, like other diabetic patients. CFRD is no reason to stop physical activities.
Since 2012, there is a new class of medication for CF patients on the market. These drugs are called “CFTR modulators.” They are CFTR mutation specific and are administered orally. This offers the chance that these drugs might affect different organs that are reached by the bloodstream. The regulation of glucose homeostasis is a complex process and CFTR modulators might interfere at different steps.
Ivacaftor is a CFTR potentiator and acts with gating mutations (e.g., G551D). It increases pulmonary function, weight, and quality of life (QoL) and decreases sweat chloride concentration [67].
In two siblings, insulin secretion and glucose AUC were measured during an OGTT before and 16 weeks after initiation of ivacaftor [12]. This paper described the beneficial effect of 4-month ivacaftor treatment on the pathologic OGTT of two patients with CF carrying the S549R gating mutation. This beneficial effect may be partially due to the increased earlier insulin secretion capacity [12]. Two other studies also reported an increase in insulin secretion after ivacaftor was initiated in CF patients with a gating mutation [68, 69]. As of now, reports have included only small numbers of patients and/or are uncontrolled studies. Sufficiently powered studies are still missing. In a registry study using data from the US and the UK with a follow-up of more than 5 years, a trend to a reduced prevalence of CFRD in ivacaftor-treated patients [14] was reported. If this observation will be corroborated in future studies, many CF patients would benefit from a postponed CFRD treatment burden.
The combination therapy with ivacaftor/lumacaftor was administered to patients with the del F508 mutation [70]. The overall clinical effect regarding pulmonary function, weight, and QoL was low compared to ivacaftor in patients with a gating mutation [67]. Using CGM and OGTT to control glucose homeostasis in five patients after initiation of ivacaftor/lumacaftor treatment, glycemic abnormalities persisted [71]. A consistent impact of the combination of ivacaftor/lumacaftor on insulin secretion or glucose tolerance was not detected in five patients [15]. In a very recent article from France [72], the change of OGTT categories after 1 year of lumacaftor/ivacaftor treatment was described in an uncontrolled study design. The reported improvement, for example, from CFRD to IGT is within the range of the well-known high variability of OGTT results in CF patients [73]. It is not surprising that the combination treatment, which had less of an effect on clinical outcome in gating mutations compared to ivacaftor, has so far no proven effect on CFRD, even if only a small number of CF patients were investigated.
The recently published results with a triple combination CFTR modulator therapy in patients with a del phen 508 allele are impressive regarding pulmonary function increase, sweat chloride decrease, and other outcomes [74]. With a highly clinically effective CFTR modulator treatment and a sufficient number of patients, the demonstration of a positive influence on glucose homeostasis in a prospective study seems realistic.
However, there is currently no evidence-based information that CFTR modulators have a relevant influence on the complex pathophysiology regarding glucose homeostasis.
CFRD is still a highly relevant comorbidity in CF. Nevertheless, there are many questions regarding its optimal handling from both patients’ and physicians’ point of view. CFRD is a team approach, which includes the CF team but also the diabetes team.
Adherence to all aspects of CFRD diagnosis and treatment is low and needs urgent efforts to increase.
As long as no better screening procedure is established, 2h of OGTT should be used annually as screening for CFRD.
Education regarding CFRD should include patients, families, physicians, and the entire team.
Treatment as recommended by guidelines prefers only insulin. The recently published controlled prospective trials may endorse the use of oral antidiabetic drugs, at least in a subgroup of patients.
Monitoring must include all the measurements that are recommended for other types of diabetes. HbA1c target value for treatment should be lower than in type 1 or 2 diabetes.
Typical microvascular complications are reported and patients should be regularly checked for these.
In future, the new and effective CFTR modulator therapies might also influence the prevalence of CFRD. In a perfect world, they might also improve glucose homeostasis in patients with CFRD and postpone CFRD entirely.
The authors declare no conflict of interest.
Ove Odredbe i uvjeti ističu pravila i regulacije u svezi korištenja IntechOpenove stranice www.intechopen.com i svih poddomena u vlasništvu IntechOpena, tvrtke sa sjedištem u 5 Princes Gate Court, London, SW7 2QJ, Ujedinjeno Kraljevstvo.
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\\n\\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\\n\\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\\n\\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\\n\\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\\n\\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\\n\\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\\n\\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\\n\\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\\n\\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\\n\\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\\n\\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\\n\\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\\n\\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\\n\\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\\n\\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
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\n\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\n\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\n\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\n\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\n\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\n\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\n\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\n\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\n\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\n\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\n\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\n\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\n\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\n\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\n\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. 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The chapter is focused on the bimodal actions of ROS, which can be summarized as both beneficial and negative. The beneficial aspects of ROS are related to their effects on the redox state of cells and the important role that some ROS play in signaling cascade. The detrimental effects of ROS are related excess amounts of these chemical moieties, which are caused by excessive production and/or insufficient actions of endogenous antioxidants. The generation of these species is also discussed.",book:{id:"6333",slug:"reactive-oxygen-species-ros-in-living-cells",title:"Reactive Oxygen Species (ROS) in Living Cells",fullTitle:"Reactive Oxygen Species (ROS) in Living Cells"},signatures:"Roma Patel, Lindsey Rinker, Joanna Peng and William M. Chilian",authors:[{id:"192680",title:"Dr.",name:"Wiliam M.",middleName:null,surname:"Chilian",slug:"wiliam-m.-chilian",fullName:"Wiliam M. Chilian"},{id:"212032",title:"Ms.",name:"Lindsey",middleName:null,surname:"Rinker",slug:"lindsey-rinker",fullName:"Lindsey Rinker"},{id:"212033",title:"Ms.",name:"Roma",middleName:null,surname:"Patel",slug:"roma-patel",fullName:"Roma Patel"},{id:"212034",title:"Ms.",name:"Joanna",middleName:null,surname:"Peng",slug:"joanna-peng",fullName:"Joanna Peng"}]},{id:"58369",doi:"10.5772/intechopen.72747",title:"Reactive Oxygen Species in Skin Repair, Regeneration, Aging, and Inflammation",slug:"reactive-oxygen-species-in-skin-repair-regeneration-aging-and-inflammation",totalDownloads:2101,totalCrossrefCites:15,totalDimensionsCites:29,abstract:"As the most important and largest surface barrier, the skin provides a necessary protection to the organism from the external factors, including chemical, biological, and physical irritation, injury, and others. External environmental irritants or their metabolites are inherent oxidants and/or directly or indirectly drive the production of various reactive oxidants, reactive oxygen species (ROSs), owing to the redox imbalances. ROSs, the most common free oxygen radicals, participate in a series of physiological and pathological skin processes. Here, we discussed the role of oxidative events in injury, repair, photoaging, and cutaneous disease development. Intrinsic and extrinsic factors lead to the skin barrier damage, which leads to the disequilibrium in oxidant and antioxidant balance and induces excessive ROS production. The underlying mechanisms include DNA damage, MAPK/AP-1, NF-κB, and JAK/STAT-signaling pathways, apoptosis and autophagy, and autoimmune reaction of melanocytes and keratinocytes. The skin employs a number of antioxidant agents to protect the oxidative balance, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), ascorbic acid, and tocopherols. The results presented here indicate that antioxidant treatments may be effective when applied in the therapy of cutaneous diseases where oxidative stress plays a prominent pathogenic role.",book:{id:"6333",slug:"reactive-oxygen-species-ros-in-living-cells",title:"Reactive Oxygen Species (ROS) in Living Cells",fullTitle:"Reactive Oxygen Species (ROS) in Living Cells"},signatures:"Hui Xu, Yun-Wen Zheng, Qi Liu, Li-Ping Liu, Feng-Lin Luo, Hu-Chen\nZhou, Hiroko Isoda, Nobuhiro Ohkohchi and Yu-Mei Li",authors:[{id:"63284",title:"Prof.",name:"Nobuhiro",middleName:null,surname:"Ohkohchi",slug:"nobuhiro-ohkohchi",fullName:"Nobuhiro Ohkohchi"},{id:"216569",title:"Associate Prof.",name:"Yun-Wen",middleName:null,surname:"Zheng",slug:"yun-wen-zheng",fullName:"Yun-Wen Zheng"},{id:"216572",title:"Dr.",name:"Hui",middleName:null,surname:"Xu",slug:"hui-xu",fullName:"Hui Xu"},{id:"216574",title:"Dr.",name:"Qi",middleName:null,surname:"Liu",slug:"qi-liu",fullName:"Qi Liu"},{id:"216576",title:"Dr.",name:"Yu-Mei",middleName:null,surname:"Li",slug:"yu-mei-li",fullName:"Yu-Mei Li"},{id:"234877",title:"BSc.",name:"Feng-Lin",middleName:null,surname:"Luo",slug:"feng-lin-luo",fullName:"Feng-Lin Luo"},{id:"234878",title:"BSc.",name:"Zhou",middleName:null,surname:"Hu-Chen",slug:"zhou-hu-chen",fullName:"Zhou Hu-Chen"},{id:"234880",title:"Prof.",name:"Hiroko",middleName:null,surname:"Isoda",slug:"hiroko-isoda",fullName:"Hiroko Isoda"},{id:"234884",title:"Dr.",name:"Li-Ping",middleName:null,surname:"Liu",slug:"li-ping-liu",fullName:"Li-Ping Liu"}]},{id:"34558",doi:"10.5772/35847",title:"The Epididymis: Embryology, Structure, Function and Its Role in Fertilization and Infertility",slug:"the-epididymis-embryology-structure-function-and-its-role-in-fertilization-and-infertility",totalDownloads:13361,totalCrossrefCites:9,totalDimensionsCites:21,abstract:null,book:{id:"1699",slug:"embryology-updates-and-highlights-on-classic-topics",title:"Embryology",fullTitle:"Embryology - Updates and Highlights on Classic Topics"},signatures:"Kélen Fabiola Arrotéia, Patrick Vianna Garcia, Mainara Ferreira Barbieri, Marilia Lopes Justino and Luís Antonio Violin Pereira",authors:[{id:"106080",title:"Prof.",name:"Luis",middleName:"Antonio",surname:"Violin Pereira",slug:"luis-violin-pereira",fullName:"Luis Violin Pereira"},{id:"112722",title:"Dr.",name:"Kélen",middleName:null,surname:"Arrotéia",slug:"kelen-arroteia",fullName:"Kélen Arrotéia"},{id:"112724",title:"MSc.",name:"Patrick",middleName:null,surname:"Garcia",slug:"patrick-garcia",fullName:"Patrick Garcia"},{id:"112726",title:"BSc.",name:"Mainara",middleName:null,surname:"Barbieri",slug:"mainara-barbieri",fullName:"Mainara Barbieri"},{id:"112727",title:"BSc.",name:"Marília",middleName:null,surname:"Justino",slug:"marilia-justino",fullName:"Marília Justino"}]},{id:"58039",doi:"10.5772/intechopen.72217",title:"Role of Antioxidant Phytochemicals in Prevention, Formation and Treatment of Cancer",slug:"role-of-antioxidant-phytochemicals-in-prevention-formation-and-treatment-of-cancer",totalDownloads:1687,totalCrossrefCites:8,totalDimensionsCites:17,abstract:"Reactive oxygen species (ROS) played an important role in cancer. Although low levels of ROS can be beneficial in normal physiological functions, chronic exposure to ROS is associated with increased risk of cancers. Increased ROS levels can also induce apoptosis and cell death in various types of cancer. Taken together, the role of ROS in cancer prevention, formation and therapy is extremely complex and very challenging to study. Although the antioxidant activity of phytochemicals is well recognized and generally used to prevent cancer, they can have pro-oxidant and ROS generating activities under certain conditions, especially at high doses or in the presence of metal ions. The basal redox levels of cancer cells are also different from those of normal cells. Therefore, higher levels of free form of metal ions and higher levels of endogenous ROS production in cancer cells sensitizes them to phytochemicals mediated pro-oxidant cytotoxicity. In conclusion, people tend to intake of antioxidant phytochemicals for the detrimental effects of ROS. However, excessive intake of phytochemicals could have cancer development or therapeutic potential by generating ROS. In this section, the role of phytochemicals in the prevention, development and removal of cancer has been discussed.",book:{id:"6333",slug:"reactive-oxygen-species-ros-in-living-cells",title:"Reactive Oxygen Species (ROS) in Living Cells",fullTitle:"Reactive Oxygen Species (ROS) in Living Cells"},signatures:"Abdurrahim Kocyigit, Eray Metin Guler and Murat Dikilitas",authors:[{id:"87750",title:"Dr.",name:"Murat",middleName:null,surname:"Dikilitas",slug:"murat-dikilitas",fullName:"Murat Dikilitas"},{id:"213091",title:"Prof.",name:"Abdurrahim",middleName:null,surname:"Koçyiğit",slug:"abdurrahim-kocyigit",fullName:"Abdurrahim Koçyiğit"},{id:"223224",title:"Dr.",name:"Eray Metin",middleName:null,surname:"Guler",slug:"eray-metin-guler",fullName:"Eray Metin Guler"}]},{id:"62993",doi:"10.5772/intechopen.80056",title:"Role of Apoptosis in Cancer Resistance to Chemotherapy",slug:"role-of-apoptosis-in-cancer-resistance-to-chemotherapy",totalDownloads:1811,totalCrossrefCites:9,totalDimensionsCites:16,abstract:"Cancer is a leading cause of death in human beings. Surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy are common modalities for cancer treatment. However, cancer resistance is common in chemotherapy and often leads to therapeutic failure. This chapter addresses the role of apoptosis in tumor’s resistance to chemotherapy and the underlying mechanisms. Cancer cells are always resistant to apoptotic signals via a series of biochemical changes. Cancer cells are resistant to chemotherapeutic agents that are potent apoptosis inducers via multiple mechanisms, such as upregulated anti-apoptotic signals and downregulated pro-apoptotic signals, faulty apoptotic signaling, faulty apoptosis initiation and implementation, etc. We also discuss the possible approaches to overcoming cancer resistance to chemotherapy due to altered apoptosis.",book:{id:"6618",slug:"current-understanding-of-apoptosis-programmed-cell-death",title:"Current Understanding of Apoptosis",fullTitle:"Current Understanding of Apoptosis - Programmed Cell Death"},signatures:"Lichan Chen, Yanyun Zeng and Shu-Feng Zhou",authors:[{id:"229027",title:"Prof.",name:"Shu-Feng",middleName:null,surname:"Zhou",slug:"shu-feng-zhou",fullName:"Shu-Feng Zhou"}]}],mostDownloadedChaptersLast30Days:[{id:"18220",title:"How do Mesenchymal Stem Cells Repair?",slug:"how-do-mesenchymal-stem-cells-repair-",totalDownloads:6051,totalCrossrefCites:9,totalDimensionsCites:16,abstract:null,book:{id:"216",slug:"stem-cells-in-clinic-and-research",title:"Stem Cells in Clinic and Research",fullTitle:"Stem Cells in Clinic and Research"},signatures:"Patricia Semedo, Marina Burgos-Silva, Cassiano Donizetti-Oliveira and Niels Olsen Saraiva Camara",authors:[{id:"28751",title:"Prof.",name:"Niels",middleName:"Olsen Saraiva",surname:"Camara",slug:"niels-camara",fullName:"Niels Camara"},{id:"30464",title:"Prof.",name:"Patricia",middleName:null,surname:"Semedo",slug:"patricia-semedo",fullName:"Patricia Semedo"},{id:"30465",title:"BSc.",name:"Cassiano",middleName:null,surname:"Donizetti-Oliveira",slug:"cassiano-donizetti-oliveira",fullName:"Cassiano Donizetti-Oliveira"},{id:"30466",title:"BSc.",name:"Marina",middleName:null,surname:"Burgos-Silva",slug:"marina-burgos-silva",fullName:"Marina Burgos-Silva"}]},{id:"57536",title:"Reactive Oxygen Species: The Good and the Bad",slug:"reactive-oxygen-species-the-good-and-the-bad",totalDownloads:3607,totalCrossrefCites:23,totalDimensionsCites:42,abstract:"This chapter summarizes recent research on the biology of reactive oxygen species (ROS). The chapter is focused on the bimodal actions of ROS, which can be summarized as both beneficial and negative. The beneficial aspects of ROS are related to their effects on the redox state of cells and the important role that some ROS play in signaling cascade. The detrimental effects of ROS are related excess amounts of these chemical moieties, which are caused by excessive production and/or insufficient actions of endogenous antioxidants. The generation of these species is also discussed.",book:{id:"6333",slug:"reactive-oxygen-species-ros-in-living-cells",title:"Reactive Oxygen Species (ROS) in Living Cells",fullTitle:"Reactive Oxygen Species (ROS) in Living Cells"},signatures:"Roma Patel, Lindsey Rinker, Joanna Peng and William M. Chilian",authors:[{id:"192680",title:"Dr.",name:"Wiliam M.",middleName:null,surname:"Chilian",slug:"wiliam-m.-chilian",fullName:"Wiliam M. Chilian"},{id:"212032",title:"Ms.",name:"Lindsey",middleName:null,surname:"Rinker",slug:"lindsey-rinker",fullName:"Lindsey Rinker"},{id:"212033",title:"Ms.",name:"Roma",middleName:null,surname:"Patel",slug:"roma-patel",fullName:"Roma Patel"},{id:"212034",title:"Ms.",name:"Joanna",middleName:null,surname:"Peng",slug:"joanna-peng",fullName:"Joanna Peng"}]},{id:"62993",title:"Role of Apoptosis in Cancer Resistance to Chemotherapy",slug:"role-of-apoptosis-in-cancer-resistance-to-chemotherapy",totalDownloads:1811,totalCrossrefCites:9,totalDimensionsCites:16,abstract:"Cancer is a leading cause of death in human beings. Surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy are common modalities for cancer treatment. However, cancer resistance is common in chemotherapy and often leads to therapeutic failure. This chapter addresses the role of apoptosis in tumor’s resistance to chemotherapy and the underlying mechanisms. Cancer cells are always resistant to apoptotic signals via a series of biochemical changes. Cancer cells are resistant to chemotherapeutic agents that are potent apoptosis inducers via multiple mechanisms, such as upregulated anti-apoptotic signals and downregulated pro-apoptotic signals, faulty apoptotic signaling, faulty apoptosis initiation and implementation, etc. We also discuss the possible approaches to overcoming cancer resistance to chemotherapy due to altered apoptosis.",book:{id:"6618",slug:"current-understanding-of-apoptosis-programmed-cell-death",title:"Current Understanding of Apoptosis",fullTitle:"Current Understanding of Apoptosis - Programmed Cell Death"},signatures:"Lichan Chen, Yanyun Zeng and Shu-Feng Zhou",authors:[{id:"229027",title:"Prof.",name:"Shu-Feng",middleName:null,surname:"Zhou",slug:"shu-feng-zhou",fullName:"Shu-Feng Zhou"}]},{id:"58369",title:"Reactive Oxygen Species in Skin Repair, Regeneration, Aging, and Inflammation",slug:"reactive-oxygen-species-in-skin-repair-regeneration-aging-and-inflammation",totalDownloads:2101,totalCrossrefCites:15,totalDimensionsCites:29,abstract:"As the most important and largest surface barrier, the skin provides a necessary protection to the organism from the external factors, including chemical, biological, and physical irritation, injury, and others. External environmental irritants or their metabolites are inherent oxidants and/or directly or indirectly drive the production of various reactive oxidants, reactive oxygen species (ROSs), owing to the redox imbalances. ROSs, the most common free oxygen radicals, participate in a series of physiological and pathological skin processes. Here, we discussed the role of oxidative events in injury, repair, photoaging, and cutaneous disease development. Intrinsic and extrinsic factors lead to the skin barrier damage, which leads to the disequilibrium in oxidant and antioxidant balance and induces excessive ROS production. The underlying mechanisms include DNA damage, MAPK/AP-1, NF-κB, and JAK/STAT-signaling pathways, apoptosis and autophagy, and autoimmune reaction of melanocytes and keratinocytes. The skin employs a number of antioxidant agents to protect the oxidative balance, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), ascorbic acid, and tocopherols. The results presented here indicate that antioxidant treatments may be effective when applied in the therapy of cutaneous diseases where oxidative stress plays a prominent pathogenic role.",book:{id:"6333",slug:"reactive-oxygen-species-ros-in-living-cells",title:"Reactive Oxygen Species (ROS) in Living Cells",fullTitle:"Reactive Oxygen Species (ROS) in Living Cells"},signatures:"Hui Xu, Yun-Wen Zheng, Qi Liu, Li-Ping Liu, Feng-Lin Luo, Hu-Chen\nZhou, Hiroko Isoda, Nobuhiro Ohkohchi and Yu-Mei Li",authors:[{id:"63284",title:"Prof.",name:"Nobuhiro",middleName:null,surname:"Ohkohchi",slug:"nobuhiro-ohkohchi",fullName:"Nobuhiro Ohkohchi"},{id:"216569",title:"Associate Prof.",name:"Yun-Wen",middleName:null,surname:"Zheng",slug:"yun-wen-zheng",fullName:"Yun-Wen Zheng"},{id:"216572",title:"Dr.",name:"Hui",middleName:null,surname:"Xu",slug:"hui-xu",fullName:"Hui Xu"},{id:"216574",title:"Dr.",name:"Qi",middleName:null,surname:"Liu",slug:"qi-liu",fullName:"Qi Liu"},{id:"216576",title:"Dr.",name:"Yu-Mei",middleName:null,surname:"Li",slug:"yu-mei-li",fullName:"Yu-Mei Li"},{id:"234877",title:"BSc.",name:"Feng-Lin",middleName:null,surname:"Luo",slug:"feng-lin-luo",fullName:"Feng-Lin Luo"},{id:"234878",title:"BSc.",name:"Zhou",middleName:null,surname:"Hu-Chen",slug:"zhou-hu-chen",fullName:"Zhou Hu-Chen"},{id:"234880",title:"Prof.",name:"Hiroko",middleName:null,surname:"Isoda",slug:"hiroko-isoda",fullName:"Hiroko Isoda"},{id:"234884",title:"Dr.",name:"Li-Ping",middleName:null,surname:"Liu",slug:"li-ping-liu",fullName:"Li-Ping Liu"}]},{id:"61053",title:"Adult Stem Cell Membrane Markers: Their Importance and Critical Role in Their Proliferation and Differentiation Potentials",slug:"adult-stem-cell-membrane-markers-their-importance-and-critical-role-in-their-proliferation-and-diffe",totalDownloads:1337,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The stem cells are part of the cells that belong to the stromal tissue. These cells remain in a quiescent state until they are activated by different factors, usually those generated by an alteration in the parenchymal tissue. These cells have characteristic membrane markers such as CD73, CD90, and CD105. Those are a receptor, which in response to their ligand induces strong changes in different metabolic pathways that lead to these cells, both to generate molecules with different activities and to leave their stationary phase to reproduce and even differentiate. This review describes the metabolic pathways dependent on these membrane markers and how they influence on parenchymal tissue and other stromal cells.",book:{id:"6658",slug:"stromal-cells-structure-function-and-therapeutic-implications",title:"Stromal Cells",fullTitle:"Stromal Cells - Structure, Function, and Therapeutic Implications"},signatures:"Maria Teresa Gonzalez Garza",authors:[{id:"181389",title:"Ph.D.",name:"Maria Teresa",middleName:null,surname:"Gonzalez Garza",slug:"maria-teresa-gonzalez-garza",fullName:"Maria Teresa Gonzalez Garza"}]}],onlineFirstChaptersFilter:{topicId:"171",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81298",title:"Roles of Extracellular Vesicles in Cancer Metastasis",slug:"roles-of-extracellular-vesicles-in-cancer-metastasis",totalDownloads:36,totalDimensionsCites:0,doi:"10.5772/intechopen.103798",abstract:"Extracellular vesicles (EVs) are biological active vesicles and carriers of information in intercellular communication. In cancer settings, EVs especially exosomes (Exo), play a focal role in modulating the tumor microenvironment mainly by increasing tumor proliferation, facilitating the crosstalk between tumor and tumor-neighboring cells, and influencing the host immune response. Amongst these functions in tumor growth, Exo modulate fundamental steps of tumor progression, such as growth, invasion, and immune modulation. On the endocrine level, Exo released from tumors were shown to mediate distant cell-cell communication processes via secretory factors and miRNAs, which result in the set-up of pro-tumorigenic microenvironments supportive of metastatic dissemination. This is achieved through processes such as fibroblast activation, extracellular matrix ECM production, angiogenesis, and immune modulation.",book:{id:"10796",title:"Extracellular Vesicles - Role in Diseases, Pathogenesis and Therapy",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg"},signatures:"Eman Helmy Thabet"},{id:"80871",title:"Tumor-Derived Exosome and Immune Modulation",slug:"tumor-derived-exosome-and-immune-modulation",totalDownloads:56,totalDimensionsCites:0,doi:"10.5772/intechopen.103718",abstract:"Tumor cells, like most other cells, release exosomes called tumor-derived exosomes (TEX) and are vital for intercellular communication. TEX are membrane-bound extracellular vesicles (EVs), containing unique cargo reminiscent of the parent tumor cells and possess immunomodulatory functions. TEX carries factors that directly promote immunosuppression in the tumor microenvironment and indirectly attract immunosuppressive T-regulatory (Treg) cells. The tumor-secreted exosomes can transfer their cargo by multiple mechanisms like fusion, phagocytosis, and receptor-mediated endocytosis, activating the recipient cells. TEX directly engages and releases cytokines, inactivating natural killer (NK) cells and T-cells and activating apoptosis. Tumor-derived exosomes also release soluble factors to suppress dendritic cell (DC) maturation while activating the expansion of immune-suppressive cells like Myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells. Several studies have shown the relevance of TEX containing tumor-associated antigens (TAA) in reducing the efficacy of cancer immunotherapy and adoptive cell therapy. Hence understanding the basic biology and mechanism of TEX-mediated immunosuppression is critical in discovering cancer biomarkers and finding better immunotherapy and cell therapy approaches. In this chapter, we have discussed TEX biogenesis, TEX’s structural and molecular features, TEX-mediated immunosuppression, and its relation to immunotherapy.",book:{id:"10796",title:"Extracellular Vesicles - Role in Diseases, Pathogenesis and Therapy",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg"},signatures:"Deepak S. Chauhan, Priyanka Mudaliar, Soumya Basu, Jyotirmoi Aich and Manash K. Paul"},{id:"79834",title:"Morphology and Formation Mechanisms of Cellular Vesicles Harvested from Blood",slug:"morphology-and-formation-mechanisms-of-cellular-vesicles-harvested-from-blood",totalDownloads:61,totalDimensionsCites:0,doi:"10.5772/intechopen.101639",abstract:"Theoretical and experimental evidence on cellular vesicles (CVs) isolated from blood is presented. It is suggested that comparison of the observed shapes with theoretical shapes obtained by minimization of membrane-free energy in combination with electron microscopy is key in the assessment of CV identity. We found that shapes of CVs isolated from blood by repetitive centrifugation (up to 20.000 g) and washing, and observed by scanning electron microscopy (SEM) agreed well with theoretically observed shapes. It is indicated that these CVs are colloids deriving from residual blood cells, mostly platelets. SEM images of washed erythrocytes undergoing budding and transmission electron microscopy (TEM) images of isolated erythrocyte microvesicles likewise showed smooth shapes that we described as characteristic for colloidal CVs. Besides these, the CV isolates may contain other small particles, such as exosomes and viruses, as observed in isolates from tomato homogenate, however, we could not identify such particles in isolates from healthy human blood. Theory of deviatoric elasticity underlaying minimization of the membrane free energy and simulated two-component vesicles with the orientational ordering of anisotropic constituents are presented to indicate the interdependence of curvature—sorting of membrane constituents and their orientational ordering in strongly anisotropically curved regions.",book:{id:"10796",title:"Extracellular Vesicles - Role in Diseases, Pathogenesis and Therapy",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg"},signatures:"Veronika Kralj-Iglič, Gabriella Pocsfalvi and Aleš Iglič"},{id:"80195",title:"Diversity of Extracellular Vesicles (EV) in Plasma of Cancer Patients",slug:"diversity-of-extracellular-vesicles-ev-in-plasma-of-cancer-patients",totalDownloads:81,totalDimensionsCites:0,doi:"10.5772/intechopen.101760",abstract:"Extracellular vesicles (EVs) are produced by all cells and are found in all body fluids. They function as intercellular messengers that carry and deliver signals regulating cellular interactions in health and disease. EVs are emerging as potential biomarkers of diseases and responses to therapies, and much attention is being devoted to understanding their role in physiological as well as pathological events. EVs are heterogenous in their origin, size, molecular characteristics, genetic content and functions. Isolation of EV subsets from plasma and characterization of their distinct properties have been a limiting factor in ongoing efforts to understand their biological importance. Here, we discuss the immunoaffinity-based strategies that are available for isolating distinct subsets of EVs from plasma and provide a road-map to their successful immunocapture and molecular profiling, with special attention to tumor-derived EVs or TEX.",book:{id:"10796",title:"Extracellular Vesicles - Role in Diseases, Pathogenesis and Therapy",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg"},signatures:"Theresa L. Whiteside and Soldano Ferrone"},{id:"79955",title:"The Role of Extracellular Vesicles in Immunomodulation and Pathogenesis of Leishmania and Other Protozoan Infections",slug:"the-role-of-extracellular-vesicles-in-immunomodulation-and-pathogenesis-of-leishmania-and-other-prot",totalDownloads:112,totalDimensionsCites:0,doi:"10.5772/intechopen.101682",abstract:"Extracellular vesicles (EVs) have lately emerged as crucial mediators in parasite infections. Recent research suggests that protozoan parasites, including Leishmania, employ EVs as transport vehicles to deliver biologically active effector molecules such as parasitic virulence factors to modulate the host immune system and their microenvironment. The immunomodulatory effects of EVs play an essential role in the formation and progression of parasitic diseases. The immunomodulatory strategies applied by EVs of protozoan origin have similarities to the development and progression of other infections or diseases such as cancer. In this chapter, we will provide recent insights into the role of EVs in host-pathogen interactions, intercellular-communication, immunomodulation and pathogenesis of Leishmania and other protozoan parasites, including Plasmodium spp., Toxoplasma spp. and Trypanosoma spp. In addition, biologically inspired by the immunomodulation strategies of protozoan parasites, new immunotherapeutic models are being currently investigated to implement EVs more intensively in both therapy and diagnostics. Therefore, besides highlighting the role of EVs in protozoan infections, this chapter sheds light briefly on new immunotherapeutic approaches utilizing the strategies of protozoan EVs in medicine.",book:{id:"10796",title:"Extracellular Vesicles - Role in Diseases, Pathogenesis and Therapy",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg"},signatures:"Zeynep Islek, Batuhan Turhan Bozkurt, Mehmet Hikmet Ucisik and Fikrettin Sahin"},{id:"80126",title:"Extracellular Vesicles as Biomarkers and Therapeutic Targets in Cancers",slug:"extracellular-vesicles-as-biomarkers-and-therapeutic-targets-in-cancers",totalDownloads:107,totalDimensionsCites:1,doi:"10.5772/intechopen.101783",abstract:"Extracellular vesicles refer to exosomes, apoptotic bodies, microvesicles and large oncosomes, which are membrane bound structures secreted by cells including cancer cells. The pathological role and translational potential of extracellular vesicles (EVs) in cancers are receiving research attention recently. The cargoes of cancer-derived EVs retain the molecular properties of their sources and cancer cells actively release EVs into body fluids that are easy to access. EVs released from cancer cells not only promote cancer progression through the delivery of cancer-associated molecules but also reflect alterations in the state of cancers during therapy. They are considered promising biomarkers for therapeutic response evaluation, especially resistance to therapy and diagnostics. 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He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. 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He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. 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She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. 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Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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