\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"6351",leadTitle:null,fullTitle:"Vasculitis In Practice - An Update on Special Situations - Clinical and Therapeutic Considerations",title:"Vasculitis In Practice",subtitle:"An Update on Special Situations - Clinical and Therapeutic Considerations",reviewType:"peer-reviewed",abstract:'"Vasculitis" describes an inflammatory process that involves the blood vessels and contributes to vascular damage. Autoimmunity, infections, drugs, and malignancies have been considered among potential etio-pathogenic factors. In vasculitis, the inflammation might develop in either a systemic or an organ-specific form and might exist as an independent pathology "primary vasculitis" or as a presentation of an existing primary pathology, that is, "secondary vasculitis". This book Vasculitis In Practice-An Update on Special Situations - Clinical and Therapeutic Considerations unlike many publications in the field, uses a different evidence-based approach to organ-specific vascular inflammatory diseases. The authors highlighted the unmet needs from the 1994 Chapel Hill Consensus Conference introducing the latest clinically relevant definitions for the different forms of vasculitis revised in 2012. The identification, classification, and management of kidney disease with different types of vasculitis with an evidence-based update on proposed therapeutic strategies are presented in this publication.',isbn:"978-1-78923-699-6",printIsbn:"978-1-78923-698-9",pdfIsbn:"978-1-83881-423-6",doi:"10.5772/intechopen.69793",price:119,priceEur:129,priceUsd:155,slug:"vasculitis-in-practice-an-update-on-special-situations-clinical-and-therapeutic-considerations",numberOfPages:112,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"9213792932243386d6a3875223e8f474",bookSignature:"Reem Hamdy Abdellatif Mohammed",publishedDate:"September 19th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6351.jpg",numberOfDownloads:5353,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 20th 2017",dateEndSecondStepPublish:"July 11th 2017",dateEndThirdStepPublish:"October 21st 2017",dateEndFourthStepPublish:"January 5th 2018",dateEndFifthStepPublish:"March 6th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"36290",title:"Prof.",name:"Reem Hamdy A.",middleName:null,surname:"Mohammed",slug:"reem-hamdy-a.-mohammed",fullName:"Reem Hamdy A. Mohammed",profilePictureURL:"https://mts.intechopen.com/storage/users/36290/images/system/36290.png",biography:'Professor Reem Hamdy Abdellatif Mohammed graduated from the School of Medicine, Cairo University, Egypt, where she is currently a Professor of Rheumatology and Clinical Immunology. She is a fellow of the Royal College of Physicians and a Certified International Professional Trainer (CIPT) at the Faculty and Leadership Development Center (FLDC), Cairo University, and at the Management Development Institute, Missouri State University, USA, carrying on teaching and training on the \\"Establishment of the Evidence-Based Strategy in Medical Research and Practice.\\" Dr. Mohammed is a verified editor, reviewer, and advisory board member for several reputable international journals. She is also a member of the “Capacity Building Team\\" at Cairo University. She is the author and co-author of several books and an international speaker in the field of rheumatology and immunology. \n\nScopus Author ID: 35280107100\n\nORCID ID: ORCID logohttps://orcid.org/0000-0003-4994-7687\n\nCU Scholar account: https://scholar.cu.edu.eg/?q=reemhamdy/publications',institutionString:"Cairo University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1035",title:"Clinical Immunology",slug:"immunology-allergology-and-rheumatology-clinical-immunology"}],chapters:[{id:"63077",title:"Introductory Chapter: Vasculitis",doi:"10.5772/intechopen.79560",slug:"introductory-chapter-vasculitis",totalDownloads:955,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Reem Hamdy A. Mohammed",downloadPdfUrl:"/chapter/pdf-download/63077",previewPdfUrl:"/chapter/pdf-preview/63077",authors:[{id:"36290",title:"Prof.",name:"Reem Hamdy A.",surname:"Mohammed",slug:"reem-hamdy-a.-mohammed",fullName:"Reem Hamdy A. Mohammed"}],corrections:null},{id:"62722",title:"Pauci-Immune Vasculitides with Kidney Involvement",doi:"10.5772/intechopen.76175",slug:"pauci-immune-vasculitides-with-kidney-involvement",totalDownloads:1203,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The clinical entity of pauci-immune vasculitis encompasses a group of diseases that may involve any organ system of the body and may be fatal if left untreated. This chapter will review these diseases, with a special interest in the clinical setting of kidney involvement. Small vessel vasculitides associated with the presence of antineutrophil cytoplasmic autoantibodies in the circulation will be the main part, since the vast majority of patients with histopathological proof of pauci-immune vasculitis are positive for these antibodies. Pauci-immune glomerulonephritis often manifests with rapidly deteriorating kidney function, while it may be accompanied by systemic necrotizing small vessel vasculitis such as microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis. Importantly, antineutrophil cytoplasmic autoantibody specificity has been shown to be associated with distinct clinical syndromes and different prognostic profiles among patients with pauci-immune vasculitis allowing easier recognition of the disease and long-term prognosis. Each of the clinical phenotypes will be described thoroughly with respect to the criteria required for establishment of diagnosis, the specific characteristics of renal and extrarenal histopathology, the clinical picture, the therapeutic management, and prognosis in short and long terms.",signatures:"Sophia Lionaki, Chrysanthi Skalioti, Smaragdi Marinaki and John N.\nBoletis",downloadPdfUrl:"/chapter/pdf-download/62722",previewPdfUrl:"/chapter/pdf-preview/62722",authors:[{id:"213115",title:"M.D.",name:"Sophia",surname:"Lionaki",slug:"sophia-lionaki",fullName:"Sophia Lionaki"}],corrections:null},{id:"62193",title:"Immune Complex Small-Vessel Vasculitis with Kidney Involvement",doi:"10.5772/intechopen.77226",slug:"immune-complex-small-vessel-vasculitis-with-kidney-involvement",totalDownloads:1028,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The term immune complex small-vessel vasculitis encompasses anti-glomerular basement membrane disease, cryoglobulinemic vasculitis, IgA vasculitis and hypocomplementemic urticarial vasculitis. These disorders affect predominantly small vessels, and renal involvement is frequent. In this chapter, we shall discuss thoroughly anti-GBM disease, cryoglobulinemic and IgA vasculitis with respect to the criteria required for the establishment of diagnosis, the specific characteristics of renal histopathology, the clinical picture, prognosis, and therapeutic management.",signatures:"Smaragdi Marinaki, Chrysanthi Skalioti, Sophia Lionaki and John N.\nBoletis",downloadPdfUrl:"/chapter/pdf-download/62193",previewPdfUrl:"/chapter/pdf-preview/62193",authors:[{id:"189888",title:"Prof.",name:"John",surname:"Boletis",slug:"john-boletis",fullName:"John Boletis"}],corrections:null},{id:"60045",title:"p53 and Vascular Dysfunction: MicroRNA in Endothelial Cells",doi:"10.5772/intechopen.75461",slug:"p53-and-vascular-dysfunction-microrna-in-endothelial-cells",totalDownloads:1077,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"In many cancer cells, p53 gene is mutated and accumulated, which is considered as a mechanistical target of tumorigenesis. The role of p53 in non-cancerous cells has been focused on, since p53 activation diversely affects as human diseases, including vascular dysfunctions. p53 regulates vascular events, including vascular inflammation and senescence as well as cardiac dysfunction. Many researchers also have paid attention to the role of noncoding RNAs (ncRNAs), especially small-sized microRNAs (miRNAs) for the last decade and their noble biological cellular functions have been discovered. miRNAs expressed in endothelial cells (endothelial miRNAs) have been shown to control vascular events. Firstly, the importance of p53 in a variety of vascular events, such as vascular inflammation and senescence, are summarized. Secondly, the way to regulate miRNAs by p53 and the involvement of miRNAs on p53 function are demonstrated. Finally, several endothelial miRNAs that have important roles are focused on. The aim of this chapter is to understand the role of p53 in vascular diseases in the view of endothelial cell biology and the contribution of miRNAs related to p53.",signatures:"Munekazu Yamakuchi, Sushil Panta and Teruto Hashiguchi",downloadPdfUrl:"/chapter/pdf-download/60045",previewPdfUrl:"/chapter/pdf-preview/60045",authors:[{id:"217082",title:"Associate Prof.",name:"Munekazu",surname:"Yamakuchi",slug:"munekazu-yamakuchi",fullName:"Munekazu Yamakuchi"},{id:"243041",title:"Dr.",name:"Sushil",surname:"Panta",slug:"sushil-panta",fullName:"Sushil Panta"},{id:"243042",title:"Prof.",name:"Teruto",surname:"Hashiguchi",slug:"teruto-hashiguchi",fullName:"Teruto Hashiguchi"}],corrections:null},{id:"59613",title:"Buerger’s Disease: Clinical Aspects and Evidence-Based Treatments",doi:"10.5772/intechopen.74603",slug:"buerger-s-disease-clinical-aspects-and-evidence-based-treatments",totalDownloads:1091,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Buerger’s disease (thromboangiitis obliterans) is a nonatherosclerotic, segmental, occlusive, and recurring progressive inflammatory form of vasculitis that most commonly affects the small- and medium-sized arteries, veins, and nerves in the upper and lower extremities. The cause is unknown, but it is most common in young men with a history of tobacco abuse. It is responsible for ischemic ulcers and extreme pain in the hands and feet. In many cases, notably in patients with the most severe presentations, there is no possibility of improving the condition with surgery (limb revascularization), and therefore, alternative therapies (e.g., sympathectomy, pharmacological agents, and many others) are used. This chapter discusses clinical aspects of Buerger’s disease and evidence-based treatment available currently.",signatures:"Daniel Guimarães Cacione",downloadPdfUrl:"/chapter/pdf-download/59613",previewPdfUrl:"/chapter/pdf-preview/59613",authors:[{id:"216255",title:"Ph.D.",name:"Daniel",surname:"Cacione",slug:"daniel-cacione",fullName:"Daniel Cacione"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9104",title:"Lupus",subtitle:"Need to Know",isOpenForSubmission:!1,hash:"3bf7e412a25b5e723ece6658aaf36917",slug:"lupus-need-to-know",bookSignature:"Reem Hamdy A. Mohammed",coverURL:"https://cdn.intechopen.com/books/images_new/9104.jpg",editedByType:"Edited by",editors:[{id:"36290",title:"Prof.",name:"Reem Hamdy A.",surname:"Mohammed",slug:"reem-hamdy-a.-mohammed",fullName:"Reem Hamdy A. 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Plants are exposed to various adverse conditions that limit their growth in areas where they are grown. Conditions that prevent growth, development, and metabolism in plants are called stress [1]. Due to the continuation of climate change and the increase in extreme climatic conditions, it is reported that the negative impact of environmental stress factors on plant production will increase in many regions of the world [2]. Stress factors can simultaneously show their effects on plants [3]. On the reducing amount of agricultural product, abiotic stress has reached a massive quantity of 71% although other stresses are on 29% [4]. It is estimated that only 10% of the arable land in the world is far from some forms of stress. It has been reported that abiotic stress factors are the main limiting factors of crop production in the world and cause more than 50% reduction in the yield of most products [5]. In the last decade, different irrigation techniques, soil improvement, and the use of suitable fertilizers have been intensified in order to reduce the impact of major stress factors. As a different approach, the use of some externally applied healers during plant growth has been tried in recent years, and it has been observed that the applications using MEL may have an effect of increasing stress tolerance in the plant.
MEL (N-acetyl-5-methoxytiprimamine) was discovered in 1958 in the cattle pineal gland [6]. MEL has been one of the most investigated biological molecules, which is extensively researched in animals. MEL was first explored in plants in 1995 and is an indoleamine neurohormone [7, 8]. There has been an increasing interest in MEL’s roles and impacts on metabolic processes. It was found to play a major role in various plant reactions such as growth, flowering, development, and stress [9, 10, 11]. Most of the reports that provide information about these processes are based on analytical analysis to determine the internal MEL content in response to a stimulus, treatment, or mutation, whereas administration usually requires prolonged exposure or treatment of plants under in vitro or greenhouse conditions [9].
Several studies have reported that MEL can be considered a growth regulator because it plays a role in specific physiological events in plants. Indeed, MEL regulates the growth of leaf, shoots and explants, and the leaf senescence. The natural antioxidant capacity of MEL can be explained by its ability to increase tolerance in plants exposed to abiotic stresses such as drought, cold, heat, salinity, chemical pollutants, herbicides, and UV rays [12]. MEL’s capability to behave as a plant biostimulator for biotic and abiotic stress conditions and the ability to regulate plant growth can regulate plant vegetative growth processes such as rooting, leaf aging, photosynthetic yield, and biomass yield, and it plays a potential regulatory role in flowering processes and the formation and maturation of fruit and seeds [10, 12, 13].
In this study, the effects of MEL on plant growth and physiology against some abiotic stress factors that have important impacts on plant growth and development have been given according to the findings of various researches.
MEL regulates various metabolic processes in animals and plants. MEL is an endogenously produced molecule in all plant species that have been investigated. Its concentration in plant organs varies in different tissues, e.g., roots versus leaves, and with their developmental stage [10].
MEL, tryptophan, tryptamine, and serotonin are structural biogenic indoleamine and also related to indole-3acetic acid (IAA) and indolic compounds, which are very important in plant physiology such as common auxin. Metabolic pathways of tryptophan in mammals and plants as proposed by Murch et al. [14] are shown in Figure 1. MEL was determined in the roots, leaves, fruits, and seeds of various plant species. Melatonin has been suggested to function as an auxin to promote vegetative growth in a number of plant species [15]. For instance, Murch et al. [16] used auxin, serotonin, and MEL inhibitors to demonstrate the role of MEL in plant growth and found that the high intrinsic MEL concentration promotes root growth in the
Metabolic pathways of tryptophan in mammals and plants as proposed by Murch et al. [
Earlier researchers have inspected the physiochemical effects of MEL on plants. These reports indicated that MEL has a role in various plant metabolic processes as the modulation of the flowering physiology and development. Furthermore, it also postpones flower formation, countenances plant growth and biomass production, and hinders chlorophyll degradation [20, 21]. It has been shown that MEL roles in plants could be: growth promoters as auxins, antioxidants for ROS, and other roles as signal molecules [15]. It acts in various plant cellular metabolic and biological processes, including rooting [22], chlorophyll catabolism [20], and stress tolerance [23, 24]. Plants can synthesize MEL, and it plays a role as an antioxidant or a modulator of growth and development in plants [25].
Similar effects (growth induction or inhibition at high levels because of auxin-stimulated ethylene biosynthesis) of MEL were determined in the monocotyledons [26]. Furthermore, MEL applications enhanced photosynthetic capacity, redox homeostasis, and root formation in various crops [22, 27, 28]. According to another report, a coating of soybean seed with MEL notably increased plant growth and seed yield [19].
It has been reported that MEL affects lateral root formation in lupin, and this effect is very similar to the effect of IAA [29]. In these studies, auxin-induced root and cytokinin-induced shoot organogeneses were inhibited by alterations in the endogenous concentration of MEL and inhibitors of the transport of serotonin and MEL [30]. MEL has been reported to regulate seed germination, growth of roots, shoots and explants, and leaf senescence [12]. In addition, Tan et al. [31] pointed out that high MEL content in plants increased the germination rate of seeds under adverse conditions, increasing the life expectancy and improving the quality of plant production. In lupin, MEL increased plant root and shoot biomass with similar results to IAA for root biomass in concentrations used [32]. Exogenous MEL was applied to etiolated wild mustard, and the effect on root growth and endogenous indole-3-aceticacid (IAA) levels was detected in wild mustard. Exogenous lower MEL concentrations also elevated the endogenous IAA content in roots, whereas higher levels did not significantly affect the IAA content. The specific mechanism which leads exogenous MEL to increase the IAA content in roots, associated with root formation, continues to emerge [21].
Increased MEL levels in plants have been suggested to mitigate various pollutant effects via behaving as a ROS scavenger and antioxidant. MEL can detoxify the OH−, H2O2, nitric oxide, ONOO−, HNO3, and HClO, which are biosynthesized under stress conditions. Moreover, MEL treatments elevate antioxidant enzyme activities under abiotic stress conditions. One MEL molecule has the ability to scavenge up to 10 free radicals [33]. MEL has also been suggested to have a significant effect on nitrogen and carbohydrate metabolism and on transcription rearrangement [34]. Thus, it is suggested that MEL affects signal transduction and also has an important role in regulating physiological and biological processes. As a conclusion, MEL could be considered as a biological growth regulator to increase the production capacity in crops.
Extreme salinity in soil solution is the major abiotic stress factor that drastically limits crop productivity worldwide. Salinity affects 110 million hectares in arid and semi-arid regions. According to FAO, an estimated 20–30 million ha area is severely deteriorated due to salinity [34]. In addition to the natural conditions, problems with salinity have increased with the fact that water tables have increased and concentrated in a large part of the land that has been recently irrigated [35]. Moreover, use of the treated and untreated wastewater at increasing proportions due to the insufficient clean water resources in the world can promote the soil salinity. Salinity causes osmotic stress by reducing the water potential and increasing the energy required for the intake of water and nutrients. Ionic stress is caused by the accumulation of sodium and chlorine ions in sensitive plant tissues [36, 37, 38]. Therefore, it has been reported that high concentrations of salt (especially NaCl) in soils or irrigation water disrupt the morphological and physiological processes in plants and prevent growth [39].
In addition, salinity conditions may lead to nutritional disorders and deficiencies [40]. In the short term, while the water availability reduces due to inducing osmotic stress under salty conditions, in the long term, the nutrient imbalances induce ion toxicity [41]. Salinity increases ROS formation and stimulates oxidative stress [42], which causes substantial injury to membranes and other cellular structures [43]. Salt stress affects plant physiology at both plant and cellular levels by osmotic and ionic stress. High salt concentrations may adversely affect seed germination, seedling growth, vegetative growth, flowering and fruit behavior, and photosynthetic activity and ultimately reduce economic yield and quality [44].
Lately, the positive roles of MEL in plant salt stress resistance have been progressively evolved by two ways: the exogenous application of MEL or genetic modification of the enzymes involved in MEL synthesis [45]. Indeed, exogenous MEL applications improved growth, photosynthetic capacity, antioxidant activity, and chlorophyll content, but decreased the ROS level and oxidative injury in cucumber grown under salinity stress conditions [46]. Dawood et al. [47] indicated that exogenous MEL applications enhanced plant biomass, relative water content, photosynthetic activity, phenolic matter, and plant nutrient uptake, and reduced the Na and Cl content in fava bean under salinity stress conditions. 500 mM of MEL was more effective than 100 mM on observed parameters.
Zhou et al. [48] investigated influences of MEL treatments on photosynthetic activity in tomato under salinity conditions. They concluded that MEL treatments mitigated the deleterious effects of salinity on growth and photosynthetic capacity. It was determined that MEL decreased the ROS levels and expedited the recovery of the photosynthetic electron transport chain and protein biosynthesis, therefore improving photosynthetic capacity under salinity stress. Similarly, MEL treatments on roots of watermelon mitigated salt-stress damage in photosynthetic capacity and oxidative stress, improving redox homeostasis and antioxidant enzyme activity [28]. In another study, it was reported that MEL treatments improved the tolerance to salt stress and K+/Na+ homeostasis in potato, increasing K+ and decreasing NaCl concentration [44].
In
Exogenous MEL treatments showed a major effect of MEL related to lipid metabolism with K+/Na+ homeostasis in a potato grown under salinity stress [44]. MEL applications on roots mitigated the deleterious effects of salinity on photosynthetic capacity by reducing oxidative stress, improving antioxidant enzyme activity in watermelon. This effect was attributed to the inhibition of stomatal closure and enhanced light energy absorption and electron transport in photosystem II [28].
Liang et al. [23] treated plants with MEL to determine its effect on physiological and biochemical properties in rice grown under salinity stress. The results of the study showed that MEL treatments decreased or inhibited chlorophyll damage and the transcripts of senescence-associated genes, thus improving salinity tolerance. It was also determined that MEL postponed the leaf senescence and cell death by counteracting the ROS.
Water scarcity has been becoming a major problem worldwide due to population growth and social and economic development. A number of countries faced to water shortage is more than 100, and approximately two thirds of the world population will be exposed to be suffering from moderate to high water stress by 2025 [53]. Increasing domestic and industrial water demand and pollution of water threatens the water used in agriculture. Therefore, drought is one of the most important agricultural problems in the world. Two-fifths of world agriculture is carried out in arid areas [54]. Studies show that in the coming years, the effect of drought will increase further and this situation will affect the negative effects of agricultural production [55]. It is reported that global climate change, in addition to the expansion of arid and semi-arid areas, will increase the duration and intensity of drought, desertification processes, salinization, and erosion [56]. It has been shown in many studies that drought has an impact on all plant growth events from plant morphology to molecular levels [57]. Drought stress causes various physiological, biochemical, and molecular responses in different plants to help them adapt to such limiting environmental conditions [58, 59]. Arid conditions have a negative effect on photosynthetic activity, cause changes in chlorophyll content and components in the cell, and damage photosynthetic parts [60]. It also inhibits photochemical activity and reduces the activity of enzymes in the Calvin circle [61].
Earlier studies pointed out that exogenous MEL treatments improved plant tolerance to water deficit stress. Increased antioxidant activity in different plants grown in drought stress has been associated with the MEL content [62]. The effect of MEL application on plant development and some biochemical properties of
It has been shown that a notable increase in photosynthetic capacity and stress-related phytohormones was associated with the endogenous MEL content under water deficit conditions. Indeed, Fleta-Soriano et al. [25] proved that MEL treatments enhanced photosystem II resulting in a preserving factor in maize under drought stress. MEL treatments helped to recover from drought stress by enhancing the Fv/Fm ratio, which could have a defensive effect in plants subjected to water deficit conditions.
Cui et al. [64] demonstrated that MEL applications alleviated the deleterious effects of drought stress in wheat by increasing antioxidant activity and decreasing ROS and membrane injury. They also showed that MEL caused a thicker epidermal cell, intact grana lamella of chloroplast and leaf structure, and higher photosynthetic activity. They explained these positive responses to MEL treatments in wheat with enhanced enzyme activity and gene expression. Moreover, Wang et al. [18] proved that MEL had an ameliorative effect on drought stress by increasing antioxidant activity. Similarly, mitigation of deleterious effects of drought stress could be attributed to its ROS scavenging functions by improving antioxidant enzyme activity and photosynthetic efficiency [65].
Ma et al. [66] showed that exogenous MEL treatments elevated ME biosynthesis gene (TDC1, SNAT1, and COMT) expression, resulting in mitigation of leaf senescence caused by water deficit in
It was determined in plants that drought increased the expression of genes related to drought stress and decreased the production of abscisic acid (ABA), which leads to the closure of stomata [69]. In addition to reducing the effect of drought stress, MEL also helps to heal the plants after drought has occurred and water is re-fed [33, 65, 69, 70].
The increment in mining, factories, and industrialization leads to the contamination of larger areas with heavy metals. It is reported that heavy metals are included in the food chain by accumulation by plants [71]. Studies on heavy metal accumulation and its effects on plants have shown that heavy metals are a potent phytotoxic and cause growth inhibition and, in some cases, death [72, 73]. Metals are the elements necessary for normal survival of plants. However, the presence of some metals in the root region has a toxic effect on the plants. These metals, which have a negative effect on growth and yield in plants, are mostly cadmium (Cd), chromium (Cr), zinc (Zn), copper (Cu), lead (Pb), and nickel (Ni) [74]. They can easily accumulate in plants and prevent plant growth and nutrient uptake [75]. The metals in question prevent the uptake of necessary minerals by making a toxic effect and by replacing the necessary minerals such as iron for the plants. Heavy metals, by activating active oxygen species in plants, cause a decrease in chlorophyll and thus photosynthesis rate. As in other stress conditions, heavy metal stress also increases the level of plant ethylene, slows down the growth of roots and shoots, reduces CO2 fixation, and limits the transport of sugar [76]. Many researchers have reported that heavy metals stimulate ROS formation, leading to oxidative stress [77, 78, 79].
The plants exposed to heavy metals (lead, zinc, cadmium, etc.) have been shown to induce MEL biosynthesis for alleviating stress effects [80]. Tan et al. [32] pointed out that MEL treatments elevated the phytoremediation capacity of pea under copper stress. Many studies have shown that exogenous MEL treatments reduced the toxic impact of various heavy metals such as cadmium, aluminum, copper, vanadium, nickel, etc. by enhancing root growth, antioxidant activity, photosynthetic capacity, and organic acid anion exudation, reducing metal concentration, and regulating MEL biosynthesis and antioxidant-related gene expression in various crops [24, 81, 82].
Tang et al. [83] reported that foliar MEL applications improved the photosynthetic capacity of eggplant under cadmium stress. They suggested that increased MEL concentration elevated photosynthetic capacity in stressed plants, and a concentration of 150 μmol·L−1 was the best for alleviating cadmium stress. Cadmium (Cd), one of the most dangerous heavy metal pollutants, is toxic to animals and plants. A significant increase in antioxidant enzyme activity and low ROS contents were related to treatment of MEL-stimulated Cd tolerance in tomato. MEL treatments induce Cd sequestration and transfer of cadmium from cytosol to the vacuole and cell wall [84]. Similarly, MEL applications mitigated Cd-stimulated oxidative stress by increasing the levels of nonenzymatic and enzymatic antioxidants. Gu et al. [85] determined that Cd stress conditions enhanced endogenous MEL concentrations in alfalfa. It was determined in their research that exogenous MEL treatments mitigated the negative effect of Cd on plant growth by reducing Cd accumulation and reestablishing the micro RNA-mediated redox homeostasis. They suggested that MEL could regulate expression of ion-channel genes in crops against Cd stress. Moreover, Safari et al. [86] concluded that excessive boron (B) decreased photosynthesis and dry matter in pepper. However, they pointed out that exogenous 1 μM MEL treatments eliminated visible B toxicity symptoms due to B, increased nutrient uptake, photosynthetic activity, antioxidant capacity, and accumulation of carbohydrates, and decreased ROS and membrane permeability.
Zhang et al. [24] tested whether exogenous MEL treatments could mitigate aluminum induced phytotoxicity in
Plants are affected at the maximum level from the environmental temperature from seed germination to product acquisition. Plants require an optimum temperature request for every stage of growth, and this requirement may vary between species and even varieties. The temperatures below the optimum negatively affect plant growth and ultimately yield. Low and high temperatures slow the seed germination and emergence, limit the intake of water and nutrients, increase the damage of diseases, negatively affect flowering, seed and fruit formation, and finally cause death of the plant [89]. Hot climate plant species are very sensitive to low temperatures [90]. It has been reported that low temperature affects the whole metabolic system of the cell and even causes water stress [91]. It has also been reported that low temperature causes damage in cell membranes, which also affects sugars, phenolics, phospholipids, protein, and ATP [92]. Low temperature is one of the most limiting abiotic stresses for crop yield and geographical distribution in plants [93, 94]. Low temperature stimulates the overproduction of ROSs in plant cells such as superoxide radical (O2.−), H2O2, and hydroxyl radical (OH−). ROS may lead to lipid peroxidation and oxidative modifications in proteins and nucleic acids [95, 96]. However, the plants have developed a specific protective mechanism to alleviate and repair damage induced by oxidative stress. The most important oxidative stress cleaning mechanisms are enzymatic systems consisting of SOD, POD, CAT, APX, and GR and nonenzymatic acetyl salicylic acid and glutathione (GSH) [97, 98]. Tolerance to low temperature in plants is positively related to activation of ROS cleaning systems. Research has shown that antioxidant activity has a substantial role in preserving plants to oxidative injury caused via stress [93].
High temperature stress is one of the most harmful stress conditions that damage the growth and yield of cool season plants. High temperature can negatively affect germination and output in many plant species. In the vegetative development period, it was reported that high temperature decreases photosynthesis capacity, CO2 assimilation, and metabolic processes [99, 100]. High temperatures can also deteriorate membrane stability, resulting in necrotic spots similar to water stress symptoms in leaves, eventually leading to premature deaths [101]. Temperature stress negatively affects the food intake in plants [102]. In the generative development period, high temperature, flower dust germination, fertilization, flowering, and seed and fruit formation can cause a significant decrease in yields [103, 104]. Like other stresses, high temperature stress also has a significant negative impact on product yield. High temperature causes oxidative stress, lipid peroxidation, membrane damage, protein degradation, enzyme inactivation, pigment bleaching, and degradation of DNA strands in plants [105].
Temperature extremes were shown to increase MEL biosynthesis. Moreover, it has been reported that exogenous MEL treatments helped to protect plants from temperature extremes [106]. Several studies indicated that antioxidant capacity of MEL could strengthen plants subjected to abiotic stresses such as cold and heat [107, 108]. There are reports showing that supplementation with MEL induced MEL biosynthesis and upregulated genes under cold stress conditions [109, 110]. Studies have also shown that MEL treatments alleviated the deleterious impact on plants by upregulating or downregulating genes and proteins related to high or low temperature stresses, scavenging ROS, modulating polyamine metabolism, increasing chlorophyll and heat shock protein synthesis, and affecting the ABA and cytokinin pathway [33, 110, 111, 112, 113].
Lei et al. [114] suggested that MEL enhanced carrot cell survival due to induced putrescine and spermidine biosynthesis under cold stress. Similarly, Balabusta et al. [115] determined that osmo-primed cucumber seeds with MEL had lower ROS levels and higher superoxide dismutase (SOD) activity, detoxifying ROS under chilling stress. It is evidenced that exogenous MEL treatments reduced photoinhibition by enhancing nonphotochemical quenching via induction of violaxanthin de-epoxidase activity in tomato plants under chilling stress [116]. Alam et al. [117] concluded that MEL-treated tall fescue plants under high temperature stress had lower ROS electrolyte leakage and malondialdehyde levels and higher chlorophyll, total protein, and antioxidant enzyme activities compared to nontreated plants. They also showed that exogenous MEL treatments improved thermo-tolerance.
In another study, maize seeds were primed with MEL (50 and 500 μM) to determine the priming-induced changes under chilling stress. Priming with MEL regulated MEL-associated proteins in seeds exposed to lower temperature and enhanced plant tolerance to chilling [118]. Foliar MEL-treated
MEL applications decreased the H2O2 and MDA content of pepper seedlings, but increased the SOD and CAT enzyme activities in pepper under chilling stress. The decrease in the peroxidation of lipids in the tissues caused an increase in the levels of antioxidant enzyme activities, thus increasing the germination and seedling emergence performance of pepper seeds [119]. Xu et al. [120] reported that external MEL applications caused a significant increase in enzymatic antioxidants such as SOD, POX, CAT, and APX peroxidase and nonenzymatic antioxidants such as ascorbic acid and vitamin E, resulting in decreased ROS levels and lipid peroxidation in cucumber under high temperature stress. Lei et al. [114] reported that MEL applications improved attenuates cold-induced apoptosis root cell suspensions in a process that does not relate to reactive oxygen species generation in carrot.
Posmyk et al. [121] investigated osmo- and hydropriming with MEL application on germination in cucumber (
Based on literature knowledge, MEL, which is considered a plant growth regulator candidate and known as tolerance to stress in plants, can be used to increase the plant productivity positively under the abiotic stress conditions. It enhances plant growth such as shoot and root biomass, induces root formation, and increases seed germination under unfavorable conditions. These positive attributes could be caused by (1) improving photosynthetic capacity, (2) reducing oxidative stress, (3) enhancing antioxidant activity, (4) downregulating or upregulating stress-related genes, and (4) elevating osmotic metabolites. There are still many unanswered questions about MEL and more areas for further research. The mechanisms by which MEL is produced are still largely unresolved and need to be elucidated by different plant cells in different situations.
Among the different pharmacological strategies for treating spinal cord injury (SCI), it has been observed that the quick intervention after the injury results in a better outcome for the patients [1]. This can be explained by the biochemical processes occurring at a cellular level that develop immediately after the mechanical damage, which define the subsequent physiological chain of events determining the evolution of pathophysiology of the SCI and, therefore, the degree of functional loss or recovery. One of the most important processes participating in the balance between the prevalence of damage or protection of tissue structure and the function in the central nervous system (CNS) is the generation of diverse reactive molecules by oxidative stress that target mainly lipids. This process is known as lipid peroxidation (LP), and its end products could modify proteins and DNA present in cellular structures, causing cell death and a lower probability of regeneration [2]. SCI is a highly disabling and irreversible condition that causes physiological complications (bowel, cardiac, urinary, respiratory) and it has a social-economic impact in patients. The research of new agents targeting degenerative processes such as oxidative stress and LP is important especially due to the lack of efficacy and safety of conventional therapies on patients with SCI [1]. Here, we review the efforts to discover new compounds aimed to offer an option in antioxidant treatments and the use of some in combination or in an innovative way, both in experimental and in clinical trials. We would like to mention that there is a wide range of antioxidant therapies in study, and we are only briefly mentioning some of them at this time.
\nThe pathophysiology of the SCI has been divided in primary and secondary injury, the latter generally described in acute and chronic phases. The mechanisms involved in the secondary injury include biochemical degenerative processes that exacerbates damage, such as the loss of blood-spinal cord barrier (BSCB) integrity, ischemia/reperfusion, hypoxia, loss of ionic homeostasis, Ca2+ overload, glutamatergic excitotoxicity, immune cell invasion, inflammation, release of cytokines, free radical (FR) production, LP, and excessive production of nitric oxide (NO•). All these events occur in the acute SCI and may be clinically targeted due to their times of action, different from the unexpected primary injury [3] (Figure 1). It has also been demonstrated that these mechanisms are related in a way that exacerbates when the levels of oxidative stress and LP molecules are increased and that attenuates its effects when the antioxidant treatment is immediately given after SCI [4].
\nProgression of the inflammatory response in spinal cord parenchyma. The condition produced by the mechanical injury induces the activation of the damage targeting mechanisms, initially propitiated by the resident microglia, which secretes pro-inflammaory cytokines. Astrocytes and endothelial cells allow the permeabilization of BSCB and express chemoattractants to facilitate the admission of immune cells from the periphery, increasing the response at site. Collateral injuries can occur, largely due to the low antioxidant capacity of neural tissue to counteract the ROS produced by inflammatory cells, spreading the damage to other uninvolved cells. The extent of the initial damage is proportional to the final capacity of the organism to recover its motor and sensory functions [
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are molecules that participate in oxidative stress. They are endogenously produced under physiological conditions, and in low amounts, they are essential for biological and immune process [4]. Oxidative stress could be defined as a disturbance in the pro-/antioxidant equilibrium, for the presence of high levels of ROS and RNS that exceeds the endogenous antioxidative defense mechanisms, and they are associated with damage to a wide range of molecular species, such as lipids, proteins, and nucleic acids, contributing to the pathophysiology of SCI [3].
\nROS are oxygen-derived compounds that include radicals (unstable molecules with a single unpaired electron), such as superoxide (O2•−), hydroxyl (HO•) and peroxyl (RO2•/HO2•) radicals, and non-radicals such as hydrogen peroxide (H2O2). Within the first minutes and hours post-injury, different sources of O2•− such as arachidonic acid cascade, mitochondrial leak, and enzymes systems [nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidases, cyclooxygenase (COX), and xanthine oxidase], present in activated microglia and infiltrating cells (macrophages and neutrophils), may act providing O2•− [5], derived from the reduction of oxygen molecules (O2) with a single electron (e−). Although O2•− itself is reactive, its direct oxidative reactivity toward biological substrates in aqueous environments is relatively weak, but it distinguishes itself as an active nucleophile and oxidizing agent that can react with hydrogen donors (e.g., ascorbate and tocopherol) [4, 5, 6]. On one hand, superoxide dismutase (SOD) rapidly catalyzes the dismutation of O2•− into H2O2 and O2 (2O2•− + 2H+ → H2O2 + O2), and at low pH, O2•− can dismutate spontaneously. In oxidative stress, this H2O2 can react with transition metal cations to form oxidizing species such as HO• and hydroxyl anion (HO−), and this occurs mainly in the presence of iron (Fe) and cooper (Cu) ions. The central nervous system (CNS) is rich in ferric iron (Fe3+), contained in transferrin in plasma, and ferritin intracellularly. This iron can be released from its transporters at pH values of 6 or less, like the one reached in hypoxia and accumulation of lactic acid in SCI, and become catalytic; a second source for Fe comes from the hemoglobin released after mechanical-induced hemorrhage. O2•− acts donating an electron to Fe3+, and the ferrous iron (Fe2+) catalyzes the conversion of H2O2 to HO• and HO−. Therefore, O2•− and H2O2 react in the presence of Fe3+/Fe2+ and promote the formation of HO• and HO− [2].
\nOn the other hand, O2•− can interact with NO•, a hydrophobic and mildly reactive radical generated enzymatically from L-arginine by nitric oxide synthase (NOS) isoforms, and give rise to one of the most important RNS, peroxynitrite ONOO− (NO• + O2•− → ONOO−), a potent oxidizing and nitrating agent in vivo, either for direct oxidation reactions, in which it reacts with targets of low molecular weight and proteins (with thiols and metal centers), and carbon dioxide, or by derived radicals from homolytic cleavage, secondary to the reaction with carbon dioxide or protonation, included in RNS [2, 7]. Under biological conditions, ONOO− exists in equilibrium with its acidic form, the peroxynitrous acid (ONOOH), which decays rapidly by homolysis to give place to highly reactive nitrogen dioxide radical (NO2•−) and HO• favored by the low pH in SCI [8]. Among the different direct reactions of ONOO−, one of the most relevant is this with CO2 (from bicarbonate buffer system), to form nitrosoperoxocarbonate (ONOOCO2), forming by cleavage strong oxidant agents, such as nitrogen dioxide (NO2•−) and carbonate (CO3•−) radicals [7, 8].
\nLipids are the most susceptible class of biomolecules to undergo oxidation; polyunsaturated fatty acids (PUFAs) are long-chain fatty acids with two or more double bonds in
The LP is a chain process that involves the participation of ROS, RNS, PUFAs, and oxidative systems, among others, where therapeutic intervention has been proposed with molecules that can both prevent FR formation and prevent those already formed from reacting with biomolecules. Because the peak of ROS production occurs within the first 24 h after the injury, or during ischemia-reperfusion, the drugs that can be used for this “first FR production” are limited by their time of intervention. However, the phases in which LP develops may persist as long as there are oxidizable substrates, so knowing the reactions involved allows the design of strategies and drugs with a greater therapeutic window [11, 12]. The nonenzymatic peroxidation of PUFAs is the principal pathway of oxidative stress; HO• participates as one of the starts of LP due to its solubility and the lack of an enzymatic system to eliminate it. This and other radicals remove an H• radical inside a lipid (LH), which provides a lipid radical (L•) [11, 12] (Figure 2). The resonance stabilization of L• produces a conjugated diene that reacts with O2 to form a lipid peroxyl radical (LOO•) and generates a lipid hydroperoxide (LOOH) when it withdraws hydrogen from an adjacent PUFA, producing a second L• [2, 12]. The LOOH are regarded as the initial product of LP, but these compounds are unstable and can be discomposed with the participation of Fe3+ or Fe2+ again in LOO• or alkoxyl (LO•) radicals, respectively. Both, the reduction of the LOO• to an LO• by Fe2+ (LOOH + Fe2+ → LO• + HO• + Fe3+) and its conversion back to LOO• (LOOH + Fe3+ → LOO• + Fe2+) reactions, have acidic pH optimal conditions and are more likely to occur in SCI tissue environment [5]. The LO• can initiate chain reactions too, such as the LOO• reactions describe above. Thus, one HO• can generate a high number of LOOH through a series of chain reactions. Finally, termination of chain reactions occurs by the stabilization of the radicals reacting between themselves, forming a new bond and eliminating the radical, or by donating electrons (generally H•) to the radicals by compounds, without turning into radicals. In the case of LOOH provided in the previous LP reactions, these undergo fragmentation in which oxidized PUFAs give rise to short-chain secondary products, such as hydroxy-alkenals (neurotoxic aldehydes) relatively stable like malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), 4-hydroxy-2-hexenal (HHE), and 2-propenal (acrolein), that can diffuse within or even escape from the cell and attack targets far from the site of the original event [13] (Figure 2). In general, the LOOH can react in different ways that lead to a cleavage of the C-C bond and formation of hydroxy-alkenals by means of different mechanisms [13].
\nThe three steps of nonenzymatic lipid peroxidation of PUFAs. In the initiation step, a hydrogen atom at a bis allylic position is removed using either a radical or a redox active metal to generate a resonance-stabilized alkyl radical. The radical isomerizes to form the more stable conjugated diene, prior to reacting with molecular oxygen. In the propagation step, radicals are able to react with new substrates, forming lipid hydroperoxides (LOOH), which can react with iron creating new radicals. This step repeats until the termination step, where radicals are “quenched” by antioxidants or react with another radical. The decomposition of LOOH generates species such as MDA, HNE, etc. LH, lipid; L•, alkyl/lipid radical; LOO•, peroxyl radical; LOOH, lipid hydroperoxide; LO•, lipid alkoxyl radical; HNE: 4-hydroxy-2-nonenal; MDA: malondialdehyde; HHE: 4-hydroxy-2-hexenal. Modified from Gaschler and Stockwell [
While the LP compromises the integrity of the cell membrane, the highly reactive secondary products can be covalently bound to proteins and DNA, compromising their structure and function. Regarding the HNE as the most studied product of LP, it must be mentioned that the HNE physiological concentration inside the cell ranges from 0.1 to 3 μM. Moreover, under oxidative stress conditions, HNE can accumulate at concentrations that range from 5 μM to 10 mM [14]. It has been demonstrated that HNE can play an important role as a signaling molecule, enhancing cellular antioxidant capacity and adaptive response at low concentrations; can promote protein and DNA damage in organelles, leading to the induction of autophagy, senescence, or cell cycle arrest; and finally can induce apoptosis or necrosis programmed cell death at a high or very high level [13, 15, 16].
\nThe oxidation of proteins for ROS can lead to the hydroxylation of aromatic groups and aliphatic amino acid (aa) side chains, nitration of aromatic aa residues, reversible nitrosylation of sulfhydryl groups, sulfoxidation of Met residues, conversion of some aa residues to carbonyl derivatives, cleavage of the polypeptide chain, and formation of cross-linked protein aggregates. Furthermore, functional groups of proteins can react with products of LP and carbohydrate derivatives (glycation/glycoxidation) to produce inactive derivatives [17], where the irreversible protein oxidation is described by four pathways: peptide bond rupture, carbonylation, formation of protein-protein bonds, and nitration [18]. The initial oxidation can form a carbon-centered radical, which can react with O2 to form a ROO•, to cleave protein backbone by either α-amidation or diamide pathways.
\nThe cleavage of side chains (glutamyl, aspartyl, and probably prolyl side chains) may occur directly or by metal-catalyzed oxidation (proline [Pro], arginine [Arg], lysine [Lys], and threonine [Thr] residues), yielding carbonyl derivatives [17, 18]. One of the most important of irreversible oxidation processes is by protein carbonylation. It involves the previous protein and aa carbonyl derivatives ,CO3•− oxidation (reacting preferentially on tryptophan [Trp], Thr, cysteine [Cys], methionine [Met], and histidine [His] residues), ketones and aldehyde reactions over Cys, Lys, His, and by glycation/glycoxidation of Lys amino groups, etc. [2, 8, 17, 18].
\nThe modification of the protein structure after oxidation can also give rise to intra- or inter-protein cross-linked derivatives by several different mechanisms. For example, the protein-protein bond may be due to the interaction of two carbon-centered radicals or two aromatic aa residues radicals, formed by direct attack of ROS [17]. Final products of LP, such as HNE and MDA, can cause cross-linked proteins, as reactions of both MDA aldehyde groups with two different residues in the same protein or two different proteins [17]. Another protein-protein bond is disulfide bridge (RSSR) that results from the oxidation of thiols (RSH) forming sulfenic acid (RSOH) as the last intermediate and reacting with another thiol, forming RSSR. This can be promoted in the presence of OONO− or driven by ROS and RNS, with the possibility of chain reactions [8]. Regarding this, some enzymes containing Cys, in its catalytic site, can act as scavengers, by direct interaction or consuming glutathione (GSH), due to the reversible modification of the RSSR bond [8]. HNE possess three functional groups in its structure (Figure 2), making this electrophilic molecule highly reactive toward nucleophilic groups such as thiol (–SH) and amino (–NH2). Thus, aa such as Cys, Lys, His, and Arg are HNE targets, whose modification inhibits the functions of a variety of enzymatic and structural cellular proteins [19]. MDA with enhanced reactivity in low pH and existing as β-hydroxyacrolein is strongly reactive to nucleophiles such as Lys, His, or Arg residues [20]. Protein modifications by RNS act over aromatic, Cys, and Met residues; OONO− reacts directly with thiol groups present in a variety of proteins such as GSH, albumin, and metalloproteins (heme, myeloperoxidase, cytochrome P450, SOD isoforms, etc.) forming nitrite (NO2−), nitrate (NO3−), or NO2•− [8]. Finally, irreversible protein tyrosine nitration by NO2•−, with substitution of a hydrogen in the position 3 of the phenolic ring, produces 3-nitrotyrosine (NT-3) as a specific footprint of induced cellular damage by OONO− [2, 8]. From all these modifications, diverse molecules can be identified both in cerebrospinal fluid and blood, both in humans and in animals, and they have been proposed as biomarkers to diagnose the severity of SCI. Some of those biomarkers derived from proteins are neurofilament proteins, glial fibrillary acidic protein (GFAP), tau, neuron-specific enolase, and S100 calcium-binding protein β (S100β), being part of the components of neurons, oligodendrocytes, and reactive astrocytes. A more detailed list can be found in the works of Lubieniecka et al. and the Hulme et al. review [21, 22].
\nThe ROS/RNS produced in oxidative stress and LP can damage the nucleic acids of DNA; cause DNA-protein cross-links, strand breaks, and modification of purine and pyridine bases; and lead to DNA mutations. More than 20 DNA adducts have been identified, such as 8-hydroxy-2′-guanosine (8-OHdG), increased in patients in whom the antioxidant systems are suspected to be deficient [23]. MDA is an important contributor to DNA damage and mutations that can react with several nucleosides (deoxyguanosine and cytidine) to form adducts, and the major resulting product is a pyrimido-purinone called M1dG [24]. HNE can also react with deoxyguanosine to form two pairs of diastereomer adducts (4-HNE-dG 1,2 and 3,4) or etheno-DNA adducts in the presence of peroxides that could further induce DNA cross-link or DNA-protein conjugates [25, 26]. Other markers of oxidative damage in DNA, among other biomolecules, were reviewed in [23].
\nThe cellular antioxidant systems are composed by antioxidant enzymes and nonenzymatic molecules able to donate electrons to different radical chemical structures. In the CNS, they are present in lower concentrations than the oxidizable substrate and are responsible of maintaining the pro-/antioxidant equilibrium, relieving oxidative stress, and reducing or interrupting uncontrolled LP, DNA mutations, protein oxidation/degradation, as well as other cell damage features. The essential endogenous components of the enzymatic antioxidant defense are SOD, catalase (CAT), glutathione peroxidases (GPx), glutathione reductases (GR), and glutathione S-transferases (GST), while the nonenzymatic antioxidants include GSH, proteins (ferritin, transferrin, ceruloplasmin, metallothionein, thioredoxin (Trx), albumin), vitamins C and E (tocopherol), trace elements, and low molecular weight scavengers, such as uric acid, coenzyme Q , and lipoic acid [4, 6, 23], which act by depleting molecular O2 or decreasing its local concentration; removing pro-oxidative metal ions; trapping aggressive ROS, such as O2•− or H2O2; scavenging chain-initiating radicals like HO•, RO2•/HO2•, or LO•; or breaking the chain of a radical sequence [4]. There are also important exogenous nonenzymatic antioxidants (vitamins A, C, E, flavonoids, carotenoids, phenolics, acetylcysteine, exogenous selenium, zinc), acquired through diet, which are being studied. A table of these enzymatic and nonenzymatic antioxidants important in the CNS was reviewed in [23]. Preventing the formation of ROS, or at least its accumulation, and blocking or capturing those radicals already formed is the first defense against oxidative stress. The O2•− generated by various sources can be converted to H2O2 by SODs [4]. The O2•− intracellularly produced in the mitochondria can be converted into H2O2 by MnSOD (SOD3) [18]. Once generated, H2O2 (but not other peroxides) is decomposed to water and oxygen O2 (2H2O2 + 2GHS → H2O + O2) by the action of CAT, a ferriheme-containing enzyme. However, small amounts of ROS escape from the antioxidant defense and can be converted to HO•, which may be scavenged by low molecular mass nonenzymatic antioxidants, such as ascorbate, tocopherol, GSH, etc. [27]. H2O2 is also reduced by the action of different peroxidases, such as GPx (H2O2 + 2GHS → H2O + GSSG), which, additionally, can reduce lipid hydroperoxides (LOOH + 2GSH → LOH + GSSG) [11, 12]. Other enzymes that catalyze this reaction include peroxiredoxin and thioredoxin reductase [4]. Some enzymes that participate in the detoxification of LP products by oxidation, reduction, and glutathione conjugation, the latter being a mechanism also used to reverse the effects of RNS, are aldehyde dehydrogenases (ALDH), alcohol dehydrogenase (ADH), aldo-keto reductase (AKR), and the aforementioned GST, GPx, and GR [28].
\nIn SCI, the primary injury causes disruption of blood flow and vascular insult, such as ischemia-reperfusion, which conducts to the loss of metabolic function of cells in gray matter with decrease of ATP, causing depolarization of membranes due to the inhibition of Na+/K+ and Ca2+ ATPases function. Ca2+ overload and glutamate excitotoxicity compromise the function and integrity of mitochondria through the activation of proteases and inactivation of important enzymes. Due to the low ratio of antioxidant systems’ oxidizable substrate in acute SCI, the mitochondrial antioxidant reserves decrease and are incapable of restoring the redox equilibrium, giving place to an increase of mitochondrial concentration of O2•− and an increase and leak of free radicals formed downstream including ONOO−, initiating LP. The damage produced by this excess of radicals or end products of LP over proteins and membranes of the mitochondria and endoplasmic reticulum potentiates the processes of secondary injury mentioned here to the local and adjacent cells to SCI [4].
\nThe early therapeutic intervention for SCI is crucial to improve the chances of maximum possible recovery. This was observed in clinical trials where the current treatment of choice, methylprednisolone sodium succinate (MP or MPSS), was effective only when administered within the first 8 h after injury, at high doses (5.4 mg/kg/h). In 48-h regimens, however, it increases the incidence of complications from infections (severe sepsis and pneumonia), while the 24-h safe regimen is not effective in the long term, at least after 3 h [1]. Being an ineffective treatment, there are no alternative therapeutic treatments that offer safety and certainty regarding the recovery of the motor function. The research of new pharmacological agents for the treatment of SCI focuses on the processes of secondary injury, being antioxidant therapies the most important. The main goals of drug therapies for SCI can be classified in neuroprotection and neuroregeneration; antioxidant therapies are cataloged within the first. Here we present some of the agents that are in experimental phase and others when mentioned, in clinical trials, either because their efficacy has been demonstrated in animal models or because of their use already approved in other pathologies. Regarding the diverse SCI models, they have been used to simulate SCI with high relevance and validity to preclinical evaluation due to the replication of human traumatic injuries. The rational use of animals is strongly controlled, and the possibility of pain and distress must be considered and minimized by veterinary staff through the appropriate use of analgesics and animal care.
\nMelatonin (N-acetyl-5-methoxytryptamine) is a pleiotropic compound that works mainly in the regulation of circadian rhythms and sleep. When reacting with ROS, such as HO−, H2O•, and LOO•, it is converted to cyclic 3-hydroxymelatonin. It stimulates the expression and activity of SOD, GPx, CAT, and GR and inhibits or decreases the expression of pro-oxidative NOs, different signaling pathways, transcription factors, and pro-inflammatory cytokines [29, 30, 31]. Decreased melatonin production has been linked to various CNS disorders, and the neuroprotective activity was detected in rat models of traumatic brain injury ischemic stroke and SCI [29, 30]. To cite only some SCI examples, in a study in Sprague-Dawley rats of 250 g with moderate lesion, 10 mg/kg of melatonin was applied subcutaneously twice a day for 4 weeks, and an increase in motor recovery and decrease in inducible nitric oxide synthase (iNOS) expression were observed. Intravenously, it decreased the synthesis of MDA and increased the synthesis of GSH and angiopoietin 1, and in mice with severe lesion, it decreased the expression of interleukin 1 beta (IL-1β) and NG-2 (neuron/glial antigen 2) [30, 32, 33]. In a model with lesion with vascular clips, the administration of 30 mg/kg alleviated post-traumatic injury associated with SCI by binding the PPARα-receptor; the administration of 50 mg/kg in moderate lesion decreased the BSCB permeability modulating the expression of brain-derived neurotrophic factor (BDNF), growth-associated protein 43 (GAP-43), and caspase-3 [33, 34, 35]. In combination therapy with dexamethasone (10–0.025 mg/kg), it showed significant anti-inflammatory effects, attenuating the synthesis of tumor necrosis factor alpha (TNF-α) and iNOS and the nitration of tyrosine residues, increasing tissue recovery and motor capacity in an experimental SCI model of mouse [36], while the combination with methylprednisolone favored neurological recovery and decreased LP; its administration with zinc activated the internal antioxidant system and also decreased the LP [37, 38, 39].
\nMinocycline hydrochloride is an available semisynthetic tetracycline antibiotic with potent anti-inflammatory (regulation of phospholipase A2 and MAPK/PIK3 pathways) and neuroprotective (protecting against glutamate-induced inflammation) activities; it also inhibits matrix metalloproteinases and mitochondrial Ca2+ influx. Minocycline has antioxidant and antiapoptotic properties, probably acting at high doses as a direct radical scavenger, like vitamin E, due to its phenolic ring structure [40]. In rats with SCI, minocycline given at oral doses of 3, 30, and 90 mg/kg 1 and 24 h after the lesion reduced MDA concentration and increased GPx and SOD activity in a dose-dependent manner [41]. Minocycline decreased pro-inflammatory cytokines and the chemokines release from microglia and their activation, including their levels of enzymes that regulate LP and NO production [42]. A recovery difference between treatment and placebo, approaching to statistical significance in patients with cervical injury, was shown in a phase II clinical trial. The trail determined safety and dose optimization, within 12 h of SCI and for 7 days, with steady-state concentrations of 12.7 µg/mL in serum and 2.3 µg/mL in in cerebrospinal fluid (ClinicalTrials.gov number NCT00559494) [43].
\nTreatment with gonadal steroid hormones (estradiol, testosterone, estrogen) has resulted in motor recovery with a reduction of the lesion volume in animal models. Through its receptors (ERα and ERβ), estrogen exerts neuroprotection at physiological concentrations, and it exerts better neuroprotection as an antioxidant at high concentrations. Estrogen modulates gene expression; promotes angiogenesis; inhibits inflammation, blocking microglia from releasing inflammatory molecules such as TNF-α, ROS, prostaglandin E2, etc.; regulates the expression of antioxidant enzymes; and induces mitochondrial GSH production [44]. Different low doses and times of administration (between 10 and 100 μg/kg/day/7 days to 4 mg/kg/15 min and 24 h, i.v.) appear to be effective, suggesting that pre-treatment or immediate posttreatment at either physiological or supraphysiological dose could minimize secondary injury in SCI and promote functional recovery, reflected in both acute and chronic stages [44, 45]. Additionally, the development of selective agonists of ER with higher affinity for ERα, ERβ, or both, such as tamoxifen, looks promising in SCI treatment, when applied in subdermal implants 7 days before, immediately, or 24 h post-injury; with an immediate release of 0.71 mg/day for 21 days, it provided motor recovery and preservation of white matter, dorsal and ventral horn neurons, with a decrease of O2•− production [46].
\nThe omega-3 fatty acids: α-linolenic acid, eicosapentaenoic acid (EPA, with five unsaturated bonds), and docosahexaenoic acid (DHA, with six unsaturated bonds) are part of the triacylglycerols that are consumed in the diet. DHA is a primary structural component of human brain, cerebral cortex, and retina. The lack of DHA may affect the fluidity and integrity of the membrane in synaptosomes; additionally, it affects the architecture of proteins that act as receptors and channels. Several studies have studied the effects of DHA in SCI, with treatments that include intravenous bolus, nutritional supplementation, and the use of transgenic [47]. In SCI in rats, a single application of DHA (250 nmol/kg, i.v., 30 min after injury) showed an improvement in motor recovery, smaller lesion size, greater survival of neurons and oligodendrocytes, and lower oxidation of DNA/RNA in comparison to rats without treatment [48]. More details of the application of DHA in SCI are mentioned in the chapter on Samaddar [47], as well as interesting effects on molecules involved in the repair and conservation of axonal integrity.
\nSeveral molecules that already act as endogenous antioxidants have been studied as candidates for application in antioxidant therapies for SCI. Vitamin C, or ascorbic acid, is a small water-soluble molecule that has a double bond and participates in various metabolic processes as a reducing agent. It is considered nontoxic because it does not accumulate and its concentration declines during SCI. In rats, it decreases tissue inflammation and necrosis and only at high doses (200 mg/kg i.p. 1-h post-injury, daily, until they were sacrificed, 4th week) showed improvements in motor evaluations [49]. Vitamin D (1,25-dihydroxyvitamin D3, VDH, active form) is a molecule with cholesterol skeleton and acts similarly to hormones and steroids on several systems. Its receptor (VDR) is widely distributed in the CNS, and it apparently acts on the same targets as progesterone through similar pathways. Its use in CNS damage models in vivo and in vitro has shown promising results on several aspects. The prolongation or exacerbation of inflammation also gives way to greater damage by oxidative stress; therefore, the effect of VDH in vivo on the inhibition of iNOS and increase of IL-4 and TGF-β and in vitro modulating the production of molecules involved in oxidative stress, neurotoxic damage, and axonal growth on various cells are of interest for being use in SCI [50]. Tocopherols are a group of four fat-soluble phenolic compounds designated α, β, γ, and δ, which are found in vegetable oils, being alpha (α-T, considered the classic vitamin E) the one with the highest proportion in blood and tissues. All tocopherols are strong chain breaking antioxidants by effectively scavenging ROS and RNS. α-T significantly reduces the activity of iNOS and COX-2 [51]; in addition, the effect of extracts or synthetic derivatives has been evaluated, decreasing cell death due to excitotoxicity and oxidative stress in astrocytes [52] and accelerating remyelination of focal demyelinated lesions chemically induced [53]. In rats with SCI, the use of α-T (600 mg/kg i.m., twice weekly, for 6 weeks) decreased the damage caused by ischemia-reperfusion, improving the levels of motor and sensory recovery and the level of oxidative stress [54]. Ubiquinol (reduced form) or coenzyme Q10 is among the antioxidants that decrease their concentration after SCI. It is a fat-soluble cofactor present in the inner mitochondrial membrane acting as an antioxidant in the respiratory chain. Previously, the effect on ischemia-reperfusion damage in the CNS has been proven, preventing LP and reducing the size of the lesions [55].
\nThe use of antibodies in the treatment of SCI is diverse and is directed to the functions of immune cells involved in inflammation and the pathological process. The initial invasion of leukocytes depends on the interaction of CD11d/CD18 (cluster of differentiation; CD) integrin with vascular cell adhesion molecule-1 (VCAM-1). In the case of the use of anti-CD11d monoclonal antibody administered in rats to determinate the therapeutic window with 1 mg/kg doses i.v. on groups at different times of application (2, 6, 12, 24, or 48 h post-lesion), it was shown that the treatment beginning even up to 6 h after the lesion resulted in an attenuation of infiltrating leukocytes (neutrophils and macrophages, sources of ROS and RNS), lowered the expression of COX-2 and iNOS, and lowered the amounts of HNE, NT-3, and dinitrophenyl (DNP) (used for the detection of protein carbonylation) therefore acting as an indirect antioxidant. This treatment also showed improvement in motor recovery vs. a control antibody [56]. Another important integrin is the dimer α4β1 also known as very late antigen 4 (VLA-4), and treatments with anti-α4 blocking monoclonal antibodies (2.5 mg/kg/2 and 24 h/i.v.) or small molecule blocker BIO5192 (10 mg/kg/2 h/continuous i.v. infusion for assessment of oxidative damage) showed a decreased influx of neutrophils/macrophages, reduced oxidant activity (COX-2, NO or iNOS, MDA), preserved white and gray matter, improved motor function in different evaluations, and decreased mechanical allodynia after SCI, when compared with the controls [57, 58].
\nModified neural peptides are peptide analogs of the myelin basic protein (MBP) epitopes that possess one or more aa substitutions and that have a partial agonist or antagonist action when in contact with the T lymphocyte (TL) receptor [59, 60].
\nSchwartz and Hauben tested the administration of non-encephalitogenic peptides of different aa sequences associated with MBP, which are named according to the position of the aa substitution that is performed: A96, G91, and A91, among others. A91 showed the best results after a traumatic injury, both in the optic nerve and in spinal cord, without showing clinical signs of autoimmune disease, hypersensitivity, immunosuppression, and controlling the destructive action of autoreactive TL [61, 62].
\nA91 is a peptide belonging to the aa 87–99 sequence of MBP with the substitution of an aa at position 91 of a lysine (VHFF
The beneficial effect of subcutaneous immunization at the base of the tail has been demonstrated with A91 at a single dose (150–200 μg/kg) after SCI due to moderate contusion. This immunization, among various factors and effects, promotes neuroprotection and motor recovery by decreasing the expression of iNOS and production of NO•, LP, caspase 3, and pro-inflammatory cytokines and increasing the release of neurotrophic factors such as BDNF and NT-3. The effect of the immunization is preserved in the chronic stage of the lesion and as a prophylactic treatment or up to 72 h after the SCI; however, it diminishes when applied to lesions due to severe contusion or complete medullar cut and is eliminated with a double immunization. It has also been determined that the severity of the lesion determines the profile of genetic expression in the lesion after immunization and that immunization plus the removal of the fibroglial scar and/or the implant of a scaffold as support for mesenchymal stem cells favors a permissive microenvironment for motor recovery and improves the electrophysiological activity in the chronic stage after a complete section of the spinal cord [67, 68, 69, 70, 71, 72, 73]. The protective response of A91 is between 4 and 6 days, indicating that it acts on subsequent mechanisms to the acute stage. During this time, the oxidative processes are not completely modulated. Regarding this, it has been shown that the therapeutic combination of A91 peptide with peptides acting at shorter times, such as glutathione monoethyl ester (GSH-MEE) or the monocyte locomotion inhibitory factor (MLIF), reduces FR and LP and induces better motor recovery, neural survival, presence of myelinated axons, and tissue protection. In the same way, it was demonstrated that the combination of A91 with GSH-MEE retains the effect if applied until 72 hrs after the lesion [68, 74, 75].
\nMLIF is a pentapeptide (Met-Gln-Cys-Asn-Ser). In vitro studies showed that MLIF decreases MN locomotion, the production of ROS (H2O2, O2•-, HO•), NO•, and cGMP, and it induces an increase of microtubules associated to the centriole and the concentration of cAMP [76, 77, 78]. The pharmacophore group of the MLIF is integrated by the Cys-Asn-Ser tripeptide, which retains the same biological activities of the factor [79, 80].
\nThe MLIF favors the Th2 response; modulates the synthesis of pro-/anti-inflammatory cytokines and the expression of genes involved in inflammation, proliferation, angiogenesis, synthesis/degradation of extracellular matrix, angiogenesis, and axonal guidance, among others; and acts mainly through the signaling pathways: NF-kB, MAPKinases, and eEF1A1/endothelial nitric oxide synthase [81, 82, 83, 84].
\nIn vivo, the factor retards the arrival of MN in Rebuck windows and inhibits cutaneous delayed hypersensitivity to dinitrochlorobenzene, while in guinea pigs, it lobs down the expression of VLA-4 and VCAM-1 adhesion molecules in postcapillary vascular endothelium and decreases the formation of pericardial adhesions in rats when applied directly to the site of injury after surgery [85].
\nStudies in cerebral ischemia showed that the penetrating, antioxidant, anti-inflammatory, and neuroprotective capacity of the pharmacophore group is favored in analogs when the N-terminal end is modified by adding one of the following aa: Asp, His, Try, or Arg. In the same way, cardioprotective effects have been seen in myocardial ischemia [86, 87]. On the other hand, pharmacokinetic studies are underway to determine the concentration of MLIF in plasma [88].
\nIn base studies of our group, rats were subjected to a moderate SCI, and a dose of 200 μg of MLIF was applied directly to the site of the lesion. The animals treated with the factor presented a greater motor recovery than the non-treated, and a decrease in the LP, the concentration of NO•, and the expression of the iNOS. An increase in the expression of the IL-10 and TGF-β (Transforming Growth Factor beta) genes was observed at 3 h and 7 days post-injury, favoring the survival of the ventral horn neurons [75]. Subsequent studies showed that four doses of the MLIF at the same concentration immediately initiating direct administration at the site of injury and subsequently one dose every 24 h for 3 days by i.p. administration are sufficient to improve motor recovery in rats subjected to SCI. In the same way, therapeutic combinations of MLIF, at different times and doses, have favored the effect of the MLIF in the experimental model of SCI modulating the synthesis of the FR and ROS.
\nGSH (Figure 3) is a tripeptide (L-γ-glutamyl-L-cysteinyl-glycine), nonprotein thiol. It is synthesized in the cellular cytoplasm by the consecutive action of two enzymes. The first, γ-glutamylcysteinyl ligase, is regulated by the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2), which is sensitive to oxidative stress. This enzyme uses glutamic acid (Glu) and Cys aa, glutamic acid (Glu) and Cys aa, as a substrate to form the γ-glutamylcysteine dipeptide (γ-GluCys), which is combined with glycine (Gly) in a reaction catalyzed by the second enzyme (glutathione synthase) to form GSH, whose concentration is regulated by the nhibition of γ-GluCys ligase, the cellular content of L-cysteine, and the final concentration of GSH. Thus, the intracellular and extracellular concentrations of GSH are determined by the balance among its synthesis, catabolism, and transport between cytosol and the different organelles [89].
\nCondensed structural chemical formula of glutathione (IUPAC name: (2S)-2-amino-4-{[(1R)-1-[(carboxymethyl) carbomoyl]-2-sulfanylethyl] carbomyl1} butanoic acid). Modified from Gaucher et al. [
GSH, by itself, is not transported effectively into the cells, and under normal physiological conditions, it is in a reduced form. During its oxidation (where the thiol group of Cys is responsible for the redox reactions) by ROS and RNS, it involves two types of reactions, a nonenzymatic reaction with the NO•, HO−, and O2•− radicals and an enzymatic one providing an electron for the reduction of peroxides in the reaction, catalyzed by GPx to form the oxidized glutathione GSSG (two GSH molecules bound by the disulfide bridge), which is regenerated by Gr, an enzyme that transfers electrons from NADPH to GSSG by reducing it [90, 91]. Thus, the redox state of GSH activates the activator protein 1 (AP-1) responsible for the expression of cytokine genes, TGF-β, and collagenase and AP-2 responsible for the activation of c-Jun-N-terminal kinases (JNK), stress-activated protein kinases (SAPK), protein kinase c (PK-C), and tyrosine kinase, while the decrease in the GSH level stimulates the activation of NF-κB, protein kinase B, c-Jun N-terminal Kinase, and mitogen-activated protein kinase with the subsequent increase in synthesis of pro-inflammatory cytokines and caspases. In suitable concentrations, GSH increases the activation, proliferation, and cellular differentiation and regulates the Ca2+ homeostasis [91], granting a fundamental role in cellular homeostasis and pathologies related to patient’s age and oxidative stress states, such as neurodegenerative, neuroinflammatory, cardiovascular diseases, and cerebral ischemia, among others [92, 93]. To increase the intracellular GSH concentration levels, GSH precursors have been used, without modifying the Cys that is critical for the functioning of the peptide. GSH precursor molecules such as N-acetyl cysteine (NAC) stimulate the biosynthesis of GSH that acts directly on ROS, RNS [89, 93, 94], and glutathione esters, mainly mono- and dimethyl esters such as glutathione monoethyl ester [γ- Glu-Cys-Gly-OEt (GSH-MEE)], where the carboxyl group of Gly is esterified and, due to its high hydrophobicity, increases its permeability to the cell membrane and facilitates its transport in brain-spinal fluid [95, 96, 97]. Once GSH-MEE is located in the cellular cytoplasm, it is hydrolyzed by the intracellular esterases to release and cause the intracellular increase in the GSH concentration and react with the FR without enzymatic intervention or it reduces the peroxides by means of GPx through its oxidation to GSSG [89, 91, 98, 99].
\nGSH-MEE has been used effectively to protect cells from oxidizing agents and various toxic compounds in various cell lines and animal models with neurodegenerative and inflammatory processes [92, 99, 100]. Studies of our group and collaborators have shown that the i.p. administration of 12 mg/kg of GSH-MEE divided into four doses in the first 24 h post-lesion in rats subjected to a moderate SCI contributes to the reduction of oxidative stress, significantly improves motor function and survival of red core neurons, and stabilizes spinal cord blood flow [100], while a therapeutic combination of GSH-MEE (at the same dose and under the same scheme) with intradermal application (i.d.) of the A91 peptide at the base of the tail at a dose of 600 μg/kg immediately after the injury promotes a better neurological recovery and morphological preservation. This combination is able to maintain its neuroprotective action even if it starts 72 h after the injury [68, 74]. In the same way, our group has demonstrated that the therapeutic combination of GSH-MEE and MLIF promotes greater motor recovery and maintains several morphological aspects on the site of lesion in rats subjected to moderate SCI.
\nA variety of ingredients and active ingredients derived from herbal extracts, known for their antioxidant and anti-inflammatory activity, have also called the attention to complement SCI treatments. Among all these, ingredients such as curcumin, resveratrol, epigallocatechin gallate, ligustrazine, quercitrin, and puerarin and herbs such as Dashen,
A highly studied antioxidant strategy consists of scavengers of FR that include, among others, thiols (lipoic acid), GSH precursors, NAC, polyphenolic compounds, hydroxyl stilbenes, nitrones, and spin trappings (noncyclic and cyclic nitrones); we will only review the latter. Most spin trappings have a nitronate or nitroxide nucleus and are chemical agents that react with FR, forming stable products (adducts), and were originally developed as a tool to detect and stabilize the FR in chemistry and later in biological oxidation processes [103, 104, 105]. The first spin trappings had short half-lives and generated toxic HO•. By designing the spin trappings with the inclusion of heterocyclic rings (pyrrolines or phenol, generating Imidazolyl-nitrones, Furil-nitrones, Arylnitrons, and others) toxicity was reduced, improving its neuroprotective, anti-inflammatory, functionality, stability, bioavailability, and trapping different types of FR centered on O2, carbon, and sulfur derivatives. In turn, this increases their solubility in high concentrations in a large number of solvents (~0.1M), producing a positive effect when administered in a varied-dose scheme before or after a traumatic event [103, 106]. A basic example of the nitrones is phenyl N-tert-butylnitrone (PBN), an arylnitrone with general formula X-CN = NO-Y, which acts by reacting with O2•− and/or HO− to produce adducts. Once the adduct is formed, the radical is inactivated and unable to damage the cell tissue [104, 107]. The general reaction is that of the formation of adduct, schematized in Figure 4. In general, it is indicated that PBN is not toxic and the suitable concentration to form adducts is 10–15 mg/100 g of weight, while the estimated lethal dose is 10 times higher (100–150 mg/100 g of weight) [108]. The first neuroprotective evidence was in neurodegenerative models administered at low doses after injury and in the prevention of stroke-induced mortality in models of ischemia in gerbils [103, 104, 109, 110, 111, 112, 113]. The pharmacological effects of PBN in animal models are extensive, protecting against death after endotoxic shock, bacterial meningitis, teratogenicity induced by thalidomide, diabetogenesis, hepatocarcinogenesis, etc. Many studies have reported a neuroprotective effect in SCI and the brain (the most studied) decreasing the expression of genes associated with apoptosis, inflammation, and iNOS by decreasing the activation of MAP p-38 NF-κB nitrogen kinase and synthesis of NO• [114]. In a process of ischemia or perfusion, PBN reduces the size of the infarct by increasing ischemic reperfusion and decreasing neurodegeneration, excitotoxicity, and the activation of microglia; it also induces neurite growth through indirect activation of the Ras-ERK pathway, increasing animal survival [106, 115, 116, 117]. The neuroprotective effect of PBN is attributed to its ability to quickly and easily penetrate the membranes and the blood-brain barrier with a half-life of 3 h in plasma; decrease the levels of oxidized proteins, 8-isoprostane, HNE, IL-1β, TNF-α, IFN-γ, c-fos, IL-3, IL-4, IL-5, and H2O2; and favor an increase of GHS and IL-10, among others [106, 117, 118, 119]. In a model of cortical contusion in rats, it was demonstrated that pre-treatment with PBN with a single intravenous dose of 30 mg/kg 30 min before the injury reduces the cognitive deficit and its volume; it has shown to have a wide therapeutic window in focal ischemia rodent models, reducing the infarct volume when administered up to 12 h after the beginning of the stroke and reducing the loss of tissue when administered by fluid percussion 30 min. After injury in rats [120]. Currently, the nitrones derived from PBN [102] are being widely studied as neuroprotective in different CNS pathologies and in traumatic lesions. For example, 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) has neuroprotective effects when applied 4–5 hr post-occlusion at equimolar doses to PBN and reduced infarct volume from 37.2 to 12.5% when 30 mg/kg was administered i.v. 1 h after reperfusion in Wistar rats [121, 122, 123, 124]. Meanwhile, stilbazulenyl nitrone (STAZN) exerts similar effects at lower doses than the one used for NXY-059; in fact, the tolerability and safety of NXY-059 were studied in patients with acute stroke in clinical trials [103, 124]. Although not all compounds have demonstrated their neuroprotective effect when administered 24 h after the traumatic event, some of them have allowed favoring the therapeutic window at repeated doses [103].
\nBasic reaction of a nitrone with FR to produce a stable spin product (adduct). Modified from Refs. [
Other derivatives are 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and diesterified nitrone (EMEPO), which have shown similarities to the action of PBN but with some other advantages, such as being less toxic and increasing the levels of antiapoptotic proteins such as Bcl2 and p-Bad and decreasing the synthesis of pro-apoptotic ones such as caspase 3, p53, and Bax [125, 126, 127]. In addition, (2, 2, 6, 6-tetramethylpiperidin-1-yl)oxyl (Tempo) and (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (Tempol) have shown antioxidant properties in radiation damage and injury [128, 129]. In a traumatic brain injury mouse model, Tempol reduced post-traumatic LP and oxidative damage induced by protein nitration, decreasing mitochondrial damage, cytoskeletal damage, and neurodegeneration and improving motor function [128, 130, 131].
\nDespite the results observed with the nitrones and the wide range of studies performed for therapeutic uses at different doses and times, their action is attributed to their ability to form adducts, but not before indicating the possible participation of other mechanisms that favor their neuroprotective activity, thus expanding the information on antioxidant therapy strategies in the clinical area.
\nPolyethylene glycol (PEG) is a surfactant that due to its hydrophilic nature allows the fusion and fluidity of the cell membrane that reduces the oxidative effects of the secondary stage and that during the acute phase of SCI, it may inhibit nerve fiber degeneration and create a favorable microenvironment for the regeneration of nerve filaments that can stimulate angiogenesis and reduce glial scar, promoting the regeneration of axonal guidance and motor recovery. PEG has been widely used as a scaffold for a large variety of molecules in treatment for SCI [132, 133, 134, 135, 136], while the SOD enzyme has antioxidant properties, as mentioned previously. The combination of SOD with PEG (PEG-SOD) allows an increase of the enzyme intracellularly and its antioxidant activity, and it may have an important role in vascular relaxation by reducing the concentration of O2•− and limiting the LP [132]. It has been used in myocardial ischemia and in lung injury models, proposed as a treatment vs. oxidative stress [132].
\nIn a controlled phase II study in patients in a coma who suffered a stroke and received a single i.v. dose of 2000, 5000, or 10,000 IU/kg 4 h after the injury, its recovery was better in comparison to the group that received placebo (44% were in a vegetative state or died); no side effects were observed in this study due to the administration of the drug [137].
\nIn a study in a cerebral ischemia model performed in rats, 10,000 IU/kg of PSG-SOD were i.v. administered, and the group presented a significant reduction in infarct size in comparison to the control group [138]. In other study with Sprague-Dawley male rats (300-350g of weight), an occlusion of the hepatic artery was performed and reperfusion was performed after 90 min to generate liver damage. A group of animals received i.v. 5000 U/kg of PEG-SOD before vascular occlusion and immediately after reperfusion, while the control group only received a saline solution following the same scheme. In the group treated with PEG-SOD, hepatic ischemia and LP were attenuated. Meanwhile, another study examined the effect of PEG-SOD on focal cerebral ischemia/reperfusion in rats; the results showed that the effect is variable, depending on the dosage [132, 139]. In a dog experiment, thoracic aortic cross-clamping was performed; a dose of 5000 U/kg of PEG-SOD was i.v. administered to one group 15–20 min before clamping, and the other group only received a saline solution. Delayed paraplegia was avoided in the group of dogs that received the conjugate, unlike the groups that did not receive it [140]. Edward et al. conducted an important review of the use of PEG-SOD in phase II and III studies in traumatic brain injury [141].
\nWhen mannitol is used for medical purposes, it is administered intravenously. Mannitol can be found in varying concentrations, dissolved in 100 mL of fluid (5, 20, and 25% mannitol). A common solution is 20% mannitol. Cruz and colleagues described the dose-response effect of preoperative mannitol on acute subdural hematomas in traumatic brain injury in which mannitol therapy has been classically directed, establishing and maintaining an osmotic gradient between the blood and brain [142, 143].
\nMaintaining an adequate spinal cord perfusion pressure is crucial after SCI. Intramedullary edema within the spinal cord and consecutively raised intrathecal pressure at the injury are important secondary injury mechanisms in the pathobiology after traumatic SCI. Increased intraspinal pressure reduces spinal cord perfusion pressure, which leads to worsen post-traumatic ischemia [144].
\nMannitol allows the control of blood flow patterns in the spinal cord; it has been used experimentally in some studies in rats that have suffered a controlled SCI and in dogs/cats that suffer an SCI within the clinical area. Mannitol is recommended to reduce the effect of inflammation and edema, an effect that has been corroborated with microangiographic and electrophysiological studies. One hour after the application of a 3 g/kg dose, an improved intramedullary vascular pattern was detected among the animals treated with mannitol compared to those that were not treated, and 4 h after the perfusion, many areas of the lateral white matter of the spinal cord were almost normal [145]. In a study in dogs, an SCI was experimentally induced, and it was reported that mannitol alone did not help to reverse the paralysis of these animals [146]; however, another study stated that the i.v. administration of mannitol at a dose of 2 g/kg had a good effect on the white matter of the spinal cord and areas of the brain [147]. In a retrospective study with Sprague-Dawley rats, a group with SCI by compression by means of a clamp, 2 g/kg mannitol were administered immediately after the injury, while the control group was given 0.9% saline solution; all groups underwent structural and electrophysiological studies. The group treated with mannitol obtained excellent results, finding significant improvement in neural structures and protection of the spinal cord after SCI [148]. In a study in dogs to which an edema was induced by severe external spinal cord trauma, 3 g/kg of mannitol was i.v. administered, and they were neurologically evaluated, and a myelography study was performed after 2 h of the treatment, to identify the edema, showing that there was reduction of it [149].
\nIn addition to its independent use, several studies have evaluated the use of one or more antioxidants together by themselves or in addition to other existing therapies for SCI, such as rehabilitation exercise or cell transplantation, expecting a synergism to enhance the recovery. Moreover, some therapies not only aim to improve the immediate treatment of SCI but also improve the effects it has on relieving the most common complications in patients. To mention some, the combination of vitamin C as antioxidant (100 mg/kg/1 h and daily/28d, i.p.) together with the transplantation of bone marrow mesenchymal stem cells (BMMSC) (3 × 106 cells) induced improvements in motor recovery in rats when compared with methylprednisolone (MP), vitamin C, or BMMSC alone in SCI [150]; simultaneous administration of vitamin D (5 μg/kg/twice daily) and progesterone (0.5 mg/kg/twice daily i.m.) for 5 days demonstrated a higher efficacy in reducing neuroinflammation in comparison to when they were administered separately, and when they were administrated early (first 4 h) in SCI patients receiving MP, there was improvement in the motor and sensory functions 6 months after starting therapy [151]. Applying once a day a combination of low-dose fluoxetine (1 mg/kg/i.p.) and vitamin C (100 mg/kg/i.p.) immediately after the event and for 14 days had a protective effect on the BSCB integrity, improving the functional recovery, showing inhibition of the expression and activation of the matrix metalloproteinase, and decreasing the infiltration of leukocytes and the expression of inflammatory and oxidizing molecules, but not when they were applied separately in rats [152]. In SCI patients, dietary supplementation for 3 months, which included three 750 mg per day of omega-3 fatty acids and antioxidants (400 mg of mixed tocopherols, coenzyme Q10, curcumin, etc.), caused a decrease of inflammatory cytokines with reduction in neuropathic pain [153]; 2 months vitamin E dietary supplementation 765–1020 IU/day in rats before SCI showed accelerated bladder recovery, significant motor improvement, and a high number of oligodendrocytes compared to the controls [154].
\nAfter a primary injury occurs on the spinal cord, destructive biochemical mechanisms are initiated (secondary injury) that play a fundamental role in the pathophysiology of spinal cord injury. Within these, oxidative stress and lipid peroxidation exacerbate the biochemical mechanisms once initiated and propagate neurodegenerative damage, so the degree of loss of long-term motor and sensory functions depends largely on their intensity. This damage suffered during the acute phase and that may be irreversible requires a timely intervention. To guarantee the antioxidant effect that will render better results, it is important to consider the new agents and therapies in the SCI treatment at the appropriate times. There is no fully restorative therapy for SCI, but strategies for the modulation of this damage contribute to neuroprotection and, although partially, to functional recovery.
\nWe are grateful for the support given to the line of research related to the evaluation of immunomodulatory peptides in oxidative stress under the support No. FIS/IMSS/PROT/G16/1605 and FIS /IMSS/PROT/G17/1676 and the scholarship granted to the students of Master’s degree Dulce M. Parra and Jonathan Vilchis by CONACYT and IMSS.
\nThe authors declare no competing financial interests.
\n\n amino acids alcohol dehydrogenase aldehyde dehydrogenase blood-spinal cord barrier bone marrow mesenchymal stem cells catalase cluster of differentiation central nervous system carbonate radical cyclooxygenase docosahexaenoic acid dinitrophenyl eicosapentaenoic acid estrogen receptor free radicals growth-associated protein 43 glial fibrillary acidic protein glutathione peroxidases glutathione reductases glutathione, reduced glutathione monoethyl ester glutathione, oxidized glutathione S-transferases 4-hydroxy-2-nonenal hydrogen peroxide hydroxyl radical hydroxyl anion interferon gamma interleukin inducible nitric synthase lipid radical lipid lipid peroxidation lipid peroxyl radical lipid alkoxyl radical lipid hydroperoxide monocyte locomotion inhibitory factor malondialdehyde methylprednisolone sodium succinate N-acetyl cysteine nicotinamide-adenine dinucleotide phosphate, reduced nitric oxide nitrogen dioxide radical nitric oxide synthase 3-nitrotyrosine superoxide peroxynitrite phenyl N-tert-butylnitrone polyethylene glycol polyethylene glycol-superoxide dismutase polyunsaturated fatty acid reactive oxygen species reactive nitrogen species peroxyl radical spinal cord injury superoxide dismutase transforming growth factor beta tumor necrosis factor alpha vascular cell adhesion molecule-1 vitamin D: 1,25-dihydroxyvitamin D3 very late antigen 4 xanthine oxidase
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",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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Due to rapid depletion of agricultural areas and soil quality by means of ever-increasing population and an excessive addition of chemical fertilizers, a rehabilitated attention is a need of the hour to maintain sustainable approaches in agricultural crop production. Biochar is the solid, carbon-rich material obtained by pyrolysis using different biomasses. It has been widely documented in previous studies that, the crop growth and yield can be increased by using biochar. This chapter exclusively summarizes the properties of biochar, its interaction with soil microflora, and its role in plant growth promotion when added to the soil.",book:{id:"7305",slug:"biochar-an-imperative-amendment-for-soil-and-the-environment",title:"Biochar",fullTitle:"Biochar - An Imperative Amendment for Soil and the Environment"},signatures:"Jyoti Rawat, Jyoti Saxena and Pankaj Sanwal",authors:null},{id:"46355",doi:"10.5772/57469",title:"Phytoremediation of Soils Contaminated with Metals and Metalloids at Mining Areas: Potential of Native Flora",slug:"phytoremediation-of-soils-contaminated-with-metals-and-metalloids-at-mining-areas-potential-of-nativ",totalDownloads:8605,totalCrossrefCites:14,totalDimensionsCites:87,abstract:null,book:{id:"3854",slug:"environmental-risk-assessment-of-soil-contamination",title:"Environmental Risk Assessment of Soil Contamination",fullTitle:"Environmental Risk Assessment of Soil Contamination"},signatures:"Paulo J.C. 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With an increasing understanding of clay structure, montmorillonite is realized viable for an enhanced performance in a variety of materials and products in the areas of catalysis, food additive, antibacterial function, polymer, sorbent, etc. Significant development in the use and application of montmorillonite is seen in recent time. This chapter provides an overview of montmorillonite, structure, and properties and particularly discusses its recent utilization in important materials. Montmorillonite is introduced in terms of its natural sources, chemical structure, physical and chemical properties, and functional utilization. The important physical and chemical properties are summarized as particle and layered structure, molecular structure and cation exchange effect, barrier property, and water sorption. This is followed by the important functional utilizations of montmorillonite based on the effects of its chemical structure. The important functional utilization of montmorillonite includes food additive for health and stamina, for antibacterial activity against tooth and gum decay, as sorbent for nonionic, anionic, and cationic dyes, and the use as catalyst in organic synthesis. The environment concerns, to date, do not indicate the adversity for particles used as additive. Studies will be useful which are clearly based on any montmorillonite structure to describe environmental effects.",book:{id:"6561",slug:"current-topics-in-the-utilization-of-clay-in-industrial-and-medical-applications",title:"Current Topics in the Utilization of Clay in Industrial and Medical Applications",fullTitle:"Current Topics in the Utilization of Clay in Industrial and Medical Applications"},signatures:"Faheem Uddin",authors:[{id:"228107",title:"Prof.",name:"Faheem",middleName:null,surname:"Uddin",slug:"faheem-uddin",fullName:"Faheem Uddin"}]}],mostDownloadedChaptersLast30Days:[{id:"46032",title:"Soil Contamination, Risk Assessment and Remediation",slug:"soil-contamination-risk-assessment-and-remediation",totalDownloads:14030,totalCrossrefCites:22,totalDimensionsCites:62,abstract:null,book:{id:"3854",slug:"environmental-risk-assessment-of-soil-contamination",title:"Environmental Risk Assessment of Soil Contamination",fullTitle:"Environmental Risk Assessment of Soil Contamination"},signatures:"Muhammad Aqeel Ashraf, Mohd. Jamil Maah and Ismail Yusoff",authors:[{id:"25185",title:"Dr.",name:"Muhammad Aqeel",middleName:null,surname:"Ashraf",slug:"muhammad-aqeel-ashraf",fullName:"Muhammad Aqeel Ashraf"},{id:"101988",title:"Dr.",name:"Ismail",middleName:null,surname:"Yusoff",slug:"ismail-yusoff",fullName:"Ismail Yusoff"},{id:"169931",title:"Prof.",name:"Mohd Jamil",middleName:null,surname:"Maah",slug:"mohd-jamil-maah",fullName:"Mohd Jamil Maah"},{id:"169932",title:"Dr.",name:"Ng Tham",middleName:null,surname:"Fatt",slug:"ng-tham-fatt",fullName:"Ng Tham Fatt"}]},{id:"71931",title:"Open Pit Mining",slug:"open-pit-mining",totalDownloads:1767,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Open pit mining method is one of the surface mining methods that has a traditional cone-shaped excavation and is usually employed to exploit a near-surface, nonselective and low-grade zones deposits. It often results in high productivity and requires large capital investments, low operating costs, and good safety conditions. The main topics that will be discussed in this chapter will include an introduction into the general features of open pit mining, ore body characteristics and configurations, stripping ratios and stripping overburden methods, mine elements and parameters, open pit operation cycle, pit slope angle, stability of mine slopes, types of highwall failures, mine closure and reclamation, and different variants of surface mining methods including opencast mining, mountainous mining, and artisan mining.",book:{id:"8620",slug:"mining-techniques-past-present-and-future",title:"Mining Techniques",fullTitle:"Mining Techniques - Past, Present and Future"},signatures:"Awwad H. Altiti, Rami O. Alrawashdeh and Hani M. 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The first stage contains the area recognition, its limitation to the target, and elimination of external factors until defining a geothermal zone with characteristics to be commercially exploited. The main studies and analysis that can be applied during the exploration stage are listed, and the major indicator to continue with the project or suspend is the prefeasibility report. The major risks in the exploration stage are due to studies that are carried out on the surface; at this stage, the costs can be considered low. The main results of the exploration are the selection of sites to drill three or four initial wells. Each well provides a direct overview of the reservoir: depth, production thicknesses, thermodynamic parameters, and production characteristics. The drilling of three to four exploratory wells is recommended, as far as there is certainty of the feasibility of the project, and the development of the field begins with drilling of sufficient wells to feed the plant. In this stage, the cost increases, but the risks decrease.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Alfonso Aragón-Aguilar, Georgina Izquierdo-Montalvo,\nDaniel Octavio Aragón-Gaspar and Denise N. Barreto-Rivera",authors:[{id:"258358",title:"Dr.",name:"Alfonso",middleName:null,surname:"Aragón-Aguilar",slug:"alfonso-aragon-aguilar",fullName:"Alfonso Aragón-Aguilar"}]},{id:"65070",title:"Biochar: A Sustainable Approach for Improving Plant Growth and Soil Properties",slug:"biochar-a-sustainable-approach-for-improving-plant-growth-and-soil-properties",totalDownloads:6979,totalCrossrefCites:61,totalDimensionsCites:101,abstract:"Soil is the most important source and an abode for many nutrients and microflora. Due to rapid depletion of agricultural areas and soil quality by means of ever-increasing population and an excessive addition of chemical fertilizers, a rehabilitated attention is a need of the hour to maintain sustainable approaches in agricultural crop production. Biochar is the solid, carbon-rich material obtained by pyrolysis using different biomasses. It has been widely documented in previous studies that, the crop growth and yield can be increased by using biochar. This chapter exclusively summarizes the properties of biochar, its interaction with soil microflora, and its role in plant growth promotion when added to the soil.",book:{id:"7305",slug:"biochar-an-imperative-amendment-for-soil-and-the-environment",title:"Biochar",fullTitle:"Biochar - An Imperative Amendment for Soil and the Environment"},signatures:"Jyoti Rawat, Jyoti Saxena and Pankaj Sanwal",authors:null},{id:"39170",title:"Study of Impacts of Global Warming on Climate Change: Rise in Sea Level and Disaster Frequency",slug:"study-of-impacts-of-global-warming-on-climate-change-rise-in-sea-level-and-disaster-frequency",totalDownloads:6708,totalCrossrefCites:14,totalDimensionsCites:32,abstract:null,book:{id:"2206",slug:"global-warming-impacts-and-future-perspective",title:"Global Warming",fullTitle:"Global Warming - Impacts and Future Perspective"},signatures:"Bharat Raj Singh and Onkar Singh",authors:[{id:"26093",title:"Dr.",name:"Bharat Raj",middleName:null,surname:"Singh",slug:"bharat-raj-singh",fullName:"Bharat Raj Singh"},{id:"118426",title:"Prof.",name:"Onkar",middleName:null,surname:"Singh",slug:"onkar-singh",fullName:"Onkar Singh"}]}],onlineFirstChaptersFilter:{topicId:"10",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82490",title:"Precision Agriculture for Sustainable Soil and Crop Management",slug:"precision-agriculture-for-sustainable-soil-and-crop-management",totalDownloads:3,totalDimensionsCites:null,doi:"10.5772/intechopen.101759",abstract:"Precision agriculture (PA) transforms traditional practices into a new world of production of agriculture. It uses a range of technologies or diagnostic tools such as global navigation satellite system (GNSS), geographic information systems (GIS), yield monitors, near-infrared reflectance sensing, and remote sensing in collecting and analyzing the in-field spatial variability data, thereby enabling farmers to monitor and make site-specific management decisions for soils and crops. PA technology enables visualization of spatial and temporal variations of production resources and supports spatially varying treatments using variable rate application technologies installed on farm agricultural field machinery. The demand for PA is driven by recognition within-field variability and opportunities for treating areas within a field or production unit differently. PA can be applied to multiple cultural practices including tillage, precision seeding, variable rate fertilizer application, precision irrigation and selective pesticide application; and facilitates other management decisions making, for example, site-specific deep tillage to remove soil compaction. PA technology ensures optimal use of production inputs and contributes to a significant increase in farm profitability. By reducing crop production inputs and managing farmland in an environmentally sensible manner, PA technology plays a vital role in sustainable soil and crop management in modern agriculture.",book:{id:"10952",title:"Soil Science - Emerging Technologies, Global Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10952.jpg"},signatures:"Md. Rayhan Shaheb, Ayesha Sarker and Scott A. Shearer"},{id:"82272",title:"Landslide Movement Monitoring with InSAR Technologies",slug:"landslide-movement-monitoring-with-insar-technologies",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.105058",abstract:"Synthetic aperture radar interferometry (InSAR) is a technology that has been widely used in many areas, such as topographic mapping, land and resource survey, geological exploration, disaster prevention and mitigation, volcanic and seismic monitor and so on. Landslide, as a representative geohazard, include a wide range of phenomena involving downhill ground movement. InSAR, a technology which can measure surface deformation at the millimeter level over serveral days or years, is suitable to detect landslides with chronical and widespread movements. In this chapter, we introduce main process methods of InSAR data, including Persistent Scatter Interferometry (PSInSAR) and Distributed Scatter Interferometry (DSInSAR). A study area, Daguan County Town, one of the most landslide-prone areas in China is induced to demonstrate the practicability of InSAR in detecting landslides. Combined InSAR results with geological, geotechnical and meterological data, the distribution of landslide in Daguan County in spatial and temporal dimensions would be displayed. We also coupling numerical modeling and InSAR for characterizing landslide movements under multiple loads. The numerical results revealed that body loads dominated the cumulative downhill movements by squeezing water and air from voids, and precipitation caused seasonal movements with the direction perpendicular to the slope surface.",book:{id:"10950",title:"Landslides",coverURL:"https://cdn.intechopen.com/books/images_new/10950.jpg"},signatures:"Peifeng Ma, Yifei Cui, Weixi Wang, Hui Lin, Yuanzhi Zhang and Yi Zheng"},{id:"82823",title:"The Metropolitan Transformation of Ioannina City from 1940 to 2015",slug:"the-metropolitan-transformation-of-ioannina-city-from-1940-to-2015",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.105884",abstract:"The chapter presents the urban and regional changes in the city of Ioannina, Greece. This city is located in the periphery of Epirus, which is in the western Balkans, Eastern Europe. The chapter examines, with the tools of aerial photos and QGIS software, the spatial transformation of Ioannina city from 1940 to 2015. Map science is a field through which the users could observe and compare maps from past to future. The plans and the planning were formed under the values, standards, and fundamentals of the mosaic of politics, good practices, urban rules, and citizen level. The urban space has already changed until nowadays. The chapter examines the reasons for urban politics and social–economic moments that became the epitome of these urban and regional changes. The results show the comparative spatial study from each historical period.",book:{id:"11488",title:"GIS and Spatial Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11488.jpg"},signatures:"Efthymios-Spyridon Georgiou"},{id:"83032",title:"Introductory Chapter: Solar Photovoltaic Energy",slug:"introductory-chapter-solar-photovoltaic-energy",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.106259",abstract:null,book:{id:"9862",title:"Solar Radiation - Measurements, Modeling and Forecasting for Photovoltaic Solar Energy Applications",coverURL:"https://cdn.intechopen.com/books/images_new/9862.jpg"},signatures:"Mohammadreza Aghaei, Amir Nedaei, Aref Eskandari and Jafar Milimonfared"},{id:"82963",title:"Evolution of Radio Source Components and the Quasar/Galaxy Unification Scheme",slug:"evolution-of-radio-source-components-and-the-quasar-galaxy-unification-scheme",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106244",abstract:"In this work, a theoretical model is developed for explanation of temporal evolution of extragalactic radio sources via beaming, orientation effects and asymmetries. Equation of the form D≈P±q1+z−m is used to account for the D ∼ P/z relation. Also, D≈D01+z−1+z1+z2 accounted properly for Ω0=1 cosmology than the Ω0=0 counterpart in linear size versus redshift of radio sources. Similarly, D=Dc1∓lnPPc1/2 model explained redshift-luminosity relationship of extragalactic radio sources. The results from the regression analyses are q = +0.003 (r = 0.04) for sources with z < 1 and q = −1.59 (r = −0.6) for all z≥1 sources. A critical linear size, Dc of 316kpc which matches the maximum theoretical linear size, Dmax of 0.15D0 at a critical redshift zc∼1 and a critical luminosity Pc=26.33WHz−1 are obtained. The indication of all these results is that the linear size of radio sources evolves up to a certain limit in D–P plane and thereafter decreases with increasing luminosity as predicted in this work.",book:{id:"11737",title:"Astronomy",coverURL:"https://cdn.intechopen.com/books/images_new/11737.jpg"},signatures:"Costecia Ifeoma Onah, Augustine A. 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For the denser genotype, clone D (E. grandis x E. urophylla x Eucalyptus tereticornis), a thicker cell wall associated to thinner fibers results in a negative effect on the fiber quality. In contrast, clone B (Eucalyptus pellita x E. grandis), which has relatively inferior pulping performance, displayed the lowest wood density associated to wider lumen and fibers. The best growth performances in response to acclimatization and adaptation to the site strongly influences the pulp productivity, which is identified as the parameter of greatest variance between genotypes, and highlighting clone E (E. grandis x E. urophylla).",book:{id:"11840",title:"Arid Environment - Perspectives, Challenges and Management",coverURL:"https://cdn.intechopen.com/books/images_new/11840.jpg"},signatures:"Deborah Rodrigues de Souza Santos, Camila Sarto, Rafael Fernandes dos Santos, Júlia Lôbo Ribeiro Anciotti Gil, Carlos de Melo e Silva-Neto, Regina Maria Gomes, Evandro Novaes, Carlos Roberto Sette-Junior, Mario Tomazello-Filho, Rafael Tassinari Resende and Matheus Peres Chagas"}],onlineFirstChaptersTotal:119},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:6,paginationItems:[{id:"82526",title:"Deep Multiagent Reinforcement Learning Methods Addressing the Scalability Challenge",doi:"10.5772/intechopen.105627",signatures:"Theocharis Kravaris and George A. Vouros",slug:"deep-multiagent-reinforcement-learning-methods-addressing-the-scalability-challenge",totalDownloads:19,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Multi-Agent Technologies and Machine Learning",coverURL:"https://cdn.intechopen.com/books/images_new/11445.jpg",subseries:{id:"27",title:"Multi-Agent Systems"}}},{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. Kleczyk, Karin Hayes and Rajesh Mehta",slug:"evaluating-similarities-and-differences-between-machine-learning-and-traditional-statistical-modelin",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Machine Learning and Data Mining - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11422.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:61,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}}]},overviewPagePublishedBooks:{paginationCount:11,paginationItems:[{type:"book",id:"7723",title:"Artificial Intelligence",subtitle:"Applications in Medicine and Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7723.jpg",slug:"artificial-intelligence-applications-in-medicine-and-biology",publishedDate:"July 31st 2019",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"a3852659e727f95c98c740ed98146011",volumeInSeries:1,fullTitle:"Artificial Intelligence - Applications in Medicine and Biology",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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His areas of scientific interest are signal and image processing, filtering, steganography, segmentation, pattern recognition, biomedical signal processing, sensors, and real-time applications.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"428449",title:"Dr.",name:"Ronaldo",middleName:null,surname:"Ferreira",slug:"ronaldo-ferreira",fullName:"Ronaldo Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428449/images/21449_n.png",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:null,institution:null},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"417317",title:"Mrs.",name:"Chiedza",middleName:null,surname:"Elvina Mashiri",slug:"chiedza-elvina-mashiri",fullName:"Chiedza Elvina Mashiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"352140",title:"Dr.",name:"Edina",middleName:null,surname:"Chandiwana",slug:"edina-chandiwana",fullName:"Edina Chandiwana",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"342259",title:"B.Sc.",name:"Leonard",middleName:null,surname:"Mushunje",slug:"leonard-mushunje",fullName:"Leonard Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"347042",title:"Mr.",name:"Maxwell",middleName:null,surname:"Mashasha",slug:"maxwell-mashasha",fullName:"Maxwell Mashasha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"2941",title:"Dr.",name:"Alberto J.",middleName:"Jorge",surname:"Rosales-Silva",slug:"alberto-j.-rosales-silva",fullName:"Alberto J. Rosales-Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"437913",title:"Dr.",name:"Guillermo",middleName:null,surname:"Urriolagoitia-Sosa",slug:"guillermo-urriolagoitia-sosa",fullName:"Guillermo Urriolagoitia-Sosa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"435126",title:"Prof.",name:"Joaquim",middleName:null,surname:"José de Castro Ferreira",slug:"joaquim-jose-de-castro-ferreira",fullName:"Joaquim José de Castro Ferreira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"437899",title:"MSc.",name:"Miguel Angel",middleName:null,surname:"Ángel Castillo-Martínez",slug:"miguel-angel-angel-castillo-martinez",fullName:"Miguel Angel Ángel Castillo-Martínez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"289955",title:"Dr.",name:"Raja",middleName:null,surname:"Kishor Duggirala",slug:"raja-kishor-duggirala",fullName:"Raja Kishor Duggirala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jawaharlal Nehru Technological University, Hyderabad",country:{name:"India"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. 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