\r\n\tRNA therapies evolved as profitable and widely applicable individualized treatment solutions. Moreover, RNA-based therapeutic vaccines (e.g., against SARS-CoV-2 infection) have been proven to be safe and effective, and several of them are approved by the United States Food and Drug Administration (FDA). \r\n\tThis book aims to present distinct classes of RNA therapeutics, ranging from single-stranded antisense oligonucleotides (ASOs), and subclasses of RNA interferences (miRNAs and other RNAi), to in vitro transcribed mRNAs and RNA vaccines. Also, it will present some of the challenges in RNA drug engineering, delivery, and specificity. Additionally, the improvement of pharmacological effectiveness will be discussed. Monumental breakthroughs in molecular biology, computational chemistry, bioinformatics, and individualized genomics, which undoubtedly propelled RNA therapeutics through the commercialization stage, will also be examined in this book. \r\n\tRNA therapeutics have had a significant impact on medicine, the economy, and overall public health; they are becoming prescription drugs, and this holds great promise for modernizing healthcare.
",isbn:"978-1-80355-658-1",printIsbn:"978-1-80355-657-4",pdfIsbn:"978-1-80355-659-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"fbffd7b2f97a65ffb0901de38a65bed0",bookSignature:"Prof. Irina Vlasova-St. Louis",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11813.jpg",keywords:"RNAi, miRNA, RNA Interference, ASO Aptamers, Decoys, Genetic Diseases, Cardiovascular and Neurological Diseases, Infectious Diseases, Cancer, Clinical Trials, Moderna, Pfizer",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 22nd 2022",dateEndSecondStepPublish:"May 20th 2022",dateEndThirdStepPublish:"July 19th 2022",dateEndFourthStepPublish:"October 7th 2022",dateEndFifthStepPublish:"December 6th 2022",remainingDaysToSecondStep:"3 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Accomplished biomedical specialist with a post-PhD from the University of Minnesota, USA. 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1. Introduction
Plants produce an amazing diversity of secondary metabolites, and the most important ones are the phenolic compounds. They are the most stable products in the plant kingdom. Humans have known them for centuries, and their role in plants’ nutrition, fertility, growth, and protection has made them compounds of interest and to understand them completely. These anti-herbivore chemicals produced by plants are one of the most common plant allelochemicals in the ecosystem. These phenolic compounds are characterized by single or more hydroxyl groups bound to a six-carbon aromatic ring. These compounds attained the leading status due to the resistant properties bestowed by them [1]. More than 8000 phenolic structures are currently known, ranging from simple phenolic acids to highly polymerized substances as tannins [2]. They are the most abundant secondary metabolites with wide distribution in the plant kingdom.
Primarily these phenolic compounds are usually involved in the plant defense responses and apart from that, they are were also seen playing a role during crop pollination and camouflage [3, 4]. These compounds are mostly found bound to the sugars. Most of them being aromatic in nature also play an important role in plant communication. At the plant’s rhizosphere, certain phenolic compounds monitor their surroundings through quorum sensing [5]. The plant growth-promoting microbes at the rhizosphere breakdown these phenolics and, in turn, enhance the soil fertility. They also aid in the chelation of the soil minerals and elements, improve the soil porosity, and in turn increase the absorption capacity of the plants [6]. During stress and pathogen invasion, these phenolic compounds are often accumulated in the plant’s subepidermal tissues. The synthesis and concentration of the accumulated phenolics depend on many internal and external factors such as plant physiology, age, development stage, climate, and the type of pathogen attack [7]. The significant nature of the phenolic compounds is their dual function as both attractants and repellent compounds. Depending on the surrounding environment, the plant produces either the attractants phenolic derivatives, namely allelochemicals and chemoattractants, to attract the pollinators, symbiotic microbes [8, 9], or repellent phenolic derivatives to repel the pests and pathogens [10].
Due to present-day environmental challenges, there is a need for eco-friendly agricultural practices, and to ensure the future demand for food, exploitation of sustainable solutions is very much necessary. This brings us to the attention of plant phenolic compounds with diverse beneficial roles as plant growth promoters, crop yield enhancers, and as protectors against varied environmental stresses. Hence, the present chapter explores the diversity of plant phenolic compounds and their role in plant development and defense toward their application in various fields of agriculture.
2. Classification of phenolic compounds
According to Harborne [2], these plant phenolic compounds are mainly classified (Table 1) into the following groups.
Classification of phenolic compounds based on the number of carbons.
C6-Simple phenols and benzoquinones are single benzene ringed structures with certain medicinal benefits. For example, embelin is a plant benzoquinone with antispermatogenic effect isolated from seeds of Embelia ribes [11].
C6–C1-Phenolic acids are those compounds possessing one carboxylic acid functional group. These naturally occurring phenolic acids contain two distinctive carbon frameworks, namely the hydroxycinnamic acid and hydroxybenzoic structures. The basic structure remains the same, but the number and position of hydroxyl groups differ between the two. Phenolic acids with hydroxycinnamic acid include cinnamic acid, coumaric acid, ferulic acid, sinapic acid, and caffeic acid. Structures with hydroxybenzoic acid include benzoic acid, p-hydroxybenzoic acid, vanillic acid, gallic acid, protocatechuic acid, syringic acid, gentisic acid, veratric acid, and salicylic acid [12]. C6–C2-Acetophenone is a naturally occurring phenol compound in apple, cheese, apricot, beef, and cauliflower. It is used in fragrances and chewing gum. Phenylacetic acid is an active auxin, a plant hormone found in fruits [13]. C6–C3-Coumarins are notably in high concentration in Dipteryx odorata [14] and produced by plants as a defense chemical to discourage predation. They are widely spread in the grasses and cloves. C6–C4-Naphthoquinones such as 2-hydroxynapthoquinone and naphthazarin show insecticidal activity against tobacco culture insects extracted from Calceolaria andina [15]. Derivatives of 1,4-naphthoquinone are known to possess antibacterial and antitumor properties. Naphthoquinones also exhibit larvicidal and molluscicidal activities. They are effective against Aedes aegypti and Biomphalaria glabrata [16].
C6–C1–C6-Xanthones are present in Bonnetiaceae and Clusiaceae families. They are generally used as an insecticide and as ovicide for codling moth eggs [17]. C6–C2–C6-Stilbenes on hydroxylation from stilbenoids acts as phytoalexins in the plant. Commonly found plant compounds with stilbene structures are trans-resveratrol, trans-piceid, pinosylvin, piceatannol, pinosylvin, trans-pterostilbene, astringin, and rhapontin [18]. Anthraquinones generally present in plants as glycosides. C6–C3–C6-Flavonoids generally occur in plants as glycosylated derivatives. The basic flavonoid structure contains a flavan nucleus. Many classes of flavonoids are present such as flavones (apigenin, luteolin, chrysin), flavan-3-ols (catechin, epicatechin, epigallocatechin), flavanones (naringenin, naringin, hesperetin, hesperidin), flavonols (quercetin, kaempferol, galangin, fisetin, myricetin), flavanonol (taxifolin), isoflavones (genistein, genistin, daidzein, daidzin, ononin), and anthocyanidins (cyanidin, cyanin, peonidin, delphinidin, pelargonidin, and malvidin) [12].
(C6–C3)2-Lignans are phytonutrients with antioxidant property. Examples include pinoresinol, podophyllotoxin, and steganacin. Flax and sesame seeds contain high levels of lignans. (C6–C3–C6)2-Biflavonoids formed through an oxidative coupling of two chalcone units and subsequent modification of the central C3 units. They are characteristic of gymnosperms, the Psilotales, Selaginallales, and several flowering plants. They are not found in Pinaceae or the Gnetales. These biflavonoids act as fungitoxins and insect feeding deterrents [19]. (C6–C3)n-Lignin and tannins are polymer forms of phenolic compounds. Lignin is the largest source of phenolic material in the plant cell walls. Tannins are distributed in plants as ellagitannins, condensed tannins, and gallotannins. These tannins reduce the digestibility of plants by herbivores.
The most crucial property of phenols is their antioxidant capacity. It protects the organism against reactive oxygen species (ROS). Plant polyphenols have multifunctional properties such as reducing agents, hydrogen-donating antioxidants, and singlet oxygen quenchers and flavonoids.
3. Role of phenols in plant kingdom
Phenolic compounds exist throughout the plant kingdom, and their presence varies according to the phylum. Bryophytes are the regular producers of polyphenols, including flavonoids, but it is in the vascular plants that the full range of polyphenols was found. These phenolics survived through natural selection and upgraded through ages in types and functions. The taxonomists often use them to classify and separate the plant species. Plants synthesize these phenolic compounds unlike animals because plants are stationary to escape their predators and therefore have evolved this chemical defense against predators. The primary established roles of plant phenolics are ecological, some having dual or even multiple functions (Figure 1). Several studies have indicated a high degree of compartmentation of phenolic compounds and of the enzymes involved in their biosynthesis that occurs through various pathways [20].
Figure 1.
Overview of functions of plant phenolic compounds.
These phenolics are widely distributed in the plant. They usually accumulate in the central vacuoles of guard cells and epidermal cells and subepidermal cells of leaves and shoots. Some found covalently linked to the plant cell wall, and others occur in waxes or on the external surfaces of plant organs. According to some findings, the deposition of flavonoids in nuclei is seen in certain tree species [21]. And it leads to a flavonoid-DNA complex that provides mutual protection against oxidative damage. In plants, phenolics were generally produced during two scenarios such as: (1) preformed phenolics synthesized during the normal development of plant tissues and (2) induced phenolics synthesized by plants in response to physical injury, infection, and response to elicitors such as heavy metal salts, UV irradiation, temperature, etc. [22].
3.1 Role of phenols in plant growth
Majority of phenols are responsible for the growth of the plant by aiding in cell wall formation. Hydroxycinnamic acids, particularly p-coumaric acid and ferulic acid, were found in the insoluble or cell wall fraction as esters. These pools of wall-bound phenolic acids act as a reservoir of phenylpropanoid units for lignin biosynthesis or even that they represent the beginnings of lignification itself. These esters with a large population of bound molecules are responsible for transduction of light energy leading to changes in plant cell wall structure, water flux, turgor pressure, and growth. Auxin (indole acetic acid), a phytohormone, plays a major role in the growth regulation of the plant [23, 24].
Plants are generally rooted and unable to move from place to another and are known to move in certain ways. The circadian rhythmic leaf movement known as nyctinasty was observed in all leguminous plants. Nyctinastic leaf movement is induced by the swelling and shrinking of motor cells in the pulvini, an organ located in the joint of the leaf and believed to be controlled by Schildknecht’s turgorins, which induce leaf-closing movement of the plants [25]. These turgorins are a new class of phytohormones that regulates the turgor of the plants. Some identified phenolic turgorins are: gallic acid 4-O-(β-D-glucopyranosyl-6′-sulfate) and gentisic acid 5-O-β-D-glucopyranoside that are pulvini-localized in Mimosa pudica L., cis-p-coumaric acid 4-O-β-D-glucopyranoside, found in Cassia mimosoides L., and cis-p-coumaroylagmatine, identified in Albizia julibrissin Durazz. Hence, phenols also aid in the movements of plants [26]. In rapidly germinating seeds, coumaric acid β-glucoside is more prevalent, and in non-germinating seeds, such as Melilotus alba found to possess a large number of free coumarins [27]. Another naturally occurring phenolic compound, which inhibits the germination of seeds, is ferulic acid. These phenolics act as germination inhibitors by inhibiting the transport of amino acids and forming of the proteins in the seeds [28].
3.2 Role of phenols in plant signaling
Allelochemicals are known to interact between two plants. Phenolic compounds influence many organic and inorganic nutrients surrounding them. They affect decomposition rate and play a role in nutrient cycle by inhibiting or stimulating spore germination. Phenols are good allelochemicals present in all parts of the plant. Leaf phenolic allelochemicals include p-hydroxybenzoic acid, p-coumaric acid, and bark, rhizosphere, root exudates including quercetin, juglone, catechin, and sorgoleone compounds [29]. Polyphenols stored in the vacuoles of plant encounter the cytoplasmatic proteins and form polyphenols-protein complex [30]. This complex aids in the senescence of plant tissues and causes the brown color of senescent leaves. Flavonoids such as eriodictyol and apigenin-7-O-glucoside isolated from pea root exudates found to play a role in the induction of nod gene expression [31]. Other natural flavanones such as naringenin, hesperitin, chalcones, and isoflavonoids such as daidzein, genistein released from legume plants inducing the nod gene expression. Phenols, in major flavonoids, are responsible for the pigmentation of flowers and fruits in plants and aid in the pollination and seed dispersal. For example, apigenin, luteolin, kaempferol, quercetin, and myricetin produce white, yellow, or ivory colors at their locations in plants [32].
4. Plant phenols during biotic stress
4.1 Insect-plant interactions
Among the chemical defensive strategies developed by the plant, phenolics generated due to insect herbivory play a significant role in plant resistance and controlling the herbivore damage. Many studies were performed to determine the qualitative and quantitative changes of phenolic compounds in plants and their influence on insects. Studies were conducted on rice plants infested with pests, and an elevated level of phenolic compounds was observed. The elevation was explained as a mechanism of defense that acts as a barrier to insect feeding [33, 34]. Interesting results were obtained in phenolic acid estimations by HPLC in the pest-infested plants. There was an enhancement in the level of phenolic acids in all the groundnut plants infested with the three pests compared with control plants. Also, a quantitative difference in phenolic acids was noted in the infested groundnut plants irrespective of the type of feeding damage [35]. The accumulation of the phenolic compounds by the phenylpropanoid pathway has been reported earlier [36]. Certain phenolic acids such as cinnamic acid derivatives, cinnamic acid, vanillic acid, syringic acid, and p-coumaric acid were found only in the pest-infested rice plants. They were totally absent in normal healthy plants. Similar results were observed with raise in the concentration of phenolic acids such as vanillic acid, syringic acid, cinnamic acid, and p-coumaric acid in the infested rice plants [37, 38] and cotton [39]. Kelly and Felton [40] and Rehman et al. [41] found that increased concentration in plant phenolic compounds is according to the extent of tissue damaged by feeding insects or due to pathogen infection.
Insect damage often alters plant physiology and chemistry. Larvae of the autumnal moth, Epirrita autumnata, on individual branches of its primary host plant, mountain birch, Betula pubescens did not lead to a systemic change of primary nutrients and phenol compounds. However, they affected the larval growth [42]. Changes in phloem phenols occur when pest infestation is seen on the bark of the trees. Phytophthora ramorum, which caused cankers on the oak trees, is analyzed for the phenolic levels against the uninfested oak tree. Ockels et al. [43], quantified nine phenolic compounds and gallic acid, tyrosol levels and showed dose-dependent inhibitory effects against P. ramorum, P. cinnamomi, Pseudocaecilius citricola, and P. citrophthora that are tested through in vitro bioassays. Seeds infested by wheat midge larvae, Sitodiplosis mosellana, showed induced changes in the dynamics of the phenolic acids. Analysis by HPLC of seed extracts produced by alkaline hydrolysis revealed rapid changes in p-coumaric and ferulic acids levels during early seed development [44]. This notified the role of phenols in seed development. Bi et al. [45] concluded that changes in the plant chemicals would induce resistance in the plant. Leaf phenolics and alkaloids variations were seen when Coffea spp. infested by leaf miner Leucoptera coffeella. The insect-plant interactions are studied by Magalhães et al. [46], to determine the pesticide activity of the plant phenols. So, sometimes the phenolic changes in specific insect-plant interaction will affect the other generalist insects of the plant.
4.2 Microbe-plant interactions
Studies indicated that microbial infection on the plant alters the plant’s chemical composition. First identified phenolics providing disease resistance were seen in onion scales infected by Colletotrichum circinans. In order, to prevent this onion smudge disease, plant accumulated sufficient amounts of catechol and protocatechuic acid [47]. A decrease in the phenolic content of the plant was observed in brown spot infection of rice due to infection of Helminthosporium oryzae [48, 49]. Infection suppressed the phenol metabolism in the rice plant due to the Helminthosporium oryzae toxin and aided in pathogen colonization. Phenolic compounds are also involved in defense response of plants by reducing the incidence of Fusarium wilt of tomatoes caused by the fungus Fusarium oxysporum [50]. Alteration in the ferulic, caffeic, and vanillic acid contents and concentrations are identified from recovered leaves and roots. Elicitors from Fusarium oxysporum f.sp. cubense accumulated soluble and wall-bound phenolics and phenolic polymers in the roots of Musa acuminate. White mold fungus, Sclerotium rolfsii Saccodes infection to Arachis hypogea reduced the total soluble phenolic content [51]. However, generally phenolic compounds induce in the infected fungal plants to confer resistance to specific fungal pathogens.
According to Beckman, phenolic compounds play an important role in reducing wilt diseases and aid in signaling for the host defense responses. 4-hydroxycinnamic acid CoA ligase enzyme is vital in the diversion of phenylpropanoids, was altered by the fungi, responsible for the changes in the phenols of the infected plant. In response to Rhizobium and vesicular arbuscular mycorrhizal (VAM) inoculation, enhancement in the phenolic compounds is seen in the Arachis hypogaea roots [52]. These phenolic compounds released at the roots help in maintaining the Rhizobium community at the rhizosphere. Furthermore, these Rhizobia species can use the phenols as a carbon source. Bacterial pathogens also affect phenol accumulation and production. Pseudomonas syringae enhanced the extracellular phenolic accumulation and changed the composition of phenolic acids in the Nicotiana tabacum [53].
Antimicrobial activity of phenolic compounds was observed in Finnish berries against probiotic bacteria and other intestinal bacteria. Myricetin inhibited the growth of lactic acid bacteria and mostly Gram-negative bacteria [54]. Phenolic acids from Olea europaea leaves, namely caffeic acid, verbascoside, oleuropein, luteolin 7-O-glucoside, rutin, apigenin 7-O-glucoside, and luteolin 4′-O-glucoside showed antibacterial and antifungal action. Many herbs and spice plant extracts contain phenols with antibacterial activity against food-borne pathogens [55]. Flavones and flavanones of fruits and vegetables are known to be active against Aspergillus sp., B. cinerea, and F. oxysporum [56]. Resveratrol from grapes is also known to possess antibacterial activity [57]. In these host-microbe interactions, the phenolic metabolites play a key role in providing signals for the interactions [58]. For example, acetosyringone, a phenolic compound produced at the wound site of plants, triggers vir genes in the pathogen. In legume-rhizobial interactions, flavonoids activate the nod genes in Rhizobium responsible for symbiotic relation [59]. The roles played by these phenolic compounds generally include phytoalexins for disease defense and lignin production for structural strength, along with antioxidant nature to combat the pro-oxidants produced during microbial stress.
4.3 Effect of plant phenols on pests
Some plants respond to herbivore damage by increasing chemical, physical, or biotic defenses and responses that can help protect the remaining tissue against further damage [60, 61, 62]. Plant phenolics are believed to play an important role in chemical defense against herbivores through specific physiological effects on insects. These phenols are often described as antifeedant, digestibility reducers, and as toxins. These phenols would promote ROS in the insect digestive tract, particularly in mid-gut, where pH is alkaline. These ROS would result in direct oxidative damage to mid-gut lipids and proteins. Elevated levels of lipid per-oxidation products, oxidized protein, and free ions due to oxidative stress are generated in mid-guts of insects, leading to death [2]. Phytoalexins will disrupt the pathogen metabolism and cellular structure. Some experimental evidence includes the medicarpin by Medicago sativa, rishitin by Solanaceae, and camalexin by Arabidopsis thaliana [63]. Tannins lead to protein inactivation in insects, by binding to salivary proteins and digestive enzymes, including trypsin and chymotrypsin. Insect herbivores that ingest high amounts of tannins fail to gain weight and eventually die [64]. Lignins, which are polymer in nature, provide strong physical barrier in the form of cell walls toward herbivores. On the other hand, furanocoumarins produced in response to the herbivore attack gets activated by ultraviolet light (UV) and integrates with the DNA of insects, leading to death [65].
5. Plant phenols during abiotic stress
Plants encounter many challenges of both biotic and abiotic stress factors in nature. Abiotic stress factors include, namely drought, salinity, heat, ultraviolet, and pesticides. Nowadays, these abiotic stresses toward plants have drastically increased due to the environment’s uneven climatic conditions and man-made pollution. The increase of these abiotic stresses will radically impact the growth and development of the plants and could reduce the overall crop yield [66]. Plants to combat these abiotic stress conditions will produce a plethora of defense metabolites [67, 68]. Among them, the plant phenolic compounds are playing a vital role in coping with the abiotic stresses. Under stressful conditions, these phenolics are drastically accumulated in the plant for survival [20, 69]. Phenolic compounds, namely esters, flavonoids, lignin, and tannins, act as antioxidants and fight against these abiotic stress conditions in the plant cells [70].
In certain leafy vegetables, the salinity conditions caused an increase in the phenolic compounds to counterattack the high salt levels in the soil [71]. This increase of phenols assists in the balancing of the mineral composition in the leaves. Heavy metals in the soil also dramatically impact the physiology and metabolic activities of the plant. During such stress conditions, it has been observed that the plant flavonoids are playing a vital defense role by chelating the heavy metals [72, 73]. Climate change is one of the significant factors affecting plant growth and development. Due to adverse climatic conditions, water stress in plants has become a serious concern. Due to the lack of rainfall, drought stress is common environmental stress in many cultivated areas, and crop yield is majorly dependent on it. Under drought stress, it has been observed that plants are producing polyphenols to cope with these stress conditions by controlling the water ions flux [74, 75]. Phenolic compounds also respond to nutrition stress, cold stress, and radiation, thus providing resistance to the plant [76, 77, 78]. Salinity is a significant stress factor that limits crop yield in many areas. Under these extreme conditions, plants adapt to stress through altered metabolic pathways (Figure 2). For example, in a medicinal plant, Salvia mirzayanii, total phenolic content was increased with higher salt levels [79]. Chlorogenic acid, caffeic acid, ellagic acid, ferulic acid, gallic acid, syringic acid, vanillic acid, and p-coumaric acid were enhanced in Aegilops spp. due to salinity conditions [80]. This trend in increase of phenolic contents was reported in many plants under salt stress [81, 82]. This increase of phenols is a tolerance mechanism to maintain redox homeostasis and improve plant health. Similarly, during drought stress, to avoid oxidative damage, plants produce various phenolic compounds. These flavonoids or phenols inhibit further loss of water in the plants through the closure of stomata [83]. Many reports support the production mechanism of phenols during drought stress in plants [84, 85]. The plant phenols are the main accumulator compounds during heavy metal stress. This tendency is for the chelation of toxic metals by phenolic compounds through their carboxyl and hydroxyl groups, which participate in the chelation of the metals [78]. Plant hormones play a vital role during the stress conditions. A wide cross talk of hormones, namely salicylic acid and jasmonic acid, takes place as defense response to the stresses [86]. Proteins associated with these hormones upregulate during defense and provide immunity to the plants through expression of pathogenesis-related genes [87]. Abiotic stresses significantly alter the crop quality and productivity, and to combat it, expression of resistance genes takes place and elevates the levels of defense compounds such as phenolic compounds [88]. These enhanced phenols ensure their endurance and survival of plants during these abiotic stress conditions.
Figure 2.
Mechanistic approach of plant responses to stress conditions.
6. Conclusion
Phenolic substances are the most resistant metabolites produced by plants. Better understanding of plant phenolics is essential, due to its wide array of functions in the plant development, and its practical applications in many streams such as agriculture, medicine, nutrition, pesticide management, and industry. These phenolic changes in the plant with respect to the herbivory correlated negatively with the larval growth, development, and survival of progeny. The enhanced phenols in plants behave as toxins toward insect feeding, microbial growth, and a mode of induced defense generated by the plant to defend against natural pests. We can summarize that the plant-insect interactions altered the phenolic levels to the pest attacking. So, a change in the phenol level is a defense strategy developed to combat the pest. This change of phytochemical composition from nature will oppose the pest from invading the plant. During abiotic stress also, the plants can produce phenols as tolerance mechanism to cope with the unfavorable conditions. Increased biosynthesis of plant phenols was observed in the plant during abiotic stress factors such as drought, heavy metal stress, salinity, and radiation. In conclusion, this review on the plant phenolic compounds and their role in the plant’s growth, development, and defense will provide the information to understand the plant mechanisms and aid us in further effective application of them in agricultural pest management strategies.
Acknowledgments
The author thanks Department of Science & Technology (DST), India, for their support.
Conflict of interest
There are no conflicts of interest.
\n',keywords:"abiotic and biotic stress, pest management, plant defense, plant phenols",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80846.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80846.xml",downloadPdfUrl:"/chapter/pdf-download/80846",previewPdfUrl:"/chapter/pdf-preview/80846",totalDownloads:105,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:0,impactScoreQuartile:0,hasAltmetrics:0,dateSubmitted:"November 19th 2021",dateReviewed:"January 26th 2022",datePrePublished:"March 15th 2022",datePublished:"April 28th 2022",dateFinished:"March 15th 2022",readingETA:"0",abstract:"Phenolic compounds are produced by the plants mainly for their growth, development, and protection. These aromatic benzene ring compounds are very much essential during the plant’s biotic and abiotic stress interactions. They constitute an essential part of plant’s secondary metabolites and play a vital role in various physiological and mechanical activities. These diverse plant phenolic compounds act both as attractants and repellents toward various organisms in the environment. They could act as attractants toward the beneficial organisms and as toxicants against the invading pests and pathogens. These metabolite compounds often enhance during a plethora of stress conditions and act as the first line of defense to provide plant disease resistance. They are also known to influence the other plant metabolic pathways, namely phytoalexin biosynthesis and reactive oxygen species generation. These phenolic compounds participate both in the above- and below-ground plant defense systems. They are produced as root exudates and influence the soil diversity and the neighboring plants. The present review provides an overview of the roles of plant phenolic compounds in the plant kingdom as signaling compounds, pigment compounds, antimicrobials, and defense compounds.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80846",risUrl:"/chapter/ris/80846",book:{id:"10795",slug:"plant-stress-physiology-perspectives-in-agriculture"},signatures:"Sambangi Pratyusha",authors:[{id:"428313",title:"Dr.",name:"Sambangi",middleName:null,surname:"Pratyusha",fullName:"Sambangi Pratyusha",slug:"sambangi-pratyusha",email:"s.pratyusha@cgiar.org",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Classification of phenolic compounds",level:"1"},{id:"sec_3",title:"3. Role of phenols in plant kingdom",level:"1"},{id:"sec_3_2",title:"3.1 Role of phenols in plant growth",level:"2"},{id:"sec_4_2",title:"3.2 Role of phenols in plant signaling",level:"2"},{id:"sec_6",title:"4. Plant phenols during biotic stress",level:"1"},{id:"sec_6_2",title:"4.1 Insect-plant interactions",level:"2"},{id:"sec_7_2",title:"4.2 Microbe-plant interactions",level:"2"},{id:"sec_8_2",title:"4.3 Effect of plant phenols on pests",level:"2"},{id:"sec_10",title:"5. Plant phenols during abiotic stress",level:"1"},{id:"sec_11",title:"6. Conclusion",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Beninger CW, Abou-Zaid M, Kistner AL, Hallett RH, Iqbal MJ, Grodzinski B, et al. A flavanone and two phenolic acids from Chrysanthemum morifolium with phytotoxic and insect growth regulating activity. Journal of Chemical Ecology. 2004;30:589-606. 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Changes in the contents of antioxidant compounds in pepper fruits at ripening stages, as affected by salinity. Food Chemistry. 2006;96:66-73. DOI: 10.1016/j.foodchem.2005.01.057'},{id:"B83",body:'Yadav B, Jogawat A, Rahman MS, Narayan OP. Secondary metabolites in the drought stress tolerance of crop plants: A review. Gene Reports. 2021;23:101040. DOI: 10.1016/j.genrep.2021.101040'},{id:"B84",body:'Gao S, Wang Y, Yu S, Huang Y, Liua H, Chena W, et al. Effects of drought stress on growth, physiology and secondary metabolites of Two Adonis species in Northeast China. Scientia Horticulturae. 2020;259:108795. DOI: 10.1016/j.scienta.2019.108795'},{id:"B85",body:'Król A, Amarowicz R, Weidner S. Changes in the composition of phenolic compounds and antioxidant properties of grapevine roots and leaves (Vitis vinifera L.) under continuous of long-term drought stress. Acta Physiologiae Plantarum. 2014;36:1491-1499. DOI: 10.1007/s11738-014-1526-8'},{id:"B86",body:'Jones JDG, Dangl JL. 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1. Introduction
Cancer has the potential to spread to nearby or distant organs, posing a life-threatening threat. For the metastatic spread of cancer tissue, the growth of the vascular network is crucial. Angiogenesis and lymphangiogenesis are the processes by which new blood and lymphatic vessels originate.
Cancer has the potential to spread to nearby or distant organs, posing a life-threatening threat. Tumour cells can enter blood or lymphatic vessels, circulate through the intravascular stream, and then spread to a new location (metastasis) [1]. The growth of the vascular network is crucial for cancer tissue metastatic dissemination. Angiogenesis and lymphangiogenesis are the processes that result in the formation of new blood and lymphatic vessels. Both are necessary for the formation of a new vascular network that will provide nutrients, oxygen, and immune cells while also removing waste. In tumour vascularization studies, angiogenic and lymphangiogenic factors are gaining popularity.
1.1 Angiogenesis in cancer
Endothelial cells, epithelial cells, mesothelial cells, and leucocytes, as well as cancer cells and host cells, all release chemicals that aid in angiogenesis. Plateletderived endothelial cell growth factor (I’D-ECGF), plateletderived growth factor (PDGF).
Angiogenesis is a series of events that are triggered by microvascular endothelial cells. Angiogenesis and lymphangiogenesis are essential for tumour growth and metastasis, and are triggered by chemical signals from tumour cells in the early stages of development. In a prior study, Muthukkaruppan and colleagues [2] looked at how cancer cells behaved when they were placed in different parts of the same organ. Blood circulation was present in the iris, but not in the anterior chamber [2]. Cancer cells without blood circulation grew to a diameter of 1–2 mm3 and then stopped growing when placed in an area where angiogenesis was possible, but they grew to a diameter of more than 2 mm3 when placed in an area where angiogenesis was possible.
If there is insufficient blood flow, tumours can become necrotic or even apoptotic [3, 4]. Angiogenesis thus aids cancer progression. The neovascularization stage of tumour angiogenesis is one of four steps in the process. Local injury to the basement membrane occurs first in tissues. Destruction and hypoxia take place almost immediately. Angiogenic chemicals cause endothelial cells to become activated and move. Endothelial cells multiply and settle in the third step of the process. Angiogenesis is still influenced by angiogenic stimuli, according to the fourth point.
Every 1000 days on average, vascular endothelial cells divide [5]. When tumour tissues need nutrition and oxygen, angiogenesis is induced. Activators and inhibitors of angiogenesis regulate the process. On the other hand, increasing angiogenic factor activity is insufficient to enhance neoplasm angiogenesis. Negative regulators or vascular growth inhibitors must also be inhibited [6].
1.2 Breast cancer: tumour angiogenesis
Clinical studies in a range of tumour types, including breast cancer, have proven the vital role of tumour neovascularization in the 3 years after the last comprehensive review of antiangiogenic therapy was published in Breast Cancer Research [7]. Bevacizumab (AvastinTM; Genentech, South San Francisco, CA, USA) was utilised in many of these trials since it was particularly intended to target vascular endothelial cell growth factor (VEGF). Bevacizumab is a recombinant VEGF antibody that binds to all known isoforms of VEGF-A and blocks receptor interaction, inhibiting angiogenesis and tumour growth. It was made from a mouse monoclonal antibody that had been humanised. One of the successes of antiangiogenic treatment, which was first suggested by Judah Folkman more than 35 years ago, is the critical contribution of this angiogenic factor in controlling many of the processes involved in angiogenesis, as well as its importance as a paradigm for the rational design of an anticancer agent.
Because all tumours (including liquid tumours like leukaemias) are angiogenesis-dependent, angiogenesis is highly restricted in adults, the endothelium of the vessels is accessible, and any treatment would be amplified through subsequent tumour infarction, the antiangiogenic approach has always appealed to researchers. Furthermore, because endothelial cells are non-neoplastic and should have a stable genome, cancer resistance should no longer be an issue [8].
To grow larger than a few centimetres in diameter, breast cancer, like other solid tumours, requires the formation of new blood vessels (neovascularization). The extra veins not only supply more nutrients to the tumour, but they also provide possible pathways for tumour dispersal and metastasis [9].
Tumour-induced angiogenesis first develops in pre-invasive high-grade ductal carcinoma in situ. In this case, a distinctive ring of microvessels emerges around the ducts, which are packed with proliferating epithelial cells. As the tumour grows, the amount of neovascularization increases [10]. Increased microvascular density or development, as well as variables that encourage new vessel growth, have been associated to poor breast cancer prognosis.
As a result, a significant amount of study has been focused on identifying the factors in the tumour microenvironment that promote and maintain angiogenesis in the hopes of limiting neovascularization and, as a result, tumour development and dissemination. Furthermore, unlike tumour cells, which are genetically unstable and can develop resistance to many therapeutic medications fast, normal vascular endothelium lacks mutations that would allow drug resistance [11, 12]. Both research lines are investigated in this paper.
Although the presence of axillary lymph nodes is the most important prognostic marker in operable breast cancer, it does not entirely explain for the wide range of disease outcomes. More precise prognostic indications would aid in the identification of patients at high risk of illness recurrence and mortality who would benefit from systemic adjuvant therapy [13]. Microvessel density (count or grade) in invasive breast cancer (a measure of tumour angiogenesis) is associated with metastasis and so may be a prognostic sign, according to recent research.
Breast tumour growth requires angiogenesis, or the rapid formation of new blood vessels, in order to acquire enough oxygen and nutrients [14]. Breast cancer cells, like all other biological tissues, rely on a vascular network of capillaries to provide food and oxygen on a regular basis. Endothelial cells (ECs), which line the interior surface of blood vessels, do not reproduce, hence capillaries do not proliferate. Hypoxia (low oxygen) triggers a variety of transcriptional responses that are mediated by transcription factors called hypoxia-inducible factors (HIFs) [15, 16, 17, 18]. HIFs are transcription factors that regulate the expression of genes involved in physiological processes like metabolism, angiogenesis, and cell division. Local angiogenesis is one of the tumour microenvironment’s long-term major responses to low O2 levels [19, 20].
It is the fusion of EC precursors that leads to the creation of capillary plexus, which thereafter evolves into blood vessels. Angiogenesis is required for a variety of normal processes, including embryonic development, growth, and wound healing [21].
As a result, the tumour activates an angiogenic switch and enters an irreversible active angiogenic state. Because of the tumour’s newly acquired status, it can recruit new capillaries, restoring oxygen and nutrients to both angiogenic and non-angiogenic cells, resulting in rapid tumour growth [9, 22, 23, 24]. Despite the fact that surgical excision of tumours is the current standard of care for breast cancer, adjuvant therapy, such as anti-angiogenic therapy, has been used after surgery in advanced disease stages when surgery is no longer an option [25].
Angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factors, are primarily involved in the initiation and progression of tumour angiogenesis (FGF). Angiogenic factor levels, as well as the number of vascular networks created as a result, have been shown to predict breast cancer survival in many studies. To put it another way, high levels imply that the tumour cells are aggressive and are linked to a poor prognosis. The rate and degree to which blood vessels permeate are controlled by these variables in connection with beginning angiogenesis [26, 27, 28, 29]. Angiogenesis-targeting compounds have recently received a lot of attention in breast cancer research.
Bevacizumab, a humanised anti-VEGF monoclonal antibody, has been the most extensively investigated molecule [30, 31, 32, 33]. After promising results in preclinical trials targeting VEGF, the FDA authorised bevacizumab in 2008 for the treatment of metastatic HER2-negative breast cancer [34, 35].
Following that, multiple anti-angiogenic medicines targeting VEGF or blocking its receptor’s action were licenced, and they are now routinely utilised in the treatment of various malignancies [36, 37, 38, 39, 40]. The FDA, however, revoked its certification in 2011 due to conflicting results from earlier trials and allegations of increased toxicity as a result [41, 42, 43, 44].
While the discovery of these anti-angiogenic drugs and small molecules was heralded as a potential victory in one aspect of the cancer fight, the agents’ modest activities, such as their inability to arrest recurrent tumours in a latent state and the moderate improvement in overall patient survival, dampened the celebration.
1.3 The angiogenic cycle
Endothelial cells in normal, quiescent capillaries are in contact with a laminin-rich basement membrane and a layer of supportive pericytes that is 1- to 2-cell thick. Angiogenesis necessitates the weakening of connections between nearby pericytes as well as the degradation of the basement membrane [45]. The integrin adhesion receptors help endothelial cells re-enter the cell cycle and infiltrate the surrounding stromal matrix. Endothelial cells begin to resynthesize a basement membrane, which aids in cell cycle exit and promotes the creation of a capillary-like morphology [46]. Pericytes are then recruited to newly formed capillaries to help mature arteries stabilise [47]. Chronic exposure to angiogenic factors in the tumour microenvironment that promote basement membrane proteolysis or antagonise endothelial–pericyte interactions leads to the formation of a relatively unstable, highly permeable network of vessels that does not fully mature but can supply nutrients to meet the tumour’s growing metabolic demands. Increased arterial permeability is thought to encourage tumour cell extravasation and, eventually, spread [48, 49].
2. Factors that promote angiogenesis
2.1 Hypoxia
Hypoxia has long been suspected as a significant angiogenic stimulator within the tumour microenvironment. Densely packed, quickly proliferating cells with limited nutritional inputs are the source of low tissue oxygen tension [50]. In recent years, researchers have made tremendous progress in understanding the biochemical and molecular reactions to hypoxia, as well as how the tissue senses low oxygen tension [51]. It was discovered that the hypoxia-inducible factor (HIF), a heterodimeric transcription factor made up of the hypoxic response factor (HIF-1) and the constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT or HIF-1), is particularly significant [52, 53].
HIF-1 binds to the von Hippel-Lindau (VHL) protein in oxygenated circumstances, causing ubiquitination and fast destruction [54]. In hypoxic settings, on the other hand, this factor is stabilised: it is unable to associate with VHL protein because prolyl hydroxylase, an enzyme that typically alters HIF-1 to facilitate its interactions with VHL protein, is inactive. As a result, the oxygen sensor has been proposed as prolyl hydroxylase [55, 56, 57, 58, 59].
Animals lacking HIF-1 had markedly reduced angiogenic responses, indicating that it plays a vital role in experimental tumour growth and tumour-associated angiogenesis. Human ductal carcinomas overexpress HIF-1, whereas benign tumours with little angiogenesis do not. In the hypoxic tumour microenvironment, stabilised HIF-1 induces the expression of a variety of proangiogenic mediators, including vascular endothelial growth factor (VEGF) and one of its receptors, VEGF receptor 1 (VEGFR1) [60, 61, 62].
2.2 Vascular endothelial growth factor
VEGF is a powerful and selective endothelium mitogen that can produce a rapid and full angiogenic response, as its name suggests. VEGF (VEGF-A), the most investigated and implicated in tumour-induced angiogenesis, is a family of glycoproteins (VEGF-A, -B, -C, and -D) that are linked to VEGF (VEGF-A). The lymphatic endothelium responds to VEGF-C and -D in a big way [63].
VEGF is produced and released by a range of normal cell types, but its expression is dramatically increased in tumour cells, including a variety of breast malignancies, as well as reactive breast tumour stromal cells [64]. In contrast to other cytokines produced by tumour cells, VEGF functions almost exclusively on endothelial cells because expression of the major VEGF receptor, VEGFR2, is confined to such cells. Interfering with VEGF or VEGFR2 allows for the specific targeting of tumour endothelium [65]. VEGFR1, on the other hand, is expressed by endothelial cells, monocytes, and macrophages, and its role was unknown until recently.
When VEGF binds to its receptor, it activates an intracellular signalling cascade that causes gene expression modifications that promote endothelial cell migration and proliferation [66]. Furthermore, because VEGF not only functions as an endothelium mitogen but also increases capillary permeability, it’s not surprising that the leakiness of tumour arteries is a fundamental distinguishing feature.
2.3 VEGF and breast tumour angiogenesis
An increase in VEGF synthesis by tumour cells and cells in the tumour stroma has been connected to angiogenesis induced by breast tumours, as previously mentioned. VEGFR2 expression was also shown to be greater in the endothelial cells of the adjacent breast tumour. Indeed, higher VEGF expression correlates with the first detectable breast-tumour driven angiogenesis in pre-invasive high grade ductal carcinoma in situ [67].
The elevated expression of VEGF in the breast tumour environment is thought to be due to a number of causes. Hypoxia and HIF-1 are clearly important factors. The fact that premenopausal women had higher levels of VEGF expression than postmenopausal women suggests that steroid hormones may also boost VEGF expression [68, 69]. Estradiol has long been known to be angiogenic, and evidence suggests that oestrogen effects may be mediated through VEGF induction. In certain breast cancer cell lines, estrogens increase VEGF expression whereas progestins lower it. Tamoxifen, an oestrogen receptor inhibitor, has recently been found to reduce VEGF transcription. However, whether oestrogen receptor expression is linked to VEGF expression and vascular density has to be determined.
VEGF production is also influenced by changes in the tumour environment. Matrix metalloproteinases, for example, are frequently secreted by numerous tumour cells, including human breast cancers [70]. Matrix metalloproteinase (MMP)-9, which is produced by tumour cells and expressed at high levels in human breast cancers, is one member of this family that has attracted a lot of attention. MMP-9 has been found to proteolyze the surrounding extracellular matrix, releasing trapped VEGF and thereby enhancing its bioavailability.
The expression of HER2 is another significant alteration in breast cancers. HER2 is a tyrosine kinase receptor that belongs to the epidermal growth factor receptor family and is expressed by the ERB2 gene [71, 72]. It signals in the lack of a known ligand. Furthermore, HER2 overexpression or heregulin stimulation causes an increase in VEGF mRNA, whereas treatment of breast tumours with an anti-HER2 neutralising antibody inhibits VEGF synthesis in a dose-dependent manner. Furthermore, HER2 was found to boost the rate of HIF-1 protein production in a new, rapamycin-dependent mechanism, rather than by blocking degradation as seen during hypoxia [73, 74].
VEGF production can also be boosted by changes in epithelial gene expression linked to tumorigenicity. The 644 integrin, which typically facilitates connections between breast epithelium and basement membrane, is upregulated and mislocalized in breast carcinoma cells, promoting tumour cell invasiveness. According to recent research, 644 signalling causes the inactivation of eIF-4E, a translational repressor, which enhances VEGF translation and, in turn, tumour cell survival [75, 76, 77]. The 644 signalling pathway, which enhances VEGF translation, converges on a rapamycin-sensitive route, similar to the HER2-mediated increases in HIF-1 and VEGF. Importantly, the tumour cells’ increased VEGF production has been shown to act in an autocrine manner, promoting epithelial cell survival directly.
2.4 Mechanisms of angiogenesis
Tumour development and metastasis are dependent on angiogenesis. Necrosis occurs when a tumour’s blood supply is cut off, preventing it from growing. After a while, any further metastatic spread into the systemic circulation is stopped. Scientists have been studying angiogenesis and the different variables that regulate it in order to better understand how it affects breast cancer and develop a strategy to limit tumour progression [25, 29]. Because of the dual nature of this process, it’s critical to understand and distinguish between normal angiogenesis processes, such as wound healing, normal growth, and embryo nutrition, and tumour-related angiogenesis mechanisms.
Angiogenesis, which involves communicating between tumour cells and a variety of other cell types within the tumour microenvironment, is initiated by some compounds known as angiogenic activators because of their capacity to stimulate cell proliferation in vitro. The generation of pro-angiogenic growth factors by tumour cells, which impact the existing vasculature, has been shown to be necessary for the induction of this process [21]. To generate and stabilise newly created blood vessels, a delicate signal balance between pro- and anti-angiogenic factors is vigorously maintained in the microenvironment during these closely regulated processes [78]. As a result, numerous investigations have demonstrated that these angiogenic activators are critical in the growth of malignancies.
Certain tumour cells express both pro- and anti-angiogenic proteins, which encourage and inhibit angiogenesis, according to previous research. Tumours are thought to turn on the angiogenic switch by reversing the balance of angiogenesis inducers and inhibitors [29, 37]. This switch can be made by altering gene transcription, as seen in various cancers where VEGF and/or FGF levels are higher than in healthy tissue. The levels of endogenous inhibitors are lowered in some cancers, on the other hand. The intricate mechanism that drives these alterations in the regulators’ balances, on the other hand, remains a fascinating subject of research (Figure 1).
Figure 1.
Angiogenesis is a physiological process that results in the formation of new blood vessels from existing ones. From pre-existing capillaries, new blood vessels emerge. The tumour receives crucial nutrients for growth from the new blood vessels that have sprouted near and within the tumour. Angiogenesis in healthy tissues is regulated by a balance of anti- and pro-angiogenic factors (bottom), but the presence of angiogenic factors in tumours disrupts this balance, resulting in abnormal blood vessel structure and function, as well as hypoxia. The vasculature is normalised and the balance is restored.
The tumours ability to switch on angiogenesis is determined by the balance of this switch. Further research revealed that a decrease in anti-angiogenic protein production activates the tumour angiogenic switch, promoting tumour growth and metastasis [79, 80, 81]. Stimulating angiogenesis in a tumour and forming the endothelial tubes that result is a multistep process governed by hypoxia at each stage. This pathway is heavily reliant on ECs expressing HIF-1, a heterodimeric transcription factor. Under hypoxic conditions, the HIF-1 protein is stabilised and forms a heterodimer with HIF-1, and this pair promotes the transcription of multiple target genes to adapt to the hypoxic environment in human cancer cells.
HIF-1, in conjunction with other members of the HIF family, has been demonstrated in certain studies to govern practically every element of angiogenesis, making the HIF pathway a master regulator of angiogenesis [82]. In various malignancies, HIF-1 and HIF-2 expression has also been linked to a poor prognosis and metastatic illness. As a result, it’s regarded as a promising therapeutic target for a variety of medical conditions (Figure 2).
Figure 2.
This figure depicts the balance hypothesis of the angiogenic switch. Angiogenesis switch mechanism is assumed to be in charge of normal angiogenesis (formation of new capillaries). By utilising angiogenesis inducers and inhibitors, which flip the switch, this balance can be tilted in favour of enhanced blood vessel formation. Reduced inhibitor levels (thrombospondin-1, 16 kD prolactin, interferon, platelet factor-4, Angiostatin, and others) or increased activator levels (aFGF, bFGF, VEGF, and others) can tip the balance and activate the switch, resulting in the formation of new blood vessels.
Hypoxia and activation of the HIF pathway in cancer cells are required for the sprouting and formation of new blood vessels because they control the expression of several pro-angiogenic genes [83]. Some of the most powerful cytokines are VEGF, an endothelial mitogen and pro-angiogenic factor, angiopoietin-1, angiopoietin-2, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) [84, 85, 86, 87, 88].
The FGF and VEGF families of angiogenetic growth factors have gotten more attention than the others. In 1983, the protein VEGF-A (vascular endothelial growth factor) was identified and sequenced. It was the first cytokine to be identified as a key contributor to tumour angiogenesis, was purified from tumour cell ascites as vascular permeability factor (VPF), and was also revealed to have pharmacological effects on EC mitogenesis; consequently, VPF is referred to as VEGF (Figure 3) [89, 90].
Figure 3.
This diagram depicts the receptor binding selectivity and signalling pathways of members of the vascular endothelial growth factor (VEGF) family. VEGF family members bind to VEGFR-1, VEGFR-2, and VEGFR-3 receptor tyrosine kinases, which activate a variety of signalling pathways and allow them to exert their physiological effects.
In vivo and in vitro, VEGF is now known to be a multifunctional peptide capable of triggering receptor-mediated endothelial cell proliferation and angiogenesis. The VEGF family contains at least five members, each of which has three VEGF receptors (VEGFR) [91, 92, 93]. These receptors use transmembrane receptor tyrosine kinases to communicate with the cell’s interior (RTKs). The VEGF gene is subject to complex transcriptional control, and four distinct RNA isoforms are produced with varying biological features as a result of alternative splicing of its pre-mRNAs. VEGF-B, VEGF-C, VEGF-D, VEGF-E, and platelet-derived growth factor are all produced as a result of this process (PDGF).
By attaching to VEGF receptors and ligands, VEGF, for example, can trigger angiogenesis. The effects of vascular endothelial growth factor (VEGF), as well as acidic and basic fibroblast growth factors (FGF1/2), can be employed to investigate the induction and progression of angiogenesis at various phases of tumour development. VEGF binds to its receptor (VEGFR) and ligands on the surface of ECs. It causes dimerization, autophosphorylation, and activation of the downstream signalling cascade after binding to and activating the transmembrane tyrosine kinase receptors on the cell’s surface [94, 95, 96]. Tube development and sprouting follow EC survival, proliferation, migration, and apoptosis avoidance through several cascade phases. Over time, this process results in the development of a complex network of new blood vessels. Vasodilation and vascular permeability, a key feature of tissue inflammation and the tumour microenvironment, are also induced by VEGF [97, 98, 99, 100, 101, 102, 103].
The activity of the ECs outlined above is caused by an increase in pro-angiogenic factors such as VEGF and proteolytic enzymes, as well as a decrease in anti-angiogenic factors. Finally, a capillary network is successfully established, supplying enough nutrition and oxygen to the growing tumour. Taking advantage of this new vascular bed, the tumour cell may reach the systemic circulation and induce distant metastases. As a result, the number of metastasis sites is proportional to the amount of cancer cells that enter the circulation at the outset [104, 105, 106, 107, 108, 109, 110, 111].
Angiogenic inducers have been implicated in the regulating process of angiogenesis in malignancies since their discovery a decade ago. Anti-angiogenic treatment decreases tumour vascular growth by interfering with VEGF and VEGFR intracellular signalling [112, 113, 114, 115, 116].
Angiogenesis was originally linked to cancer, arthritis, and psoriasis. However, the impact it has on a variety of other disorders has been documented. Tumours are innately primed for successful angiogenic development due to their nature and composition. An active vascular system is made up of adipose tissue that is encased in stromal cells and serves as a scaffold for the tumour’s vascular system to emerge [117, 118, 119].
Brown adipose tissue (made up of cells with numerous mitochondria) promotes tumour growth by supplying a steady supply of oxygen and nutrients, whereas white adipose tissue promotes the formation and progression of breast cancer in a mouse model. Both types of adipose tissues, which have been associated to breast cancer, produce angiogenic factors such as VEGF A, B, and C, basic fibroblast growth factor (bFGF)/FGF-2, matrix metalloproteinases (MMPs), and IL-8. This aberrant blood vessel creation has been linked to cardiovascular illness, cancer, blindness, and diabetic ulcers [120, 121, 122].
2.5 Non-angiogenic functions of VEGF in breast cancer
VEGF increases the formation of new blood vessels and lymphatics, as well as increasing vascular permeability, and has a variety of tumour-related effects. The importance of VEGF in vascular and lymphangiogenesis has dominated research in breast and other cancers [123]. The importance of VEGF in cancer behaviour cannot be overstated. The presence of hypoxic patches in most malignancies, on the other hand, implies that VEGF-induced angiogenesis is insufficient to alleviate hypoxia [124]. Hypoxia works as a strong selection pressure, allowing only the most aggressive and metastatic cells to thrive. Understanding the mechanisms that allow tumour cells to survive under hypoxia is therefore critical for interpreting cancer biology and developing therapeutic approaches [125, 126].
VEGF produced by tumour or stromal cells interacts to VEGF receptors on tumour cells, producing a signalling response that supports survival in the face of hypoxia and other apoptotic triggers, according to our and other labs’ research [127]. This process, which most likely operates in tandem with p53 inactivation, provides self-sufficiency to tumour cells, making it simpler for them to form tumours and increasing the possibility that they will spread to other parts of the body [128, 129]. To put it another way, we believe that hypoxia favours cells that can signal VEGF, and that the most aggressive tumour cells (metastatic cells) are determined by their dependency on VEGF.
A side effect of VEGF signalling in breast cancer cells is that it can help them move and invade more easily.
3. Breast carcinoma cells and VEGF signalling
3.1 Survival signalling by autocrine VEGF
Tumour cells receive signals from various sources as a result of the complex microenvironment of solid tumours, and these signals alter the activity of other cells. However, it is becoming obvious that cancer cells can attain a certain level of self-sufficiency by creating autocrine signalling pathways that aid critical tasks such as growth, survival, and invasion [130] within this web of paracrine signalling. As tumours develop towards invasive and metastatic illness, autocrine pathways become more critical as the tumour’s environment becomes increasingly hostile. As a result, autocrine signalling pathways are a major target for anti-tumour therapy. Our study on invasive breast carcinoma cell lines provided one of the first indications that VEGF may have autocrine functions in cancer [73, 131].
We discovered that a 50% reduction in VEGF expression resulted in a considerable increase in apoptosis, even in the presence of 10% serum, when we utilised an antisense oligonucleotide approach to limit VEGF expression. This evidence backs with the theory that these cells were selected in vivo because they rely on VEGF to survive [132]. The importance of VEGF in carcinoma and other cancer cell survival has now been validated by research from our lab and others.
Because it increased VEGF expression in invasive breast cancer cell lines, hypoxia inhibited apoptosis caused by serum deprivation. The mechanism by which autocrine VEGF maintains the survival of breast carcinoma cells appears to involve constitutive activation of the PI3-kinase pathway, as evidenced by the findings that reducing VEGF expression results in a significant decrease in PI3-kinase basal activity, hypoxia stimulates Akt activity, and inhibition of PI3-kinase induces apoptosis [133]. According to previous studies, VEGF inhibits apoptosis in breast cancer cells via upregulating the anti-apoptotic protein Bcl-2.
3.2 The role of VEGF in breast carcinoma migration and invasion
Carcinoma cells acquire the ability to migrate and infiltrate tissues as a result of malignant transformation and development. Although chemoattractant gradients may enhance carcinoma migration and invasion, it has been established that cells’ ability to form autocrine signalling pathways might boost their sensitivity to external stimuli [134]. Depleting VEGF expression in the presence of caspase inhibitors, which prevent apoptosis caused by VEGF expression loss, allowed us to find a role for autocrine VEGF in the migration and invasion of breast cancer cells towards chemokines. The capacity of breast cancer cells to migrate and invade in response to chemotactic stimuli is considerably diminished in such circumstances.
One mechanism for VEGF’s involvement in these events is its ability to alter the expression of the chemokine receptor CXCR4 [135]. This finding is significant for breast cancer growth since stromal-derived factor-1, the receptor’s ligand, is abundant in tumour stroma as well as organs such as the lymph and lung, which are the primary targets of invasive breast carcinoma cells, and CXCR4 inhibitors impede metastasis [136].
In addition to its survival benefits, VEGF autocrine signalling may contribute to tumour growth by boosting chemokine receptor expression and allowing tumour cells to migrate towards chemokine gradients [137].
3.3 Perspective
The revelation that breast cancer cells produce VEGF receptors is significant, but further research is needed to understand how these receptors are expressed as a result of transformation and progression, including EMT, and the mechanisms through which these receptors regulate tumour cell behaviour. Despite having inherent signalling capabilities, little is known about how NP-1 enhances VEGF165 signalling on breast cancer cells. In endothelial cells, it appears to work with either VEGFR1 or VEGFR2, although this has yet to be validated in breast cancer cells.
Another hypothesis is that NP-1 transmits NP-1 signals in neurons via interacting with non-VEGF receptors in cancer cells, such as plexins. Our findings reveal that plexin A1 is expressed in breast cancer cells and can affect cell motility. The study of plexin involvement in NP-1 signalling will require a much more in-depth understanding of plexin expression and function in breast and other cancers. In addition, more exact data on the location and relative expression of NP-1 in the mammary gland and human breast malignancies is needed.
VEGF-C and VEGF-D, for example, have been linked to angiogenesis and lymphangiogenesis in breast tumours. It’s critical to figure out whether these VEGFs have a paracrine or autocrine effect on breast cancer cells. Some data suggests that breast cancer cells can respond to VEGF-D autocrinely, although additional research is needed to confirm this.
\n',keywords:"angiogenesis, VEGF, breast cancer",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81783.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81783.xml",downloadPdfUrl:"/chapter/pdf-download/81783",previewPdfUrl:"/chapter/pdf-preview/81783",totalDownloads:1,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 28th 2022",dateReviewed:"January 31st 2022",datePrePublished:"May 14th 2022",datePublished:null,dateFinished:"May 14th 2022",readingETA:"0",abstract:"Since the last comprehensive assessment of antiangiogenic therapy was published in Breast Cancer Research 3 years ago, clinical trials in a variety of tumour types, including breast cancer, have underscored the key relevance of tumour neovascularization. Bevacizumab, a drug designed to target vascular endothelial cell growth factor, was utilised in many of these studies (VEGF). Clinical trials using antiangiogenic treatment in breast cancer have highlighted the critical role of tumour neovascularization. Personalised medicine will become increasingly important to generate maximum therapeutic benefit to the patient but also to realise the optimal economic advantage from the finite resources available, according to a report by the US Department of Health and Human Services (HHS) and the National Institute for Occupational and Environmental Health (NIH). This overview covers the history of breast tumour neovascularization in both in situ and invasive breast cancer, the processes by which it occurs, and the impact of the microenvironment, with a focus on hypoxia. The regulation of angiogenesis, as well as the antivascular drugs employed in antiangiogenic dosing schedules, both innovative and traditional, are discussed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81783",risUrl:"/chapter/ris/81783",signatures:"Pooja G. Singh, Kanthesh M. Basalingappa, T.S. Gopenath and B.V. Sushma",book:{id:"10833",type:"book",title:"Tumor Angiogenesis",subtitle:null,fullTitle:"Tumor Angiogenesis",slug:null,publishedDate:null,bookSignature:"Dr. Ke Xu",coverURL:"https://cdn.intechopen.com/books/images_new/10833.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-835-6",printIsbn:"978-1-80355-834-9",pdfIsbn:"978-1-80355-836-3",isAvailableForWebshopOrdering:!0,editors:[{id:"59529",title:"Dr.",name:"Ke",middleName:null,surname:"Xu",slug:"ke-xu",fullName:"Ke Xu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Angiogenesis in cancer",level:"2"},{id:"sec_2_2",title:"1.2 Breast cancer: tumour angiogenesis",level:"2"},{id:"sec_3_2",title:"1.3 The angiogenic cycle",level:"2"},{id:"sec_5",title:"2. Factors that promote angiogenesis",level:"1"},{id:"sec_5_2",title:"2.1 Hypoxia",level:"2"},{id:"sec_6_2",title:"2.2 Vascular endothelial growth factor",level:"2"},{id:"sec_7_2",title:"2.3 VEGF and breast tumour angiogenesis",level:"2"},{id:"sec_8_2",title:"2.4 Mechanisms of angiogenesis",level:"2"},{id:"sec_9_2",title:"2.5 Non-angiogenic functions of VEGF in breast cancer",level:"2"},{id:"sec_11",title:"3. Breast carcinoma cells and VEGF signalling",level:"1"},{id:"sec_11_2",title:"3.1 Survival signalling by autocrine VEGF",level:"2"},{id:"sec_12_2",title:"3.2 The role of VEGF in breast carcinoma migration and invasion",level:"2"},{id:"sec_13_2",title:"3.3 Perspective",level:"2"}],chapterReferences:[{id:"B1",body:'Folkman J. Tumor angiogenesis theraperutic implications. The New England Journal of Medicine. 1971;285:1182-1186'},{id:"B2",body:'Muthukkaruppan VR, Kubai L, Auerbach R. Tumor-induced neovascularization in the mouse eye. 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Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proceedings of the National Academy of Science USA. 2001;98:10857-10862'},{id:"B133",body:'Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Research. 2002;62:7203-7206'},{id:"B134",body:'Shvartsman SY, Hagan MP, Yacoub A, Dent P, Wiley HS, Lauffenburger DA. Autocrine loops with positive feedback enable context-dependent cell signaling. American Journal of Physiology: Cell Physiology. 2002;282:C545-C559'},{id:"B135",body:'Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50-56'},{id:"B136",body:'Luo Y, Raible D, Raper JA. Collapsin: A protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993;75:217-227'},{id:"B137",body:'Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ, et al. Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Research. 2003;63:5230-5233'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Pooja G. Singh",address:null,affiliation:'
Department of Nutrition and Dietetics, School of Life Sciences, JSS AHER, India
'},{corresp:"yes",contributorFullName:"Kanthesh M. Basalingappa",address:"kantheshmb@jssuni.edu.in",affiliation:'
Division of Molecular Biology, School of Life Sciences, JSS AHER, India
Department of Nutrition and Dietetics, School of Life Sciences, JSS AHER, India
'}],corrections:null},book:{id:"10833",type:"book",title:"Tumor Angiogenesis",subtitle:null,fullTitle:"Tumor Angiogenesis",slug:null,publishedDate:null,bookSignature:"Dr. Ke Xu",coverURL:"https://cdn.intechopen.com/books/images_new/10833.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-835-6",printIsbn:"978-1-80355-834-9",pdfIsbn:"978-1-80355-836-3",isAvailableForWebshopOrdering:!0,editors:[{id:"59529",title:"Dr.",name:"Ke",middleName:null,surname:"Xu",slug:"ke-xu",fullName:"Ke Xu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"351015",title:"Dr.",name:"Ali",middleName:null,surname:"Juma",email:"alijuma@me.com",fullName:"Ali Juma",slug:"ali-juma",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{id:"76356",title:"The Safe Evolution of Liposuction into Liposculpture",slug:"the-safe-evolution-of-liposuction-into-liposculpture",abstract:"Liposuction was described in the 1920s & popularised in 1977 by Illouz. He developed smaller diameter blunt cannulas. To add safety he also developed the wet technique to reduce blood loss. Tumescent anaesthesia described by Klein in 1987 made large volume liposuction safer allowing for more refined body contouring through significantly minimising blood loss. Liposuction journey started as mechanical debulking that evolved over the last 4 decades into a refined high definition body contouring and proportioning surgery, thus making sculpturing a shape of figurine possible. To achieve such high definition body sculpting technology including Laser, and Vaser not only added safety, however, they also achieved outcomes that cannot be matched with the older methods of liposuction, under local anaesthesia. In this chapter we aspire to discuss the journey of how liposuction evolved into body contouring surgery with large volume lipo-aspirates yet more safely.",signatures:"Ali Juma, Jamil Hayek and Simon Davies",authors:[{id:"343918",title:"Dr.",name:"Jamil",surname:"Hayek",fullName:"Jamil Hayek",slug:"jamil-hayek",email:"plasticsurgeonjamilhayek@gmail.com"},{id:"344364",title:"Mr.",name:"Simon",surname:"Davies",fullName:"Simon Davies",slug:"simon-davies",email:"Simon.Davies@bausch.com"},{id:"351015",title:"Dr.",name:"Ali",surname:"Juma",fullName:"Ali Juma",slug:"ali-juma",email:"alijuma@me.com"}],book:{id:"10351",title:"Enhanced Liposuction",slug:"enhanced-liposuction-new-perspectives-and-techniques",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"73035",title:"Prof.",name:"Ercan",surname:"Karacaoglu",slug:"ercan-karacaoglu",fullName:"Ercan Karacaoglu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/73035/images/322_n.jpg",biography:"E R C A N K A R A C A O G L U\r\n\r\n\r\n\r\n\r\n\r\n\r\nAcademic Title: Associate Professor of Plastic Surgery\r\n\r\nSpeciality: Plastic, Aesthetic and Reconstructive Surgery\r\n\r\nMinor Speciality: Aesthetic surgery, Aestehetic Breast Surgery, Reconstructive Breast surgery\r\n\r\nPlace of Birth : Tekirdag, Turkey\r\nDate of Birth : December 18, 1967\r\n\r\nGraduated Faculty and Year: GATA School of Medicine, 1992 \r\n\r\nPlace and date of Speciality: GATA Haydarpasa Training Hospital\r\nIstanbul, Turkey, 2000\r\n\r\nPlace and date of Minor Speciality: 1.Brown University, School of Medicine, Department of Plastic surgery, Providence, Rhode Island, U.S.A., 2001\r\n\t\t\t\t 2. Brown University, School of Medicine, Department of Plastic surgery, Providence, Rhode Island, U.S.A., 2004\r\n\r\n\r\nForeign Languages: English\r\n\r\nVocational Awards: \r\n\r\nGrants: LifeCell Corporation\r\nAssessment of In-Vivo Integration of Allograft around implants\r\nPrinciple Researcher.\r\nAward: $30,000 (2004)\r\nHonors and Awards: The second best scientific presentation award in 22nd National Congress of Turkish Plastic and Reconstructive Surgery Society (Sept 2000).\r\n\r\n-The best grade of graduation in 1990-1991 Training Year, Gulhane Military Medical \r\n Academy, School of Medicine (1991)\r\n\r\n\r\nVocational Publications: \r\n\r\n\tNumber of Foreign Publications: 26\r\n\r\n\tNumber of Turkish Publications: 14\r\n\r\n\tNumber of National Congress Presentations: 35\r\n\r\n\tNumber of International Congress Presentations: 32\r\n\t\r\n\tNumber of Book/ Chapters: 3\r\n\r\nSummary of the Career: \r\n\r\n-Since June 2009: Associate Professor of Plastic Surgery in Yeditepe University, School of Medicine, Dept of Plastic Surgery\t Istanbul, Turkey.\r\n-March 2005- June 2009: Assistant Professor \r\n-Oct 2003- Dec 2004: Fellowship in Breast Surgery (Teaching and Clinical Fellow) Brown University, School of Medicine\r\nRI Hospital, Div of Plastic Surgery Providence, RI U.S.A. \r\n-Jun 2003- Sept 2003 : Private Practicing, Istanbul, Turkey. \r\n-Sept 2001- Jun 2003 : Chief (Captain, M.D), Plastic Surgery Service Golcuk 600-Bed Naval Hospital, Golcuk, Kocaeli Turkey. \r\n-Dec 2000- Aug 2001 : Fellowship in Aesthetic and Reconstructive Breast Surgery Brown University, School of Medicine RI Hospital, Div of Plastic Surgery Providence, RI, U.S.A. \r\n-Nov 2000 : Chief (Captain, M.D), Plastic Surgery Service Golcuk 600-Bed Naval Hospital, Golcuk, Kocaeli Turkey. \r\n-Sept '95-Oct 2000 : Residency in Plastic and Reconstructive Surgery. GATA Military Medical Academy, Haydarpasa Training Hospital, Kadikoy, Istanbul Turkey. \r\n-May.’94-Sept ’95 : Chief of Emergency Medical Care Service Turkish Navy, Heybeliada Naval Hospital, Heybeliada, Istanbul Turkey. \r\n-June’93-May.’94 : Emergency Care Staff and Destroyer Doctor, Turkish Navy, Golcuk 600-Bed Naval Hospital, 41657 Golcuk, Kocaeli Turkey. \r\n-Sept ’92- June ’93 : Postgraduate Internship \r\nGATA 1200-Bed Military Medical Academy Hospital Etlik, Anakara Turkey\r\n\r\n\r\nMemberships in Associations/Clubs: \r\n\r\nSince 2006: Fellow, EBOPRAS Board Certificate (EBOPRAS, European Board of Plastic, Reconstructive and Aesthetic Surgery)\r\n\r\nSince 2006: ASPS (American Society of Plastic Surgeons)\r\n\r\nSince 2004: ISAPS ( International Society of Aesthetic Plastic Surgery)\r\n\r\nSince 2004: TASSSA (Turkish American Scientists Scholars Association)\r\n\r\nSince 2007: Society of Turkish Aesthetic Surgeons\r\n\r\nSince 1995 : Society of Turkish Plastic and Reconstructive Surgeons \r\n\r\nSince 1992 : Association of Turkish Medical Doctors \r\n\r\n\r\n\r\nE-Mail: drercanka@yahoo.com",institutionString:null,institution:{name:"Yeditepe University",institutionURL:null,country:{name:"Turkey"}}},{id:"342452",title:"Dr.",name:"Roger E.",surname:"Amar",slug:"roger-e.-amar",fullName:"Roger E. Amar",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"343312",title:"Dr.",name:"Engin",surname:"Selamioglu",slug:"engin-selamioglu",fullName:"Engin Selamioglu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bahçeşehir University",institutionURL:null,country:{name:"Turkey"}}},{id:"343659",title:"Dr.",name:"Stephen",surname:"Mulholland",slug:"stephen-mulholland",fullName:"Stephen Mulholland",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"343782",title:"M.D.",name:"Igumnov Vitaliy",surname:"Aleksandrovich",slug:"igumnov-vitaliy-aleksandrovich",fullName:"Igumnov Vitaliy Aleksandrovich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"343918",title:"Dr.",name:"Jamil",surname:"Hayek",slug:"jamil-hayek",fullName:"Jamil Hayek",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"344364",title:"Mr.",name:"Simon",surname:"Davies",slug:"simon-davies",fullName:"Simon Davies",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"344434",title:"Ph.D.",name:"Yanko",surname:"Castro-Govea",slug:"yanko-castro-govea",fullName:"Yanko Castro-Govea",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"344573",title:"Dr.",name:"Vaishali B.",surname:"Doolabh",slug:"vaishali-b.-doolabh",fullName:"Vaishali B. Doolabh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/344573/images/15430_n.jpg",biography:null,institutionString:null,institution:null},{id:"347622",title:"Ph.D.",name:"Michael",surname:"Kreindel",slug:"michael-kreindel",fullName:"Michael Kreindel",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"OA-publishing-fees",title:"Open Access Publishing Fees",intro:"
The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
\\n\\n
The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
\\n\\n
OAPF Publishing Options
\\n\\n
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1,400 GBP Chapter - Edited Volume
\\n\\t
850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
\\n\\t
4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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\\n\\n
During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\\n\\n
Services included are:
\\n\\n
\\n\\t
An online manuscript tracking system to facilitate your work
\\n\\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\\n\\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\\n\\t
Discoverability - electronic citation and linking via DOI
\\n\\t
Permanent and unrestricted online access to your work
\\n
\\n\\n
What isn't covered by the Open Access Publishing Fee?
\\n\\n
If your manuscript:
\\n\\n
\\n\\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\\n\\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\\n
\\n\\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\\n\\n
Open Access Funding
\\n\\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\\n\\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\\n\\n
Added Value of Publishing with IntechOpen
\\n\\n
Choosing to publish with IntechOpen ensures the following benefits:
\\n\\n
\\n\\t
Indexing and listing across major repositories, see details ...
\\n\\t
Long-term archiving
\\n\\t
Visibility on the world's strongest OA platform
\\n\\t
Live Performance Metrics to track readership and the impact of your chapter
\\n\\t
Dissemination and Promotion
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\\n\\n
Benefits of Publishing with IntechOpen
\\n\\n
\\n\\t
Proven world leader in Open Access book publishing with over 10 years experience
\\n\\t
+5,700 OA books published
\\n\\t
Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
\\n\\t
Currently strongest OA platform with over 175 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
\n\n
OAPF Publishing Options
\n\n
\n\t
1,400 GBP Chapter - Edited Volume
\n\t
850 GBP Chapter - Book Series Topic (Annual Volume)
\n\t
10,000 GBP Monograph - Long Form
\n\t
4,000 GBP Compacts Monograph - Short Form
\n\t
850 GBP Journal Article (Across Portfolio)
\n
\n\n
During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
\n\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
\n\n
\n\t
An online manuscript tracking system to facilitate your work
\n\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\n\t
Assurance that your manuscript meets the highest publishing standards
\n\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
\n
\n\n
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,700 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes that assure your research is made available to the scientific community without delay
\n\t
Personal support during every step of the publication process
\n\t
+184,650 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 175 million downloads
\n
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.",book:{id:"7328",slug:"melatonin-molecular-biology-clinical-and-pharmaceutical-approaches",title:"Melatonin",fullTitle:"Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches"},signatures:"Aysun Hacışevki and Burcu Baba",authors:[{id:"248612",title:"Associate Prof.",name:"Aysun",middleName:null,surname:"Hacışevki",slug:"aysun-hacisevki",fullName:"Aysun Hacışevki"},{id:"248614",title:"Ph.D.",name:"Burcu",middleName:null,surname:"Baba",slug:"burcu-baba",fullName:"Burcu Baba"}]},{id:"75377",title:"Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020",slug:"pathophysiologic-approach-to-type-2-diabetes-management-one-centre-experience-1980-2020",totalDownloads:777,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This overview summarizes the evolution of pathophysiologic treatment of diabetes type 2 (T2D) in the period of the last 40 years. 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Hence, individually adopted education, lifstyle, technical equipment, incretin receptor agonists and/or metformin and/or gliflozins and/or insulin analogs appear to be the core of an effective pathophysiologic approach. Scientific conclusions from RCTs, RWE trials and own clinical case reports may prevail over clinical inertia and induce early implementation of effective methods into routine T2D treatment.",book:{id:"9517",slug:"type-2-diabetes-from-pathophysiology-to-cyber-systems",title:"Type 2 Diabetes",fullTitle:"Type 2 Diabetes - From Pathophysiology to Cyber Systems"},signatures:"Rudolf Chlup, Richard Kaňa, Lada Hanáčková, Hana Zálešáková and Blanka Doubravová",authors:[{id:"278357",title:"Prof.",name:"Rudolf",middleName:null,surname:"Chlup",slug:"rudolf-chlup",fullName:"Rudolf Chlup"},{id:"346119",title:"Dr.",name:"Richard",middleName:null,surname:"Kaňa",slug:"richard-kana",fullName:"Richard Kaňa"},{id:"346120",title:"BSc.",name:"Lada",middleName:null,surname:"Hanáčková",slug:"lada-hanackova",fullName:"Lada Hanáčková"},{id:"346121",title:"BSc.",name:"Hana",middleName:null,surname:"Zálešáková",slug:"hana-zalesakova",fullName:"Hana Zálešáková"},{id:"346122",title:"Dr.",name:"Blanka",middleName:null,surname:"Doubravová",slug:"blanka-doubravova",fullName:"Blanka Doubravová"}]},{id:"61064",title:"Secretions of Human Salivary Gland",slug:"secretions-of-human-salivary-gland",totalDownloads:2766,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The salivary glands play an important role in our body by the virtue of its ability to secrete saliva. Saliva has a role to play in maintaining the health of the oral cavity and for carrying out physiological functions like mastication, taste perception, speech etc. It also acts as a mirror to the systemic status of an individual owing to its ability to act as a diagnostic fluid for detecting a number of conditions and diseases. Saliva is a potential noninvasive diagnostic fluid for detection of a number of biomarkers of disease and health. Advancement in diagnostic methods has helped in identifying biomarkers of disease in saliva. In order to understand and diagnose pathological changes, a thorough understanding of the salivary gland anatomy, physiology and regulation of its secretion is warranted. This chapter aims to provide the basic understanding of the secretions of saliva.",book:{id:"6246",slug:"salivary-glands-new-approaches-in-diagnostics-and-treatment",title:"Salivary Glands",fullTitle:"Salivary Glands - New Approaches in Diagnostics and Treatment"},signatures:"Anahita Punj",authors:[{id:"226076",title:"Dr.",name:"Anahita",middleName:null,surname:"Punj",slug:"anahita-punj",fullName:"Anahita Punj"}]},{id:"63301",title:"Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake",slug:"role-of-pi3k-akt-pathway-in-insulin-mediated-glucose-uptake",totalDownloads:3541,totalCrossrefCites:11,totalDimensionsCites:27,abstract:"Glucose uptake is regulated by several mechanisms, where insulin plays the most prominent role. This powerful anabolic hormone regulates the transport of glucose into the cell through translocation of glucose transporter from an intracellular pool to the plasma membrane mainly in metabolically active tissues like skeletal muscles, adipose tissue, or liver (GLUT4). This translocation occurs through multiple steps of PI3K/AKT signaling pathway. In this chapter, we will focus on molecular events leading to GLUT4 translocation, starting with activation of insulin receptors through signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) and finally, the action of their effectors. 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The poor long- and short-term perinatal and postnatal results associated with this context make it necessary to establish an early diagnosis and a therapeutic strategy, which can be challenging due to the compromise between the threat of intrauterine permanence and the prematurity problem. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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Valarmathi",profilePictureURL:"https://mts.intechopen.com/storage/users/69697/images/system/69697.jpg",institutionString:"Religen Inc. | A Life Science Company, United States of America",institution:null},{id:"205081",title:"Dr.",name:"Marco",middleName:"Vinícius",surname:"Chaud",fullName:"Marco Chaud",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDGeQAO/Profile_Picture_1622624307737",institutionString:null,institution:{name:"Universidade de Sorocaba",institutionURL:null,country:{name:"Brazil"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"bookSubject",path:"/subjects/178",hash:"",query:{},params:{id:"178"},fullPath:"/subjects/178",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()