The amount of total phenolic contents (mg GAE/g d.w.) and content of total flavonoids (mg QE/g d.w.) in L. nobilis extracts.
\r\n\tThe purpose of the book is to bring together the latest knowledge about genetic diversity by presenting the studies of some of the scientists who are engaged in development of new tools and ideas used to reveal genetic diversity, often from very different perspectives. The book should prove useful to students, researchers and experts in the area of biology, medicine and agriculture.
",isbn:"978-1-80356-945-1",printIsbn:"978-1-80356-944-4",pdfIsbn:"978-1-80356-946-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"0b1e679fcacdec2448603a66df71ccc7",bookSignature:"Prof. Mahmut Çalışkan and Dr. Sevcan Aydin",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11643.jpg",keywords:"PCR Based Methods, Protein Based Methods, Sequencing, Conservation of Genetic Resources, Natural Variation, Molecular Markers, Genetic Manipulation in Animals, Resistance to Disease, Genetic Manipulation in Plants, Use of Microorganisms in Biotechnology, Genetic Differentiation, Gene Therapy and Gene Editing",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"16 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor of genetics and molecular biology and Head of Biotechnology division at İstanbul University in Turkey whose main research areas include plant molecular genetics, microbial biotechnology and characterization and biotechnological use of halophilic archaeal strains.",coeditorOneBiosketch:"Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Turkey whose main research areas include genetics, environmental biotechnology and bioengineering.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"51528",title:"Prof.",name:"Mahmut",middleName:null,surname:"Çalışkan",slug:"mahmut-caliskan",fullName:"Mahmut Çalışkan",profilePictureURL:"https://mts.intechopen.com/storage/users/51528/images/system/51528.png",biography:"Mahmut Çalışkan is a Professor of Genetics and Molecular Biology in the Department of Biology, Biotechnology Division, Istanbul University, Turkey. He obtained a BSc from Middle East Technical University, Ankara, and a Ph.D. from the University of Leeds, England. His main research areas include the role of germin gene products during early plant development, analysis of genetic variation, polymorphisms, and the characterization and biotechnological use of halophilic archaea.",institutionString:"Istanbul University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"8",institution:{name:"Istanbul University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:{id:"462767",title:"Dr.",name:"Sevcan",middleName:null,surname:"Aydin",slug:"sevcan-aydin",fullName:"Sevcan Aydin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003QRfRpQAL/Profile_Picture_2022-03-24T08:49:06.jpg",biography:"Sevcan Aydın is an Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Türkiye. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65331",title:"Flavonoids and Phenolic Acids as Potential Natural Antioxidants",doi:"10.5772/intechopen.83731",slug:"flavonoids-and-phenolic-acids-as-potential-natural-antioxidants",body:'The history of medicinal herb usage dates back to the distant past, many centuries and civilizations ago. Plants have played an important role in many cultures in the treatment of various diseases, and floral fragrances have been used to refine the spirit and body, to attract partners, and to establish a psychophysical balance. The first written testimonials on the use of herbs for treatment are found in China. Emperor Kin-Nong knew about 100 medicinal plants in 3000 years BC. One of the oldest classical medical texts of ancient China is “Pent-Sao,” which was written 2500 years BC and is composed of 52 books; of which, two books are dedicated to herbal remedies. In the nineteenth century, medicinal and exotic plants have become lucrative, as more and more people began growing plants in their homes. China, Japan, and South America were overwhelmed by collectors from plant companies who looked for tropical plants to meet the needs of society. This instigated scientific pharmacy and the start of chemical and physiological research on medicinal herbs. It can be said that the nineteenth century was the century of alkaloids, because hundreds were isolated from plants from all over the world. The beginning of the twentieth century threatened medicinal herbs to be completely thrown out of use. Thus, “medicines” that have been successfully used for thousands of years have become subject to mockery and disdain. The expulsion of medicinal herbs from therapy can be compared to the darkness of the Middle Ages that had ruled Europe.
In the last four decades, especially in the developed countries of Europe and America, scientists have shown increasing interest in plant research. It is estimated that today about 60% of the total world population in treatment relies on herbs and natural products that are thus recognized as an important source of drugs [1]. Phytochemistry studies a huge variety of organic substances that have been discovered and which accumulate in plants. Furthermore, phytochemistry is also defining the structure of these compounds, their biosynthesis, metabolism, natural distribution, and biological activities [2]. An important place among them is occupied by aromatic plants, whose aroma is associated with the presence of essential oils and complex mixtures of volatile compounds, dominated by mono- and sesquiterpenes. In addition to essential oils, aromatic plants are characterized by the presence of plant phenolic compounds, primarily coumarins and phenylpropanoids, that have been shown to possess multiple pharmacological activities. Investigations of these secondary biomolecules intensified when some commercial synthetic antioxidants were found to exhibit toxic, mutagenic, and carcinogenic effects [3]. It was also found that excessive production of oxygen radicals in the body initiates the oxidation and degradation of polyunsaturated fatty acids. It is known that free radicals attack the highly unsaturated fatty acid membrane systems and induce lipid peroxidation, which is a key process in many pathological conditions and one of the reactions that cause oxidative stress. Particularly, the biological membrane lipids in the spinal cord and brain are vulnerable, because they contain high levels of polyunsaturated fatty acids. Moreover, the brain contains significant amounts of transitional prooxidant metals and consumes a lot of oxygen. These features facilitate the formation of oxygen radicals involved in the processes of aging, Alzheimer’s and Parkinson’s disease, ischemic heart damage, arthritis, myocardial infarction, arteriosclerosis, and cancer. Phenolic antioxidants “stop” free oxygen radicals and free radicals formed from the substrate by donating hydrogen atoms or electrons. Many plant species and aromatic plants have been tested because of their antioxidant and antiradical activities [4].
The aim of this chapter was to show the antioxidant role of phenolic acids and flavonoids presented in aromatic plants and to assess their potential capacity as scavengers of different free radicals.
Atmospheric oxygen (O2) is present as a biradical with two unpaired electrons, which have the same spin quantum number and are located opposite the orbited orbits. This electronic structure of molecular oxygen determines its chemical reactivity and allows the absorption of individual electrons, with the formation of numerous intermediate, partially reduced oxygen species that are commonly referred to as reactive oxygen species (ROS) [5, 6]. These reactive oxygen species are able to react with basic cellular structures and biomolecules [7] and are responsible for the emergence of many diseases and degenerative damage [8].
The normal concentration of free radicals in the body is very low. However, the effects are very disruptive, as the chain reaction allows one free radical to cause changes in thousands of molecules and damage DNA, RNA, and enzymes in cell membranes and leads to the formation of lipoxygenation products before being inactivated. Which part of the cell (proteins, nucleic acids, membrane lipids, cytosolic molecules) or the extracellular component (hyaluronic acid, collagen) will react with free radicals depends on the nature of the radical and the site of its formation (e.g., cytosolic membranes, mitochondria, endoplasmic reticulum, peroxisome, cell membranes). Due to the presence of molecular oxygen in aerobic organisms and its ability to easily receive electrons, free radicals of oxygen origin start more reactions in the cell. The reactions responsible for their formation are respiration, processes of autoxidation of hydroquinone and catecholamine, reduced transition metals, some herbicides and drugs, as well as irradiation that causes water decomposition.
Any disorder of oxygen species’ regulation resulting from a disturbance in the balance between the formation of reactive oxygen metabolites and their elimination by the antioxidant protection system is the state of oxidative stress. In oxidative stress, the formation and accumulation of reactive metabolites are increased, resulting in oxidative processes of destruction of cellular components and genetic material.
ROS, RNOS, and LP are considered to be the major contributors to the etiology of atherosclerosis and various chronic disorders such as coronary disease, stroke, and ischemic dementia [9]. Antioxidants introduced through food can reduce the occurrence of cardiovascular diseases by inhibiting the production of free radicals and oxidative stress, protecting LDL from oxidation and aggregation, and inhibiting the synthesis of proinflammatory cytokines [10].
Oxidative stress often occurs in the brain, because although it represents only 2% of the body weight, the brain uses up to 20% of oxygen added. Also, the brain contains large amounts of polyunsaturated fatty acids subject to lipid peroxidation under conditions of high oxygen concentration [11, 12].
Although there are insufficient facts to confirm that the presence of free radicals is necessary in the process of carcinogenesis, it is clear that they can lead to mutations, transformations, and cancers [13]. Regarding the development of cancer, the most important target for ROS is DNA. Carcinogenesis is the result of successive mutations in DNA molecules leading to uncontrolled growth and cell phenotypic modification. One of the first steps in this process is the direct interaction of electrophiles or free radicals with cellular DNA in which promutagen lesions develop. If no repair is performed, these lesions result in mutations in the next generation of cells [14]. An increased intake of antioxidants through diet or dietary supplements is associated with a reduction in the onset of cancer.
A reduced amount of free radicals or a reduction in the speed of their production postpones the aging process and a whole series of diseases related to the aging process [15]. A certain maximum life potential characterizes each animal species. There is a reciprocal correlation between the speed of oxygen consumption (and therefore the production of free radicals) and the maximum life potential. Some studies have shown that the aging process can be slowed by increased food intake that increases antioxidant capacity (e.g., fruit and vegetables) or by supplemental intake of vitamins E, C, and β-carotene [16].
The process of oxidative modification of proteins, carbohydrates, DNA, and lipids is a universal mechanism of damage to the cell, especially at the membrane level. On the other hand, the numerous roles of free radicals in physiological processes make their creation a mandatory precondition of life, which is why a protective system has been established during evolutionary development. The basic role of this protection system is to reduce the amount and uncontrolled creation of free radicals and their precursors in the cell.
From a functional point of view, the antioxidant protection of the organism includes three levels of action:
Antioxidant protection systems that prevent the endogenous formation of free radicals. This level of protection is ensured by the spatial separation of processes in which free radicals are formed.
Engagement of the system in conditions of normal and enhanced formation of free radicals. According to the nature and method of action, antioxidants are divided into two types:
Enzymatic (superoxide-dismutase, catalase, xanthine oxidase, peroxidase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase). These enzymes make the so-called primary line of antioxidant protection.
Nonenzymatic or the so-called secondary line of defense.
Enzymatic antioxidants involved in the reparation of oxidative damage of lipids, proteins, carbohydrates, and nucleic acids.
During the evolution, the plants developed effective defense mechanisms against the harmful effects of visible, ultraviolet light and radiation and are a natural source of various antioxidants. Several thousands of biologically active secondary biomolecules of higher plants for phenolic compounds (vitamin E, flavonoids, biflavonols, benzophenones, xanthones, stilbene, quinones, betacities, phenolic acids, acetophenones, phenylpropanoids, coumarins, isocoumarins, chromones, phenols, and diterpenic alcohols) and different nitrogen compounds (alkaloids, amines, amino acids, and chlorophyll derivatives) have been shown to exhibit strong antioxidant activity, but antioxidant activity of essential oils of many spice plants is intense. Their significance is higher because it has been found that many synthetic antioxidants exhibit undesired effects after a prolonged use (e.g., some of them are withdrawn from the market as a possible carcinogen). These biomolecules exhibit their activity through various mechanisms: removing free radicals, binding metal ions, inhibiting enzymatic systems that produce free radical forms, increasing the concentration of biologically important endogenous antioxidants, and inducing the expression of a variety of genes responsible for the synthesis of enzymes that inhibit oxidative stress [14]. The term “herbal phenols” encompasses a wide range of plant substances that form one of the most numerous classes of secondary biomolecules that have a common characteristic of an aromatic ring carrying one or more hydroxyl groups as substituents, including functional derivatives (esters, glycosides, etc.). However, this broad definition also includes some non-phenolic substances. For this reason, it is recommended to combine a definition that includes a chemical description and a biogenetic origin. In nature, there are two general biosynthetic pathways for the synthesis of plant phenols: (1) a polyacetate route and (2) a phenylpropanoid route with scrub acid as an intermediate. Some phenols are formed by a combination of these two times [17].
The efficiency of phenolic compounds in protection against oxidative stress depends on their reactivity in relation to toxic oxygen species and the reactivity of phenoxy radicals relative to critical biomolecules. Chemical or enzymatic oxidation of phenolic components of plant tissue results in a dark color which is of particular importance in food technology. Their susceptibility to oxidation allows their use in the protection of fats and oils.
Phenolic compounds also increase the activity of antioxidant enzymes, thus indirectly affecting the concentration of harmful oxygen radicals in the living cell. In high concentrations, radical reactions such as DNA damage, superoxide anion production, etc. can also be act as a prooxidant [18].
The term “phenolic acid” includes hydroxy and other functional derivatives of benzoic acid (C6▬C1) and cinnamic acid (C6▬C3) [19, 20]. Figures 1 and 2 give the structures of the basic representatives of these acids.
Chemical compounds of basic benzoic acid derivatives.
Chemical formulas of basic derivatives of cinnamic acid.
Cinnamic acids, especially hydroxy-cinnamic acids, have the role of basic precursors in the biosynthesis of various plant phenols. The cinnamic acid and its derivatives are produced by condensation of the acidic acids with phosphoenolpyruvate to give the horizmic acid. Additional reactions of interconversion, decarboxylation, transamination, and disinfection lead to the formation of cinnamon (3-phenylpropenoic acid) and hydroxy-cinnamic acid. Subsequent reactions of hydroxylation, methoxylation, etc. produce cimetic acid derivatives such as p-coumaric acid (p-hydroxy cinnamic acid), β-acid (2,3-dihydroxy cinnamic acid), ferulic acid (2-methoxy-3-hydroxy cinnamic acid), and synapartoic acid (2,4-dimethoxy-3-hydroxy cinnamic acid).
The derivatives of cinnamic acid, in particular hydroxy-cinnamic acids, are the basis of the overall phenylpropanoid metabolism consisting of complex biochemical reactions which as a result supply the plant with important phenolic components [21].
The term “flavonoids” was proposed by Geisman and Heinseiner [21] to describe all plant pigments having a C6▬C3▬C6 skeleton, in which two benzene rings are linked via the C3 unit. These natural products, varying in color from white to yellow, except anthocyanidins responsible for almost all pink and violet shades [20], are widely distributed in the plant kingdom with the exception of algae and fungi. So far, more than 4000 flavonoids have been found in plants, fruits, and vegetables [22]. The most common are seeds, citrus fruits, olive oil, tea, and red wine [23]. They are found in vacuoles, chloroplasts, and chromoplasts, in the form of glycosides, and in the extinct cells free of glycosides. The presence of OH groups directly linked to the carbon atoms of the benzene ring determines the antioxidant role of flavonoids, phenolic acids, and their esters. The expressed activity is shown by compounds with two hydroxyl groups, arranged as for catechol, and three hydroxyl groups arranged as in pyrogallol.
The structure of all flavonoids is based on the C15 skeleton of the chromatic structure for which the secondary ring (B) is attached (Figure 3) [24, 25].
Basic structure of flavonoids.
Flavonoids are divided according to the substitution profile of the heterocyclic ring. In the classification of flavonoids, the oxidation state of the heterocyclic ring as well as the position of the secondary aromatic ring is taken into account. A total of about 12 subgroups of flavonoids are distinguished. The secondary (B) ring may be in position 2 (flavones, flavonols, dihydroflavonols, catechins, flavans, and anthocyanidins), position 3 (isoflavonoids), or position 4 (4-phenyl-coumarins, neoflavonoids). In a few cases, the six-membered heterocyclic ring occurs in an open isomeric form (chalcones and dihydrochalcones) or is replaced by a five-membered ring.
The most widespread of all flavonoids are flavonols (3-hydroxyflavones) and flavones. The most commonly used flavonoids are quercetin, kaempferol, and myricetin. Quercetin is considered the most widespread component of all plant phenols. More than 100 glycosides of quercetin are known. Among flavonols there are about 200–300 known aglycons of these compounds [26].
Phenolic acids are important not only for ensuring the construction of lignin but also for regulating plant growth and disease resistance. Hydroxy-cinnamic acids are associated with the role of growth regulators and proteins in the development of certain diseases. In addition, it is possible that they are important for chloroplasts and the process of photosynthesis itself. Benzoic acid has been shown to inhibit photosynthesis in chloroplasts of spinach [17]. p-Coumaric acid is the most widespread compound among plant phenols. Furthermore, rosmarinic acid has antioxidant, anti-inflammatory, and antimicrobial effects. Its antioxidant effect is stronger than vitamin E. Rosemary acid prevents damage to cells caused by free radicals and reduces the risk of cancer and atherosclerosis. Unlike antihistamines, rosemary acid prevents the activation of immune system cells that cause swelling and fluid collection. It is used in the treatment of stomach ulcers, arthritis, cataracts, cancer, and bronchial asthma [27, 28]. Caffeic acid far exceeds other antioxidants because it reduces the production of α-toxin by more than 95%. It has been proven that high doses of coffee acids have a detrimental effect on the rats because they cause gastric papillomas. However, the combination of different antioxidants, including baconic acid, had a pronounced effect on the reduction of colon tumors in the same rats. The harmful effects of bicarbonate on human health are not known [29]. Calcium acid and its derivative caffeic acid phenethyl ester (CAPE) show a reduction in tumors and show anti-inflammatory and anticancer effects on ultraviolet-exposed skin, especially UVC and UVB rays [30]. Anticancer activity was observed in mice whose skin was treated with bee propolis and a papilloma-causing agent (TPA). CAPE significantly reduced the number of papillomas [31].
Flavonoids have a high ecological significance. They function as pigments that attract insect pollinators, not only as signal molecules for microorganisms that are useful for the plant but also as antimicrobial agents [32]. In this sense, yellow flavones and flavonols are particularly important. Because of the intense absorption of UV radiation, flavonoids protect the plant tissue from UV radiation, thereby influencing vital processes in chloroplasts.
In a pharmacological view, flavonoids show antiviral, antiallergic, antitumor, antibacterial, antifungal, and antithrombotic activity [33]. They act on blood vessels, namely, flavanones and catechins, that increase the resistance of the capillaries. They show an anti-inflammatory activity that depends on the structure of flavonoids [34]. The flavonoid anti-inflammatory activity was also confirmed by in vitro testing of the ability to inhibit lipoxygenase and cyclooxygenase [35]. Flavonoids eliminate pathological changes on capillaries and are used against diabetes, hypertension, and atherosclerosis. Flavonoids have been found to stimulate the secretion of bile and inhibit enzymes and enzymatic systems. Many flavonoids have antimicrobial and antiviral activity. A certain number of flavonoids show some cytotoxic activity. The common structural feature of cytotoxic flavonoids is trisubstituted ring A, methylation at position C4 [21].
For many flavonoids, high antioxidant activity has been demonstrated in various in vitro systems [36, 37, 38]. It has been shown that quercetin, rhamnetin, and isorhamnetin can reduce the amount of serum and liver cholesterol in addition to the in vivo antioxidant activity they show [39]. Flavonoids have been found to inhibit the activity of XOD and have the ability to capture superoxide radicals. Based on this, it is assumed that flavonoids can help in the treatment of gout and ischemia by reducing the amount of uric acid and superoxide anion of radicals in tissues [40]. Two flavonol glycoside-gallate esters showed inhibitory activity on human immunodeficiency virus-1 (HIV-1) integrase [41]. The HIV-1 integrase manages the process of incorporating viral DNA into the DNA of the host cell molecule, which is necessary for the virus to reproduce and produce virions. In this way, the inhibition of the given enzyme can be effective in anti-AIDS therapy. For example, quercetin has a beneficial effect on human health: it improves heart rate and reduces the risk of cancer. It has an anti-inflammatory and antiallergic effect. All of these effects are caused by a strong antioxidant effect of quercetin. Like many other flavonoids, quercetin inhibits the oxidation of LDL cholesterol, and its anti-inflammatory activity derives from inhibition of lipoxygenase enzyme and inhibition of inflammatory mediators. Quercetin also inhibits the release of histamine. Studies have shown that quercetin lowers the risk of prostate, uterine, breast, tissue, and colon cancer. It is presumed to reduce the production of uric acid by inhibiting XOD. It also shows NO inhibitory activity. Rutin has a strong antioxidant effect, as well as the ability to build chelates with metal ions (e.g., iron) and reduces Fenton’s reaction in which harmful oxygen radicals are produced. It is supposed to stabilize vitamin C. If rutin is taken along with vitamin C, the activity of ascorbic acid increases. Rutin strengthens the capillaries, which helps people who easily bleed or get bruises. It prevents the formation of various edemas, which is an early symptom of a chronic vein disease. It has an anti-inflammatory effect. There are indications that rutin can inhibit some carcinogenic and precancerous conditions, prevent atherogenesis, and reduce the cytotoxicity of oxidized LDL cholesterol [22]. Furthermore, kaempferol prevents arteriosclerosis by inhibiting the oxidation of low-density lipoproteins and the formation of blood platelets. It has a role of a chemopreventive agent, which means it prevents the formation of cancer cells. Quercetin has a synergistic effect in reducing the proliferation of malignant cells, so treatment with quercetin and kaempferol combinations is more effective than their individual use [42]. In addition, tangeretin acts as an anticancer agent, and in in vitro studies, it has been shown to act against some forms of malignant cells. It strengthens the cell wall and protects it from attack. It also causes apoptosis of cells suffering from leukemia, while normal cells remain undamaged [43]. Tangeretin prevents tumor suppression of intercellular bonds when transmitting the signal [44]. In the G1 phase of the cell cycle, it “freezes” the cancer cells and prevents their replication. In short, in vitro studies have shown that tangerine exhibits antimutagenic, noniinvasive, and antiproliferative activity [45]. Animal studies have shown that tangeretin reduces cholesterol levels [46] and has a potentially protective effect from Parkinson’s disease [47].
The Lauraceae family comprises over 2500 species, which occur within the subtropics and tropics of Eastern Asia and South and North America. Most species possess aromatic roots, stems, and fruits. One of the most well-known and most frequently used plants from this family is
Laurus nobilis L [
Laurel is a tree or a large bush of pyramidal shape with aromatic, constantly green leaves and shiny gray corn. It reaches a height of up to 5.5 m, but the cultivated form is usually lower (1–3 m). The leaves are elliptical, fairly thick, leathery, and shiny green. Clusters of tiny, yellow, single-polar flowers appear in the spring. Berries (fruit) (
The distillation of laurel leaves produces green-yellow volatile oil that contains a high percentage of oxidized components. Essential oil leaf (0.8–3%) contains mainly 1,8-cineol (50%) and then eugenol, acetyleugenol, methyl eugenol, α- and β-pinene, felsenren, linalool, geraniol, and terpineol. Dried berries can extract green mass (melting point about 30°C) containing several percent essential oils (0.6–10%), depending on the conditions of breeding and storage. Berries contain both volatile and fixed oils. The others are known under the common name “laurel oil” (Oleum Lauri expressum, Oleum laurinum, and Oleum Lauri unguinosum). As essential ingredients, the oil contains laurosterin, glycerol ester with lauric acid, and sesquiterpenoid (the costume and dehydrocostus lactone), while the rest is made up of fats: triglycerides with lauric, myristic, and elastic acids. As with leaves, the aroma is mainly due to terpenes (cineol, terpineol, α- and β-pinene, citral) but also cinnamic acid and its methyl ester [51].
The main flavonoids in bay leaf are quercetin, kaempferol, rutin, and their derivatives (Figure 5).
Structures of the main flavonoids present in L. nobilis [
Kaempferol appears in the form of four nonpolar glycosides (Figure 6) [52, 53].
Structures of kaempferol and its glucosides present in L. Nobilis [
Structures of two phenolic acids in L. nobilis.
As a medicinal plant, bay leaves and fruits have been employed against rheumatism, skin rashes, and earaches. In addition, it has been used as a stomachic, astringent, carminative, diaphoretic, stimulant, emetic, emmenagogue, abortifacient, and insect repellent. The essential oil is used by the cosmetic industry in creams, perfumes, and soaps.
Numerous investigations of qualitative composition of plant extracts have revealed the presence of high concentration of phenols in the extracts obtained using polar solvents [54]. The extracts that display the highest antioxidant activity have the highest concentration of phenols. Because of that, our research on laurel was recently extended to the comprehensive in vitro and in vivo studies of antioxidant activity of different extracts of leaves, to assess their potential capacity as scavengers of free radicals. Results of determination of total phenolic contents and total flavonoid contents in laurel leaf extracts are given in Table 1.
Extracts | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
---|---|---|---|---|---|
Total phenolic content | 2.41 | 2.85 | 4.53 | 3.96 | 3.20 |
Total flavonoid content | 0.76 | 1.02 | 1.56 | 1.07 | 0.68 |
The amount of total phenolic contents (mg GAE/g d.w.) and content of total flavonoids (mg QE/g d.w.) in L. nobilis extracts.
The amount of total phenolics in
It should be considered that the number of identified and quantified compounds in MeOH extract of
Compounds | Extract | |
---|---|---|
Phenolic acid | p-Hydroxybenzoic acid | 38.46 |
Protocatechuic acid | n.d. | |
p-Coumaric acid | n.d. | |
Vanillic acid | n.d. | |
Gallic acid | n.d. | |
Caffeic acid | 16.18 | |
Quinic acid | n.d. | |
Ferulic acid | n.d. | |
Syringic acid | n.d. | |
Chlorogenic acid | 13.11 | |
Cinnamic acid | n.d. | |
Flavonoids | Apigenin | n.d. |
Naringenin | n.d. | |
Luteolin | 5.19 | |
Kaempferol | 11.97 | |
Apigenin-7-O-β-glucoside | n.d. | |
Luteolin-7-O-β-glucoside | n.d. | |
Kaempferol-3-O-glucoside | 56.15 | |
Quercetin-3-O-glucoside | 31.18 | |
Rutin | 17.44 | |
Quercetin | 21.62 | |
Quercitrin | 7.14 |
LC-MS-MS quantification of bioactive compounds presented in L. nobilis L. crude MeOH extract (μg/g d.w.).
The results indicate that the major bioactive compounds in
Furthermore, antioxidant activity was observed in the study of laurel leaf extracts in different solvents on the content of DPPH•, O2•−, NO•, and OH• radicals (Table 3).
Extract | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
---|---|---|---|---|---|
DPPH radical | 127.38 | 139.42 | 83.24 | 181.35 | 161.83 |
O2•− radical | 327.60 | 429.43 | 163.57 | 288.64 | 486.32 |
NO radical | 168.77 | 322.84 | 158.63 | 386.80 | 618.42 |
OH radical | 442.84 | 241.18 | 121.84 | 213.36 | 187.65 |
IC50 values (μg/mL) of L. nobilis for different antioxidant assays.
The obtained results could point to strong quenching activities of flavonoids present in the leaves of laurel against DPPH radicals, and a high degree of correlation is observed between total phenol content and the ability of EtOAc extract to neutralize DPPH radicals. This is indicated by the fact that phenolic compounds play a key role in neutralizing free radical species which occurs by the mechanism of electron transfer. But, it can be supposed that such antiradical activity is also caused, besides flavonoids, by terpenoids, since nonpolar solvents also exhibited high antiradical potential. When investigating neutralization of O2•− and NO radicals, ethyl acetate extract has also exhibited the greatest ability of their scavenging. These results can be attributed to the presence of sesquiterpene lactones isolated from the plant that possess certain biological and pharmacological activity [60, 61]. Matsuda et al. [62] have also established that the methanolic extract from the leaves of
One of the paradoxes of life on Earth is that, on the one hand, oxygen is necessary for the life of aerobic organisms. On the other hand, increased concentrations of oxygen and especially its reactive metabolites (reactive oxygen species) may lead to the development of numerous diseases. A major source of free radicals in biological systems is molecular oxygen (O2). The results of our in vitro assays of examined five different extracts of
This work was supported by the Ministry of Science and Environmental Protection of the Republic of Serbia (Project No. 172058).
The authors declare that there is no conflict of interest.
“Eating”, especially glucose ingestion is essential for brain function. When we get tired either physically or mentally, we may want “sweet stuff”. Some people prefer “fatty food”. These unconscious impulses imply fundamental roles of glucose and fatty acid in the brain. The human brain is a complex, organized organ consisting of numerous cell types including neurons and glial cells [1, 2]. In addition, the microvasculature, which supplies oxygen and glucose, is also an essential component [3]. The human adult brain weighs 1.4 kg, or approximately 2% of the body weight, and consumes 20% of the total oxygen consumption and 25% of the glucose consumption in the body (Figure 1) [4, 5]. Brain function mainly consists of intellectual information processing, which is based on the generation of action potentials resulting from ionic flux across the cellular membrane. The ratio of the cerebral metabolic rate of oxygen (CMRoxy) to glucose (CMRglc) consumption is approximately 6, implying the complete oxidation of one molecule of glucose (6 carbon molecules) for every 6 molecules of oxygen, producing CO2 and H2O (Figure 1) [4, 5]. The first step in glucose metabolism is glycolysis, which generates 2 ATPs; pyruvate/lactate is the end-product of glycolysis, and this product then enters the tricarboxylic acid (TCA) cycle, where ATP is produced more efficiently (resulting in 36 ATPs). Continuous ATP production is essential to generate action potentials, maintaining consciousness as well as intellectual function. Surprisingly, however, ATP production in the brain is solely dependent on glucose and oxygen as energy substrates [4, 5]. Moreover, these essential energy substrates must be supplied from outside of the brain through the microvasculature, since there is virtually no storage of glucose or oxygen in the brain. As a result, even a short period of cessation in cerebral blood flow (CBF) induces an immediate impairment of brain function [6]. Longer periods of ischemia cause irreversible damage to brain cells, making the restoration of function in stroke patients difficult even after vigorous rehabilitation [6, 7].
Cerebral metabolic rate of glucose (CMRglc) and oxygen (CMRoxy) in human adults (adapted from [
Regarding the maintenance and restoration of brain function, the topic of synaptic plasticity is essential. The theoretical basis of the beneficial effects of physical exercise on brain function relies on the facilitation of synaptic transmission and plasticity. Brain-derived neurotrophic factor (BDNF) plays a pivotal role in maintaining the neural network, improving its function, and restoring the network after damage [8, 9]. BDNF is a neurotrophic factor that was identified in the pig brain for the first time in 1982 [9]. BDNF, which is produced in both neurons and glial cells, improves a wide variety of neuronal functions including both motor functions and memory [8, 9]. Physical exercise does, indeed, improve not only motor function, but also mental function [10, 11, 12]. Unfortunately, however, the exact mechanism by which physical exercise induces BDNF production in the brain has not yet been elucidated. Recently, two nutrient molecules that are closely related to brain energy metabolism have become points of focus: lactate [13, 14] and beta-hydroxybutyrate (BHB) [15, 16]. The former is an end-product of glycolysis, and the latter is a type of ketone body, which are metabolites of fatty acid produced through beta-oxidation. Importantly, the concentrations of both lactate and BHB have been widely recognized as being elevated after exercise as a result of increases in their production by skeletal muscle and in the liver, respectively. Furthermore, both lactate and BHB are transported into the brain via monocarboxylate transporters (MCTs) (Figure 2) [17]. Therefore, lactate and BHB are also cable of acting as signal molecules resulting in BDNF production in the brain.
Physical activity, brain, muscle, liver, and BDNF: hypothetical model 1. BDNF, brain-derived neurotrophic factor; MCT1, monocarboxylate transporter 1 (expressed on brain microvessels).
As described above, brain energy metabolism is solely dependent on exogenous glucose and oxygen supplied from outside the brain under normal physiological conditions [4, 5]. Importantly, however, it has also long been known that exogenous lactate and BHB can fuel the brain as alternative energy substrates under non-physiological conditions such as starvation, insulin-resistance and so on [4, 5]. Lactate enters the TCA cycle of the neurons after the conversion of acetyl-CoA by the pyruvate dehydrogenase complex (PDHC), while BHB can enter the TCA cycle directly without the action of PDHC (Figure 3) [4, 5]. These mechanisms imply that the exercise-induced production of lactate and BHB provides (1) energy substrates for the short-term maintenance of brain function, and (2) signal molecules capable of inducing BDNF production in the brain for the long-term maintenance of brain plasticity.
Transportation and metabolic pathway of lactate and ketone bodies (β-hydroxybutyrate and acetoacetate) into neural cells. MCT, monocarboxylate transporter; Glut, glucose transporter; TCA, tricarboxylic acid; PDHC, pyruvate dehydrogenase complex.
The brain, muscle, and liver therefore compose a metabolic network that is linked through physical exercise. Of note, physical exercise (voluntary movement) is initiated by neuronal excitation (Figure 2) [4, 5]. Generally, the functional activation of the brain increases both local CMRglc and local CMRoxy to produce more ATPs. Under normal resting conditions, neither lactate nor BHB is present in the blood in sufficient quantities to be transported into the brain because of the slow transportation kinetics of MCTs [4, 5]. As a result, their roles as energy substrates for the brain seem to be limited. Importantly, however, the brain itself, or more exactly its astroglia, can produce both lactate and BHB upon neuronal excitation (Figure 4) [3, 4, 5]. Our research has focused on the metabolic compartmentalization between neurons and glial cells [18, 19, 20, 21, 22, 23, 24, 25, 26, 27], revealing that astrocytes produce both lactate and BHB, both of which can fuel neurons as energy substrates, via processes that are coupled with neuronal excitation [3]. Accumulating evidence supporting the actions of exogenous lactate and BHB as signal molecules that induce BDNF converge in this intracerebral metabolic compartment between neurons and astrocytes, where astrocyte-derived lactate and BHB support neuronal function in terms of both energy metabolism and synaptic plasticity [3].
Physical activity, brain (neurons and glial cells), muscle, liver, and BDNF: hypothetical model 2. BDNF, brain-derived neurotrophic factor; MCT2, monocarboxylate transporter 2 (expressed on neurons), MCT4, monocarboxylate transporter 4 (expressed on astroglia).
Physical activity is known to elevate lactate levels in the blood [13, 14]. Since physical activities are beneficial for the maintenance of both mental and physical health, an exploration of the mechanisms by which physical exercise improves neuronal function is an important target. Energetically, human brain function is solely dependent on the oxidative metabolism of glucose [4, 5]. Glucose is continuously supplied by the blood stream, since virtually no glucose storage exists in the brain. Besides the brain, only the testis is known to rely on glucose as an energy substrate [4, 5].
Glucose in the blood is taken up by glucose transporter 1 (Glut1) in the endothelium of brain microvessels [3, 4, 5, 17]. In addition to this glucose transporter, MCTs expressed in the brain microvessels allow lactate and ketone bodies (especially BHB) to cross the blood–brain barrier (BBB) [3, 4, 5, 17]. Neural cells (neurons and glia) are thus able to take up glucose, lactate, and BHB via glucose transporters or MCTs (Figure 2) [17]. Once lactate or BHB is transported into the brain cells, they enter the TCA cycle to act as energy substrates, similar to glucose (Figure 3). Although neither lactate nor BHB is an efficient energy substrate because of the slow transportation kinetics of MCTs, elevations in their blood concentrations allow them to act as energy sources supplied externally from the brain [3, 4, 5]. The concentrations of both lactate and BHB do, indeed, increase after physical exercise [28, 29]. The sources of the elevated lactate and BHB levels in the blood after physical activity are the skeletal muscles and liver, respectively [3, 4, 5]. Under starvation and insulin-resistance in diabetic patients, glucose availability in the peripheral tissue is limited, and BHB can fuel brain function in the place of glucose.
In addition to their roles as energy substrates, both lactate and BHB can improve brain function through synaptic plasticity. Ample evidence supports BDNF being a key molecule in the induction of neuronal plasticity [8, 9]. BDNF is a member of the neurotrophin family and is produced in neurons as well as glial cells [8, 9]. BDNF promotes neurite outgrowth, facilitates synaptic transmission, and regenerates the neuronal network. Recent evidence suggests that both lactate and BHB, which are produced outside the brain during physical exercise, act as signal molecules in the brain after crossing the BBB [13, 14, 15, 16]. Lactate induces BDNF expression, and this action of lactate is dependent on the activation of Sirtuin1 deacetylase. Silent information regulator 1 (SIRT1) increases the levels of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the secreted molecule fibronectin type III domain-containing protein 5 (FNDC5), which are known to mediate BDNF expression [13, 14]. In contrast, BHB induces BDNF expression by acting as a direct Class I histone deacetylase (HDAC) inhibitor. By inhibiting HDAC2 and HDAC3 and by preventing their recruitment to BDNF promoter I, BHB induces BDNF expression [15, 16].
In addition to skeletal muscles, numerous cells in the body generate lactate. Especially under a hypoxic/anoxic state, virtually all cell types generate lactate through glycolysis, since the further oxidation of lactate in the mitochondrial TCA cycle is inhibited because of oxygen unavailability [3, 4, 5]. Importantly, even under a sufficient supply of oxygen, lactate production can occur (aerobic glycolysis). Although brain function is dependent on the complete oxidation of glucose, cellular differences in the cell types should be noted. In fact, astroglia seem to be more glycolysis-dependent, compared with neurons (Figure 5) [3, 23]. Astroglia exhibit normal mitochondrial function and are capable of oxidizing glucose as well as lactate/pyruvate in mitochondria (Figures 6–8), albeit lactate/pyruvate does not seem to be an ideal substrate [3, 23].
Glucose consumption and lactate production measured directly in culture medium for rat astroglia and neurons (adapted from [
Competition assay 1: [14C]glucose oxidation is inhibited by lactate by approximately half in neurons but not in astroglia (adapted from [
Competition assay 2: [14C]lactate oxidation is somewhat inhibited by glucose in neurons but is markedly inhibited in astroglia (adapted from [
Competition assay 3: [1-14C]pyruvate oxidation is somewhat inhibited by glucose in neurons.
Astroglial endfeet envelope brain microvessels as well as synapses (Figure 9) [30, 31, 32]. This anatomical location of astroglia seems to be suitable for the direct uptake of glucose from the microvessels [3]. Glucose is metabolized glycolytically in the astroglial cytosol, generating lactate/pyruvate (Figure 9). In contrast to neurons, however, ATP consumption by astroglia is much smaller than that by neurons, since astroglia do not generate action potentials. In fact, approximately one half of the total neuronal ATP consumption reflects Na+,K+-ATPase activity, which restores and maintains the ionic gradient across the cell membrane to maintain the generation of action potentials [4, 5]. Astroglial Na+,K+-ATPase also plays a role in maintaining the ionic gradient, and this helps astroglia to take up glutamate released into the synaptic cleft (Figure 9) [3, 18, 33]. Glutamate is the most widely distributed excitatory transmitter, and primary motor neurons in the motor cortex release glutamate, which in turn activates secondary motor neurons in the spinal cord to induce muscle contraction. Whether glutamate re-uptake stimulates astroglial CMRglc and CMRoxy remains controversial [3, 18, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53]. In an in vitro culture model, at least, the application of glutamate increased glucose consumption (Figure 10) as well as lactate production (Figure 11), suggesting the activation of glycolysis in an CMRoxy-independent manner [3, 18, 33].
Astrocyte-neuron lactate shuttle hypothesis (ANLSH) (adapted from [
Glutamate stimulates [14C]deoxyglucose phosphorylation through a Na+-dependent glutamate transporter in rat cultured astroglia (adapted from [
Effects of L-glutamate on lactate release measured directly in culture medium for rat astroglia (adapted from [
Classically, cultured astroglia prepared from rats or mice have been used to assess the metabolic properties of astroglia in vitro [3]. Basal glucose consumption by cultured rodent astroglia seems to be comparable to that by cultured rodent neurons. Interestingly, however, the amount of lactate that is released into the culture media is much higher in astroglial cultures than in neuronal cultures (Figure 5) [3, 23], suggesting the occurrence of active aerobic glycolysis in astroglia. Although the glucose consumption of astroglia seems to be comparable to that of neurons, the in vivo location of astroglia in the brain may make glucose uptake more suitable [30, 31, 32]. In contrast, neurons are not in direct contact with microvessels. Therefore, avid glucose uptake by cultured neurons may not reflect glucose metabolism in vivo. Of course, glucose supplied from the microvessels diffuses into the extracellular space and can be taken up by neurons via their glucose transporters (Glut 3) (Figure 9) [3, 17]. In addition to glucose, lactate generated by astroglia and released into the extracellular space can also be taken up by neurons via neuronal MCT2 (Figure 9) [3, 17]. When both glucose and lactate are available, cultured neurons metabolize lactate preferentially (Figures 6 and 7) [3, 23].
Neuronal activation causes glutamate release in the synaptic cleft. The maximal concentration of glutamate can reach 1 mM, which is toxic to neurons. To prevent glutamate toxicity, the end-feet of astroglia, which envelope the synapse (tripartite synapse) [32], remove glutamate via glutamate transporters together with the co-transportation of Na+ based on an inwardly lower Na+-gradient across the membrane [3, 16, 33]. This inwardly lower ionic concentration gradient is maintained by Na+,K+-ATPase; thus, ATP production requires glucose as an energy substrate. So far, cultured astroglia typically show high glucose utilization and lactate production, and these profiles are exaggerated by the addition of glutamate. Recently, we evaluated astroglia that had differentiated from human induced-pluripotent stem (iPS) cells and observed the conservation of similar metabolic profiles [54]. These results suggest that glutamate uptake enhances the consumption of glycolysis-derived ATP. Of note, glutamate in astroglia is converted into glutamine and recycled back to neurons (glutamate-glutamine cycle) (Figure 5) [3]. In addition, some of this glutamate is converted to alfa-ketoglutarate and utilized as a TCA cycle substrate (Figure 12) [3, 4, 5]. The capacity for glutamate oxidation is greater in astroglia than in neurons (Figure 13) [unpublished data]. Moreover, recent findings suggest that malate, an intermediate TCA metabolite, contributes to lactate production through its conversion into lactate via malic enzyme (Figure 14) [3].
Glutamate taken up by Na+-dependent glutamate transporters enhances astroglial energy metabolism (both glycolytic and/or oxidative) (adapted from [
[1-14C]glutamate oxidation (CO2 production from glutamate) in astroglia and neurons.
Glutamate taken up by Na+-dependent glutamate transporters enhances lactate production through a glycolytic pathway as well as through malic enzyme activation in astroglia (adapted from [
Whether lactate produced and released from astroglia can be used as an energy substrate by neurons has long been debated [36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53]. Theoretically, MCT4 in astroglia export lactate outside such cells, and MCT2 in neurons take up lactate [3, 17]. Once lactate enters a neuron, it could become a preferential energy substrate, compared with glucose; this pathway is known as the astrocyte-neuron lactate shuttle model (Figure 5) [3, 33]. In our in vitro culture model, increasing the concentrations of lactate enhanced the neuronal oxidation of lactate (Figure 15) [23]. The argument against this model is based on the high affinity of MCT2, which results in the rapid saturation of lactate transportation into neurons [52, 53]. Thus, astroglial lactate production does not favor neuronal lactate utilization. The validity of this model should be elucidated in vivo.
Increasing lactate concentrations (1–3 mM) enhance [14C]lactate oxidation in cultured neurons (adapted from [
Lactate plays a role as a signal molecule. BDNF expression can also be induced by lactate through the activation of Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC-1α and the secreted molecule FNDC5, known to mediate BDNF expression [13, 14]. Moreover, hydroxycarboxylic acid receptor 1 (HCAR1) has been found to act as a lactate receptor that results in the suppression of neuronal activity [55, 56, 57]. Lauritzen et al. showed that HCAR1 at the BBB was essential for mediating the effects of exercise on angiogenesis in a mouse model [56]. Furthermore, lactate binding to HCAR1 on neurons inhibits adenylate cyclase and thus decreases cAMP, thereby reducing neuronal activity and gene regulation. The potential negative modulation of BDNF production by lactate through HCAR1 should be examined more closely in the future.
In addition to BHB, acetoacetate and acetone are listed as ketone bodies. During starvation, ketone body production by hepatocytes in the liver is enhanced [3, 4, 5]. Astroglia in the brain function similar to hepatocytes and generate more ketone bodies than neurons (Figure 16) [3, 25]. The production of BHB is regulated by the AMP/ATP level, or the cellular energy state. AMP-activated protein kinase (AMPK) can sense a decrease in ATP and the resultant increase in AMP, which induces the activation of AMPK. Decreased malonyl-CoA stimulates the beta-oxidation of long-chain fatty acids, enhancing the production of acetoacetate and BHB. 5-Amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR), an activator of AMPK, stimulates these two ketone bodies in astroglia (Figure 17) [3, 25]. Similar to lactate, BHB is exported via MCT4 and is then imported into neurons through MCT2 and used as an alternative energy substrate [3, 17]. Unlike glucose-derived lactate, which needs to be converted to acetyl-CoA by PDHC to enter the TCA cycle, BHB enters the TCA cycle in an PDHC-independent manner. PDHC is susceptible to cellular stressors like reactive oxygen species (ROSs). Enhanced lactate production under brain ischemia triggers the accumulation of lactate. Unfortunately, however, re-perfusion therapy might not be helpful when PDHC is damaged, since lactate is incapable of being utilized even in the presence of re-supplied oxygen (Figure 18). In contrast, neurons can utilize BHB instead of lactate, and ATP production can be restored after re-oxygenation (Figure 18) [3, 25].
[1-14C]palmitic acid (PA) derived-CO2 and acid-soluble fractions (ketone bodies: KBs) in rat neurons and astroglia (adapted from [
Ketogenesis by astroglia and neurons by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AMPK (500 μM) (adapted from [
Effects of 1% hypoxia (24 h) on oxidative metabolism of lactate (LAC), pyruvate (PYR), or β-hydroxybutyrate (BHB) in neurons (adapted from [
Vigorous physical exercise induces BHB production by the liver, but astroglial BHB production under similar conditions has not been confirmed. Liver-derived BHB acts as a direct Class I HDAC inhibitor. By inhibiting HDAC2 and HDAC3 and preventing their recruitment to the BDNF promoter I, BHB induces BDNF expression [15, 16]. As described above, ischemic insults do, indeed, activate astroglial BHB production. Therefore, BHB-induced BDNF may help neuronal regeneration after ischemic damage. Further study is warranted. BHB released from astroglia also acts as a ligand of hydroxycarboxylic acid receptor 2 (HCAR2) and exerts neuroprotective effects by activating HCAR2, which in turn promotes the downstream activation of silent information regulator 1 (SIRT1) and inhibits nuclear factor-kappa B (NFκB) to protect against oxidative stress [58, 59, 60, 61].
In terms of functional recovery, both the neuronal structure and myelination are essential [3, 7]. As for the energy supply, the white matter axons of neurons are myelinated by oligodendrocytes. The astroglial end-feet are in direct contact with neurons only at Ranvier nodes, implying that neither glucose nor lactate can reach neurons easily. In fact, axonal metabolic demand is fulfilled by lactate supplied by oligodendrocytes. How lactate is generated by oligodendrocytes remains to be elucidated. Since astroglial end-feet are suitable for the uptake of glucose from microvessels, lactate generated in astroglia could be transported to oligodendrocytes; alternatively, a pathway involving the direct uptake of glucose by oligodendrocytes could be involved. Importantly, myelin damage (demyelination) can occur in various neurological disorders, while the remyelinating capacity can potentially restore damaged myelin (remyelination). Myelin cholesterol synthesis is essential for such a process, and BHB could be a possible substrate [62, 63, 64, 65]. Moreover, BDNF reportedly facilitates myelination [66].
Brain function is dependent on glucose, which is supplied from outside the brain as food. The unavailability of glucose forces the brain to utilize ketone bodies, especially BHB. In addition to glucose and BHB, lactate is another possible energy source for the brain. Physical exercise enhances the production of both lactate and BHB. The former is generated in skeletal muscles, while the latter is generated in liver hepatocytes. Interestingly, astroglia can generate both lactate and BHB inside the brain upon neuronal excitation. Astroglia-derived lactate and BHB can serve as alternative energy substrates, since physical activities are initiated by neuronal excitation, which cause astroglia to generate lactate and BHB inside the brain. Irrespective of the origins of lactate and BHB, both can be transported into neurons and simulate BDNF production, facilitating neurotransmission and synaptic plasticity. Thus, physical activity helps the human brain to function in a healthy manner through a metabolic compartment composed of glial cells, skeletal muscles, and liver.
The author thanks the Departments of Neurology and Physiology, Keio University School of Medicine, for their support. This work was supported in part by JSPS KAKENHI Grant Number 19 K08002 and 17 K09762.
The author declares no conflicts of interest.
AICAR | 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide |
AMPK | AMP-activated protein kinase |
BHB | beta-hydroxybutyrate |
BBB | blood–brain barrier |
BDNF | brain-derived neurotrophic factor |
CBF | cerebral blood flow |
CMRglc | cerebral metabolic rate of glucose |
CMRoxy | cerebral metabolic rate of oxygen |
FNDC5 | fibronectin type III domain-containing protein 5 |
Glut1 | glucose transporter 1 |
Glut3 | glucose transporter 3 |
HDAC | histone deacetylase |
HCAR1 | ydroxycarboxylic acid receptor 1 |
HCAR2 | hydroxycarboxylic acid receptor 2 |
iPS cell | induced-pluripotent stem cell |
MCTs | monocarboxylate transporters |
NFκB | nuclear factor-kappa B |
PGC-1α | peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PDHC | pyruvate dehydrogenase complex |
ROSs | reactive oxygen species |
SIRT1 | silent information regulator 1 |
TCA | tricarboxylic acid |
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\n\nCustomers have the right to terminate the contract without giving any reason (written notice of termination). The deadline for said termination is fourteen (14) days from the date of receipt of goods. Returns are at the expense of the Customer and must be made within the fourteen (14) days from the date of the written notice of termination. Intech Limited will process refunds to the Customer without undue delay.
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This chapter outlines some of the potential solutions to the issues that are identified.",book:{id:"7927",slug:"selected-topics-in-child-and-adolescent-mental-health",title:"Selected Topics in Child and Adolescent Mental Health",fullTitle:"Selected Topics in Child and Adolescent Mental Health"},signatures:"Jonathan Glazzard and Samuel Stones",authors:[{id:"294281",title:"Prof.",name:"Jonathan",middleName:null,surname:"Glazzard",slug:"jonathan-glazzard",fullName:"Jonathan Glazzard"},{id:"309587",title:"Mr.",name:"Samuel",middleName:"Oliver James",surname:"Stones",slug:"samuel-stones",fullName:"Samuel Stones"}]},{id:"57269",doi:"10.5772/intechopen.71265",title:"Enhancing Young Children’s Access to Early Childhood Education and Care in Tanzania",slug:"enhancing-young-children-s-access-to-early-childhood-education-and-care-in-tanzania",totalDownloads:1494,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter draws on the current situation of limited access of young children to early childhood education and care (ECEC) settings in Tanzania. It offers information and evidence on early childhood education and care (ECEC) from an international perspective to those who are, directly or indirectly, involved with young children and their families. Basically, early childhood education and care in Tanzania is still unsatisfactory. Many children have no access to early childhood settings for various reasons including: lack of parents’ awareness on the importance of early investment in education, lack of support from the government, low socio-economic status of parents, gender discrimination, and traditional norms and cultural values. To improve the situation, there is need for a forging of partnership between the government, parents, and the community. Government policy-makers have to set clear policies regarding how quality early childhood education and care can be equitably funded and conducted throughout the country.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ignasia Mligo",authors:[{id:"212055",title:"Dr.",name:"Ignasia",middleName:null,surname:"Mligo",slug:"ignasia-mligo",fullName:"Ignasia Mligo"}]},{id:"57391",doi:"10.5772/intechopen.71287",title:"Influence of Parental Divorce on Anxiety Level of Adolescents",slug:"influence-of-parental-divorce-on-anxiety-level-of-adolescents",totalDownloads:1897,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Family divorce might have an effect on some aspects of child development. Adolescence as a transitional stage is marked by process of seeking identity, the need for intimate relationship, as well as the struggle for psychological independence from family. Anxiety is defined as a state of extreme worry, fear, and uncertainty which results from the expectation of a threatening event or situation. The aims of study are: to explore the differences in anxiety levels among adolescents from divorced and intact families; to explore the level of anxiety of adolescents from divorced and intact families with respect to their genders. A demographic questionnaire was created and The Beck Anxiety Inventory was applied to measure anxiety. The scale was applied with 162 participants who were chosen randomly from 5 different high schools in Istanbul province. The study found out that there are statistically significant differences in anxiety level of adolescents between children from divorced and intact families. Descriptive measures are in range as follows: (17.67 ± 9.645). The adolescents from divorced families had a higher level of anxiety (t = 17.322; p < .05). The result related to the second study aim shows that there are no statistically significant differences in anxiety between male and female adolescents from divorced and intact families (p > .05).",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Senija Tahirović and Gokce Demir",authors:[{id:"214445",title:"Dr.",name:"Senija",middleName:null,surname:"Tahirovic",slug:"senija-tahirovic",fullName:"Senija Tahirovic"},{id:"214465",title:"MSc.",name:"Gokce",middleName:null,surname:"Demir",slug:"gokce-demir",fullName:"Gokce Demir"}]},{id:"57686",doi:"10.5772/intechopen.71672",title:"Children and Young People’s Vulnerabilities to Grooming",slug:"children-and-young-people-s-vulnerabilities-to-grooming",totalDownloads:2237,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Child abuse is evolving, pervasive and complex and children are vulnerable to its widespread reach in many aspects of their lives, from face-to-face interactions to those they have online. This chapter aims to review contemporary literature which outlines the vulnerabilities of children to face-to-face and online grooming as part of a process leading to child abuse and exploitation. The chapter will undertake a review of literature on two aspects of grooming: child sexual exploitation (CSE) and radicalisation. It will draw on contemporary case examples to illustrate grooming drawn from UK Serious Case Reviews (SCR) on CSE and, on radicalisation, the case of the three girls from Bethnal Green who were groomed for travel to Syria. It will then reflect on the push and pull factors of grooming to highlight the similarities between CSE and radicalisation. Moving on, the chapter will then consider how and if interactive social media simulations, linked to an innovative, preventative educational approach and designed with reference to Vygotsky’s social construction theory, have the potential to educate young people to help protect them from being groomed. The chapter will then make reference to the findings of a small pilot study which evaluated the use of this approach with young people.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jane Reeves, Emma Soutar, Sally Green and Tracy Crowther",authors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"},{id:"211838",title:"Dr.",name:"Tracy",middleName:null,surname:"Crowther",slug:"tracy-crowther",fullName:"Tracy Crowther"},{id:"211839",title:"Mrs.",name:"Emma",middleName:null,surname:"Soutar",slug:"emma-soutar",fullName:"Emma Soutar"},{id:"211840",title:"Mrs.",name:"Sally",middleName:null,surname:"Green",slug:"sally-green",fullName:"Sally Green"}]}],mostDownloadedChaptersLast30Days:[{id:"57686",title:"Children and Young People’s Vulnerabilities to Grooming",slug:"children-and-young-people-s-vulnerabilities-to-grooming",totalDownloads:2237,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Child abuse is evolving, pervasive and complex and children are vulnerable to its widespread reach in many aspects of their lives, from face-to-face interactions to those they have online. This chapter aims to review contemporary literature which outlines the vulnerabilities of children to face-to-face and online grooming as part of a process leading to child abuse and exploitation. The chapter will undertake a review of literature on two aspects of grooming: child sexual exploitation (CSE) and radicalisation. It will draw on contemporary case examples to illustrate grooming drawn from UK Serious Case Reviews (SCR) on CSE and, on radicalisation, the case of the three girls from Bethnal Green who were groomed for travel to Syria. It will then reflect on the push and pull factors of grooming to highlight the similarities between CSE and radicalisation. Moving on, the chapter will then consider how and if interactive social media simulations, linked to an innovative, preventative educational approach and designed with reference to Vygotsky’s social construction theory, have the potential to educate young people to help protect them from being groomed. The chapter will then make reference to the findings of a small pilot study which evaluated the use of this approach with young people.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jane Reeves, Emma Soutar, Sally Green and Tracy Crowther",authors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"},{id:"211838",title:"Dr.",name:"Tracy",middleName:null,surname:"Crowther",slug:"tracy-crowther",fullName:"Tracy Crowther"},{id:"211839",title:"Mrs.",name:"Emma",middleName:null,surname:"Soutar",slug:"emma-soutar",fullName:"Emma Soutar"},{id:"211840",title:"Mrs.",name:"Sally",middleName:null,surname:"Green",slug:"sally-green",fullName:"Sally Green"}]},{id:"68639",title:"Social Media and Young People’s Mental Health",slug:"social-media-and-young-people-s-mental-health",totalDownloads:2107,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Evidence suggests that social media can impact detrimentally on children and young people’s mental health. At the same time, social media use can be beneficial and have positive effects. This chapter outlines the detrimental and positive effects of social media use for young people. Schools play a critical role in educating young people about how to use social media safely and responsibly. However, schools cannot address all the issues and parents, social media and advertising companies also have a responsibility to protect children and young people from harm. This chapter outlines some of the potential solutions to the issues that are identified.",book:{id:"7927",slug:"selected-topics-in-child-and-adolescent-mental-health",title:"Selected Topics in Child and Adolescent Mental Health",fullTitle:"Selected Topics in Child and Adolescent Mental Health"},signatures:"Jonathan Glazzard and Samuel Stones",authors:[{id:"294281",title:"Prof.",name:"Jonathan",middleName:null,surname:"Glazzard",slug:"jonathan-glazzard",fullName:"Jonathan Glazzard"},{id:"309587",title:"Mr.",name:"Samuel",middleName:"Oliver James",surname:"Stones",slug:"samuel-stones",fullName:"Samuel Stones"}]},{id:"57391",title:"Influence of Parental Divorce on Anxiety Level of Adolescents",slug:"influence-of-parental-divorce-on-anxiety-level-of-adolescents",totalDownloads:1897,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Family divorce might have an effect on some aspects of child development. Adolescence as a transitional stage is marked by process of seeking identity, the need for intimate relationship, as well as the struggle for psychological independence from family. Anxiety is defined as a state of extreme worry, fear, and uncertainty which results from the expectation of a threatening event or situation. The aims of study are: to explore the differences in anxiety levels among adolescents from divorced and intact families; to explore the level of anxiety of adolescents from divorced and intact families with respect to their genders. A demographic questionnaire was created and The Beck Anxiety Inventory was applied to measure anxiety. The scale was applied with 162 participants who were chosen randomly from 5 different high schools in Istanbul province. The study found out that there are statistically significant differences in anxiety level of adolescents between children from divorced and intact families. Descriptive measures are in range as follows: (17.67 ± 9.645). The adolescents from divorced families had a higher level of anxiety (t = 17.322; p < .05). The result related to the second study aim shows that there are no statistically significant differences in anxiety between male and female adolescents from divorced and intact families (p > .05).",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Senija Tahirović and Gokce Demir",authors:[{id:"214445",title:"Dr.",name:"Senija",middleName:null,surname:"Tahirovic",slug:"senija-tahirovic",fullName:"Senija Tahirovic"},{id:"214465",title:"MSc.",name:"Gokce",middleName:null,surname:"Demir",slug:"gokce-demir",fullName:"Gokce Demir"}]},{id:"57167",title:"The Early Childhood Educators’ Attitudes Towards Innovative Instructional Applications about Digital Learning Activities for Young Children",slug:"the-early-childhood-educators-attitudes-towards-innovative-instructional-applications-about-digital-",totalDownloads:1197,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The innovative value and practices of digital learning activities assist early childhood educators in employing effective instruction to improve young children’s performance as well as advance their own professional autonomy to implement digital learning activities for young children. This study examined the factors and relationships about early childhood educators’ attitudes towards the integration and behavioral intention of digital learning tools into young children’s innovative pedagogical activities using a questionnaire survey. The questionnaire consisted of five factors, including digital innovative value (DIV), digital innovative practices (DIP), perception of instructional use (PIU), instructional professional autonomy (IPA), and behavioral intention to use (BIU). The researcher used structural equation modeling to analyze the survey data. The results showed that early childhood educators’ perceptions about innovative value and applications of digital learning activities play a key role in the success of young children’s performance and competence in preschool. The early childhood educators with positive attitudes towards the innovative consideration and practical instructional applications of digital learning activities had more behavioral intention to plan and design instructional activities with innovative applications of digital learning tools.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ru-Si Chen",authors:[{id:"211677",title:"Prof.",name:"Ru-Si",middleName:null,surname:"Chen",slug:"ru-si-chen",fullName:"Ru-Si Chen"}]},{id:"57680",title:"Thinking and Learning Demands in Contemporary Childhood",slug:"thinking-and-learning-demands-in-contemporary-childhood",totalDownloads:1477,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Is today’s childhood is the same as the past’s? Frankly speaking, we cannot answer this question as a clear yes. It is obvious that children today are more into tablet computers, social networks and online games than traditional child games. Besides, our communication styles have been changed significantly for the past years. We, no longer need to meet others face to face to ask for help or to chat. Artificial intelligence, machine learning and robots are another story of the contemporary world. Robots capable of perceiving their surroundings and making decisions have started to deprive many people of their jobs. But what kind of jobs will human beings perform? The increasing emphasis on innovation, cooperation, critical thinking, being creative, problem solving, communication skills and project management is an indicator of what kind of a business world will today’s children meet in the future. This on-going trend also includes clues about how should children be educated. This study is focusing on thinking and learning demands expected contemporary children to meet. Throughout the chapter, the changing world was depicted briefly and then demands of the contemporary age on critical thinking, creative thinking, problem solving and learning were explored respectively.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Cenk Akbiyik",authors:[{id:"212205",title:"Associate Prof.",name:"Cenk",middleName:null,surname:"Akbiyik",slug:"cenk-akbiyik",fullName:"Cenk Akbiyik"}]}],onlineFirstChaptersFilter:{topicId:"1390",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"June 11th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,annualVolume:11418,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,annualVolume:11419,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",fullName:"Abdulsamed Kükürt",profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",institutionString:null,institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}},{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/318510",hash:"",query:{},params:{id:"318510"},fullPath:"/profiles/318510",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)}()