Antioxidant, chemical structure, antioxidant activity, and sources.
\r\n\tRecent advances regarding pathogenesis, cardiovascular risk assessment, prediction of damage, and recent advances in treatment, including tolerogenic and biological agents, are welcome to be included in this book. Relevant contributions regarding standard therapies and their optimal use, as well as the role of new therapeutic options, either in combination with previous agents or alone are of interest.
",isbn:"978-1-80356-348-0",printIsbn:"978-1-80356-347-3",pdfIsbn:"978-1-80356-349-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"7005f26b225e5923d4ce4cd7c52f6fe9",bookSignature:"M.D. Sophia Lionaki and Dr. Minas Karagiannis",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11726.jpg",keywords:"Epidemiology, Genetics, Clinical Picture, Physical Examination, Pathogenesis, Histopathology, Nomenclature, Clinical Syndromes, Clinical Picture, Evaluation, Pregnancy Planning, Risk Assessment",numberOfDownloads:20,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 17th 2022",dateEndSecondStepPublish:"March 17th 2022",dateEndThirdStepPublish:"May 16th 2022",dateEndFourthStepPublish:"August 4th 2022",dateEndFifthStepPublish:"October 3rd 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"5 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"A researcher devoted to clinical research related to autoimmune diseases of the kidney and especially ANCA vasculitis and lupus nephritis. Dr. Lionaki obtained her MD from the National and Kapodistrian University of Athens and has a Ph.D. degree in \"Membranous Nephropathy”. She is an expert in the field of 'Glomerular Diseases' as a result of a fellowship for more than 2 years at the Nephrology Department of the University of North Carolina, at Chapel Hill in the USA.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"213115",title:"M.D.",name:"Sophia",middleName:null,surname:"Lionaki",slug:"sophia-lionaki",fullName:"Sophia Lionaki",profilePictureURL:"https://mts.intechopen.com/storage/users/213115/images/system/213115.png",biography:"Sophia Lionaki, MD, PhD is an Assistant Professor In Nephrology in the National and Kapodistrian University of Athens, Greece. She obtained her MD from National and Kapodistrian University of Athens, Greece in 1996 and has a Ph.D degree on \"Membranous Nephropathy”. She is an expert in the field of 'Glomerular Diseases' as a result of a fellowship for more than 2 years at the Nephrology Department of the University of North Carolina, at Chapel Hill in USA under the mentorship of Professors Ronald J. Falk and J.Charles Jennette. \nHer research interests include: ANCA vasculitis and glomerulonephritis, lupus nephritis, primary glomerulonephritides, immunology of the kidney.",institutionString:"National and Kapodistrian University of Athens",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"National and Kapodistrian University of Athens",institutionURL:null,country:{name:"Greece"}}}],coeditorOne:{id:"451879",title:"Dr.",name:"Minas",middleName:null,surname:"Karagiannis",slug:"minas-karagiannis",fullName:"Minas Karagiannis",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:"National and Kapodistrian University of Athens",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National and Kapodistrian University of Athens",institutionURL:null,country:{name:"Greece"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:[{id:"82979",title:"Lupus Genetics",slug:"lupus-genetics",totalDownloads:3,totalCrossrefCites:0,authors:[null]},{id:"82899",title:"Anti-Non-Bilayer Phospholipid Arrangement Antibodies Trigger an Autoimmune Disease Similar to Systemic Lupus Erythematosus in Mice",slug:"anti-non-bilayer-phospholipid-arrangement-antibodies-trigger-an-autoimmune-disease-similar-to-system",totalDownloads:9,totalCrossrefCites:0,authors:[null]},{id:"82748",title:"Recent Advances in SLE Treatment Including Biologic Therapies",slug:"recent-advances-in-sle-treatment-including-biologic-therapies",totalDownloads:8,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444316",firstName:"Blanka",lastName:"Gugic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/444316/images/20016_n.jpg",email:"blanka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Deficiency of THs has serious issues on the development on all types of tissues including brain leading to severe thyroid disorders and as a result imposes overall metabolic malfunctioning of all system organs. Endemic goiter was probably first described with cretinism by Paracelsus (1493 -1541) and by other physicians of the Alps and Central Europe. However, the relationship between cretinism and involvement of thyroid gland was lacking over centuries. Thyroid gland was literally described by Wharton in 1656. Since then the progress of research on thyroid gland gained attention particularly for its most observed pleiotypic action in number of species from aquatic animals to humans. Developments of new scientific technologies and the progress in the area of molecular biology from time to time are continually changing our concepts of the regulation of the functions of THs at the subcellular level [1,2].
Immunocytochemical localization studies revealed that TH receptors (TR) in adult vertebrates are highly concentrated within choroids plexus, dentate gyrus, hippocampus, amygdaloid complex, pyriform cortex, granular layer of cerebellum, mammillary bodies and medial geniculate bodies. Although specific nuclear receptors for THs in adult brain have been identified, their functions are unclear about target gene expression. Imunohistochemical mapping further documented that locus coeruleus norepinephrine stimulates active conversion of L-tetraiodothyronine (L-T4) to L-triiodothyronine (L-T3). A morphologic linking between central thyronergic and noradrenergic systems has been established. This changes in TH ontogeny gradually started drawing attention that possible TH action in mature brain switches its role which may be different from its classical action mediated through nuclear receptors. As the brain approaches adulthood, nuclear levels of iodothyronines decline gradually reaching a plateau and maintain it, and the TH levels increase within nerve terminals of adult vertebrates [1]. In particular, it showed decrease in nuclear L-T3 receptor binding in adult brain compared to developing brain. These switching differences in TH ontogeny between developing and adult vertebrate brain has gradually interested investigators to search for new functional role and mechanism of action of TH. Nevertheless, the action of THs remained limitedly judged in mature mammalian central nervous system (CNS) [3,4].
Recent research highlights about the nonconventional nongenomic action of THs and its metabolites. Adult mammalian CNS is of specific interest. Clinical observations specifically have shown that the adult-onset thyroid disorders lead to several neuropsychological diseases including but not limited to anxiety, depression, mood disorders etc. in humans. These complications can be improved with appropriate adjustment of circulatory THs [5-8]. However, the defined mechanism to explain this is inadequate. The involvement of TH nuclear receptors in ameliorating these neuropsychiatric dysfunctions in mature CNS is controversial. Current knowledge about the TH-responsive gene expression in adult mammalian CNS is largely unavailable except some few discrete reports with differential effects in certain brain areas. Indication of new rapid nongenomic effects of THs and its metabolites, within seconds to minutes, poses special significance.
The interest about the action of TH in brain originated because like the classical neurotransmitters, catecholamines, THs are also derived from the amino acid, tyrosine. Tyrosine is decarboxylased by specific aromatic amino acid decarboxylase to produce catecholamines. There are possibilities that THs can also undergo decarboxylation and form biogenic amine-like neuroactive compounds, such as thyronamines or iodothyronamines as hypothesized. However recent experiment challenges this initial hypothesis since aromatic amino acid decarboxylase failed to produce this and thus presence of TH specific decarboxylase is speculated [9]. For example, L-T4 and L-T3 can be decarboxylated to produce L-T4-amine and L-T3-amine respectively (Figure 1). L-T3-amine can further be deiodinated to form L-T2-amine and then further deiodination can generate L-T1-amine. Important deaminated metabolites of L-T4 and L-T3 are tetraiodothyroacetic acid (TETRAC) and triiodothyroacetic acid (TRIAC) respectively [9,10]. Thyronamines may have neurotransmitter-like actions. However, no evidence is present to-date to identify physiologic formation of thyronamines that describe their physiologic functions, except one new report which identified 3-iodo-thyronamine in adult brain including other tissue homogenates in sub-picomolar concentrations [10]. Few pharmacologic actions for these synthetically prepared iodothyronamines are known in other tissues. This theory of action of thyroid hormones could be like classical neurotransmission led to search for the nongenomic mechanism of action of THs.
Thus, besides the genomic concepts, a parallel idea of nongenomic of TH action was emerging with demonstration of direct plasma membrane-TH interaction and expression of some hormonal effects in a variety of cells. These studies include activation on Ca2+-ATPase
Thyroid hormones and their deaminated and decarboxylated products of interest.
in red blood cells, acetylcholinesterase in neuronal plasma membrane, inhibition of synaptosomal membrane Na+-K+-ATPase (NKA), rapid action of L-T3 on synaptosomal Ca2+-influx, identification of specific L-T3-binding sites in rat thymocyte membrane, synaptosomal membrane, depolarization of actin filaments in cultured astrocytes by TH, and changes in second messengers and their corresponding regulatory systems following TH treatment [1,11,12].
Selective uptakes of THs have also been documented within the nerve terminals. Intravenous administration of [125I]-L-T4 in rats followed by thaw mount autoradiography has described selective distribution of L-T4 in specific adult rat brain areas particularly within the nerve terminals. Within the nerve terminal this was concentrated as L-T3 [10]. Other reports about the transportation of TH in adult brain also indicated role of transthyretin as a major serum binding protein for TH required for its transportation in cerebrospinal fluids and ultimately enable crossing of TH of the blood brain barrier directing to the brain. A role of monocarboxylate anion transporter protein-8 (MCT-8) also has been found to play a major role in TH transportation across the plasma membrane [10]. Three important enzymes called monodeiodinase are involved in TH metabolism. These are 5’-deiodinase type I (D-I), 5’-deiodinase type II (D-II) and 5’-deiodinase type III (D-III). D-I and D-II catalyzes conversion of the L-T4 to L-T3. D-I is the major deiodinating enzyme in the peripheral tissues. In brain D-II is predominantly localized in glial cells, astrocytes, and in the tanycytes lining the lower part of the third ventricles. D-III catalyzes the conversion of L-T3 to L-T2. Concentration of L-T3 within the nervous system has been attributed to the brain D-II which has major functions in regulating the overall neuronal homeostasis for TH. Expression of D-II in nervous tissue is implicated in the neuronal uptake of the circulatory L-T4 and its conversion to L-T3 followed by its supply to the neuronal targets. Expression of D-II is an important protective mechanism against hypothyroidism. This prevalence of TH homeostasis is a preventive measure and thought to be neuroprotective [1,13-16].
Interest also materializes to explore further the nongenomic mechanism of action of THs in adult mammalian CNS. In this context TH-mediated signal transduction pathways are also being investigated. Particularly the regulation of the activation of the second messenger systems and subsequent protein phosphorylation are of much awareness. Understanding of the mechanism of action of TH in adult mammalian brain has key implications in the higher mental functions, learning and memory, and in the regulation of several neuropsychiatric disorders developed during adult-onset thyroid dysfunctions in humans.
The major goal of this article is to search, discuss and review the nongenomic rapid actions of THs in mature mammalian CNS. This article aims to begin with observations describing subcellular distribution, and concentrations of THs within the brain and its biochemical and physiologic consequences, specific binding of THs onto the neuronal plasma membrane to examine for specific plasma membrane receptors of THs and correlate the receptor-binding followed by a specific cellular function. Next, the molecular basis of the TH and plasma membrane receptor interaction-mediated signals are evaluated via possible activation of G-protein signaling pathway, second messenger systems, and subsequent target protein phosphorylation.
Thyroid hormones exercise a nongenomic action on the adult mammalian brain possibly by binding to neuronal membrane receptors followed by activation of second messenger cascade systems leading to substrate level protein phosphorylation and dephosphorylation by protein kinases and protein phosphatases (Figure 2).
Author’s experiments and results reported in this manuscript are obtained from the purified synaptosomes prepared from young adult rat brain cerebral cortex. Synaptosomes are subcellular nucleus-free preparation purified through density gradient centrifugation [17]. The question may arise why synaptosome? Synapses are the ultimate routes of communications in neurons where electrical impulses are normally translated to chemical signals from one neuron to the other leading to subsequent biochemical and physiologic events. This preparation is a fragment of neurons containing the neuronal membrane,
Hypothesis: Proposed nongenomic action of thyroid hormones in adult mammalian brain.
a) A typical neuron. (b) Cartoon of a neuron showing synaptosome. (c) Scanning electron microscopic image of synaptosome.
Synaptic vesicles, and the other intracellular components (Figure 3). Synaptosomes can be considered as isolated nerve terminals. Synaptosomes are obtained after homogenization and fractionation of nerve tissue. The fractionation step involves several centrifugations steps to separate various organelles from the synaptosomes. Synaptosomes are formed from the phospholipid layer of the cell membrane and synaptic proteins such as receptors. Synaptosomes are frequently used to study synaptic signal transduction pathways because they contain almost the entire molecular machinery necessary known for the uptake, storage, release of neurotransmitters, receptor properties, and enzyme actions etc.
As the brain approaches adulthood, nuclear iodothyronine concentrations gradually decreases reaching a plateau and maintains it, and the TH levels increase within nerve terminals of adult vertebrates [1,18-21]. It also demonstrated decrease in L-T3-binding in adult brain compared to developing brain.
Although, evidence of transportation 125I-L-T3 and 125I-L-T4 within the nerve terminal was demonstrated following intravenous injection in adult rat brain [10,18,19,22], its euthyroid concentrations and subcellular distribution was never been evaluated until recently [13,23]. Intravenous administration of [125I]-L-T4 in rats followed by thaw mount autoradiography showed distribution of L-T4 in selective areas of adult brain in a saturable manner. Gradually L-T4 was concentrated more within nerve terminals fractions, where L-T4 was monodeiodinated to produce L-T3, the active form of TH [10]. L-T4 and L-T3 transportation within neurons are shown to occur by two different mechanisms. L-T3 is actively taken up in a saturable manner, while L-T4 transportation occurs by diffusion and in a non-saturable way. L-T4-transporation within the neuron is dependent upon L-T4-concentration gradient between extracellular and intracellular compartments and is maintained by high deiodination rate of L-T4 to L-T3 [24]. Role of transthyretin has also been described as a major binding protein in cerebrospinal fluid. Transthyretin has been implicated to facilitate L-T4 transportation across the blood-brain-barrier and finally into the brain. Recently MCT-8 has been ascribed to be the most effective TH transporter [25]. These MCT-8 are 12 transmembrane spanning proteins, and in particular plays a major role for very specific transportation of L-T3 within the neurons followed by the active conversion of the prohormone L-T4 to L-T3 by the D-II within the CNS [26]. D-II is essentially important for the conversion of the prohormone L-T4 into the active L-T3 within the CNS. However, understandings of the levels of THs within the neurons are imperative. This information is crucial to explore the role of L-T3 in neural signal transmission in mature brain. To help meet this requirement the following study was performed to quantify and compare the levels of THs in adult rat brain cerebral cortex.
While serm levels of L-T4 (~ 41 ng/ml) and L-T3 (~ 0.7 ng/ml) were found consistent with the normal peripheral results, this assay system could not detect L-T4 in either synaptosomal or non-synaptic mitochondrial fractions. However, the L-T3 levels in synaptosomes (0.45±0.06 ng/mg synaptosomal protein), and non-synaptic mitochondria (1.44±0.12 ng/mg mitochondrial protein) were significant. The levels of L-T3 in non-synaptic mitochondria were ~3.2-fold higher compared to synaptosomal values in cerebral cortices [13,16]. The finding of undetectable levels of synaptosomal L-T4 was consistent with other studies [14,27,28]. A higher fractional rate of D-II activity that converts L-T4 to L-T3 is attributed [29,30].
This study quantifies the TH concentrations from adult rat brain synaptosomal and non-synaptic mitochondria. Although L-T4 levels could not be detected in synaptosomal and non-synaptic mitochondrial fractions, fair amounts of L-T3 were detected in these fractions purified from adult rat brain cerebral cortex [13,16]. Undetectable levels of synaptosomal L-T4 levels were also supported within synaptosomal fractions obtained from adult rat brain [27].
Despite very low levels of TH in hypothyroid condition as determined by serum levels of TH, previous report has shown that L-T3 production in brain is pretty high in stress situations like hypothyroidism [13]. D-II has also been shown to be activated in other stressful conditions and indicated to have a protective role in stressed brain [31]. Stimulated levels of D-II have been described during hypothyroidism. This supports the first initial report [13] of elevation of brain L-T3 levels during n-propylthiouracil (PTU)-induced hypothyroid conditions [14,15,32]. In brain, approximately 80% of the L-T3 is produced locally from L-T4 by D-II. The fractional rate of conversion of L-T4 to L-T3 is remarkably high in brain [29]. This might be a possible reason for undetectable L-T4 levels due to rapid conversion of L-T4 to L-T3 in these fractions. To detect the endogenous TH levels the subcellular fractions were ruptured hypo-osmotically. The use of 8-anilinonaphtho-sulfonic acid in the radioimmunoassay medium excluded the possibility of the non-detectable protein bound form of the hormone by releasing the endogenously bound form of the hormones [13].
Comparatively higher levels of L-T3 in the mitochondria may have implications on the mitochondrial bioenergetics such as, cellular oxygen consumption, oxidative phosphorylation and ATP synthesis, mitochondrial gene expression. These are few of the major regulatory functions of TH. THs also have been shown to affect mitochondrial genome mediated through imported isoforms of nuclear TH receptors and influence various mitochondrial transcription factors [3,33]. Concentration and localization of radiolabeled L-T3 within the nerve terminal was the first landmark research described in adult rat brain. This further followed with the immunohistochemical mapping demonstrating locus ceruleus norepinephrine stimulating active conversion of L-T4 to L-T3. This established a morphologic co-localization of central thyronergic and noradrenergic systems. Overall TH levels within different compartment of brain may have discrete, differential and potential regulatory function for neurotransmission in adult mammalian brain [10].
Synaptosomal levels of L-T3 were also studied in different thyroidal conditions. Serum levels of L-T3 and L-T4 confirmed establishment of peripheral hypothyroidism induced by 14 days of intra-peritoneal (i. p.) injections of PTU (2 mg/g BW). However, surprisingly hypothyroid rat brain showed ~9.5-fold higher amount of L-T3 (126 nM) in synaptosomes compared to euthyroid control values. A single i. p. injection of L-T3 (2 μg/g BW) to the hypothyroid rats decreased the synaptosomal levels of L-T3 by ~1.6-fold compared to the hypothyroid rats and was still ~6-fold higher than the euthyroid value. An increase in ~2.5-fold of the L-T3 levels was noticed in euthyroid plus L-T3 (2 μg/g BW) group (Figure 4) [13]. Although the levels of L-T3 in whole rat brain homogenate was found to be in low nanomolar ranges [22], two concurrent reports estimated synaptosomal levels of L-T3 to be ~14.6 nM [23], and ~13 nM [13] in adult rat brain synaptosomes. Observation of high levels of synaptosomal L-T3 were also supportive [15] in hypothyroid rat cerebral cortex by ~1.7-fold compared to the control values maximally at day 4 of induction of hypothyroidism while the serum levels of L-T3 remained at the hypothyroid levels.
Hypothyroid condition shows an appreciable decline in both serum L-T4 and L-T3 level in rats in a usual way as found by other investigators [34]. Although it has been shown earlier that in hypothyroid condition, the whole brain, or different regions of the brain, maintain similar levels of L-T3 compared to the euthyroid control rats through increased activity of D-II, and corresponding high fractional rate of L-T4 to L-T3 conversion [35,36], insufficient evidence is available except for a few recent reports to quantitate the synaptosomal concentration of thyroid hormones. Approximately 8-fold higher concentration of L-T3 has been found in synaptosome compared to the whole brain in euthyroid rats. Our observation of approximately 9.5-fold higher L-T3 content in synaptosome of hypothyroid rats compared to the euthyroid controls may be the result of a higher fractional rate of L-T3 production by increased activity of D-II, and a correspondingly higher selective uptake and concentration of L-T3 molecules in the synaptosomes to cope up with the physiological need of THs in this tissue at this condition [13,23,37,38].
L-T3 levels in rat cerebrocortical synaptosomes in various thyroid states. (Ref. Sarkar and Ray 1994, Neuropsychopharmacology 11: 151-155 acknowledged [
In euthyroid rat brain, selective uptake of 125I-L-T3 and its concentration in synaptosomal compartment have been demonstrated [10]. In addition, the use of hypothyroid animals only after 14 days of PTU treatment, where some adaptive mechanisms still unknown in nature prevail, do not reach the equilibrium as compared to the animals kept in chronic hypothyroid condition for a much longer duration as used by other workers. This may be one of the reasons for maintaining a high level of synaptosomal L-T3 in our hypothyroid rats. Expression of the data in different forms such as per gram organ (brain) basis, or per mg compartmental (synaptosomal) protein basis, as presented in our experiment, also becomes an additive factor for discrepancies among different groups of workers regarding the quantitative aspects of L-T3 or L-T4 in the brain [23,34,38,39]. The fall in L-T3 concentration in synaptosomes prepared from L-T3-treated hypothyroid rat cerebral cortex may be the result of inhibition of D-II activity after 24 hours of the L-T3 administration, in the presence of the considerable amount of exogenous L-T3. An inhibition in the activity of D-II has been noticed within 4 hours of L-T3 treatment to the thyroidectomized rats. A rise in the synaptosomal L-T3 level in the hypothyroid rats, and a fall in the same in the L-T3-treated hypothyroid animals after 24 hours of L-T3-treatment, also reflects the tendency for a compensatory regulatory mechanism of thyroid hormone metabolism in the adult rat brain in altered thyroid conditions, although the nature of the mechanism remains unknown. L-T3-treated control rats have shown higher levels of synaptosomal L-T3, compared to the control values. This may be a result of the extra L-T3 transport influenced by a high dose of exogenously administered L-T3 (2 μg/g) [18,19,24].
Observation of undetected levels of L-T4 within cerebrocortical synaptosomes may reflect a state of rapid conversion of L-T4 to L-T3 in the brain by D-II enzyme. Other researchers have already shown that after intravenous administration of radiolabeled L-T4 and L-T3, the hormone is concentrated as L-T3 in a synaptosomal fraction of the whole rat brain, and L-T4 to L-T3 conversion occurs very rapidly within the nerve cells. L-T3 formed in the neuronal cell body then may be translocated down the axon to the synaptic ends. Saturable and nonsaturable uptake of L-T3 and L-T4 in isolated synaptosomes in an
The prediction of a role of D-II as suggested [13] is further supported by few other studies [15,31]. Increased D-II activity is suggested in hypothyroid brain. This is attributed to the maintenance of normal brain concentrations of L-T3 even under low peripheral levels of L-T4 [31]. The high level of L-T3 as observed by us is supported and suggested for maintenance of brain homeostasis. This demonstrated onset of a central homeostasis for THs in adult hypothyroid brain between the 1st and 2nd day, its maintenance for about 16-18 days and thereafter declined between the 18-20th day [15]. This report also confirms and confers higher activity of D-II (~ 1.6-fold higher compared to control) within the cerebrocortical synaptosomal fraction during short-term brain-hypothyroidsm. It is described as a protective mechanism of brain by raising the brain L-T3 levels. Another study also documents an increase in D-II activity within various brain regions and decrease in D-III activity, except in cerebrellum and medulla where specific D-III activity remained undetected [40]. However, controversially, although these investigation did observe higher D-II activity within various areas of adult brain during hypothyroidism, the changes in L-T3 levels remained lower than normal values as was noticed in case of serum levels of hypothyroidism. This investigation could not explain this high D-II activity and lower L-T3 levels in brain regions. The levels of THs measured in this study also were shown to be lower than found by other investigators. Some assay in brain regions was also performed in tissue homogenates instead of particular subcellular fractions. Possibly differences in the concentrations of THs could be due to a different method of severe extraction procedure employed to extract brain tissue THs resulting in loss of it.
The data emerged from our study reveal the quantitative aspects of involvement of L-T3 in synaptosomes in different thyroid states, and favors its role in neuronal functions as formerly described [10,41]. A stimulation of synthesis of synapsin-1 protein (related to neurotransmission) by L-T3 in the developing brain has been reported [42]. Although, the synaptosomal L-T3 levels varied widely with different treatments, our result illustrates a unique, but unknown regulatory mechanism of the TH metabolism in the mature mammalian brain.
Subsequently the idea of concentration, distribution and metabolism of THs within the mature brain generated interest to search for potential role of TH and its nongenomic interaction, if any, with neuronal plasma membrane. TH is well known for its regulation of energy metabolism in developing tissues including brain. However, adult brain has not shown this effect on energy metabolism under the influence of TH until recently. Maintenance of ionic gradients by plasma membrane Na+-K+-ATPase (NKA) is one of the important cellular events by which TH regulate energy metabolism. NKA is an ion pump responsible for maintaining Na+ and K+ ion gradients across the cellular plasma membrane in eukaryotic cells. The Na+ and K+ ion gradients are important for establishment of resting membrane potentials as well as for transport of certain molecules. NKA has special significance in maintaining membrane potentials in neurons. Inhibition of NKA has been shown to release acetylcholine [43] and norepinephrine [44] from rat cortical synaptosomes, presumably as a result of depolarizing effects of lowered K+ gradients. The level of NKA activity could therefore have consequence for the regulation of the neurotransmitter release and uptake across the synaptic membrane [43].
A dose-dependent inhibition of synaptosomal NKA activity by L-T3 both in
The presence of high affinity low capacity nuclear TH receptors in adult rat brain has been reported. Further evidence shows selective uptake of [125I]-L-T3 and rapid conversion of L-T4 to L-T3 in synaptosomal fraction of adult rat brain. Specific [125I]-L-T3 binding sites have also been demonstrated in the synaptosomes of adult rat brain [47] and chick embryo [48]. However, no functional relationship could be established due to the interaction of TH and its membrane receptor so far in adult brain.
Scatchard plot analysis demonstrated two sets of specific L-T3 binding sites: one with high affinity (Kd1: 12 pM; Bmax1: 3.73±0.07 fmols/mg protein), and the other with low affinity (Kd2: 1.4±0.05 nM; Bmax2: 349±7 fmols/mg protein). Kd represents dissociation constant. Bmax represents maximum binding capacity. Rationale between gradual L-T3 binding and the corresponding dose-dependent L-T3-induced inhibition of synaptosomal NKA was established
The relative order of potencies of binding affinities for the synaptosomal L-T3 binding sites and relative inhibition of NKA activity in the presence of different L-T3 analogues were as follows: L-T3>L-T3-amine>L-T4=L-TRIAC>r-T3>L-T2, and L-T3>L-T3-amine>L-T4>L-TRIAC>r-T3>L-T2, respectively. The concentrations of TH analogues required to displace 50% specific binding (ED50 value) of 125I-L-T3 to its synaptosomal binding sites were 10-, 63-, 63-, 1000- and 6250 nM, respectively. This study showed the nature of inhibition of synaptosomal NKA activity as a function of L-T3 occupancy of synaptosomal receptor sites in mature rat brain [46].
This investigation demonstrates a novel action of TH in mature rat brain. This is the first report presenting a relationship between the inhibitions of synaptosomal NKA as a functional effect of L-T3 binding to its synaptosomal receptor in the cerebral cortex of adult rat. Occupancy of specific high affinity L-T3 binding sites demonstrated a concentration-dependent inhibition of the NKA activity with a maximum of 59%. At 1x10–10 M L-T3 concentration the enzyme inhibition was ~35% and the saturation of the L-T3 binding sites was ~74%. This appears to be physiological. Further inhibition of NKA activity as found with higher concentrations of L-T3 (5x10–10 – 1x10–7 M), corresponds to the increase in the occupancy of the L-T3 binding sites (maximum of ~80%) at the low affinity binding range. However, this site was not saturated by 15.4 μM L-T3 used for determining non-specific binding. Hence, it is possible that this low affinity binding is due to non-specific effects of several other proteins located in synaptosomes. The relationship between the binding of L-T3 to its synaptosomal binding sites and the concentration dependent inhibition of the enzyme activity appears to hold good only with the occupancy of high affinity sites up to 5 x 10–10 M L-T3 [46]. Synaptosomes prepared from chick embryo cortex were also reported to have two sets of L-T3 binding sites [48]. Their properties and ontogeny showed a marked difference from those of nuclear receptors. Even though NKA activity was suppressed beyond the saturating concentration of L-T3 at high affinity binding sites, this may be non-specific and non-physiological. The relative order of binding affinities for TH analogues to the L-T3 binding sites and the inhibitory potencies for NKA activity were also correlated in the synaptosomes. L-T3-amine was used to examine its potency to inhibit specific [125I]-L-T3 binding in synaptosomes with the idea that it may be a decarboxylated product of L-T3 and may have actions like L-T3. The ED50 value for L-T3-amine was determined as 10 nM. At this dose, L-T3-amine also inhibited the synaptosomal NKA activity by ~51% compared with L-T3. This result is also in good agreement with earlier studies, in which L-T3-amine was shown to be ~71% as effective as L-T3 in stimulating Ca2+-ATPase activity at a dose of 10 nM in human RBC [49]. In earlier studies, L-T3-induced increase in NKA activity in the developing brain [50] and kidney cortex [51] of rat was reported to be due to an increase in the mRNA levels of α, α+ and β-subunits of the enzyme, while the NKA in adult was not responsive to L-T3. However, a dose-dependent inhibition and regulation of synaptosomal NKA activity in different
In conclusion this study demonstrates, for the first time, a correlation between the binding of TH to its putative receptors and inhibition of NKA activity in the synaptosomes of adult rat brain [46]. This may have implications in the involvement of thyroid hormone on important mental functions in adult mammalian brain.
The evidence of L-T3-synaptosomal membrane interaction in association with the inhibition of the synaptosomal membrane NKA activity led us to search for if the L-T3-induced action is mediated via activation or regulation of the second messenger cascade systems. Besides the cyclic nucleotide cyclase systems calcium (Ca2+) also plays an important role in cellular signal transmission. Ca2+-influx is a major event in neurotransmission. Keeping such visions we further intended to explore the role of Ca2+ in L-T3-induction.
Metabotropic events are often initiated at the membrane level, mediated and amplified through G-protein coupled receptors (GPCR) and/or ion channels followed by activation of second messenger system and subsequent substrate protein phosphorylation. Ca2+-influx is an important physiological function in brain, following which cascades of membrane events occur finally leading to neurosignaling. Disruption in this crucial membrane phenomenon may lead to variety of Ca2+-dependent neuropsychological disorders. Although TH-mediated Ca2+ entry in adult rat brain synaptosomes [54,55], and in hypothyroid mouse cerebral cortex [56] have been reported, it’s synaptic functions in adult neurons in dysthyroidism is unclear. Keeping in mind the role of Ca2+ ions as a messenger in the signaling pathway the effect of L-T3 on intracellular Ca2+-influx,
Effect of L-T3 on intrasynaptosomal Ca2+-concentration in euthyroid and PTU-induced hypothyroid rat cerebral cortex
Our study demonstrates a regulation and homeostatic mechanism of Ca2+ accumulation within cerebrocortical synaptosomes of hypothyroid adult rat [57]. Application of brain physiologic concentrations of L-T3 (0.001 nM to 10 nM),
Present study validates the role of Ca2+ ions under the influence of L-T3 in the synaptosomes from adult rat brain cerebral cortex. L-T3-induced dose-dependent Ca2+-entry both in euthyroid and PTU-induced hypothyroid rat brain synaptosomes at low L-T3 doses (0.001 nM to 10 nM). This evidence indicates role of Ca2+ as a second messenger in synaptic functions. L-T3 also has been documented to increase 45Ca uptake and Ca2+-influx in adult euthyroid rat synaptosomes, and in hypothyroid mouse cortex. An enhancement of nitric oxide synthase (NOS) activity in adult rat cerebrocortical synaptosomes was shown [55]. This present study demonstrated a significant increase in Ca2+ accumulation in hypothyroid rat brain cerebrocortical synaptosomes compared to euthyroid control at below (0.1 nM) and at about brain physiologic concentrations (10 nM) of L-T3. At present clear understanding for the L-T3-induced release of intracellular calcium is not known; however possibility for L-T3-induced action in neuronal cells cannot be left out. Use of sodium azide blocked any mitochondrial accumulation of calcium. Our earlier studies have shown that 10 nM and 100 nM dose of L-T3 could saturate the specific synaptosomal L-T3-binding sites by ~69% and ~74% respectively. L-T3-mediated physiological increase in synaptosomal Ca2+ accumulation could be attributed to receptor-mediated physiological response having its maximal effect at 10 nM dose of L-T3. The differences in the observation of increased rate of Ca2+ accumulation in hypothyroid synaptosomes compared to the euthyroid values reflected an adaptive mechanism. This could be credited to homeostatic mechanism to overcome PTU-induced stress conditions persisted in the adult neuron. High intrasynaptosomal L-T3 level (~9.5-fold higher; 2.56 ng/mg synaptosomal protein
The important functional role of Ca2+ and several calcium-dependent proteins in neuronal signal transduction are well recognized. Ca2+ has been shown to inhibit neuronal NKA activity. Ca2+-influx also lead to Ca2+-dependent activation of protein kinase C and/or Ca2+/CaM-dependent protein kinases followed by direct or indirect activation of phosphorylation of several target proteins. This indicated a rapid nongenomic action of L-T3.
G proteins are GTP-binding proteins that couple activation of seven-helix receptors by neurotransmitters at the cell surface for the activation of the effector enzymes-adenylate cyclase (AC) or guanylate cyclase (GC), which synthesize the corresponding cyclic nucleotides, cAMP or cGMP respectively and regulate protein kinases., such as protein kinase A (PKA), protein kinase C (PKC) etc. Metabotropic events are often initiated at the membrane level, mediated and amplified through GPCR followed by activation of second messenger system and subsequent substrate protein phosphorylation. Phospholipase C (PLC), another effector enzyme, generates inositol triphosphate (IP3) and diacylglycerol (DAG), the latter of which releases intracellular stores of calcium. The cAMP, cGMP, Ca2+, DAG and IP3 act as second messengers and activate protein kinases with broad substrate specificity. The kinases phosphorylate key intracellular proteins, including ion channels, enzymes, and transcription factors which modulate cellular biological processes [58,59]. Guanine nucleotides are known to have dual effects on most hormone-sensitive AC systems. This modulates activation of AC and binding of hormone to receptor. In neuronal membranes guanylate nucleotides has been shown to be required for the stimulation of AC. However, no modulation of TH binding at appropriate guanylate nucleotide concentrations has been reported. It is well established that cholera toxin enhances the activity of Gsα (stimulatory G protein α-subunit) by ADP-ribosylating Gsα subunit and inhibiting GTPase activity associated with the protein. This increases cAMP production.
The activity of NKA is regulated by various catecholamines [45,46,60] as well as by L-T3 [45,46]. Inhibition of NKA has been demonstrated in intact cell preparations by phorbol esters, dibutyryl cAMP, and phospho-DRPP-32 (dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kD), a protein phosphatase inhibitor [61-63].
Some information focuses to effect of TH or its metabolites on noradrenergic like responses. This idea develops since TH has possibility to produce a family of biogenic amine-like neurotransmitter compounds catalyzed by aromatic amino acid decarboxylase, such as iodothyronamines. Physiologic identification of these family of TH-derived iodothyronamines have not yet been discovered until recently in rat brain and in rat and human blood. These two compounds are monoiodothyronamine and thyronamine [10]. Thinking this could be a possibility before this identification of monoiodothyronamine and thyronamine were reported we studied the effect of L-T3 on synaptosomal NKA activity using various β- and α-adrenergic agonists and antagonists known to regulate Gs and Gi proteins of the neuronal signal transduction system,
Our studies showed that although both L-T3 and isoproterenol (β-adrenergic receptor [ADR] agonist and activator of Gs-protein) similarly inhibited synaptosomal NKA activity, propranolol (β-ADR antagonist) could only block the effect of isoproterenol, but not the effect of L-T3. Instead propranolol produced a dose-dependent potentiation of the inhibitory influence of L-T3 (Figure 6). The augmentation of L-T3-effect by propranolol appeared to be a type of synergistic action and it might be due to some changes in the pre-synaptic membrane properties, the mechanism of which is unclear at present. However, clonidine (α2-ADR agonist, and Gi-protein activator) (Figure 7) and glutamate (acts through metabotropic glutamate receptors and activator of Gi protein) (Figure 8) attenuated L-T3-effect, suggesting its possible coupling with GPCR. Equimolar concentration of clonidine (1 nM – 100 nM) counteracted the inhibitory effect of L-T3 on the NKA activity (Figure 7). This counteraction by clonidine, α2-ADR agonist, appears to be mediated through the inhibition of adenylate cyclase activity with the activation of inhibitory G protein (Gi) followed by inhibition of cAMP synthesis and protein phosphorylation cascade mechanism. It is known that α2-adrenergic receptor agonist system act through Gi protein activation [64].
Thus it seems that the L-T3 action could be ascribed more to stimulate Gs protein during beta-blockade which might be directed to manage this adverse condition. The results also suggest that the L-T3-effect on the synaptosomal NKA activity was not mediated via the β-ADR-dependent systems, since it was not blocked by propranolol. Based on these results it was also hypothesized that L-T3-effect would alter adenylate cyclase activity. In cultured neuroblastoma plasma membrane increased adenylate cyclase activity was noticed followed by L-T3-treatment [65]. In fact, later, increased adenylate cyclase activity was noticed in brain hypothyroid condition which increases brain L-T3 levels. This observation was correlated well with increased D-II activity to the increased brain L-T3 levels in brain hypothyroid situations [15]. Guanosine 5\'-O-(3-thiotriphosphate) or pertussis toxin also has been reported to inhibit TH-induced mitogen-activated protein kinase (MAPK) phosphorylation nongenomically in 293T cells which is consistent with a cell membrane mechanism mediated via a G-protein [66]. 3-iodothyronine (T1AM), an endogenous and rapid-acting derivative of TH, is associated with Gs-protein coupled-trace amine receptor TAR1 in HEK cells. However, no modulation of TH binding at appropriate guanylate nucleotide concentrations in adult brain has been reported [67]. Determination of whether activation or inactivation of a specific type(s) of G-protein influences TH-effects on protein phosphorylation is crucial.
Attenuation of L-T3-effect on synaptosomal NKA activity by glutamate,
A diverse nongenomic effect of TH has been observed in non-neural tissues including liver, heart, adipocytes, and blood [12,68]. Some possible nongenomic actions of THs include modulation of GABA uptake, regulation of NKA activity and increase of presynaptic Ca2+-influx. In synaptoneurosomes TH inhibits the stimulation of chloride flux by GABA [69]. L-T4 has been shown to stimulate the MAPK pathway in a variety of cultured cell lines including HeLa and CV-1 cells which lack functional nuclear TH receptors [66,70-73], consistent with a cell membrane mediated mechanism via G-proteins. L-T4 and L-T3 were found to inhibit Go-protein activities in synaptosomes from developing chick brain [48].
Direct interactions of G protein subunits with Ca2+-channels are not well documented. However, increased evidences showed receptor activated G proteins modulate activities of ion channels by membrane-confined mechanisms [74]. Isoproterenol induced phosphorylation of ventricular Ca2+-channels via PKA has been reported [75]. Gs protein also has been shown to regulate Ca2+-channels both in a cAMP-independent membrane-confined mechanism [74] and in a cAMP-dependent phosphorylation of one of the subunits of L-type Ca2+-channel [76]. Synaptosomal NKA has previously been described to be inhibited by cAMP in a dose-dependent manner suggesting a role of PKA. The activated form of this protein kinase was further phosphorylated a substrate protein which in turn depressed the total Na+-dependent phosphorylation of the synaptosomal NKA [77]. Overall, our data indirectly support the involvement of second messenger system (cAMP and/or Ca2+) mediated through G protein activation after specific L-T3-membrane receptor interaction. The membrane NKA has been implicated in several aspects of physiologic processes including its role in neurotransmitter release [43].
Protein phosphorylation and dephosphorylation are now recognized to be major regulatory mechanisms by which neural activities are controlled by external physiological signals or stimuli. Several nongenomic mechanisms are coordinated by rapid post-transcriptional modifications, such as protein phosphorylation and dephosphorylation reactions, which act like a molecular switch to control intracellular signaling mechanisms. Abnormalities of these imperative regulatory signaling processes produce deleterious effects on the CNS. As a consequence, variety in unusual protein phosphorylation is the end result of many major neuropshychological dysfunctions leading to diseases [78]. Numerous second messenger molecules regulate cellular physiology by effects on protein kinases and phosphatases. Protein kinases catalyze the transfer of the terminal γ-phosphate group of ATP or GTP to the hydroxyl group of serine, threonine or tyrosine in substrate proteins. Their structure, subcellular localization and substrate specificity allow them to control cellular physiology. These proteins largely make up the cell signaling pathways that transmit, amplify and integrate signals from the extracellular environment. Protein phosphorylation promotes enzyme activation or deactivation. Phosphorylated proteins are substrates for protein phosphatases and dephosphorylation occur to serve as a molecular switch to fine tune a cellular response [79].
Variety of agents regulating the activity of NKA raises the possibility of the NKA as a substrate molecule that is subject to regulation by phosphorylation or dephosphorylation. Indeed, inhibition of NKA is associated with the phosphorylation of the enzyme by both PKA and PKC. This inhibition of NKA has been attributed to the phosphorylation of α1-subunit of the NKA molecule at serine residues by PKA and PKC site-specifically. Isoproterenol (β-adrenergic agonist that activates adenylate cyclase to produce cAMP, an activator of PKA), forskolin (adenylate cyclase activator), and okadaic acid (an inhibitor of protein phosphatase-1 and -2A) have been reported to increase significantly the level of phosphorylation of wild-type α1-subunit of the NKA in COS cells, accompanied by a significant inhibition of the enzyme activity [62,63]. Among nine distinct isoforms of adenylate cyclase (AC), three isoforms are Ca2+/calmodulin-dependent, including type I-AC, III-AC [80,81], and VIII-AC. The Ca2+/calmodulin-dependent AC is an integral membrane protein [82]. Hence, one possible role of Ca2+/calmodulin may be to stimulate Ca2+/calmodulin-dependent AC followed by cAMP production and phosphorylation of the NKA, exactly as β-adrenergic receptor agonists do.
While a direct effect of TH on protein kinase activity has not been formerly studied in tissues from mature brain, hypothyroidism has been linked with reduced levels of phosphorylated MAPK in the hippocampus [83]. Based on these observations, possibility of a metabotropic pathway for rapid actions of TH on protein phosphorylation in synaptosomes from adult rat brain was investigated.
Representative autoradiogram of SDS-PAGE separation of proteins incorporating 32P in the presence of L-T3. Lanes were loaded with synaptosomal lysates which had been preincubated at 0°C for 60 min and 37°C for 5 min with (from left): 1mM Na3VO4 (V), 1, 3, 10, 30, 100, 300, 1000, or 0 (C = control) nM L-T3 and then incubated with 20μM of [γ-32P]-ATP (3 μCi) for 1 min at 37°C. Left panel (a): Silver-stained gel for visualization of protein bands. Right panel (b): Autoradiogram of same gel showing increased incorporation of 32P in four prominent bands (α: 38±1 kD, β: 53±1 kD, γ: 63±1 kD, δ: 113±1 kD). (c) Normalized data showing effect of
Our observation demonstrated that TH induces rapid changes in synaptosomal protein phosphorylation. Incubation with L-T3 or L-T4 specifically showed significant biphasic dose-dependent effects on the phosphorylation of 38±1, 53±1, 62±1, and 113±1 kD proteins.
Our next interest was to see which amino acids present in these phosphoyraled proteins are targets. Hence phospho-specifc antibodies for tyrosine and serine were used in western bolt analysis. Immunoblot analysis of synaptosomal lysates incubated with L-T3 (1 nM-1 μM) confirmed phosphorylation at the seryl residues of a ~112 kD protein and phosphorylation at tyrosyl residues of a distinct ~ 95 kD protein. These data support that THs have a diversity of rapid nongenomic pathways for regulation of protein phosphorylation in mature mammalian brain [11]. Especially, the α-subunit of NKA is a ~112 kD membrane protein. Indeed, inhibition of NKA is associated with the phosphorylation of its subunits by both PKA and PKC. This inhibition of NKA has been attributed to the site-specific phosphorylation of the α1-subunit of the NKA at seryl residues by PKA and PKC [61-63]. In adult rat alveolar epithelial cell L-T3 induced translocation of NKA to plasma membrane. NKA stimulation by L-T3 was assigned to L-T3-induced stimulation of PI3K/PKB pathway via the Src family of tyrosine kinases nongenomically [84]. These data suggest possible involvement of membrane components in TH-induced protein phosphorylation.
Examples of nongenomic control of protein phosphorylation by L-T3 also have been reported in few other tissues. Nongenomic relationship of MAPK and MAPK-mediated protein phosphorylation at the seryl residue of nuclear TH receptor has been described in 293T cells [68]. This indicated a control of nongenomic mechanism on genomic mechanism. In developing brain, inhibition of PKA transcriptionally blocked L-T3-induced actin gene expression, whereas PKC and tyrosine kinase did not influence it significantly [85].
In other studies, L-T3 induction has also been shown to nongenomically regulate Ca2+ influx and nitric oxide synthase activity within seconds in adult rat brain [57]. Thus, THs are likely to have numerous rapid nongenomic effects on signaling mechanisms in neural tissue, including alterations in the levels of intracellular second messengers (cAMP and Ca2+) which regulate cAMP- and/or Ca2+/calmodulin (CaM)-dependent protein kinases leading to protein phosphorylation. Effects of TH on Ca2+-dependent activation of PKC and/or Ca2+/CaM-dependent protein kinases are also possible, followed by direct or indirect activation of phosphorylation of the proteins. Thus further investigation demonstrated for the first time the rapid nongenomic second messenger mediated regulation of protein phosphorylation by TH in mature mammalian brain and provided additional support for the contention that TH has a unique and complex signaling function in adult brain [12].
Many nongenomic mechanisms are modulated by phosphorylation–dephosphorylation of substrate proteins. Multiple Ca2+/calmodulin (CaM)-dependent protein kinases (CaM kinases) and Ca2+/phospholipid-dependent protein kinases (PKCs) have been identified in brain. Among these, CaMPK-II is the most abundant Ca2+/CaM-stimulated protein kinase in brain. CaMPK-II is important in several neuronal functions, including neurotransmitter release and the modulation of the functional properties of ion channels and receptors. CaMPK-II is differentially expressed in different brain regions of cells, exists in both cytosolic and membrane-associated forms and is especially concentrated in the postsynaptic density and synaptic vesicles. A distinct property of CaMPK-II is that autophosphorylation of its threonine residue near the calmodulin binding domain converts it to a Ca2+-independent state. Further, it has been shown that calmodulin-dependent autophosphorylation of CaMPK-II induces a conformational changes in the region of the calmodulin binding domain that allows additional stabilizing interactions with calmodulin. This autophosphorylation may involve in extending the effects triggered by a transient calcium signal. PTU-induced mild hypothyroidism in chick brain during posthatch development has been shown to increase the level of Ca2+/CaM-stimulated phosphorylation in cytosol, but lower it in the membrane, indicating a role of thyroid hormones in distributing CaMPK-II during developmental changes [78,86].
5.4.1.1.1. Effect of L-T3 on total protein phosphorylation
The effect of Ca2+ and calmodulin on TH-induced total protein phosphorylation and their regulation was explored. L-T3 significantly and dose-dependently (10 nM-1 μM) increased total 32P- incorporation into synaptosomal proteins,
Physiological concentrations L-T3 in nerve terminals are difficult to measure. Predictable levels of L-T3 within the nerve terminals range from ~10 nM to 64 nM. PTU-induced peripheral hypothyroidism in adult rats showed endogenous synaptosomal level of L-T3 is about ~126 nM. Thus L-T3 (1 µM) is well above this range, and would be considered to have a more pharmacological type of action on 32P- incorporation to synaptosomal phosphoproteins. Treatment with agents regulating Ca2+ could be a potential strategy for enhancing clinical treatment of conditions, such as certain affective disorders, which may be responsive to pharmacological doses of TH. In an earlier
Numerous phosphoproteins are greatly influenced by PKA and PKC in a Ca2+- and/or CaM-dependent way. Often Ca2+ also functions in combination with CaM or with phosphoinositides/diacylglycerol to induce additional signal transduction pathways within the synaptic network. Regulation of intracellular Ca2+, CaM and subsequent protein phosphorylation are important for brain and cognitive functions affected by various psychiatric disorders. Membrane depolarization-induced Ca2+-influx activates extracellularly regulated kinases/MAPK in a Ca2+/CaM-dependent way in PC12 cells. THs also promote MAPK-mediated serine phosphorylation of the nuclear TH receptor β-1 isoform nongenomically in 293T cells. Ca2+ and CaM also differentially regulate of TH-induced neuronal protein phosphorylation [12,87].
5.4.1.1.2. L-T3-induced stimulation of phosphorylation of 63- and 53 kD proteins was regulated by Ca2+ and calmodulin
After getting an idea of L-T3-induced total protein phosphorylation within neuronal membrane it was an obvious interest to look for specific proteins phosphorylated under the influence of L-T3.
A. L-T3-stimulated phosphorylation of 63- and 53 kDa proteins are regulated by Ca2+/CaM-dependent protein kinase II. (a) Representative autoradiogram of the 63- and 53 KD proteins followed by various treatment conditions as described. (b) Corresponding protein bands from silver stained gel used for normalization of the data and demonstrates comparable equal amounts of sample loading. B. The quantification of the L-T3 (10 nM)-induced phosphorylation presented as a graph of ratio of the band densities of the phosphorylated proteins in the autoradiogram (a) and the corresponding protein in the silver stained gel (b) at different treatment conditions as indicated. * represents the level of significance of P<0.05 compared to the corresponding basal level (control). The data presented are normalized results (mean ± S.E.M.) for an indicated protein band (Ref. Sarkar 2008 Life Sciences 82: 920-927 acknowledged [
5.4.1.1.3. Inert action of Ca2+ and calmodulin on the independent effect of L-T3 on the phosphorylation of 38- and 23 kD proteins
L-T3 also increased the phosphorylation of 23- and 38 kD proteins. The effect was independent of EGTA or KN62. L-T3 only slightly enhanced the phosphorylation of the 38 kD protein (p<0.05, F = 3.74) by ~1.2-fold in the presence of Ca2+/CaM compared to Ca2+/CaM control group. Although addition of Ca2+ decreased the level of L-T3-induced phosphorylation of 38 kD protein (P = non-significant), it was significantly increased (P<0.05) in the presence of CaM compared to Ca2+ + L-T3 treatment and only L-T3 effect. However, the presence of Ca2+ or the Ca2+/CaM did not further affect the phosphorylation status of the 38 kD protein. This further suggested no involvement of Ca2+/CaM-dependent pathways mediated through CaMK-II.
The study also described the phosphorylation status of a 23 kD protein. Phosphorylation level of 23 kD protein was highest among all the proteins. L-T3 significantly increased the phosphorylation level of 23 kD by ~2.2-fold compared to the basal level. Especially of interest, EGTA or KN62 did not show any more or less influence on the L-T3-induced increase in the phosphorylation status of the 23 kD protein suggesting lack of significant regulation by CaMK-II (Figure 11).
A. Ca2+/CaM do not modulate L-T3-stimulated phosphorylation of 23- and 38 kD proteins. (a) A representative autoradiogram of the 23- and 38 kD protein separated by SDS-PAGE showing independent stimulatory action of L-T3 upon the phosphorylation of the 23- and 38 kD proteins. B. The quantification of the L-T3-induced phosphorylation presented as a graph of ratio of the band densities of the phosphorylated proteins in the autoradiogram (a) and the corresponding protein in the silver stained gel (b) at different treatment conditions as indicated. The data presented are normalized results (mean ± S.E.M.) for an indicated protein band. * Indicates levels of significance P<0.05 (Ref. Sarkar 2008 Life Sciences 82: 920-927 acknowledged [
5.4.1.1.4. Calmodulin dephosphorylated 16 kD protein following L-T3-induction
Immunoblotting experiment with anti-phosphoserine antibodies also showed significant enhancement of seryl residue phosphorylation of this protein by Ca2+/CaM (Figure 13). Abolition of this effect by EGTA and KN-62 further suggested an important role of CaMK-II. This study identified the role of Ca2+/CaM in the regulation of L-T3-induced protein phosphorylation and supported a unique nongenomic mechanism of second messenger-mediated regulation of protein phosphorylation by TH in mature rat brain.
A. Phosphorylation of 16 kD protein by L-T3 was conquered by the dephosphorylation activity of CaM. (a) A representative autoradiogram of the 16 kD protein separated by SDS-PAGE is showing independent stimulatory action of L-T3 upon the phosphorylation of the 16 kD protein. (b). Corresponding protein bands of silver stained gel. B. The quantification of the L-T3 (10 nM)-induced phosphorylation and its dephosphorylation by CaM are presented as a graph of ratio of the band densities of the phosphorylated proteins in the autoradiogram (a) and the corresponding protein in the silver stained gel (b) at different treatment conditions as indicated. The data presented are normalized results (mean ± S.E.M.) for an indicated protein band. * Indicates levels of significance P<0.05, compared to the basal level (control group) (Ref. Sarkar 2008 Life Sciences 82: 920-927 acknowledged [
L-T3 induced phosphorylation of the 53 kD protein is regulated by Ca2+/calmodulin protein kinase II: Serine residue phosphorylation. (A) Phosphorylation status of the 53 kD protein immunoblotted with anti-phosphoserine (PS) antibody. (B) Corresponding protein band of silver stained gel. (C) Graphical representation of the levels of phosphorylation of the 53 kD protein at various treatment conditions. The data presented are normalized results (mean ± S.E.M.) for an indicated protein band. * Indicates levels of significance P<0.05, compared to the basal level (control group).
5.4.1.2. Role of cAMP on synaptosomal protein phosphorylation, in vitro
After searching for whether Ca2+ plays a major role as second messenger following L-T3 induced protein phosphorylation, our next step was to examine for the role of cyclic AMP (cAMP) as another second messenger upon L-T3-induction, in vitro, to explore furthermore the nongenomic mechanism of TH. To search for any role of cAMP-dependent protein kinase (PKA) the effects of cAMP and H7 (a specific blocker of PKA) were studied. In vitro addition of H7 significantly diminished the effect of L-T3-induced increase in serine phosphorylation of two closely associated proteins with 51- and 53 kD by ~14-fold and ~11-fold respectively (Figure 14). This suggested prevalence of a PKA-mediated mechanism in L-T3-induced synaptosomal protein phosphorylation. To test further whether THs exert adrenergic-like actions by binding to or modulating adrenergic receptor activities another study was performed to test this hypothesis. The idea of formation of thyronamines and its possible binding to the ADR is considered here. Effect of clonidine was studied on the L-T3-induced protein phosphorylation and on the L-T3-binding to the synaptosomal membrane receptors. Scatchard plot analysis revealed clonidine and yohimbine (α2-ADR antagonist) could not alter specific L-T3 binding at the high affinity L-T3 synaptosomal membrane binding sites. L-T3 induced phosphorylation of this 51-/53 kD protein was blocked by H7, a PKA inhibitor. Activation of α2-ADR by clonidine normally decreases the levels of cAMP via inhibiting adenylate cyclase activity. Possibly in the absence of adequate cAMP levels during clonidine treatment, the phosphorylation status of the 51-/53 kD protein remained unchanged. This suggests L-T3-membrane interaction was independent of the activation of the α2-ADR system. Overall these data implicate that PKA and CaMK-II both contribute for L-T3 regulated protein phosphorylation in adult mammalian brain and reveals a nongenomic mechanistic pathway in relation to higher mental functions.
L-T3 induced phosphorylation of the 51-/53- kD proteins are abolished by Protein Kinase A Inhibitor (H7). (A) One representative phosphorylation status of the 51-/53-kD protein immunoblotted with anti-phosphoserine (PS) antibodies. (B) Corresponding protein band of silver stained gel. (C) Graphical representation of the levels of phosphorylation of the 51-/53-kD protein at various treatment conditions. dbcAMP is dibutyryl cyclic AMP. The data presented are normalized results (mean ± S.E.M.) for an indicated protein band. * Indicates levels of significance p<0.05, compared to the basal level (control group).
In conclusion the recent evidence-based information regarding the nongenomic mechanism of action of THs are opening new signal transduction clues to be studied and to reveal the underlying mechanism in mature mammalian brain. The results of the study conducted will advance our knowledge of the fundamental molecular mechanism of TH action in mature CNS, likely in future will lead to more rational and effective approach to the development of novel therapeutic agents, and thus will shed insights on to the neuropshychological manifestations of adult on-set thyroid disorders in humans, particularly in relation to higher mental functions.
Recent information regarding nongenomic mechanism of thyroid hormone action in various tissue types including mammalian CNS is interesting. These studies are diligently engaged in decoding the molecular consequences of thyroid hormone action from the specific gene expression to the nongenomic rapid actions of the hormone. Open-minded investigators are desperately searching for the truth and the relationship of thyroid hormone action explicated through its classical well-known doctrine which is mediated via activation of specific nuclear receptors to the newly emerging idea of rapid nongenomic actions of the hormone and an association to enlighten the both. In particular, adult mammalian brain are of best curiosity since clinical observations of numerous thyroid dysfunction related neuropsychological disorders produced during mature conditions in humans can be corrected with the adjustment of the thyroid hormone levels. However the mechanism of action is lacking. Nongenomic rapid events mediated by thyroid hormones could have connection to the long-term genomic actions. Deciphering the nongenomic molecular mechanism of action of thyroid hormones has future prospects to study its importance regulating higher mental functions in humans. This fundamental knowledge could be the basis to find novel strategies to treat adult-onset thyroid dysfunctions including neuropsychological diseases many of which are precisely controlled by demarcated cellular fine-tuning of the protein phosphorylation mechanisms related to neuronal signal transmission.
Financial support was provided by Parker University, Dallas, Texas, USA.
The word antioxidant is commonly heard nowadays, especially whenever there comes a topic of health concern. People consume antioxidants as a symbol of a healthy lifestyle to fight against various health problems, better skin, and anti-aging benefits. What makes antioxidants so important? The trait responsible for such importance of antioxidants is their ability to stop free radical reactions that can have potentially deleterious effects [1]. This gives rise to various questions, such as What are the free radicals? What are the sources of free radicals? What are their harmful effects? What are antioxidants? What are the common sources of antioxidants? How do they work against free radicals? Answers to these questions are discussed in the present chapter.
Free radicals are those atoms or molecules with an unpaired electron in their outer orbit [2]. Any electron present alone in an orbital is referred to as an unpaired electron, and it is accountable for the reactive and unstable state of the free radical. The vital class of free radicals generated in a living system is usually derived from oxygen and reactive oxygen species (ROS) [3]. Hydroperoxyl (HO2o), alkoxy (ROo), peroxyl (RO2o), hydroxyl (OHo), and superoxide radical (HO2o) are common among oxygen free radicals. Nitrosative stress is the condition that occurs due to the overproduction of reactive nitrogen species (RNS) [3, 4]. Nitric oxide (NOo) and nitrogen dioxide (NO2o), the nitrogen-free radicals can also be converted into other nonreactive species under the antioxidant-dependent reactions. Thus, ROS and RNS include radicals and nonradical species, such as hydrogen peroxide, singlet oxygen, ozone, organic peroxide, peroxynitrite, nitrosyl cation, nitroxyl cation, dinitrogen trioxide, and nitrous acid [5]. When reactive oxygen species (ROS) react with thiols, they give rise to reactive sulfur species (RSS) [6].
The most reactive hydroxyl free radical is formed by exposure to ionizing radiations. These radiations lead to the formation of Ho and OHo by causing the fission of OH bonds in water.
Harmful effects are initiated when the hydroxyl radical reacts with macronutrients such as carbohydrates, protein, and lipids along with DNA, the genetic material [7].
Molecular oxygen receives one electron and is converted to superoxide anion, a reduced form [8]. Superoxide anion is formed in the mitochondria during the initial step of the electron transport system [9]. Oxygen is reduced to water during the electron chain reaction. The electrons escape a chain reaction and react directly with oxygen in its formation [8].
Many other reactive oxygen species are also formed in the living system by the formed superoxide anions. These include hydrogen peroxide, hydroxyl radicals, or singlet oxygen [10].
Hydrogen peroxide (H2O2) is a nonradical that is formed by the superoxide radical when it undergoes nonenzymatic or enzyme-catalyzed (superoxide dismutase, SOD) dismutation reaction. It is very diffusible within and between the cells [11].
In the presence of metal ions and superoxide anion, hydrogen peroxide generates hydroxyl radical.
Nitric oxide is formed during the metabolization of arginine to citrulline by the enzyme nitric oxide synthase (NOSs) via five electron oxidative reactions [12]. Nitric oxide readily diffuses through cytoplasm and plasma membranes due to its solubility in both liquid and liquid media [13].
Oxygen, an essential element of life, also has harmful effects on the human body by forming reactive oxygen species [14]. Free radicals are produced internally as well as due to external factors.
Internally
Normal metabolism within mitochondria during electron transport reactions and another mechanism [15]
Xanthine oxides
Inflammation processes – by neutrophils and macrophages
Phagocytosis
Ischaemia
Peroxisomes [14]
External factors
Radiation
UV rays, X rays,
Environmental pollutants
Certain drugs, pesticides, anesthetics
Ozone
Cigarette smoke [16]
Reactive oxygen species mediate damage to cells structures, including lipids and membrane protein and the nucleic acid under the presence of its higher concentration. This condition is termed oxidative stress [17]. These free radicals’ processes are also associated with various food products. The rancidity of fatty foods, such as potato chips and butter, is due to free radical chain oxidation. Oxidation of polyunsaturated fatty acid (PUFA) is also associated with free-radical processes [18]. The importance of antioxidants is because of their property to stop the free radical chain reaction.
An antioxidant is a chemical compound that has free radical scavenging properties, can delay or inhibit cellular damage and neutralize the effect of free radical by donating an electron [19]. Antioxidants thus counteract oxidative stress. A series of defense mechanisms have been developed to combat the exposure to free radicals from various sources [20]. Antioxidants further contribute to disease prevention and protect cells from the toxic effects of free radicals by neutralizing their excess. Antioxidants can be endogenous, generated in situ or exogenous, supplied through food [21].
To prevent condition like oxidative stress, it is essential to maintain a balance between the production of free radicals and antioxidants defense [22]. Fruits and vegetables are consumed by people as a source of antioxidants, as they are rich in flavonoids and antioxidants. It contributes by protecting the human being from cancer and cardiovascular problems, the ill effects of free radicals [23].
Antioxidants remove free radical intermediates and prevent or slow down the oxidation of other molecules by being oxidized themselves and terminate the chain reactions [24].
Antioxidants can act as
Scavenging the peroxidation initiating species
Decomposition of lipid peroxide
prevent the generation of reactive species by chelating metal ion
Preventing the formation of peroxides by quenching activity
Reducing localized O2 concentrations [25]
Antioxidants also play an essential role in food products by preventing oxidation reactions, browning in fruits and vegetables, and rancidity in fats and oil [23].
Antioxidants may be of natural or synthetic origin. Natural antioxidants are the important secondary metabolites of plant origins mainly explored in preparing some functional foods. In food systems, during storage, the use of nutritional antioxidants and the micro-nutrient, such as Vitamin E, helps maintain the color, texture, and flavor of the food product by preventing or retarding lipid peroxidation and reducing lipid peroxidation protein oxidation [26].
Ascorbic acid is a water-soluble vitamin commonly known as vitamin C and was reckoned as L-ascorbic acid in 1965 by the IUPAC-IUB commission on biochemical nomenclature. Ascorbic acid has a 2,3-enediol group responsible for its antioxidant activity [27]. It is a 6-carbon lactone and cannot be synthesized in the human body, and is water-soluble, it must be regularly supplied through external means.
It plays an essential role in the biosynthesis of collagen, carnitine, and neurotransmitters [27]. The normal metabolic respiration process of the body produces potentially damaging free radicals. These free radicals can be efficiently quenched by ascorbic acid due to its reducing nature [28].
Ascorbic acid, after oxidation, leads to the formation of a dimer called dehydroascorbic acid (DHA). DHA is an oxidized form of ascorbic acid and can be reduced back to ascorbic acid by the action of glutathione (GSH) [29]. In aqueous solutions, dehydroascorbic acid exists as hydrated hemiketal [30].
The formation of dehydroascorbic acid from ascorbic acid is a two-step reversible oxidation process, during which ascorbyl radical is formed as an intermediate [31]. Ascorbyl radical is involved in the termination of free radical reactions, due to the delocalized nature of unpaired electrons present in it, it reacts with free radicals [32].
Dehydro-ascorbate is irreversibly converted to 2,3-diketo-L-gluconic acid with the hydrolysis of lactone ring [33, 34]. Diketo-L-gluconic acid is unstable and does not have biological activity [35].
In fruits and vegetables with low levels of antioxidant (Vitamin C), on cutting, there is the exposure of the phenolic group to oxygen, and the cresolase and catecholase activity act and form quinone, which converts further to dopachrome before its polymerization into brown melanin pigment. Ascorbic acid can reverse this reaction, which converts quinones back to phenolic form [36].
Termination of lipid peroxidation chain reaction is carried by ascorbic acid by donating an electron to lipid radical, which gets converted to ascorbate radical. These ascorbate radicals further react with each other to form ascorbate and dehydroascorbate molecules. Dehydroascorbate molecule on the addition of two electrons is converted back to ascorbate molecule because DHA does not have the antioxidant capacity, and this process is carried out by oxidoreductase [37].
Ascorbic acid prevents the formation of N-nitrosamines in nitrate-cured meats. It results in NO’s formation, which is desirable for cured meats color [36]. L-ascorbic acid protects against oxidation of low-density lipoprotein implicated in the development of atherosclerosis by scavenging reactive oxygen species, which prevent oxidative stress [38].
Vitamin E is a fat-soluble vitamin found in tocopherol and tocotrienol structures that exists in eight different isomeric forms equal configurations for both forms [39]. All eight forms are lipophilic. Chromanol group is responsible for antioxidant activities, and its methylation differs among all the members of the Vitamin E group [40].
The amount of methyl groups attached to phenol ring and pattern of methylation are responsible for reactive antioxidant activities for these isomers, which is found to be
Vitamin E repairs the oxidizing radicals during lipid auto-oxidation and halts the propagation step, thus acting as a chain-breaking antioxidant [42].
Ascorbic acid is responsible for the regeneration of
Vitamin E consumption plays an essential role in preventing the oxidation of low-density lipoprotein cholesterol and reduces the risk of heart diseases [44]. Otherwise, it may lead to atherosclerosis. Vitamin E intake is associated with preventing several diseases, such as cancer, cardiovascular diseases, eye disorders, neurological disorders, and aging [22].
Carotenoids are yellow-red pigments synthesized naturally by plants and some microorganisms [45]. They have an isoprenoid polyene structure [46]. These are a group of tetra terpenoids that contain eight isoprene units with 40 carbon atoms.
Carotenoids can be categorized into two groups, which are as follows:
Carotenoid hydrocarbons (carotenes) contains specific end group as in
Oxygen carotenoids (xanthophylls) as zeaxanthin and lutein [45].
Consumption of foods that are a rich source of carotenoids is related to a decrease in age-related diseases. Coronary heart diseases associated with oxidation of LDL cholesterol can be prevented by lycopene and
Antioxidant activities of carotenoids are due to their structure that contains conjugated double bond, and their ability to delocalize unpaired electrons [48]. Singlet molecular oxygen 1O2 and peroxyl radicals are among the two reactive oxygen species that are most likely to be scavenged by carotenoids [49]. At a low concentration of oxygen, the antioxidant activity of carotenoids increases, and at higher concentrations, it acts as a pro-oxidant (Ruth [50]).
Scavenging of superoxide anions (•O2−) by
Carotenoids can hinder free radical chain reactions that occur during lipid peroxidation due to their antioxidant activity. Free radical reactions proceed in the following manner [52].
Initiation
Propagation
Termination
This chain reaction can be inhibited by carotenoids in three ways [53].
Electron transfer:
Hydrogen abstraction:
Addition of radical species:
The photooxidative process leads to eye and skin diseases on exposure to light. The light filtering effect and antioxidant activity of carotenoids can protect against the ill effects of these processes [54]. β carotene acts as a provitamin and precursor for the formation of Vitamin A in the human body.
Polyphenols are chemical compounds having phenolic structures and are obtained from plant sources [55]. These have several bioactive properties, such as they may act as attracting agents for pollinators, contribute to pigmentation of plants, as an antioxidant, and protection from UV light [56].
The chemical structure of these compounds comprises an aromatic ring with one or more hydroxyl groups. These can be simple phenolics or in polymeric form having high molecular mass [57]. The most important group of polyphenols is flavonoids (glycosides with benzopyrone nucleus). Flavonoids include flavones, flavonols, flavanone, flavonols, and anthocyanins [58]. Flavonoids consist of 15 carbon atoms having an arrangement, as shown below in the figure. These are compounds having a low molecular weight [59].
The antioxidant activity of these compounds is due to their ability to donate hydrogen and metal ion chelation [60]. Phenolic radicals formed after presenting hydrogen atoms do not readily participate in other radical reactions, as they become resonance stabilized [61]. Flavonoids can form a complex with metals and thus prevents metal-initiated lipid oxidation [62].
The difference in structure and glycosylation patterns of these compounds are responsible for their different antioxidant activity. Glycosides of anthocyanidins are called anthocyanins. These are the most extensive water-soluble pigments, commonly present in flowers and fruits [60].
Tannins are an important group of polyphenolic compounds, having high molecular weight. These are categorized as hydrolyzable and condensed tannins [63]. Hydrolyzable tannins are derived from the esterification of gallic acid (3,4,5-trihydroxy benzoic acid). Galloyl group of core polyol (formed from esterification of gallic acid) is further esterified to obtain hydrolyzable tannins [64]. Condensed tannins are the polymeric compounds obtained from polyhydroxy flavan-3-ol. These are also known as pro-anthocyanidins [63]. Tannins have metal ion chelating properties, act as an agent for protein precipitation, and possess antioxidant activity [64].
Polyphenolic compounds act as antioxidants to inactivate free radicals by two mechanisms, which are as follows:
Hydrogen atom transfer mechanism.
single electron transfer mechanism.
It is supposed that an antioxidant ArOH transfers its hydrogen atom to react with free radical in the hydrogen atom transfer mechanism.
In the single electron transfer mechanism, it is supposed that an oxidant donates an electron to the antioxidant molecule [65]:
Antioxidants play an essential role in problems related to oxidative stress, such as neurodegenerative and cardiovascular diseases. People nowadays are more focused on antioxidant-rich foods, so it is vital to assess these components’ antioxidant activity or free radical scavenging capacity. There are various ways of measuring antioxidant activity (Figure 1). Different methods follow different reaction mechanisms. These can be classified according to the reaction mechanism as:
Antioxidant assay techniques.
Hydrogen atom transfer (HAT) method is based on the determination of free radical scavenging activity of antioxidants by donating a hydrogen atom. These are rapid reactions and do not depend on pH and solvent but are affected by the existence of reducing agents [66]. In contrast, the single electron transfer (SET) method is based on the ability of an antioxidant component to reduce the compounds such as carbonyls, radicals, or metal ions by transferring a single electron [67]. The most commonly used method is the oxygen radical absorbance capacity (ORAC) assay. This method is based on the principle of decrease in intensity of fluorescent compounds, such as β-phycoerythrin or fluorescein, due to the oxidative degradation by radicals (which leads to the formation of non-fluorescent compound) generated from thermal decomposition of AAPH (2, 2′-azobis (2-amidino propane) dihydrochloride) that is used as a free radical generator. The antioxidant activity is measured as a decrease in the amount and rate of formation of non-fluorescent products [68, 69]. This method provides an advantage that by altering the solvent and source of free radicals, it is possible to determine the hydrophilic and hydrophobic antioxidants. In this method, a controlled source of radicals is provided that simulates the reactions between lipids and antioxidants in food [70, 71].
The total radical-trapping antioxidant parameter (TRAP) assay is based on the same principle as ORAC. The antioxidant activity is measured as the moles of peroxyl radicals that are trapped by 1 L of antioxidant solution. Like the ORAC method, the loss of fluorescence is monitored. Trolox is used as a standard to compare the plasma-induced lag phase to that induced by antioxidant sample solution in the same plasma sample. It determines the activity of non-enzymatic antioxidants, such as ascorbic acid and glutathione, but this method is time-consuming and requires expertise [67].
Ferric reducing antioxidant power (FRAP) assay is based on the formation of the blue-colored ferrous complex by the antioxidants by reducing ferric 2,4,6-tripyridyl-s-triazine complex [Fe3+-(TPTZ)2]3+ in an acidic medium [72]. Reactions were carried out under acidic conditions (pH 3.6) to maintain the solubility of iron. Reducing 1 M ferric ions to ferrous ions is known as one FRAP unit [73].
In the method of DPPH (2,2-Diphenyl-1-picryl hydrazyl) assay, the ability of an antioxidant to scavenge DPPH radical (purple color) and reduce it to diphenyl picryl hydrazine (yellow color) is measured. The reaction is carried out in an alcoholic solution [74]. Generally, the results are described as efficient concentration (EC50). To bring about a 50% decrease in the concentration of DPPH, the amount of antioxidant required is reported as EC50 value [75].
Besides providing essential nutrients, fruits and vegetables also contain substantial amounts of biologically active secondary metabolites [76]. The secondary metabolites of plants that provide numerous health benefits are covered elsewhere [77, 78]. The principal dietary components found in the antioxidant properties of fruits and vegetables are polyphenols, flavonoids, carotenoids, Vitamin C, Vitamin E, glutathione, selenium indoles, and protease inhibitors (Table 1) [79].
Antioxidant, chemical structure, antioxidant activity, and sources.
The varying amounts of waste material are generated during the preparation of cut or processed fruits and vegetables [80]. Peels and seeds are the byproducts generated in large amounts during minimal processing of fruits and vegetables and comprise of large quantities of phytochemical components with antimicrobial and antioxidant properties [81, 82, 83]. All of these can be effectively utilized as a source of antioxidants. The fruits and vegetable tissues are rich in bioactive compounds, such as phenolics, vitamins, and carotenoids. These are even present in higher amounts in byproducts compared to the final product [84].
Fresh grapes, grape juice, and grape wine are excellent sources of phenolic antioxidants (Figure 2). Flavonoids and other phenolic compounds present in grapes have anticarcinogenic, anti-allergic, anti-inflammatory, hepatotoxic, and antioxidative effects [85, 86, 87]. The majority of phenolics present in grapes are 60–70% in seeds and 28–35% in the skin, whereas pulp contains utmost to 10%. These phenolics can act as free radical scavengers and act as antioxidants. The grape seed oil also offers various health benefits, such as improving vision, protection of skin from sun damage, improved blood circulation, reduced oxidation of low-density lipoproteins, and reduced risk of coronary heart disease [88]. The antioxidant activity of grape juice is highest among the commercial juices, followed by grapefruit juice, tomato, orange, and apple [89]. Phenolic antioxidants obtained from grape pomace were found to exhibit the property to retard oxidation of human low-density lipoprotein (LDL) cholesterol [90].
Antioxidants present in grapes.
“An apple a day keeps the doctor away,” can be attributed to the number of phytochemicals present in apples. Apple is a rich source of polyphenols, vitamins, and carotenoids that prevent free radical damage due to their high antioxidant activity. Antioxidant compounds in apples are quercitin-3-glucoside, quercitin-3-galactoside, catechin, epicatechin, procyanidin, cyanidin-3-galactoside, chlorogenic acid, coumaric acid, and gallic acid [91]. The amount of these compounds varies with the cultivars and between the flesh and peel of an apple. These phytochemicals are rice in peels as compared to flesh. Peels contain a high amount of quercetin conjugates whereas, chlorogenic acid is present in higher concentrations in the flesh [92]. Phloridzin, an antioxidant compound, mainly present in apple seeds [93], is a derivative of chalcone, also having anti-diabetic activity because of its ability to inhibit sodium-linked glucose transport, thus limiting the absorption of glucose in the intestine and kidney [94, 95].
Berries are highly perishable, soft fruits, including strawberries, raspberries, blueberry, blackberry, blackcurrant, bilberry, and cranberry are rich sources of bioactive compounds, mainly phenolics [96]. Blackcurrant, bilberry, and chokeberry contain a higher amount of phenolic content as compared to other berries [97]. Phenolic acids present in berry fruits include
Other than cut fruits, most of the berries are used as raw material for the preparation of various processed products, such as jams, jellies, and juices. During the processing, a large amount of waste is generated. This waste can be used to recover highly valuable bioactive compounds. Blackberry and raspberry seeds can be used for the extraction of oil that is rich in antioxidant compounds such as phenols, carotenoids, and tocopherols along with linoleic acid (omega −6) and α-linoleic acid (omega-3) in 2 to 4:1 ratio [101]. Leaves and pomace from cranberry juice processing have more antioxidant activity and contain a higher amount of polyphenols than the juice [102].
Pomegranate (
Pomegranate peels and seeds that are the byproducts of juice processing are wasted or used as animal feed. But, it has been found that the amount of bioactive compounds or the antioxidant activity of the extracts of peel is higher than that of juice [105]. Pomegranate seeds can be used for oil extraction, that contain bioactive components. The oil extracted from pomegranate seeds has a fatty acid called punicic acid (conjugated linoleic acid isomer) [106] that constitutes about 70–76% of the seed oil and has high phytosterol content [107]. There are various health benefits of this pomegranate seed oil due to its unique chemical composition. Some of these benefits include modifying blood lipid profile in people suffering from hyperlipidemia [108].
Orange segments are a rich source of carotenoids (a class of natural pigments), such as zeaxanthin, β-cryptoxanthin, antheraxanthin, violaxanthin, and mutatoxanthin. Consumption of carotenoids is linked with reducing the risk of degenerative diseases in the body [109]. Oranges are rich in various antioxidant compounds, mainly ascorbic acid and phenolic compounds [110].
During the processing of oranges for juice manufacturing, a large amount of waste comprises peels and seeds. These are an abundant source of phytochemicals that are associated with a reduction of free radical damages. Various flavonoids have been identified in the orange peel, including hydroxylated poly ethoxy flavones and methylated flavonoids. These bioactive compounds are found to have protective action against oxidative stress [111].
Banana is a global food that belongs to the genus
Banana offers several health benefits, such as retardation of the aging process, reducing the risk of degenerative diseases like heart problems, atherosclerosis, brain dysfunction, and inflammation. It also provides resistance against oxidative changes in low-density lipoprotein and reduces oxidative stress due to bioactive compounds, such as dopamine and ascorbic acid. Serotonin stimulates the intestinal smooth muscles and thus inhibiting gastric secretion [117]. Banana peel can be utilized as a potential source of antioxidant compounds instead of discarding it.
Mango comes second, after the banana, regarding production. India is the largest producer of mango. The edible slices of mongo consist of significant amounts of antioxidant compounds. Xanthones are found in high concentrations comprising mainly of mangiferin (1,3,6,7-tetrahydroxyxanthone 2-glucopyranoside) and c-glucoside xanthone [118].
Mango byproducts, mainly peels, have shown high antioxidant activity. The phenolics and flavonoid content of mango peels is responsible for its anti-proliferative potential against cancer cells [119]. Mangiferin content of peels is about three times higher than that of pulp [120]. Gallo-tannins are found in higher amounts in mango kernels (15.5 mg/g dry matter) followed by peel (1.4 mg/g dry matter) and lowest in pulp (0.2 mg/g) [121]. Mango peel extracts can scavenge singlet oxygen (1O2), hydroxyl radical, and superoxide anion due to the presence of compounds, such as ethyl gallate and penta-o-galloyl glucoside [122].
Tomato is an important and widely consumed vegetable (M. W. [123]). It is considered beneficial for health as it provides carotenoids, flavonoids, and phenolic acids [124]. During the production of tomato juice, about 3–7% of raw material is wasted, which comprises skin and seed.
Tomatoes are a rich source of carotenoid, the lycopene responsible for their characteristic red color [125]. The lycopene content of tomato peel is five times higher than pulp [126]. Thus, the hot break method is preferred in tomato juice extraction to get the tomato product of intense redness due to higher lycopene concentration.
Carrot is a significant and widely consumed root vegetable that is a rich source of dietary fiber and secondary metabolites, mainly carotenoids and phenolics [77, 127, 128]. Carrots provide substantial health benefits [129] due to compounds like tocopherol, ascorbic acid, and β-carotene and hence is also called vitaminized food [130].
Carotenoids acts as a precursor of Vitamin A, especially the β-carotene, which are the major bioactive components present in carrots [131]. The most prevalent phenolic acid present in carrots is caffeic acid and thiamin, folic acid, riboflavin, and Vitamin C, which are in considerable amounts of carrot roots [132]. Carrot peel, the by-product of the processing industry, accounts for about 11% of the fresh carrot and can provide 54.1% of the total phenolic content of carrot. Therefore, these peels can be utilized for the value addition of various food products [133].
Garlic is widely consumed as a spice and flavoring agent. Because of its preventive and curative action against various ailments, it is widely utilized for dietary and medicinal values [134, 135]. Garlic consists of a high content of γ-glutamylcysteine, which is believed to be responsible for various health benefits provided by garlic, along with other sulfur-containing compounds [136]. The chief bioactive component of garlic is allicin (diallyl this sulphonate). Raw garlic homogenate also consists of other significant sulfur-containing compounds, including allyl methyl sulphonate,
Garlic has been found to increase the resistance against LDL oxidation and thus is beneficial for heart and blood vessels because oxidative modification of LDL can lead to the formation of plaque in blood vessels by deposition of fatty streaks [138]. Garlic in the form of 10% homogenate in a salt solution and its supernatant fraction was found to be capable of reducing the free radicals generated from the Fenton reaction, and it was also effective in reducing the free radicals in cigarette smoke [139].
Garlic shows protective action against oxidative damage of tissues induced by nicotine. It was also found to be effective against carbon tetrachloride damage. Rats intoxicated with carbon tetrachloride were given an oral dosage of garlic oil, and it was found to prevent liver damage by peroxidation of lipids, alkaline phosphatase, and serum transaminase. These results are similar to that of Vitamin E [140].
Onion consists of substantial bioactive compounds, mainly flavonoids [141]. Flavonols are the significant flavonoids present in onions, quercetin derivatives being the most important ones [142]. Quercitin 3,4′-diglucoside and quercitin 4′-glucoside accounts for around 80–95% of total flavonols [143].
Some varieties of red onions also consist of anthocyanins. Anthocyanins are mainly concentrated in the outer skin of the onion (63%), and flavonoids in the skin are present mainly in aglycone forms [144]. So, the onion skin, which is generated as a waste, can be used to extract bioactive components.
Potato is considered the king of vegetables. It is the most widely consumed vegetable and the significant raw material for processed products, such as chips, fingers, and fries, during the processing of potatoes; peels are a considerable waste. Potato waste consists of various antioxidant compounds: caffeic acid, chlorogenic acid, protocatechuic acid, gallic acid, and para-hydroxybenzoic acid [145]. The antioxidant capacity of polyphenolic extracts obtained from potato peels is found to be analogous to that of synthetic antioxidants [BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene)]. It was found that soybean and sunflower oil thermal degradation was suppressed when potato peel extract was incorporated in these oils, which may be attributed to chlorogenic and gallic acid in the extract [146].
Beetroots are an abundant source of valuable bioactive components such as carotenoids [147], betacyanins [148], betanin, flavonoids, and polyphenols [149]. The antioxidant activity of beetroots is primarily attributed to the total phenolic content of about 50–60 μmol/gm of dry weight [150]. The entire phenolic content in different portions of beetroot is found to be in the following order: Flesh (13%) < crown (37%) < peel (50%) [151]. Beetroot peel’s major phenolic compounds are p-coumaric acid, ferulic acid, and cyclodopa glucoside derivatives [152].
Betacyanins found in red beets have antioxidant activity and free-radical scavenging properties [153]. These are responsible for the inhibition of cervical and ovarian cancer cells [154]. Betalains improve the antioxidant profile of humans by reducing the oxidative degradation of lipids by scavenging the free radicals [155].
A large amount of horticultural waste is generated when preparing either cut fruits and vegetables or processed products. So, it can be a better option to utilize these wastes into valuable byproducts by extracting various phytochemicals to utilize in pharmaceuticals, cosmetics, and food products as functional ingredients. These bioactive compounds can be used in vegetable oils to prevent oxidation and edible coatings to increase shelf life.
Antioxidants prevent oxidative damage in food products and protect the human body from damage caused by reactive species, such as ROS, RNS, RSS, and free radicals. Antioxidants prevent the damage induced by free radicals acting through different mechanisms, such as free radical scavenging, prevention of free radical formation, or decomposition of reactive species. Antioxidants such as ascorbic acid, Vitamin E, carotenoids, and polyphenols can be obtained from plant sources, mainly fruits and vegetables fresh and processed products. The by-products obtained during the processing of fruits and vegetables can be utilized as a potential source for the extraction of antioxidants as these consist of high amounts of bioactive compounds. Secondary metabolites in peels and seeds of some fruits and vegetables, such as grapes, berries, pomegranate, garlic, and onion, can be higher than their pulp and juice. Such horticultural by-products can be utilized as a source of bioactive compounds in pharmaceutical, cosmetic, and food products.
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He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"17",type:"subseries",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.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11413,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,series:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983"},editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-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",slug:"attilio-rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of 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