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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"}]},book:{item:{type:"book",id:"2034",leadTitle:null,fullTitle:"Brain Injury - Functional Aspects, Rehabilitation and Prevention",title:"Brain Injury",subtitle:"Functional Aspects, Rehabilitation and Prevention",reviewType:"peer-reviewed",abstract:'The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. 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His papers are well-published in high-impact journals.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"339234",title:"Dr.",name:"Johnny",middleName:null,surname:"Chahine",slug:"johnny-chahine",fullName:"Johnny Chahine",profilePictureURL:"https://mts.intechopen.com/storage/users/339234/images/system/339234.jpg",biography:"Graduated from medical school in 2016 and moved to Cleveland for my Internal Medicine residency in 2017. Currently in the twin cities as a cardiology fellow at the University of Minnesota. I strive for excellence in my medical knowledge but also for a friendly environment for my colleagues and patients. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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The mechanisms of generation of free radicals occur mostly in the mitochondria, cell membranes and cytoplasm. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as unavoidable by-products of metabolism. During the metabolic processes, these radicals act as mediators for the transfer of electrons in various biochemical reactions. Its production, in appropriate proportions, is possible to generate adenosine triphosphate (ATP) through the electron transport chain; fertilization of the ovum; activation of genes and participation of defense mechanisms during the infection process [1]. The continuous production of free radicals during the metabolic processes culminated in the development of antioxidant defense mechanisms (enzymes and substances such as glutathione, metallothionein, vitamin A, vitamin C and vitamin E). These are intended to limit the intracellular levels of these reactive species and control the occurrence of damage caused by them. However, excessive production can lead to oxidative damage. The structural modifications in the molecules of nucleic acids, proteins and lipids caused by increased concentration of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) lead to various metabolic changes that may contribute to the development of neurological diseases, cardiovascular diseases, cancer, among others [2].
\nThe installation process of oxidative stress arises from an imbalance between oxidants and antioxidants in favor of excessive generation of free radicals or removal speed thereof. This process leads to the oxidation of biomolecules with consequent loss of its biological functions and/or homeostatic imbalances, whose manifestation is the potential oxidative damage to cells and tissues. Accumulation of ROS/RNS can result in a number of deleterious effects such as lipid peroxidation, protein oxidation and DNA damage [3].
\nDNA and RNA are chemically unstable and vulnerable to hydrolysis, nonenzymatic methylation and oxidation, due to its susceptibility to endogenous and exogenous damage. The endogenous genotoxic agents are mainly produced by cellular metabolism and composed of ROS and RNS, estrogen metabolites and aldehydes produced by lipid peroxidation [4, 5].
\nThere are two major endogenous oxidants causing nucleic acids damage: hydroxyl radicals (HO•) and peroxynitrite (ONO2−). One major source of ROS is the mitochondrial respiration because up to 5% of oxygen undergoes single electron transfer and generates superoxide anion radical (O2−). The superoxide dismutase (SOD) converts O2− to hydrogen peroxide that should be reduced by catalase (CAT) or glutathione peroxidase (GPx), however when transition metals are present, it is reduced to hydroxyl radicals (HO•). These radicals have a high reactivity, so it must be generated close to DNA or RNA in order to oxidize them. The generation of peroxynitrite (ONO2−) occurs by the reaction of nitric oxide (NO) and superoxide, both produced simultaneously in macrophages. Although these specimens can directly oxidize the nucleic acids, there is a secondary synergic mechanism of RNS to break the oxidative balance: the RNS are able to inhibit the enzyme FAPY glycosylase, a DNA repair mechanism to oxidation [6].
\nOxidative stress can lead to different lesions in DNA, including direct modification of nucleotide bases, training sites apurinic/apyrimidinic, single strand break and much less frequently, breaking double strands. Considering all the bases of the nucleotides, guanine is most susceptible to oxidative changes because it has lower reduction potential and hydroxyl radicals interact with the imidazole ring of this nitrogenous base at positions C4, C5 and C8 [7].
\nThe most studied marker for DNA oxidation is 8-hydroxydeoxyguanosine, a product of guanosine oxidation by HO• [6, 8]. This product is able to pair with adenine, generating a GC/TA mutation upon replication [6]. It is also known that oxidative stress regulates DNA methylation, playing a role in epigenetics regulation. Epigenetics constitutes several mechanisms of controlling gene expression without changing DNA sequence, but responding fast and precisely to environmental changes. One of the most characterized methods of epigenetic regulation is DNA methylation. The methylation of DNA CpG islands is mediated by DNA methyltransferases (DNMTs), but when the ROS or RNS interacts with cytosine, it is chemically modified from 5-methylcytosine to 5-hydroxymethylcytosine, which prevents DNMT binding and alters methylation patterns [9].
\nFor RNA oxidation, the most relevant marker is the homologue 8-hydroxyguanosine. It has been made clear that RNA is more often oxidized than DNA, due to its cellular location closer to ROS and RNS occurrence. The major consequences of RNA oxidization are the breakage of the strand and ribosomal dysfunction, preventing correct protein production [8].
\nThe effects of oxidation in proteins can be observed in impaired protein folding, side-chain oxidation and backbone fragmentation, resulting in loss of function and stop a variety of biochemical processes. Among the amino acids, the cysteines and methionines are more easily oxidizable, but this reaction is reversible through disulfite reductases activity. However, the cysteine can also suffer irreversible oxidation reactions leading to the formation of S-carboxymethylcysteine and S-(2-Succinyl)cysteine, which implies the formation of fumarate and dicarbonyl groups covalently bound to cysteine residues. When the amino acids lysine, proline, arginine and threonine are oxidized, occurs the production of carbonyl derivatives, which are used as markers for oxidative stress. In the oxidation of aromatic amino acids, such as tyrosine, different products are formed due to interaction with ROS – dityrosine or RNS – 3-nitrotyrosine [8].
\nThese oxidized-modified proteins are usually recognized and degraded in the cells, but some of them can accumulate over time and lead to cellular dysfunction. A physiological example is the lipofuscin, a brown-yellow pigment that is a product of iron-catalyzed oxidation (polymerization) of proteins and lipids, as it is extremely resistant to proteolysis, it accumulates and it is used as an aging marker [10].
\nIn biological systems, lipid peroxidation occurs in two forms, one enzymatically, involving the participation of cyclooxygenase and lipoxygenase in the oxidation of fatty acids and other nonenzyme medium, involving transition metal, the reactive species oxygen, nitrogen and others [11]. Excess peroxidation results are very damaging to the cell, despite contribute to the inflammatory response, due to its importance in the cascade reaction from arachidonic acid to prostaglandin formation. The action of free radicals on lipids leads to the formation of lipid hydroperoxides and aldehydes, such as malondialdehyde, 4-hydroxynonenal and isoprostanes that contribute further to increased cellular toxicity and can be detected in biological samples to measure oxidative stress. Lipid peroxidation disrupts the normal structure and function of lipid bilayers surrounding both the cell itself and in the membranes of organelles. In particular, the lipid peroxidation can alter membrane permeability, transportation and fluidity [12]. The chronicity of the process in question has important implications for the etiologic process of many chronic diseases, including atherosclerosis, diabetes, obesity, neurodegenerative disorders and cancer [1].
\nThe antioxidant defense system has the primary objective to maintain the oxidative process within physiological limits and subject to regulation by preventing oxidative damage from spreading, culminating in systemic irreparable damage. The enzymatic defense system includes enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). These enzymes act through mechanisms of preventing and/or controlling the formation of free radicals and species nonradical, involved with the initiation of chain reactions that culminate in propagation and process amplification and, consequently, the occurrence of oxidative damage. CAT and GPx enzymes act with the same purpose, to prevent the hydrogen peroxide accumulation. Such integrated action is of great importance, since this reactive species through the reactions of Fenton and Haber-Weiss, with the participation of iron and copper metals, culminates in the generation of OH• radical against which there is no enzyme system defense [13, 14].
\nThe human organism is constantly exposed to a vast number of molecules that can lead to oxidative stress, such as drugs and alcohol. However, there is a conserved cellular component to oxidative stress response, which is constituted by over 100 genes responsible for detoxification and antioxidant protein production. The first line of the antioxidant defense to exogenous toxins includes the enzymes involved in phase I and II metabolism. The phase I metabolism is responsible for increased compound polarity through oxidation, reduction or hydrolysis reactions. The phase II metabolism, in the other hand, is responsible for facilitating the cellular export of those compounds; its reactions are mainly glucuronidation, acetylation and sulfation [15].
\nThe enzymes that compose the cytochrome P450 are the most responsible for oxidation of drugs, chemicals and various endogenous substrates, such as eicosanoids, cholesterol, vitamin D3 and arachidonic acid [16]. The P450 is a superfamily of heme-thiolated enzymes with over 2000 members [17]. In humans, 57 functional genes and 58 pseudogenes are grouped according to the sequence similarity in 18 families and 44 subfamilies. The CYP-enzymes that belong to the families 1, 2 and 3 are responsible for metabolizing up to 90% of the drugs, this phase I drug oxidation system is frequently redundant, but many drugs are metabolized to a clinical concentration by one or few CYPs only [18].
\nIn steroidogenic tissues (converts cholesterol into pregnenolone via the P450 side chain cleavage enzyme) there is a prevalence of CYP450 enzymes located in mitochondria and the electron transport system is very susceptible to oxidative stress. During the electron transport, a leakage of electron to the ultimate acceptor leads to their binding to oxygen, being considered a primary source of ROS, this may result in acceleration of ROS production in mitochondria. In this context, it is considered the effectiveness of electron transfer from NADPH to CYP enzymes for monooxygenation of substrates as a source of ROS because during the uncoupling reaction, without the presence of any substrates, the electron-transfer chain oxidizes NADPH and yields ROS. During CYP2E1 metabolism is frequently observed this kind of uncoupling reactions, thus this enzyme is strongly associated to ROS production and oxidative stress [16]. The enzyme CYP2E1 is associated with the metabolism of small molecules, and can be induced by ethanol, obesity, diabetes and polyunsaturated fatty acids; this induction is related to toxicity and oxidative stress. Another mechanism of CYP2E1 activation is the reduction of glutathione levels, upon acetaminophen administration, for example. Besides, this drug increases lipid peroxidation and protein carbonylation, enhancing the ROS production due to higher activity of CYP2E1 and being associated to hepatotoxicity mediated by MAP-kinase pathway [16, 19].
\nGlutathione S-transferase (GST) is a family of intracellular enzymes that prevent the action of endogenous and exogenous toxins on the cells. GSTs are multifunctional enzymes that participate in the phase II of the xenobiotic metabolism and catalyze the nucleophilic attack of the reduced form of glutathione (GSH) to potentially hazardous compounds. How are involved in the metabolism of many carcinogens, environmental pollutants and cancer-fighting drugs, it is therefore reasonable to assume that the lack of specific isoenzymes has a significant effect on the tolerance of an organism to carcinogens [20]. Human GSTs are categorized into cytosolic/nuclear, mitochondrial and microsomal. Based on their amino acid sequences and/or nucleotide substrate specificity and immunological properties, seven classes of cytosolic GSTs are described: Alpha, Mu, Pi, Sigma, Theta, Omega and Zeta. Microsomal GSTs are designated MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) and the only mitochondrial GST confirmed in humans is GST-kappa, which is also present in peroxisomes. GSTs are normally found in biological medium as homo or heterodimers and these dimers have two active sites whose activities are independent. After combining with reduced glutathione (GSH), these enzymes have higher specificity for a second substrate (the electrophilic). GST enzymes participate in the metabolism of endogenous and exogenous compounds, for example, polycyclic aromatic hydrocarbons, phenylalanine and tyrosine amino acids, testosterone and progesterone. These enzymes target endogenous compounds, maybe derived from peroxidation of polyunsaturated fatty acids present in cell membranes and the activity of reactive oxygen species [21–23].
\nConclusive evidence suggests that oxidative stress is a major contributor to the pathophysiology of a variety of neurodegenerative diseases, including Alzheimer\'s, Parkinson\'s, Huntington’s, tardive dyskinesia (TD), epilepsy and acute diseases of the central nervous system, such as spinal cord injuries and/or brain traumatic. The human brain is vulnerable to oxidative stress due to many facts such as (i) metabolism of catecholamines; (ii) decrease in antioxidants; (iii) presence of transition metals; (iv) occurrence of brain trauma/injury; and also (v) the brain is a organ that proportionally requires more oxygen and (vi) expresses low levels of antioxidant enzymes, which contribute to formation of ROS. As a consequence of redox unbalance in brain, one of the most affected structures is the lipid membrane [24].
\nParkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta of the brain, leading to rigidity or slowing movements and postural instability. Most of the cases of PD are idiopathic and some cases are genetic-related, but in general context, aging is a determinant factor. In both idiopathic and genetic cases of PD, the oxidative stress plays a critical role in pathogenesis, being a common underlying mechanism. There is an elevated level of oxidized lipids, proteins and DNA associated with decreased glutathione level in the brain of PD patients. This increased susceptibility to oxidative damage in the dopaminergic neurons is due to (i) the presence of ROS generating enzymes, such as tyrosine hydroxylase and monoamine oxidase and (ii) these neurons contain iron, a catalyser of Fenton reaction (Fe(II) + H2O2-> Fe(III) + OH• + OH−) that leads to superoxide radicals and hydrogen peroxide production [25].
\nA fact of Alzheimer’s disease is the dysregulation of iron and copper homeostasis and various evidence of oxidative stress, mainly RNA oxidation. Neurons usually do not store big amounts of iron, but with aging there is an accumulation of iron in the brain, especially in microglia, astrocytes and neurons from cortex and hippocampus. If iron levels increase much more than ferritin, an iron-storage protein, it becomes free to catalyze Fenton’s reaction [26].
\nThe tardive dyskinesia (TD) is an adverse effect of antipsychotic use, it affects up to 25% of schizophrenic patients. However, as the majority of patients do not develop TD, it is considered that genetics factors may define its occurrence but TD pathophysiology remains unclear. One of the strongest hypotheses suggests that it is caused by oxidative stress originated from neurotoxic free-radical production upon antipsychotic medication. This affirmation is supported by genetic polymorphisms evaluated in genes that encode a mitochondrial enzyme that prevents oxidative damage due to energetic metabolism (manganese superoxide dismutase) and a cytosolic flavoenzyme that prevents quinone reduction (NADPH quinone oxidoreductase), playing a role in antioxidant defense [27].
\nMetabolic syndrome is a term that designates a cluster of health problems often associated to modern life style, including obesity, insulin resistance, dyslipidemia, impaired glucose tolerance and high blood pressure. The metabolic syndrome is diagnosed when at least three of the following alterations are present: visceral obesity (waist circumference >102 cm in men or >88 cm in women); raised arterial blood pressure (>130/85 mm Hg); dysglycemia (fasting plasma glucose >100 mg dL); raised triglyceride concentrations (>150 mg dL) and low high-density lipoprotein (HDL) cholesterol (<40 mg dL in men or < 50 mg dL in women) [28].
\nThe oxidative stress is related to metabolic syndrome in several ways: (i) H2O2 promotes insulin signaling, being associated with increased insulin resistance; (ii) superoxide anion is generated by angiotensin stimulation of NADPH and angiotensin II/angiotensin II type I receptor (AT1R), which plays a critical role in blood pressure control; (iii) hyperglycaemia leads to overproduction of superoxide by mitochondrial electron transfer chain, activating oxidative stress; (iv) elevated low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) are correlated with oxidative stress and the dyslipidemia treatment with rosuvastatin is known to reduce oxidative stress through raise of antioxidant enzymes [28].
\nDue to oxidative DNA damage there is a direct correlation between diabetes and cancer. Diabetic patients present high levels of ROS because of elevated glucose, fatty acids and insulin blood levels; combined to lower antioxidative capacity derived from reduced glutathione synthesis. To support those findings, it has been proved that polymorphisms in peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) – a protein that regulates mitochondrial electron transport, leads to decontrolled redox activity [29].
\nAtherosclerosis is defined as an arterial disease characterized by fibrous and cholesterol rich plaques. Atherosclerosis progression causes blood flow obstruction, hemorrhage due to rupture and thrombosis leading to strokes or myocardial infarctions. Many risk factors are associated with atherosclerosis development, the most widely known are serum low-density lipoprotein (LDL) cholesterol, low serum high-density lipoprotein (HDL) cholesterol, diabetes, hypertension, smoking, aging and oxidative stress [30].
\nDuring LDL oxidation, a progressive process and very important for the beginning of the formation of atheromatous plaque, the cholesterol is target of oxidants, which generate a variety of oxysterols. On the other hand, lipid peroxidation products (MDA and 4-HNE) can react with histidine, cysteine or lysine residues of proteins, leading to formation of stable Michael adducts with a hemiacetal structure or to Schiff bases that undergo a rearrangement generating the Amadori products. These aldehydes can derivatize Lys residues of apoB, which decreases the number of positive charges and interferes on LDL binding to LDLR and scavenger receptors [31].
\nIn endothelial cells, besides stimulating the antioxidant defense (mainly by glutathione), Nrf2 (nuclear factor (erythroid-derived 2)-like 2) suppresses inflammation-associated expression of adhesion molecules and cytokines, which are associated with the early stage of atherogenesis [29]. NAD(P)H oxidases (NOXs) are major sources of ROS in the vasculature, producing superoxide from molecular oxygen using NAD(P)H as the electron donor and endothelial NO synthase (eNOS) produce NO which represents a key element in the vasoprotective function of the endothelium. However, pathological conditions associated with oxidative stress may become eNOS inefficient and promote the rapid inactivation of NO by excess superoxide [32].
\nThere is growing evidence that reversal of oxidative stress with antioxidants can reduce the degree of myocardial ischemic injury and heart dysfunction [33].
\nThe pathological effects of NO and O2− in virus infection are in clear contrast to their beneficial antimicrobial effects in bacterial and fungal infections. In virus infections, NO and ONOO−, which are primitive host-defense molecules, cause nonspecific oxidative damage in virus-infected tissue, leading to various pathological events. Virus-induced oxidative stress has been reported during HIV, influenza virus, HBV, hepatitis C virus, encephalomyocarditis virus (EMCV), respiratory syncytial virus (RSV), dengue virus (DENV) and others [34].
\nStudies including rotavirus-infected patients showed that viral infection stimulates NO production, decreases superoxide dismutase and glutathione peroxidase activities and increases inducible nitric oxide synthase (iNOS) mRNA and iNOS expression in murine ileum [35].
\nInfluenza virus is probably the best characterized pathogen modulating redox homeostasis. Influenza-induced ROS production has been associated with host immune and inflammatory responses, as well as modulation of viral replication. Oxygen radicals and their derivatives are recognized as principal mediators of influenza virus-induced lung injury [36].
\nWithin the Flaviviridae family, hepatitis C virus infection promotes oxidative stress and manipulates antioxidant systems, leading to liver damage and chronic disease. Elevated levels of reactive oxygen species (ROS) are considered as a major factor contributing to HCV-associated pathogenesis. HCV core protein is considered as a major regulator affecting the release of ROS from mitochondria. In this context, mitochondria play a crucial role for the production of ROS in HCV-infected cells. Several pathways are affected upon HCV infection to result in an induction of autophagy that interferes with various steps of the viral life cycle to promote a permanent viral infection. The assembly and release of viral particles are closely linked to the VLDL synthesis and occur via the secretory pathway. Elevated glucose production, enhanced fatty acid uptake or upregulation of genes involved in lipid and cholesterol synthesis may contribute to oxidative stress-induced insulin resistance linked to HCV infection [36].
\nInduction of iNOS and production of NO, accumulation of ROS and RNS, as well as perturbation of the reduced glutathione (GSH) content are all signatures of Dengue virus (DENV) infection in different human cells and animal models. DENV infection resulted in an intracellular accumulation of NAD(P)H oxidase (NOX2)-derived ROS in monocyte-derived dendritic cells (Mo-DCs). Alteration in the redox status of DENV-infected patients has been associated with increased inflammatory responses, cell death and correlated with different parameters associated with dengue disease [37].
\nThe HPV infection, although necessary, is not sufficient to cause cancer and several studies have been devoted to the search for concurrent carcinogenic factors. Among these cofactors, many evidence support the role of ROS. It is clear that viral infection induces ROS that in turn causes damage to all types of biological macromolecules. Two different types of cooperative mechanisms are presumed to occur between ROS and HPV: (i) the ROS genotoxic activity and the HPV-induced genomic instability concur independently to the generation of the molecular damage necessary for the emergence of neoplastic clones. This first mode is merely a particular form of cocarcinogenesis and (ii) ROS specifically interacts with one or more molecular stages of neoplastic initiation and/or progression induced by the HPV infection [38, 39].
\nTherefore, it seems reasonable to hypothesize that, while in most cases the cells react to HPV infection and can overcome the virus-induced ROS by activating apoptosis leading to termination of viral replication and lesion regression, in some of the infected cells a steady state balance between ROS generation and detoxification is established, partly due to viral-induced antioxidant response. Thus, infected cells can aberrantly proliferate, paving the way to neoplastic progression HPV, exploit host cell survival mechanisms, through modulation of redox homeostasis, increasing the activity of catalase, SOD among other, as an adaptive response to the high ROS conditions of preneoplastic lesions. Elevated GST and GSH provide the HPV hosting cell with improved oxidative damage detoxifying systems, but suppression of p53 and iNOS together with induction of vascular endothelial growth factor (VEGF) and resistance to ROS leads to the suppression of apoptosis and generates an oxidant fitting cell phenotype. Therefore, the tumor cell adapts their metabolism in order to support their growth and survival, creating a paradox of high ROS production in the presence of high antioxidant levels [38, 39].
\nMany signaling pathways that regulate the metabolism of ROS are also linked to tumorigenesis [40, 41]. However, ROS can also promote tumor formation by inducing DNA mutations and pro-oncogenic signaling pathways. The production of low level of ROS is required for homeostatic signaling events. It can be driven by NAD(P)H and NAD(P)H oxidase (NOX), leading to the increase of cell proliferation and survival through the posttranslational modification of kinases and phosphatases. At moderate levels, ROS induce the expression of stress-responsive genes such as
The regulation of oxidative stress is an important factor not only for tumor development but also for the responses to anticancer therapies. As high ROS levels are harmful to cells, oxidative stress can have a tumor-suppressive effect. This imparts pressure on cancer cells to adapt by developing strong antioxidant mechanisms. But despite having an enhanced antioxidant system, cancer cells maintain higher ROS levels than normal cells. At high levels, ROS can cause damage to macromolecules, including DNA; induce the activation of protein kinase Cδ (PKCδ), triggering senescence; and/or cause permeabilization of the mitochondria, leading to the release of cytochrome
The role of ROS in carcinogenic process can be either pro or anti oncogenic, and it can be summarized as follows: (i) regulating tumor development and signaling pathways for cell progression through ERK1/2 activation and ligand-independent RTK activation; (ii) regulating chronic inflammation for example through NF-kB activation; (iii) controlling tumor suppressor expression and cell cycle inhibitors; (iv) mediating angiogenesis by the release of vascular endothelial growth factor (VEGF) and angiopoietin; (v) favoring metastasis and tissue invasion due to metalloproteinase secretion; (vi) avoiding cellular death by activating SRC and PI3K/AKT pathway. Additionally, generating ROS is the mechanism of attack used by most of chemotherapies and radiotherapy [43, 44].
\nKeap1 (Kelch-like ECH-associated protein 1) sequesters Nrf2 (nuclear factor erythroid-derived 2) in the cytoplasm by binding to its aminoterminal regulatory domain. Keap1 is a sulfhydryl (S)-rich protein, and several cysteine residues mediate the Keap1–inducer interaction. When the interaction between Keap1 and Nrf2 disrupts, it allows Nrf2 to translocate to the nucleus. In the nucleus, Nrf2 controls several different antioxidant pathways by activating the expression of GSTs and other genes. This control is important to avoid cellular wear caused by oxidative stress, thus hindering the onset of various diseases.
The interindividual variation of the activity of antioxidant enzymes, for example, GST, considered by both environmental factors (e.g., diet and exposure to toxins such as cigarette) and genetic, is directly related to the etiology of cancer. Cytosolic GST present polymorphisms in humans and, this is probably the cause for differences in interindividual response to xenobiotics. The first studies in this area have addressed the correlation between GSTM1 null and/or GSTT1 null genotypes and a higher incidence of lung cancer, bladder, breast, colorectal head/neck. The discovery of allelic variants of GSTP1, encoding enzymes with reduced catalytic activity, led many researchers to examine the hypothesis that the combinations of polymorphisms of the Mu class, Pi and Theta of GST contribute to disorders with environmental factors [45, 46]. Studies with mice that exhibited a homozygous deletion of Nrf2 showed that Nrf2 is critical for inducing hepatic glutathione S-transferase (GST), NAD(P)H: quinone oxidoreductase (NQO1) and regulating levels of glutathione (Figure 1) [47].
\n\nBesides genetic variants of GST, changes in phase I enzyme activity as encoded by the cytochrome P450 family can also have implications for the metabolism of specific nitrosamines from the tobacco, alcohol and other carcinogenic substances [48].
\nThe GST enzymes are part of an integrated protection system, so it is important to note that the efficiency of this system depends on the combined action of other enzymes, such as γ-glutamylcysteine synthase γGluCysS) and glutathione synthase, in order to provide glutathione as well as carriers to facilitate the elimination of glutathione conjugates [21].
\n\nThe modulation of intracellular ROS levels is crucial for cellular homeostasis, and different ROS levels can induce different biological responses. It can occur due to the accumulation of intrinsic and/or environmental factors, such as hypoxia, enhanced cellular metabolic activity, mitochondrial dysfunction, increased activity of oxidases, lipoxygenases and cyclooxygenases. The accumulation of free radicals can lead to important changes in the structure of nucleic acids, proteins and lipids, altering their functions with consequent impact on cellular metabolism. These changes create conditions favorable to the onset of different diseases. The determination of oxidative stress markers and plasma antioxidants can suggest a targeted therapy against deficiencies in cell protection systems and it could be useful in an attempt to minimize complications caused by increased oxidative stress, leading to a better prognosis of various diseases.
\nGlycans, as potential biomarkers of health and illness, deserve attention in clinical glycomics for early-stage disease diagnosis [1, 2]. It is not surprisingly that abnormal (aberrant) glycosylation of proteins and lipids have been observed in many diseases, including cancer, cardiovascular disease, immune deficiencies and diabetes [3].
Diabetes mellitus (DM) is one of the most common endocrine diseases that have been identified as one of the priority issues for national health systems around the world. Type 1 DM is characterized by a progressive autoimmune destruction of pancreatic β-cells, leading to insulin deficiency and chronic hyperglycemia [4]. The social significance of this problem is that DM associated with development of numerous concomitant diseases, early disability, and metabolic complications [5]. Insufficient control of glucose level in blood may increased the risk of microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (peripheral artery disease, coronary artery diseases, congestive heart failure, myocardial infarction, stroke) complications. In addition, individuals with DM have increased risk of physical and cognitive disability, depression and cancer [6]. The various complications related to diabetes are determined by changes of blood components. Blood cells (leukocytes, erythrocytes and thrombocytes) are of particular interest because they are directly exposed to high glucose concentrations [7]. Blood cells aggregate strongly to the vessel wall and adhere to each other, which leads to the development of pathological changes in capillary blood flow and microcirculation disorders in diabetes [4, 5, 6].
Leukocytes are the major cells of the inflammatory and immune response that defends against different type of infection, consequently these cells are important object for investigation [5]. The сlinical and experimental studies of human blood in case of DM and animals with streptozotocin-induced diabetes demonstrate significant violations of the morphofunctional state of leukocytes. The dysfunction of chemotaxis capacity, adhesion and migration, reduction of phagocytic activity and bactericidal ability of leukocytes correlate with the level of hyperglycemia in blood [8, 9].
The impairment in the functions of immunocompetent cells leads to a decrease in immune defense and the development of chronic infectious/inflammatory processes in organism of people with type 1 diabetes [10]. Chronic inflammation is the main cause of progression of diabetic complications which leads to dysfunction of the extremities, retina, kidneys, nerves, heart and blood vessels. According to statistics, most of patients die from angiopathic complications of diabetes. Screening of complications provides with possibility to reduce the risk for their development and progression [11]. Therefore, expansion of diagnostic methods for characterization of changes in the morphofunctional state of leukocytes and the search for preventive remedies that would ameliorate the clinical condition of patients is a relevant problem today.
Experimental studies have shown that cells of the immune system are exposed to the direct and indirect effects of high blood glucose concentrations in patients with diabetes [4, 5]. Glucose metabolism pathways are activated under conditions of hyperglycemia include the autooxidation of glucose, caused glycation of long-lived proteins; the hexosamine pathway, which leads to the glycosylation of hydroxyl-containing amino acid residues; sorbitol metabolism, accompanied by the formation of free radical; and oxidative phosphorylation leading to mitochondria electron transport chain intensification and the generation of superoxide-anion radicals [12, 13]. Glucose autooxidation and glycation of proteins and lipids leads to an accumulation of advanced oxidation protein products and advanced glycation end products (AGEs), which are difficult to eliminate from the blood and remain in circulation [14]. They are also the source of reactive oxygen species (ROS) since they imitate metal containing oxidation systems. Excessive formation of ROS and reactive nitrogen species (RNS) leads to the development of oxidative-nitrative stress [15]. These changes create a favorable background for the formation of micro- and macrovascular diabetic complications [15, 16].
In condition of hyperglycemia, leukocytes are preactivated by ROS and RNS, angiotensin II, and AGEs. The interaction of AGEs with their receptors, RAGE, causes intracellular signal transduction, which leads to changes in gene expression, overproduction of free radicals, the release of pro-inflammatory molecules (tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), IL-2, IL-6 etc.), and changes in the activity of intracellular enzymes [17].
Glycosyltransferases and glycosidases, which involved in the synthesis of glycans of glycoconjugates, pay much interest among cellular enzymes [18]. In general, mammalian glycans are the product of several types of glycohydrolases and dozens of glycosyltransferases, which act sequentially in the process of oligosaccharide chains synthesis. Each of the glycosyltransferases uses one type of sugar substrate and forms a specific bond between one monosaccharide and a glycan precursor. Thus, the set of glycosyltransferases in the cell determines what type of glycans, among the large number of possible structures, will be formed [19].
The variety of monosaccharides is very large, but most often the carbohydrate components of glycoconjugates of eukaryotic cells include glucose (Glc), N-acetylglucose (GlcNAc), galactose (Gal), N-acetylgalactose (GalNAc), mannose (Man), N-acetylneuraminic acid (Neu5Ac), also known as sialic acid (Sia). Different monosaccharides, combined in a specific sequence by glycosyltransferases, form a glycan, which at one end attaches to a protein or lipid molecule. The formed glycoconjugates are the main macromolecular constituents of biomembranes [19, 20].
The diversity of glycans attached to proteins and lipids makes it possible to form unique glycoconjugates with a wide range of cellular functions. Glycoconjugates play an important role in various biological processes, in particular, glucose homeostasis, protein quality control, cellular differentiation, adhesion, intercellular signaling and inflammation. It is known that carbohydrate residues increase the solubility of glycoproteins, protect against proteolysis, influence on their folding, intracellular transport and secretion. Glycoconjugates are components of the glycocalyx, providing specific interactions with ligands, intercellular contacts and communication. Glycans of glycoconjugate are involved in the formation of the immune response, blood clotting and provide the individuality of organisms and their plasticity [20].
The immune system is highly controlled and fine-tuned by glycosylation, through the addition of a variety of glycans to virtually all adhesion molecules and receptors of leukocytes. Glycoconjugates are implicated in fundamental cellular and molecular processes. Glycans perform function of molecular recognition that regulates both stimulatory and inhibitory immune pathways [21]. The presence of modified carbohydrate determinants in the glycan structure modifies the biological activity of the entire glycoconjugate. The interaction of specific ligand with its modified receptor leads to violations at the level of transmembrane and intracellular signaling [22]. In according to the importance of glycans in the immune system, scientific researches emphasize the essential contributions of glycosylation in the regulation of innate and adaptive immune responses [21]. Therefore, today the scientists (biochemists, molecular biologists, immunologists, pathologists and pharmacologists) are making the great efforts to explore the interrelations of carbohydrate determinants with their glycobiology. Establishing changes in the glycans structure of membrane glycoconjugates of immunocompetent cells makes it possible to understand the mechanism of pathological changes in condition of diabetes and diabetic complications.
Thus, changes in intracellular metabolism, intensification of glycation processes and the development of oxidative-nitrative stress in blood cells under conditions of prolonged hyperglycemia are the main factors that induce pathological changes in the structure of their components and affect their functional state [12, 20].
Glycoconjugates of leukocytes contain sialic acid as the terminal sugar and play important roles in many physiological processes. Sialic acid normally exists in the periphery of non-reducing end of the oligosaccharide chains of many glycoproteins and glycolipids. They are involved in carbohydrate-protein interactions during cell recognition, in cell–cell interactions involving functional receptors, in the binding of pathogens such as viruses, bacteria or parasites [19, 23]. Sialic acids are also implicated in the processes of activation, differentiation, survival and apoptosis of leukocytes. Sialoglycoconjugates affects cellular adhesiveness, antigenicity, action of some hormones, catalytic properties of enzymes, modulating the affinity of cell surface receptors and transmembrane signaling [19, 20]. It is obvious that sialic acids are important molecular determinants of many immune processes. To implement these functions, organisms have a range of proteins (sialospecific lectins) that recognize surface-exposed sialic acids in glycoconjugates [19].
The variety of functions indicates the importance of sialic acid in cell biology. The biology of sialic acids should be considered from the point of view of their dual function. On the one hand, sialic acid acts as biological mask agent by masking recognition sites such as receptor molecules of cell membranes. On the other hand, sialic acid plays a role as recognizable cell patterns. Sialic acids as ligands are recognized by lectins, antibodies, hormones or as receptors recognize extracellular markers in the molecular processes of cell interactions [23, 24, 25]. Activation of cells can lead to the opening of ligand-binding sites with a subsequent increase in binding affinity, lowering the cellular activation threshold, or removal of inhibitory signals [26, 27].
Sialic acids can participate directly or indirectly in multiple cellular events and overall immune response [28]. Sialic acids contribute to cells being “self” and, thus, weakens immunoreactivity. That is why they are not recognized by immune system cells or macrophage lectins. The loss of these masking monosaccharides makes the cell “foreign”, activating the body’s immunoreactive response. Therefore, sialic acids can be considered components of innate immune protection [29]. These acids have recently been recognized as being involved in most important phenomena of molecular and cellular interactions in immune regulation [30, 31]. In this respect, sialic acids have been associated with inflammatory diseases, malignancies, cardiovascular disease and diabetes [32].
Sialic acids are group of monosaccharides with high structural diversity, which are chemically derived from nine carbon acidic sugars – neuraminic acids. The most abundant member of the family carries an acetyl moiety linked to the amino group of fifth carbon (C5) giving the Neu5Ac. A feature of its structure is the presence of a carboxyl group near C1, which determines the negative charge of the molecule at physiological pH and characterizes it as a strong organic acid (pK 2.2). More than fifty derivatives of neuraminic acids have been found in nature. The most common sialic acid derivatives found in mammals are Neu5Ac and N-glycolylneuraminic acid (Neu5Gc), whereas in humans Neu5Ac is the dominant sialic acid [19, 23, 33].
Due to their negative charge at physiological pH and hydrophilic property sialic acids stabilize conformation of molecules, can impact protein oligomerization, the interactions of proteins with other proteins and the extracellular matrix. Sialic acids as an essential compound of all cell membranes play an important role in maintaining the structure, permeability and integrity of the cell membrane [28, 34]. Not surprisingly, sialic acid exponation is dynamic, changes during development and is altered in numerous diseases [35]. Changes in sialylation are associated with oxidative stress induced by several disorders including diabetes. It has been proven that level of sialic acid increased in plasma in condition of inflammatory processes and DM [36]. The relation between sialic acid and diabetes duration most likely follows from the association sialic acid with microvascular complications, which are well established to be related to glycemic control [37]. Therefore, sialic acid concentrations in the blood may be a useful marker of the development of diabetic complications, but there have been no many studies examining the link between sialoglycoconjugates and complications in type 1 DM.
The structural diversity of sialoglycoconjugates is due not only to the diversity of derivatives of sialic acids in their composition, but also depends on the type of glycosidic linkages (2,3, 2,6, 2,8, and 2,9) with subterminal sugars. The sialylation of oligosaccharide chains of glycoconjugates is carried out with the participation of the family of enzymes sialyltransferases (STs). About 20 STs have been characterized [19]. STs are divided in four main subfamilies, namely the ST3Gal, ST6Gal, ST6GalNAc and ST8Sia, depending on the glycosidic linkage formed and the monosaccharide acceptor recognized [35, 38]. ST3Gal, ST6Gal, ST6GalNAc and ST8Sia link Neu5Ac via its C2 to the C3, C6 positions of other carbohydrates or the C8, C9 positions of another sialic acids, generating α2,3-, α2,6-, α2,8, or α2,9-linked sialic acids, respectively [19, 39]. Sialyltransferase-mediated addition of sialic acid on glycans usually stops their further growth and modifies charge, steric hindrance, conformation and flexibility, underlying the importance of STs in shaping the structures and functions of sialoglycans [35, 40].
In the structure of leukocytes’ glycans sialic acids are frequently the terminal residues of glycans and are mostly attached either by a 2,3- or 2,6-glycosidic bond to Gal or GalNAc of oligosaccharide chains [19]. The ST6Gal and ST6GalNAc, which are present in leukocytes, catalyze the transfer of Neu5Ac from CMP-Sia (cytidine-5′-monophospho-N-acetylneuraminic acid) to the C6 hydroxyl group of a terminal Gal or GalNAc residues, respectively, with the formation of α2,6-linkaged sialic acids in the oligosaccharide chains of glycans [19, 20, 38]. The ST3Gal comprises family with six members (ST3Gal I–VI). The expression of ST6Gal-I is tissue specific and regulated by multiple transcriptional promoters [41, 42]. An inducible and liver-specific promoter drive high ST6Gal-I expression during inflammation with increase in secreted ST6Gal-I in blood [43]. Activated platelets release the CMP-Sia that serves as the donor for circulating ST6Gal-I, allowing for the remodeling of the glycans of hematopoietic stem cells and multipotent progenitors (HSC/MPPs) [44]. Thus, inducible promoter is important for regulation of hematopoiesis [45]. The ST3Gal-V add a sialic acid to terminal Gal residues with the formation of α2,3-glycosidic linkage, while ST3Gal-IV sialylates Galβ1,3GalNAc terminated structures in glycoconjugates and Galβ1,4(3)GlcNAc structures found on N- and O-glycans [46]. The ST3Gal-IV and ST3Gal-VI involved in the synthesis of the sialyl LewisX (sLeX) determinant on leukocyte E-, L- and P-selectin ligands [19, 46]. Leukocytes express a number of different selectin ligands, including E-selectin ligand-1, P-selectin glycoprotein ligand-1, CD43, CD44, β2-integrins, ets. [35, 47].
Glycosylation of cell-surface structures of leukocytes is important in the accomplishment of the immune function by these cells in organism. The membrane structures of leukocytes are decisive in the processes of extravasation, the migration of leukocytes from blood vessels into the extracellular space. In order to penetrate the vascular wall, leukocytes initially interact with the endothelium, roll over its surface, undergo dense adhesion, dissolve, and finally move through or between endothelial cells of the blood vessel [48, 49, 50]. Leukocyte chemotaxis depends on the surface sLeX and E-selectin of vascular endothelial cells. E-, L- and P-selectins are exposed by endothelial cells, leukocytes and platelets, respectively. Selectins are carbohydrate-binding proteins that recognize the sLeX structure (Neu5Acα2,3Galβ1,4(Fucα1,3)GlcNAcβ-R), capping N- and O-glycans as specific ligands [51, 52, 53]. These sialic acid-containing moieties are required for leukocyte binding to selectins on endothelial cells and their rolling [54, 55]. Combinatorial knockout of ST3Gal-IV and ST3Gal-VI that are the involved in sLeX synthesis leds to a decrease in neutrophil binding to E- and P-selectins, selectin-dependent rolling, and lymphocyte homing [46]. The selectin profile of cells can change under the influence of cytokines in case of development of inflammatory process, infection or under the influence of ROS. In tissue inflammation, cytokines stimulated endothelial cell production of E-selectin, which could recognize sLeX on the leukocyte surface and bind it, promoting leukocyte adhesion to the vascular endothelium and, subsequently, to the inflammatory tissue or locations of injury [32, 56]. Therefore, the recognition of all types of selectins is mediated with sialic acid residues [19].
In the catabolism of sialoglycans of glycoconjugate involved extracellular and intracellular sialidases, a glycoside hydrolase, that specifically hydrolyze release α-linked sialic acid residues through hydrolysis of the glycosidic bond between the acidic sugar(s) and the internal acceptor. Four different sialidases (also termed as neuraminidases – NEUs) in mammalian cells, NEU1, NEU2, NEU3 and NEU4, have been described [57]. These NEUs exhibit differences in cellular localization, substrate specificities, physiological functions and expression patterns in different tissues and physio/pathological conditions [35, 57, 58]. The NEU1 is found in the lysosome and on the cell surface and is the most highly expressed of this sialidase family [35]. The level of NEU2 is extremely low and the content of NEU3 and NEU4 are about 10% of NEU1 in tissue separately [57]. The lysosomal sialidase NEU1 initiates the degradation of sialoglycoconjugates [59]. The NEU1 is capable of hydrolyzing a wide range of glycoproteins, oligosaccharides and ganglioside near neutral pH. It exclusively acts on glycoproteins and preferentially cleaves α2,3-linkages over α2,6- or α2,8-linkages [19, 35]. In addition, NEU1 may have extralysosomal localization and focus on the periphery of activated lymphocytes. The NEU1 controls several aspects of the immune response by the desialylation of molecules, such as Toll-like receptor 4 and adhesion molecules involved in the recruitment of leukocytes to inflammatory sites [35, 57]. Desialylation of sialyl α2,3-linked Gal residues of Toll-like receptor 4 is essential for receptor activation and cellular signaling [60]. The cytosolic sialidase (NEU2) can hydrolyze sialic acids from glycoproteins and gangliosides [61]. The plasma membrane-associated sialidase (NEU3) is a key enzyme for ganglioside hydrolysis [57]. The NEU4 is localizing in the lysosomal lumen or bound to the outer mitochondrial membranes via protein–protein interactions or the ER membrane-associated. Its exhibits the highest activity with gangliosides as well as sLeX and sLea antigens [35, 57, 58]. Sialic acid is actively exfoliated from the cell surface by extracellular sialidases during leukocyte activation. This process plays an important regulatory role in cell activation and differentiation [62].
Metabolism of sialic acids includes the cooperation of enzymes that catalyze the biosynthesis, activation, transfer of sialic acids to glycoconjugates, as well as the removal and degradation of sialic acids [63]. The aberrant expression of STs and NEUs accelerates and sustains sialylation status on glycoconjugates [64]. Therefore, knowledge in this field of glycobiology allows to predict biological events in case of increase or decrease in the amount of sialoglycoconjugates on the cell surface or under conditions of modification or structural changes of these acids in certain types of cells. Thus, STs, NUEs and sialic acids itself represent important therapeutic targets for medicinal chemistry and biopharmaceutical industry [65, 66].
Glycocode information is read in living organisms with the help of specific compounds – lectins. Lectins are sugar-binding proteins that can specifically recognize glycans of glycoconjugates without disrupting the structure of the recognizable carbohydrate-containing ligands.
Since surface glycoconjugates have a unique structure for each cell type, they can be identified, quantified and characterised structural changes in glycans using specific lectins. Nowadays, lectins, their properties, the importance of these proteins in the life of organisms and their applying in experimental biology and medicine are the subject of research in the world’s science laboratories. Lectins excluded from living objects are valuable biochemical reagents that are used in experimental cytochemistry, in the diagnosis of some diseases, and in biotechnology for isolating certain carbohydrate-containing molecules [20, 67].
Interactions of sialic acids with lectins play a leading role in many physiological and pathological processes. Therefore, sialospecific lectins are used to recognize sialic acids with specific linkages to subterminal sugars. Wheat germ lectin (WGA) specifically binds to β,DGlcNAc and Neu5Ac. The
Examples of uses of lectins in glycobiology. Many plant and animal lectins are multivalent. In particular, the lectin is shown with four carbohydrate binding domains. (A) Lectins bind of surface glycoconjugates of leukocytes, causes cell aggregation. (B) Histochemical analysis of surface glycans. (C) Enzyme linked lectin assay: biotinylated lectins bind to glycoconjugates on the surface of cells immobilized to the bottom of the well of a flat-bottomed plate; bound lectins are detected by antibodies to biotin with horseradish peroxidase.
Blood leukocytes are similar in structural organization, and, at the same time, they differ significantly in biochemical structure. It is very important to understand the morphofunctional state of the cell is to be able to detect these differences. Numerous methods are used for this purpose [70]. Aggregatometry is one of the assays used to evaluate the functional properties of platelets, leukocytes and erythrocytes in the dynamics, monitor antiplatelet therapy, study the mechanisms of aggregation. The aggregation capacity of cells is assessed by such parameters as the degree, rate and time of aggregation [20].
The substances of protein (lectins, proteolytic enzymes, chemoactive peptides); lipid (metabolites of arachidonic acid, liposomes); carbohydrate (heparin, dextransulfates) or other nature (phorbol esters, amphotericin B, ADP, organic dyes – alcyanine blue, ruthenium red) can be inducers of aggregation. Lectins used in aggregatometry are divided into lectins-mitogens (СonA, PHA) and polyvalent lectins (WGA, SNA). Polyvalent lectins have two or more binding centers of carbohydrate determinants (carbohydrate-recognition domains) on the cell surface. The aggregation of cells by such lectins is due to the formation of intercellular molecular bridges. The ability of each subunit of lectin to bind sugars individually leads to the formation of a cross-linked structure of the aggregate. The efficiency of lectin-induced aggregation is determined by the processes of clustering of lectin receptors on the cell surface [20, 75].
The aggregation capacity of leukocytes is studied to model their pre-migratory state before leaving the bloodstream, i.e. before diapedesis, or to analyze phagocytic activity. It is consider that phagocytosis involving lectin-carbohydrate interactions is one of the oldest evolutionary forms of this process [76]. Phagocytosis during evolution was significantly displaced by antigen–antibody interactions, but did not lose importance in the formation of a nonspecific immune response [77].
Leukocytes are markers of the immune homeostasis and receive signals from the microenvironment through the glycans of receptors. Lectins of certain carbohydrate specificity are ligands that selectively activate chemokine receptors. The response of cells to lectins
Lectins WGA, SNA and MAA, which specific to sialic acids, are used to determination sialylated glycoconjugates and differentiation various types of sialic acid links with subterminal carbohydrates of glycans (SNA recognizes α2,6-links, while МАА identifies α2,3-links, Figure 2) [75, 79].
The structure of leukocyte sialic acid-containing membrane glycans in physiological state of cells and in type 1 diabetes. Sialic acids, depending on the type of glycosidic bond in the structure of the glycan, are recognized by WGA, SNA and MAA lectins.
Alteration of the amount of sialic acids on the surface of leukocytes is an additional level of regulation of cells affinity to signaling molecules (cytokines, hormones), pathogenic microorganisms and determines the nature of cell–cell interactions [20].
The most significant changes of increasing lectin-induced aggregation of leukocytes in type 1 diabetes have been observed using lectin WGA. An increase in the degree and rate of WGA-induced aggregation of neutrophils in diabetes is a sign of increased of N-acetyl-β,D-glucosamine-containing and sialic acid-containing glycoconjugates on surface of leukocytes [80]. This indicates that synthesis of hybrid types of N-glycans is occured by activated N-acetylglucosaminyltransferase-III (GnT-III) and incomplete glycosylation of proteins and lipids [20]. As a result, glycoconjugates with terminal β,D-GlcNAc residues are exhibited on the leukocyte surface and determined high rates of WGA-induced aggregation [81].
The structural characterization of neutrophils glycoconjugates showed that cell surface N-glycans are highly sialylated, and many of their “antenna” play an important role in selectin-mediated neutrophil circulation [82]. Glycome of neutrophils is consisted mainly of complex bi- tri- and tetra-antennary N-glycans (Figure 2). Their antennae are predominantly terminated with Neu5Ac and LeX (Galβ1,4(Fucα1,3)GlcNAc) epitopes [83]. The ST3Gal-IV knockout results in significant reduction in the synthesis of sLeX structures in neutrophils. These cells show significant impairment in rolling and adhesion to the endothelial cells [84]. All these structural changes in the carbohydrate chains of glycoconjugates of leukocytes induce disturbances of molecular signals perception from the microenvironment, affecting interaction of leukocytes with other circulating blood cells and vascular endothelium in condition of diabetes [7, 20, 85].
Sialic acids can mask, i.e. change the structure of carbohydrate components of various specific receptors on the cell surface [19]. There is the receptor to N-formyl-methionyl-leucil-phenylalanine, C5a component of the complement system, IL-8, the receptor of granulocyte-monocyte colony-stimulating factor and the cell receptor 3 (Mac-1) among WGA-binding glycoproteins. The interaction of neutrophils with the intercellular adhesion molecule 1 (ICAM-1, CD54), which is involved in the adhesion of leukocytes to the vascular endothelium occurs via the Maс-1 receptor. On the other hand, WGA-specific receptors are involved in the stimulation of respiratory burst in neutrophils by activating NADPH oxidase and followed formation of ROS [86, 87, 88].
The content of GlcNAc and Neu5Ac residues in glycans of glycoconjugates of the plasma membrane of neutrophils increases in type 1 diabetes [72]. It may be one of the main causes of nonspecific damage of tissues and cells, which are close to stimulated neutrophils. Under such conditions, neutrophils produce ROS and cause erythrocytes, platelets, fibroblasts and endotheliocytes death, inactivate enzymes, lead to changes in the structure of proteins and lipid peroxidation [6, 20].
Interaction of glycoconjugates of polymorphonuclear leukocytes with lectin SNA changes significantly under DM [80]. The level, velocity and time required for the maximum neutrophilic granulocyte aggregation in patients with type 1 DM duration of up to 5 years have been different from these indicators in patients with diabetes lasting more than 10 years. In particular, in the early stages of the disease, the degree of neutrophils aggregation, as well as the rate of SNA-induced aggregation have been four times higher than in patients with the disease over ten years [20, 80]. It is assumed that with the disease progresses, changes in leukocytes are associated with neutrophil subactivation processes that lead to the release of granule contents into the extracellular space, especially intravascularly. Degranulation leads to the lowering of cells aggregation [88, 89]. It is known that elevated glucose levels inside the cell have an inhibitory effect on a number of enzymes that are involved in the biosynthesis of the oligosaccharide chain of glycans. One of such enzymes is STs, which catalyze the attachment of sialic acid to the terminal sugar in glycan structure [19, 39]. Hyperglycemia is probably one of the factors that mediates the glycan profile violation of leukocytes in diabetes.
Decreased aggregation of neutrophils in patients with DM under the addition of MAA lectin indicates the presence sialic acids in the structure of glycoconjugates of neutrophil membranes in a small amount. These α2,3-linked sialic acids affect both the dynamic and kinetic parameters of the neutrophil aggregation process [72, 90]. The decrease in sialic acid content in the cellular glycocalyx is most often due to the enhanced desialylation of the membrane glycoconjugate. It is worth noting that sialic acids which are linked to subterminal sugars of the glycoconjugates oligosaccharide chains by the α2,3-glycoside bond are much more likely to undergo hydrolytic cleavage by sialidases than α2,6-linked residues of these sugars [90]. Cleavage of sialylated oligosaccharide fragments from glycoconjugates or exfoliation of the whole molecules of sialoglycoconjugates can be another reason of loss of sialic acids from the cell surface. However, there is often a combination of all these factors [20, 81]. Decreased α2,3-linked sialic acid on the surface of leukocytes leads to impaired perception of signals from the extracellular space, interaction with other cells, as well as numerous bacteria, protozoa and viruses. Desialylation of surface glycoconjugates of polymorphonuclear leukocytes leads to increasing of their adhesive properties, which promotes the migration of neutrophils through the vascular endothelium [91].
The interaction of glycoconjugates of mononuclear leukocytes with lectin MAA, which reacts with Neu5Acα2,3 Gal/GalNAc terminal endings glycan, have been markedly inhibited under diabetes [90, 92]. It has been found that the decrease in sialic acid content usually occurs due to increased activity of endogenous sialidases in activated T cells and monocytes [46]. This leads to increased production of cytokines by lymphocytes and interaction of monocytes with hyaluronic acid – a component of extracellular matrix [93, 94]. The NEU1 and NEU3 are expressed in monocytes in the process of their differentiation into macrophages. Desialylation of glycans on the surface of monocytes by exogenous NEU resulted in activation of ERK1/2 and p38 MARK signaling pathways and increased production of IL-6, IL-1β, MIP-1α and MIP-1β [94, 95]. Рro-inflammatory cytokines cause endothelial dysfunction by increasing capillary permeability, inducing prothrombotic properties, promoting leukocyte recruitment by synthesis of adhesion molecules and chemoattractants, and play a role in macroangiopathy by promoting dyslipidemia. Thus, it is unlikely that the increased circulation of sialic acid is the result of desialylation of glycoconjugates. However, there is evidence that sialic acid is reduced in endothelium and erythrocytes in diabetes, which may be important in the pathophysiology of vascular disease [37].
Due to fact that terminal α2,3-linked sialic acids are included, in particular, in the structure of the CD45 receptor, which mediated an increasing of T cell proliferation [96], the decrease content of sialic acids in type 1 diabetes indicates a violation of this function in immunocompetent blood cells. Studies showed that the sialylation of T cell CD45 by ST6Gal-I blocks galectin-1 clustering of CD45 and resulting cell death [97]. The α2,6-sialylation of FasR blocks binding of Fas-associated adaptor molecule to the FasR death domain, thus inhibiting the formation of the death-inducing signaling complex [98].
Lectins SNA and MAA interact with CD45+ leukocytes [96]. CD45 is a transmembrane glycoprotein found on T, B, NK cells, granulocytes, and monocytes. It has a cytoplasmic tail with cytosolic phosphotyrosine phosphatase activity. CD45 is the antagonist of tyrosine kinase of insulin receptor, whereas it can show high activity towards membrane-bound molecules (receptors of insulin and epidermal growth factor) [96, 99]. The increased content of sialoglycans in CD45 may cause masking of insulin receptors on organs and tissues, preventing the effect of minimal amounts of the hormone, which can still be produced in type 1 diabetes. This effect may disimprove complications during the development of the disease [96].
The α2,6-sialylation of leukocyte glycoconjugates undergoes certain changes in type 1 DM (Figure 2) [100]. Therefore, the quantity of sialic acids linked by α2,6-glycosidic bonds correlate with the disease duration. The content of sialoglycoconjugants on leukocytes surfaces increases for patients with the disease up to five years, while it decreases for patients with the disease duration over ten years. The pathology is accompanied by an increase of linkage places for SNA, which indicates the replacement of α2,3-linked sialic acids by α2,6-linked acids. It is likely to as a result of quantitative changes in the cells or in the enzyme activity of ST6Gal and/or ST6GalNAc [45]. The activity of α2,6 sialyltransferase decreases during the biosynthesis of O-glycans of T lymphocyte in the process of their activation. Thus, an increase in the content of α2,6-linked sialic acids of leukocyte cell surfaces along with a decline in the number of α2,3-linked sialic acids may indicate an increased sensibilization towards B lymphocyte stimulation and the inhibition of T lymphocyte activity under type 1 DM [20, 58].
Under cell–cell interaction, not only the presence of certain glycoconjugate, but also the type of linkage of sialic acids to the oligosaccharide chaine is informative. Against the general increase in the number of sialic acid-containing glycoconjugates on leukocytes surface under type 1 DM, there were small quantities of sialic acids linked by α2,3-glycosidic bond to subterminal carbohydrates in structure of glycans. Whereas, the quantity of sialic acid linked by α2,6-glycosidic bonds in the structure of sialoglycans correlated with the duration of diabetes. Such peculiarities of the structure of sialoglycoconjugates of leukocytes may affect both dynamic and kinetic indices of cell aggregation. Leukocytes aggregation affected by lectins may be used as a model of adhesion and migration of these cells. Тhe abnormal redistribution of glycoconjugates on leukocytes membrane under type 1 DM causes changes in their aggregation and adhesion to the vascular endothelium, as well as impairment of the phagocytic function of neutrophils. Thus, the accumulation of leukocyte aggregates in microvessels and violation of disaggregation mechanisms lead to damage of blood vessels. Such changes are etiological preconditions for the development of complications and chronic diseases resulting in deterioration in diabetics’ conditions.
The authors declare no conflict of interest.
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