\r\n\tThis book aims to offer readers a comprehensive understanding of ceramic materials. The detailed guidance provided in this book will help not only the students, researchers and professionals in the field of materials science and allied disciplines but the researchers and professionals in other fields.
\r\n\r\n\tThe book aims to provide the latest developments on the advanced ceramics and their latest applications in a wide variety of fields. The key features of this book intend to provide the reader with an understanding of how ceramics are applied, explores recent characteristics and properties of these materials, taking into account their structures and compositions, and discusses the various processing of ceramics.
\r\n\r\n\tThis book will rapidly become the reference work on the subject of ceramic materials.
",isbn:"978-1-83881-212-6",printIsbn:"978-1-83881-204-1",pdfIsbn:"978-1-83881-213-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"9adbe58d10d5ca2b61e9ff2b6b138f40",bookSignature:"Dr. Mohsen Mhadhbi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9894.jpg",keywords:"New Ceramics, Traditional Ceramics, Crystallography, Composition and Structure, Processing of Ceramics, Grain Size, Dislocations, Nanoindentation, Corrosion Cracking, YoungÃÂs Modulus, Mechanical Testing, Applications of Ceramics",numberOfDownloads:642,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 29th 2020",dateEndSecondStepPublish:"August 5th 2020",dateEndThirdStepPublish:"October 4th 2020",dateEndFourthStepPublish:"December 23rd 2020",dateEndFifthStepPublish:"February 21st 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Mohsen Mhadhbi is a reviewer and editorial board member of different scientific publishers and congresses, as well as a member of a number of international associations, to name a few: American Association for Science and Technology, International Association of Advanced Materials (IAAM).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"228366",title:"Dr.",name:"Mohsen",middleName:null,surname:"Mhadhbi",slug:"mohsen-mhadhbi",fullName:"Mohsen Mhadhbi",profilePictureURL:"https://mts.intechopen.com/storage/users/228366/images/system/228366.jpeg",biography:"Dr. Mohsen Mhadhbi obtained his Ph.D. degree from the Faculty\nof Sciences of Sfax, Tunisia. He is currently Assistant Professor\nof Chemistry in the National Institute of Research and Physical-chemical Analysis, Tunisia. His research interests include\ninorganic chemistry, material engineering, intermetallics, and\npowder technology. He has published works in national and\ninternational impacted journals and books. He is a teacher in\ninorganic chemistry. He has supervised several researchers in materials science. He\nis a member of various scientific journals and associations and has been serving as\nan editorial board member of repute.",institutionString:"National Institute of Research and Physical-Chemical Analysis",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Tunis El Manar University",institutionURL:null,country:{name:"Tunisia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"14",title:"Materials Science",slug:"materials-science"}],chapters:[{id:"73232",title:"Ceramics Coated Metallic Materials: Methods, Properties and Applications",slug:"ceramics-coated-metallic-materials-methods-properties-and-applications",totalDownloads:65,totalCrossrefCites:0,authors:[null]},{id:"74485",title:"Three-Dimensionally Ordered Macroporous-Mesoporous Bioactive Glass Ceramics for Drug Delivery Capacity and Evaluation of Drug Release",slug:"three-dimensionally-ordered-macroporous-mesoporous-bioactive-glass-ceramics-for-drug-delivery-capaci",totalDownloads:33,totalCrossrefCites:0,authors:[null]},{id:"74215",title:"Ferroelectric Glass-Ceramic Systems for Energy Storage Applications",slug:"ferroelectric-glass-ceramic-systems-for-energy-storage-applications",totalDownloads:89,totalCrossrefCites:0,authors:[null]},{id:"74406",title:"The Effect of Ceramic Wastes on Physical and Mechanical Properties of Eco-Friendly Flowable Sand Concrete",slug:"the-effect-of-ceramic-wastes-on-physical-and-mechanical-properties-of-eco-friendly-flowable-sand-con",totalDownloads:57,totalCrossrefCites:0,authors:[null]},{id:"74064",title:"From the Laser Plume to the Laser Ceramics",slug:"from-the-laser-plume-to-the-laser-ceramics",totalDownloads:64,totalCrossrefCites:0,authors:[null]},{id:"73186",title:"Self-Healing of Concrete through Ceramic Nanocontainers Loaded with Corrosion Inhibitors and Microorganisms",slug:"self-healing-of-concrete-through-ceramic-nanocontainers-loaded-with-corrosion-inhibitors-and-microor",totalDownloads:83,totalCrossrefCites:0,authors:[{id:"306484",title:"Emeritus Prof.",name:"George",surname:"Kordas",slug:"george-kordas",fullName:"George Kordas"}]},{id:"73127",title:"The Investigation on the Fabrication and Characterization of the Multicomponent Ceramics Based on PZT and the Relaxor PZN-PMnN Ferroelectric Materials",slug:"the-investigation-on-the-fabrication-and-characterization-of-the-multicomponent-ceramics-based-on-pz",totalDownloads:50,totalCrossrefCites:0,authors:[null]},{id:"73977",title:"Nanostructured Multilayer Composite Coatings for Cutting Tools",slug:"nanostructured-multilayer-composite-coatings-for-cutting-tools",totalDownloads:108,totalCrossrefCites:0,authors:[null]},{id:"73538",title:"New Bismuth Sodium Titanate Based Ceramics and Their Applications",slug:"new-bismuth-sodium-titanate-based-ceramics-and-their-applications",totalDownloads:97,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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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Shaheer Akhtar and Hyung-Shik Shin",coverURL:"https://cdn.intechopen.com/books/images_new/6517.jpg",editedByType:"Edited by",editors:[{id:"52613",title:"Dr.",name:"Sadia",surname:"Ameen",slug:"sadia-ameen",fullName:"Sadia Ameen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6320",title:"Advances in Glass Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6d0a32a0cf9806bccd04101a8b6e1b95",slug:"advances-in-glass-science-and-technology",bookSignature:"Vincenzo M. 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Churchill, Maja Dutour Sikirić, Božana Čolović and Helga Füredi Milhofer",coverURL:"https://cdn.intechopen.com/books/images_new/8812.jpg",editedByType:"Edited by",editors:[{id:"219335",title:"Dr.",name:"David",surname:"Churchill",slug:"david-churchill",fullName:"David Churchill"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7960",title:"Assorted Dimensional Reconfigurable Materials",subtitle:null,isOpenForSubmission:!1,hash:"bc49969c3a4e2fc8f65d4722cc4d95a5",slug:"assorted-dimensional-reconfigurable-materials",bookSignature:"Rajendra Sukhjadeorao Dongre and Dilip Rankrishna Peshwe",coverURL:"https://cdn.intechopen.com/books/images_new/7960.jpg",editedByType:"Edited by",editors:[{id:"188286",title:"Associate Prof.",name:"Rajendra",surname:"Dongre",slug:"rajendra-dongre",fullName:"Rajendra Dongre"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7676",title:"Zeolites",subtitle:"New Challenges",isOpenForSubmission:!1,hash:"4dc664fa55f94b38c13af542041fc3cc",slug:"zeolites-new-challenges",bookSignature:"Karmen Margeta and Anamarija Farkaš",coverURL:"https://cdn.intechopen.com/books/images_new/7676.jpg",editedByType:"Edited by",editors:[{id:"216140",title:"Dr.",name:"Karmen",surname:"Margeta",slug:"karmen-margeta",fullName:"Karmen Margeta"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"39159",title:"Oxidative Stress in Diabetes Mellitus and the Role Of Vitamins with Antioxidant Actions",doi:"10.5772/51788",slug:"oxidative-stress-in-diabetes-mellitus-and-the-role-of-vitamins-with-antioxidant-actions",body:'\n\t\tDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects of insulin action, insulin secretion or both [1]. Diabetes has taken place as one of the most important diseases worldwide, reaching epidemic proportions. Global estimates predict that the proportion of adult population with diabetes will increase 69% for the year 2030 [2].
\n\t\t\tHyperglycemia in the course of diabetes usually leads to the development of microvascular complications, and diabetic patients are more prone to accelerated atherosclerotic macrovascular disease. These complications account for premature mortality and most of the social and economical burden in the long term of diabetes [3].
\n\t\t\tIncreasing evidence suggests that oxidative stress plays a role in the pathogenesis of diabetes mellitus and its complications [4]. Hyperglycemia increases oxidative stress, which contributes to the impairment of the main processes that fail during diabetes, insulin action and insulin secretion. In addition, antioxidant mechanisms are diminished in diabetic patients, which may further augment oxidative stress [5, 6]. Several studies have addressed the possible participation of dietary antioxidants, such as vitamins, in ameliorating the diabetic state and retarding the development of diabetes complications [7, 8].
\n\t\t\tThe aim of this chapter is to revise the current knowledge of the role of oxidative stress in the pathogenesis of diabetes mellitus and its complications, and to discuss the existing evidence of the effects of vitamins as antioxidant therapy for this disease.
\n\t\tAt the beginning of life, the organisms obtained their energy (ATP) by anoxygenic photosinthesis, for which oxygen was toxic. Most of the metabolic pathways were developed during this anaerobic stage of life, in which oxygen came later. Cyanobacteria started producing oxygen from photosynthesis, which raised the atmospheric oxygen, and favored those organisms which have evolved into eukaryotic cells with mitochondria, able to use oxygen for a more efficient energy production [9].
\n\t\t\tWhenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption. This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells [9]. Therefore, ROS formation is a physiological response to stress.
\n\t\t\tThe term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal. Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA [10]. Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism [11].
\n\t\t\tROS and RNS are highly reactive molecules, which can be free radicals such as superoxide (•O2\n\t\t\t\t\t-), hydroxyl (•OH), peroxyl (•RO2), hydroperoxyl (•HRO2\n\t\t\t\t\t-), nitric oxide (•NO) and nitrogen dioxide (•NO2\n\t\t\t\t\t-), or nonradicals such as hydrogen peroxide (H2O2), hydrochlorous acid (HOCl), peroxynitrite (ONOO-), nitrous oxide (HNO2), and alkyl peroxynitrates (RONOO). Most of the studies regarding diabetes and its complications have addressed the role of superoxide (•O2\n\t\t\t\t\t-), nitric oxide (•NO), and peroxynitrite (ONOO-) in this disease. There are basically two pathways for •O2\n\t\t\t\t\t- production: NADPH oxidases and mitochondrial function, while •NO and ONOO- are produced by the Nitric Oxide Synthase pathway [10].
\n\t\t\t\tOxidases are enzymes which catalyze redox reactions involving molecular oxygen (O2). Superoxide is generated by oxidases via one-electron reduction of oxygen and the oxidation of their substrates. Several oxidases exist in the body, such as xantine oxidase, glucose oxidase, monoamine oxidase, cytochrome P450 oxidase, and NADPH oxidases.
\n\t\t\t\t\tNADP in the cell exists in its reduced (NADPH) and oxidized (NADP+) forms. NADPH supplies reducing power in reactions for biosynthesis, and it also serves as electron donor substrate for the NADPH oxidase. This enzyme is a membrane-bound electron transport complex which pumps electrons from NADPH in the cytosol across biological membranes and into intracellular and extracellular compartments, such as nucleus, endoplasmic reticulum, endosome, phagosome, mitochondria and extracellular space. It is the only enzyme whose primary function is generating superoxide and/or hydrogen peroxide, mainly for preventing the transfer of pathogens and for cellular bactericidal function[12, 13].
\n\t\t\t\tMitochondrion is the site of eukaryotic oxidative metabolism. It contains the enzymes needed for converting pyruvate into Acetyl-CoA, the citric acid cycle (also known as the Krebs cycle) and for fatty acid oxidation. Additionally, it performs the electron transport and oxidative phosphorylation. Substrate (amino acid, fatty acid and carbohydrate) oxidation in the citric acid cycle release electrons, which are transferred to the coenzymes NAD+ and FAD to form NADH and FADH2. These electrons then pass into the mitochondrial electron-transport chain, a system of linked electron carrier proteins comprised by Complexes I, II, III and IV. Complex I, III, and IV drive the exit of protons from the mitochondrial matrix, producing a proton gradient across the inner mitochondrial membrane. The free energy stored in this electrochemical gradient drives the condensation of ADP with inorganic phosphate in order to form ATP by oxidative phosphorylation. Along this electron transport, molecular oxygen is the final electron acceptor, which will be then reduced to H2O [14, 15]. However, between 0.4 and 4% of all oxygen consumed will be converted into superoxide anion [16]. There is also a normal threshold for protonic potential above which electron transfer is inhibited at complex III, causing the electrons to go back to complex II where there are transferred to molecular oxygen prematurely and not to complex IV as it naturally occurs. Therefore, the endproduct of this transfer is superoxide [17].
\n\t\t\t\t\tMitochondria play an important role in the maintenance of cellular redox status, acting as a redox sink and limiting NADPH oxidase activity. However, when the proton potential threshold is surpassed, mitochondria is also a significant source of ROS, which may further stimulate NADPH oxidases, creating a vicious cycle of ROS production [18]. When mitochondria cannot further extract oxygen, cell and tissue oxygen levels rise, decreasing the tissue extraction of oxygen from the blood. This results in tissue vascularity reduction, which may be associated with peripheral vascular disease and, in time, chronic tissue hypoxia and ischemia [9].
\n\t\t\t\tNitric oxide •NO is produced by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: neural (nNOS or NOS-I) expressed in neurons, inducible (iNOS or NOS-II) expressed in smooth muscle of bold vessels, hepatocites, macrophagues and neuroendocirne tissue, and endothelial (eNOS or NOS-III) expressed constitutively in endothelial cells. iNOS and eNOS can be stimulated by the redox state in the cell, cytokines, hormones and nutrients [19, 20]. NOS catalyze the oxidation of the terminal guanidine nitrogen of the L–arginine, in presence of oxygen and NADPH, to yield L-citruline and •NO [21].
\n\t\t\t\t\tOnce produced and released, •NO can diffuse freely through membranes or act on different cellular targets. •NO participates as mediator of several physiological effects such as vasorelaxation, macrophague activation, gene expression and apoptosis. Usually, •NO is considered as a vasculoprotective molecule. However, one of its multiple effects is also protein nitrosilation at the thiol groups and RNS generation such as peroxynitrite (ONOO-), as •NO easily reacts with •O2\n\t\t\t\t\t\t-. Therefore, the amount of •O2\n\t\t\t\t\t\t- determines whether •NO acts as a protective or harmful molecule [10, 22].
\n\t\t\t\tAs a small part the oxygen consumed for aerobic processes will be converted into superoxide anion [16], which will have to be scavenged or converted into less reactive (and harmful) molecules. The main enzymes that regulate this process are Superoxide dismutase (SOD), Glutathione Peroxidase (GSH-Px) and Catalase (Figure 1). When ROS overproduction or chronic hyperglycemia occurs, the activity of these enzymes is insufficient, leading to more ROS and RNS formation and activation oxidative stress pathways.
\n\t\t\t\tAntioxidant defenses in the organism.
SOD is considered a first-line defense against ROS. This enzyme is present in nearly all cells, and converts •O2\n\t\t\t\t\t- into H2O2. Mitochondrial and bacterial SOD contain Mn, while cytosolic SOD is a dimer containing Cu and Zn. As the H2O2 may still react with other ROS, it needs to be degraded by either one of the other two antioxidant enzymes, GSH-Px or catalase [10, 12].
\n\t\t\t\tGSH peroxidase is located in the mitochondria. It catalyzes degradation of H2O2 by reduction, where two gluthathione (GSH) molecules are oxidized to glutathione disulfide (GSSG). Regeneration of GSH by GSH-reductase, requires NADPH, which is oxidized to NADP+. Catalase, on the other hand, is localized primarily in peroxisomes, and so it detoxifies the H2O2 that diffuses from the mitochondria to the cytosol, converting it into water and molecular oxygen [10, 12].
\n\t\t\t\tThere are also nonenzymatic antioxidant mechanisms, which mostly help regenerate GSSG back into GSH. Antioxidant vitamins such as A, C, E and alpha-lipoic acid are among these mechanisms. Although all these antioxidant defenses work together to eliminate H2O2 (and thus superoxide) from the cell, in the presence of reduced transition metals (Cu, Fe), H2O2 can be transformed into •OH, which is a highly reactive ROS, by the Fenton reaction [10, 23].
\n\t\t\t\t\n\t\t\tThere are several molecular pathways involved in ROS formation and ROS induced damage. Here we will review the ones that have been related to oxidative stress in diabetes. Not surprisingly, most of them are related to glucose and/or lipid metabolism.
\n\t\t\t\tIn order to generate energy, glucose needs to be first oxidized inside the cells by glycolysis. In this process, once glucose enters the cells, it is phosphorylated to form glucose-6-phosphate, a reaction mediated by hexocinases. Glucose-6-P is then converted to Fructose-6-P by phosphoglucoisomerase, which can undergo two fates: the pentose phosphate pathway, where reduction of NADP+ to NADPH occurs, or to continue glycolysis to yield Gliceraldehyde-3-P. Glyceraldehyde-3-P dehydrogenase (GAPDH) phosphorylates this product and glycolysis is further completed until its end product pyruvate, which enters the Krebs cycle and mitochondrial metabolism (Figure 2).
\n\t\t\t\t\tIt has been proposed that hyperglycemia-induced mitochondrial superoxide production activates damaging pathways by inhibiting glyderaldehyde-3-phosphate dehydrogenase (GAPDH) [4, 24], an enzyme that normally translocates in and out of the nucleus [25, 26]. ROS inhibit glyderaldehyde-3-phosphate dehydrogenase through a mechanism involving the activation of enzyme poly-ADP-ribose polymerase-1 (PARP-1). This enzyme is involved in DNA repair and apoptotic pathways. ROS cause strand breaks in nuclear DNA which activates PARP-1. PARP-1 activation results in inhibition of glyderaldehyde-3-phosphate dehydrogenase by poly-ADP-ribosylation [27]. This results in increased levels of all the glycolytic intermediates upstream of GAPDH. Accumulation of glyceraldehyde 3-phosphate activates two major pathways involved in hyperglycemia-complications: a) It activates the AGE pathway deriving glyceraldehyde phosphate and dihydroxyacetone phosphate to the nonenzymatic synthesis of methylglyoxal. b) Increased glyceraldehyde 3-phosphate favors diacylglycerol production which activates PKC pathway. Further upstream, levels of the glycolytic metabolite fructose 6-phosphate increase, which then increases flux through the hexosamine pathway, where fructose 6-phosphate is converted by the enzyme glutamine-fructose-6-phosphate amidotransferase (GFAT) to UDP–N-Acetylglucosamine. Finally, inhibition of GAPDH favors the accumulation of the first glycolytic metabolite, glucose. This increases its flux through the polyol pathway, consuming NADPH in the process [24].
\n\t\t\t\tThe family of aldo-keto reductase enzymes catalyzes the reduction of a wide variety of carbonyl compounds to their respective alcohols. These reactions utilize nicotinic acid adenine dinucleotide phosphate (NADPH). Aldo-keto reductase has a low affinity (high Km) for glucose, and at the normal glucose concentrations, metabolism of glucose by this pathway is a very small percentage of total glucose metabolism. However, in a hyperglycemic environment, increased intracellular glucose results in its increased enzymatic conversion to the polyalcohol sorbitol, with concomitant decreases in NADPH [4] (Figure 2). Since NADPH is a cofactor required to regenerate reduced glutathione, an antioxidant mechanism, and this compound is an important scavenger of reactive oxygen species (ROS), this could induce or exacerbate intracellular oxidative stress [24]. Moreover, sorbitol is oxidated to fructose by sorbitol dehydrogenase, which can lead to PKC activation via the increased NADH/NAD+ ratio [4]. Although this mechanism does not produce ROS in a direct way, it takes part in the redox imbalance causing oxidative stress.
\n\t\t\t\tWhen glucose levels are within normal range, a relatively low amount of fructose-6-P is drived away from glycolysis. If intracellular glucose rises, excess fructose-6-phosphate is diverted from glycolysis to provide substrate for the rate-limiting enzyme of this pathway, GFAT. This enzyme converts fructose 6-phosphate to glucosamine 6-phosphate, which is then converted to UDP-NAcetylglucosamine, which is essential for making the glycosyl chains of proteins and lipids. Specific O-Glucosamine-N-Acetyl transferases use this metabolite for post-translational modification of specific serine and threonine residues on cytoplasmic and nuclear proteins [24, 28].
\n\t\t\t\tThe Protein Kinase C (PKC) family comprises at least eleven isoforms of serine/threonine kinases, which participate in signaling pathways activated by phosphatidyl serine, Calcium and Diacylglycerol (DAG). DAG levels are elevated chronically in the hyperglycemic or diabetic environment due to an increase in the glycolytic intermediate dihydroxyacetone phosphate (figure 2). This intermediate is reduced to glycerol-3-phosphate, which, conjugated with fatty acids, increases de novo synthesis of DAG [29]. Evidence suggests that the enhanced activity of PKC isoforms could arise from inhibition of the glycolytic enzyme glyceraldehide-3-phosphate dehydrogenase by increased ROS intracellular levels [4, 24]. Other studies suggest that enhanced activity of PKC isoforms could also result from the interaction between AGEs and their extracellular receptors [30]. PKC isoforms constitute a wide range of cellular signals, including activation of NADPH oxidase and NF-κB, resulting in excessive ROS production. They also increase vascular permeability, stabilize vascular endothelial growth factor (VEGF) mRNA expression and increase leukocyte-endothelium interaction [11].
\n\t\t\t\tAccumulation of glyceraldehyde 3-phosphate, besides activating the AGE formation and the PKC pathway, it can oxidate itself. This autoxidation generates H2O2, which further contributes to oxidative stress [31].
\n\t\t\t\tIntracellular hyperglycaemia is the primary initiating event in the formation of both intracellular and extracellular AGEs [32]. AGEs can arise from intracellular auto-oxidation of glucose to glyoxal, decomposition of the Amadori product (glucose-derived 1-amino-1-deoxyfructose lysine adducts) to 3-deoxyglucosone (perhaps accelerated by an amadoriase), and nonenzymatic phosphate elimination from glyceraldehyde phosphate and dihydroxyacetone phosphate to form methylglyoxal. These reactive intracellular dicarbonyl glyoxal, methylglyoxal and 3-deoxyglucosone react with amino groups of intracellular and extracellular proteins to form AGEs [4]. Intracellular production of AGE precursors can damage cells by three general mechanisms: 1) Intracellular proteins modified by AGEs have altered function, 2) Extracellular matrix components modified by AGE precursors interact abnormally with other matrix components and with matrix receptors (integrins) that are expressed on the surface of cells, and 3) Plasma proteins modified by AGE precursors bind to AGE receptors (such as RAGE and AGE-R1,2 and 3) on cells such as macrophages, vascular endothelial cells and vascular smooth muscle cells. AGE receptors binding induces the production of ROS, which in turn activates PKC. It also activates NF-κB and NADPH oxidase, and disturbs MAPK signaling [31].
\n\t\t\t\tIn addition to direct damage of biomolecules in the cells, oxidative stress is also involved in activation of several stress-sensitive signaling pathways, which can result in inflammation, cytokine release, and even apoptosis. Among these pathways we find the transcription factor NF-κB, which together with PARP acts as a transcriptional coactivator of inflammation molecules such as iNOS, intracellular adhesion molecule-1 (ICAM-I), and histocompatibility complex class II [33]. p38 MAPK pathway and c-Jun Nterminal kinase (JNK) (also known as stress-activated protein kinase (SAPK) participate in cellular responses to stress due to osmotic shock, cytokines and UV light, playing a role in cellular proliferation, apoptosis, and inflammatory responses [33]. Jak/STAT is another important signaling pathway, which initiates and mediates cellular responses to cytokines such as interferons and interleukins [33].
\n\t\t\t\t\tOxidative stress-related pathways derived from glucose metabolism.
Being highly reactive species, ROS may modify and damage nucleic acids, proteins, lipids and carbohydrates, finally leading to cell damage. Among the motifs that can react with ROS we have the metal ligand from metalloproteases and Fe from oxihemoglobin. •O2\n\t\t\t\t\t- can also modify and inhibit catalases, while •OH can bind to the histidine residue from SOS causing its inhibition. ROS react mostly with insaturated and sulfur containing molecules, thus, proteins with high contents of tryptophan, tyrosine, phenylalanine, histidine, methionine and cysteine can suffer ROS modifications. Finally, ROS may also break peptidic bonds after oxidation of proline residues by •O2\n\t\t\t\t\t- or •OH [31].
\n\t\t\t\tROS and RNS may also modify fatty acids, lipoproteins, and phospholipids, a process termed lipid peroxidation, where •OH and •O2\n\t\t\t\t\t- form hydroperoxide lipids. Hydroperoxyde products cause severe damage to plasma membranes, or they can diffuse to other cells in the organisms and cause vascular permeability and inflammation by binding to (oxidized low-density lipoprotein) LOX receptors, and apoptosis [31].
\n\t\t\t\tH2O2 in cells can function as a signaling molecule leading to cellular proliferation or can result in cell death. At low concentrations, H2O2 serves as a second messenger to activate NF-κB and various kinases (p38 MAPK, ERK, PI3K, Akt, JAK2, STAT). H2O2 at slightly higher concentrations can induce the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into the cytosol where they trigger the activation of caspase, leading to cell death by apoptosis [12].
\n\t\t\tDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, caused by a defect on insulin production, insulin action or both [1]. There are two main types of diabetes: type 1 and type 2 diabetes.
\n\t\t\tType 1 diabetes is due to an autoimmune destruction of the insulin producing pancreatic beta-cells, which usually leads to absolute insulin deficiency. Patients with type 1 diabetes require insulin for survival. This type of diabetes accounts for 5-10% of the total cases of diabetes worldwide. Type 2 diabetes represents approximately 90% of the total diabetes cases, and it is characterized by impairment in insulin action and/or abnormal insulin secretion [1].
\n\t\t\tThe origins of type 2 diabetes are multifactorial. Obesity, age, ethnic origin and familiar history of diabetes are among the factors that contribute to its development. Even though a strong genetic component has been recognized, genotype only establishes the conditions for the individual to be more or less prone to environmental effects and lifestyle factors [34].
\n\t\t\tType 2 diabetes develops when insulin secretion or insulin action fails. The impairment of insulin actions is known as insulin resistance, presented as a suppression or retard in metabolic responses of the muscle, liver and adipose tissue to insulin action. This failure is located at the signaling pathways held after insulin binding to its specific receptor [35]. Chronic insulin resistance leads to hyperglycemia.
\n\t\t\tWhen the beta cells cannot secrete enough insulin in response to the metabolic demand caused by insulin resistance, frank diabetes type 2 occurs. This failure in the beta cell may be due to an acquired secretory dysfunction and/or a decrease in beta-cell mass [36]. All type 2 diabetic patients have some defect in the ability of beta cells to produce or secrete insulin [37].
\n\t\t\tOnce secreted to the portal circulation, insulin is transported to peripheral tissues, on which it will exert mainly anabolic actions [38]. Insulin starts its action by binding to insulin receptor, a transmembrane protein belonging to protein tyrosine kinase activity receptors superfamily, which can autophosphorylate. This initiates a series of events involving protein and membrane lipid phosphorylation, coupling proteins and cytoskeleton activity [39] [40]. The three main signaling pathways activated in response to insulin receptor phosphorylation are 1) PI3K 2)MAPK, and 3) Cb1. These pathways act in a concerted way to translate the signal of insulin receptor into biological actions in target organs, such as glucose transport by transporting GLUT4 vesicles to the membrane, protein, lipid and glycogen synthesis, mitosis and gene expression [40] (Figure 3).
\n\t\t\t\tAs protein phosphorylation activates these signaling pathways, dephosphorylation inhibits them. Different phosphatases such as protein-tyrosine phosphatase 1B (PTP1B), Phosphatase and tensin homolog (PTEN), SH2-containing tyrosine- protein phosphatase (SHO2), and suppressor of cytokine signaling 3 (SOCS-3) dephosphorylate and shut down insulin signaling [35]. Any alteration in the insulin pathway, being inefficient phosphorylation or increment in phosphatase acticity, causes impairment in insulin action. This is the molecular mechanism leading to insulin resistance.
\n\t\t\t\tMolecular mechanisms of insulin signaling.
Beta-cells in the endocrine pancreas are responsible for secreting insulin in response to rises in blood nutrient levels during the postprandial state. Glucose is the most important nutrient for insulin secretion. The process by which glucose promotes insulin secretion requires glucose sensing and metabolism by the beta-cell, a process called glucose-stimulated insulin secretion (Figure 4). In the first phase of insulin secretion, glucose enters the cell by glucose transporters (GLUT2 in rodents, GLUT1 in humans). Glucose is then phosphorylated to form glucose-6-phosphate by glucokinase [41]. The generation of ATP by glycolysis, the Krebs cycle and the respiratory chain closes the ATP-sensitive K+ channel (KATP) [42], allowing sodium (Na+) entry without balance. These two events depolarize the membrane and open voltage-dependent T-type calcium (Ca2+) and sodium (Na+) channels. Na+ and Ca2+ entry further depolarizes the membrane and voltage-dependent calcium channels open. This activation increases intracellular Ca2+ ([Ca2+]i) [43], which leads to fusion of insulin-containing secretory granules with the plasma membrane and the first phase insulin secretion [44, 45].
\n\t\t\t\tMechanisms of biphasic glucose-stimulated insulin secretion.
Besides increasing ATP/ADP ratio, glucose metabolism in the beta cell can generate a series of metabolic coupling signals that can initiate and sustain a second insulin secretion phase. Some of these coupling factors participate in mitocondrial metabolism and anaplerosis, constituting cycles involving NADPH, pyruvate, malate, citrate, isocitrate, Acyl-CoA and glutamate [46]. Diverse signaling pathways can also contribute to glucose-induced insulin secretion such as CaMKII [47-49], PKA [50, 51], PKC [51, 52] y PKG [53, 54]. Most secretagogues and potentiators of insulin secretion, such as nutrients, hormones and neurotransmitters, use these pathways to modulate insulin secretion.
\n\t\t\tHyperglycemia and free fatty acid intake are among the causes for oxidative stress conditions [23]. Hence, it may not be surprising that diabetic subjects tend to have more oxidative cell and organism environments than healthy subjects, i.e. an increase in ROS generation [5, 55, 56]. Moreover, diabetic patients present a decrease in antioxidant defenses. The antioxidant enzyme levels are affected by diabetes, which further increase oxidative stress [5, 6].
\n\t\t\tOxidative stress has been proposed as a major participant in the patophysiology of diabetic complications [27]. Nevertheless, regarding diabetes onset and development, oxidative stress has also shown to affect the two major mechanisms failing during diabetes: insulin resistance and insulin secretion.
\n\t\t\tROS and RNS affect the insulin signaling cascade [5]. As with other ROS effects, low doses play a physiological role in insulin signaling. After insulin stimulation of its receptor in adipocytes, H2O2 is produced via NADPH oxidase, which by inhibits PTP1B catalytic activity, thus increasing tyrosine phosphorylation [57].
\n\t\t\t\tHowever, oxidative stress caused by hyperglycemia in diabetes may impair insulin signaling, leading to insulin resistance. Although no mechanisms have been completely established, several responses to ROS excess in the insulin signaling have been proposed.
\n\t\t\t\tDisturbs in cellular redistribution of insulin signaling components may alter the insulin cascade, a process mediated by NF-κB [58]. A decrease in GLUT4 gene transcription and increase in GLUT1 (insulin independent glucose transporter) has also been observed, as well as increases in phosphorylation of IRS protein in an insulin receptor-independent fashion (perhaps by the stress kinases). Altogether, hyperglycemia and insulin resistance may also lead to altered mitochondrial function, and insulin action impairment by cytokines in response to metabolic stress [59, 60]. An increase in the hexosamine pathway has also been linked to insulin resistance. Moreover, it has been proposed that this pathway acts as a cellular sensor for the glucose excess. From that point of view, insulin resistance may be a protective mechanism from the glucose excess entrance [28].
\n\t\t\tPancreatic beta-cells are especially sensitive to ROS and RNS, because their natural enzymatic antioxidant defenses are lower compared to other tissues such as liver. Moreover, they lack the ability to adapt their low enzyme activity levels in response to stress such as high glucose or high oxygen [61]. Glucose enters to the beta-cell in an insulin independent fashion, because besides providing energy, glucose sensing in the beta-cell is crucial for insulin secretion. It has been suggested that hyperglycemia can generate chronic oxidative stress by the glucose oxidation pathway [62], leading to an excess in mitochondrial superoxide production, which further activates uncoupling protein-2 (UCP-2). This protein lowers ATP/ADP relationship through proton leak in the beta-cell, which reduces insulin secretion [63].
\n\t\t\t\tROS also increase the stress signaling pathways in the beta cells, such as NF-κB activity, which potentially leading to beta-cell apoptosis [64], and the JNK pathway which has been related to suppression of insulin gene expression, possibly by reduction of PDX-1 DNA binding activity, a major regulator of insulin expression [65]. It has also been shown that the activation of the hexosamine pathway in beta-cells leads to suppression of PDX-1 binding to the insulin and other genes involved in insulin secretion, perhaps contributing to the beta-cell dysfunction present in diabetes mellitus [66].
\n\t\t\t\tAs in other cell types, NO in beta-cells has physiologic roles. NO may regulate glucokinase activity by s-nitrosilation [67] in the beta-cell, and possibly increase insulin secretion. However, NO excess and concomitant NRS may cause apoptosis through caspase-3 activation and decrease in ATP levels [68].
\n\t\t\t\tBesides ROS hyperproduction, excess mitochondrial metabolism resulting form hyperglycemia in the beta-cell may also alter mitochondrial shape, volume and behavior, uncoupling K-ATP channels from mitochondrial activity and thus altering glucose-induced insulin secretion [69].
\n\t\t\tHyperglycemia, is the responsible of the development of diabetes complications as well. Hyperglycemia damage is produced in cells in which glucose uptake is independent of insulin, which, similarly to what happens in beta-cells, explains that the cause of the complications resides inside the cells [4]. Prolonged exposure to high glucose levels, genetic determinants of susceptibility and accelerating factors such as hypertension and dyslipidemia participate in the development of diabetic complications. Moreover, the development and progression of damage is proportional to hyperglycemia, which makes the lowering of glucose levels the most important goal for preventing complications and treating diabetes.
\n\t\t\tThe main tissues affected by diabetes complications at the microvasculature levels are retina, renal glomerulus, and peripheral nerves. Diabetes is also associated with accelerated atherosclerotic disease affecting arteries that supply the heart, brain, and lower extremities. In addition, diabetic cardiomyopathy is a major diabetic complication [24].
\n\t\t\tOxidative stress plays a pivotal role in the development of diabetes complications, both at the microvascular and macrovascular levels. Results derived from two decades of diabetes complications investigation point towards mitochondrial superoxide overproduction as the main cause of metabolic abnormalities of diabetes. Thus, all of the above reviewed pathways are involved in microvasculature and macrovasculature hyperglycemic damage [24].
\n\t\t\tDiabetic retinopathy: Diabetic retinopathy appears in most patients after 10 to 15 years after diabetes onset. Background retinopathy presents small hemorrhages in the middle layers of the retina, appearing as “dots”. Lipid deposition occurs at the margins of the hemorraghe, and microaneurisms (small vascular dilatations) and edema may appear. Proliferative retinopathy occurs when new blood vessels on the surface of the retina cause vitreous hemorrhage, and eventually, blindness. As the cells of the retina contain high amounts of aldo-ketoreductase, they have high susceptibility to increase the polyol pathway in the presence of excess glucose, with concomitant decreases in NADPH [4]. Sorbitol produced in this process increases osmotic stress, which has been linked to microaneurysm formation, thickening of the basement membranes and loss of pericytes. It is also thought that retina cells are damaged by glycoproteins, particularly form AGEs. Additionally, ROS by themselves may damage the cells. Importantly, VEGF, growth hormone and TGF-beta increases during diabetes may be the cause of proliferation of blood vessels [70].
\n\t\t\t\tDiabetic nephropaty: this complication causes glomerular basement membrane thickness, microaneurism formation, and mesangial nodule formation, all which are reflected in proteinuria and, in the end, renal insufficiency. The mechanisms for injury also involve the increased polyol pathway and AGE formation. AGE binding to its receptors has been proven to play a role as well in renal damage, fibrosis and inflammation associated with diabetic nephropaty. This actions of AGE also potentiate oxidative stress, while synergizing with rennin-angiotensin system activation, which leads to a vicious cycle causing kidney failure. As mentioned, diabetic patients, and particularly those with nephropaty, have lowered antioxidant defenses. Moreover, AGE receptors are significantly increased [71].
\n\t\t\t\tDiabetic neuropathy: Diabetic neuropathy is defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in diabetic patients after exclusion of other causes. Peripheral neuropathy in diabetes may manifest in several different forms, including sensory, focal/multifocal, and autonomic neuropathies. [72]. Mechanisms of nerve injury are less known but likely related also to the polyol pathway, AGE formation and ROS themselves [70]. Oxidized proteins and lipoproteins also interact with receptors in the membrane of neurons, initiating inflammatory signaling mechanisms which further produce ROS, damaging cellular components and leading to neuronal injury [73].
\n\t\t\tThe central pathological mechanism in macrovascular complications is atherosclerotic disease. Atherosclerosis occurs as a result of chronic inflammation and injury to the arterial wall in the peripheral or coronary vascular system. This damages cause accumulation of oxidized lipids from LDL particles in the endothelial wall of arteries, whose rupture leads to acute vascular infarction. Additionally, platelet adhesion and hypercoagulability also occurs in type 2 diabetes, increasing the risk of vascular occlusion [70]. It has been proposed that increased superoxide production is the central and major mediator of endothelial tissue damage, causing direct inactivation of two antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase and that the activation of oxidative stress pathways is involved in the pathogenesis of complications [24].
\n\t\t\t\tEndothelial cells also contain high amounts of aldo-keto reductase, and are thus prone to increased polyol pathway activation. Moreover, a large body of evidence supports hypothesis that hyperglycemia or diabetes leads to vascular diacylglycerol accumulation and subsequent PKC activation, causing a variety of cardiovascular defects [29]. PKC activation has been associated with vascular alterations such as increases in permeability, contractility, extracellular matrix synthesis, cell growth and apoptosis, angiogenesis, leukocyte adhesion, and cytokine activation and inhibition [29]. Hyperglycemia-induced activation of PKC has also been implicated in the overexpression of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) [74]. In smooth muscle PKC hyperactivity is associated with decreased NO production [75] and has been shown to inhibit insulin-stimulated expression of eNOs in endothelial cells.
\n\t\t\t\tIn arterial endothelial cells O-glucosamine-acylation participates in vascular complications interfering with the action of Akt/PKB, a critical insulin signaling protein, on eNOS [76]. GFAT activity is associated with increased transcription of transforming growth factor (TGF) alpha and beta and PAI-1, factors involved in the proliferation of vascular smooth-muscle and endothelial cells. This effect appears to be mediated by O-glucosamine-acylation of the transcription factor, Sp1 [77]. Increased TGF-beta and PAI-1 are associated with capillary and vascular occlusion by mechanisms associated with collagen and fibronectin expression causing capillary occlusion, in the case of TGF-beta, and decreased fibrinolysis in the case of PAI-1. O-GlcNAcylation impairs cardiomyocyte calcium cycling decreasing sarcoplasmic reticulum calcium ATPase 2a (Serca 2a) [78-80].
\n\t\t\t\tOxidative stress pathways in diabetes mellitus.
As mentioned above, vitamins C, E, and A constitute the non enzymatic defense against oxidative stress, by regenerating endogenous antioxidants (Figure 1). Vitamin C has a role in scavenging ROS and RNS by becoming oxidated itself. The oxidized products of vitamin C, ascorbic radical and dehydroascorbic radical are regenerated by glutathione, NADH or NADPH. In addition, vitamin C can reduce the oxidized forms of vitamin E and gluthatione [81]. Vitamin E is a fat-soluble vitamin which may interact with lipid hydroperoxides and scavenge them. It also participates, together with vitamin C, in gluthatione regeneration by interaction with lipoic acid [23]. Vitamin A has a plethora of cellular actions. Besides modulating gene expression, cell growth and differentiation, this vitamin may also act as antioxidant, although the mechanisms of action in this role are not fully deciphered. The antioxidant potential of carotenoids (vitamin A) depends on their distinct membrane-lipid interactions, while some carotenoids can decrease lipid peroxidation, others can stimulate it [82].
\n\t\t\tSince oxidative stress is present during the progression of diabetes and its complications, amelioration of oxidative status, mainly by increasing antioxidant non-enzymatic defenses, has been largely proposed and studied. Several clinical observational trials have particularly studied the correlation between vitamin E status in plasma and/or diet, and markers of oxidation, inflammation, type 2 diabetes incidence, and diabetic complications. Although inverse association has been found for vitamin E in some studies [7, 83, 84], the association found in other study disappeared after adjustment for cardiovascular risk factors such as obesity, smoking, and hypertension [85], or have observed no beneficial effect at all [7, 8]. Such contrasting results have also been reported for studies looking association of vitamin A and C consumption and amelioration of diabetes status and/or complications [7, 8, 81, 86].
\n\t\t\tOn the other hand, in interventional trials with vitamin supplementation, the effects of vitamins E, C and A, alone or in diverse combinations, have yielded barely any promising result. There appears to be no beneficial effect of vitamin supplementation on diabetes or macrovascular complications [7, 8, 81]. Some of these studies have even evidenced associations between vitamin supplementation and an increased incidence of stroke [7]. Likewise, supplementation with antioxidant vitamins can even block beneficial ROS production during exercise, inhibiting the health-promoting effects of exercise in humans [87].
\n\t\t\tParadoxically, in spite of the solid evidence of increased oxidative stress in diabetes, and the well established actions of vitamins as antioxidants, the association studies between antioxidant vitamin status and its beneficial effects in diabetes has no consistent results at all. What is more, interventional studies have failed in demonstrating a favorable effect of vitamin supplementation, discouraging its use as antioxidant therapy for diabetes.
\n\t\t\tSeveral reasons have been suggested for these contradictory observations. First, as vitamins may be easily oxidized, a vitamin may have antioxidant or oxidant properties, depending on the presence of other vitamins and the oxidative state in the cells i.e., if the oxidized form of a vitamin is not correctly reversed into the reduced form. Additionally, some vitamins may also activate oxidative stress pathways and further increase the oxidative stress, such as the activation of PKC by retinoids [88].
\n\t\t\tVitamin doses may also be part of the problem, as the effect of vitamins depends on dietary concentrations and/or supplement intake. The wide variety of doses reached with diet and supplements, and the lack of an established “pharmacological” dose of vitamins, makes it difficult to ascertain the true net effect of vitamin status or supplementation needed to generate beneficial effects. As well, the required dose for antioxidant effects versus the required for the vitamin’s role in the body may differ, which, together with vitamin’s bioavailability and its interaction with other vitamins, are caveats for assessing and finding vitamins’ effects, if any [7, 88].
\n\t\t\tFinally, the antioxidant effects of vitamins may not be sufficient to scavenge the great amount of ROS present in diabetes. Certainly, glucose levels have been correlated to the presence and severity of the complications. However once hyperglycemia has established, the incidence of complications after tight glycemic control remains the same. This effect has been termed glycemic memory, and is the cause for accumulative damage rendering diabetic complications. Considering that hyperglycemia is the main cause of oxidative stress in diabetes, in a similar way, the chronic undesirable effects that occur by ROS production may generate a vicious cycle difficult to break, in which ROS damage exacerbates the diabetic state, increasing glucose levels, which will further induce more oxidative imbalance [24].
\n\t\tDiabetes mellitus has reached epidemic proportions in the last decade, becoming one of the most important diseases worldwide. Several studies indicate oxidative stress is present in the dysfunction of insulin action and secretion that occur during diabetes, as well as in the development of diabetic complications. Nevertheless, oxidative stress is not the primary cause of diabetes, but rather a consequence of nutrient excess, given that oxidative stress is a natural response to stress, in this case, to glucose and/or lipid overload.
\n\t\t\tVitamins such as E, C and A with antioxidant properties constitute the physiological non-enzymatic defense against oxidative stress. However, the evidence in favor of the use of vitamin supplementation as antioxidant therapy remains uncertain. Although some beneficial effects have been proven in observational studies, the results of interventional trials are still ineffective. Perhaps more studies on the physiopathology of oxidative stress and the role of vitamins in it, as well as standardizing vitamin dosage and assessing their undesirable effects are needed in order to determine a clear participation of vitamin supplementation in amelioration of the oxidative balance. More studies addressing the possibility of targeting directly at the enzymes and mechanisms involved in ROS production and not by antioxidants are needed as well.
\n\t\t\tGiven that it is mostly dietary vitamin intake which has shown an association with ameliorating the diabetic state, and that oxidative stress is a response to excess of nutrients, it seems that attending the cause of excessive ROS production represents the best therapeutic option. Thus, adequate dietary interventions that reduce hyperglycemia, and increases in oxygen consumption (i.e. improve mitochondrial function) by exercise remain the primary choices for diabetes treatment and prevention of its complications.
\n\t\tThis work was supported by grants from CONACyT and from the Dirección General de Asuntos del Personal Académico, UNAM.
\n\t\tThe contamination of soil, water and air by toxic chemicals represents one of the major worldwide environmental problems. From this point of view, the European Union (EU) is paying attention to the improvement of soil protection and recovery and to the prevention of soil contamination, since there are still many historical and new contaminated sites that require remediation [1, 2]. The main classes of soil pollutants in Europe have been reported in [3].
\nBioremediation is a simple and cost-effective method that, in the last decades, has received worldwide a particular attention. The general term “bioremediation” indicates the use of living organisms (i.e. bacteria, fungi, algae and plants) in the detoxification of polluted soils and wastewaters. In a bioremediation process, organic and inorganic hazardous substances may degrade, accumulate or immobilize, resulting in a significant reduction of the contamination level.
\nIn the last decay, the role of fungi in bioremediation has been increasingly recognized [4, 5]. About this, various authors have highlighted the ability of fungi, mainly saprotrophic and biotrophic basidiomycetes, to degrade or to transform toxic compounds [6, 7]. Mycoremediation is the bioremediation technique which employ fungi in the removal of toxic compounds; it could be carried out in the presence of both filamentous fungi (moulds) [8] and macrofungi (mushrooms) [9, 10]. Both classes possess enzymes for the degradation of a large variety of pollutants [11, 12].
\nFungi are well known for their ability to colonize a wide range of heterogeneous environments and for their ability to adapt to the complex soil matrices, also at extreme environmental conditions. Furthermore, they can decompose the organic matter and easily colonize both biotic and abiotic surfaces [13, 14].
\nFilamentous fungi show some peculiar characteristics that make them more advisable in soil bioremediation than yeasts and bacteria [14, 15]. The most important are the type of growth (i.e. the development of a multicellular mycelial network) suited to soil colonization and translocation of nutrients and water, the production of many bioactive compounds and extracellular enzymes and the unique capability to co-metabolize many environmental chemicals [16].
\nMycoremediation represents thus a biological tool to degrade, transform or immobilize environmental contaminants.
\nThe state of the art of soil mycoremediation is reviewed in the present chapter. A particular attention is given to the fungal species and enzymes involved in the biodegradation processes, together with the classes of toxic compounds that could be biodegraded. Bioremediation strategies (i.e. biostimulation and bioaugmentation) and significant examples of microcosm and field studies are also discussed. Finally, the application of mushrooms as emerging technology in soil mycoremediation is reported.
\nThe most suitable fungi to be used in soil remediation are basidiomycetes and, in particular, the ecological groups of saprotrophic and biotrophic fungi [17].
\nThe saprotrophic basidiomycetes, which use dead organic matter as a carbon source, include the wood-degrading fungi. Among them, white-rot fungi (WRF) are considered for the leading role in biodegradation [18]. WRF can degrade efficiently both lignin and cellulose biopolymers till the complete mineralization [19], thanks to the production of an extracellular enzymatic complex, which comprehend lignin peroxidases (LiPs), manganese-dependent peroxidases (MnPs), versatile peroxidases (VPs), laccases, H2O2-generating oxidases and dehydrogenases, produced during the idiophase, usually under nitrogen depletion.
\nSome of the most representative WRF, able to degrade pollutants, include Phanerochaete chrysosporium, Pleurotus ostreatus, Trametes versicolor, Bjerkandera adusta, Lentinula edodes, Irpex lacteus, Agaricus bisporus, Pleurotus tuber-regium and Pleurotus pulmonarius [20, 21]. Among these fungi, Phanerochaete chrysosporium has been the most investigated for its ability to degrade toxic or insoluble compounds to CO2 and H2O, more efficiently than other fungi. In 1985, for the first time, Bumpus et al. proposed the application of Phanerochaete chrysosporium in bioremediation studies, and the fungus became a model system in the mycoremediation field [22].
\nThe biotrophic basidiomycetes comprehend ectomycorrhizas which obtain the carbon source from a mutualistic plant partner: the fungal hyphal network envelopes the root and penetrates between the cells of the root cortex [17]. Ectomycorrhizal fungi (ECM) can assemble and recycle the nutrients from the organic matter of the soil [23]. ECM comprehends about 10,000 fungal species; the most representatives are Amanita spp., Boletus spp., Gautieria spp., Hebeloma spp., Lactarius spp., Morchella spp., Suillus spp. and Rhizopogon spp. [16, 24]. ECM fungi secrete enzymes to get nutrients by means of the degradation of molecules in the soil organic matter. ECM possesses extracellular and cytosolic enzymes which attack molecules containing N and P atoms. Hydrolytic enzymes comprehend β-glucosidases and phosphatases, while the oxidative ones are peroxidases and phenol oxidases [25]. The ECM fungi application is important in habitat where the litter layer is restricted and consequently ligninolytic enzymes, typical of wood fungi, are not so efficacious; in this contest, ECM fungi are able to produce enzymes to sequester nutrients directly from the soil. The same enzymes allow ECM to degrade many persistent organic pollutants [26].
\nMost of the biodegradation studies at the laboratory and field scale are concerned to microfungi, but in the last years, much attention has been given to mushrooms which are broadly present in soil and also easily soil-cultivated [27]. Bioremediation by macrofungi basidiomycetes is reported by [28] to be advantageous because, together with remediation, soil is enriched with organic matter and nutrients and plant growth results enhanced. These macrofungi are potent degraders thanks to the secretion of the same non-specific enzymes (LiP, MnP and laccase) described for the wood-degrading fungi and, for this reason, are interesting in the bioremediation field. At the same time, they grow to a great extent producing high biomass quantities, in particular when cultivated on carbon sources, such as straw or sawdust [29]. The mushroom biomass can be a protein source or can contain biologically active compounds such as phenols with antioxidant activity [12, 30]. Furthermore, mushroom biomass can be applied in biosorption treatment thanks to its ability to accumulate ions and xenobiotics from contaminated soils [31].
\nThe biodegradation capability of different hydrocarbon classes such as mineral oils, polycyclic aromatic hydrocarbons (PAHs), monoaromatic hydrocarbons and chlorinated hydrocarbons (CHCs), together with phenols, was demonstrated for many fungal species [17]. Moreover, the possibility to decrease the risk associated with heavy metals, metalloids and radionuclides in soil has been described [16].
\nCd, Cr, Hg, Pb, Cu, Zn and As are the most common heavy metals found in soil. In the EU, more than 80,000 contaminated sites are counted. Heavy metals can be generated by natural processes, like the metal-enriched rock erosion, and anthropogenic activities (e.g. mining, smelting, fossil fuel combustion, waste disposal, corrosion and agricultural practices) [32, 33]. Heavy metals that enter the environment can be transported or transformed by means of photo-, chemical- or biodegradation; moreover, they can also be biotransformed [34]. Fungi are potential heavy metal accumulators; in particular basidiomycetes mushrooms can uptake heavy metals from soil by means of their mycelia and accumulate them in the fruiting bodies, irrespective of their age [35]. As reported by [10], species of Agaricus, Amanita, Cortinarius, Boletus, Leccinum, Suillus and Phellinus are some of the mushroom applicable for the mobilization/complexation of different heavy metals in soil.
\nIn the EU, mineral oils, together with heavy metals, represent the main source of soil contamination, significantly greater than 60% of the total contaminants. Mineral oils, refined from crude petroleum oil, are a group of various hydrocarbons, straight and branched-chain paraffinic, naphthenic and aromatic ones, with 15 or more C numbers [2]. They can be used for the preparation of lubricant products (e.g. engine oils or hydraulic fluids) or “non-lubricant” ones (e.g. agricultural spray oils). Their industrial application is at a large scale, and the soil contamination can occur during transport, storage or refining or also for accidental leakages [36]. Hydrolases, dehydrogenases and membrane-bound cytochrome P450 enzymes constitute the fungal hydrocarbon-degrading system [37]. Fungal species belonging to Rhizopus, Paecilomyces, Alternaria, Mucor, Gliocladium, Aspergillus, Fusarium, Cladosporium, Geotrichum, Penicillium and Pleurotus are capable of utilizing crude oil as the sole carbon and energy source [37, 38, 39].
\nPolycyclic aromatic hydrocarbons (PAHs), molecules with multiple carbon rings, derive from the incomplete combustion of organic materials. Their origin can be both natural (e.g. open burning, natural losses of petroleum and volcanic activities) and predominantly anthropogenic (e.g. residential heating, coal gasification, carbon black, activities in petroleum refineries). PAH contamination corresponds to 13%: these compounds tend to bound to soil particles and to remain absorbed [40]. Both ligninolytic and non-ligninolytic fungi are able to degrade PAHs by means of the extracellular lignin-degrading enzymatic system, which contribute to the first attack on PAHs, and of the P450 monooxygenase [41]. Apart from the model P. chrysosporium, species belonging to Aspergillus, Penicillium, Rhizopus, Fusarium, Cladosporium and Trichoderma are capable of degrading PAHs [42].
\nAnother group of crude petrol-derived hydrocarbons, which represent the 6% of soil contaminants, is that of monoaromatic hydrocarbons, and in particular those grouped in the acronym BTEX (benzene, toluene, ethylbenzene and xylene). Fungi are efficient in aromatic hydrocarbon degradation, as for PAH degradation, thanks to the ligninolytic enzymatic system. WRF, such as P. chrysosporium and Trametes versicolor, are reported to be good BTEX degraders together with soil and mycorrhizal fungi [43].
\nPhenols consist of one or more aromatic rings with hydroxyl functional groups; they are present in the waste streams of almost all the phenolic-using industries (e.g. chemical, paper, food and textile industries) and contaminate the soil as leachates or particulate matter [44, 45]. The percentage of soil contamination is one of the lowest, being around 4% [33]. The biodegradation of phenols is mainly concerned to the production of phenol oxidase enzymes (laccases, tyrosinases and peroxidases) by basidiomycetes: they act on phenols and incorporate one or two atoms of oxygen [46, 47]. Due to the production of these multiple oxidative enzymes, Trametes spp., Lentinus spp., Pleurotus spp. and Ganoderma spp. are some of the most efficacious fungal species involved in phenol compound biodegradation [48].
\nThe soil contamination of CHCs is about 2%. These compounds contain Cl atoms substituted for hydrogen atoms normally bonded to a carbon. This group of chemicals comprehends highly toxic pollutants such as polychlorinated biphenyls (PCBs) and chlorinated pesticides, e.g., DDT [49]. As for PAH biodegradation, WRF have been intensively proposed as biodegraders of CHCs due to their unspecific oxidative enzymes. However, also non-WRF, in particular soil ascomycetes and zygomycetes, are able to enzymatically transform these pollutants; in particular, they have the advantage over WRF to tolerate neutral pH and adverse growth conditions [50].
\nIn the last years, emerging contaminants have become of great interest [51]. Among them, the anthropogenic chemicals, endocrine-disrupting chemicals (EDCs) and pharmaceutical-personal care products (PPCPs) are relevant due to their biological effects on nontarget organisms; in particular, EDCs simulate or antagonize the endogenous hormone effects and are toxic to organisms also at very low concentrations. Estrone, 17β-estradiol, 17α-ethinylestradiol, bisphenol A and triclosan are the most detected and studied in soil. EDCs and PPCPs mainly enter the soil environment via irrigation with contaminated wastewater [52, 53, 54]. As reviewed by [55], ligninolytic fungi are able to transform EDCs allowing a reduction of the endocrine-disrupting activity or their ecotoxicity; moreover, these fungi are also reported to be able to degrade the heterogeneous class of PPCPs thanks to their broadly unspecific enzymatic systems [56].
\nSince 1985, after the discovery of Bumpus [22] about the degradation potentialities of P. chrysosporium, a plethora of authors have described the fungal enzymatic machinery and its role in the transformation of a wide range of organic pollutants in soils. Most of the enzymes are extracellular and allow to attack and then degrade large molecules into smaller units which can enter the cells for further transformations [57].
\nExtracellular laccases start ring cleavage in the biodegradation of aromatic compounds [8]. They are multicopper oxidases with low substrate specificity and can act on o- and p-phenols, aminophenols and phenylenediamines thanks to a four-electron transfer from the organic substrate to molecular oxygen. The laccase-mediator systems (LMSs) have an effect on the electron transfer chain increasing the laccase substrate range [58].
\nFungal peroxidases generate oxidants which initiate the substrate oxidation in the extracellular environment [8]. They belong to the class II peroxidases [59] and catalyse the oxidative conversion of various compounds utilizing H2O2 as electron acceptor. As previously reported, LiPs, MnPs and VPs are the main fungal high-redox class II peroxidases. They are involved in the biodegradation of the complex lignocellulose structure and, consequently, can degrade various organic substrates and transform some inorganic ones [46]. Fungi can also secrete the dye-decolorizing peroxidases (DyPs), which have oxidative and hydrolytic activities on phenolic and non-phenolic organic compounds [60]. Heme-thiolate peroxidases (HTPs) transfer peroxide-oxygen, from H2O2 or R-COOH to substrate molecules; in this group chloroperoxidases (CPOs) and the unspecific or aromatic peroxygenases (UPOs or APOs) are included. In particular, UPOs can mainly operate on heterogeneous substrates thanks to aromatic peroxygenation, double-bond epoxidation or hydroxylation of aliphatic compounds [59].
\nIntracellular detoxification pathways comprehend multigenic families of cytochrome P450 monooxygenases and glutathione transferases, mainly owned by wood and plant litter fungi but also by some symbiotic species [46]. These intracellular enzymes have functional roles in fungal primary and secondary metabolism.
\nP450 cytochrome monooxidases, heme-thiolate-containing oxidoreductases, can act on various substrates in stereo- and regioselective manner, needing O2 for the reaction. They are activated by a reduced heme iron and add one atom of molecular oxygen to a substrate. Hydroxylation, epoxidation, sulfoxidation and dealkylation can occur and require NAD(P)H as electron donor [61].
\nGlutathione transferases are located in different cellular compartments and catalyse the nucleophilic attack of an electrophilic C, N or S atom in non-polar compounds by means of reduced glutathione (GSH). When electrophilic substrates are conjugated with GSH, they become more water-soluble. These enzymes have a wide substrate specificity and take part in the detoxification of different endogenous toxic metabolites and exogenous toxic chemicals [62].
\nIn general, chemical-physical characteristics of soil, such as pH, temperature, water content and redox potential, show a significant impact on the microbial growth and consequently on the success of a bioremediation process.
\nIn particular, the biodegradation activity of the microorganisms depends on macro- and micronutrient availability in soil and on the presence of any other factor that influence the microbial metabolism, such as the contaminant type and concentration, and their bioavailability, toxicity and mobility [33].
\nA proper amount of nutrients for microbial growth is usually present in soil; nevertheless, nutrients can also be added in a functional form which serves as an electron donor to stimulate bioremediation process [63]. The biodegradation of a toxic compound mainly depends on the genetic characteristics of the microorganism, in particular on both the extracellular and intracellular enzymatic systems [64]. The contaminant concentration directly influences the microbial activity: a high concentration may produce a variety of toxic effects on the different microbial classes, whereas a low concentration could not be enough to activate degradative enzyme synthesis. Filamentous fungi, able to form extended mycelial network and to synthetize a lot of aspecific enzymes, generally show a higher resistance to high contaminant concentration than bacteria [16]. Moreover, thanks to the low substrate specificity, the synthesis of degradative enzymes occurs also at low contaminant concentrations. The intracellular metabolic pathways involved in mycoremediation show remarkable similarities with those that regulate the secondary metabolism in fungi, in particular those of mycotoxin production [64]. Filamentous fungi which produce mycotoxins (e.g. Aspergillus and Penicillium spp.) exhibit the ability to degrade a wide variety of pharmaceutical compounds [65], among them the emerging pollutants EDCs [16, 66], ineffectively degraded by bacteria. The contaminant bioavailability is one of the most important factors that can be improved to optimize and accelerate the biodegradation; this fact has been demonstrated in the mycoremediation of aged PAH-contaminated soils [67]. The fungal ability to chemically modify or affect the contaminant bioavailability by means of biosurfactant production has been reported in different reviews [68, 69]. Penicillium and Aspergillus species have been reported to be biosurfactant producers [70, 71]. A wide range of microbial biosurfactant applications have been reported in the environmental protection field (e.g. enhancing oil recovery, controlling oil spills, biodegradation and detoxification of oil-contaminated soils) [69].
\nBiostimulation and bioaugmentation are the two most developed approaches among the bioremediation techniques. Their main purposes are the reduction of bioremediation time and the achievement of a complete removal of contaminant [4].
\nIn biostimulation, nutrients and electron exchangers are injected into the contaminated site in order to stimulate the degrading ability of indigenous microorganisms [72]. As regards lab-scale tests, nutrients are generally added as inorganic salts and as defined chemical species, while at the field scale, the nutrients are frequently added in the form of agro-wastes, organic wastes or inorganic fertilizers [63]. The main inorganic nutrients, usually added, are nitrogen and phosphorous, because the presence of organic toxic chemicals frequently induces an imbalance in the C:N:P ratio [73]. The main advantages of biostimulation approach are the low cost and the exploitation of indigenous microorganisms without the necessity of adaptation required by allochthonous species.
\nIn bioaugmentation, allochthonous or enriched autochthonous microorganisms, able to metabolize a specific contaminant, are introduced in soil. In both cases, the homogeneous dispersion of the added biomass and its proliferation, in competition with native microorganisms, are the great challenges [63]. Moreover, bioaugmentation and biostimulation could be also coupled in order to further stimulate introduced biomass [74].
\nIn fungal augmentation, high-quality inocula with high potentiality are necessary; consequently, specific methods have been developed for the production of fungal inocula. These inocula can be in the form of pelleted solid substrates, colonized by fungal mycelium, prepared from cheap agricultural and industrial by-products [4, 75]. Pelleted fungal inocula can be optimized in substrate composition to enhance fungal growth, degradation abilities and competitiveness against autochthonous soil microorganisms.
\nThe bioaugmentation with autochthonous filamentous fungi for the cleanup of a historically contaminated site has been shown to be a successful bioremediation approach as described by [76]. These fungi were able to grow under nonsterile conditions and to degrade various aromatic hydrocarbons in the same contaminated soil.
\nIn a recent review [77], the role of saprotrophic fungi in the biodegradation of xenobiotics and toxic metals in co-contaminated sites has been discussed along with the metabolic interactions between fungi and bacteria in a microbial consortium. Considering the occurrence of a mixed organic-inorganic contamination in brown field sites, the bioremediation mechanisms for combined pollution of PAHs and toxic metals by fungi and bacteria are also well documented [78].
\nMicrocosm studies are needed, before the in-field treatment, to evaluate microbial potential to degrade soil pollutants, the activity of the indigenous biomass and the most effective bioremediation strategy (i.e. biostimulation and/or bioaugmentation). In order to obtain information on the contaminant biodegradation in soil, the use of microcosms is a better approach than other kinds of laboratory tests [79]. Even if trials carried out at the lab scale do not always guarantee reproducible results on-site, due to chemical, physical and biological factors, they allow to verify the biodegradability of a certain compound. Hereafter, some of the most significant soil microcosm studies with fungi are reported.
\nOne of the first studies, about PAH degradation in soil microcosm, was carried out with P. chrysosporium and T. harzianum, grown on wheat straw and then inoculated in naphthalene-contaminated soil. The biodegradation behaviour was monitored by means of naphthalene concentration measurement, CO2 evolution as well as phytotoxicity tests [80].
\nPhanerochaete velutina and many litter-decomposing fungi (LDF) are potential degraders of soil organic matter. In the work of [81], they showed good growth, respiratory activity and MnP production on pine bark as co-substrate in microcosm. In the work of [82], the addition of P. velutina, cultivated on pine bark, to a PAH-contaminated soil was evaluated in microcosm and at the field scale. In the microcosm treatment (about 1 kg of soil), the bioaugmentation with fungi showed a positive effect on the biodegradation of the high molecular weight PAHs. On the contrary, in the field-scale experiment (about 2 tons of soil), carried out at lower starting concentration of PAHs, the degradation percentage (%) was similar in both the inoculated and non-inoculated soils.
\nThe bioremediation of an aged PAH-contaminated soil in microcosm was demonstrated for an isolate of Trichoderma reesei [83]. The fungus metabolized benzo[a]pyrene in the presence of glucose as a co-metabolic substrate.
\nAn isolate of Chaetomium aureum was able to halve the free Pb concentration in soil in about 2 months, irrespective of its association with indigenous microorganisms when inoculated in Pb-contaminated soil microcosms [84].
\nA microcosm study was conducted to optimize the degradation of weathered total petroleum hydrocarbons (TPH) in arid soils contaminated for more than a decade. Among fungi, Aspergillus, Acremonium, Cryptococcus, Geotrichum and Penicillium were the most widespread in these soils [85].
\nDifferent fungal strains (Aspergillus, Fusarium, Rhizomucor and Emericella spp.), isolated from a higher As contaminated agricultural soil, showed different detoxification mechanisms (biosorption/bioaccumulation and biovolatilization). They were able to reduce As contamination under in situ conditions as reported by [86].
\nIn a study on bioremediation of petroleum hydrocarbons, a periodic biostimulation and bioaugmentation (PBB), by a single strain or a fungal consortium, was reported as the best biodegradation strategy [87]. PBB maintained the enzymatic activities of a fungal co-culture (Pestalotiopsis sp., Polyporus sp. and Trametes hirsuta) and enhanced the biodegradation rate, in particular during the early stage of remediation [73].
\nThe biodegradation activity of Byssochlamys nivea and Scopulariopsis brumptii was evaluated in agricultural soil microcosms contaminated with pentachlorophenol (PCP), added with solid urban waste compost [88]. A synergistic effect of compost and fungal strains was observed with a reduction of more than 95% of PCP after 28 days of incubation. The detoxification role of the two fungal strains in the contaminated soil was also confirmed by toxicity assays [89].
\nMushroom application in the bioremediation field could be considered as an emerging technology; nevertheless, a lot of scientific works have appeared in the last years.
\nThe biodegradation potential of mushroom species in soil has been reviewed by [9]. In this chapter, the mycelial capability of hyperaccumulate chemical elements, in particular heavy metals and radionuclides, along with the nutritional potential hazards due to mushroom consumption has been extensively discussed.
\nThe biodegradation of recalcitrant pollutants like PAHs by WRF, the bioremediation of soil contaminated with engine oil by Lentinus squarrosulus and the decontamination of soils polluted with cement and battery wastes using Pleurotus pulmonarius were also reported by [29].
\nMany works on the edible mushroom P. ostreatus have been published. The biodegradation of the carcinogenic secondary metabolite aflatoxin B1 (AFB1), produced by Aspergillus flavus on rice straw [90] and on maize [91], was reported for this species. The mycoremediation of heavy metal-contaminated soils by means of different Pleurotus species was also reviewed in the work of [92]. In general, Pleurotus spp. are reported to be able to accumulate high levels of heavy metals; each species is characterized by different sensitivities towards the different metals and their concentration.
\nIn the review of [10], mushroom bioaccumulation of different potentially toxic trace elements (PTEs) in the fruiting bodies was reported for Phellinus badius, Amanita spissa, Lactarius piperatus, Suillus grevillei, Agaricus bisporus, Tricholoma terreum and Fomes fomentarius. The accumulation capability was higher than that of plants, vegetables and fruits.
\nThe bioremediation of crude oil-contaminated soil by an unidentified Agaricomycetes was demonstrated in the work of [93]. The addition of 10% of spent mushroom compost (SMC) allowed to degrade petroleum hydrocarbons over a short period of time.
\nThe capability of micro- and macrofungi to degrade organic pollutants and to decrease heavy metal concentration in soil is a matter of fact. The growth morphology in soil (i.e. extended hyphal network), the low specificity of extracellular enzymatic complexes and the possibility to use toxic compounds as the growth substrate make filamentous fungi more advantageous in bioremediation processes when compared to other microorganisms. However, in the design of a soil mycoremediation process, some important aspects have to be considered such as the choice of the appropriate fungal strain and the evaluation of its possible interaction with the contaminated soil microbiota. To this end, microcosm studies represent a useful and simple method which allows to evaluate the feasibility of a biodegradation process.
\nEdited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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