Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
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\r\n\tWhen materials undergo stress, two classic extreme responses can be expected: they can be elastic, that is to say that once the applied stress is removed they recover their original form, or they can have a viscous response, which enables the material to flow during the induced stress. However, there are materials that have complex responses when subjected to stress or strain and present a combination of both responses; such compounds have viscoelastic or viscoplastic responses. The term viscoelasticity is used to describe materials that when subjected to a deformation, have a combination of responses and can flow and at the same time have an elastic response, indicating that such materials can recover from deformation. This type of response in materials is most commonly represented by macromolecular materials. A material which exhibits viscoplastic response, when subjected to stress, can no longer recover its original form. In this book we seek to compile works on materials that exhibit both viscoelastic and viscoplastic responses when subjected to stress or defined strain, and present new methodologies for the evaluation of these types of materials.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"68c9f6836be98c144b843db45dd48f3c",bookSignature:"Dr. Jose Luis Rivera Armenta and Dr. Beatriz Adriana Salazar-Cruz",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7675.jpg",keywords:"Viscoelasticity, Viscoelastic Materials, Fractional Viscoelastic Model, Pseudoplastic Fluid, Damping, Viscoelastic Phenomena, Viscoelastic Models, Linear Viscoelasticity, Viscoplasticity, Kernels Model, Finite Element Model, Rheological Test, Viscoleastic Tests, Deformation Stress Tests, Stress Relaxation, Creep Test, Rheology Of Reinforced Composites",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 11th 2019",dateEndSecondStepPublish:"April 1st 2019",dateEndThirdStepPublish:"May 31st 2019",dateEndFourthStepPublish:"August 19th 2019",dateEndFifthStepPublish:"October 18th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"107855",title:"Dr.",name:"Jose Luis",middleName:null,surname:"Rivera Armenta",slug:"jose-luis-rivera-armenta",fullName:"Jose Luis Rivera Armenta",profilePictureURL:"https://mts.intechopen.com/storage/users/107855/images/system/107855.jpeg",biography:"José Luis Rivera-Armenta was born in Tampico, Mexico, in 1971. He earned his BSc in Chemical Engineering in 1994, an MSc in Petroleum Technology and Petrochemicals in 1998, and a Ph.D. in Chemical Engineering in 2002 at the Technological Institute of Madero City (ITCM). Since 2003 he has been a full-time professor in postgraduate programs at ITCM and a project manager of several developments sponsored by the National Technologic of Mexico and CONACYT. He has been a member of the National Research System at CONACYT level 1 since 2005. His responsibilities include injection and extrusion and thermal analysis at the laboratory at the Petrochemical Research Center at ITCM. He has advised on nine Ph.D\\'s, 16 master’s degrees, and four bachelor theses and also supervised three post-doctorate students. He has published 50 articles and five book chapters.",institutionString:"Instituto Tecnológico de Ciudad Madero",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Instituto Tecnológico de Ciudad Madero",institutionURL:null,country:{name:"Mexico"}}}],coeditorOne:{id:"171043",title:"Dr.",name:"Beatriz Adriana",middleName:null,surname:"Salazar-Cruz",slug:"beatriz-adriana-salazar-cruz",fullName:"Beatriz Adriana Salazar-Cruz",profilePictureURL:"https://mts.intechopen.com/storage/users/171043/images/system/171043.jpeg",biography:"Beatriz A. Salazar Cruz attained her Ph.D. in 2014, and has been an associate member of MATCO since 2016 and an associate professor of the Technological Institute of Madero City since 2012. From 1995 to 2008 she gained experience in the chemical process industry (Dynasol Elastomers) developing projects with SBS, SBR and SEBS polymers and characterizing and innovating the quality of products in a wide range of applications: asphalts, adhesives, and compounds. Dr. Salazar-Cruz is the author or coauthor of several scientific publications in English and Spanish, and author or coauthor of several book chapters. She has taught several rheology courses and has also collaborated in several projects supported by the National Technologic of Mexico and CONACYT. She has been an advisor for master degree thesis and has also supervised engineering students.",institutionString:"Technological Institute of Ciudad Madero",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"14",title:"Materials Science",slug:"materials-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"6702",title:"Polymer Rheology",subtitle:null,isOpenForSubmission:!1,hash:"c24234818cd4b2ce3ed569c2b29f714c",slug:"polymer-rheology",bookSignature:"Jose Luis Rivera-Armenta and Beatriz Adriana Salazar Cruz",coverURL:"https://cdn.intechopen.com/books/images_new/6702.jpg",editedByType:"Edited by",editors:[{id:"107855",title:"Dr.",name:"Jose Luis",surname:"Rivera Armenta",slug:"jose-luis-rivera-armenta",fullName:"Jose Luis Rivera Armenta"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6522",title:"Modified Asphalt",subtitle:null,isOpenForSubmission:!1,hash:"3f759084429ece2b3f7ec329b8242459",slug:"modified-asphalt",bookSignature:"Jose Luis Rivera-Armenta and Beatriz Adriana Salazar-Cruz",coverURL:"https://cdn.intechopen.com/books/images_new/6522.jpg",editedByType:"Edited by",editors:[{id:"107855",title:"Dr.",name:"Jose Luis",surname:"Rivera Armenta",slug:"jose-luis-rivera-armenta",fullName:"Jose Luis Rivera Armenta"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6188",title:"Solidification",subtitle:null,isOpenForSubmission:!1,hash:"0405c42586170a1def7a4b011c5f2b60",slug:"solidification",bookSignature:"Alicia Esther Ares",coverURL:"https://cdn.intechopen.com/books/images_new/6188.jpg",editedByType:"Edited by",editors:[{id:"91095",title:"Dr.",name:"Alicia Esther",surname:"Ares",slug:"alicia-esther-ares",fullName:"Alicia Esther Ares"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6802",title:"Graphene Oxide",subtitle:"Applications and Opportunities",isOpenForSubmission:!1,hash:"075b313e11be74c55a1f66be5dd56b40",slug:"graphene-oxide-applications-and-opportunities",bookSignature:"Ganesh Kamble",coverURL:"https://cdn.intechopen.com/books/images_new/6802.jpg",editedByType:"Edited by",editors:[{id:"236420",title:"Dr.",name:"Ganesh Shamrao",surname:"Kamble",slug:"ganesh-shamrao-kamble",fullName:"Ganesh Shamrao Kamble"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6517",title:"Emerging Solar Energy Materials",subtitle:null,isOpenForSubmission:!1,hash:"186936bb201bb186fb04b095aa39d9b8",slug:"emerging-solar-energy-materials",bookSignature:"Sadia Ameen, 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"}}]},chapter:{item:{type:"chapter",id:"21456",title:"Haptoglobin and Hemopexin in Heme Detoxification and Iron Recycling",doi:"10.5772/18241",slug:"haptoglobin-and-hemopexin-in-heme-detoxification-and-iron-recycling",body:'\n\t\t
\n\t\t\t
1. Introduction
\n\t\t\t
The acute phase reaction is an early response aimed at the defence of the organism and at the re-establishment of homeostasis in response to acute infection, inflammation and other pathological states (Kushner, 1982).
\n\t\t\t
The putative mechanism responsible for this reaction is based on an initial signal derived from macrophages and other cells that synthesize and secrete several factors (probably cytokines) capable of inducing, in hepatocytes, a series of events. One of the most important mediators of the liver acute phase response is the monokine Interleukin (IL)-6 (Gauldie et al., 1987). The acute phase response consists in a change in the concentration of several plasma proteins, generally synthesized in the liver, including (1-glycoprotein (AGP), complement factor C3, serum amyloid A, Haptoglobin and Hemopexin.
\n\t\t
\n\t\t
\n\t\t\t
2. Haptoglobin
\n\t\t\t
\n\t\t\t\t
2.1. Gene structure
\n\t\t\t\t
The Haptoglobin (Hp) locus is located on chromosome 16 in humans (chromosome 8 in mice) and shows an unusual polymorphism involving duplication, and, rarely, also triplication of parts of the coding region. Some Hp polymorphisms are linked to cardio-vascular and renal diseases.
\n\t\t\t\t
A second gene exists, adjacent to the Hp gene and highly homologous to it, called Hpr (Haptoglobin related). Hpr arose by gene duplication and subsequent modification by a 7-kilobase retrovirus-like insertion into the first intron of the Hp gene (Marinkovic and Baumann, 1990). Both Hp and Hpr gene are transcribed in liver, but Hpr transcript level is only approximately 6% of that of Hp (Nielsen and Moestrup, 2009).
\n\t\t\t\t
Although the primary site of Hp expression is the liver, it can also be detected in several other organs, including the nervous system, lung, spleen, thymus and heart (Nielsen and Moestrup, 2009).
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.2. Protein structure
\n\t\t\t\t
Hp is a tetrachain ((2(2) glycoprotein synthesized in the adult (but not fetal) liver and secreted into the plasma. The pro-Hp form is proteolytically processed into an (− and a (−chain. The two α-subunits and the two β-subunits of Hp protein are joined by inter-chain disulfide bonds. In humans, the precise structure of Hp protein is different according to the different Hp alleles, that give rise to an (αβ)-dimer or to various (αβ)-multimers (Figure 1). Hp has a high binding affinity for hemoglobin that is bound to the β-chain (Adams and Weiss, 1969; Nielsen and Moestrup, 2009).
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.3.Gene, mRNA and protein regulation
\n\t\t\t\t
Regulation of the expression of the Hp gene occurs at least at three levels: (i) developmental control, responsible for the lack of expression in fetal liver; (ii)tissue-specific control, responsible for the selectivity of the expression of the gene in the hepatocyte; (iii)modulation of its expression during the acute phase reaction (Oliviero et al., 1987).
\n\t\t\t\t
A short DNA segment of the 5\' flanking region of Hp gene contains sufficient information for tissue-specific expression and transcriptional activation by acute phase stimuli (Oliviero et al., 1987). Among these cis-acting elements in the Hp promoter, there are two IL-6 responsive elements, accounting for dramatic increase of Hp mRNA levels in the presence of this monokine (Oliviero and Cortese, 1989). Hp production is also regulated by glucocorticoids, but no information is available about a glucocorticoid-responsive element (GRE) in the human Hp gene (Marinkovic and Baumann, 1990). Transcription factor C/EBPβ and the nuclear matrix protein p55 were identified as the major proteins that bound the hormone-responsive cis-element of Hp gene during the acute phase response, at least in rat (Poznanovic et al., 1999).
\n\t\t\t\t
The Hp gene is transcribed quite selectively in hepatocytes about fifty times more in adult than in fetal liver nuclei, compared to about a twenty-fold increase in the case of the hemopexin gene (Oliviero et al., 1987). As a consequence, Hp is found in very low concentrations in fetal plasma, whereas its levels in the adult are about 0.45-3 mg/ml.
\n\t\t\t\t
Regarding cell lines, the Hp mRNA is present in some human hepatoma cell lines, such as HepG2, but it is completely absent in others, such as Hep3B.
\n\t\t\t\t
Finally, ectopic production of Hp was reported in cases of inflammation and cancer. In fact, the expression of Hp mRNA was observed in a small number of pancreatic cancer cell lines. Moreover, some pancreatic cancer cells, thanks to secretion of IL-6, are able to induce the production of fucosylated Hp in hepatoma cell lines and, according to this, high levels of fucosylated Hp can be found in sera from patients with pancreatic cancer (Narisada et al., 2008). A similar condition is also common in cases of advanced ovarian cancer, mammary carcinomas and severe inflammation diseases, such as rheumatic arthritis and inflammatory bowel disease.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.4. Conservation of gene, protein and regulation
\n\t\t\t\t
New World primates and rats possess only a single Hp gene, while Old World monkeys carry two to three tightly clustered Hp genes. In humans, four structural alleles have been identified: HplS, HplF, Hp2, and Hp3. Hp2 and Hp3 differ from Hp1 by having seven rather than five exons resulting in an increase of the α-subunit amino acids content.
\n\t\t\t\t
Hp1 and Hp2 are the two major allelic forms of human Hp and they can give rise to three major Hp genotypes: Hp1-1, Hp2-1 and Hp2-2 (Nielsen and Moestrup, 2009).
\n\t\t\t\t
An extensive study has been made on rat Hp, demonstrating that rat Hp cDNA sequence shows a high degree of similarity to the human Hp1 allele and that no Hpr gene can be found in rat genome. The rat Hp shows 75% amino acid sequence homology for the α-subunit and 86% for the β-subunit when compared with the human Hp1 gene product. Rat β-subunit contains two potential N-glycosylation sites, in contrast to the human β-subunit, which has four sites. Finally, rat Hp gene responsiveness to IL-6 is lower than in humans, and in rat cells the combination of IL-1, IL-6 and glucocorticoids (as dexamethasone) is required for maximal Hp expression (Marinkovic and Baumann, 1990).
\n\t\t\t
\n\t\t
\n\t\t
Figure 1.
Model of the human Haptoglobin isoform 1 monomer. α-Helices and β-strands are shown in pink and yellow, respectively. Loops are drawn in blue. The Hp model was generated using CPHmodels available at http://www.expasy.org/tools. The model was drawn with the Rasmol available at http://www.expasy.org/tools.
\n\t\t
\n\t\t\t
3. Hemopexin
\n\t\t\t
\n\t\t\t\t
3.1. Gene structure
\n\t\t\t\t
The Hemopexin (Hx) gene is an 11Kb long gene located on human chromosome 11 (chromosome 7 in mice), the same location as the β-globin gene cluster (Law et al., 1988).
\n\t\t\t\t
It is mainly expressed in the liver and, to a lesser extent, in neurons and astrocytes of the central nervous system, ganglionic and photoreceptor cells of the retina, Schwann and fibroblast-like cells of the peripheral nervous system, kidney mesangial cells and skeletal muscle (Tolosano et al., 1996).
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
3.2. Protein structure
\n\t\t\t\t
Hx is a plasma 60-kD β-1B-glycoprotein composed of a single 439 amino acids long peptide chain, which forms two domains resembling two thick disks that lock together at a 90 angle and are joined by an interdomain linker peptide.
\n\t\t\t\t
It contains about 20% carbohydrate, including sialic acid, mannose, galactose, and glucosamine and it does not present free sulfhydryl groups (Takahashi et al., 1984). Twelve cysteine residues were found in the protein sequence, probably accounting for six disulfide bridges.
\n\t\t\t\t
The structure of human Hx is characterized by its unique clustering of histidine and tryptophan residues. The histidine residues are present in His-Gly sequences presumably exposed at the surface, while tryptophan mostly occurs in four clusters (Takahashi et al., 1984) (Figure 2).
\n\t\t\t\t
Figure 2.
Model of the human Hemopexin precursor. α-Helices and β-strands are shown in pink and yellow, respectively. Loops are drawn in blue. The Hx model was generated using CPH models available at http://www.expasy.org/tools. The model was drawn with the Rasmol available at http://www.expasy.org/tools.
\n\t\t\t\t
Hx has the highest known heme affinity (Kd<1 pM) of any characterized heme-binding protein. It binds heme in an equimolar ratio, but there is no evidence that heme is covalently bound to the protein (Takahashi et al., 1984). The heme ligand is bound between the two domains of Hx in a pocket formed by the interdomain linker peptide. Heme binding and release results from opening and closing of the heme binding pocket, through movement of the two domains and/or interdomain linker peptide. The heme affinity decreases on lowering pH, on reduction of the heme iron atom, on nitric oxide (NO) binding to the ferrous heme iron atom, and in the presence of the chloride anion and of divalent metal ions, while the sodium cation increases the heme affinity for Hx (Tolosano et al., 2010).
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Other than heme, Hx can also interact with a wide variety of natural and synthetic metalloporphyrins. As in cytochrome b5 (with which Hx shares several chemical and physical properties), two histidines in the N-terminal domain are proposed to be the ligands to heme iron, while tryptophan residues seem to reinforce the interaction of Hx with heme (Takahashi et al., 1984).
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Regarding the C-terminal domain, its structure is common to that found in other proteins such as metalloproteinases which, for this reason, are indicated as “hemopexin-like domain” containing proteins (Bode, 1995).
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3.3. Gene, mRNA and protein regulation
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In murine development, Hx mRNA expression appears in the fetal life and the hepatic production of the protein and its serum concentration increase considerably during postnatal development, reaching the maximum level in the adult (Takahashi et al., 1984).
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Similarly, Nikkilä et al. showed that hepatic Hx mRNA in rat is first detected on day 14 after gestation. Hx gene expression is not present in yolk sac, placenta, decidua, uterus or early embryonic tissues (Nikkila et al., 1991).
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Apart from liver, other sites of Hx synthesis are the nervous system, skeletal muscle, retina and kidney, while Hx mRNA is not detectable in lung, heart, gastrointestinal tract and spleen (Poli et al., 1986).
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Among human hepatoma cell lines, Hep3B cells have been shown to produce the highest amount of Hx mRNA (Poli et al., 1986).
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After its synthesis, Hx is released in plasma where it can reach a concentration of about 0.5-1mg/ml. Its level can, however, increase during hemolyses or inflammatory events (Tolosano and Altruda, 2002; Tolosano et al., 1996).
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Hx production is known to be regulated in large part at the transcriptional level. The tissue specific and the temporal expression of the Hx gene is directed by a 500bp fragment located upstream of the transcription start point in the Hx promoter. This region contains a specific cis-acting element, called Hpx A site, which, apart from being important for the cell-specific transcription of Hx, is also responsible for its regulation during the acute phase response (Poli et al., 1989).
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Among inducers of Hx expression there are the cytokines IL-6, IL-11, leukaemia inhibitory factor (LIF), oncostatin M, IL-1β and Tumor Necrosis Factor (TNF)α (Immenschuh et al., 1995), while unlike most acute-phase proteins the serum amount of Hx is only slightly affected by dexamethasone. The regulation of Hx expression in response to IL-6 is mediated by a liver specific nuclear protein, IL6DBP (a member of the C/EBP family), which binds to the Hpx A site, and by the IL6RE-BP, an inducible nuclear factor which binds to another similar, but functionally distinct, IL6-responsive element in the Hx promoter (Tolosano et al., 1996).
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Besides being regulated during inflammation, Hx production increases in response to extracorpuscular heme, while the levels of other acute-phase proteins remain unchanged after this kind of stimulus. Interestingly, rat Hx expression is also promoted by hyperoxia (Nikkila et al., 1991).
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3.4. Conservation of gene, protein and regulation
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The physiological importance of Hx is suggested by the extensive homologies in the sequence of this protein in different species and by the fact that its structure is very similar in all vertebrates.
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As an example, the N-terminal domain of Hx has been identified as the heme-binding domain in human, rabbit and pig. Moreover, human and rat Hx share a high degree of homology at the amino acid level (76%) and a comparison of the interdomain disulfide bond formation reveals a similarity in their N-terminal and C-terminal domain structure.
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Finally, the perfect conservation of the cysteine residues of rat and human Hx indicates that the same disulfide configuration is present in both proteins (Nikkila et al., 1991).
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Beside protein structure conservation, gene expression regulation was maintained during evolution. Indeed, at least in human, rabbit, rat and chicken Hx gene expression is quite entirely confined to the liver and follows a peculiar temporal pattern during development, increasing several folds from fetal to adult life.
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4. Haptoglobin and Hemopexin function into the bloodstream
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4.1. Antioxidant and cytoprotective function of both Haptoglobin and Hemopexin
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Hp and Hx belong to the acute-phase proteins whose expression can be induced by various cytokines in a context of inflammatory processes and act as soluble scavengers of free hemoglobin and heme, respectively.
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Before starting to discuss in detail the role of Hp and Hx in heme metabolism, we want to open a short parenthesis on why heme scavenging from circulation is crucial.
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4.1.1. Heme
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Heme (protoporphyrin IX and iron) plays critical roles in several biological processes as it is the prosthetic group of a lot of essential proteins, such as hemoglobin, myoglobin, catalases, peroxidases and cytochromes (Tsiftsoglou et al., 2006).
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On the other hand, free heme is highly toxic as it is a source of redox-active iron. In the cytoplasm, iron can participate in the Fenton reaction to produce the highly toxic reactive oxygen species (ROS) that damage lipid membranes, proteins and nucleic acids (Papanikolaou and Pantopoulos, 2005). Heme toxicity is further exacerbated by its ability to intercalate into lipid membranes. Heme-iron may initially lodge within the hydrophobic interstices of the phospholipid bilayer. Within this highly oxidizable matrix, iron catalyzes the oxidation of cell membrane constituents and assists in the formation of cytotoxic lipid peroxide, which enhances permeability and membrane disorder. Oxidation of membrane components may promote cell lysis and death.
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Free heme is also a potent hemolytic agent. It affects erythrocyte membrane stability as a result of ROS formation and oxidative membrane damage thus shortening erythrocyte life span. Finally, free heme is an important source of iron for pathogenic microorganisms, predisposing to infections (Kumar and Bandyopadhyay, 2005).
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Release of hemoglobin into the bloodstream is a physiologic process due to intravascular hemolysis that occurs during enucleation of erythroblasts and destruction of senescent erythrocytes. It has been calculated that, even if senescent red blood cells are mostly phagocytosed by macrophages, intravascular hemolysis accounts for at least 10% of red cell breakdown in normal individuals. However intravascular hemolysis becomes a severe pathological complication when it is accelerated in various disorders, such as hemorrhage, hemolytic anemia and hemoglobinopathies, polycitemia vera, malaria, ischemia reperfusion and muscle injury (Ascenzi et al., 2005; Stuart and Nagel, 2004). Under physiologic conditions, released hemoglobin is bound by Hp and transported to macrophages and hepatocytes. After massive hemolysis, when the buffering capacity of plasma Hp is overwhelmed, hemoglobin is quickly oxidised to ferrihemoglobin, which releases free heme (Tolosano et al., 2010). Ferriheme then binds to albumin [Kd~10nM] and is subsequently transferred to Hx [Kd<1pM]. Heme is initially associated with albumin, presumably because the molar concentration of albumin in plasma is considerably greater than that of Hx (300 µM vs. 20 µM). After heme binding, Hx specifically delivers heme to the liver (Figure 3).
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Figure 3.
Hemoglobin catabolism. Heme contained in red blood cells is mostly recycled by macrophages through erythrophagocytosis. During this process heme is degraded by HO-1 and iron recycled. A minor part of erythrocytes undergoes intravascular destruction, releasing hemoglobin which is bound by Hp and the complexes are subsequently delivered to hepatocytes and macrophages of the reticuloendothelial system, where they are internalized through CD163 receptor–mediated endocytosis. When the buffering capacity of Hp is exceeded, hemoglobin liberates heme, which binds to albumin and is subsequently transferred to Hx. (Hb: hemoglobin).
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Under these conditions, the physiological mechanisms of removing free hemoglobin and heme from the circulation collapses, allowing nonspecific hemoglobin and heme uptake and heme catalyzed oxidation reactions (Kumar and Bandyopadhyay, 2005; Wagener et al., 2003b).
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The vasculature is one of the most susceptible tissue to heme-mediated oxidative injury as it is continuously exposed to circulating erythrocytes, exogenous hemoglobin and heme released by damaged cells, (Balla et al., 2000; Jeney et al., 2002; Ogita and Liao, 2004; Wagener et al., 2001a). Heme can threaten vascular endothelial cell integrity directly by promoting intracellular ROS formation (Balla et al., 2000; Stocker and Keaney, 2004; Wagener et al., 2001a; Wagener et al., 2003a) and indirectly by its ability to oxidize low density lipoproteins (LDLs) (Grinshtein et al., 2003). The initial step of heme-mediated LDL oxidation involves the spontaneous insertion of heme into LDL particles. The inserted heme directly promotes extensive oxidative modification of LDL. Accordingly, when endothelial cells are exposed to LDL from plasma containing hemoglobin or free heme, oxidative endothelial damage ensures (Grinshtein et al., 2003).
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Under physiological condition, the endothelial layer is non-adhesive for leukocytes. However, when exposed to free heme, activated endothelial cells increase the surface expression of adhesion molecules, as Intercellular Cell Adhesion Molecule (ICAM)-1, Vascular Cell Adhesion Molecule (VCAM)-1 and selectins (Belcher et al., 2003; Wagener et al., 2001a) which may subsequently promote the recruitment of leukocytes at the site of inflammation. By enhancing adhesion molecule expression and generating oxidative stress known to damage cells, heme also acts as a pro-inflammatory molecule and starts the inflammatory cascades (Wagener et al., 2001b). Finally free heme is considered a trigger of vasopermeabilization, which results from the partial retraction of endothelial cells of venules in the vicinity of inflammation, leaving small intercellular gaps. Vascular leakage results in slower blood flow by allowing the passage of water, salts and small proteins from the plasma into the damaged area (Mehta and Malik, 2006).
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Other than for the vessels, free heme is also highly toxic for other tissues and organs causing oxidative stress and damage.
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4.1.2. Haptoglobin
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Following intravascular hemolysis, stable hemoglobin-Hp complexes are formed in plasma and are delivered to the reticuloendothelial system by CD163 receptor-mediated endocytosis and to liver parenchymal cells through a yet unidentified receptor. CD163 is a member of the cysteine-rich scavenger receptor family and is exclusively expressed by cells of monocyte/macrophages lineage (Kristiansen et al., 2001; Nielsen and Moestrup, 2009). The existence of another receptor for hemoglobin-Hp complexes in hepatocytes has been hypothesized as it has been demonstrated that after injection of labeled hemoglobin-Hp complexes in rats, most of labeled hemoglobin is taken up by liver parenchymal cells (Higa et al., 1981; Kino et al., 1982; Ship et al., 2005; Weinstein and Segal, 1984). In macrophages, upon endocytosis, the receptor–ligand complex enters early endosomes where hemoglobin-Hp complexes are released from CD163. The receptor then recycles to the cell surface while hemoglobin-Hp complexes continue through the endocytic pathway to end up in lysosomes where the protein moieties and the ligand are degraded (Nielsen and Moestrup, 2009).
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In this manner, Hp reduces the loss of hemoglobin through the renal glomeruli hence protecting against peroxidative kidney injury and allows heme-iron recovery.
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This has been extensively confirmed by studies in Hp-null mice which have shown that the loss of Hp did not affect hemoglobin clearance (Fagoonee et al., 2005; Lim et al., 1998) but influences the pattern of hemoglobin distribution. Following the injection of low doses of labeled hemoglobin, hemoglobin-Hp complexes are mainly delivered to hepatocytes and Kupffer cells in the liver and to macrophages in the spleen of wild-type animals; in the absence of Hp, hemoglobin is mainly recovered by the kidney instead of the liver and spleen suggesting that Hp is important for the delivery of hemoglobin complexes to the liver and spleen. In a similar way, when high doses of labeled hemoglobin were injected into wild-type mice, causing the saturation of Hp binding capacity, in addition to the liver and spleen, hemoglobin is also delivered to the kidney thus mimicking what occurs during pathological conditions such us chronic hemolysis.
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The role of Hp in preventing hemoglobin filtration through the glomerular barrier is further supported by the observation that Hp-null mice develops kidney iron overload with ageing (Fagoonee et al., 2005). Particularly, hemoglobin derived iron accumulate mainly in the proximal tubular cells of the kidney. Similarly, HO-1 knockout mice which completely lack macrophages expressing the hemoglobin-Hp receptor CD163 also develop kidney iron loading (Kovtunovych et al., 2010).
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Moreover, excessive hemolysis or transfusion of hemoglobin solution have been shown to result in Hp depletion and subsequent renal failure, particularly acute tubular necrosis (Tam and Wong, 1988).
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In the absence of Hp, hemoglobin is filtered through the glomerular barrier and is reabsorbed by proximal tubular cells through the endocytic receptors megalin and cubilin. Megalin and cubilin are multiligand endocytic receptors expressed at the apical membrane of proximal tubules. Their primary function is to reabsorb small molecules that pass the glomerular filtration barrier. It has been previously demonstrated that hemoglobin is one of their ligands (Christensen and Birn, 2001; Gburek et al., 2002). Once in tubular cells, hemoglobin is degraded in the endosomal compartment and heme is catabolized by heme oxygenase (HO) (Figure 4).
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Figure 4.
Haptoglobin and Hemopexin prevent kidney iron loading. Under basal conditions hemoglobin and heme are targeted to macrophages and hepatocytes by Hp and Hx, respectively. Under pathologic conditions when Hp and Hx binding capacity is overwhelmed, hemoglobin and heme are filtered through the glomerular barrier and are re-absorbed by proximal tubular cells. Hemoglobin is recognized by the endocytic receptors megalin and cubilin while heme enters into the cells through a yet unidentified mechanism. Into the cells, heme is degraded by HO and iron stored bound to ferritin (Ft).
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In agreement with renal iron loading, Hp-null mice show higher basal level of renal lipid peroxidation and suffered greater tissue damage, as evidenced by the induction of the hepatic acute phase response resulting in increased AGP levels (Lim et al., 1998). Moreover, these mice showed increased susceptibility to acute hemolysis induced by phenylhydrazine treatment and are more sensitive to kidney injury than wild-type animals. Accordingly, an increased susceptibility to hemoglobin driven lipid peroxydation has been observed in human patients with hypo- or anhaptoglobinemia.
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4.1.3. Hemopexin
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Hx represents the primary line of defence against heme toxicity thanks to its ability to bind heme with high affinity and to function as a heme specific carrier from the bloodstream to the liver (Tolosano et al., 2010). The formation of heme-Hx complexes has been demonstrated to promote heme delivery to the parenchymal cells of the liver (Smith and Morgan, 1978, 1979). On the contrary, the heme-albumin complex appears to act only as a heme depository, before transport to the liver as heme-Hx, and there is no experimental evidence that albumin has a transport function in vivo (Smith and Morgan, 1981). Nowadays, several lines of evidence support the fact that the liver is the main target tissue for heme-Hx complex internalization and heme-derived iron recycling. In vivo studies showed that the liver is the major site of radioactive heme uptake after intravenous injection of 55Fe-heme-125I-Hx: nearly 90% of the administered heme is transported to the liver within 2 hours (KD700nM) without significant urinary excretion of either isotope (Smith and Ledford, 1988, Smith and Morgan, 1978, 1979, 1981, 1984). Hx-mediated heme uptake by the liver has been shown in vivo and in vitro to be a saturable process: saturation is indicative of an interaction with a rate-limiting step and a finite number of binding sites and is characteristic of receptor-mediated uptake. Furthermore, heme-Hx internalization has been demonstrated to be a highly tissue-specific process, time-, temperature- and energy-dependent (Smith and Morgan, 1978, 1979). Occurring within minutes, the association is on the same time scale as the receptor-mediated uptake of asialoglycoproteins (LaBadie et al., 1975) and of iron-transferrin complexes (Gardiner and Morgan, 1974). Nowadays, the only known Hx receptor on hepatocytes is represented by the LDL receptor-related protein 1 (LRP1), a multi-ligand scavenger receptor, involved in the metabolism of lipoprotein and expressed in several cell types including macrophages, hepatocytes and neurons (Boucher et al., 2003; Lillis et al., 2005). LRP1 has been shown to mediate heme-Hx internalization, resulting in cellular heme uptake (Hvidberg et al., 2005). Once entered the cell, the heme-Hx complex is dissociated by lysosomal activity: LRP1 is then recycled to the plasma membrane, whereas Hx destiny, after complex internalization, is somewhat controversial. Some studies have suggested that Hx can be recycled as an intact molecule to the extracellular milieu (Smith and Morgan, 1979). However, it has also been proposed that following hepatic uptake of heme from heme-Hx, varying proportion of the protein are either returned to the circulation or degraded in the liver (Potter et al., 1993). Recently, Hvidberg et al. have shown that most Hx is degraded in lysosomes (Hvidberg et al., 2005). Accordingly, in a model of heme overload, plasma Hx level has been found to decrease, thus indicating that Hx is actively involved in heme scavenging and subjected to degradation (Vinchi et al., 2008). Furthermore, a decrease in plasma Hx concentration reflects a recent release of heme compounds in the extracellular compartment. Invariably, high concentrations of heme are associated with low concentration of Hx (Muller-Eberhard et al., 1968). Hx is in fact found to decrease in plasma after hemolytic stress associated to pathologies like hemolytic anemias, acute intermittent porphyria and chronic neuromuscular diseases.
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As a consequence of Hx-mediated heme delivery to the liver, heme deleterious effects are efficiently counteracted as demonstrated by several experimental data. First, heme binding to Hx has been demonstrated to reduce the heme-mediated free radical formation from organic peroxides (Timmins et al., 1995). Furthermore, in vitro studies demonstrated that Hx strongly decreases the peroxidative and catalatic activity of heme by forming inactive heme-protein complexes. Interestingly, these hemin activities were found to be inhibited by 80-90% with Hx but only by 50-60% with either human or bovine albumin (Grinberg et al., 1999). The marked effectiveness of Hx at inhibiting heme toxicity was most probably the result of its very high affinity to heme with a dissociation constant KD of 10-13M. Moreover, binding to Hx was shown to inhibit heme-catalyzed lipid peroxidation in artificial liposomes (Gutteridge and Smith, 1988), rat liver microsomes (Vincent et al., 1988) and plasma LDL (Miller et al., 1996). Thus, Hx has an essential role in the prevention of heme-induced oxidative damage and cell death (Eskew et al., 1999).
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Many experimental evidences also support the antioxidant function of Hx in vivo. Hx-null mice have been demonstrated to be particularly sensitive to heme overload and more prone to heme-induced oxidative damage and inflammation during hemolytic processes (Tolosano et al., 1999, Vinchi et al., 2008). Furthermore, in vivo studies showed that the most damaged tissues upon heme overload conditions are the vasculature, the liver and the kidney.
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It has been demonstrated that Hx has a crucial role in the protection of the endothelial wall against heme toxicity. It has been observed an increased induction of the adhesion molecules ICAM-1 and VCAM-1 in the endothelium and increased vascular permeability in Hx-null mice compared to wild-type mice, after intravenous heme injection (Vinchi et al., 2008), thus demonstrating that Hx activity is required to prevent heme-induced vasopermeabilization and endothelial activation.
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Oxidative stress has already been shown to induce vascular HO-1 expression in rats, mice, and humans. Even if HO-1 induction is significantly higher in the vascular endothelium of Hx-null mice compared to controls, it cannot prevent endothelial damage (Vinchi et al., 2008). On the other hand, the induction of HO-1 before intravenous heme injection preserved endothelial integrity in Hx-null mice, thus indicating that the lack of Hx may be tolerated if the cells are already equipped to metabolize an excess of heme and suggesting that Hx and HO-1 work in sequence to counteract the toxic effect of heme, Hx being the first line of defence.
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Besides the vasculature, other tissues have been described as particularly sensitive to heme-mediated damage. Studies on Hx-null mice have demonstrated that these animals are particularly sensitive to acute hemolysis. These mice recover more slowly after phenylhydrazine-induced hemolysis and suffer from more severe renal damage compared to wild-type mice. In fact, after hemolytic stimulus, Hx-null mice present prolonged hemoglobinuria, higher kidney iron loading and lipid peroxidation than wild-type mice (Tolosano et al., 1999). These findings emphasize the protective role of Hx in hemolytic processes. Moreover, Hx-null kidneys exhibit increased lipid peroxidation not only after phenylhydrazine treatment but also after intravenous injection of hemin (Vinchi et al., 2008). Therefore Hx, together with Hp, plays a fundamental role in the kidney during hemolysis: Hp has a major function in the protection of renal tubules from hemoglobin-mediated oxidative damage; then, once Hp disappears from the circulation, the delayed presence of Hx in the plasma takes on a relevant role in the protection against heme derived from hemoglobin oxidation.
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Interestingly Hx and Hp compound mutant mice subjected to phenylhydrazine-induced hemolysis presented, other than kidney damage, a more severe injury in the liver characterized by inflammation, necrosis and fibrosis (Tolosano et al., 2002). The liver is also the most sensitive organ to heme overload in Hx-null mice. Indeed the liver of heme-overloaded Hx-null mice developed a marked congestion characterized by red blood cell stasis and sinusoidal dilation around the centrolobular area (Figure 5). Hepatic congestion was found to be associated with abnormal iron deposits, increased lipid peroxidation and massive leukocyte infiltrates (Vinchi et al., 2008).
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Figure 5.
Liver congestion in heme-overloaded Hemopexin-null mice. Liver sections of a wild-type and a Hx-null mouse injected with heme into the tail vein and sacrificed 6 hours later. Note the marked congestion around the centrolobular vein in Hx-null animal. Hematoxylin and eosin staining; X200.
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This phenotype underlines the increased susceptibility of Hx-null mice to acute hepatic damage in condition of heme overload and highlights a role for Hx in the protection from liver injury. Liver damage in Hx-null mice may be prevented by induction of HO-1 before heme overload, thus confirming once again that Hx and HO-1 work together to ensure tissue protection against heme toxicity.
Since all the disorders mentioned above are usually related to pathological conditions wherein extracellular hemoglobin and free heme are released in massive amounts, it could be speculated that heme represent a predisposing factor for vaso-occlusion and that Hx is important to counteract its pro-occlusive effects. This hypothesis is also in agreement with the mentioned role of Hx as a detoxification mechanism that prevents endothelial damage by removing free heme from circulation.
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In conclusion in vivo studies highlight the critical importance of Hx in preventing firstly vascular inflammation and acute liver injury and secondly renal damage, thanks to its ability to limit heme-induced oxidative stress. Interestingly all the toxic effects of heme are exacerbated in Hx-null mice, indicating not only that Hx has an important protective role in plasma but also that none of the plasma proteins able to bind heme (ie, albumin, α1-microglobulin, high- and low-density lipoproteins) may substitute for Hx after heme overload.
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4.2. Role of Haptoglobin and Hemopexin in iron recycling
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4.2.1. Haptoglobin- and Hemopexin-mediated heme recovery
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Besides their function as hemoglobin and heme scavengers respectively, Hp and Hx are essential in the re-utilisation of heme-bound iron and represent a fundamental part of the iron-conservation mechanisms of the body (Hershko,1975; Davies,1979).
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As reported above, the hemoglobin-Hp complexes are mainly taken up by macrophages through the specific receptor CD163, whereas the heme-Hx complexes enter into hepatocytes through LRP1. Once in macrophages or hepatocytes, heme is degraded by HO-1 to iron, biliverdin and CO (see next section). Iron is then stored in cells bound to ferritin or exported to the plasma and transported throughout the body. The contribution of Hp to iron recovery is further highlighted by the observation that the Hp phenotype modify iron loading in hemochromatosis both in humans and in mice (Delanghe and Langlois, 2002, Langlois et al., 2000, Tolosano et al., 2005, Van Vlierberghe et al., 2004; Van Vlierberghe et al., 2001). In addition, deletion of the Hx gene in mice results in abnormal extrahepatic iron deposits (Morello et al., 2008), thus suggesting that also in humans mutations in the Hx gene might modify iron distribution and accumulation in the body.
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Other than by Hp and Hx other mechanisms have been reported to mediate hemoglobin or heme delivery to cells. Recent data suggest that in macrophages CD163 is also able to mediate the entrance of free hemoglobin through a low affinity binding. Particularly, (a)hemoglobin uptake has been observed in the absence of Hp in human macrophages and in CD163 transduced HEK293 cells but not in CD163-negative cells; (b)highly purified hemoglobin inhibits CD163 mediated uptake of labeled hemoglobin-Hp complexes or free hemoglobin, implying a common receptor binding site; (c)free hemoglobin induces transcriptional induction of HO-1, an indirect measure of hemoprotein internalization and degradation, in CD163 expressing cells in a dose dependent manner; (d)disruption of the hemoglobin interaction with Hp by chemical cross-linking of hemoglobin between its alpha chains or, alternatively, by proteolytic cleavage does not significantly affect the CD163-hemoglobin interaction.
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Moreover, other than free hemoglobin, macrophages may also take up free heme, or, in other words, heme not bound to Hx. Treatment of primary macrophages or macrophage cell lines with heme resulted in the induction of HO-1 and ferritin indicating that heme enters in these cells and is degraded (Hvidberg et al., 2005, Liang et al., 2009). Moreover, Hx-deficient mice showed a prolonged HO-1 induction in Kupffer cells after acute hemolysis (Tolosano et al., 2002) and intravenous heme injection (Vinchi et al., 2008), thus suggesting that Hx limits heme delivery and thus heme-mediated HO-1 induction in these cells. Moreover, several other cell types, other than macrophages, may take up free hemoglobin and heme.
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Nevertheless these alternative mechanisms do not ensure an adequate protection against oxidative damage nor an efficient iron recovery as demonstrated by the observation that, under conditions of massive hemolysis, free hemoglobin and heme accumulate in proximal tubular cells of the kidney. As mentioned in section 4.1.2,, Hp-null mice accumulated heme-derived iron in proximal tubular cells during ageing and after phenylhydrazine-induced hemolysis. This is true also for Hx-null that, after phenylhydrazine treatment show renal iron loading. Moreover, heme overloaded-Hx-null mice upregulate HO-1 and ferritins in the kidney. These data indicate that excess of free heme is recovered by the kidney, during hemolytic stress, when the buffering capacity of Hp and Hx is overwhelmed (Figure 4). (Lim et al., 1998, Tolosano et al., 1999).
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In conclusion as shown in Figure 6, Hp plays a major role in mediating haemoglobin recovery in macrophages through CD163, whereas Hx promotes heme uptake by
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Figure 6.
Role of macrophage and hepatocyte in hemoglobin and heme recovery respectively. Macrophage takes up the hemoglobin-Hp complexes through CD163, whereas the hepatocyte recovers the heme-Hx complexes through LRP1. Once into the cell heme is degraded by HO to iron, which is bound to ferritin, CO and biliverdin (see section 4.2.2 for details). As depicted in the figure iron by itself may control the expression of ferritin (see section 4.3.2).
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hepatocytes through LRP1. These mechanisms ensure an adequate protection against heme-mediated oxidative stress and mediate heme-iron reutilization. Under conditions of massive hemolysis when Hp and Hx are saturated free hemoglobin and heme may be taken up by macrophage through not well-characterized mechanisms. However, under these conditions heme pro-oxidant potential is not adequately inactivated and the vasculature and tissues are damaged.
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4.2.2. Role of HO and Ferritin in heme iron recovery
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Once that the hemoglobin-Hp or the heme-Hx complexes are respectively taken up by macrophages and hepatocytes, heme is released in the cytoplasm and presumably used to build new hemoproteins or catabolized by HO.
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Microsomal HO is the rate-limiting enzyme in the degradation of heme and plays a key role in the protection of cells from heme-induced oxidative stress (Ferris et al., 1999). It breaks down the pro-oxidant heme into the antioxidant biliverdin, the vasodilator carbon monoxide (CO) and iron. Biliverdin is then reduced to bilirubin by the enzyme biliverdin reductase. Hitherto, three isoforms of HO have been identified: HO-1, HO-2, and HO-3.
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HO-1 is highly inducible by a variety of stimuli including oxidative stress, heat shock, hypoxia, heavy metals, ischemia-reperfusion, cytokines and its substrate heme. The constitutively expressed HO-2 participates in the normal heme capturing and metabolism, while the function of HO-3 is still under investigation (Wagener et al., 2003b). HO-1 plays a crucial function in regulating heme degradation and protects against heme-mediated oxidative injury.
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HO-1 can prevent the deleterious effects of free heme by several mechanisms. These include inhibiting (a)the release of free heme from hemoproteins, (b)the accumulation of free heme in cells, and/or (c)the pro-oxidant effects of free heme.
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HO-1 can prevent heme release from hemoproteins by producing CO, a final product of heme degradation. Once bound to the heme groups of hemoproteins, CO inhibits heme-iron oxidation, thus limiting the oxidation of hemoproteins and preventing heme release. It has been recently demonstrated that by this mechanism HO-1 inhibits the accumulation of free heme in plasma following Plasmodium infection, thus preventing the onset of severe malaria in mice (Ferreira et al., 2008, Pamplona et al., 2007, Pamplona et al., 2009, Seixas et al., 2009).
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Analysis of HO-1-null mice has shown that these animals accumulated, with age, hepatic and renal iron that contributed to oxidative damage, tissue injury and chronic inflammation. On the other hand, HO-1-null mice presented low serum iron concentration and developed anemia (Koizumi, 2007, Yachie et al., 1999). These data demonstrated that, although HO-1 is a stress-induced protein, it is important under basal conditions to protect liver and kidney from oxidative damage and that it is an essential regulator of iron metabolism and homeostasis.
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Overexpression of HO-1 is associated to the resolution of inflammation through the generation of beneficial molecules like CO, bilirubin, and ferritin resulting from catabolism of toxic heme (Kapturczak et al., 2004, Wagener et al., 2001b). Some of the end products of heme catabolism by HO-1 might prevent the pro-oxidant effects of free heme. This is probably the case for biliverdin, which has antioxidant properties by itself but in addition can be converted by biliverdin reductase into the potent lipid-soluble antioxidant bilirubin. Owing to its lipophilic nature, free heme might act as a pro-oxidant primarily within cellular membranes. This deleterious effect may be inhibited by lipophilic bilirubin, that efficiently scavenges peroxyl radicals, thereby inhibiting lipid peroxidation and attenuating heme-induced endothelial activation. This mechanism would explain the ability of HO-1 to inhibit, via the production of bilirubin, lipid peroxidation in cells exposed to free heme and TNF. CO controls the activity of several heme proteins and causes vasodilation. It also exerts anti-inflammatory effects by inhibiting the expression of pro-inflammatory cytokines through a pathway involving the mitogen-activated protein kinases (Ndisang et al., 2002). In the last years several studies have shown the therapeutic potentialities of HO-1 and its products in counteracting the toxic effect of heme associated to pathologic conditions (Farombi and Surh, 2006, Lindenblatt et al., 2004).
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Heme catabolism by HO-1 should also prevent the accumulation of free heme within cells. This cytoprotective mechanism must, however, be coupled to the induction of ferritin (Ft) expression to avoid the pro-oxidant effects of labile iron produced via heme catabolism. This notion is consistent with the observation that overexpression of Ft can mimic the cytoprotective effects of HO-1.
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Ft is the major intracellular depot of non-metabolic iron and acts as a heme-detoxification system by scavenging free iron and protecting cells from its adverse effects. Ft is a multimeric protein composed of 24 subunits of two types, the heavy chain (H-Ft) and the light chain (L-Ft) and has a very high capacity for storing iron (up to 4500 mol of iron per mol of Ft). In the Ft shell, the proportion of heavy and light subunits depends on the iron status of the cell or tissue and varies among organs and species. H-Ft manifests ferroxidase activity that catalyses the oxidation of ferrous iron to ferric iron to allow intracellular iron storage in L-Ft, which acts as intracellular iron deposit (Arosio and Levi, 2002). Iron released during heme catabolism has been demonstrated to be rapidly stored in Ft (Davies et al., 1979).
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Together, HO and Ft allow rapid iron shifting from heme into Ft core where iron is less available to catalyze deleterious reactions. Hence their potent antioxidant role. By increasing the expression of HO-1 and Ft, cells can survive lethal heme-induced oxidative stress (Balla et al., 2005).
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Interestingly, in vivo work showed that Hx-null mice failed to up-regulate Ft in the liver after heme overload, thus demonstrating that the lack of Hx decreases the ability of the liver to recover heme-iron, under heme overload condition. Conversely, up-regulation of Ft in wild-type liver indicates a strong iron detoxifying capacity and an active iron storage and demonstrates, once again, that Hx is crucial to mediate heme delivery to hepatocytes.
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4.3. Regulation of gene expression by hemoglobin-Haptoglobin and heme-Hemopexin complexes.
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4.3.1. Haptoglobin mediated regulation of Ferroportin expression
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Recent studies suggest an important role of Hp in modulating iron export from the duodenum. Hp-null mice showed increased iron export from the duodenum compared to wild-type mice, while iron uptake was normal (Marro et al., 2007). Iron export out of the duodenum was due to the increased expression of the iron exporter Ferroportin.
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Following the injection of a low dose of hemoglobin into wild-type and Hp-null mice, a little amount of hemoglobin is delivered to the duodenum, suggesting the existence of a yet unknown mechanism for hemoglobin uptake into duodenal cells (Fagoonee et al., 2005). So, it has been proposed that hemoglobin taken up into duodenal cells could regulate Ferroportin transcription.
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In vitro data on macrophages, showed that hemoglobin and heme directly activate the transcription of Ferroportin through the transcription factors Bach1 and Nrf2 (Marro et al., 2010). Thus, Hp, by controlling plasma levels of hemoglobin, participates in the regulation of ferroportin expression, thus contributing to the regulation of iron export. In the same way it is possible to speculate that Hx by controlling heme uptake by the cells may contribute to the control of ferroportin expression.
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4.3.2. Hemopexin-mediated regulation of genes involved in iron recycling and cell survival
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By its ability to mediate heme uptake into the liver, Hx promotes an increase in intracellular concentrations of heme, that directly affects the surface expression of transferrin receptor (TfR) and the expression level of HO-1 and ferritin. Heme has been shown to regulate the expression of several genes, including HO-1, by inhibiting the transcriptional repressor Bach1. Moreover, when intracellular heme increases, a rapid downregulation of TfR on the plasma membrane and concomitant induction of ferritin synthesis occur. It has been demonstrated that incubation of mouse Hepa cells with heme-Hx causes a rapid dose- and time-dependent decrease in the level of TfR mRNA. These regulatory effects have been observed not only in hepatic cells but also in human promyelocitic HL-60 cells (Alam and Smith, 1989), in human leukemic U937 cells and in HeLa cells (Taketani et al., 1990). Down-regulation of TfR on the plasma membrane was the result of multiple steps: a rapid redistribution of the protein between the plasma and intracellular membrane compartments and a decrease in the biosynthesis of the receptor. The latter is due to iron released from heme, that affects the stability of iron regulatory proteins (IRP), which regulate TfR mRNA stability and ferritin mRNA translation by binding to the iron responsive elements (IRE) in their 3’ and 5’ UTRs, respectively (Hentze et al., 2004). In this manner heme-derived iron enhance the expression of the iron storage protein ferritin and down-regulates the uptake of inorganic iron.
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Furthermore, binding of heme–Hx to the plasma membrane Hx receptor stimulates the expression of metallothionein (MT)-1 (Alam and Smith, 1992, Ren and Smith, 1995). Metallothioneins are cysteine-rich proteins thought to play a role in heavy metal detoxification, zinc and copper homeostasis, and cellular adaptation to stress. Upon incubation with heme-Hx, MT-1 mRNA steady state levels rapidly increase in both mouse hepatoma and human HL-60 cells. Regulation is controlled primarily at the level of MT-1 gene transcription in Hepa cells. Non protein-bound heme, although an effective inducer of HO gene transcription, was found to be a poor inducer of MT-1. This indicated that occupation of the Hx receptor itself by the heme-Hx complex is necessary for efficient accumulation of MT-1 transcripts. Activation of MT-1 gene transcription as a consequence of Hx-mediated heme transport may occur during endocytosis or via an indirect mechanism triggered by the interaction of heme-Hx with the Hx receptor on the cell surface. Recently Smith et al. demonstrated that the correct hypothesis was the first one: mainly copper, than the heme-Hx complex has been found to have an essential role in MT-1 induction (Smith et al., 2008). Copper endocytosis together with that of heme-Hx provides a mean to facilitate heme release from Hx in the maturing endosomes, by preventing the rebinding of heme to Hx. In this manner copper promotes heme export from endosomes and renders it available for HO-1 degradation. On the other hand, MT-1 induction is proposed to take place in response to a rise in cytosolic copper that directly contribute to MT-1 gene transcription. Therefore, cytosolic copper provide a link for the simultaneous regulation of HO-1 and MT-1 by heme-Hx.
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5. Haptoglobin and Hemopexin function in the nervous system
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Heme is an essential cofactor for many proteins involved in the normal function of neuronal tissue, such as enzymes required for neurotransmitter synthesis and myelination of axons (Connor and Menzies, 1996). On the other hand, excess of heme is usually associated to pathologic conditions as intracerebral or subarachnoid hemorrhages and ischemia reperfusion injury. In addition, some neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases, are associated with iron accumulation in specific brain regions (Berg and Youdim, 2006, Zecca et al., 2004). As the central nervous system is separated from the body by the blood-brain barrier, it has evolved mechanisms of local heme and iron management.
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5.1. Haptoglobin and Hemopexin expression in the central nervous system
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Both Hp and Hx were found in the human cerebrospinal fluid and their expression increases in several pathologic conditions including Parkinson’s disease, Alzheimer’s disease and Guillain-Barré syndrome (Arguelles et al., Roher et al., 2009, Yang et al., 2008).
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Hp was found to be expressed in human gliobastoma cell lines, in reactive astrocytes after transient forebrain ischemia in rats and in oligodendroglia in mice (Lee et al., 2002). Hx expression was demonstrated in cortical neurons and astrocytes (Morris et al., 1993). Moreover, detection of beta-galactosidase activity on brain sections from Hx-null mice, carrying the lacZ gene into the Hx genomic locus, demonstrated that Hx was expressed primarily by ependymal cells lining the ventricular system and hippocampal neurons (Morello et al., 2008). Finally, both Hp and Hx are expressed in the neural retina (Chen et al., 1998).
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5.2. Neuroprotective roles of both Haptoglobin and Hemopexin
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In humans Hp haplotypes were found to be correlated with the extent of cerebral deep white matter lesions in hypertensive patients and with cerebrovascular disease, thus suggesting that the efficiency of hemoglobin scavenging may be crucial for the resolution of neuronal injury.
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Moreover, by using a mouse model of intracerebral hemorrhage, Zhao and co-authors demonstrated that Hp plays an important role in defending neurons from damage induced by hemolysis (Zhao et al., 2009). In vitro studies demonstrated that oligodendroglia-released Hp protects neurons and oligodendrocytes against hemoglobin-mediated toxicity (Zhao et al., 2009).
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A protective role against intracerebral hemorrhage has also been reported for Hx by Chen and co-authors that demonstrated increased striatal injury and behavioral deficits in Hx-null mice subjected to intracerebral hemorrhage (Chen et al.). Moreover, it has recently been reported that, in a mouse model of transient ischemia, Hx is protective as neurologic deficits and infarct volumes were significantly greater in Hx-null than in wild-type mice (Li et al., 2009). Exogenous free heme was shown to decrease cell survival in primary mouse cortical neuron cultures, whereas the heme bound to Hx was not toxic and protection was achieved through heme-Hx-mediated induction of HO-1 (Li et al., 2009).
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6. Other functions
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Recent works highlighted a role for Hp and Hx in the control of the immune response, mainly achieved through their ability to control inflammation. Hp modulates both innate and adaptive immune responses. Hp has been demonstrated to bind activated neutrophils, to inhibit several of their functions and to suppress secretion of TNF-α, IL-10, and IL-12p70 by macrophages upon LPS triggering (Arredouani et al., 2005; Rossbacher et al., 1999). CD11b has been identified as a macrophage receptor for Hp (El Ghmati et al., 1996). The binding of hemoglobin-Hp complex to the CD163 molecule on macrophages leads to anti-inflammatory cytokine secretion (Nielsen and Moestrup, 2009). Hp acts on Langerhans cells of the skin, preventing their differentiation and function during in vitro culture and affects proliferation and cytokine production by stimulated T cells and B cells (Huntoon et al., 2008, Xie et al., 2000). Recently, Galicia et al. demonstrated that, in a model of experimental autoimmune encephalomyelitis, Hp-null mice suffered from a more severe disease that was associated with increased expression of IL-17A, IL-6, and interferon (IFN)-γ mRNA in the CNS and with a denser cellular infiltrate in the spinal cord. During the recovery phase, a significantly higher number of myeloid DC, CD8+ cells, IL-17+ CD4+ and IFN-γ+ CD4+ cells persisted in the CNS of Hp-null mice. Absence of Hp affected the priming and differentiation of T cells after induced encephalomyelitis (Galicia et al., 2009).
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On the other hand, Hx-null mice produced significantly less autoantibodies and had less immune complex deposits than their wild-type counterpart in a model of mercury-induced autoimmunity and this response has been correlated to a blunted response of CD4+ T cells from Hx-null mice to IFN. Some data suggested that Hx, by controlling heme-iron availability to T lymphocytes may control the expression of IFNR at the cell membrane thus regulating IFN responsiveness (Fagoonee et al., 2008). However, other data demonstrated that Hx, like Hp, down-regulates LPS-induced proinflammatory cytokines from macrophages and suppresses neutrophil adhesion and phagocytosis by a mechanism unrelated to heme-binding (Liang et al., 2009). Furthermore, Spiller et al. have recently reported that Hx by inhibiting neutrophil migration leads to increased mortality in septic mice (Spiller et al., 2010).
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All these results suggest that Hp and Hx play a modulatory role on the immune response likely by controlling cytokine production.
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\n\t\t\t
7. Conclusion
\n\t\t\t
As discussed in the previous sections, Hp and Hx, by acting as plasma scavengers of hemoglobin and heme respectively, play a major role in the protection against heme-mediated oxidative stress and in preventing heme-iron loss during the acute phase response associated to massive intravascular hemolysis. In addition, they play a “local” role in the nervous system by limiting the pro-oxidant effect of heme after ischemia or intracerebral hemorrhage. Finally, they have a modulatory role in the immune system by regulating the inflammatory response.
\n\t\t\t
Most of the work in the past decades has been focused on the definition of the mechanisms underlying the Hp- and Hx-mediated protection against heme toxicity. Nevertheless, recently, Schaer and co-authors investigated the potential of Hp supplementation as a strategy to counteract the intrinsic hypertensive and oxidative toxicities of free hemoglobin and demonstrated that the induction of Hp synthesis in dogs by glucocorticoid treatment prevented free hemoglobin-mediated hypertension. In a similar way, the co-infusion of exogenous Hp and hemoglobin in guinea pig prevents hemoglobin peroxidative activity and oxidative tissue damage (Boretti et al., 2009).
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Thus, it is time to speculate that therapeutics that could increase Hp and/or Hx levels or act as Hp/Hx agonists might help to limit heme toxic effects in pathologic conditions associated to massive hemolysis as hemolytic anemia, sickle cell disease, ischemia-reperfusion injury.
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\n\t
Acknowledgments
\n\t\t\t
We wish to thank people that in the past years worked with us and contributed to our knowledge in the field, Sharmila Fagoonee, Samuele Marro and Noemi Morello, and Fiorella Altruda for helpful discussion.
\n\t\t
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/21456.pdf",chapterXML:"https://mts.intechopen.com/source/xml/21456.xml",downloadPdfUrl:"/chapter/pdf-download/21456",previewPdfUrl:"/chapter/pdf-preview/21456",totalDownloads:3283,totalViews:713,totalCrossrefCites:5,totalDimensionsCites:15,hasAltmetrics:0,dateSubmitted:"October 26th 2010",dateReviewed:"April 27th 2011",datePrePublished:null,datePublished:"October 5th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/21456",risUrl:"/chapter/ris/21456",book:{slug:"acute-phase-proteins-regulation-and-functions-of-acute-phase-proteins"},signatures:"Deborah Chiabrando, Francesca Vinchi, Veronica Fiorito and Emanuela Tolosano",authors:[{id:"30837",title:"Prof.",name:"Emanuela",middleName:null,surname:"Tolosano",fullName:"Emanuela Tolosano",slug:"emanuela-tolosano",email:"emanuela.tolosano@unito.it",position:null,institution:{name:"University of Turin",institutionURL:null,country:{name:"Italy"}}},{id:"48270",title:"Dr.",name:"Deborah",middleName:null,surname:"Chiabrando",fullName:"Deborah Chiabrando",slug:"deborah-chiabrando",email:"deborah.chiabrando@unito.it",position:null,institution:null},{id:"48271",title:"Dr.",name:"Francesca",middleName:null,surname:"Vinchi",fullName:"Francesca Vinchi",slug:"francesca-vinchi",email:"francesca.vinchi@unito.it",position:null,institution:null},{id:"48272",title:"Dr.",name:"Veronica",middleName:null,surname:"Fiorito",fullName:"Veronica Fiorito",slug:"veronica-fiorito",email:"veronica.fiorito@unito.it",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Haptoglobin",level:"1"},{id:"sec_2_2",title:"2.1. Gene structure",level:"2"},{id:"sec_3_2",title:"2.2. Protein structure",level:"2"},{id:"sec_4_2",title:"2.3.Gene, mRNA and protein regulation",level:"2"},{id:"sec_5_2",title:"2.4. Conservation of gene, protein and regulation ",level:"2"},{id:"sec_7",title:"3. Hemopexin",level:"1"},{id:"sec_7_2",title:"3.1. Gene structure",level:"2"},{id:"sec_8_2",title:"3.2. Protein structure",level:"2"},{id:"sec_9_2",title:"3.3. Gene, mRNA and protein regulation",level:"2"},{id:"sec_10_2",title:"3.4. Conservation of gene, protein and regulation",level:"2"},{id:"sec_12",title:"4. Haptoglobin and Hemopexin function into the bloodstream",level:"1"},{id:"sec_12_2",title:"4.1. Antioxidant and cytoprotective function of both Haptoglobin and Hemopexin",level:"2"},{id:"sec_12_3",title:"4.1.1. Heme",level:"3"},{id:"sec_13_3",title:"4.1.2. Haptoglobin",level:"3"},{id:"sec_14_3",title:"4.1.3. Hemopexin",level:"3"},{id:"sec_16_2",title:"4.2. Role of Haptoglobin and Hemopexin in iron recycling",level:"2"},{id:"sec_16_3",title:"4.2.1. Haptoglobin- and Hemopexin-mediated heme recovery",level:"3"},{id:"sec_17_3",title:"4.2.2. Role of HO and Ferritin in heme iron recovery",level:"3"},{id:"sec_19_2",title:"4.3. Regulation of gene expression by hemoglobin-Haptoglobin and heme-Hemopexin complexes.",level:"2"},{id:"sec_19_3",title:"4.3.1. Haptoglobin mediated regulation of Ferroportin expression",level:"3"},{id:"sec_20_3",title:"4.3.2. Hemopexin-mediated regulation of genes involved in iron recycling and cell survival",level:"3"},{id:"sec_23",title:"5. Haptoglobin and Hemopexin function in the nervous system",level:"1"},{id:"sec_23_2",title:"5.1. Haptoglobin and Hemopexin expression in the central nervous system",level:"2"},{id:"sec_24_2",title:"5.2. Neuroprotective roles of both Haptoglobin and Hemopexin",level:"2"},{id:"sec_26",title:"6. 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Gastroenterology\n\t\t\t\t\t133\n\t\t\t\t\t1261\n\t\t\t\t\t1271 .\n\t\t\t'},{id:"B64",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarro\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChiabrando\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMessana\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStolte\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTurco\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTolosano\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuckenthaler\n\t\t\t\t\t\t\tM. U.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tHeme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position-7007 of the FPN1 promoter.\n\t\t\t\t\tHaematologica\n\t\t\t\t\t95\n\t\t\t\t\t1261\n\t\t\t\t\t1268 .\n\t\t\t'},{id:"B65",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehta\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMalik\n\t\t\t\t\t\t\tA. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tSignaling mechanisms regulating endothelial permeability.\n\t\t\t\t\tPhysiological reviews\n\t\t\t\t\t86\n\t\t\t\t\t279\n\t\t\t\t\t367 .\n\t\t\t'},{id:"B66",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tY. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmith\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorgan\n\t\t\t\t\t\t\tW. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShaklai\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996\n\t\t\t\t\tRole of hemopexin in protection of low-density lipoprotein against hemoglobin-induced oxidation.\n\t\t\t\t\tBiochemistry\n\t\t\t\t\t35\n\t\t\t\t\t13112\n\t\t\t\t\t13117 .\n\t\t\t'},{id:"B67",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorello\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTonoli\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLogrand\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFiorito\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFagoonee\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTurco\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilengo\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVercelli\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAltruda\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTolosano\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Hemopexin affects iron distribution and ferritin expression in mouse brain. Journal of cellular and molecular medicine.\n\t\t\t'},{id:"B68",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorris\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCandy\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdwardson\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBloxham\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmith\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993\n\t\t\t\t\tEvidence for the localization of haemopexin immunoreactivity in neurones in the human brain.\n\t\t\t\t\tNeuroscience letters\n\t\t\t\t\t149\n\t\t\t\t\t141\n\t\t\t\t\t144 .\n\t\t\t'},{id:"B69",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuller-Eberhard\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJavid\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiem\n\t\t\t\t\t\t\tH. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanstein\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanna\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1968\n\t\t\t\t\tPlasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases.\n\t\t\t\t\tBlood\n\t\t\t\t\t32\n\t\t\t\t\t811\n\t\t\t\t\t815 .\n\t\t\t'},{id:"B70",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNarisada\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawamoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuwamoto\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoriwaki\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakagawa\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAsahi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoyama\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyoshi\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tIdentification of an inducible factor secreted by pancreatic cancer cell lines that stimulates the production of fucosylated haptoglobin in hepatoma cells. Biochem Biophys Res Commun 377\n\t\t\t\t\t792\n\t\t\t\t\t796 .\n\t\t\t'},{id:"B71",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNdisang\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tSelective regulation of blood pressure by heme oxygenase-1 in hypertension.\n\t\t\t\t\tHypertension\n\t\t\t\t\t40\n\t\t\t\t\t315\n\t\t\t\t\t321 .\n\t\t\t'},{id:"B72",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNielsen\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoestrup\n\t\t\t\t\t\t\tS. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tReceptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging. Blood\n\t\t\t\t\t114\n\t\t\t\t\t764\n\t\t\t\t\t771 .\n\t\t\t'},{id:"B73",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNikkila\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGitlin\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuller-Eberhard\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1991\n\t\t\t\t\tRat hemopexin. Molecular cloning, primary structural characterization, and analysis of gene expression.\n\t\t\t\t\tBiochemistry\n\t\t\t\t\t30\n\t\t\t\t\t823\n\t\t\t\t\t829 .\n\t\t\t'},{id:"B74",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOgita\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tEndothelial function and oxidative stress. 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E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tden.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoff\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdema\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFigdor\n\t\t\t\t\t\t\tC. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003a\n\t\t\t\t\tThe heme-heme oxygenase system: a molecular switch in wound healing.\n\t\t\t\t\tBlood\n\t\t\t\t\t102\n\t\t\t\t\t521\n\t\t\t\t\t528 .\n\t\t\t'},{id:"B117",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWagener\n\t\t\t\t\t\t\tF. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVolk\n\t\t\t\t\t\t\tH. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWillis\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbraham\n\t\t\t\t\t\t\tN. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoares\n\t\t\t\t\t\t\tM. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdema\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFigdor\n\t\t\t\t\t\t\tC. 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L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStreilein\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tHaptoglobin is a natural regulator of Langerhans cell function in the skin. 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R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrichton\n\t\t\t\t\t\t\tR. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIron, brain ageing and neurodegenerative disorders.\n\t\t\t\t\tNature reviews\n\t\t\t\t\t5\n\t\t\t\t\t863\n\t\t\t\t\t873 .\n\t\t\t'},{id:"B123",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStrong\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrotta\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAronowski\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tNeuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 29\n\t\t\t\t\t15819\n\t\t\t\t\t15827 .\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Deborah Chiabrando",address:null,affiliation:'
Molecular Biotechnology Center, University of Torino, Italy
Molecular Biotechnology Center, University of Torino, Italy
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1. Introduction
Pro-ecological technologies for the production of activated, functional products with unique properties are being vigorously developed in the field known as green chemistry. Of particular significance is the production of novel materials based on polymers of natural origin, such as lignin and its derivatives.
Lignin is a byproduct in the paper and pulp industry and has been mostly used as a fuel to provide energy for technological processes. This biopolymer is a main source for the production of biofillers. It can also be used as an effective sorbent of organic compounds and hazardous metal ions, as a polymer filler, in the synthesis of polyethers, polyurethanes and epoxy resins, and as a component of abrasive tools. Lignin can be applied in its untreated state. However, to fully exploit its properties, its natural conformation has to be improved through certain structural modifications, which will be described in this chapter.
Activation of lignin is carried out to modify functional groups while leaving the aromatic base of the polymer intact. Originally, lignin was subjected to oxidation to better understand its structure and to identify its bonds. At present, it is known that the use of strong oxidants breaks up the aromatic ring of the polymer, whereas using milder ones changes only its functional groups. The lignin surface contains many hydroxyl groups, which can be oxidized to carbonyl groups. These functional groups are more reactive than the hydroxyl groups and hence the resulting compound can offer more potential applications, including in electrochemistry.
2. Lignin—an overview
There is an ever increasing importance to polymers of natural origin. They are widely used in many branches of science and industry, chiefly because of their distinctive or unique properties and their renewability. Of particular interest are materials obtained from biomass, broadly defined. These include lignin and its derivatives.
Lignin is a biopolymer that occurs in the cell walls of plants. It enables plants to retain rigidity, mechanical strength and integrity between the other natural polymers contained in the basic plant cell: cellulose and hemicellulose [1]. Depending on the species of tree, lignin may account for between 20 and 30% of the total mass of wood (lower values in tropical and subtropical hardwoods, and higher in softwood from conifers) [1]. It is estimated that lignin is the source of approximately 30% of the organic carbon occurring in nature [2].
Lignin has a complex structure, which is still not completely understood, and is thus currently the subject of intense research efforts among a large group of scientists. It is known that the basic monomers making up the structure of the biopolymer include p-coumaryl, coniferyl, and sinapyl alcohols, generally called monolignols (see Figure 1), which link together in an unsystematic manner [1, 2, 3]. The content of particular monolignols varies depending on the type of wood.
Figure 1.
Basic monomers making up the structure of the biopolymer, based on [1, 2, 3].
Characteristic bonds occurring in the lignin structure include carbon–oxygen bonds (β-O-4, α-O-4, 4-O-5), which account for almost two-thirds of all of the bonds present, as well as carbon–carbon bonds (β-5, 5-5, β-1, β-β)—see Figure 2 [2, 3, 4]. Of the linkages occurring in the structure, the most easily decomposed are the β-O-4 bonds [5]. It should also be noted that the lignin macromolecules contain various functional groups that affect its reactivity. These are mostly methoxy and hydroxyl groups, as well as carbonyls and carboxyls. Only some of the hydroxyl groups are free to react, since most form bonds with neighboring structural units.
Figure 2.
Characteristic bonds occurring in the structure of lignin, based on [2, 3, 4].
3. Application of lignin and its derivatives
Lignin, which is being produced in greater and greater quantities each year, not only as a byproduct of the paper industry but also as a valuable raw material obtained from biofuel production, is becoming the object of increasing interest in many branches of science and industry.
Approximately, 98% of the lignin produced by the paper industry is burnt for energy recovery, with only 2% being used for commercial purposes. At present, this market consists mainly of low-value products, such as binders and emulsifiers, low-quality fuel, carbon fibers, and phenolic resins. The complex structure of lignin and the fact that methods for its modification and depolymerization are relatively expensive and hard to carry out on an industrial scale, limit possibilities of its wider use [6]. Nonetheless, lignin is constantly finding new potential fields of application.
In recent years, lignin has come to be commonly used in the preparation of multifunctional hybrid systems. There are reports in the literature concerning silica–lignin materials, which may be used as effective and relatively cheap sorbents of environmentally hazardous metal ions [7], polymer fillers [8, 9, 10, 11], innovative systems with antibacterial properties [12], components in abrasive products [13, 14], and substances used in the catalytic reduction of synthetic dyes, in sensors, and in surface-enhanced Raman spectroscopy [15, 16]. There are also reports of systems in which lignin is combined with titanium dioxide [17], magnetite [18], and the oxide systems MgO·SiO2 [19, 20] or TiO2·SiO2 [17], as well as chitin, another natural polymer occurring as a waste product [21, 22]. All of these systems have been used as effective sorbents of environmentally hazardous metal ions, and the chitin-lignin system can also be used as an enzyme carrier.
4. Depolymerization of lignin
Lignin, which has a complex chemical structure, is often subjected to a process of depolymerization. This has the aim of decomposing the biopolymer into low-molecular-weight products (monomers) by breaking the intermolecular bonds. Depolymerization of lignin may be carried out under a number of factors, including catalysts or high temperatures, which determine the mechanism of decomposition. The depolymerization process may lead to numerous useful low-molecular-weight compounds—see Figure 3 [23, 24].
Figure 3.
The most important low-molecular-weight compounds obtained from the depolymerization of lignin, based on [24, 25, 26].
Due to depolymerization of lignin, the following fractions are obtained: waste carbon, residual lignin, an aqueous phase, and oil, which consists of a mixture of phenolic monomers (such as 2-hydroxy-1,3-dimethoxybenzene and guaiacol) and oligomers. This last is the most desired fraction, as it contains the greatest quantity of valuable chemical compounds which can be used in industry. The residual lignin consists of particles which have repolymerized or which have not undergone decomposition. The waste carbon fraction contains unwanted products of the depolymerization reaction. Any gaseous products will chiefly be a mixture of oxides of carbon and hydrocarbons. There may also be an aqueous phase, which may contain alcohols, as well as hydrophilic aromatic compounds which cannot be isolated. The quantity and composition of each fraction depends on the process conditions [24, 25, 26].
Numerous research projects have helped determine the most effective methods of depolymerization, which lead to large quantities of phenolic monomers. The most important of these methods includes (i) depolymerization in supercritical fluids, (ii) pyrolysis, (iii) the use of metallic catalysts, (iv) acidic catalysts, (v) alkaline catalysts, and (vi) the use of ionic liquids.
4.1. Depolymerization in supercritical liquids
It is becoming increasingly common for the depolymerization of lignin to be carried out with the use of supercritical liquids [27, 28, 29, 30]. The thermochemical depolymerization of lignin in supercritical methanol with various catalysts was studied by Singh et al. [27]. Zeolites, sodium hydroxide, and iron filings were used in the process. Analysis of the results led to suggested mechanisms of the decomposition reaction. Depolymerization and demethoxylation of lignin result from the donation of a proton to ether bonds. The proton donor is the solvent, which as a result forms a formaldehyde capable of further reaction, particularly with ring compounds. The presence of NaOH in the reaction system not only accelerates the reaction but also enables the initiation of a demethylation reaction. The intermediate products undergo a condensation reaction, leading to a final product which is rich in solid carbon residues. This phenomenon is not observed in the case of zeolites, due to the presence of acid centers capable of catalyzing the direct methylation of the aromatic ring, which retard or prevent any potential condensation reactions [27].
In another study, Erdocia et al. used as the supercritical phase a triple system of methanol, ethanol, and acetone, determining their impact on the decomposition of lignin [28]. The largest content of monomeric phenol derivatives was found in the product obtained in an acetone environment. Detailed analysis confirmed the high degree of degradation of lignin, leading to a high content of solid carbon residues and catechol and cresol in the sample, which resulted from a reaction involving the detachment of alkyl and methoxy groups.
Depolymerization of the biopolymer in supercritical fluids was also studied by Kim et al. [29]. The process was conducted at 350°C in the presence of gaseous hydrogen and at a pressure of 13–19 MPa, using systems consisting of various alcohols in supercritical state—methanol, ethanol, and propan-2-ol—and metallic catalysts deposited on active carbon. The best-performing system proved to be Pd/C/ethanol, with which a very large quantity of oil and the lowest quantity of byproducts were obtained. This can be explained by the catalyst’s high surface area and the fact that ethanol is the most effective hydrogen donor among the alcohols used.
Gosselink et al. used a system of carbon dioxide, acetone, and water as the supercritical phase, carrying out depolymerization of lignin in an organic solvent using formic acid as catalyst [30]. The process was carried out at the temperatures of 300 and 370°C under a pressure of 10 MPa. The quantity of products obtained was found to be affected by the depolymerization reactions taking place, which led to the formation of byproducts.
4.2. High-temperature depolymerization of lignin
Depolymerization of lignin also takes place at very high temperatures without the presence of oxygen, in a process known as pyrolysis. The high temperature causes cracking of the ether and carbon–carbon bonds, and the absence of oxygen prevents oxidation of the products. The process leads to, among others, liquid products containing monomeric phenolic compounds, gaseous products consisting mainly of hydrocarbons and oxides of carbon, and solid carbon residues. The proportions of individual compounds depend on the process conditions, including the temperature. Above 500°C, bonds are broken in the aromatic ring and hydrogen is formed. The process carried out at such high temperatures is called gasification, and gases account for more than 80% of the products in that case. There are two ways in which pyrolysis may be carried out—slow (conventional) and fast. In conventional pyrolysis, the lignin is heated more slowly, and the products consist of approximately 40% gases, 30% carbon, and only 10% oil containing monomeric compounds. Fast pyrolysis leads to as much as 60% oil, with only about 10% carbon and 15% gases, and the time of the process is shortened from 5–30 min to 2 s. A disadvantage is the presence of a large number of oxygen compounds in the resulting oil, which means that it cannot be used as a fuel. Research is being done, however, with the aim of improving the pyrolysis process by reducing the number of organic oxide compounds (pyrolysis with the addition of polyolefin) and increasing the content of phenolic compounds in the oil (pyrolysis with the addition of substances whose chain contains compounds of phenol, such as polystyrene) [25, 31].
4.3. Depolymerization of lignin using metallic catalysts
The depolymerization of lignin is often carried out at a high temperature in the presence of hydrogen (hydrogenolysis) with the use of metallic catalysts. Catalysts used include palladium, platinum, rhodium, nickel, ruthenium, and copper with the addition of carbon or aluminum oxide. At temperatures as high as 450°C, in the presence of hydrogen gas and under pressures of 2–35 MPa, various substances are obtained, including cyclohexanols, phenolic decomposition products, and cyclic alkanes.
Kloekhorst and Heeres carried out depolymerization in the presence of hydrogen on various different metal catalyst systems, without the use of a solvent. Analysis of the resulting products showed a Ru/TiO2 system to be the most promising, in view of the variety of monomeric phenolic products obtained. Gaseous products, including methane, were also formed during depolymerization [32].
Depolymerization of lignin without the addition of a solvent was also investigated by Kumar et al. [26]. As catalysts, they used NiMo and CoMo deposited on various basic and acidic media. Apart from lignin and the catalyst, the reaction mixture also contained dimethyldisulfide, which served to create the system S-NiMo/medium or S-CoMo/medium. The introduction of sulfur into the catalyst causes the formation of new active sites with catalytic ability. It was found that the depolymerization was influenced by the type of medium, as well as by other factors. Acid media led to the largest quantities of repolymerization products. The best medium for the catalyst proved to be MgO-La2O3, which makes it possible to obtain a large number of monomers (particularly alkylphenols), while reducing the content of residual lignin in the post-reaction mixture [26]. Based on the results of the study, a mechanism for the process was proposed (see Figure 4).
Figure 4.
Mechanism of the process of depolymerization of lignin, adapted from Kumar et al. [26].
Wang and Rinaldi investigated the ability of nickel catalysts to decompose a model lignin molecule—diphenyl ether, having a strong ether bond [33]. Various media were used for the metallic catalyst, and their impact on the hydrodeoxygenation of the compound was studied. A high degree of transformation of the ether was found to be linked to the acidity of the medium and its surface area.
Das et al. carried out depolymerization using niobium(V) oxide as catalyst and hydrogen peroxide and potassium permanganate as oxidizing agents [34]. The main decomposition products were vanillin and its derivatives. Due to the presence of trace quantities of acids in the post-reaction mixture, the possibility was suggested that the lignin is adsorbed by the catalyst and aldehydes are formed as a result of reactions taking place on the catalyst’s surface.
4.4. Depolymerization of lignin using acidic catalysts
Valuable low-molecular-weight products can also be obtained from lignin with the use of catalysts of acid origin.
Sturgeon et al. investigated the mechanism of decomposition of the β-O-4 bond, adding the following model molecules to a 0.2 M solution of H2SO4 at 150°C: 2-phenoxy-1-phenylethanol (PE), 2-phenoxy-1-phenylpropan-1,3-diol (PD), 1-(4-hydroxyphenyl)-2-phenoxypropan-1,3-diol (HH), and 1-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy) propan-1,3-diol (GG), which represent the phenolic (HH and GG) and non-phenolic (PE and PD) groups [35]. Depolymerization was shown to take place by way of an ionic mechanism, via protonation of the hydroxide group on the α-carbon, followed by the separation of a water molecule and the formation of a carbocation as an intermediate stage (see Figure 5). It was also observed that the presence of a phenolic hydroxyl group accelerates the decomposition of the β-O-4 bond.
Figure 5.
Mechanism of the depolymerization of lignin as established by Sturgeon et al. [35].
Deepa and Dhepe carried out depolymerization of lignin using a solid acid catalyst [36]. Several types of lignin were selected to undergo depolymerization in a mixture of water and methanol in a nitrogen atmosphere, at a temperature below 250°C, using various types of zeolites, aluminosilicates, and metal oxides as catalysts. It was found that a very large quantity of monomers could be obtained, particularly when zeolites were used (the yield in that case reached 60%). However, the susceptibility of zeolites to poisoning with metal ions (such as sodium) led to their deactivation and also caused instability during the reaction. It was therefore decided to focus further attention on the possible use of the amorphous SiO2-Al2O3 catalyst. Following optimization of the process, a method was proposed for obtaining a large quantity of monomers and for recovering the catalyst for reuse [36].
There also exists the possibility of using organic acids as catalysts in the decomposition of lignin. Rahimiet al. used formic acid and sodium formate for this purpose, carrying out depolymerization on previously oxidized lignin extracted from aspen [37]. Desirable properties of this system include the relatively low process temperature (110°C) and the very large quantity of low-molecular-weight aromatic compounds produced (approximately 61% of the initial mass of lignin).
Güvenatam et al. investigated the possibility of carrying out depolymerization of lignin and its model compounds using trifluoromethane sulfonates of various metals [38]. These compounds are known for their high acidity. The process took place in a mixture of water and ethanol in a supercritical state. It was found that a significant quantity of ether bonds in the model lignin molecules was broken. It was also discovered that ethanol not only served as a solvent but also played an active part in the reaction, attaching itself to the aromatic ring and to the alkyl chain of the molecules. Further investigation confirmed the ability of liquids with a trifluoromethane sulfonate anion to catalyze the decomposition of lignin, proving the significant role played by that anion in the depolymerization process. In the proposed mechanism, the catalyst is capable of interacting with various oxygen functional groups in lignin, causing them to regroup and forming a carbocation, which can react further with nucleophiles, and also with the solvent. There exists a possibility of further dehydration and hydrogenation of the resulting compound (see Figure 6). The chief products of the reaction were hydrocarbons, both aromatic and non-aromatic, accompanied by a small quantity of monomeric phenolic derivatives. The absence of residual lignin in the post-reaction mixture was explained by the interaction of ethanol with the carbocation, which prevented repolymerization reactions [38].
Figure 6.
Mechanism of the process of depolymerization of lignin proposed on the basis of studies by Güvenatam et al. [38].
4.5. Depolymerization of lignin using basic catalysts
The reaction of the decomposition of lignin into low-molecular-weight products is also carried out using inorganic basic catalysts such as NaOH [24, 39]. During the process, alkyl-aryl ether bonds are broken under the action of the sodium ion, which polarizes the bond, making it easier to break (see Figure 7).
Figure 7.
Low-molecular-weight products resulting from the depolymerization of lignin with the use of NaOH, based on [24].
Optimization of the depolymerization process using a basic catalyst was performed by Roberts et al., who investigated the effect of temperature, the quantities of NaOH and lignin, and the pressure and reaction time on the quantities of monomer particles formed [24]. The largest quantity of monomers as a percentage of the original quantity of lignin was obtained using 4% NaOH. The process was most successful when carried out at a temperature of 300°C for 4 min. With increasing reaction pressure, the concentration of monomers decreased, possibly as a result of the stronger intermolecular interactions. The quantity of depolymerized lignin behaved analogously. It was also shown that the process temperature has a strong impact on the quantity of particular monomers occurring in the mixture [24].
A study by Erdocia et al. also investigated how the decomposition products depend on the type of lignin used [28]. Three types of lignin dissolved in organic solvents (acetone, formaldehyde, and a mixture of the two) were subjected to the action of NaOH at a temperature of 300°C and a pressure of 9 MPa. A large quantity of residual lignin (approximately one quarter of the original quantity) was present following the depolymerization process, due to repolymerization of the compounds formed during that process. These recombine with each other or with the original lignin, forming new C–C and C–O bonds, and this process is promoted by the presence of formic acid. The quantity of monomeric phenolic particles formed was found to depend on the average molecular weight of the lignin used—the smaller the molecular weight, the greater the quantity of particles formed during depolymerization [28].
Santos et al. also investigated the depolymerization of the biopolymer using NaOH [40]. Based on the analysis of the oil produced, it was shown that the principal decomposition products were catechol and phenol. Small amounts of cresol, guaiacol, and 2-hydroxy-1,3-dimethoxybenzene were also formed. The authors not only analyzed the product but also suggested a potential application: the antiseptic and insecticidal properties of catechol, in combination with the preserving and disinfecting action of phenol, meaning that the mixture might potentially be used as an antifungal treatment for wood. Preliminary studies showed that the oil indeed increased the resistance of wood panels to fungal action, thus confirming its potential for use as a wood preservative [40].
An investigation of the effect of the catalyst on the depolymerization of lignin was carried out by Toledano et al. [39]. Lignin was dissolved in an organic solvent with the addition of potassium, calcium, lithium and sodium hydroxides and sodium carbonate, and the biopolymer underwent depolymerization at 300°C under a pressure of 90 MPa. The large differences in the quantities of phenolic particles (from around 10% for Ca(OH)2 to 20% for NaOH) and residual lignin (above 37% for almost all of the catalysts apart from calcium carbonate) show that the catalyst used affects the mechanism of the reactions taking place during depolymerization.
Although metal hydroxides would appear to be the most popular catalysts, they are not the only compounds used in the depolymerization process. Long et al. used magnesium oxide, together with the solvent tetrahydrofuran, which increases the power of the catalyst [41]. The quantity of phenolic monomers produced (more than 13%) and their increased ease of separation from the mixture mean that this is a promising catalyst for the decomposition of lignin.
In turn, Widyay et al. studied the impact of different catalysts (magnesium and calcium oxides, potassium acetate, and potassium hydroxide) on the depolymerization of lignin in ethanol [42]. In spite of the very good results obtained for the potassium catalysts, in view of their high solubility in the reaction medium, further tests were carried out using magnesium oxide. At the next stage, an analysis was made of the effect of the polarity of the solvent on the products obtained. Among the various solvents used, the best results were obtained for ethanol. The post-reaction mixture contained large quantities of hydroxyl (aromatic and non-aromatic) and carboxyl groups, probably due to the oxidation reactions taking place. Also noted was the degradation of some of the carbon–carbon bonds and the structural units of lignin. The authors further drew attention to the possibility of reusing the catalyst without detriment to its activity or structure [42].
4.6. Depolymerization of lignin using ionic liquids
The unique properties of ionic liquids are exploited in a number of new multifunctional applications, including their possible use in the depolymerization of lignin. A number of important studies of such depolymerization processes have been carried out by Jia et al. [43]. Since the most frequently occurring bond in lignin is the β-O-4 bond, the model compounds used were 1-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)propan-1,3-diol and 1-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)propan-1,3-diol (VG). Although both of these contain the β-ether bond, in view of the different substitutions, they represent, respectively, the phenolic and non-phenolic character of the subunits of the biopolymer. One of the experiments was carried out in the presence of the ionic liquid [HMIM][Cl] (acting as both catalyst and solvent) with varying quantities of water. A significant percentage (more than 70%) of the ether bonds was broken, and the product formed most often and in the largest quantities was guaiacol. It was also found that a larger quantity of water favors the decomposition of the β-O-4 bond. Importantly, it was confirmed that the ionic liquid can be reused without loss of activity [43]. Further studies were made to analyze the ability of the N-base-[BDMIM][Cl] system to break β-O-4 bonds. Following heating of the systems to a temperature of 150°C, the principal decomposition product was found to be enol-ether (EE) [44].
The same researchers have also evaluated the effect of the anion on the depolymerization process. Using the aforementioned model substances (VG and GG), they carried out a depolymerization reaction at 150°C for the first substance and at 110, 130, and 150°C for the second, selecting appropriate ionic liquids with the 1-methylimidazole cation and various anions. A determination was also made of the Hammett acidity of particular ionic liquids (with the use of 3-nitroaniline), showing them to be strongly acidic. Although no dependence was found between the acidity of the liquid and the effectiveness of depolymerization, the results indicated a link between the possible formation of anion–molecule hydrogen bonds and hydrolysis of the β-O-4 bond. This was found to be a factor that favored the decomposition of the bond, and thus the depolymerization of the molecule [45].
Yan et al. also studied the depolymerization of lignin using a liquid with the imidazole cation, confirming the dependence between the anion of the ionic liquid used and the resulting depolymerization products [46]. Moreover, factors affecting the process of decomposition of lignin were found to include the pH of the reaction mixture, the quantity of ionic liquid used, and the presence in the system of a cosolvent. In this case, however, the addition of water to the reaction system was found to limit depolymerization. It was concluded that there is a clear need to seek new model lignin molecules which better imitate the structure of the biopolymer.
Liu et al. developed an innovative catalyst containing choline methane sulfonate and palladium deposited on carbon [47]. This produced a system which combined the acidic properties of the ionic liquid with the oxidizing properties of the metal and was at the same time a very good solvent of lignin. Studies carried out using kraft lignin confirmed the selectivity of the hydrogenolysis process, as well as the high content of phenol and its derivatives, particularly 2-hydroxyphenol. In addition, in an experiment using a model lignin molecule, the reaction mechanism was investigated. It was found that the hydrolysis of the substrate leads to breaking of the ether bond and the formation of phenol derivatives. The intermediate products may subsequently undergo hydrogenolysis or a retro-aldol reaction (see Figure 8) [47].
Figure 8.
Mechanism of the depolymerization reaction of a model lignin molecule with the use of choline methane sulfonate, adapted from [47].
Another method used to carry out the depolymerization of lignin used a model lignin molecule in an environment of 1-benzyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, with phosphoric(V) acid as catalyst [48]. Following thorough analysis of the product, which was rich in phenol and benzoic acid, a possible mechanism of the decomposition was proposed, according to which the ionic liquid not only interacts with the molecule undergoing decomposition but also has the ability to take part in a reaction with atmospheric oxygen leading to the formation of radicals, these being capable of further interaction with the depolymerized compound. As a result, peroxy acid is formed, which via acidic hydrolysis is transformed into the final decomposition products—phenol and organic acids [48].
In the search for effective solvents, Rashid et al. investigated the ability of protonic ionic liquids to dissolve lignin [49]. Various pyridine ionic liquids with methanoate, ethanoate, and propanoate anions were synthesized. Among the systems obtained, the largest quantity of lignin was dissolved in pyridine methanoate, demonstrating that an increase in the length of the alkyl chain in the anion has an unfavorable effect on the solubility of lignin. In the next stage, the regeneration of lignin was carried out and its properties were analyzed. The regenerated lignin was found to have a significantly smaller average molecular weight, showing that the material underwent defragmentation during dissolution. There was also a decrease in the quantity of hydroxyl groups linked to the aromatic ring and an increase in the quantity of quinone groups. This meant that the properties of the material were more favorable for further chemical treatment. An effective process of regeneration of the solvent was also carried out, obtaining a liquid suitable for reuse [49].
An innovative depolymerization solution was proposed by Caiet al., who carried out the process in an emulsion reactor [50]. They used a solution of water and an ionic liquid—1-butyl-3-(butyl-4-sulfone)imidazolium hydrogen sulfate(VI)—as a catalyst and an n-butanol/n-hexane system as the oil phase. Lignin was used as a surfactant, in view of the presence in that material of both hydrophilic and hydrophobic groups. The lipophobic nature of the ether groups in lignin facilitates contact between the compound and the catalyst and thus favors the decomposition process. Detailed analysis of the results confirmed the high effectiveness of the process and the significant increase in the quantity of monomeric phenolic products obtained compared with traditional techniques, thereby confirming the good potential of the method for practical application [50].
The ability of ionic liquids to dissolve lignin is exploited not only in depolymerization processes but also in extraction from lignocellulose materials. Prado et al. combined both processes, carrying out the depolymerization of lignin present in the black liquor formed during one of the stages of delignification. For this purpose, butylimidazolium hydrogen sulfate(VI) and triethylammonium hydrogen sulfate(VI) were used, with hydrogen peroxide as an oxidizing agent. The oils obtained were rich in phenol derivatives, particularly acids, including vanillic and benzoic acids [51]. In a subsequent study, titanium(IV) oxide was used as an oxidizing agent alongside hydrogen peroxide. Analysis of the products showed the inorganic oxide to be an effective catalyst, enabling a large quantity of monomeric phenolic compounds to be obtained. The product also contained no significant quantity of molecules originating from the process of oxidation of carbohydrates, which indicates that titanium(IV) oxide exhibits greater selectivity than hydrogen peroxide in the oxidation of lignin [52].
Stärk et al. investigated the effect of systems of various ionic liquids and salts of iron(III), copper(II), and manganese(II), used as catalysts, on the degree of conversion of lignin in organic solvent [53]. Aerobic depolymerization was carried out for over 10 h at a temperature of 100°C under increased pressure. Among 40 systems investigated, the best parameters were obtained for [EMIM][OTf] combined with manganese(II) nitrate(V) as catalyst; this produced a conversion yield of more than 50%.
Nanayakkara et al. carried out an experiment to determine the effect of adding 4-tert-butyl-2,6-dimethylphenol (TBDMP, blocked in the ortho and para positions to prevent a polymerization reaction) on the products obtained from depolymerization via a redistribution reaction [54]. Using Klason lignin, an organic solvent and a Cu/EDTA complex as catalyst, the depolymerization reaction was carried out at 180°C with the addition of TBDMP in two ionic liquids: [EMIM][ABS] and [BMIM][MeSO4]. The process produced numerous oligomers which could not be obtained without the addition of the catalyst and TBDMP, which demonstrates that these two components are essential for the depolymerization of the biopolymer in the proposed ionic liquids [54].
Binder et al. investigated the possible depolymerization of lignin in an organic solvent and of its model molecules—eugenol (2-methoxy-4-(2-propenyl)phenol), 1-phenoxy-2-phenylethane, and 4-ethyl-2-methoxyphenol—at temperatures below 200°C [55]. A Brønsted acid catalyst was used, with the ionic liquids [EMIM][OTf] and [EMIM][Cl]. From the first two model compounds, guaiacol and phenol, respectively, were obtained, but in the case of 4-ethyl-2-methoxyphenol and lignin itself, no depolymerization reaction could be achieved. This indicates the need to seek better model substances and to gain a more precise understanding of the mechanism of depolymerization.
The depolymerization of lignin (extracted from oak) was also investigated in a study by Cox and Ekerdt, who used acidic [HMIM][Cl] [56]. It was shown that this ionic liquid may serve both as a solvent and as a catalyst for the depolymerization reaction, and confirmation was obtained for a proposed mechanism of decomposition via hydrolysis of the alkyl-aryl ether bond.
It can therefore be concluded, based on an exhaustive survey of the latest literature, that the catalytic properties of ionic liquids, in combination with their ability to dissolve lignin, give them great potential for practical applications in the conversion of lignin materials. They are also made more attractive in comparison with existing methods by their low toxicity and the ability to create liquids with specified parameters. It is expected that research efforts in this area will lead to further progress in the near future.
5. Modification of the lignin structure
In the preceding chapters, attention has been drawn to the potential for practical applications of lignin and of the products obtained as a result of its depolymerization. Nonetheless, this biopolymer may alternatively be used following preliminary processing or modification of its structure. Such an operation can be used to introduce new functional groups into lignin by way of chemical reactions of many kinds and also to achieve mild oxidation of the surface hydroxyl groups [57]. These groups, which are substituted not only on the aromatic ring but also in aliphatic chains, are of decisive importance for the modification of lignin. Modification of the structure of functional groups serves to increase the chemical reactivity of the biopolymer, improve its solubility in polar or non-polar solvents, facilitate the creation of a network of interactions between lignin and polymers in composites or inorganic compounds in functional materials, and simplify the processing of the final product. These goals may be achieved by creating new active centers. By this means, it is possible to increase the biopolymer’s reactivity using, for example, hydroxyl groups (inductive effect) or substituents in the ortho position of the aromatic ring (mesomeric effect) [57]. It is significant that hydroxyl groups occur in lignin both in aliphatic chains in the Cα and Cγ positions and as substituents on the aromatic ring. In view of their weak acidity, it is phenyl groups that determine the reactivity of the whole lignin molecule [57]. The types of reaction used to obtain new active centers include sulfonation [1, 58], hydroxyalkylation [59], nitration [57], amination [60, 61], halogenation [57], and alkylation/dealkylation [57].
The sulfonation of lignin and of its previously sulfonated equivalents enables improvement of its solubility in aqueous solutions, irrespective of their pH. In the reaction, the biopolymer is acted on by a 95% solution of sulfuric(VI) acid, with intense mixing, at a temperature of 40°C [62]. Lignosulfonates can also be included in the group of modified lignins produced as a result of sulfite pulping [1]. An alternative method of sulfonation was described by Ouyang et al. [58]. The first stage involved hydroxymethylation of alkaline lignin with the use of formaldehyde in a basic environment (see Figure 9). Following this substitution, the lignin underwent sulfonation with the use of Na2SO3, where the hydroxymethyl substituent undergoes a reaction. The mechanism of this modification of the lignin structure is shown in Figure 9 [58]. Compared with the lignosulfonates commonly used in concrete mixtures, lignin prepared in this way exhibits a higher degree of sulfonation, a lower surface tension, and a stronger interaction with the surface of cement particles. It also produces desirable electrostatic repulsion forces among the cement particles, providing further confirmation of its potential for use in concrete mixtures [58].
Figure 9.
Mechanism of hydroxymethylation and sulfonation of lignin, adapted from [58].
The hydroxymethylation of lignin was also investigated in a study by Sen et al. [63], where a sample of the biopolymer was dissolved in sodium hydroxide and then subjected to the action of formaldehyde. In this way, the content of aliphatic hydroxyl groups and carbonyl groups was increased, as was confirmed by various analytical techniques. Based on the results, it was proposed that the derivative obtained might be used in glues or for wood preservation [63]. A similar modification of the lignin structure was studied by Malutan et al. [64]. They used lignin extracted from annual plants, subjecting it to hydroxymethylation with formaldehyde in an alkaline environment at room temperature. It was found that the reaction took place chiefly in the ortho position of the aromatic ring. At higher temperatures, methylene bonds are formed between the substituted lignin fragments. The desired reaction is the Lederer–Manasse reaction, in which a hydroxymethyl group is substituted on the aromatic ring, increasing the reactivity of the molecule. Based on literature data, it can be stated that the hydroxymethylation reaction is dependent on the type of lignin used (the raw material and the method of isolation) and also on the process conditions.
In a study by Du et al., amination of lignin took place via the Mannich reaction [60]. The authors also investigated the impact of preliminary phenolation of the biopolymer structure on the effectiveness of the amination reaction. For a successful Mannich reaction, it is very important to select a lignin with a free C-5 position in the aromatic ring of the guaiacyl units. This carbon has very high electron density, which promotes the introduction of amino-alkyl groups in the ortho position relative to the hydroxyl group. Irrespective of the pH of the reaction, although it may proceed according to different mechanisms, these lead to the same product, with substitution at C-5. The mechanism of the reaction of amination of lignin is shown in Figure 10 [60]. The study also showed that preliminary phenolation of the lignin sample increases the content of unsubstituted C-5 carbons, which subsequently improves the yield of the amination reaction. However, in view of the toxicity of this reactant, it must be considered whether such pretreatment is reasonable [60].
Figure 10.
Mechanism of the reaction of amination of lignin in a basic or an acidic environment, adapted from [60].
Corresponding results on the formation of aminated lignin were published by Ge et al. [61]. They used alkaline lignin, which they modified at pH 8–13 with methylamine, adding appropriate doses of formaldehyde to the reactor. The product was evaluated as a possible sorbent of lead ions from aqueous solutions. Aminated lignin may be used successfully as a surfactant, in polycationic materials, in slow-release fertilizers [60], and in the sorption of lead ions from waste water [61].
The aforementioned use of the phenolation of lignin to unblock a greater number of C-5 carbons in the aromatic ring was also investigated by Podschun et al. [65]. The purpose of the study was to determine optimum conditions for the modification of lignin with phenol, to give a product with better solubility in various thermosetting resins. The reaction took place in an acidic environment at an elevated temperature, via the mechanism shown in Figure 11. In addition, some of the ether bonds are broken during the process, which leads to a reduction in molecular weight [66]. In the process used by Hu et al., the phenolation of lignin took place in ethanol at 70°C, over a time of several hours [66].
Figure 11.
Mechanism of the reaction of phenolation of lignin, adapted from [65].
Lignin may also be successfully subjected to alkylation or dealkylation, by which means alkyl groups can be introduced into the biopolymer molecule. Here, the alkylating agent reacts with the nucleophilic centers of the biopolymer (oxygen atoms). In the case of lignin, atoms with an excess of electrons are attacked not only in the aromatic ring but also in the aliphatic chains. Sen et al. carried out methylation of kraft lignin with the use of dimethyl carbonate (DMC) [63]. They confirmed the possibility of controlling the degree of methylation by varying the quantity of DMC used. There was no drop in the thermal stability of the methylated lignins, although the glass transition temperature was reduced. This was achieved by a reduction in the number of sites capable of forming intermolecular hydrogen bonds [63]. It was also shown that the use of DMSO enables the reaction to be carried out at higher temperatures, thus increasing the degree of methylation of lignin. Moreover, the use of a polar aprotic solvent further catalyzed the substitution of the nucleophilic center [63].
Lignin has also been successfully subjected to cationization, which leads to a material that may function as a flocculant of dyes from aqueous solutions. Cationic modification of the lignin structure was performed with the use of glycidyl-trimethylammonium chloride, which in a basic environment (pH=12.6) is joined to the phenol group of the aromatic ring in the biopolymer. The resulting material can be subjected to hydrolysis, with separation of the biopolymer from the quaternary ammonium salt. The mechanism of the modification of the biopolymer and hydrolysis is shown in Figure 12 [67]. The resulting material may interact with the dye being removed, and in addition, the aromatic part of the lignin may develop hydrophilic/hydrophobic interactions with the pollutant [67].
Figure 12.
Mechanism of the cationization of lignin (A) and its hydrolysis (B), adapted from [67].
Another method for modifying the structure of lignin is epoxidation of the phenol groups of the aromatic ring, carried out in an alkaline environment [59, 68, 69, 70]. Pan et al. performed such an action using epichlorohydrin, which was mixed with alkaline lignin in an appropriate ratio at 50°C [68]. The solid product was further subjected to amination using propandiamine. This Lewis base reacts with the ether oxygen, lengthening the chain of the alkyl substituent. The use of diamine makes possible a reaction with a further epoxy substituent, which finally increases the degree of crosslinking of the biopolymer. The epoxy lignin prepared in this way, or aminated crosslinked derivative, can be used as an active bioorganic additive to epoxy resins. This solution is friendly to the environment and can reduce the costs of resin production [68]. In a similar study by Feng and Chen [69], lignin was obtained by pulping of raw material in acetic acid, followed by phenolation of the biopolymer. This pretreatment enables an increase in the content of phenolic hydroxyl groups, which in the next stage are attacked by the epoxidation agent. Moreover, phenolation of lignin enables reduction of the molecular weight and thermal stability, compared with the unmodified biopolymer [66, 69]. It was shown that the addition of epoxidated lignin to an epoxy resin mixture increases its adhesive shear strength and water-absorbing power. Based on the results of the study, it was proposed that lignin might be used in the manufacture of cheap epoxy resins [69]. An oxypropylation reaction can also be used in the case of other biopolymers, such as chitin and chitosan [70]. A general mechanism for this reaction is given schematically in [70], see Figure 13.
Figure 13.
Schema for the oxypropylation (epoxidation) of hydroxyl groups in biopolymers, adapted from [70].
Esterification of lignin was investigated by Thielemans and Wool [71]. This modification was catalyzed using 1-methylimidazole, where acetic anhydride acted on the hydroxyl groups of lignin. At this stage, a cation is formed from N-alkyl-N’-methyl imidazolium, which acts on the hydroxyl group (aliphatic or aromatic). This leads to a protonated catalyst and acetylated lignin. The study showed that phenyl hydroxyl groups undergo acetylation significantly more easily. It was also found that the modification improves the solubility of lignin in styrene and butanoic acid, confirming its potential for use in the processing of thermosets [71].
An alternative focus of research is the optimization of the structure and degree of polymerization of the lignin molecule. For example, Duong et al. carried out polycondensation from sebacoyl chloride catalyzed with triethylamine [72]. The resulting material offered better thermal stability than kraft lignin, giving it potential for use in environmentally friendly composites [72].
Interest in the use of lignin in many areas of chemistry and everyday life is motivated by the high potential for its reproduction by plant organisms. The annual production of the biopolymer is certainly large enough not only to meet some of the demands for low-molecular-weight organic compounds obtained in refineries but also to serve as a functional material. This would also enable a reduction in atmospheric CO2, which is taken up by plants and transformed into more complex compounds via photosynthesis. In addition, the use of lignin would appear to be favorable not only in terms of the trend toward policies focused on protecting the natural environment but also for economic reasons. Fluctuations in the prices of petroleum-based products therefore make lignin and other renewable biopolymers into attractive alternatives to the products currently in common use [70].
6. Summary and a look at the future
In recent years, many techniques and methods have been developed for the depolymerization and modification of lignin, making use of a variety of substances offering catalytic properties or the ability to dissolve the biopolymer. Nonetheless, their use in technological processes on a wider scale remains very limited. This is primarily a result of the lack of sufficient fundamental information on the structure of lignin itself, which makes it harder to gain a precise understanding of the mechanism of depolymerization and thus to propose appropriate means to enable its degradation, in addition to further optimization of the process. It is therefore important that wide-ranging research into lignin be continued, enabling its detailed physicochemical properties to be determined and consequently the most effective and efficient techniques to be developed for converting it into valuable products.
Acknowledgments
This work was supported by the Polish Ministry of Science and Higher Education research project number IP2015 032574 (Iuventus Plus) in the years 2016–2019.
\n',keywords:"biopolymers, lignin, depolymerization, ionic liquids, modification",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/56949.pdf",chapterXML:"https://mts.intechopen.com/source/xml/56949.xml",downloadPdfUrl:"/chapter/pdf-download/56949",previewPdfUrl:"/chapter/pdf-preview/56949",totalDownloads:1421,totalViews:681,totalCrossrefCites:0,dateSubmitted:"March 29th 2017",dateReviewed:"July 12th 2017",datePrePublished:"December 20th 2017",datePublished:"March 21st 2018",dateFinished:null,readingETA:"0",abstract:"A very important topic in present-day research is the depolymerization of lignin, meaning the multi-parametric decomposition of the biopolymer into low-molecular-weight products (monomers) by breaking of the intermolecular bonds. Depolymerization can occur under many different factors, such as high temperature or catalysts, which determine the mechanism of disintegration. In the case of lignin, this process is carried out in order to obtain many valuable low-molecular-weight compounds. It is becoming more and more popular as a result of the use of ionic liquids, but methods using alkaline, acidic, and metallic catalysts, as well as pyrolysis and supercritical fluids, are also known. All of these methods will be described in detail in this chapter.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/56949",risUrl:"/chapter/ris/56949",signatures:"Łukasz Klapiszewski, Tadeusz J. Szalaty and Teofil Jesionowski",book:{id:"6185",title:"Lignin",subtitle:"Trends and Applications",fullTitle:"Lignin - Trends and Applications",slug:"lignin-trends-and-applications",publishedDate:"March 21st 2018",bookSignature:"Matheus Poletto",coverURL:"https://cdn.intechopen.com/books/images_new/6185.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"140017",title:"Dr.",name:"Matheus",middleName:null,surname:"Poletto",slug:"matheus-poletto",fullName:"Matheus Poletto"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"203552",title:"Prof.",name:"Teofil",middleName:null,surname:"Jesionowski",fullName:"Teofil Jesionowski",slug:"teofil-jesionowski",email:"teofil.jesionowski@put.poznan.pl",position:null,institution:null},{id:"207919",title:"Ph.D.",name:"Łukasz",middleName:null,surname:"Klapiszewski",fullName:"Łukasz Klapiszewski",slug:"lukasz-klapiszewski",email:"lukasz.klapiszewski@put.poznan.pl",position:null,institution:{name:"Poznań University of Technology",institutionURL:null,country:{name:"Poland"}}},{id:"207922",title:"MSc.",name:"Tadeusz Jan",middleName:null,surname:"Szalaty",fullName:"Tadeusz Jan Szalaty",slug:"tadeusz-jan-szalaty",email:"tadeusz.h.szalaty@doctorate.put.poznan.pl",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Lignin—an overview",level:"1"},{id:"sec_3",title:"3. Application of lignin and its derivatives",level:"1"},{id:"sec_4",title:"4. Depolymerization of lignin",level:"1"},{id:"sec_4_2",title:"4.1. Depolymerization in supercritical liquids",level:"2"},{id:"sec_5_2",title:"4.2. High-temperature depolymerization of lignin",level:"2"},{id:"sec_6_2",title:"4.3. Depolymerization of lignin using metallic catalysts",level:"2"},{id:"sec_7_2",title:"4.4. Depolymerization of lignin using acidic catalysts",level:"2"},{id:"sec_8_2",title:"4.5. Depolymerization of lignin using basic catalysts",level:"2"},{id:"sec_9_2",title:"4.6. Depolymerization of lignin using ionic liquids",level:"2"},{id:"sec_11",title:"5. Modification of the lignin structure",level:"1"},{id:"sec_12",title:"6. Summary and a look at the future",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Calvo-Flores FG, Dobado JA. Lignin as renewable raw material. ChemSusChem. 2010;3(11):1227-1235. DOI: 10.1002/cssc.201000157'},{id:"B2",body:'Boerjan W, Ralph J, Baucher M. Lignin biosynthesis. Annual Review of Plant Biology. 2003;54:519-546. DOI: 10.1146/annurev.arplant.54.031902.134938'},{id:"B3",body:'Vanholme R, Demedts B, Morreel K, Ralph J, Boerjan W. Lignin biosynthesis and structure. Plant Physiology. 2010;153(3):895-905. DOI: 10.1104/pp.110.155119'},{id:"B4",body:'Neutelings G. Lignin variability in plant cell walls: Contributions of new models. Plant Science. 2011;181(4):379-386. DOI: 10.1016/j.plantsci.2011.06.012'},{id:"B5",body:'Wong DWS. Structure and action mechanism of ligninolytic enzymes. Applied Biochemistry and Biotechnology. 2009;157(2):174-209. DOI: 10.1007/s12010-008-8279-z'},{id:"B6",body:'Chatel G, Rogers RD. Review: Oxidation of lignin using ionic liquids—An innovative strategy to produce renewable chemicals. ACS Sustainable Chemistry & Engineering. 2014;2(3):322-339. DOI: 10.1021/sc4004086'},{id:"B7",body:'Klapiszewski Ł, Bartczak P, Wysokowski M, Jankowska M, Kabat K, Jesionowski T.Silica conjugated with kraft lignin and its use as a novel ‘green’ sorbent for hazardous metal ions removal. Chemical Engineering Journal. 2015;260:684-693. DOI: 10.1016/j.cej.2014.09.054'},{id:"B8",body:'Bula K, Klapiszewski Ł, Jesionowski T. A novel functional silica/lignin hybrid material as a potential bio-based polypropylene filler. Polymer Composites. 2015;36(5):913-922. DOI: 10.1002/pc.23011'},{id:"B9",body:'Klapiszewski Ł, Pawlak F, Tomaszewska J, Jesionowski T. Preparation and characterization of novel PVC/silica-lignin composites. Polymers. 2015;7(9):1767-1788. DOI: 10.3390/polym7091482'},{id:"B10",body:'Grząbka-Zasadzińska A, Klapiszewski Ł, Bula K, Jesionowski T, Borysiak S. Supermolecular structure and nucleation ability of polylactide-based composites with silica/lignin hybrid fillers. Journal of Thermal Analysis and Calorimetry. 2016;126(1):263-275. DOI: 10.1007/s10973-016-5311-3'},{id:"B11",body:'Borysiak S, Klapiszewski Ł, Bula K, Jesionowski T. Nucleation ability of advanced functional silica/lignin hybrid fillers in polypropylene composites. Journal of Thermal Analysis and Calorimetry. 2016;126(1):251-262. DOI: 10.1007/s10973-016-5390-1'},{id:"B12",body:'Klapiszewski Ł, Rzemieniecki T, Krawczyk M, Malina D, Norman M, Zdarta J, et al. Kraft lignin/silica-AgNPs as a functional material with antibacterial activity. Colloids and Surfaces B. 2015;134:220-228. DOI: 10.1016/j.colsurfb.2015.06.056'},{id:"B13",body:'Strzemiecka B, Klapiszewski Ł, Voelkel A, Jesionowski T. Functional lignin-SiO2 hybrids as potential fillers for phenolic binders. Journal of Adhesive Science and Technology. 2016;30(10):1031-1048. DOI: 10.1080/01694243.2015.1115602'},{id:"B14",body:'Strzemiecka B, Klapiszewski Ł, Jamrozik A, Szalaty TJ, Matykiewicz D, Sterzyński T, et al. Physicochemical characterization of functional lignin–silica hybrid fillers for potential application in abrasive tools. Materials. 2016;9(7):517-530. DOI: 10.3390/ma9070517'},{id:"B15",body:'Konował E, Modrzejewska-Sikorska A, Motylenko M, Klapiszewski Ł, Wysokowski M, Bazhenov VV, et al. Functionalization of organically modified silica with gold nanoparticles in the presence of lignosulfonate. International Journal of Biological Macromolecules. 2016;85:74-81. DOI: 10.1016/j.ijbiomac.2015.12.071'},{id:"B16",body:'Milczarek G, Motylenko M, Modrzejewska-Sikorska A, Klapiszewski Ł, Wysokowski M, Bazhenov VV, et al. Deposition of silver nanoparticles on organically-modified silica in the presence of lignosulfonate. RSC Advances. 2014;4(94):52476-52484. DOI: 10.1039/C4RA08418G'},{id:"B17",body:'Klapiszewski Ł, Siwińska-Stefańska K, Kołodyńska D. Preparation and characterization of novel TiO2/lignin and TiO2-SiO2/lignin hybrids and their use as functional biosorbents for Pb(II). Chemical Engineering Journal. 2017;314:169-181. DOI: 10.1016/j.cej.2016.12.114'},{id:"B18",body:'Klapiszewski Ł, Zdarta J, Antecka K, Synoradzki K, Siwińska-Stefańska K, Moszyński D, et al. Magnetite nanoparticles conjugated with lignin: A physicochemical and magnetic study. Applied Surface Science. 2017;422:94-103. DOI: 10.1016/j.apsusc.2017.05.255'},{id:"B19",body:'Ciesielczyk F, Bartczak P, Klapiszewski Ł, Jesionowski T. Treatment of model and galvanic waste solutions of copper(II) ions using a lignin/inorganic oxide hybrid as an effective sorbent. Journal of Hazardous Materials. 2017;328:150-159. DOI: 10.1016/j.jhazmat.2017.01.009'},{id:"B20",body:'Ciesielczyk F, Klapiszewski Ł, Szwarc-Rzepka K, Jesionowski T. A novel method of combination of Kraft lignin with synthetic mineral support. Advanced Powder Technology. 2014;25(2):695-703. DOI: 10.1016/j.apt.2013.10.016'},{id:"B21",body:'Wysokowski M, Klapiszewski Ł, Moszyński D, Bartczak P, Szatkowski T, Majchrzak I, et al. Modification of chitin with kraft lignin and development of new biosorbents for removal of cadmium(II) and nickel(II) ions. Marine Drugs. 2014;12(4):2245-2268. DOI: 10.3390/md12042245'},{id:"B22",body:'Zdarta J, Klapiszewski Ł, Wysokowski M, Norman M, Kołodziejczak-Radzimska A, Moszyński D, et al. Chitin-lignin material as a novel matrix for enzyme immobilization. Marine Drugs. 2015;13(4):2424-2446. DOI: 10.3390/md13042424'},{id:"B23",body:'Pandey MP, Kim CS. Lignin depolymerization and conversion: A review of thermochemical methods. Chemical Engineering & Technology. 2011;34(1):29-41. DOI: 10.1002/ceat.201000270'},{id:"B24",body:'Roberts VM, Stein V, Reiner T, Lemonidou A, Li X, Lercher JA. Towards quantitative catalytic lignin depolymerization. Chemistry—A European Journal. 2011;17(21):5939-5948. DOI: 10.1002/chem.201002438'},{id:"B25",body:'Erdocia X, Prado R, Corcuera MA, Labidi J. Base catalyzed depolymerization of lignin: Influence of organosolv lignin nature. 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DOI: 10.1016/j.polymdegradstab.2011.01.011'},{id:"B46",body:'Yan B, Li K, Wei L, Ma Y, Shao G, Zhao D, et al. Understanding lignin treatment in dialkylimidazolium-based ionic liquid-water mixtures. Bioresource Technology. 2015;196:509-517. DOI: 10.1016/j.biortech.2015.08.005'},{id:"B47",body:'Liu F, Liu Q, Wang A, Zhang T. Direct catalytic hydrogenolysis of kraft lignin to phenols in choline-derived ionic liquids. ACS Sustainable Chemistry & Engineering. 2016;4(7):3850-3856. DOI: 10.1021/acssuschemeng.6b00620'},{id:"B48",body:'Yang Y, Fan H, Song J, Meng Q, Zhou H, Wu L, et al. Free radical reaction promoted by ionic liquid: A route for metal-free oxidation depolymerization of lignin model compound and lignin. Chemical Communications. 2015;51(19):4028-4031. DOI: 10.1039/C4CC10394G'},{id:"B49",body:'Rashid T, Kait CF, Regupathi I, Murugesan T. Dissolution of kraft lignin using protic ionic liquids and characterization. Industrial Crops and Products. 2016;84:284-293. 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DOI: 10.1002/cssc.200900242'},{id:"B54",body:'Nanayakkara S, Patti AF, Saito K. Lignin depolymerization with phenol via redistribution mechanism in ionic liquids. ACS Sustainable Chemistry & Engineering. 2014;2(9):2159-2164. DOI: 10.1021/sc5003424'},{id:"B55",body:'Binder JB, Gray MJ, White JF, Zhang ZC, Holladay JE. Reactions of lignin model compounds in ionic liquids. Biomass & Bioenergy. 2009;33(9):1122-1130. DOI: 10.1016/j.biombioe.2009.03.006'},{id:"B56",body:'Cox BJ, Ekerdt JG. Depolymerization of oak wood lignin under mild conditions using the acidic ionic liquid 1-H-3-methylimidazolium chloride as both solvent and catalyst. Bioresource Technology. 2012;118:584-588. DOI: 10.1016/j.biortech.2012.05.012'},{id:"B57",body:'Laurichesse L, Averous L. Chemical modification of lignins: Towards biobased polymers. Progress in Polymer Science. 2014;39(7):1266-1290. DOI: 10.1016/j.progpolymsci.2013.11.004'},{id:"B58",body:'Ouyang X, Ke L, Qiu X, Guo Y, Pang Y. Sulfonation of alkali lignin and its potential use in dispersant for cement. Journal of Dispersion Science and Technology. 2009;30:1-6. DOI: 10.1080/01932690802473560'},{id:"B59",body:'Malutan T, Nicu R, Popa VI. Lignin modification by epoxidation. BioResources. 2008;3(4):1371-1376. DOI: 10.15376/biores.3.4.1371-1376'},{id:"B60",body:'Du X, Li J, Lindstrom ME. Modification of industrial softwood kraft lignin using Mannich reaction with and without phenolation pretreatment. Industrial Crops and Products. 2014;52:729-735. DOI: 10.1016/j.indcrop.2013.11.035'},{id:"B61",body:'Ge Y, Song Q, Li Z. A Mannich base biosorbent derived from alkaline lignin for lead removal from aqueous solution. Journal of Industrial and Engineering Chemistry. 2015;23:228-234. DOI: 10.1016/j.jiec.2014.08.021'},{id:"B62",body:'Peter Dilling, A sulfonation of lignins. Patent US 5049661. 1989'},{id:"B63",body:'Sen S, Patil S, Argyropoulos DS. Methylation of softwood kraft lignin with dimethyl carbonate. Green Chemistry. 2015;17(2):1077-1087. DOI: 10.1039/c4gc01759e'},{id:"B64",body:'Malutan T, Nicu R, Popa VI. Contribution to the study of hydroxymethylation reaction of alkali lignin. BioResources. 2008;3(1):13-20. DOI: 10.15376/biores.3.1.13-20'},{id:"B65",body:'Podschun J, Saake B, Lehnen R. Reactivity enhancement of organosolv lignin by phenolation for improved bio-based thermosets. European Polymer Journal. 2015;67:1-11. DOI: 10.1016/j.eurpolymj.2015.03.029'},{id:"B66",body:'Hu L, Pan H, Zhou Y, Zhang M. Methods to improve lignin’s reactivity as a phenol substitute and as replacement for other phenolic compounds: A brief review. BioResources. 2011;6(3):1-11. DOI: 10.15376/biores.6.3.3515-3525'},{id:"B67",body:'Kong F, Parhiala K, Wang S, Fatehi P. Preparation of cationic softwood kraft lignin and its application in dye removal. European Polymer Journal. 2015;67:335-345. DOI: 10.1016/j.eurpolymj.2015.04.004'},{id:"B68",body:'Pan H, Sun G, Zhao T. Synthesis and characterization of aminated lignin. Industrial Journal of Biological Macromolecules. 2013;59:221-226. DOI: 10.1016/j.ijbiomac.2013.04.049'},{id:"B69",body:'Feng P, Chen F. Preparation and characterization of acetic acid lignin-based epoxy blends. BioResources. 2012;7(3):2860-2870. DOI: 10.15376/biores.7.3.2860-2870'},{id:"B70",body:'Anicento JPS, Portugal I, Silva CM. Biomass-based polyols through oxypropylation reaction. ChemSusChem. 2012;5(8):1358-1368. DOI: 10.1002/cssc.201200032'},{id:"B71",body:'Thielemans W, Wool RP. Lignin esters for use in unsaturated thermosets: Lignin modification and solubility modeling. Biomacromolecules. 2005;6(4):1895-1905. DOI: 10.1021/bm0500345'},{id:"B72",body:'Duong LD, Luong ND, Thanh Binh NT, Park I, Lee SH, Kim DS, et al. Chemical and rheological characteristics of thermally stable kraft lignin polycondensates analyzed by dielectric properties. BioResources. 2013;8(3):4518-4532. DOI: 10.15376/biores.8.3.4518-4532'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Łukasz Klapiszewski",address:"lukasz.klapiszewski@put.poznan.pl",affiliation:'
Faculty of Chemical Technology, Institute of Chemical Technology and Engineering, Poznan University of Technology, Poznan, Poland
'},{corresp:null,contributorFullName:"Tadeusz J. Szalaty",address:null,affiliation:'
Faculty of Chemical Technology, Institute of Chemical Technology and Engineering, Poznan University of Technology, Poznan, Poland
Faculty of Chemical Technology, Institute of Chemical Technology and Engineering, Poznan University of Technology, Poznan, Poland
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There is great interest from the medical community and also much concern from the lay press about the potential benefits and harms of genetic screening, gene therapy, and even the possibility of cloning individuals. The current use of genetic tests for the detection and treatment of endometriosis is still at an early stage but very important. The determination of susceptibility markers will be increasingly explored in clinical studies and their uses will be much more defined. Still, it seems increasingly likely that major changes will occur over the next decade in how we evaluate and treat our patients. In particular, surgeons and clinicians will have the opportunity to use a number of new tests to predict the future appearance of endometriosis in patients still free of the disease. They may have the power to explore the best therapeutic modality for a particular patient according to his/her genetic makeup. And they will be able to more specifically target prevention measures for family members of people already affected by the disease. It should be understood that molecular diagnosis, especially in asymptomatic individuals, does not mean disease but an increased risk of developing a disease. Ethical implications exist and should not be underestimated. Patients should be advised about the likely implications of such tests, not only after but especially before the achievement of these. A major step has already been overcome and we currently have the basic tools for a new leap in understanding human pathologies responsible for much of the world's mortality. 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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Dissemination and Promotion
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Proven world leader in Open Access book publishing with over 10 years experience
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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Most competitive prices in the market
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+108,170 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
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