General phenotypic features of mycolate genera classified in the order
\r\n\t
",isbn:"978-1-80356-678-8",printIsbn:"978-1-80356-677-1",pdfIsbn:"978-1-80356-679-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"6dcb071a2e978694b6b1cb9c20afc1a3",bookSignature:"Prof. Hai-Zhi Song",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11494.jpg",keywords:"Electric Field Effect, Nano-Materials, Electric Field Design, Antenna, Microelectronics, Optoelectronics, Electric Field Stimulation, Brain and Nerve, Electric Field Imaging, Atomic Electric Field, Space Science, Climate",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in the fields of new materials, optoelectronic devices, and quantum information processing, appointed vice director of the Science and Technology Committee of SWITP, author/co-author of more than 170 research papers, and holder of 40 patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"196114",title:"Prof.",name:"Hai-Zhi",middleName:null,surname:"Song",slug:"hai-zhi-song",fullName:"Hai-Zhi Song",profilePictureURL:"https://mts.intechopen.com/storage/users/196114/images/system/196114.jpg",biography:"Curriculum Vitae\n\nName: Hai-Zhi Song \nGender: male\nDate of Birth: Oct. 20, 1968\nPlace of Birth: Shanxi, China\nAffiliation and Address: \nSouthwest Institute of Technical Physics\nNo.7, Section 4, Renminnan Road, Chengdu 610041, China\nAnd\nInstitute of Fundamental and Frontier Sciences,\nUniversity of Electronic Science and Technology of China,\nNo. 4, Section 2, Jianshebei Road, Chengdu 610054, China\n\nWork Phone: +86-28-68180751, +86-28-83208728\nMobile Phone: +86-158-28239155\nFax: +86-28-83201896\nE-mail: hzsong1296@163.com, hzsong@uestc.edu.cn\n \nEducation \nSept, 1990 – July, 1995:Peking University, PhD, Thesis “Visible luminescence of porous silicon and its mechanism”, Researches on hydrogen-influenced Schottky diodes and silicon-based light-emitting materials. \nSept, 1986 – July, 1990:Nanjing University, Bachelor of Science, Thesis “Study of refractory metal silicides”, Research on Ohmic contact of semiconductors.\n\nWork Experience \nJuly, 1995 – Sept. 1997: Nanjing University, Nanjing, China, Postdoctoral Researcher, Research on silicon-based light-emitting materials. \nOct, 1997 – Sept. 1998: Catholic University Leuven, Leuven, Belgium, Visiting free Researcher, Research on amorphous semiconductors. \nOct, 1998 – Sept. 2001: Tsukuba University, Tsukuba, Japan, Assistant Professor, Research on semiconductor quantum dots. \nOct, 2001 – March 2012: Fujitsu Lab. Ltd., Atsugi, Japan, Researcher/Senior Researcher, Researches on Semiconductor Quantum Dots for Quantum Information, Semiconductor Optoelectronic Materials and Devices. \nApril, 2012 – March 2014: University of Tokyo, Tokyo, Japan, Senior Researcher, Researches on Quantum Information Processing Devices. \nApril, 2014 – now: Southwest Institute of Technical Physics, Chengdu, China, Professor, Researches on Semiconductor Optoelectronic Materials and Devices. \nJune, 2015 – now: University of Electronic Science and Technology, Chengdu, China, Professor, Researches on Nanoscaled Semiconductors and Quantum Information Processing Devices.\n \nAchievements\nSystematically studied the property of porous silicon materials and verified their mechanism; found green and ultraviolet luminescence, and clarified the multiple luminescence mechanisms of nanocrystalline-silicon embedded in SiO2, which is valuable to silicon-based optoelectronic integration; realized enhanced hole mobility in amorphous silicon, verified the existence of deep trap states in amorphous selenium, providing ways to improve amorphous optoelectronic materials. \nDiscovered lateral coupling between self-assembled quantum dots (QDs) and their tuning effect to 2D electron gas; illustrated and deeply explained the metal-insulator transition in 2D ordered QD arrays, all of which are worth in optoelectronic application of semiconductor QDs. \nDeveloped Sb-free technique to double the InAs/GaAs QD density and suppress the atomic interdiffusion, helped producing 1.3 um QD lasers, which won Japanese national prizes and had been merchandized; developed 1.06 um quantum-well lasers, which have been used to produce pure-green lasers robust against high temperature. \nFound a way to access buried QDs by scanning tunneling microscope; achieved a way to prepare diluted QDs by post-annealing and clarified its mechanisms; invented a technique to control the size and site of QDs by atomic-force microscopy lithography, and an apparatus to detect single electron spin states by optically-detected magnetic resonance; designed a few types of micropillar cavities applicable to realize 1.55 um highly-efficient, even coherent (strongly coupled) InAs/InP QD single photon sources; produced fiber-integrated photon-entangled sources, all of which are very useful to the applications of QDs in quantum information processing. \nDeveloped focal-plane single-photon avalanche detectors, providing central devices for 3D laser detecting and ranging system; explored antimonide middle- and long-wavelength infrared detectors and the surface plasmon enhancement effect in such detectors; advanced the acetone-sensing function of Eu-doped SnO2 nano-belt; found Nickle Phosphide serving as a good catalyst in hydrogen-producing. Realized a series of optoelectronic quantum devices for quantum information processing, such as fiber-integrated photon-pair-entangler, chiplet heralded single photon emitter, fiber quantum memories, quantum number generator, etc.\n\nHonor and Group Memberships \nSelected Scholar of the Recruitment Program of Global Experts, China\nEditorial member of “Laser Technology”\nEditorial member of “Journal of Electronic Science and Technology”\nEditorial member of “Internal J. Mat. Sci. Appl”\nMember of APS (American Physics Society)\nMember of OSA (Optical Society of America)\nPermanent Member of China Physical Science and Technology\nPermanent Member of the Chinese Optical Society\nTechnical committee member of PIERS, organizing a series of “quantum information processing and devices” sessions\nTechnical committee member of ICICM",institutionString:"Southwest University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Southwest University",institutionURL:null,country:{name:"China"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41210",title:"DNA Methylation, Stem Cells and Cancer",doi:"10.5772/53263",slug:"dna-methylation-stem-cells-and-cancer",body:'Cancer has been traditionally seen as a disease characterized by many genetic alterations, but recent studies have proven the implications of epigenetic abnormalities along carcinogenesis [1, 2].
The fundamental base of carcinogenesis is described by two major models: clonal evolution and cancer stem cell (CSC) model [3-5].
In the past few years ‘cancer stem cells’ (CSCs) area has become an interesting field of cancer research. In 19th century, Durante and Conheim [6] and after one hundred year Sell and Pierce [6, 7] issued the hypothesis that stem cells could induce cancer in all type of tissues. Unlike normal tissue stem cells, cancer stem cells are characterized by an abnormal differentiation rate, which can lead to tumor [8, 9].
The five principal factors, reported to be involved in carcinogenesis are:
chemicals – John Hill, in 1761, was the first who showed that the chemicals agents produce cancer of the nasal cavity [6];
infections – Francis Peyton Rous was the pathologist awarded the Nobel Prize in Medicine for his research that reported that the viral agents are involved in the origin of cancer [10];
mutations – Theodor Heinrich Boveri and Von Hansemann argued the association between development of cancer and abnormal mitoses [11];
teratocarcinomas – the field theory, which explains that in pathology of cancer are implicated a mixture of mature and differentiated cells and also embryonic tissue [12];
epigenetic alterations – coerce to development of abnormal phenotypes, without any structural changes of DNA [13];
The term epigenetic was introduced by Conrad Waddington in 1942, to explain the relationship between environment and genome. Model of „cancer stem cells” indicates that epigenetic changes occurred in stem or precursor cell are the earliest events that take place in cancer [14].
There are two primary mechanisms involved in the epigenetic process: methylation of DNA and covalent modification of histones [15].
DNA methylation is an inheritance mechanism, fundamentally important in normal development and cellular differentiation in mammalian organisms. This is a post-replication DNA modification, by the addition of a methyl group to carbon 5 (C5] of the pyrimidine ring of cytosines, predominantly in cytosine-phospho-guanine (CpG) dinucleotides.
In the eukaryotic cells, the pattern of methylation is the result of complex interactions between three types of normal methylation processes:
The decisive developmental effect of DNA-methylation on gene expression is the long-term silencing of gene expression. In human, the process of DNA-methylation is associated with transcriptional silencing imprinted genes and X-chromosome inactivation. Both genomic imprinting and X-chromosome inactivation are suggested to regulate gene expression in embryonic and fetal growth.
Dysregulated normal imprinting is supposed to induce embryonic death and to impair fetal growth. Defects in DNA-methylation process may also have major consequences for embryonic development and are associated with congenital defects, autoimmunity, aging and malignant transformation.
In recent years, the human methylation profile of the whole genome has been investigated by DNA methylomic studies and altered DNA methylation has been found in cancer DNA [2, 17] The transformation of normal cells into dysplastic and cancerous cells is due to a broad range of genetic and epigenetic changes. Some of the epigenetic mechanisms of initiation and progression of cancer are strongly related to post translational modifications of histones, among which the methylation process is highly involved. The resistance of various types of cancer to therapy led to the hypothesis that cancers present some cells, able to self renew and differentiate into all types of cells that compose a tumor, named cancer stem cells [8]. During embryonic development, characteristic patterns of CpG methylation are produced in the different cell lineages that are then well conserved in normal adult cells, while in tumor cells, DNA methylation patterns become altered. A family of germline-specific genes that use DNA methylation as a primary silencing mechanism, has been indicated as a stem cells signature. These germline-specific genes expression in tumors, has also been hypothesised to reflect the expansion of constitutively expressing cancer stem cells [8].
Post-translational modification of histone proteins is an important area of regulation epigenetic. The post-translational modifications of the N-terminal tail domains include: methylation, acetylation, phosphorylation, citrullination, ADP-ribosylation, sumoylation and ubiquitination [18-20]. The most studied of these modifications are methylation and acetylation. Modifications of histone N terminal ends by methylation and acetylation processes are closely related to cancer and are done by the competition of two families of enzymes: histone acetyltransferases (HAT) and histone acetylases (HDAC). Lysine residues acetylation in the histone H3 and H4 by (HAT and lysine 4 methylation in the histone H3 (H3K4me) by histone methyltransferase (HMT) are generally correlated with active transcription of chromatin. In contrast, methylation of lysine 9 and lysine 27 (H3K9, H3K27me) in the histone 3, have been considered as markers in transcriptionally silenced-chromatin [21, 22].
Dysregulation of epigenetic mechanisms in stem cells may induce alteration in stem cells function, (i.e. self-renewal and differentiation potential), leading to cancer initiation and progression. During the last years, a major challenge in cancer biology is to elucidate how the histone modifications in stem cells influence carcinogenesis.
Thus, epigenetic control of gene expression patterns in embryogenesis, stem cells and cancer stem cells is a very important aspect for our understanding of human cancer development, progression and therapy.
According to the cancer stem cell theory, aberrant epigenetic changes may allow the transformation of stem cells in cancer stem cells [14].
Epigenetic regulation is realized by modifications that consist in four important mechanisms: DNA methylation, covalent modification of histone, nucleosome positioning and changes of microRNA expression [23].
The biological process of DNA methylation is found in both eukaryotic and prokaryotic cells and it can be involved in pathogenesis of several diseases, especially in cancer. This is the most studied mechanism of epigenetic regulation, consisting in addition of a methyl group to the carbon-5 position of the pyrimidine base cytosine (C) from the nucleotide structure cytidine-5’-monophosphate (CMP). S-adenosyl-L-methionine (SAM), the active form of amino acid methionine, is the donor of methyl group resulting S-adenosylhomocysteine (SAH) [23].
In the mammalian genome, cytosine is coupled to guanine (G) to form a base pair, commonly called cytosine-phosphate-guanine (CpG) dinucleotides. These dinucleotides are generally methylated (CpG-poor regions) with the exception of GC-rich regions known as the CpG islands [24, 25]. In human normal cells, it was observed that CpG islands are often hypomethylated. In oncogenesis CpG islands suffer a hypermethylation process whereas the entire pool CpG-poor regions are hypomethylated. DNA hypermethylation and hypomethylation coexist in cancer cells, both processes demonstrating the importance of DNA methylation in sustaining a normal gene expression pattern, genomic imprinting and silencing of genes involved in X-chromosome inactivation [1, 23, 26-29].
The DNA methylation process is catalyzed by specific DNA methyltransferase (DNMTs). In human cells, five types of DNMTs enzymes have been reported [23, 30-33]. DNMT1 - DNA (cytosine-5-)-methyltransferase 1, with role in regulation of normal tissue-specific methylation; unusual methylation is related to the appearance of human cancer. DNMT2 has an uncertain role in human health and illness [34]. Grant A Challen et al. have shown that DNMT3A and DNMT3B are implicated in embryonic stem cells differentiation [35] and DNMT3L was reported to stimulate the activity of both DNMT3A and DNMT3B [36].
Methylation of cytosine. Cytosine methylation is one of the most extensive studied epigenetic processes. The donor of the methyl group is the active form of methionine, S-adenosyl-L-methionine (SAM) and its addition to cytosine is realised at the carbon-5 position.
Over the past two decades, it was shown that DNA methylation plays a major role in the regulation of the specific gene expression, during mitotic cell division, in the normal mammalian cell, as well as in the stem cell [13, 37, 38].
A new hypothesize about tumorigenesis consists in dysregulation of the stem cell self-renewal process. Dissemination of cancer stem cells is suggested to be induced by gene mutations and epigenetic modifications that may lead to metastasis [39].
DNA hypomethylation was found to activate cancer-germline (CG) genes or cancer-testis (CT) gene family in tumours. The promoter region of CG genes is demethylated in a several tumour types, inducing genes transcriptional activation. In their study, Costa et al. hypothesized that expression of CG genes may be indispensable for stem cell biology [40, 41].
In addition to DNA hypermethylation and hypomethylation, a DNA demethylation process was also described. While the active DNA demethylation process takes place in presence of enzymes that catalyzed specific reactions, passive DNA demethylation can occur during replication cycles and operates on DNA methyltransferases [42, 43]. Although the demethylation process is not fully elucidated, there are many studies showing transient involvement of this process in various types of tumors, especially in advanced stages of their development [44]. The mechanism of DNA demethylation in cancer has been relatively less studied
It is well-known that Wingless gene encodes the Wnt protein family that control the self–renewal and tumorigenesis processes. Wnt protein is well preserved from Drosophila melanogaster and has an essential role during normal embryonic development. Wnt protein is a part of a particularly signalling pathway, common to humans and Wnt protein dysregulation was reported to be involved in the development of tumors. It has been demonstrated that some genes implicated in the Wnt signaling pathway, are inactivated by promoter hypermethylation, generating lung metastasis from primary tumors [48].
The Notch signaling pathway was also suggested to have an important role in stem cell differentiation, proliferation and oncogenesis as well. Scientists have shown that in humans, exist four Notch paralogs (i.e. Notch 1, 2, 3, and 4) and five ligands (i.e. Delta-like 1, 3, 4 and Jagged 1 and 2). Activation of these Notch paralogs are found in stem cell self-renewal but also in many types of cancers [49].
Some epigenetic changes like histone methylation and downregulation of gene expression, which collaborate with the Notch developmental pathway during oncogenesis, were also described [50].
Chromatin is represented by the mandatory association between nuclear DNA and proteins. Chromatin presents different compression degrees during to cell cycles. It exists in two different types: euchromatin and heterochromatin.
Euchromatin has more non repetitive DNA with prevailing of guanine and cytosine bases and nonhistonic proteins; it is also less condensed and represents the active and transcriptional part of the chromatin; it replicates early at the beginning of S faze, being R positive bands from bands marked chromosomes [51].
Heterochromatin has more repetitive DNA with predominating adenine and thymine bases and histones; it is very compact, genetically inactive, with late replication. Heterochromatin functions are to stabilize the centromere and the telomeres of the chromosome, playing an important role in meiosis and in cellular differentiation [52]. Heterochromatin is expressed as constitutive or facultative chromatin. Constitutive heterochromatin is constantly found in a condensed form. It doesn’t have functional genes and it is made of highly repetitive DNA (satellite DNA).
Facultative heterochromatin is a chromosome region, densely packed and inactive in a particular cells, having lost gene expression [53]. Both constitutive and facultative heterochromatin, are regulated by the DNA silencing in the mammalian cells. Constitutive heterochromatin is mandatory transcriptional silenced while facultative heterochromatin is conditionally silenced [53].
Electronic microscope analysis shows a hierarchical system of chromatin fibers with different dimensions, made of DNA, histones and nonhistone proteins. The supramolecular organization of DNA has four different levels. The first level is represented by four core histone proteins (H2A, H2B, H3 and H4) which form an octamer wrapped around 1.75 times by 146 base of DNA, making together nucleosomes [54]. Nucleosomes are linked by a short fragment of free DNA (approximately 60 pairs of bases), closed tight by histone H1. The compactness of DNA at this level is 10:1 [54]. Nucleosomes seem to be dynamic structures, since they have to suffer structure modifications during transcription, replication or recombination of DNA. The second level of chromatin economy is represented by the chromatin fiber of 30 nm, creating a solenoid aspect. A fundamental unit in the interphase, this chromatin plays an important role by putting together regions of linear DNA, stimulating genic interaction. The solenoid has a heterogeneous structure, characterized by an alternation of spiral and not spiraled areas, creating a proper configuration for RNA polymerase action, during transcription. The third level of chromatin organization results from creation of lateral loops of 300 nm diameter, attached to a protein nonhistonic matrix. At the beginning of prophase, a matrix will be formed by a 20 times compaction a chromatid, the highest level of chromatin organization [55]. So, the basic DNA will suffer an overall 10000 times compaction, being able to fit a small place into a nucleus. This conformation offers sterically occlusion for nucleosomes, which will be there for protected against nucleases cleavage, while the linker DNA doesn’t have this kind of protection [56].
Many cancers are associated with translocations which can be explained by mutual rearrangements due to misfit of two unrepaired double stranded breaks, determined by the close proximity of some genetic regions, thus suggesting the dynamic properties of chromatin [57, 58]. Translocation that characterizes tumorigenesis may depend on the physical distance between individual genetic elements. Chromatin is a dynamic structure, with its own mobility that influences either gene regulation (local diffusion of chromatin) or genomic stability (global chromatin immobility) [57]. In normal cells, as well as in tumor cells, there are similar nuclear layers, defined as center of nucleus-to-locus distance, with a random distribution of genetic loci inside it [59]. Polarization of some chromosomes, with their genes located in the interior of the nucleus and their centromeres located at the nuclear periphery, along with all the other data already presented, strongly support the existing relation between the chromatin pattern and tumor development, but still many aspects remain to be proved.
The debate concerning chromatin remodeling as a cause or a consequence of tumorigenesis is still on.
Many works indicate that DNA methylation and chromatin remodeling are in reciprocal causal relationship: DNA methylation may cause chromatin modifications and specific chromatin modification may induce DNA methylation [1]. Recent data suggest that chromatin remodeling is a combination between a CIS effect determined by the action of a proximal genetic sequence and a TRANS effect induced by sequence independent complexes, most likely by ATP dependent nucleosomes remodeling complexes [60, 61].
Alu sequences are a class of repetitive DNA characterized by a pattern of CG dinucleotides (CpG) repeating every 31-32 bases. They may modulate the nucleosome strength when the CG elements are methylated. Thus, epigenetic nucleosomes within Alu sequences may have methylation-dependent regulatory functions [62].
Emerging data are suggesting that since genome regulation might be influenced by nucleosome positioning and their compositional modifications, nucleosomes are regulating the initiation of transcription, therefore nucleosomes positioning is leading to cancer or developmental effects [17]. Nucleosomes adopt preferential positions near promoter regions and random positions inside genes [63]. Transcription needs exposed binding sites consisting in nucleosome free regions at the 5′ and 3′ ends of the genes, so any change in nucleosome positioning at this level might determine gene activation [64, 65].
Nucleosome positioning is also influenced by another protein complex that activates or represses transcription through biochemical processes, such as octamer transfer, nucleosome remodeling or nucleosome sliding: switch/sucrose nonfermentable (Swi/Snf) complex. It consists in approximately 10 subunits of 2 MDa, with many variants of combinations, first discovered in Saccharomyces cerevisiae [16, 66]. The multiple varieties of Swi/Snf complexes exist in many cell types [67]. Swi/ Snf performs a crucial function in gene regulation and chromosome organization by directly altering the contacts between nucleosomes and DNA [68], using the energy of ATP hydrolysis [69]. The
Radiations have the ability to paradoxically induce or cure tumors. It seems that chromatin structure might be influenced by UV and gamma radiation. To study the changes in chromatin pattern under irradiation conditions, Fluorescence In Situ Hybridization (FISH), combined with high-resolution confocal microscopy has been used [93, 94]. FISH studies were performed in leukemia cells for tumor suppressor gene TP53, revealing that TP53 genes are getting closer to each other, as well with the nuclear center within 2 hours of exposure to gamma-radiation, returning during the following 2 hours to its pre-irradiation conditions [95, 96]. There is increasing evidence that CSCs have a higher intrinsic radioresistance than non-CSC tumor cells [97], explaining the difference of CSCs and non-CSC in their response to cancer therapy.
Such repressive complex for chromatin is “Nucleosome Remodeling and Histone Deacetylase” (NuRD) [98], suggested to play a role in acute promyelocytic leukemia (APL) [99]. Human APL is characterized by PML-RARa translocation, which represses gene transcription through several distinct epigenetic mechanisms: DNA methylation, chromatin compaction, heterochromatinization, histone deacetylation, histone modification. NuRD complex is strongly implicated in the epigenetic silencing, by PML-RARa. Earlier findings regarding carcinogenesis, such as the combination of both genetic and epigenetic factors, were confirmed. in this case, PML-RARa oncogenic fusion protein recruiting, induces DNA hypermethylation [100] and result in blocking of hematopoietic differentiation [101].
Covalent modification of histones is an important mechanism, involved in the epigenetic processes. Five types of histones are known to be involved in chromatin building: H1/H5, H2A, H2B, H3, and H4 [15, 102]. In their structure, histones have three distinct domains: a central globular conserved domain and two terminal domains; one short N-terminal tail and one longer C-terminal tail [54].
Generally, histone modifications affect gene transcription, DNA replication and DNA repair mechanisms. The post-translational modifications of the N-terminal tail domains include: methylation, acetylation, phosphorylation, citrullination, ADP-ribosylation, sumoylation and ubiquitination [18-20]. The most studied of these modifications are methylation and acetylation. Lysine residues acetylation in the histone H3 and H4 by histone acetyltransferase (HAT) and lysine 4 methylation in the histone H3 (H3K4me) by histone methyltransferase (HMT), are generally correlated with active transcription of chromatin. In contrast, methylation of lysine 9 and lysine 27 (H3K9, H3K27me) in the histone 3 have been reported as markers in transcriptionally silenced-chromatin [21, 22].
During the last years, a major challenge in cancer biology is to elucidate how the histone modifications in stem cells, influence carcinogenesis.
Histones methylation is a post translational modification that occurs at the lysine residues and is considered a reversible process [103]. Transcriptional activation or repression, correlates with different degrees of methylation of histones. The binding of one to three methyl groups at each lysine amino acid in the histone structure, give rise to unmethylated, monomethylated, dimethylated and trimethylated degrees of methylation [104, 105]. The mono-methylation state of histone has been reported to be associated with an open chromatin structure that lead to transcriptional activation. In contrast, the trimethylation state was shown to be associated with a condensed chromatin structure, which in turn inhibits transcription [106].
Some important exceptions from this rule have been reported by Strahl BD et al., they showed that H3K4 histone methylation state (mono-, di-, or tri-methylated level) is invariably associated with active chromatin, while H3K9 trimethylation can be connected to both transcriptionally active and inactive chromatin [107]. To explain this exception from the general rule, Vakoc et al., described a mechanism by which an association between meH3K9 with RNA polymerase II complexes induces chromatin modification and transcriptional activation [108]. However, it is not fully understood why these markers differs from the general rule.
The binding of the methyl group of each lysine 4, 36 or 79 in the histone 3 (H3K4, H3K36, H3K79) and H4 (k20, H2BK5) induces trnascriptional activation. In contrast, the binding of three methyl group of lysine 9, 27 in the histone 3 (H3K9, H33K27) AND h4k20 was show to be associated with inhibiton of transcription [109, 110]. The histone modifications are arising from the action of enzymes which are responsible for methylation/demethylation activity in the pattern of histone H3 and H4. The enzymes involved in histone modifications are histone acetyltransferases (HATs) and histone deacetylases (HDACs), histona methyltransferases (HMTs) and histone demethylases (HDMs). These enzymes add or remove acetyl or methyl groups, respectively [111, 112]. Several enzymes, like histone methyltransferase (HMTs), histone demethylases (HDMs) and histone deacetylases (HDACs), are connected with each other to create a strong link between chromatin state and transcription.
In addition to changes in histone acetylation, widespread changes in histone methylation patterns are described in cancer. Accordingly, in cancer, aberrant gene silencing was shown to be associated with changes in H3K9 and H3K27 methylation patterns [113].
A recent analysis in the context of histone modifications in cancer, illustrates different scenarios such as histone methylation and its consequences, describing the role of histone methyltransferases (HMTs) and histone demethylation (HDMS) by adding or removing a methyl group. It has been reported that the level of transcriptional activation is largely maintained by HMTs and HDMs which are involved in the histone methylation [103].
The histone lysine methyltransferase (HMT) that is responsible for the histone methylation, has a catalytically active site known as SET domain, which is formed by de 130 amino acid sequence. The major function of the SET domain is to modulate gene activity [114].
The binding of the methyl group at several lysine sites in histone H3 (H3K9, H3K27, H3K36, H3K79) and loss of acetylated H4 lysine 16 and H4 lysine 20 trimethylation have been reported to be associated with changes that occur during tumorigenesis[115]. The enzymes HDACs and HATs have been suggested to be responsible for these changes and are commonly found to be altered in various forms of cancer [116].
Various observations suggest the presence of a novel chromatin pattern in embryonic stem cell, which consists of lysine 27 and lysine 4 tri-methylation superposition, termed “bivalent domains” [117].
The bivalent domains have been analysed by the genome mapping of histone methylation profiles in embryonic stem cell and was reported to include both active and repressive chromatin marks. Developmentally, the “bivalent domains” is responsible for maintaining epigenomic plasticity, enabling embryonic stem cells to regulate gene expression [117]. Bivalency is lost during stem cell differentiation, allowing epigenetic plasticity and lineage commitment. Epigenetic plasticity in association with bivalent gene promoters is suggested to induce a transcriptionally repressive and permissive histone mark in embryonic stem cells [117, 118].
In cancer, bivalency has been suggested to stigmatize specific genes for DNA methylation, inducing aberrant reprogramming [119-121]. In analogy with embrionic stem cells, bivalent gene promoters were reported to be DNA-methylated in cancer cells, suggesting the provenience of cancer cells from embryonic stem cells [122]. In absence of DNA methylation, the repressive H3K27 trimethylation mark was also demonstrated to induce gene silencing in cancer cells.
Chromatin regulating complexes are commonly observed in cancer, and is hypothesized to involve multiple mechanisms, including DNA methylation and Polycomb repressive complexes (PRCs). Chromatin regulating complexes including two families of Polycomb repressive complexes (PRC1 and PRC1), mediate trimethylation on H3K27 in cancer cells [123, 124]. PRC2 complex has also been reported to intermediate H3K27 trimethylation in embryonic stem cell [125].
MicroRNAs (miRNAs) was first discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda Feinbaum. The recent definition of miRNA is: small non-coding RNA molecules (21-24 nucleotides long), implicated in posttranscriptional gene expression, regulation by two different mechanisms: splitting and subsequent degradation of targeted RNAm or inhibiting translation, both determining the stop or stimulation of cell reproduction [126-130].
However, the entire mechanism of miRNA is not yet fully understood [131, 132].
The study on Caenorhabditis elegans (C. elegans) has permitted the clonation of first miRNA, lin-4 and let-7 and their targets [133, 134]. This study discovered that the gene lin-14 was able to transcribe a precursor that matured to a 22 nucleotide mature RNA, which contained sequences partially complementary to multiple sequences in the 3’ UTR of the lin-14 mRNA, ensuring inhibition of translation of lin-14 mRNA. In addition, in 2000, along with the discovery that gene let-7 repressed the genes lin-41, lin-14, lin-28, lin-42 and daf12 mRNA during transition in developmental stages in C. Elegans, it was also established that non-coding RNA identified in 1993, was part of a wider phenomenon [133].
More than 700 miRNAs have been identified in humans and over 800 more are predicted to exist. These molecules have an important role in cellular physiological processes (e.g. cell cycle, cell proliferation, apoptosis, cell differentiation and development), by implication in gene regulation; miRNA has been found to control about 30% of all human genes.
In human embryonic stem cells and the differentiated embryonic bodies, over 100 miRNAs have been already described [101]. The self-renewal and pluripotency of embryonic stem cells are regulated by an array of protein-coding genes in a regulatory circuitry [135], which includes OCT4, SOX2, and KLF4 genes. Extensive studies have indicated the importance of OCT4 in self-renewal and pluripotency of embryonic stem cells [136, 137]. Multipotent cell lineages in early mouse development, have also been reported to be dependent on SOX2 function [138, 139] in the process of embryonic stem cells self-renewal and pluripotency. The miRNA genes are also connected to the transcriptional regulatory circuitry of embryonic stem cells [140] and are overexpressed in their differentiating processes.
The three key proteins of pluripotent cells, Oct4, Nanog and SOX2, and TCF3 were found in the promoters of miRNA specific stem cells, but also in promoters of miRNA, which controls cell proliferation (mir 92 si let7g) and differentiation (e.g., mir-9 or mir-124a for neutral line). OCT4 was reported to bind and repress miR-145 promoter in human embryonic stem cells. On the other hand, inhibition of Oct 4 increases the activity of these miRNAs that in turn inhibit the stem cell renewal.
miRNAs, occasionally causes DNA methylation of promoter sites and can regulate other epigenetic mechanisms. An altered miRNA gene methylation patterns in human cancers was reported to sustain in tumorigenesis. Half of these genes are associated with CpG islands and several studies indicated that miRNA gene methylation was often detectable, both in normal and malignant cells. Recent works have identified many types of miRNA, which allow cancer cells to multiply indefinitely by avoiding natural cellular aging mechanisms, thus suggesting a close relation between cancer development and miRNA expression [141].
There are several mechanisms which may lead to modification of mi RNA in cancer [142-145].
Oncogenic activity of miRNA, initially determined for mir-17-92 and mir-155, was further sustained by the discovery of other potentially oncogenic miRNA [150]. Therefore it is logical that this classification of miRNA in oncogenes or tumor supressor genes may facilitate the identification of different tissues where they are expressed [151].
Embryonic stem cells gene expression of Oct4, Sox2, Klf4, and Nanog was observed in highly aggressive human tumors [152]. It has been reported that miR-200 known to mediate transcriptional repression, also play an important role in both cancer stem cells andembryonic stem cells [153, 154].
Several miRNAs have been reported to be overexpressed in human cancer. The mir-17-92 polycistron (cluster) is overexpressed in B-cell lymphoma [155, 156] and in testicular germ cell tumors miR-372 and miR-373 were identified as possible oncogenes [157].
Another theory supports the idea that some cancers such as Kaposi `s sarcoma, were induced by viral oncogenic miRNA [158]. It is clear that discovery of miRNA involvement in cancer stem cells function will be a crucial step in elucidating the process of oncogenesis [159].
Recently, several epigenetic drugs targeting epigenetic mechanisms have been tested
DNA methylation is the most studied epigenetic marker. Abnormal DNA methylation of several regulatory genes is usually associated with cancer. The methylation process is reversible, therefore the reactivation of silenced genes can be realized using substances with hypomethylating activity [161].
The new development cancer therapies are based on molecules that can inhibit the classes of DNA methyltransferases (DNMT), histone deacetylases (HDACs), histone acetyltransferases (HATs) and new substances that target chromatin and nucleosome remodeling proteins. DNMT inhibitors (DNMTi) can be natural or synthetic compounds [148, 162].
As mentioned before, DNMTs are enzymes that catalyze the reaction between methyl groups and pyrimidine base cytosine. The methyl group donor is S-adenosyl-L-methionine (SAM), which is the active form of amino acid methionine.
The DNA hypomethylating agents are divided into two categories
Nucleoside analog drugs. Their structure allows incorporation into the DNA and subsequent hypomethilation.
Other substances from this group are: 1-β-D-arabinosyl-5-azacytidine (fazarabine) [166], dihydro-5-azacytidine (DHAC), 5-fluoro-2’-deoxycytidine (FCDR) and zebularine [163]. Incorporation into the DNA structure of nucleoside analogs is facilitated by their similar chemical structure.
5-azacytidine is used as single-agent therapy or in combination with other therapies in treatment of myelodysplastic syndromes (MDS), acute myeloid leukemias (AML) and solid tumor. As associated substances are utilized valproic acid, cytarabine, entinostat, etanercept etc [137, 164].
5-aza-2’-deoxycytidine (DAC) has benefited as monotherapy in myelodysplastic syndromes, chronic myelomonocytic leukemia (CMML) and has been FDA approved on May 2006. The drug has been associated with: carboplatin useful in solid tumors treatment [167], valproic acid in acute myeloid leukemias and advanced leukemia [168, 169], imatinib mesylate in chronic myelogenous leukemia (CML) [170] and IL-2 in metastatic melanoma, renal carcinoma [171].
Zebularine (2-pyrimidone-1-β- D-riboside) is other nucleoside analog with hypomethylation activity [172] and also implicated in tumor gene expression [173].
Structure of Zebularine. Zebularine is another nucleoside analog drug, with hypomethilation effect.
There are recent studies about another two molecules: NPEOC-DAC and SGI 110 (S110). NPEOC-DAC is the result of chemical reaction between azacytosine molecule and 2-(p-nitrophenyl) ethoxycarbonyl, with reported effect on DNA methyltransferases inhibition. Byun et al. demonstrated that NPEOC-DAC inhibited DNA methylation in two cell lines of liver cancer. The authors, also showed that SGI 110 (S110) has a pronounced effect on DNA methylation inhibition [174].
The non-nucleoside analogs category contains compounds with hypomethylation effect. This group contains hydralazine (the widely known as vasodilatator), procainamide (anti-arhythmic), RG108 and SGI-1027.
Physiologically, acetylation of chromatin is realized by specific enzymes - histone deacetylases and acetyltransferases. A possible change in their normal function can promote tumors.
At first glance, HDACs are enzymes that play a role in elimination of acetyl radical just from lysine molecules of histones, but their actions is not limited to histones, they can also act on non-histone proteins [175].
HDAC inhibitors are classified into four classes, based on their chemical structure: short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides (hybrid molecules) [176].
HDAC inhibitors. There are four classes of curently known HDAC inhibitors: short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides, with a great potential use as detection and prognosis markers.
Exemples of short-chain fatty acids are: sodium n-butyrate, sodium phenylacetate, phenylbutyrate, valproate, substances that in millimolar concentrations are involved in inhibition the growth of some carcinomas but their mechanism of action is not fully understood [163, 177-179].
One of the most studied agent from class of small fatty acids, is valproic acid (VPA), an antiepileptic drug reported to target histone deacetylase. Numerous research studies
Structure of valproic acid. Valproic acid is a small fatty acid commonly used as an antiepileptic drug, but with recently emerged antitumor effects.
The class of hydroxamic acids include synthesized compounds such as: belinostat, panobinostat, vorinostat (SAHA) etc. Belinostat and panobinostat, have been used in clinical trials to treat solid tumors and blood malignancies [181-183]; MDL and CML [184-186], vorinostat (SAHA) that was approved by FDA for the treatment of chronic T-cell lymphoma (CTCL) and used in clinical trials for hematologic malignancies, mesothelioma, breast and ovarian cancer, etc [175].
A natural compound from cyclic peptides class is romidepsin, also known as Istodax (FK228), which was clinical tested in various lymphomas. The drug was shown to induce apoptosis in different tumor cell lines, due to blocking of HDACs [187].
Hybrid molecules (i.e. benzamides) includes two synthetic compounds: Entinostat (MS-275) and Mocetinostat (MGCD 0103). The mechanism by which Entinostat induced cytotoxic effect on tumor cells was suggested to be due to the upregulation of some tumor suppressor genes (p21]. Both Entinostat and Mocetinostat are currently approved by the FDA and are used in cancer treatment. Entinostat is used in the treatment of blood and lung tumor [181, 183] and Mocetinostatin in the treatment of chronic lymphocytic leukemia (CLL) [175].
HATs are a class of enzymes discovered twenty years ago, enzymes with demonstrated role in gene transcription [188]. HATs have been reported to be implicate in numerous types of diseases (i.e. viral infection, respiratory maladies, cancer etc). It has been suggested that the HATs enzymes may be used as biological markers for cancer prediction or recurrence [14]. Four families of HATs are known that share primary-structure homology: GNAT (Gcn5-related N-acetyltransferase), p300/CBP and MYST, Rtt109 [189]. The HAT enzymes have various chemical structure and their classification is still unclear.
Histone methylation process plays an important task in epigenetic regulation, which lead to synthesizing of new target drugs for cancer therapy [163].
Researchers describe a class of enzymes called histone methyltransferases. This class of enzymes includes lysine methyltransferases and arginine methyltransferases, both of them linked to many types of cancer.
There are 8 known lysine methyltransferases (KMT1-8) with suggested role in the epigenetic gene silencing in malignancies like: prostate, liver, colon, breast cancer [190, 191].
Few of the many types of arginine methyltransferases (PRMTs), are also closely linked to cancer [191].
Thus, the importance of DNMTs and HDACs, two classes of enzymes involved in epigenetic targeted therapy of malignant diseases, is obvious. The enzymes implicated in histone methylation and demethylation are mainly attractive as validated targets for cancer therapy.
Epigenetic is a heritage mechanism involved in the process of stem cells differentiation to more specialized cells. According to the cancer stem cell model, dysregulation of epigenetic mechanisms (i.e. DNA methylation and histone modification) in pluripotent stem cells enable their transformation in cancer cells with high proliferation rates and poor prognosis.
DNA methylation is considered the most largely studied part of the epigenetic, but recent works associate the methylation with other epigenetic changes, such as histone modifications, chromatin remodeling and microRNA, suggesting a reciprocal relationship between them in cancer cells. The similarities between chromatin regulation process in stem cells and cancer cells have been mentioned in several studies.
It is therefore important to understand the epigenetic alterations that take place in cancer cells compared with normal cells and the importance of these modifications in carcinogenesis, according to the cancer stem cell theory. In addition, it is very useful to understand the potential of epigenetic marks in designing more effective treatment strategies that specifically target cancer stem cells.
Grant support: 134/2011 UEFISCDI Romania
Members of the class
Membership of the mycolic acid-containing actinobacterial (MACA) group has expanded considerably over the past 20 years with revisions to the classification of existing species and the publication of copious new mycolate species and genera [2]. This substantial and metabolically diverse group therefore warrants further attention in the search for valuable biosurfactants. This chapter provides an overview of the current knowledge on biosurfactants produced by members of this group and describes approaches to the recovery, screening and biosurfactant-producing strains from the environment and their growth requirements. Methodologies applied to screen for biosurfactant production and for extraction, purification, and structural elucidation of biosurfactant compounds are also described. Current and potential future applications of biosurfactants derived from MACA are examined with particular focus on potential biomedical and environmental possibilities.
Microbial biosurfactants are amphipathic compounds, with both hydrophilic (polar) and hydrophobic (non-polar) moieties. The hydrophobic portion has saturated, unsaturated, or hydroxylated long-chain fatty acids and the hydrophilic portion can contain amino acids, carbohydrate, carboxyl acid, peptides, phosphate, or alcohol [3]. Biosurfactants may be categorised according to molecular weight (low or high), ionic charge (anionic, cationic, neutral, or non-ionic) or according to chemical composition and structure. The main classes of biosurfactants include fatty acids, glycolipids, lipopeptides, lipoproteins, neutral lipids, phospholipids, and polymeric biosurfactants. Their amphipathic nature enables biosurfactants to partition at water-air, oil-air, or oil-water interfaces thereby reducing surface and/or interfacial tension. They exhibit many other useful properties including de-/emulsification, dispersion, foaming, lubrication, softening, stabilisation, viscosity reduction and wetting [4].
Biosurfactants may be located intracellularly, on the cell surface (cell-bound) or excreted extracellularly (free) [5] and are produced during growth on both hydrophilic and hydrophobic substrates, to reduce surface or interfacial properties of the microbial cell or the surrounding environment. Biosynthesis of these compounds is required for gliding, motility, swarming, and biofilm formation. Biosurfactants also mediate between cells and hydrophobic compounds, enabling enhanced solubilisation and uptake across the cell membrane for utilisation as a substrate for growth and energy (Figure 1).
Emulsification of hydrocarbons by microbial biosurfactants to enhance bioavailability.
Many microbially derived biosurfactants are already used in diverse industries including agriculture, bioremediation, cosmetics, food, healthcare and medicine, and the petrochemical industry (Figure 2). In addition to being multifunctional, biosurfactants have several advantages over chemically synthesised surfactants. They are less/non-toxic and biodegradable, have higher surface activity and lower critical micelle concentrations (CMC), greater biocompatibility and selectivity, they function over wide pH, salinity, and temperature ranges, and can be produced using renewable and waste substrates [6]. These unique eco-friendly features make biosurfactants particularly attractive options as industries focus on longer-term sustainability and working towards a circular economy.
Various sectors of application for microbial biosurfactants.
The MACA form a phylogenetically coherent group that resides in the order
Mycolic acids, which are high molecular weight 3-hydroxy fatty acids with a long alkyl branch in the 2-position, represent the major lipid constituents of the cell envelope of these organisms. They show structural variations from relatively simple mixtures of saturated and unsaturated compounds in corynebacteria to highly complex mixtures in mycobacteria. Mycolic acids also vary in the number of carbons on the 2-alkyl-branch from C22–C38 in corynebacteria to C60–C90 in mycobacteria [9]. Mycolic acids play an essential role in the architecture and functions of the cell envelope, where attached to the cell wall arabinogalactan they help to form a barrier that contributes to impermeability and resilience and conveys hydrophobicity to the cell surface. Trehalose mycolates, also termed cord factors, play an important role in pathogenicity in mycobacterial species that cause infection [9]. The presence and carbon chain length of mycolic acids can be used as taxonomic markers for the identification and classification of actinobacteria to the order
Members of order
Genus | Micro-morphology | Acid-fastness | Aerial hyphae | Visible colonies (days) | Strictly aerobic |
---|---|---|---|---|---|
Pleomorphic rods, often club-shaped in palisade or angular arrangements | Some weakly acid-fast | Absent | 1–2 | No | |
Short rods and cocci | No | Absent | 1–3 | Yes | |
Rods, cocci and/or moderately branching hyphae | Partially acid-alcohol fast | Absent | 1–3 | Yes | |
Cocci occur singly, in pairs, tetrads or in groups | Slightly acid–alcohol-fast | Absent | 2 | Yes | |
Pleomorphic bacilli and cocci | Partially acid-fast | Absent | 5–7 | No | |
Short rods | Acid-alcohol fast | Absent | 1–3 | Yes | |
Rods, occasionally branched filaments that fragment to rods and cocci | Strongly acid-fast | Rare | 2–40 | Yes | |
Mycelia that fragment into rods and cocci | Partially acid-fast | Present | 1–5 | Yes | |
Rods to extensive substrate mycelia that fragment to irregular rods and cocci | Partially acid-fast | Absent | 1–3 | Yes | |
Rods | Acid-alcohol fast | Absent | 3–4 | Yes | |
Acute angled branched mycelia | No | Only visible under the microscope | 10–21 | No | |
Coccoid | ND | Absent | 7–14 | Yes | |
Irregular rods | ND | Absent | ND | Yes | |
Single rods or in pairs or masses, sometimes rudimentary filaments and coccobacillary forms | Partially alcohol-acid fast | Absent | 1–3 | Yes | |
Thin rods or cocci in pairs or clusters | ND | Present | 1–4 | Yes |
General phenotypic features of mycolate genera classified in the order
ND, not determined.
Adapted from [2].
The appearance of (a)
Chemotaxonomy is the study of the distribution of various cell wall components to classify and identify strains and is particularly useful to differentiate between the various mycolic acid-containing genera. Cell wall markers typically used to differentiate between MACA genera are summarised in Table 2. Some of the methods used to analyse these chemotaxonomic markers provide quantitative or semi-quantitative data, as in the case of fatty acids, whereas other techniques provide only qualitative data as in the case of muramic acid type and phospholipid pattern.
Genus | Mycolic acids (chain length) | Fatty acids* | Phospholipid type | Major menaquinone(s) | Muramic acid type | gDNA G + C (mol%) |
---|---|---|---|---|---|---|
22–38 | S,U | I | MK-8(H2) | Acetylated | 51–67 | |
34–38 | S,U,T | II | MK-8(H2) | Acetylated | 65.5–73 | |
46–66 | S,U,T | II | MK-9(H2) | Glycolated | 63–69 | |
30–38 | II | MK-8 | Acetylated | 49.3–61.8 | ||
α+-mycolate | S,U | I | MK-9 | Acetylated | 58.6 | |
44–52 | S,U, T | II | MK-8(H2) | Glycolated | 64.7 | |
60–90 | S,U,T | II | MK-9(H2) | Glycolated | 57–73 | |
48–60 | S,U,T | II | MK-8(H4, Ѡ-cycl) | Glycolated | 63–72 | |
30–54 | S,U,T | II | MK-8(H2) | Glycolated | 63–73 | |
α+-mycolate | T | 68–72 | ||||
58–64 | S,U,T | II | MK-8(H4, Ѡ-cycl) | Glycolated | 67.5 | |
43–49 | S,U | II | SQA-8(H4, Ѡ-cycl) SQB(H4, dicycl) | Glycolated | 63.7 | |
42–52 | S,U | II | MK-9(H2) | Glycolated | 67.5–71.6 | |
64–78 | S,U,T | II | MK-9 | Glycolated | 67–78 | |
50–56 | S,U,T | II | MK-9(H2) | Glycolated | 64–65 |
Chemotaxonomic features of mycolate genera classified in the order
S, straight-chain saturated fatty acids; U, straight-chain unsaturated fatty acids; T, tuberculostearic acid.
Adapted from [2].
Reliable identification of MACA strains to species level depends upon phylogenetic analysis of the gene encoding 16S rRNA and DNA:DNA homology determination provides definitive delineation of species with 70% homology and above signifying membership of same species [11]. Increasingly, whole-genome sequencing (WGS) is becoming a standard technique and comparative genomic analysis is providing useful insights to the relatedness and divergence of MACA species [11]. Protein sequences from
In addition to
Types and key structural features of various biosurfactants produced by MACA. (Adapted from [
MACA are widely distributed in the environment including natural habitats such as mangroves, soil, freshwater, and deep ocean sediments as well as man-made sites such as activated sludge foams, biofilters, industrial wastewater and indoor building materials. Although predominantly saprophytic, many species are opportunistic pathogens forming parasitic associations with plants and animals, including humans, notably immunocompromised individuals. Several members of the genus
MACA capable of producing various biosurfactants have been isolated from environments (Table 3) including oil-contaminated soils [24, 25], water from oil wells [26], wastewater from the rubber industry [21], activated sludge, and effluent and sediment from pesticide manufacturing facilities [23]. The ability of MACA to produce biosurfactants in these habitats appears to be driven by the environmental conditions to which they are exposed whereby the biosurfactants act as mediators for the biodegradation of hydrophobic carbon substrates. Genes involved in biosynthesis of rhamnolipids by
MACA species | Source of isolation | Biosurfactant type | References |
---|---|---|---|
Deep-sea hydrothermal field | Di-rhamnolipid (DRL) | [15] | |
Water and sediments collected from oil-polluted seasonal ponds | Methylated ester | [16] | |
Oil contaminated seawater | Rhamnolipid | [17] | |
Activated sludge foam | THL | [18] | |
HS-11 | Oil contaminated soil | Glycolipid | [19] |
Agricultural soil | Glycolipid | [20] | |
Water polluted by rejections of 2-mercaptobenzothiazole and its derivatives used in the rubber industry | Fatty acid methyl esters | [21] | |
Fell field soil | Rhamnose-containing glycolipid | [22] | |
Effluent-sediment collected from a pesticide manufacturing facility | THLs | [23] |
Various environmental sources of biosurfactant-producing MACA.
Isolation of biosurfactant producers largely relies on selective isolation strategies, utilising hydrophobic compounds as sole carbon sources for energy and growth. Typically, strains are isolated and cultivated using mineral salt medium containing essential trace elements supplemented with a hydrocarbon substrate such as crude oil, diesel, n-alkanes, n-hexadecane, paraffin, polyaromatic hydrocarbons (PAHs), or vegetable oils such as olive oil and rapeseed oil, as the sole carbon source. These may be incorporated into the liquid or solid medium, spread across the agar surface or soaked onto a filter in the lid of petri dishes. Besides the selectivity of the culture medium, pre-enrichment techniques utilising hydrophobic compounds as the sole carbon source, can be used [27]. The principle of enrichment is to provide growth conditions that are favourable for the organisms of interest but not for competing organisms. This selective advantage allows target populations to expand through a series of passages, maximising the chances of successful recovery at the isolation stage. Incorporating antibiotics into the isolation media may provide a useful additional selective pressure to eliminate or reduce unwanted fungi and bacteria.
The ability of an organism to grow on hydrophobic compounds is a good indicator of biosurfactant production but is not a guarantee. It is therefore important that isolates of interest are tested in pure culture for biosurfactant production using further screening assays. It is also possible that biosurfactant-producing organisms may be present in an environment but not enriched by in the conditions provided or indeed producers may be recovered from the environment but not synthesize biosurfactants under the culture conditions imposed. Mining genomes for cryptic biosurfactant biosynthesis pathways, and metagenomic screening of DNA from environmental samples promise an alternative approach to biosurfactant discovery that may circumvent some of the issues associated with culture-dependent strategies [28].
A variety of methods, both qualitative and quantitative, have been applied to screen microbial cultures and cell-free media for total (intracellular, surface-bound, and freely released) and freely released biosurfactants, respectively. As biosurfactants are structurally diverse, complex molecules, most of these methods are indirect, reliant on physico-chemical properties such as emulsification, surface activity or hydrophobicity. Commonly reported screening methods used to detect biosurfactant production amongst MACA strains are listed in Table 4. Besides the bacterial adhesion to hydrocarbons (BATH) assay [37] other tests based on cell surface hydrophobicity include salt aggregation [38] and hydrocarbon overlay [39] assays. The atomized oil assay [40] may be used to directly screen colonies growing on primary isolation plates and is therefore useful as an initial screen for novel-producing strains recovered from the environment. The microplate assay [41] which relies on the wetting properties of biosurfactants and the penetration assay [42], which relies on the reduction of interfacial tension are also considered useful for screening large numbers of strains. Recently, a rapid, high throughput assay that utilises Victoria pure blue BO dye, and is based on surface-active properties, has been developed for quantitative screening, but has not yet been applied to MACA [43].
Detection property | Screening method | MACA species | Reference |
---|---|---|---|
Surface activity | Oil spreading | [29] | |
[30] | |||
[31] | |||
Drop collapse/ modified drop collapse | [20] | ||
[29] | |||
Surface and interfacial tension measurement | [14, 26, 29] | ||
[20, 30, 32] | |||
[18] | |||
[31, 33] | |||
[17] | |||
Emulsification | Emulsification assay | [34] | |
Emulsification index | [14, 22, 35] | ||
[30, 32] | |||
[18] | |||
[31, 33] | |||
[17] | |||
Cell-surface hydrophobicity | Microbial adhesion to hydrocarbons (MATH)/BATH assay | [22] | |
[36] | |||
[33] | |||
[17] |
Examples of screening methods used to detect biosurfactant production by MACA.
These assays are simpler and more rapid than chemical analytical procedures, and most enable larger-scale screening for biosurfactant production. However, perhaps owing to the general and indirect nature of these assays and various limitations associated with some, test results between assays are not always congruent and no one assay is considered definitive for biosurfactant production. It is thus advisable to use several methods in combination, adopting simple methods to undertake preliminary screening of large strains collections prior to further investigation of those found to be most promising. The development of high-throughput screening, metabolic profiling technologies, and whole-genome analysis promise a more thorough investigation of potential biosurfactant producing strain in the future [28].
Crude biosurfactant extracts may be obtained from cell cultures (cell-associated and free surfactants) or cell-free broth (free surfactant only) by acidification and solidification followed by solvent extraction of the precipitate. In the case of MACA commonly used solvents include MTBE, dichloromethane, or varying ratios of chloroform–methanol or MTBE–chloroform [44]. Various analytical techniques are used in combination to detect, quantify, and characterise biosurfactants. Thin layer chromatography (TLC) is a straightforward method to separate biosurfactant fractions present in crude extracts. Samples are spotted at the base of a silica plate before development in a solvent system, then air-dried and sprayed with a particular reagent to detect certain chemical groups based on spot colour and/or
High-performance liquid chromatography-mass spectrometry (HPLC-MS) allows more precise and accurate characterisation and quantitation of biosurfactant compounds. Isocratic HPLC-UV has been reported for structural and yield determination of THLs produced by
A combination of Fourier transform infrared spectroscopy (FTIR), NMR, and liquid chromatography-mass spectrometry (LC-MS) enabled structural characterisation of a novel cyclic lipopeptide, Coryxin, produced by
Biosurfactants produced by rhodococci and related MACA have been investigated primarily for their potential application in oil remediation but are otherwise under-studied and under-exploited. However, research studies reveal various potential applications for these molecules, including in environmental and medical fields as summarised in Figure 5.
Promising medical and environmental applications for biosurfactants produced by MACA.
Biosurfactants produced by microorganisms are reported to have various potential biomedical and pharmaceutical applications which have been reviewed widely [1, 51, 52]. This stems from an array of biological properties including anti-adhesion and antibiofilm, anti-inflammatory, antimicrobial (anti-bacterial, anti-fungal and anti-viral), antioxidant, anti-tumour, and wound healing activities. Other potential applications include adjuvants for antigens in vaccines, pulmonary surfactants, drug delivery systems, enhanced vehicles for gene therapy and in dermatological care. Biosurfactants also have several applications in therapeutic dentistry [53]. Daptomycin, a cyclic lipopeptide produced by the actinobacterium
Strain (origin) | Biosurfactant | Biomedical properties | Reference |
---|---|---|---|
Purified Coryxin (lipopeptide) | Antibacterial activity, biofilm inhibition and disruption of pre-formed biofilms of Gram-positive | [48] | |
Aliphatic macrolide (Brasilinolide) | Moderately antifungal against | [56] | |
THL | Anti-tumour activity: cytotoxic effects on human tumour cell lines BV-173 and SKW-3, and to a lesser extent, HL-60. Mediated cell death by the induction of partial apoptotic DNA laddering | [57] | |
Complex of amino lipids; neutral lipids (mycolic and | Anti-adhesive activity against Gram-negative bacteria | [58] | |
Purified STL-1 | [59, 60] | ||
Complex of trehalose mono- and di-mycolates; neutral lipids (cetyl alcohol, palmitic acid, methyl ether of | Antibacterial activity against Gram-positive bacteria | [58] | |
Anti-adhesive activity against Gram-negative bacteria and fungus | |||
THL | Antibacterial activity against | [61] | |
Extracellular complex of glycolipids (crude extracts and purified fractions) | Antiviral activity against HSV-1 and human coronavirus HCoV-OC43. Antiproliferation activity against human prostatic carcinoma cell line PC3 | [62] | |
Crude trehalolipids | Anti-adhesive activity against exponentially growing Gram-positive bacteria | [63] | |
Mixture of TDM, diacyltrehalose and monoacyltrehalose isolated by column chromatography | [64] | ||
[65] | |||
Glycolipid | [66] | ||
Monoacyltrehalose fraction (MAT) | [67] | ||
Analogues of STL-3 | Inhibited growth and induced the differentiation of human HL-60 promyelocytic leukaemia cell line | [66] | |
Purified oligosaccharide lipids | Antimicrobial activity against Gram-positive bacterial strain of | [67] |
Biomedical research on biosurfactants produced by MACA.
The amphipathic nature of biosurfactants makes them suitable for anti-adhesion and anti-biofilm applications such as the development of anti-adhesive coatings for intra-urinary devices that are prone to the formation of intractable biofilms, to prevent or delay the onset of biofilm growth by pathogens such as
Glycolipid bearing mycolic acids, such as trehalose dimycolate (TDM) have attracted extensive investigation as they play a central role in pathogenesis during infection by intracellular pathogens such as
Although biologics including surfactants are generally regarded as less toxic than synthesized pharmaceuticals not much work has focussed on this with respect to MACA surfactants. However, a THL from
Biosurfactants have a range of promising, and increasingly important, applications in the environmental, industrial, and agricultural sectors (Table 6). These include bioremediation of both organic pollutants (especially hydrocarbons) and metals, microbial enhanced oil recovery (MEOR), cleaning and maintenance of tanks and pipelines in the petroleum industry, wastewater treatment, and agricultural applications such as promotion of plant growth/health and inhibition of phytopathogenic fungi [1, 78]. MACA-derived surfactants have been investigated in some of these contexts, although the focus is on well-known species such as
Application | Examples of MACAs | Reference/s |
---|---|---|
Bioremediation: enhanced hydrocarbon solubility and degradation | [15] [33] [34] [32] [17] [29] [23] | |
Bioremediation: soil washing | [30] [71] | |
MEOR | [72] [73] [74] [24] | |
Bio-demulsification: treatment of water-oil emulsions generated during processing of petroleum | [75] | |
Paraffin control in oil transport pipelines | [76] | |
Bioflocculation (e.g., for oil recovery from wastewater) | [77] |
Various potential environmental applications of biosurfactants produced by MACA.
Pollution of soils with organic and inorganic chemical compounds is a major environmental issue. Biosurfactants are used to improve the solubility of hydrocarbon organic compounds, either to make them available for subsequent biodegradation or to facilitate removal by soil washing. A remediation agent called JE1058BS containing biosurfactant from
The properties and actions of biosurfactants make them particularly relevant to the petroleum industry. MEOR is perhaps the most well-known application in this area. Biosurfactants, or biosurfactant-producing microorganisms, are used to extract some of the oil remaining in reservoirs after primary and secondary processing has been carried out. Mechanisms include reduction of capillary forces holding the oil in porous rock, stabilisation of desorbed oil in water and increased viscosity of oil for easier removal [83].
Biosurfactants may also be used to de-emulsify water–oil emulsions that form during oil production in the oilfields, as well as during transportation, and processing and offer a more ecologically friendly solution than chemically synthesized de-emulsifiers. A lipopeptide bio-demulsifier produced by
Biosurfactants have been shown to reduce phytotoxicity of heavy metals, and pre-treatment of seeds could allow plants to be grown successfully in contaminated soil, facilitating phytoremediation of the environment. Crude biosurfactant from
The use of biosurfactants in environmental and industrial applications is limited by the current high costs of production, and the large amounts of biosurfactant required. However, using waste and/or renewable substrates would be cheaper, and a highly purified product is not essential so costs of downstream processing can also be reduced. In addition, different approaches such as selective stimulation of biosurfactant producers
Currently, commercial production of biosurfactants is not economically competitive with chemical surfactant production as there are various challenges to overcome. Bioprocesses presently achieve low biosurfactant productivity and yield and substrates are expensive [6]. Foam formation can cause serious operational issues and downstream biosurfactant recovery can be technically involved and costly. Development work to optimise bioprocesses should focus on enhancing biosurfactant yield and potency. Approaches include the search and discovery of novel biosurfactant-producing organisms and strain improvement by various genetic engineering methods and/or stress-fermentation including co-cultivation [84]. Yield can also be enhanced through the optimisation of culture conditions and costs reduced through the introduction of renewable or waste products [6, 28, 77] as cheaper feed stocks. The effects of biosurfactants on human health and the environment also require further assessment to ensure safe production and use.
Biosurfactants offer an attractive proposition for biotechnological application across various sectors and are considered superior to synthetic surfactants. Diverse MACA produce biosurfactants with interesting properties that have been explored in the context of biomedicine and environmental remediation. However, many MACA have not yet been investigated for biosurfactant production and various potential applications are yet to receive significant research. Rapid, reliable methods for high throughput screening for biosurfactant production are essential as are robust standard methods for biosurfactant purification and characterisation. Efforts to evaluate and expand the knowledge of structural characteristics and gene regulation of biosurfactants are warranted to improve their effectiveness and productivity. Commercial-scale production will need to employ various existing and new strategies to become economic and sustainable. Cutting-edge technologies such high-throughput omics-based tools should accelerate the development of commercial production of biosurfactants. Furthering our understanding of biosurfactants produced by MACA will facilitate their commercial exploitation thereby contributing to a sustainable bio-based economy.
The authors declare that there is no conflict of interest.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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This chapter aims to highlight the multiformity of granulomatous diseases, characterize the pathologic features of different infectious and noninfectious granulomatosis, and delineate the diagnostic approach.",book:{id:"7168",slug:"sarcoidosis-and-granulomatosis-diagnosis-and-management",title:"Sarcoidosis and Granulomatosis",fullTitle:"Sarcoidosis and Granulomatosis - Diagnosis and Management"},signatures:"Maria V. Samsonova and Andrey L. 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This chapter looks with key interest in the existing and evolving role of NSAIDs in therapeutics with emphasis on the current insights into their mechanism of action and side effect profiles associated with its use in pain and inflammation as well as its potential therapeutic benefits in cancer chemotherapy.",book:{id:"5872",slug:"nonsteroidal-anti-inflammatory-drugs",title:"Nonsteroidal Anti-Inflammatory Drugs",fullTitle:"Nonsteroidal Anti-Inflammatory Drugs"},signatures:"Newman Osafo, Christian Agyare, David Darko Obiri and Aaron\nOpoku Antwi",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"196452",title:"Dr.",name:"Newman",middleName:null,surname:"Osafo",slug:"newman-osafo",fullName:"Newman Osafo"},{id:"197415",title:"Prof.",name:"David",middleName:null,surname:"Darko Obiri",slug:"david-darko-obiri",fullName:"David Darko Obiri"},{id:"197428",title:"Mr.",name:"Aaron",middleName:null,surname:"Antwi",slug:"aaron-antwi",fullName:"Aaron Antwi"}]},{id:"31773",title:"Enzymatic and Chemical Modifications of Food Allergens",slug:"enzymatic-and-chemical-modifications-of-food-allergens",totalDownloads:3783,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"934",slug:"allergic-diseases-highlights-in-the-clinic-mechanisms-and-treatment",title:"Allergic Diseases",fullTitle:"Allergic Diseases - Highlights in the Clinic, Mechanisms and Treatment"},signatures:"Dragana Stanić-Vučinić and Tanja Ćirković Veličković",authors:[{id:"69834",title:"Dr.",name:"Dragana",middleName:null,surname:"Stanic-Vucinic",slug:"dragana-stanic-vucinic",fullName:"Dragana Stanic-Vucinic"},{id:"69858",title:"Prof.",name:"Tanja",middleName:null,surname:"Cirkovic Velickovic",slug:"tanja-cirkovic-velickovic",fullName:"Tanja Cirkovic Velickovic"}]},{id:"49960",title:"Asthma-COPD Overlap Syndrome (ACOS): Current Understanding and Future Perspectives",slug:"asthma-copd-overlap-syndrome-acos-current-understanding-and-future-perspectives",totalDownloads:2284,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"This chapter resumes our current understanding of asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), pretending to offer a comprehensive approach for the practicing physician, and provides some future perspectives on this entity.",book:{id:"5126",slug:"asthma-from-childhood-asthma-to-acos-phenotypes",title:"Asthma",fullTitle:"Asthma - From Childhood Asthma to ACOS Phenotypes"},signatures:"Irina Bobolea and Luis Alejandro Pérez de Llano",authors:[{id:"178233",title:"Dr.",name:"Irina",middleName:null,surname:"Bobolea",slug:"irina-bobolea",fullName:"Irina Bobolea"},{id:"178739",title:"Dr.",name:"Luis Alejandro",middleName:null,surname:"Pérez De Llano",slug:"luis-alejandro-perez-de-llano",fullName:"Luis Alejandro Pérez De Llano"}]},{id:"54761",title:"Adverse Effects and Drug Interactions of the Non‐Steroidal Anti‐Inflammatory Drugs",slug:"adverse-effects-and-drug-interactions-of-the-non-steroidal-anti-inflammatory-drugs",totalDownloads:3020,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The aim of this chapter is to increase the awareness of health‐care professionals concerning potential adverse effects and drug interactions of non‐steroidal anti‐inflammatory drugs (NSAIDs), which are among the most widely prescribed medicines, globally. They have a variety of clinical applications due to their anti‐inflammatory, analgesic, antipyretic, or antithrombotic effect, but these drugs are not entirely innocuous, since they could increase the risk of gastrointestinal and cardiovascular complications. Furthermore, the drugs from this class have the potential of altering the pharmacokinetics of associated drugs, and also pharmacodynamic interactions have been reported. The clinical significance, mechanisms, and epidemiology of the adverse effects and drug interactions of NSAIDs are presented in this chapter. Prevention strategies for particularly high‐risk groups of patients are also exposed. Detailed and up‐to‐date information regarding the adverse effects and drug interactions of NSAIDs are needed for all healthcare professionals in order to maximize efficacy in treating various illnesses while minimizing the risks for the patients.",book:{id:"5872",slug:"nonsteroidal-anti-inflammatory-drugs",title:"Nonsteroidal Anti-Inflammatory Drugs",fullTitle:"Nonsteroidal Anti-Inflammatory Drugs"},signatures:"Oliviu Vostinaru",authors:[{id:"198574",title:"Dr.",name:"Oliviu",middleName:null,surname:"Vostinaru",slug:"oliviu-vostinaru",fullName:"Oliviu Vostinaru"}]}],onlineFirstChaptersFilter:{topicId:"1035",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,annualVolume:11413,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,annualVolume:11414,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:2,paginationItems:[{id:"82297",title:"The Climate Change-Agriculture Nexus in Drylands of Ethiopia",doi:"10.5772/intechopen.103905",signatures:"Zenebe Mekonnen",slug:"the-climate-change-agriculture-nexus-in-drylands-of-ethiopia",totalDownloads:18,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Vegetation Dynamics, Changing Ecosystems and Human Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11663.jpg",subseries:{id:"40",title:"Ecosystems and Biodiversity"}}},{id:"81999",title:"Climate Change, Rural Livelihoods, and Human Well-Being: Experiences from Kenya",doi:"10.5772/intechopen.104965",signatures:"André J. Pelser and Rujeko Samanthia Chimukuche",slug:"climate-change-rural-livelihoods-and-human-well-being-experiences-from-kenya",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Vegetation Dynamics, Changing Ecosystems and Human Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11663.jpg",subseries:{id:"40",title:"Ecosystems and Biodiversity"}}}]},overviewPagePublishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"10843",title:"Persistent Organic Pollutants (POPs)",subtitle:"Monitoring, Impact and Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10843.jpg",slug:"persistent-organic-pollutants-pops-monitoring-impact-and-treatment",publishedDate:"April 13th 2022",editedByType:"Edited by",bookSignature:"Mohamed Nageeb Rashed",hash:"f5b1589f0a990b6114fef2dadc735dd9",volumeInSeries:1,fullTitle:"Persistent Organic Pollutants (POPs) - Monitoring, Impact and Treatment",editors:[{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",biography:"Prof. Mohamed Nageeb Rashed is Professor of Analytical and Environmental Chemistry and former vice-dean for environmental affairs, Faculty of Science, Aswan University, Egypt. He received his Ph.D. in Environmental Analytical Chemistry from Assiut University, Egypt, in 1989. His research interest is in analytical and environmental chemistry with special emphasis on: (1) monitoring and assessing biological trace elements and toxic metals in human blood, urine, water, crops, vegetables, and medicinal plants; (2) relationships between environmental heavy metals and human diseases; (3) uses of biological indicators for monitoring water pollution; (4) environmental chemistry of lakes, rivers, and well water; (5) water and wastewater treatment by adsorption and photocatalysis techniques; (6) soil and water pollution monitoring, control, and treatment; and (7) advanced oxidation treatment. Prof. Rashed has supervised several MSc and Ph.D. theses in the field of analytical and environmental chemistry. He served as an examiner for several Ph.D. theses in analytical chemistry in India, Kazakhstan, and Botswana. He has published about ninety scientific papers in peer-reviewed international journals and several papers in national and international conferences. He participated as an invited speaker at thirty international conferences. Prof. Rashed is the editor-in-chief and an editorial board member for several international journals in the fields of chemistry and environment. He is a member of several national and international societies. He received the Egyptian State Award for Environmental Research in 2001 and the Aswan University Merit Award for Basic Science in 2020. 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In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"8",type:"subseries",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11404,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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