P2X7, connexins and pannexins antagonists blocked the permeability to anionic and cationic dyes.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"8043",leadTitle:null,fullTitle:"Monoclonal Antibodies",title:"Monoclonal Antibodies",subtitle:null,reviewType:"peer-reviewed",abstract:"Immune-based therapies are being studied extensively in a variety of immunological conditions due to their high precision and sensitivity. Monoclonal antibody (mAb) technology is a major advancement in the treatment of several infectious diseases, malignancies, and immunological disorders. This book provides comprehensive information about technologies, characterization, and application of mAbs in the clinic and laboratory.",isbn:"978-1-83968-370-1",printIsbn:"978-1-83968-369-5",pdfIsbn:"978-1-83968-371-8",doi:"10.5772/intechopen.77874",price:119,priceEur:129,priceUsd:155,slug:"monoclonal-antibodies",numberOfPages:170,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"91da3371c910d66deb7b8c434948b834",bookSignature:"Nima Rezaei",publishedDate:"June 23rd 2021",coverURL:"https://cdn.intechopen.com/books/images_new/8043.jpg",numberOfDownloads:3817,numberOfWosCitations:2,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:10,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 8th 2020",dateEndSecondStepPublish:"July 29th 2020",dateEndThirdStepPublish:"September 27th 2020",dateEndFourthStepPublish:"December 16th 2020",dateEndFifthStepPublish:"February 14th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"116250",title:"Dr.",name:"Nima",middleName:null,surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei",profilePictureURL:"https://mts.intechopen.com/storage/users/116250/images/system/116250.jpg",biography:"Professor Nima Rezaei obtained an MD from Tehran University of Medical Sciences, Iran. He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"7",institution:{name:"Tehran University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"147",title:"Applied Immunology",slug:"applied-immunology"}],chapters:[{id:"77035",title:"Introduction on Monoclonal Antibodies",doi:"10.5772/intechopen.98378",slug:"introduction-on-monoclonal-antibodies",totalDownloads:792,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Monoclonal antibodies (mAbs) are a group of antibodies produced by identical clones of B lymphocytes against a particular antigen. mAbs are identical in several properties such as protein sequence, antigen-binding site region, binding affinity for their targets, and identical downstream functional effects. These characteristics of mAbs highlight their differences with the polyclonal antibodies which have heterogenous activities and recognize different epitopes on an antigen. Murine mAbs was the first generation of mAbs developed by hybridoma technology however, because of their murine origin, they can trigger the anti-mouse antibody response in the host which could accelerate mAb clearance and undesirable allergic reactions upon repeated administration. This issue was resolved by developing engineering methods toward producing less immunologic chimeric or humanized antibodies. mAbs applications have become a novel way of targeting antigens in a wide variety of diseases such as autoimmunity, malignancies, and asthma. In addition, high specificity and high affinity binding properties of mAbs make them effective biological reagents in immunodiagnostic assays. They can be used in diagnosis of infectious diseases and detection of certain antigens or in serological assessments for detection of antibodies against a certain antigen. This chapter summarizes the general properties of mAbs, their production processes, and their important diagnostic and therapeutic applications.",signatures:"Mona Sadeghalvad and Nima Rezaei",downloadPdfUrl:"/chapter/pdf-download/77035",previewPdfUrl:"/chapter/pdf-preview/77035",authors:[{id:"116250",title:"Dr.",name:"Nima",surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei"},{id:"353771",title:null,name:"Mona",surname:"Sadeghalvad",slug:"mona-sadeghalvad",fullName:"Mona Sadeghalvad"}],corrections:null},{id:"74640",title:"Alternative Methods to Animal Use for Monoclonal Antibody Generation and Production",doi:"10.5772/intechopen.95485",slug:"alternative-methods-to-animal-use-for-monoclonal-antibody-generation-and-production",totalDownloads:645,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Monoclonal antibody (mAb) has broad applicability in research, diagnosis, and treatment. After the introduction of hybridoma technology in 1975, the mAb market has increased dramatically, moving a large industry of more than US$ 140 billions in 2020. In 1954, the concept of the 3R’s was proposed and much changed the animal use scenario, including the recent ban on inducing ascites in mice for the production of mAb. In light of this, the generation and production of antibodies had to be reassessed. In this chapter, we present an overview of the main alternative technologies to the use of animals in the generation and production of mAb. Antibody display libraries and in silico modeling are very promising technologies that may provide mAb genetic constructs that, in the sequence, may be expressed on mammalian, bacterial, yeast or plant systems. Although the total replacement of the use of animals in the entire process is not currently feasible, it is possible to find ways to reduce and refine the use of animals in obtaining and producing mAb.",signatures:"Jane Zveiter de Moraes, Barbara Hamaguchi, Camila Braggion, Enzo Speciale, Fernanda Cesar, Gabriela Soares, Juliana Osaki, Rodrigo Aguiar and Tauane Pereira",downloadPdfUrl:"/chapter/pdf-download/74640",previewPdfUrl:"/chapter/pdf-preview/74640",authors:[{id:"327477",title:"Dr.",name:"Jane",surname:"Moraes",slug:"jane-moraes",fullName:"Jane Moraes"},{id:"327479",title:"M.Sc.",name:"Barbara",surname:"Hamaguchi",slug:"barbara-hamaguchi",fullName:"Barbara Hamaguchi"},{id:"327480",title:"M.Sc.",name:"Camila",surname:"Braggion",slug:"camila-braggion",fullName:"Camila Braggion"},{id:"327482",title:"BSc.",name:"Enzo",surname:"Speciale",slug:"enzo-speciale",fullName:"Enzo Speciale"},{id:"327483",title:"Ms.",name:"Fernanda",surname:"Cesar",slug:"fernanda-cesar",fullName:"Fernanda Cesar"},{id:"327484",title:"MSc.",name:"Gabriela",surname:"Soares",slug:"gabriela-soares",fullName:"Gabriela Soares"},{id:"327485",title:"Dr.",name:"Juliana",surname:"Osaki",slug:"juliana-osaki",fullName:"Juliana Osaki"},{id:"327486",title:"Dr.",name:"Rodrigo",surname:"Aguiar",slug:"rodrigo-aguiar",fullName:"Rodrigo Aguiar"},{id:"327487",title:"BSc.",name:"Tauane",surname:"Pereira",slug:"tauane-pereira",fullName:"Tauane Pereira"}],corrections:null},{id:"74906",title:"Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance",doi:"10.5772/intechopen.95235",slug:"monospecific-and-polyreactive-monoclonal-antibodies-against-human-leukocyte-antigen-e-diagnostic-and",totalDownloads:266,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"A monoclonal antibody (mAb) binds to an antigen recognizing an epitope (a sequence of amino acids). A protein antigen may carry amino acid sequence unique to that antigen as well as sequences found in other proteins. Human leukocyte antigens (HLA), a family of proteins expressed by the Major Histocompatibility Complex gene family represent a special case, in that it displays a high degree of polymorphism. Every HLA molecule possesses both specific (private) epitopes and epitopes shared (public) with other HLA class Ia and class Ib molecules. HLA-E is overexpressed in cancer cells more than any other HLA Class I molecules. Therefore specific localization of HLA-E with mAbs is pivotal for developing targeted therapy against cancer. However, the commercially available mAbs for immunodiagnosis are polyreactive. We have developed anti-HLA-E mAbs and distinguished monospecific from polyreactive mAbs using Luminex multiplex single antigen bead (SAB) assay. HLA-E-binding of monospecific-mAbs was also inhibited by E-restricted epitopes. The amino acid sequences in the region of the epitopes bind to CD94/NKG2A receptors on CD8+ T cells and NK cells and block their antitumor functions. Monospecific-HLA-E mAbs recognizing the epitopes sequences can interfere with the binding to restore the anti-tumor efficacy of NK cells. Also, monospecific-mAbs augment the proliferation of CD4-/CD+ cytotoxic T-lymphocytes. Therefore, anti-HLA-E monospecific-mAb can serve as a double-edged sword for eliminating tumor cells.",signatures:"Mepur H. Ravindranath and Fatiha E.L. Hilali",downloadPdfUrl:"/chapter/pdf-download/74906",previewPdfUrl:"/chapter/pdf-preview/74906",authors:[{id:"327872",title:"Dr.",name:"Mepur",surname:"Ravindranath",slug:"mepur-ravindranath",fullName:"Mepur Ravindranath"},{id:"327875",title:"Dr.",name:"Fatiha",surname:"E.L. Hilali",slug:"fatiha-e.l.-hilali",fullName:"Fatiha E.L. Hilali"}],corrections:null},{id:"74660",title:"Analytical Characterization of Monoclonal Antibodies with Novel Fc Receptor-Based Chromatography Technique",doi:"10.5772/intechopen.95356",slug:"analytical-characterization-of-monoclonal-antibodies-with-novel-fc-receptor-based-chromatography-tec",totalDownloads:717,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Most clinically approved large biotherapeutics are monoclonal antibodies (mAbs), primarily belonging to immunoglobulin G subclass-1 (IgG1) and, to a lesser extent, IgG2 and IgG4. Glycosylation is the main source of post-translational heterogeneity of mAbs, impacting their drug therapeutic mechanism of action (MOA). Glycosylation is also one of the critical factors in drug product solubility, kinetics, stability and efficacy. Thus, monitoring glycan critical quality attributes (CQAs) is an essential part of any biopharmaceutical development. The binding affinity of an IgG to its cellular Fc receptor (FcR) depends on both its IgG subclass and Fc domain glycosylation pattern. Since composition of the N-glycans also correlates to the Antibody-Dependent Cellular Cytotoxicity (ADCC), the glycosylation pattern needs to be monitored for consistency in potency and efficacy. This applies for the original mAb biologics as well as biosimilars. In this chapter, we present a truly novel way to assess the variances in mAb glycoforms using FcγRIIIa-based affinity chromatography. First, a brief overview of the Fc receptor function is presented. Then, the principle of FcR-based affinity chromatography is explained including how this column’s potential to analyze a variety of mAbs according to their N-glycan content is highly selective and robust. Finally, we provide examples of the FcR column’s potential to improve analytical characterization of mAbs with practical applications such as effective cell line screening, monitoring of glycoengineering, process development and process control in manufacturing.",signatures:"Atis Chakrabarti, Jukka Kervinen, Egbert Müller, Toru Tanaka and Kazuaki Muranaka",downloadPdfUrl:"/chapter/pdf-download/74660",previewPdfUrl:"/chapter/pdf-preview/74660",authors:[{id:"199389",title:"Ph.D.",name:"Atis",surname:"Chakrabarti",slug:"atis-chakrabarti",fullName:"Atis Chakrabarti"},{id:"337524",title:"Dr.",name:"Jukka",surname:"Kervinen",slug:"jukka-kervinen",fullName:"Jukka Kervinen"},{id:"337525",title:"Dr.",name:"Egbert",surname:"Müller",slug:"egbert-muller",fullName:"Egbert Müller"},{id:"337526",title:"Mr.",name:"Toru",surname:"Tanaka",slug:"toru-tanaka",fullName:"Toru Tanaka"},{id:"337528",title:"Mr.",name:"Kazuaki",surname:"Muranaka",slug:"kazuaki-muranaka",fullName:"Kazuaki Muranaka"}],corrections:null},{id:"73768",title:"In silico Techniques for Prospecting and Characterizing Monoclonal Antibodies",doi:"10.5772/intechopen.94366",slug:"-em-in-silico-em-techniques-for-prospecting-and-characterizing-monoclonal-antibodies",totalDownloads:776,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"In the past few years, improvement in computational approaches provided faster and less expensive outcomes on the identification, development, and optimization of monoclonal antibodies (mAbs). In silico methods, such as homology modeling, to predict antibody structures, identification of epitope-paratope interactions, and molecular docking are useful to generate 3D structures of the antibody–antigen complexes. It helps identify the key residues involved in the antigen–antibody complex and enable modifications to enhance the antibody binding affinity. Recent advances in computational tools for redesigning antibodies are significant resources to improve antibody biophysical properties, such as binding affinity, solubility, stability, decreasing the timeframe and costs during antibody engineering. The immunobiological market grows continuously with new molecules, both natural and new molecular formats, such as bispecific antibodies, Fc-antibody fusion proteins, and mAb fragments, requiring novel methods for designing, screening, and analyzing. Algorithms and software set the in silico techniques on the innovation frontier.",signatures:"Tania M. Manieri, Carolina G. Magalhaes, Daniela Y. Takata, João V. Batalha-Carvalho and Ana M. Moro",downloadPdfUrl:"/chapter/pdf-download/73768",previewPdfUrl:"/chapter/pdf-preview/73768",authors:[{id:"200873",title:"Dr.",name:"Ana M.",surname:"Moro",slug:"ana-m.-moro",fullName:"Ana M. Moro"},{id:"329088",title:"Dr.",name:"Tania Maria",surname:"Manieri",slug:"tania-maria-manieri",fullName:"Tania Maria Manieri"},{id:"329089",title:"MSc.",name:"Carolina Georg",surname:"Magalhães",slug:"carolina-georg-magalhaes",fullName:"Carolina Georg Magalhães"},{id:"329090",title:"Ph.D. Student",name:"Daniela Y.",surname:"Takata",slug:"daniela-y.-takata",fullName:"Daniela Y. Takata"},{id:"329091",title:"Ph.D. Student",name:"João Victor",surname:"Batalha-Carvalho",slug:"joao-victor-batalha-carvalho",fullName:"João Victor Batalha-Carvalho"}],corrections:null},{id:"75760",title:"Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management - An Update",doi:"10.5772/intechopen.96911",slug:"therapeutic-applications-of-monoclonal-antibodies-in-urologic-oncology-management-an-update",totalDownloads:280,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The idea of utilizing immunotherapy for the treatment of cancers has been appealing to scientists and clinicians for over a several decades. Immunotherapy for cancers encompasses knowledge gained from a wide range of disciplines and has the potential to procure the ‘magic bullet’ for the treatment of cancer. Monoclonal antibody-based treatment of cancer has been recognized as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumours in the last 20 years. The discovery of hybridoma technology in late 1975 and the development of chimeric, humanized, and human antibodies have increased the availability and utility of immunotherapy for the treatment of cancer. Metastatic or recurrent cancer continues to be the bane of the urological oncologist. Despite recent improvements in therapeutic management and outcomes for clinically localized disease overall survival rate in patients with the majority of metastatic and recurrent genitourinary malignancies remains relatively unchanged. By targeting tumours through specific or associated antigens, it is possible to selectively eliminate tumour cells and maintain an acceptable toxicity profile. Therapeutic antibodies that target immune cells are also being developed with the goal of breaking local tolerance and stimulating the patient’s anti-tumor immune response. As with other treatment modalities, immunotherapy is far from perfect and requires additional study to optimize clinical response and overcome therapeutic resistance. Modern advances in the field of immunotherapy hold the promise of providing the clinical urologist/oncologist with new tools to fight urological cancer. However, the literature on monoclonal antibody-based immunotherapy with a particular emphasis on target antigens, monoclonal antibody design and potential applications in the field of urology is limited. Hence, the present chapter focuses on the applications of Immunotherapy using monoclonal antibodies for urologic oncology settings such as prostate, bladder, renal, testicular and penile with a hope to highlight its clinical efficacy and also its mechanisms of action in each of these cancer types.",signatures:"Maya Kulshekar, Shridhar C. Ghagane, Sridevi I. Puranik, Rajendra B. Nerli and Murigendra B. Hiremath",downloadPdfUrl:"/chapter/pdf-download/75760",previewPdfUrl:"/chapter/pdf-preview/75760",authors:[{id:"27304",title:"Dr.",name:"Murigendra B.",surname:"Hiremath",slug:"murigendra-b.-hiremath",fullName:"Murigendra B. Hiremath"},{id:"227286",title:"Dr.",name:"Shridhar C.",surname:"Ghagane",slug:"shridhar-c.-ghagane",fullName:"Shridhar C. Ghagane"},{id:"227446",title:"Prof.",name:"Rajendra B.",surname:"Nerli",slug:"rajendra-b.-nerli",fullName:"Rajendra B. Nerli"},{id:"328243",title:"Mrs.",name:"Maya",surname:"Kulshekar",slug:"maya-kulshekar",fullName:"Maya Kulshekar"},{id:"328244",title:"Dr.",name:"Sridevi I.",surname:"Puranik",slug:"sridevi-i.-puranik",fullName:"Sridevi I. Puranik"}],corrections:null},{id:"73659",title:"Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma",doi:"10.5772/intechopen.94196",slug:"emerging-monoclonal-antibodies-for-the-treatment-of-multiple-myeloma",totalDownloads:341,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Therapeutic measures designed to treat multiple myeloma (MM) have undergone a fundamental shift over the past two decades as a number of small molecules that attack this cancer by different mechanisms, including proteasome blockade, immunomodulation, and histone deacetylase (HDAC) inhibition, have been introduced. The insertion of monoclonal antibodies (mAbs) into the mix began in 2015 with the U.S. Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, which target CD38 and SLAMF7, respectively. In 2020, they were joined by another anti-CD38 mAb, isatuximab, and the bispecific antibody-drug conjugate (ADC) belantamab mafodotin, which targets the B-cell maturation antigen (BCMA). This review focuses on additional mAbs currently under clinical study for MM. These include several BCMAxCD3-directed bispecifics (AMG 420, AMG 701, REGN5458, REGN5459, teclistamab, and TNB-383B), the ADCs indatuximab ravtansine and STRO-001, and checkpoint inhibitors, although the future status of the latter is in a state of flux due to toxicity issues that arose in trials in which these drugs, especially PD-1 or PD-L1 blockers, were combined with immunomodulators.",signatures:"Hanley N. Abramson",downloadPdfUrl:"/chapter/pdf-download/73659",previewPdfUrl:"/chapter/pdf-preview/73659",authors:[{id:"236768",title:"Prof.",name:"Hanley",surname:"Abramson",slug:"hanley-abramson",fullName:"Hanley Abramson"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5975",title:"Physiology and Pathology of Immunology",subtitle:null,isOpenForSubmission:!1,hash:"b31eea21dfa90b753604f34bf1c0b8a5",slug:"physiology-and-pathology-of-immunology",bookSignature:"Nima Rezaei",coverURL:"https://cdn.intechopen.com/books/images_new/5975.jpg",editedByType:"Edited by",editors:[{id:"116250",title:"Dr.",name:"Nima",surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited 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It is estimated that HIE occurs between 1 and 8 per 1000 newborns, although this number can be widely more expressive accordingly to the region, especially in low-income countries [3, 4]. Besides, HIE is considered to be the third major cause of neonatal mortality, accountable for 23% of newborn deaths and averaging about 1 million children annually [5, 6]. In consonance, the morbidity is not far behind: HIE accounts for 10% of all cerebral palsy cases, compromising the quality of life of these patients and their families [7, 8, 9]. In this scenario, understanding the factors and mechanisms involved in HIE etiology is crucial to the development of new therapeutic strategies and improvement of mortality and morbidity rates.
Over the last years, several studies emerged intending to explain the pathophysiology of HIE [10, 11, 12, 13]. The gaps in these topics are highlighted as particular priorities among the many critical areas that remain to be integrated. It is a consensus that the primary event for HIE burden is a global reduction of blood flow to the fetal brain during pregnancy or birth process [13]. This ischemic-hypoxic insult may result from various maternal or fetal conditions such as umbilical cord prolapse, rupture of the uterus and placental insufficiency [1, 14, 15]. One of the most intriguing features of HIE, however, is not even the ischemic injury per se, but the ability of the initial lesion to expand to previously undamaged areas (i.e., secondary lesions) [16]. Much of this process remains undefined and saving perilesional regions at risk, termed penumbra, challenges physicians and scientists. In this context, increasing evidence supports extracellular ATP and purinergic receptors as significant players in HIE pathophysiology and, consequently, a unique addition as interventional targets for the limited repertoire of drugs currently available as therapeutic approaches for HIE [17, 18, 19].
Purinergic receptors are a class of ligand-gated receptors divided into two groups P1 and P2, responsive to nucleosides and nucleotides, respectively. P1 receptors have four members described (A1, A2A, A2B e A3) [20, 21, 22]. On the other hand, P2 receptors are subdivided into two families P2Y and P2X. Both P2Y receptors and the P1 receptors are G coupled protein receptors (GPCRs), and the P2X receptors are ionotropic receptors. Those receptors are expressed in various systems in the organism, as the vascular system, the immune system, the gastrointestinal system, the renal system, and the central nervous system (CNS) [20, 21, 22]. Specifically, in the CNS, it is believed that some purinergic receptors could play essential roles in ischemia decreasing the symptoms and the extent of brain damage [23, 24].
Along with purinergic signaling, there are strong pieces of evidence in the literature correlating spreading depression (SD), a phenomenon characterized by self-sustained waves of depolarization of a sizeable population of cells, and hypoxic-ischemic insults [25, 26]. HIE-mediated SDs erupt in the brain, encumbering tissue structure and function, and raising fascinating—and still unanswered—questions concerning their initiation (i.e., genesis) and propagation. Even more ominously, erupting SDs accelerate tissue damage following HIE or traumatic brain injury (TBI) [27, 28]. Studies by many authors, including our group [29], suggest that lesions act as a site of origin to these waves, which slowly propagate through the brain surface [30]. So far, the role of glia (astrocytes and microglia) in initiation, propagation, and recovery of SD is poorly understood [31, 32]. Although there is evidence that SD has an impact on astrocytes and microglia [31, 32], the consequences of their activation need to be further explored. Considering SD as an electrochemical event, ionic changes in the extracellular medium are important to the genesis and maintenance of propagated SDs. In this regard, recent studies present pannexins and connexins paved the way for sustainable SD propagation [26]. Hence, HIE detains a multifactorial mechanism, compelling not only purinergic signaling but also spreading depression, connexins, pannexins and many other biological processes yet to be defined.
This article intends to review the aspects and empirical evidence made on HIE-mediated brain injury through the functional interaction between purinergic signaling, connexins, pannexins, and SDs. To the best of our knowledge, this is the first review to discuss the functional interplay among purinergic signaling and the above mentioned “players” as key elements to trigger and to either support or to interrupt the propagation of waves of SD within the HIE’s penumbra. Understanding the underlying mechanisms of HIE is expected to develop more effective neuroprotective approaches during the highly prevalent condition of perinatal hypoxic distress.
Since the first description of the physiological effects of purines and pyrimidines, by Drury and Szent-Györgyi in 1929, several pieces of evidence increased the discussion on their activity in the context of the CNS [23, 24, 33, 34, 35]. This novel family of receptors is virtually expressed in all human cells types, including neurons and glial cells at central nervous system, hence raising the several hypotheses on their role in the context of a myriad of neurological disorders, such as, neurodegenerative diseases, traumatic brain injury, CNS tumors, epilepsy, psychiatric disorders, and ischemic encephalopathy [36, 37].
The early 1970s classification of the novel receptor family—then called purinoreceptors—proposed by Geoffrey Burnstock is considered to be one of the first steps to current comprehension and systematic research of purinergic receptors, which stratifies them into two groups, taking in consideration their molecular characteristics and downstream signaling [38].
The adenosine-activated receptors, or P1 receptors, present four subtypes (A1, A2A, A2B, and A3), each of these consisting of seven folds of transmembrane protein domains (TM1-TM7) linked to an N-terminal extracellular domain and a C-terminal intracellular domain. In contrast, P2 receptors are subdivided into two families: metabotropic P2Y receptors and ionotropic P2X receptors. Among several other mammal species, humans present eight members of the metabotropic P2Y, (described as P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), and seven members of the ionotropic P2X receptors, numbered P2X1 to P2X7 [22, 39, 40, 41, 42].
The P1A2A and P1A2B molecules are Gs-protein-coupled receptors, therefore stimulating adenylate cyclase and leading to downstream production of cyclic adenosine 3′,5′-monophosphate (cAMP) second signaling, once they are bound to their active ligand. On the other, hand P1A1 and P1A3 subtypes molecules are Gi protein-coupled receptors, leading to adenylate cyclase inhibition and cAMP degradation. In addition, some of the A2B receptor isoforms may also be associated with Gq domains, leading to a phospholipase C and inositol triphosphate second signaling pathways [42] (Figure 1).
Structural features of Cx43, P2X7 and Panx1. Each functional P2X7 receptor is a trimer, with the three protein subunits arranged around a cation-permeable channel pore. The subunits all share a common topology, possessing two plasma membrane spanning domains (TM1 and TM2), a large extracellular loop with the ATP binding site, and containing 10 similarly spaced cysteines and glycosylation sites, and intracellular carboxyl (C) and amino termini (N). (Left) Connexin 43 (Cx43) and pannexin 1 (Panx1) (right) share similar membrane topology, with four α-helical transmembrane domains (M1–M4) connected by two extracellular loops and one cytoplasmic loop, where both amino NH2 (N) and carboxy COOH-termini (C) are intracellular. However, different from connexins, the pannexins possess an extracellular glycosylation site which impedes gap junction formation by these channels. Upper panel—(left) a Cx hemichannel (HC) and pannexon (right) are formed by connexins and pannexins, respectively, that oligomerize laterally.
Metabotropic P2Y receptors are G protein-coupled receptors activated by different nucleotide types, including ATP, ADP, UTP, UDP, and UDP-glucose. Similarly to P1 receptors, the seven transmembrane domain/ns, three extracellular and three intracellular loops, and C-terminal intracellular and extracellular N-terminal ends are found in their structure. P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors are associated with Gq protein, leading to an increase of the intracellular calcium through the internal stores culminating in a protein kinase C activation, whereas P2Y12, P2Y13, and P2Y14 are coupled to Gi protein, inhibiting adenylate cyclase and cyclic AMP [39]. Concerning the ionotropic P2X receptors, they are non-selective cation channels modulated by ATP [43]. Once activated these receptors act as transmembrane channels, allowing the flow of mono and divalent cations, such as, K+, Ca2+, and Na+ accordingly to their gradient [44, 45]. Although some data in this context is found to be controversial, it is important to mention that some subtypes as P2X2, P2X4, and P2X7 are described to open a non-selective transmembrane pore, if submitted to high concentrations or prolonged exposure to their ligand. In this condition, these receptors allow the passage of molecules up to 900 Da, which includes organic ions and most of the frequently used fluorescent dyes [46, 47, 48] (Table 1). P2X receptors present two transmembrane domains connected by an extracellular loop, besides a C-terminal and an N-terminal domain in the intracellular milieu [56]. They are capable of homotrimeric and heterotrimeric assemble [57, 58] (Figure 1).
Channel | Blockers | Dye | Permeability |
---|---|---|---|
P2X7 | BBG, oATP and AZ11645373 [49] | Iodide propidium (+) | – |
A-438079, AZ11645373 and probenecid [50] | Ethidium bromide (+) and Lucifer yellow (−) | – | |
A-740003, PPADS and BBG [51] | Yo-Pro-1 (+) | – | |
Connexin Hemichannel | Heptanol, octanol, CBX, La3+, FFA and AGA [52] | Lucifer yellow (−) | – |
CBX and Gap26 [53] | Ethidium bromide (+) | – | |
CBX and mefloquine [54] | Iodide propidium (+) | – | |
CBX, FFA, AGA and NFA [55] | Not used | – | |
Pannexin | 10Panx [50, 53] | Ethidium bromide (+) | No change |
P2X7, connexins and pannexins antagonists blocked the permeability to anionic and cationic dyes.
Nomenclature: –, decreased permeability/no permeability. BBG, brilliant blue G; oATP, periodate-oxidized adenosine triphosphate; CBX, carbenoxolone; AGA, 18alpha-glycyrrhetinic acid; FFA, flufenamic acid; PPADS, pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic acid; NFA, niflumic acid. The (+) and (−) indicates valency of the dye used.
As suggested before, the ischemic CNS context, purinergic receptors might represent an important molecular target to restrain the condition’s irreversible burden. In this scenario, ATP and adenosine are released to the extracellular space after injury through vesicles from neurons, besides exocytosis and membrane channels including ABC transporters, pannexin 1, calcium homeostasis modulator 1 (CALHM1) channels and P2X7 pore in glial cells [59]. Estimated extracellular ATP concentrations have been described to reach up to 700 nM after ischemic events leading to tissue necrosis, whereas adenosine levels can reach up to 1000 nM [17], due to ectonucleotidases’ activity, which catabolizes AMP and generates adenosine consequently. These extracellular concentrations of adenosine and ATP after ischemic events are high enough to activate P1 and P2 receptors [60].
Even though purinergic receptors in the CNS are believed to play different roles during HIE, while the protective role of adenosine P1A1 receptors during ischemia is well accepted, through the reduction of infarct volume and improvement of neurological functions [61, 62], P2 receptors activation have been associated with inflammation, neurodegeneration and cell death [45, 63]. The evidence supporting an “adenosine neuroprotection” dates from 1997, when Halle and cols reported that pretreatment with 2-amino-3-benzothiophene (PD 81,273)—to increase adenosine binding to P1A1 receptors—conferred neuroprotection following HIE [24]. As expected, the neuroprotection afforded by adenosine is antagonized by theophylline (dimethylxanthine), an inhibitor of phosphodiesterase (PDE) isoenzymes, which break down cyclic nucleotides in the cell and leads to increased concentrations of [cAMP]i and [cyclic 3´,5´ guanosine monophosphate]I [64, 65], antagonizing P1A1 and P1A2 receptors at therapeutic concentrations [23]. Along the same line, Ådén et al. (2003) reported that the absence of P1A2A receptors (P1A2A KO mice) aggravated brain damage after neonatal HI [62].
All mammalian cell types express multiple P2 receptor subtypes, each of which presenting variable affinities for purine and pyrimidine nucleotides [66]. In the neonatal HI CNS, Wang et al. (2009) suggested that P2X7 downregulation in oligodendrocyte precursor cells confers neuroprotection [67], while the use of P2X7 antagonists, such as, A-438079 and JNJ-47965567, can antagonize the occurrence of seizures. In this context, P2X7 could represent a novel and effective therapeutic target in the condition mentioned above [68]. There is accumulating evidence that P2X1, P2X2, P2X3, P2X4 and P2X5 are potentially involved in direct neuronal death [69, 70] and that P2X7 are expressed in glial cells [71]. It remains a matter of debate whether neurons express P2X7.
Connexins are a family of trans-membrane proteins related to several functions, such as, intercellular communication and tissue differentiation. These proteins are best known for being the assembling subunits of connexons, a hexameric structure composed of six units of connexins [72, 73, 74]. The apposition of connexons in adjacent cells forms intercellular conduits named gap junctions (GJs), which allow the transfer of small molecules, ions and second messengers between cells [75]. The connexins family comprises 21 genes in the human genome [76], and their genetic expression varies according to the tissue and extracellular conditions. It is noteworthy that several cell types can express more than one type of connexin simultaneously [73, 77]. Connexins isoforms possess very similar and conserved structures, consisting of two extracellular loops, four transmembrane domains, one cytoplasmic loop, the C-terminus and the N-terminus [78]. When six units of identical connexins assemble, the resulting connexon is termed homomeric, whereas a connexon formed of different types of connexins is named heteromeric. Following the same rule, gap junctions are homotypic if derived from two identical connexons or heterotypic when two different connexons assemble [73] (Figure 1).
Among all connexins isoforms, connexin 43 (Cx43) is the more widely expressed, being present in more than 30 different tissues [77]. Predominantly found in astrocyte’s membrane, novel studies suggest important participation of Cx43 connexons and GJs in the pathophysiology of several diseases [73, 79, 80, 81, 82]. In the field of CNS hypoxic-ischemic insults, including neonatal asphyxia, some groups argue that GJs allows redistribution of nutrients, such as, glucose, and ATP [19], hence providing neuroprotection in this context. On the other hand, a myriad of studies presents Cx43 hemichannels as protagonists in processes of brain blood barrier disruption, calcium disbalance and mitochondrial dysfunction [83, 84, 85]. In addition, Cx43 may play an important role in the propagation of SD waves, possibly promoting the expansion of the initial injury to previously undamaged areas [26].
Under normal conditions, GJs may open or close accordingly to cell demands, while undocked connexons remain closed [86, 87]. Nevertheless, in cell death scenarios, hemichannels may open, allowing molecules to flow through the cell membrane, from and into the extracellular space [84, 88, 89, 90]. The release of substances, such as, ATP, glutamate and nicotinamide adenine dinucleotide (NAD+) in the extracellular medium promotes paracrine signaling to the surrounding cells, triggering cell death cascades and, consequently, expanding the primary injury [87].
Purinergic receptors in both neurons and glial cells can be activated from dying cell’s ATP release, leading to calcium influx through the receptor channel [83]. An increase of intracellular calcium might induce or worsen mitochondrial dysfunction in the context of brain injury, which leads to both secondary energy deficit and apoptosis [83]. In addition, ATP can also activate pattern recognition receptors (PRR), highlighting NOD-like receptor protein-3 (NLRP3) [84]. Finally, P2X7 and P2X4 receptors are involved in inflammasome activation and the secretion of pro-inflammatory molecules.
One of the most widely characterized approach intending to prevent the inflammatory responses of purinergic receptors activation is Cx43 blockade. However, the effects of Cx43 blockade are still controversial. Several
Pannexins are a class of monomeric proteins capable of forming cell membrane hemichannels, resembling structural and functional homology with the connexins as mentioned earlier. Likewise the formers, these molecules can assemble as oligomeric forms, namely pannexons. There are several different subtypes of pannexons in which pannexins can be assembled, depending on the cell type and physiologic condition of the cell surroundings. Among these, the three human isotypes are expressed virtually in all tissues: Panx1 (426 amino acids, 47.6 kDa), Panx2 (677 amino acids, 74.4 kDa) and Panx3 (392 amino acids, 44.7 kDa) [84, 95, 96].
The characterization of the assembled pannexin polymers upon cell membrane is still controversial since several groups suggest their action to be in the hemichannel fashion—such as connexins—while other findings indicate their function to resemble full transmembrane channels between cells [84, 95, 96]. Despite the fact pannexins and connexins share several similar pharmacologic properties and expression patterns, unlike connexons, it is now believed that pannexons are not capable of forming functional gap junctions between neighbor cells and hence not being capable of promoting the connection between their cytoplasm [95, 97, 98].
Regarding molecular characterization, human pannexin isotypes share 50–60% of membrane sequence similarity, and their extracellular C-terminal sequences are the most variable among them, defining their subtype characterization based on their pattern of glycosylation [96, 98]. Novel structural studies of pannexin membrane characterization suggest that the physiologic interplay between Panx2 and other subtypes, and functional gap junction formation are very unlikely in experimental scenarios due to glycosylated domain ionic repulsion [97, 98]. Panx2 is believed to be exclusive to CNS cells, even though its molecular properties are not elucidated as well as Panx1 subtypes [95, 96] (Figure 1).
In contrast, Panx1 subtypes can be subdivided accordingly to their different expressed conformations, mostly determined by the several possible types of channel activation [97, 99]. Recent studies suggest that in the absence of specific ligands, Panx1 is a Cl-selective channel expressed in astrocytes, oligodendrocytes, and microglia [100]. In contrast, once activated by K+ ions, Panx1 can isomerize into a highly conductant non-selective channel (500 pS), permeable to molecules such as ATP and other nucleotide polymers. Alternatively, voltage-activation of Panx1 opens a lower conductance conformation (50 Ps) [97, 99]. Nonetheless, it is important to mention that caspase activity, mechanical stretching, osmotic changes, purinergic receptor activation (such as P2X7 bound to adenosine nucleotides), and other cell biomolecular survival pathways are indicated as panx1 activators [19, 43, 101]. Additionally, this suggests that tissue injury and cell death processes can mediate Panx1 activity and might explain one of the early mechanisms of ATP leakage through the cell membrane [97, 99] and intercellular activation through purinergic receptors, and coupling through functional gap junctions. The influence of extracellular ATP in astrocytes downstream signaling is further discussed in this review.
The evidence against the pannexin role as intercellular hemichannels is based on three major aspects of these protein characteristics. Firstly, their well-recognized function as ATP and other macromolecule releasers. In addition, their distribution is described mostly in the apical domains of ubiquitous cells, which makes hemichannel coupling very unlikely [95]. Lastly, the aforementioned glycosylated extracellular domain acts repealing the near plasmatic membrane and does not talk in favor of their gap junction formation [95, 96, 97, 98].
Although it seems that hemichannel opening occurs only at the downhill of cell stress, Panx opening is also observed under physiological situations, such as, the glucocorticoid release throughout the circadian cycle and neuronal coordination under sleep pattern changing [102, 103]. Panx1 role was also described in inflammasome formation and the release and cleavage of IL-1β [101, 104], which might suggest a role in the triggering of early inflammatory response and cell death [105].
In 1906, Sir William Gowers described migraine pathophysiology as an intense, yet slow activity of the cortical centers of the brain spreading as “ripples in a pond into which a stone is thrown”—“occupying 20 min or so in passing through center affected” leaving a state of “molecular disturbance of the structures” [106]. This phenomenon was confirmed and described 38 years later in rabbit’s cerebral cortexes by Aristides Leão, who coined the term spreading depression (SD) [107], nowadays associated not only with migraine pathophysiology but also with several other neurological disorders, such as, traumatic brain injury, spinal cord injury, subarachnoid and intracranial hemorrhage, stroke and HIE [28, 108, 109, 110, 111] (Figure 2).
Waves of Leão spreading depression (SD) and purinergic receptors. Three-step models have been proposed to explain genesis and propagation of SDs, a phenomenon believed to play a major role in the pathophysiology of HIE. Firstly, HIE-mediated primary injury leads to a surge in [K+]o, ATP, reactive oxygen species (ROS) and a number of neurotransmitters (NT) in the extracellular space through Cx hemichannels and Panx1 opening in dying cells (gray cell). The upcoming activation of purinergic receptors at glia [
Characterized as an intense change in ionic homeostasis and extracellular space (ECS) features, SD is an all-direction depression of neural activity that does not respect any tissue cellularity boundaries in the cortex [30, 112]. Although it is described as a negative shift in DC moving a few millimeters per minute, SD also involves fast electrical events, as seen in a burst of activity at the wavefront, followed closely by the numbness of preview neuronal tissue [27, 28, 30, 113, 114]. SD used to be described by Professor Hiss Martins-Ferreira as an “electrical tsunami” spreading among a neuronal mass that encompasses dendritic swelling, gap junction channels assemble and opening, mitochondrial changes, up-regulation, and down-regulation of several other proteins of the CNS [26, 115, 116].
Among this complex electrochemical phenomenon that revolves in the CNS extracellular space, the intracellular spaces of neuronal-glial populations, and cellular coupling, many factors have been attributed as key players to its genesis and sustenance, such as, Ca2+, K+, and glutamate and purinergic receptors [30]. Highly increased K+ concentration was demonstrated in SD scenarios, which lead to several experimental models intending to recapitulate SD waves through artificially increasing this ionic concentration on the cortical surface [29]. It was also observed that the levels of this ion in the ECS reaches typically a plateau, being trespassed once SD is elicited [117] and those higher amounts of K+ deliverance increase wave frequencies. Moreover, the fast electrical burst at SD wavefront is possibly explained by high extracellular K+ concentrations inducing high neuronal activity. Imaging studies assessing initial changes in Ca2+, glutamate, and K+ concentrations at SD wavefront revealed earlier and more significant changes in K+, suggesting its role as the first responder in SD initiation and propagation [118] (Figure 2).
Astrocytic Ca2+ waves are also intrinsically related to SD, sharing its “velocity of propagation and stimulation paradigms” initiation stimuli, refractory period, and signaling characteristics, which are postulated not only as involved with the initiation of SD, but also as fundamental for its propagation [30, 119, 120, 121]. However, Ca2+ waves are not a sine qua non player for SD genesis, as observed in a Ca2+ free medium, in ion chelating experimental contexts, in which SD genesis was not inhibited, albeit it caused a lower onset and faster recovery [119] (for further evidence against this Ca2+ role, see [122, 123, 124]). It is noteworthy that, gap junction blockers, purinergic blockers, ATP hydrolase inducers, and desensitization of the purinergic receptors were reported as potential Ca2+ wave inhibitors [30, 125, 126, 127, 128].
The myriad of aforementioned cationic changes in SD scenarios implies in several anionics unbalances in the ECS, being Cl− the most affected inorganic anion [30]. Consequently, Na+ follows the elicited Cl− influx, decreasing ECS tonicity leading to cell swelling and morphologic changes in dendritic spines [129]. The dendritic spines recovery depends on mitochondrial membrane potential integrity, an already impaired function in hypoxic-ischemic scenarios [130].
Glutamate concentration is not only found to be higher during and after SD but also its release to be synchronic and excitotoxic processes are triggered by NMDAr activation. Despite these events, the blockade of this neurotransmitter is not able to inhibit SD onset [131, 132, 133].
The roles of purinergic signaling in neurodegeneration following perinatal HIE contexts is also well documented. Levels of extracellular ATP in the brain increase during ischemia, activating both P1 and P2 receptors expressed on neural cells (neuronal and glial). Hence, extracellular ATP levels are postulated to be involved in the pathophysiology of post-ischemic inflammation and extent of brain injury [17, 45, 81, 83, 134]. Despite this factor is being considered to be one of the key players in triggering SD through Panx1 and Cx hemichannels in dying cells, the propagation of the waves requires the participation of gap junctional channels within the ischemic penumbra [19, 30, 115, 135]. Therefore, the hypothesis of a functional interplay between P2X7, Panx1, and Cx, and its impact in the injury enlargement is very plausible in the context of the HI newborn cerebral cortex development [19, 104, 130, 136]. In consonance with this conclusion, the blockade of genesis and propagation of SD through purinergic antagonists and GJ blockers may represent a viable therapeutic approach, not only to prevent post-HIE neonatal brain injury expansion, but also in other neurovascular disorders, including migraine, trauma, and ischemic stroke [19] (Figure 2).
Mitochondrial activity is fundamental to cell maintenance, carrying in itself an intricate and distinct pattern of protein, ionic and electrical activity [137, 138, 139]. Both oxygen and glucose deprivations unbalance the primary source of cellular ATP production through the disruption of mitochondrial oxidative phosphorylation chain [140, 141, 142, 143]. This described powerhouse organelle failure generates a toxic [Ca2+]i increase, caspase activation, and ROS production, which induces necrotic features of the HIE-mediated primary injury [142, 143]. We are lead to believe that this characteristic of cell membrane rupture is the main contributing path for Cx hemichannel opening; acting synergically with the Panx1 heightening of ATP and K+ in ECS. Henceforth, we postulate this described cascade of hemichannel events to be the first step for SD genesis and propagation in HIE [95, 99, 136, 144]. The opening of these pores induces several other cell-signaling events, such as P2X7 activation and glutamate excitotoxic activity that is leading to significant Ca2+ concentration increase in the ECS. Ionic shifts and DC change is followed by gap junction-mediated spiral waves, promoting secondary SD-mediated injury [29] (Figure 2).
In conclusion, Cx hemichannels opening may elicit Ca2+ waves—responsible for the faster onset of SD-ATP, caspases, NO and other second signaling molecules flow, contributing to the bystander cell killing effect among coupled astroglial cells [145]. This highway-rail for SD waves intensifies its onset, as longs as [Ca2+]i augmentation is followed by Cl−, Na+ influx, leading to ECS changes (“Chemical Tsunami”) [30]. Depolarizing wavefront will also elicit neuronal bursts, contributing to K+ and ATP increase in the biophase [146]. The cited secondary injury appears to behave in a positive feedback-like fashion, into which further ionic and ATP release will lead to SD frequency increase and the ECS changes to mechanical panx1 activation.
Inflammation plays a critical role in HIE [147, 148] by the complex interplay between neutrophils, lymphocytes, adhesion molecules, cytokines, and chemokines, causing injury in neurons, glial cells, and white matter. The blood-brain barrier is disrupted leading to egress of brain chemicals, normally only found in the CNS, and circulate peripherally. These chemicals can serve as important biomarkers that may help in disease risk stratification and clinical decision-making.
Hypoxia-ischemia induces activation of microglia and astrocytes [149, 150], resulting in secretion of inflammatory cytokines and chemokines that influence neuronal viability and recovery [149]. Following brain injury, purinergic P2 receptors and extracellular ATP play an important role in the microglial inflammatory response [151]. While P2 receptors are activated during oxygen-glucose deprivation (OGD) leading to microglia activation with cytokine release [70, 152] and subsequent neuronal death, the enhanced expression of P2X4 mediates ATP induced amoeboid microglial cell activation for production of proinflammatory cytokines [153] in postnatal hypoxic rats. In particular, P2X7 expression is increased 24 h after neonatal hypoxia-induced seizures in mouse pups following global hypoxia and injection of P2X7 antagonist reduced the frequency of electrographic seizures and EEG abnormality [68]. Therefore, purinergic biomarkers have been proposed for both cerebral ischemia diagnosis and prognosis [45].
Microglia responds vigorously to hypoxic-ischemic attack and produce excess inflammatory cytokines [148]. Newborns with HIE have higher levels of interleukins IL-1, IL-6, IL-8, IL-10, tumor necrosis factor TNF-α, transforming growth factor TGF-β and monocyte chemoattractant protein MCP-1 that correlate positively with brain injury severity [154, 155, 156, 157]. IL-1β plays an important role in brain injury during ischemia [158]. The mechanism of brain damage induced by IL-1β involves the release of free radicals, enhancing the toxicity of excitatory amino acids and increasing vascular permeability resulting in secondary cerebral edema. Blood and cerebrospinal fluid (CSF) IL-1β, IL-6, and TNF-α concentrations were found higher in HIE neonates compared to control group and a high CSF/serum ratio suggested cytokine production in the brain in addition to the systemic cytokines crossing the blood-brain barrier [154, 159]. Therapeutic hypothermia (TH), a well established treatment for neonates with HIE [8, 10, 157, 159, 160], has been shown to perform a role in the prevention of inflammatory process by maintaining proinflammatory IL-6 at low levels and anti-inflammatory IL-10 at high levels [160] (Figure 2).
HIE remains one of the leading causes of neonatal deaths [5, 6]. Although multiple factors have been implicated in this disorder, the HIE underlying mechanisms are yet to be elucidated. To the best of our knowledge, we provide herein a summary of the described functional interplay among purinergic signaling, pannexins, connexins, and SD waves in HIE pathophysiology. Based on this interaction, the present work intends to review the current information on potential biomarkers on HIE diagnosis and prognosis.
SD waves spread across the cortex at rates of 2–5 mm/min [30, 107, 161], accompanied by a slow negative extracellular voltage and ions movement depolarizing neurons and astrocytes followed by a period of electrical suppression of distinct neuronal populations. The propagation of the SD waves is more significant in fields enriched with dendrodendritic synapses [162], such as, those described in the inner plexiform layer of the retina [30]. At this time, there are no comprehensive reviews of SD, from genesis to sustained propagation for which gap junctions have been reported to be essential [30]. However, the fact that the temporal and spatial characteristics of intercellular Ca2+ waves in astrocytes are remarkably similar to those of SDs “contributed, in part, to the mischaracterization of this phenomena” [30, 113]. Even though both events fail when gap junctions are blocked, the latest (i.e., Ca2+ waves) is neither antagonized by glutamate receptor blockers nor by purinergic receptor antagonists [30] (Tables 1 and 2).
Channel | Model | Blocker(s) | Effects |
---|---|---|---|
P2X7 | RB2 (10–100 mg/kg) | RB2 improved neurological score and reduced brain-damaged area [163] | |
BBG and oATP (1, 5 and 10 μg) and A-438079 (0.03, 0.3 and 3 μg) | P2X7 antagonists | ||
BBG (50 mg/kg) and A-740003 (0.04 mm/kg) | P2X7 antagonist, BBG, reduced cell death, microglial microvesicle-like components, expression of IL-1β, p-38 phosphorylation and glial activation. BBG and A-740003 improved memory functions [165] | ||
BBG (20–40 mg/kg) | BBG abolished neuroprotective effects produced by post-conditioning, such as memory, and motor performance improvement [166] | ||
P2Y | Culture of rat primary cortical neurons subjected to OGD | N/A | Ischemic tolerance [167] |
Culture of astrocytes exposed to sublethal OGD and subsequent lethal OGD | N/A | Ischemic tolerance [168] | |
Connexin | Perinatal ischemia-intrauterine hypoxia-ischemia (rat) | Carbenoxolone (105 mg/kg) | Decreased neuronal death, apoptosis, histopathologic damage and developmental impact. Decreased clustering of dying cells [169] |
Perinatal ischemia-bilateral carotid ligation (sheep) | Cx43 mimetic peptide (50 μmol/kg) | Reduced seizure activity and status epilepticus. Improved neuronal and oligodendrocytes survival [170] | |
Neonate 7D hypoxia/ischemia-carotid ligation and hypoxic chamber (rat) | Cx43 mimetic peptide (25–50 μg/kg) | Reduced infarct volume, astrogliosis, glutamate release and improved neurological function [171] | |
Pannexin | In vivo 4-VO (rat) | Probenecid (2 mg/kg) | Probenecid attenuated neuronal death, cathepsin B translocation in neurons and glial reactivity [172] |
Probenecid (1 mg/ml) | Probenecid reduced infarct size, neurological deficit, brain water content, astrocytic activation and inhibited HMGB1 and AQP4 expression [173] |
Key findings of P2X7, P2Y, connexins and pannexins blockade in brain ischemia models.
MCAO, middle cerebral arterial occlusion; 4-VO, four-vessel occlusion; RB2, reactive blue 2; BBG, brilliant blue G; oATP, periodate-oxidized adenosine triphosphate; OGD, oxygen-glucose deprivation; N/A: not applied.
Considering the role of spreading depression waves in HIE etiology, a new panel of biomarkers are being proposed to improve accuracy in diagnosis and prognosis, especially in the disease earlier stages or milder presentations. Unfortunately, ATP and adenosine, with short half-lives, do not offer good performance as biomarkers [174]. Recent studies have supported the use of proton magnetic resonance spectroscopy (MRS), a quantitative, noninvasive method of detecting energy metabolism disturbances in the neonate’s brain as a marker in outcome prediction for HIE patients [175]. In these studies, it seems that the ratios including Lactate/N-acetylaspartate and N-acetylaspartate/creatine could be a potential prognostic biomarker to evaluate neurodevelopmental outcomes [176, 177]. However, larger prospective multicenter studies with a standardized protocol for both measurement protocols and analysis methods are required to validate such protocols.
As discussed, cytokines are key players in the inflammatory mechanism, contribute to the progression of ischemic damage and are released by SD-activated glia. Waves of SD cause a considerable perturbation of the ionic environment in the brain, which are readily detected by microglia—although the role of microglial activation in SD-related neurological disorders remains a matter of debate. There is increasing evidence that supports that glia (astrocytes, oligodendrocytes and microglia) may play a key role in triggering SD waves. It is known that CNS microglia become activated due to the increase in extracellular ATP from the depolarization of neurons and glia, by propagated waves of SD and from the release of chemicals through damaged plasma membranes of dying cells [178]. Activated microglia secrete pro-inflammatory mediators such as cytokines and develop phagocytic and major histocompatibility complex (MHC) class II-restricted antigen presenting characteristics. Although microglia express almost all P2X members (P2X1, P2X4, P2X5, and P2X7), these receptors are expressed in different levels and contribute distinctly to neuroinflammation [148]. One of the central cytokines produced by these cells is IL-1β, which plays essential roles in brain injury during ischemia, such as, IL-6 secretion [89, 179]. In bone marrow-derived macrophages, P2X7 activation plays a significant role in the release of IL-1β [180]. In microglia, however, evidence suggests that other receptors, highlighting P2X4, may be protagonists along with P2X7 in IL-1β release [180]. Hence, despite the fact that purinergic biomarkers are not available, cytokines induced by P2X activation are measurable in serum and might be useful as diagnostic and prognostic indicators.
Although TH is a current standard therapy for neonatal HIE [8, 10, 157, 159, 160], no serum biomarker is in current clinical use for this high-risk population. Using a serum panel of biomarkers rather than a single biomarker and combining them with acid-base values, Apgar score, clinical signs of encephalopathy, early EEG and MRI could help in identifying the infants with the highest risk of compromise. None of the proposed biomarkers, so far, has yet been established as clearly better than clinical evaluation of HIE for recruitment of infants at risk of adverse outcomes. Also, even though some of the putative biomarkers show good correlations with outcome, they do so only after the onset of the subsequent deterioration (e.g., 12 or 24 h or even later). In practice, this means that the search continues for a panel of biomarkers with high diagnostic and prognostic accuracy that can be identified early in the disease process to aid the bedside clinician in tailoring treatment to individual HIE newborns.
4-VO | four-vessel occlusion |
AGA | 18alpha-glycyrrhetinic acid |
BBG | brilliant blue G |
CALHM1 | calcium homeostasis modulator 1 |
cAMP | cyclic adenosine monophosphate |
CBX | carbenoxolone |
CNS | central nervous system |
CSF | cerebrospinal fluid |
Cx | connexin |
ECS | extracellular space |
FFA | flufenamic acid |
GJ | gap junction |
GPCRs | G coupled protein receptors |
HI | hypoxic-ischemia |
HIE | hypoxic-ischemic encephalopathy |
MCAO | middle cerebral arterial occlusion |
MCP-1 | monocyte chemoattractant protein-1 |
MHC | major histocompatibility complex |
MRS | proton magnetic resonance spectroscopy |
NFA | niflumic acid |
oATP | periodate-oxidized adenosine triphosphate |
OGD | oxygen-glucose deprivation |
Panx | pannexin |
PDE | phosphodiesterase |
PPADS | pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid |
RB2 | reactive blue 2 |
ROS | reactive oxygen species |
SD | spreading depression |
TBI | traumatic brain injury |
TH | therapeutic hypothermia |
Despite all recent improvements in early detection and pleiotropic therapeutics, cancer is still the leading cause of death all over the world [1]. It is one of the most prevalent diseases with complex risk factors, and the mortality rate is similar to its morbidity, which reflects its poor prognosis. It has been projected that approximately 3.12 million new cases of cancer and a cancer death toll of 2.5 million will occur per year in China, which brings a huge burden on society [2]. To date, there are three conventional cancer therapies for cancer, including surgical resection, chemotherapy, and radiotherapy. However, diverse drawbacks and limitations have been observed in these cancer therapies either alone or in combination. For example, most cancer patients are not suitable to undergo the surgical resection due to the late diagnosis and other factors. As the major therapies for cancer patients in middle and advanced stages, chemotherapy and radiotherapy have been shown to present serious side effects and complications, such as myelosuppression, hematological toxicity, cardiac damage, and liver and kidney dysfunction [1, 3]. Moreover, tumor cells have the ability to develop resistance to evade cell death, and the therapeutic efficacy of the current chemotherapeutic drugs is significantly reduced by the increasingly acquired drug resistance [4]. Therefore, it imminently deserves to develop more effective and less toxic adjuvant therapies for cancer prevention and treatment.
It has been reported that cell metabolism has an essential role in the pathological progression of cancer and metabolic reprogramming is a remarkable hallmark of cancer [5]. Cancer cells have been shown to own a predominantly unique metabolic phenotype to facilitate their rapid proliferation, which is dramatically different from normal cells. Cancer cells tend to acquire energy via glycolysis rather than the much more efficient oxidative phosphorylation pathway even in aerobic conditions, which is the famous phenomenon of cancer called the “Warburg effect” [6]. Besides the consumption of glucose, cancer cells have also been reported to favor glutamine as a preferential fuel [7]. Accumulating evidences indicate that mutations in metabolic enzymes can promote the development of cancer. For example, mutations in the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase, succinate dehydrogenase, and fumarate hydratase can affect the corresponding metabolites a-ketoglutarate, succinate, and fumarate. These changes can further affect the 2-oxoglutarate-dependent dioxygenases and then result in some cancers, such as paraganglioma and renal cell cancer [8, 9, 10]. What is more, the drug resistance of cancer cells is also shown to be associated with their metabolic alterations [11]. In this perspective, cancer metabolism has become a potentially fertile area, and therapies targeting cancer metabolism can be highly specific and effective. Nowadays metabolism-targeting anticancer therapies are drawing researchers’ great attention and becoming a new therapeutics for cancer treatment [12].
As a valuable complement to emerging “omics” science including genomics, transcriptomics, and proteomics, metabolomics utilizes leading-edge analytical chemistry technologies and advanced computational approaches to characterize the small endogenous and exogenous molecule metabolites in various biochemical metabolisms from complex biochemical mixtures [13]. Metabolomics can provide us a direct readout on dynamically metabolic responses of living systems to certain genetic modifications or pathophysiological stimuli [14], which has been extensively adopted in the field of disease diagnosis, pharmacodynamic evaluation, therapeutical monitoring, and drug discovery [15]. There are three main analytical chemistry platforms in metabolomics research, namely, nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography mass spectrometry (LC-MS), and gas chromatography MS (GC/MS). Each platform has its own strengths and limitations. There are three main methodological approaches to analyze the small metabolites in metabolomics, namely, targeted, untargeted, and stable isotope-resolved metabolomics (SIRM). Numerous systemic reviews have shown in detail how each analytical platform and methodological approach works in metabolomics studies [16, 17, 18, 19, 20].
As mentioned above, cell metabolism has an essential role in the pathological progression of cancer, and metabolic reprogramming is a remarkable hallmark of cancer. In this context, it would be conducive to employ metabolomics in the field of cancer research for exploration of tumorigenesis mechanisms, diagnosis and monitoring of tumor, as well as discovery of novel anticancer therapies [21, 22, 23].
Due to their various biological activities and low toxicity, natural products derived from Chinese medicines are reported to be an excellent source for anticancer drugs as a complementary and alternative approach [24]. Chinese medicines have evolved with their own unique theoretical system in Asian countries, especially China over thousands of years. Chinese medicines are usually divided into pure compounds, herb extracts, and formulations. Formulations from Chinese medicines are extensively employed in Chinese hospitals for clinical cancer treatment [25]. Numerous Chinese herb extracts have been reported to show inhibitory effects on cancers [26]. An increasing number of pure compounds derived from Chinese medicine herbs have been shown to inhibit the development of cancers through various mechanisms [27, 28, 29, 30]. Besides, a large number of studies have revealed that Chinese medicines in combination with conventional chemotherapy and radiotherapy could increase the therapeutic efficacy and decrease the serious side effects and complications of these therapies [31, 32]. It is convinced that Chinese medicines are gaining increasing reputation and credibility as adjuvant therapies for cancer prevention and treatment.
Although Chinese medicines have been employed in cancer prevention and treatment for a long time, the underlying mechanisms on how they work remain to be fully elucidated because of their unique medical system with multicomponent nature. In accordance with the holistic perspective of Chinese medicines, metabolomics opens up a unique and novel insight into efficacy evaluation and action mechanism exploration of Chinese medicines as adjuvant therapies for cancer prevention and treatment.
Increasing excellent reviews have been focused on the application of metabolomics in the metabolic changes and the possible underlying mechanisms behind these alterations in the pathogenesis of different kinds of cancer [33, 34, 35]. Little reviews have been highlighted on the metabolism-based anticancer therapies. Since Chinese medicine has been suggested to be a great source of alternative treatments to human cancers, in this chapter we systematically reviewed recent studies from 2015 to March 2019 on metabolism-targeting anticancer therapies based on metabolomics in terms of glucose, lipid, amino acid, and nucleotide metabolisms and other altered metabolisms, with special emphasis on the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines. The typical flowchart of metabolomics studies on antineoplastic Chinese medicines is shown in Figure 1. Table 1 summarized the recent metabolomics studies on anticancer therapies of pure compounds from Chinese medicines. At the same time, the trends of future development of metabolism-targeting anticancer therapies were also discussed.
The typical flowchart of metabolomics studies on antineoplastic Chinese medicines.
References | Pure compound | Cancer | Study | Method | Significantly changed metabolites or pathways | Main findings |
---|---|---|---|---|---|---|
26,700,591 | Geranylgeranoic acid | Hepatoma | HuH-7 cells in vitro | UPLC/TOF/MS | GGA induced a time-dependent increase in the cellular contents of fructose 6-phosphate and decrease of fructose 1,6-diphosphate | GGA may shift HuH-7 cells from aerobic glycolysis to mitochondrial respiration through the immediate upregulation of TIGAR and SCO2 protein levels |
26,160,839 | Halofuginone | Colorectal cancer | HCT116 cells in vitro | UPLC-MS/MS, GC/MS and UPLC/LTQ-Orbitrap MS | Metabolomics delineated the slower rates in both glycolytic flux and glucose-derived tricarboxylic acid cycle flux | HF regulates Akt/mTORC1 signaling pathway to dampen glucose uptake and glycolysis in CRC cells |
29,589,762 | (−)-5-Hydroxy-equol | Hepatocellular Carcinoma | SMMC-7721 cells in vitro | 1H NMR | (−)-5-Hydroxy-equol treatment significantly altered energy and amino acid metabolism | Integrated metabolomics and further verifications may facilitate the exploration of the anti-HCC mechanisms of (−)-5-hydroxy-equol |
29,802,724 | Nummularic acid (NA) | Prostate cancer (PCa) | DU-145 and C4-2 cells in vitro | ALEX-CIS GC–TOF-MS | The metabolism pathways related to glycolysis, TCA, and glutamine metabolisms were changed after NA treatment | NA may induce energy crisis to inhibit PCa |
30,391,728 | Magnoline | Prostate cancer | 22RV1 cells in vitro | UPLC-MS | Magnoline markedly restored the energy metabolism, amino acid metabolism, and fatty acid metabolism | Cancer cells may result in death because of insufficient material basis to favor their rapid proliferation |
28,651,973 | 1,25-Dihydroxyvitamin D3 | Prostate cancer | LNCaP cells in vitro | GC/ MS | 1,25(OH)2D3 decreased glucose uptake and increased citrate/isocitrate due to TCA cycle truncation | Re-wiring glucose metabolizing pathways, and induction of a “differentiated” metabolic phenotype by 1,25(OH)2D3, may prove clinically beneficial |
26,541,605 | Vitamin C | Colorectal cancer | KRAS and BRAF mutant lines and isogenic wild-type counterparts in vitro | LC-MS/MS | High levels of vitamin C increased uptake of dehydroascorbic acid (DHA) and decreased glutathione | These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations |
28,916,726 | β-Lapachone | Pancreatic ductal adenocarcinoma | MiaPaCa2 cells in vitro | GC/MS and 1H NMR | β-lap treatment was found to decrease the NAD-sensitive pathways, such as glycolysis and TCA cycle | Targeting NQO1 may sensitize the treatment of β-lap |
28,737,429 | Diethylstilbestrol | Prostate cancer | PC3 cells in vitro | 1H NMR | Lactate, phosphocreatine, and GSH were the biomarkers for DES treatment | DES upon conjugation had a more specific effect and less toxicity |
28,918,937 | Koningic acid | Colorectal cancer | HCT116 cells in vitro | Integrated pharmacogenomics and LC-HRMS metabolomics | Glycolysis was the highest scoring pathway only in KA-treated cells | KA efficacy is not determined by the status of individual genes but by the quantitative extent of the WE, leading to a therapeutic window in vivo |
30,114,709 | Omega-3 polyunsaturated fatty acids | Breast cancer | MCF7 cells in vitro | GC/MS | Glycolysis and glutamine metabolism pathways were markedly reduced when treated with the combination of Rp and ω-3 PUFAs | ω-3 PUFA could increase the anti-breast cancer potential of Rp |
28,198,625 | Curcumin | Hepatocarcinoma | Serum from DEN-induced hepatocarcinogenesis model | GC/MS | Curcumin attenuated metabolic disorders via increasing concentration of glucose and fructose, and decreasing levels of glycine and proline | Curcumin exhibited a potent liver protective agent inhibiting chemically induced liver injury through suppressing liver cellular metabolism in the prospective application |
29,448,205 | 6,7-Dimethoxy-1,2,3,4-tetrahydro-iso- quinoline-3-carboxylic acid | Colorectal carcinoma | Serum from DMH-induced CRC albino Wistar rat model in vivo | 1H NMR | M1 exhibited to reverse the perturbed metabolism pathways in CRC condition, including glycolysis, TCA cycle, choline, phosphatidylinositol and gluconeogenesismetabolisms | M1 has the anti-CRC potential via the blockade of IL-6/JAK2/STAT3 oncogenic signaling |
27,416,811 | Physapubenolide | Hepatocellular carcinoma | HepG2 cells in vitro and tumor tissues and plasma from a mouse-xenograft model bearing liver carcinoma H22 cells in vivo | GC/MS | PB disturbed the metabolic pattern and significantly decreased lactate production | PB exhibits anticancer activities through suppression of glycolysis via the Akt-p53 pathway |
30,322,263 | Naringenin | Lung cancer | Serum from the urethane-induced lung cancer rat model in vivo | 1H NMR | The glycolysis was restored to normal levels with co-therapy of Gnb and Nar | Co-therapy has the superiority over alone treatment to improve the therapeutic efficacy |
26,859,520 | Flexibilide | Colon cancer | HCT-116 cells in vitro | UPLC/Q-TOF MS | Flexibilide exhibited the therapeutic effect on colon cancer mainly via downregulating PC biosynthesis pathway | Flexibilide exhibited the therapeutic effect on colon cancer mainly via down-regulating PC biosynthesis pathway |
28,296,891 | Englerin A | Clear cell renal carcinoma | A498 cells in vitro | LC-MS/MS | Englerin A significantly reversed lipid metabolism and increase ceramides levels | Ceramides may be a mediator of some of the actions of englerin A |
28,948,276 | Isoquercitrin | Bladder cancer | T24 cells in vitro | UPLC/Q-TOF MS | Isoquercitrin treatment was found to regulate lipid and anaerobic glycolysis | ISO influenced T24 bladder cancer cell metabolism, and this process was mainly involved in activating the AMPK pathway |
28,496,003 | Peiminine | Colorectal cancer | UPLC-MS and GC/MS | UPLC-MS and GC/MS | Peiminine treatment altered several metabolites, including lignocerate (24:0), oleate (18:1n9), glutamine, and glucose | Peiminine exerted the predominant therapeutic effect mainly via the metabolic regulation of lipids, amino acids, and carbohydrates |
29,321,577 | 8u | Hepatocellular carcinoma | HepG2 cells in vitro | UPLC/Q-TOF MS | 8u was found to significantly inhibit the invasion and metastasis of HepG2 cells and regulate intracellular lipid metabolism | 8u could efficiently suppress the invasion and metastasis of HepG2 cells by decreasing the expression of HSP90α protein and inhibiting the PI3K/Akt signaling pathway |
28,125,641 | Genistein and calcitriol | Osteosarcoma | MG-63 Cells in vitro | GC/MS | Co-therapy of genistein and calcitriol was found to regulate lipids and amino acids rather than energy metabolism | The promotional effects of high level of genistein on osteosarcoma could be decreased by the co-treatment of calcitriol |
27,533,043 | Silibinin | Prostate cancer | Tumor tissues from 22Rv1 Xenograft model in vivo | 1H-NMR | Silibinin treatment did not greatly affect glucose uptake of PCa tumor but decreased the lipid synthesis | These findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling |
26,744,170 | Acyclic retinoid | Hepatocellular carcinoma | Liver tissues from mouse DEN-induced HCC model in vivo | CE-TOFMS and LC-TOFMS | ACR predominantly reversed lipogenesis but not glucose metabolism by inhibiting linoleic acid metabolites | Lipid metabolic reprogramming plays a critical role in the protective effects of ACR on HCC |
30,871,192 | Delta-tocotrienol | Non-small cell lung cancer | A549 and H1299 cells in vitro | 1H-NMR | Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment | δT treatment could suppress the glutamine uptake via suppressing glutamine transporters and then resulted in the induction of apoptosis and suppression of cell proliferation |
30,068,874 | Celastrol | Colon cancer | HCT116 cells in vitro | UPLC/MS | Metabolomics analysis found celastrol changed the levels of lipid markers, carnitine and amino acids. Tryptophan was further identified as a special biomarker by targeted metabolite analysis | The suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells |
27,754,384 | Melittin | Ovarian cancer | A2780 and A2780CR cell lines in vitro | LC-MS | Melittin treatment of cisplatin-sensitive cells decreased glutamine, proline, and arginine pathways | Melittin might have some potential as an adjuvant therapy in cancer treatment |
28,674,386 | Chlorogenic acid and caffeic acid | Hepatocellular carcinoma | Serum from DEN-induced HCC model in vivo | 16 S rRNA and LC-MS, GC/MS-MS, GC/MS | Both CaA and ChA treatment reverse 28 metabolites | The levels of ethanolamine, L-methionine, L-tyrosine, and bilirubin were associated with diminished Prevotella 9 and Lachnospiraceae incertae sedis and elevated Ruminococcaceae UCG-004 |
29,202,102 | Resveratrol, curcumin and ursolic acid | Prostate cancer | Serum from a mouse allograft model of prostate cancer in vivo | LC-MS and GC/ MS | Glutamine metabolism was regulated by the compound combinations | Compared with the individual treatment, the combined treatment has the greater antineoplastic property |
29,651,531 | Hepatoma | SMMC7721 cells in vitro | GC/MS and LC/MS | GLA treatment diminished amino acid metabolism and elevated the metabolisms of sphingolipid, purine, and pyrimidine | GC/MS- and LC/MS-based metabolomics applied to cell culture enhanced our current understanding of the metabolic response to GLA treatment and its mechanism | |
26,851,007 | Taurine | Breast cancer | Plasma from dimethylbenz[a]anthracene-induced breast carcinogenesis in rats in vivo | GC–TOFMS | Taurine treatment regulated 23 differential metabolites, which were associated with glucose, energy and amino acid, as well as nucleic acid metabolism | The antitumor activity of taurine in rats is mediated through altered metabolism of breast cancer cells |
27,374,097 | Celastrol | Acute promyelocytic leukemia | HL-60 cells in vitro and tumor tissue from mice xenograft model in vivo | UPLC-MS | Celastrol treatment regulated uridine metabolite, which further enhances apoptosis | The study firstly reveals that uridine deficiency contributes to mitochondrial apoptosis induced by celastrol in APL cells |
29,787,425 | Gamma-tocotrienol | Cancer | Serum from nonhuman primate models in vivo | UPLC/Q-TOF MS | GT3 could regulate the changed fatty acid beta-oxidation, amino acid and purine catabolism metabolism caused by irradiation | This initial assessment also highlights the utility of metabolomics in determining underlying physiological mechanisms responsible for the radioprotective efficacy of gamma-tocotrienol |
27,335,141 | Fisetin | Prostate cancer | Tumor tissues from prostate cancer xenografts in vivo | HPLC/ESI–MS | Fisetin treatment was shown to downregulate secreted and intracellular hyaluronan (HA), which conferred resistance to prostate oncogenesis | Fisetin is an effective, nontoxic, potent HA synthesis inhibitor |
29,978,476 | Galactolipid 1,2-di-O-linolenoyl-3-O- β-galactopyranosyl-sn-glycerol | Melanoma | Serum from a syngeneic mouse model implanted with B16 melanoma in vivo | LC-MS/MS | dLGG treatment markedly elevated 12/15-LOX catalyzed oxylipin products in serum | This study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma |
30,668,340 | Deoxyelephantopin | Melanoma | Kidney tissues from murine B16 metastatic allograft model in vivo | UPLC/ESI-QTOF MS | Co-therapy of DET and cisplatin could reverse the changed urea cycle metabolites and hippuric acid in renal tissues caused by cisplatin | The co-therapy of DET and cisplatin could be an effective treatment with low toxicity for melanoma |
Summary of recent metabolomic studies on anticancer therapies of pure compounds from Chinese medicines.
As mentioned above, cancer cells tend to acquire energy via glycolysis rather than the much more efficient oxidative phosphorylation pathway even in aerobic conditions. Glucose and energy metabolisms play an important role in the tumorigenesis of cancer and could be the therapeutic targets for cancer treatment. Pure compounds, herb extracts, and formulations from Chinese medicines, which target glucose and energy metabolisms, are attracting increasing attention for the development of anticancer therapies.
Geranylgeranoic acid (GGA), a kind of acyclic diterpenoids, is derived from some medicinal herbs such as turmeric. UPLC/TOF/MS-based metabolomics analysis was used to study the underlying anticancer mechanism of GGA in human hepatoma-derived HuH-7 cells [36]. It was found that GGA may shift the energetic state of HuH-7 cells from aerobic glycolysis to mitochondrial respiration, which was revealed by a time-dependent augment of fructose 6-phosphate and decline of fructose 1,6-diphosphate in HuH-7 cells after GGA treatment. Halofuginone (HF) is an active compound derived from the febrifugine which can be extracted from the Chinese herb
Silymarin, extracted from the seeds of milk thistle (
Besides the glucose and energy metabolisms having an essential role in the tumorigenesis process of cancer, it has been also reported that lipid metabolism such as de novo lipogenesis regulates the synthesis of cellular membranes and the important signaling molecules of rapidly proliferating tumor cells [55]. Targeting the lipid metabolism could be a novel therapeutics for cancer treatment. Here the recent metabolomics studies of pure compounds, herb extracts, and formulations from Chinese medicines, which target lipid metabolism, have been reviewed.
Flexibilide is a natural compound derived from the soft coral
Soft coral,
As mentioned above, besides the consumption of glucose, cancer cells have also been reported to favor glutamine as a preferential fuel. Glutamine metabolism has an essential role in the pathological progression of cancer and could be a potential therapeutic option for cancer. Besides the key metabolite glutamine, it has been reported many other amino acids also play an essential role in cancer.
Delta-tocotrienol (δT) is one of the isomers of vitamin E with antineoplastic property. To explore underlying action mechanism, a 1H-NMR-based metabolomics of A549 and H1299 cells in vitro was used [71]. In detail, δT treatment could suppress the glutamine uptake via suppressing glutamine transporters and then resulted in the induction of apoptosis and suppression of cell proliferation. Celastrol is a bioactive compound derived from
Polyphenols are characterized as a hydroalcoholic chestnut shell extract. Sorice et al. used 1H-NMR-based metabolomics of HepG2 cells in vitro to study the anti-HCC activity of polyphenols extracted from chestnut shell (PECS) [76]. PECS was found to regulate the levels of some amino acids. Annonaceous acetogenins (ACGs) are a group of C35 or C37 secondary metabolites isolated from plants in
To support the rapid proliferation of cancer cells, nucleic acid synthesis is shown to be accelerated. Accordingly, the anticancer therapy targeting nucleotide metabolism has obtained numerous attentions. Here the recent metabolomics studies of Chinese medicines targeting nucleotide metabolism have been reviewed.
Glaucocalyxin A (GLA) is an ent-kaurene diterpenoid derived from
Red kidney bean, also named as
Except for the anticancer therapies of Chinese medicine targeting the changed metabolisms mentioned above, there are also some other related metabolisms which are the targets by Chinese medicine. Fisetin is a kind of plant flavonoid with antineoplastic property. A HPLC/ESI-MS-based metabolomics of tumor tissues from PCa xenografts in vivo was conducted to explore its therapeutic benefit for PCa [87]. Fisetin treatment was shown to downregulate secreted and intracellular hyaluronan (HA), which conferred resistance to prostate oncogenesis. Yang et al. developed a LC-MS/MS-based metabolomics to study the bioefficacy of a plant galactolipid 1,2-di-O-α-linolenoyl-3-O-β-D- galactopyranosyl-sn-glycerol (dLGG) against melanoma [88]. dLGG treatment markedly elevated 12/15-LOX catalyzed oxylipin products in serum, revealing the novel therapeutic mechanism of phytoagent dLGG against melanoma. Derived from the medicinal plant
Liu et al. developed a UHPLC-MS/MS-based targeted metabolomics to evaluate the efficacy of anticancer drugs, including a traditional Chinese medicine injection Aidi injections and fluorouracil [90]. It was found that with the progression of squamous cell carcinoma of the lung, the levels of 1,3-diaminopropane, cadaverine, and N-acetylputrescine altered. The two-drug treatment alone or co-therapy reversed the levels of 1,3-diaminopropane, cadaverine, and N-acetylputrescine. The team also used this metabolomics method to evaluate the efficacy of Aidi injections on CRC [91]. It was found that Aidi injection treatment could reverse polyamine metabolism, especially agmatine and putrescine, revealing that plasma polyamine could be a biomarker for both early diagnosis and medical treatment of CRC.
In accordance with the holistic perspective of Chinese medicines, metabolomics can help to explain the underlying mechanisms of the anticancer effects of Chinese medicines or the reversion of the drug resistance of chemotherapy and radiotherapy. It can also help to rapidly compare the anticancer effects of multiple compounds from Chinese medicines and act as a quick preliminary platform to screen the most dominant compound related to anticancer bioactivity. Based on the metabolomics analyses of modern studies of Chinese medicines with antineoplastic properties, the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines is gaining numerous attentions. However, many challenges still exist in the metabolomics study of antineoplastic Chinese medicines, and there is still a long way for the wide application of metabolomics of Chinese medicines into the treatment of cancer. Firstly, it is critical to make good experimental design before starting the experiment, such as the choices of samples, analytical platforms, and methodological approaches. Secondly, it is quite essential for researchers to develop metabolomics, such as the development of data excavation and the identification and quantification of more metabolites. Thirdly, it is important for us to validate the results from metabolomics studies with more mechanical biological experiments. Fourthly, as no one single technology could achieve a comprehensive result, it is strongly suggested to combine metabolomics with some other advanced technologies for better investigation of the action mechanisms of antineoplastic Chinese medicines, such as other “omics” technologies, network pharmacology, and gut microbiome analyses. Last but not least, more attentions will be drawn to personalized treatment based on metabolomics. It has been reported that because of the interaction between genes and environment (polypharmacy, gut microbiota, xenobiotics), not all patients present the same response to drug treatment [92]. Personalized treatment has been put forward and of great importance nowadays. Although pharmacogenomics is still the only means in terms of personalized treatment, its limitation of ignoring the environmental influences has been increasingly recognized. As an alternative and complementary manner, pharmacometabolomics is an emerging “omics” and has been proposed for personalized treatment [16]. As the results of both genetic and environmental influences, pharmacometabolomics can help to understand individual phenotypic variations in drug responses by providing individual metabolic signatures of both gene-derived endogenous and environment-derived exogenous metabolites [93]. Pharmacometabolomics will offer an intriguingly avenue for personalized treatment in the future.
In this chapter, we systematically reviewed recent studies on metabolism-targeting anticancer therapies based on metabolomics in terms of glucose, lipid, amino acid, and nucleotide metabolisms and other altered metabolisms, with special emphasis on the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines. The trends of future development of metabolism-targeting anticancer therapies were also discussed. Hopefully, we expect that through the systematic review on the recent metabolomics studies targeting Chinese medicine treatment on human cancers, more attention will be drawn to the promising candidates from the resourceful Chinese medicine as effective neoadjuvant therapies for cancer treatment clinically.
The study was financially supported by grants from the research council of the University of Hong Kong (Project Codes: 104004092, 104004460, 104004746), the Research Grants Committee (RGC) of Hong Kong, HKSAR (Project Codes: 764708, 766211, 17152116), Wong’s Donation on Modern Oncology of Chinese Medicine (Project code: 200006276), Gala Family Trust (Project Code: 200007008), Innovation Technology Fund of Hong Kong (ITF. Project code: 260900263), and HMRF (Project code: 16172751).
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All published Book Chapters are licensed under a Creative Commons Attribution 3.0 Unported License. Monographs are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others. Our Copyright Policy aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. IntechOpen upholds a flexible Copyright Policy meaning that there is no copyright transfer to the publisher and Authors hold exclusive copyright to their work.
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A new sintering technique known as spark plasma sintering (SPS) appears as the only method to reach high densities while preserving the final grain size within the nanometric range, with the added advantage of carrying out the process at significantly lower temperatures and shorter times as compared with the classical processes. Recent studies have revealed that in many cases, SPS can also accomplish the solid‐state reaction to achieve the desired compound, leading to reactive SPS (RSPS). 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The role of various nano/micro-sized reinforcements in altering the structural, mechanical, and thermal properties of the microwave-extruded composites was systematically studied. The X-ray diffraction (XRD) patterns indicated that the main components were Al, SiC, Si3N4, and Al2O3 for the studied Al-SiC, Al-Si3N4,\nand Al-Al2O3 composites, respectively. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) elemental mapping confirm the homogeneous distribution of reinforcing particles in the Al matrix. Mechanistic studies revealed that the Al-Si3N4 metal matrix composite exhibited superior hardness, ultimate compression/tensile strength, and Young’s modulus, while having a lower coefficient of thermal expansion compared to other studied Al composites. Findings presented are expected to pave the way to design, develop, and synthesize other aluminum-based metal matrix composites for automotive and industrial applications.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Penchal Reddy Matli, Rana Abdul Shakoor and Adel Mohamed\nAmer Mohamed",authors:[{id:"148964",title:"Dr.",name:"A.M.A",middleName:null,surname:"Mohamed",slug:"a.m.a-mohamed",fullName:"A.M.A Mohamed"},{id:"197398",title:"Dr.",name:"Abdul",middleName:null,surname:"Shakoor",slug:"abdul-shakoor",fullName:"Abdul Shakoor"},{id:"198720",title:"Dr.",name:"Penchal Reddy",middleName:null,surname:"Matli",slug:"penchal-reddy-matli",fullName:"Penchal Reddy Matli"}]},{id:"55759",doi:"10.5772/intechopen.68872",title:"Selective Laser Sintering of Nanoparticles",slug:"selective-laser-sintering-of-nanoparticles",totalDownloads:1755,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Selective laser sintering of nanoparticles has received much attention recently as it enables rapid fabrication of functional layers including metal conductors and metal‐oxide electrodes on heat‐sensitive polymer substrate in ambient conditions. Photothermal reactions induced by lasers rapidly increase the local temperature of the target nanoparticle in a highly selective manner, and subsequent sintering steps including melting and coalescence between nanoparticles occur to fabricate interconnected sintered films for various future applications. 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The chapter describes the sintering process of porcelain body in case of different fluxing agent (different feldspar rocks, bone ash, zeolite) and binder (kaolin vs. calcium aluminate cement) utilization in the porcelain raw material mixture. Sintering process is presented according to thermodilatometrical curves and sintering temperatures especially.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Radomir Sokolar",authors:[{id:"197992",title:"Associate Prof.",name:"Radomir",middleName:null,surname:"Sokolar",slug:"radomir-sokolar",fullName:"Radomir Sokolar"}]}],mostDownloadedChaptersLast30Days:[{id:"54691",title:"Two-Step Sintering of Ceramics",slug:"two-step-sintering-of-ceramics",totalDownloads:2365,totalCrossrefCites:16,totalDimensionsCites:24,abstract:"Sintering is a critical phase in the production of ceramic bodies. 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With this background, this chapter reviews the advantages of TSS in ceramic preparation based on properties and materials and explores the future directions.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Ubenthiran Sutharsini, Murugathas Thanihaichelvan and Ramesh\nSingh",authors:[{id:"196694",title:"Dr.",name:"Sutharsini",middleName:null,surname:"Ubenthiran",slug:"sutharsini-ubenthiran",fullName:"Sutharsini Ubenthiran"},{id:"197621",title:"Prof.",name:"Singh",middleName:null,surname:"Ramesh",slug:"singh-ramesh",fullName:"Singh Ramesh"},{id:"197622",title:"Ph.D. Student",name:"Murugathas",middleName:null,surname:"Thanihaichelvan",slug:"murugathas-thanihaichelvan",fullName:"Murugathas Thanihaichelvan"}]},{id:"56484",title:"Evolution of Magnetic Properties in Ferrites: Trends of Single- Sample and Multi-Sample Sintering",slug:"evolution-of-magnetic-properties-in-ferrites-trends-of-single-sample-and-multi-sample-sintering",totalDownloads:1596,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Microstructure of magnetic materials greatly influences the performance of magnetic properties, and sintering has been used as an agent to tailor the microstructure of these magnetic materials especially ferrites. Nanostructured ferrites prepared by high-energy milling method are often inherently unstable owing to their small constituent sizes, non-equilibrium cation distribution, disordered spin configuration, and high chemical activity. Therefore, sintering of the milled ferrites recrystallizes the nanostructure and causes its transition from an excited metastable (activated) state into the low-energy crystalline state. A better understanding of the response of nanoscale ferrites with changes in temperature is crucial not only for basic science (the development of an atomistic and microscopic theory of the mechanochemical processes) but also because of the technological high-temperature applications in catalysis, ferrofluids and information storage. This chapter discusses on two different sintering schemes, which are a commonly applied multi-sample sintering and a rarely adopted single-sample sintering. Experimental results of single-sample and multi-sample sintering of NiZn ferrites and yttrium iron garnet (YIG) were highlighted, and their microstructural consequences on the magnetic properties were also discussed.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Ismayadi Ismail, Idza Riati Ibrahim and Rodziah Nazlan",authors:[{id:"185087",title:"Dr.",name:"Ismayadi",middleName:null,surname:"Ismail",slug:"ismayadi-ismail",fullName:"Ismayadi Ismail"},{id:"197659",title:"Dr.",name:"Idza Riati",middleName:null,surname:"Ibrahim",slug:"idza-riati-ibrahim",fullName:"Idza Riati Ibrahim"},{id:"197660",title:"Ph.D.",name:"Rodziah",middleName:null,surname:"Nazlan",slug:"rodziah-nazlan",fullName:"Rodziah Nazlan"}]},{id:"55983",title:"Sintering and Reactive Sintering by Spark Plasma Sintering (SPS)",slug:"sintering-and-reactive-sintering-by-spark-plasma-sintering-sps-",totalDownloads:1701,totalCrossrefCites:4,totalDimensionsCites:14,abstract:"A wide variety of technological applications, especially in electronics, requires high‐density nanostructured solids, consolidated by sintering from nanoparticles. A new sintering technique known as spark plasma sintering (SPS) appears as the only method to reach high densities while preserving the final grain size within the nanometric range, with the added advantage of carrying out the process at significantly lower temperatures and shorter times as compared with the classical processes. Recent studies have revealed that in many cases, SPS can also accomplish the solid‐state reaction to achieve the desired compound, leading to reactive SPS (RSPS). In this chapter, a review of RSPS is presented, focusing particularly on magnetic oxide materials as functional solids.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Giulia Franceschin, Nancy Flores‐Martínez, Gabriela Vázquez‐\nVictorio, Souad Ammar and Raul Valenzuela",authors:[{id:"167617",title:"Prof.",name:"Raul",middleName:null,surname:"Valenzuela",slug:"raul-valenzuela",fullName:"Raul Valenzuela"},{id:"196830",title:"Prof.",name:"Souad",middleName:null,surname:"Ammar",slug:"souad-ammar",fullName:"Souad Ammar"},{id:"198772",title:"BSc.",name:"Giulia",middleName:null,surname:"Franceschin",slug:"giulia-franceschin",fullName:"Giulia Franceschin"},{id:"198775",title:"BSc.",name:"Nancy",middleName:null,surname:"Flores-Martinez",slug:"nancy-flores-martinez",fullName:"Nancy Flores-Martinez"},{id:"198776",title:"BSc.",name:"Gabriela",middleName:null,surname:"Vazquez-Victorio",slug:"gabriela-vazquez-victorio",fullName:"Gabriela Vazquez-Victorio"}]},{id:"54832",title:"Sintering of Whiteware Body Depending on Different Fluxing Agents and Binders",slug:"sintering-of-whiteware-body-depending-on-different-fluxing-agents-and-binders",totalDownloads:1369,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The sintering of whiteware (porcelain) body can be affected by using fluxing agents or binders. The chapter describes the sintering process of porcelain body in case of different fluxing agent (different feldspar rocks, bone ash, zeolite) and binder (kaolin vs. calcium aluminate cement) utilization in the porcelain raw material mixture. Sintering process is presented according to thermodilatometrical curves and sintering temperatures especially.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Radomir Sokolar",authors:[{id:"197992",title:"Associate Prof.",name:"Radomir",middleName:null,surname:"Sokolar",slug:"radomir-sokolar",fullName:"Radomir Sokolar"}]},{id:"55759",title:"Selective Laser Sintering of Nanoparticles",slug:"selective-laser-sintering-of-nanoparticles",totalDownloads:1755,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Selective laser sintering of nanoparticles has received much attention recently as it enables rapid fabrication of functional layers including metal conductors and metal‐oxide electrodes on heat‐sensitive polymer substrate in ambient conditions. Photothermal reactions induced by lasers rapidly increase the local temperature of the target nanoparticle in a highly selective manner, and subsequent sintering steps including melting and coalescence between nanoparticles occur to fabricate interconnected sintered films for various future applications. The mechanism of laser sintering, as well as possible target materials subject to laser sintering, together with experimental schemes developed to improve the process and potential applications, is briefly summarized in this chapter.",book:{id:"5803",slug:"sintering-of-functional-materials",title:"Sintering of Functional Materials",fullTitle:"Sintering of Functional Materials"},signatures:"Sukjoon Hong",authors:[{id:"197318",title:"Prof.",name:"Sukjoon",middleName:null,surname:"Hong",slug:"sukjoon-hong",fullName:"Sukjoon Hong"}]}],onlineFirstChaptersFilter:{topicId:"1402",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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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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). 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His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. 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Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"22",type:"subseries",title:"Applied Intelligence",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence",scope:"This field is the key in the current industrial revolution (Industry 4.0), where the new models and developments are based on the knowledge generation on applied intelligence. The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11418,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. 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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.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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