\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6271",leadTitle:null,fullTitle:"Astrocyte - Physiology and Pathology",title:"Astrocyte",subtitle:"Physiology and Pathology",reviewType:"peer-reviewed",abstract:"A team of authors from prestigious academic schools contributed to draw up a project that would give a detailed account of astrocyte's morphology and physiology, examining thoroughly all the astrocyte's types; giving an accurate description of their morphology, location, function in the brain; and illustrating their physiology and pathology in terms of dealing with neurons through \"gliotransmitters,\" ionic channels, and membrane receptors expression. This book gives an overview of the crucial role of astrocytes in the physiology of the CNS and in the pathogenesis of several CNS disorders suggesting that the shift from a neurocentric view to one that incorporates astrocytes in disease models for drug discovery is a critical step in renewing drug development strategies to treat neurodegenerative diseases.",isbn:"978-953-51-3886-0",printIsbn:"978-953-51-3885-3",pdfIsbn:"978-953-51-4077-1",doi:"10.5772/intechopen.69076",price:119,priceEur:129,priceUsd:155,slug:"astrocyte-physiology-and-pathology",numberOfPages:242,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"46949616660cfdfa0f4e04e2ca8333e2",bookSignature:"Maria Teresa Gentile and Luca Colucci D’Amato",publishedDate:"March 21st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6271.jpg",numberOfDownloads:13268,numberOfWosCitations:20,numberOfCrossrefCitations:11,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:28,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:59,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 30th 2017",dateEndSecondStepPublish:"June 20th 2017",dateEndThirdStepPublish:"September 16th 2017",dateEndFourthStepPublish:"December 15th 2017",dateEndFifthStepPublish:"February 13th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"160180",title:"Dr.",name:"Maria Teresa",middleName:null,surname:"Gentile",slug:"maria-teresa-gentile",fullName:"Maria Teresa Gentile",profilePictureURL:"https://mts.intechopen.com/storage/users/160180/images/5390_n.jpg",biography:"Dr. Maria Teresa Gentile obtained her master’s degree in Molecular Biology from the University of Naples 'Federico II” and PhD degree in Pharmacology from the Second University of Naples. She has worked on projects on cardiovascular risk factors of neurodegenerative disorders such as Alzheimer’s disease and in particular on the molecular mechanisms underlying beta amyloid–induced endothelial dysfunction and its deposition in brain tissues in animal models of essential hypertension. At the moment, her interest is on the mechanisms that control cell proliferation in glioblastoma and melanoma, and possible new therapies obtained from natural compounds. She is performing her research program at the Laboratory of Molecular and Cellular Pathology of the University of Campania 'Luigi Vanvitelli.” She is the author of numerous scientific manuscripts and book chapters.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"208767",title:"Prof.",name:"Luca",middleName:null,surname:"Colucci D’Amato",slug:"luca-colucci-d'amato",fullName:"Luca Colucci D’Amato",profilePictureURL:"https://mts.intechopen.com/storage/users/208767/images/5415_n.jpg",biography:"Luca Colucci D’Amato is an associate professor of General Pathology at the University of Campania “Luigi Vanvitelli,” where he runs the Laboratory of Cellular and Molecular Pathology, after being a researcher at the National Research Council (CNR). He received his medical degree from the University of Naples “Federico II,” where he, then,obtained a PhD degree in Molecular and Cellular Pathology. He also completed his residency in neurology at the same university. Soon after that, he devoted his efforts to biomedical molecular and cellular research, spending some research periods at the National Institutes of Health, Bethesda, MD, USA, the Bristol-Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA, and the Centre National de la Recherche Scientifique, Gif-sur-Yvette, France. His scientific interests focus on the molecular mechanisms underlying neural cell proliferation, differentiation, and survival under physiological and pathological conditions.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"215",title:"Neurophysiology",slug:"neurophysiology"}],chapters:[{id:"59259",title:"Introductory Chapter: The Importance of Astrocytes in the Research of CNS Diseases",doi:"10.5772/intechopen.74710",slug:"introductory-chapter-the-importance-of-astrocytes-in-the-research-of-cns-diseases",totalDownloads:1183,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Maria Teresa Gentile and Luca Colucci D’Amato",downloadPdfUrl:"/chapter/pdf-download/59259",previewPdfUrl:"/chapter/pdf-preview/59259",authors:[{id:"160180",title:"Dr.",name:"Maria Teresa",surname:"Gentile",slug:"maria-teresa-gentile",fullName:"Maria Teresa Gentile"}],corrections:null},{id:"58019",title:"Signaling Pathways Regulating the Pathophysiological Responses of Astrocytes: A Focus on the IKK/NF-κB System",doi:"10.5772/intechopen.72283",slug:"signaling-pathways-regulating-the-pathophysiological-responses-of-astrocytes-a-focus-on-the-ikk-nf-b",totalDownloads:1107,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Astrocytes are highly responsive to changes in their microenvironment, and undergo prominent functional alterations in pathological conditions, a process called astrogliosis. In such conditions, astrocytes can gain immune cell-like functions, form glial scars and promote brain repair and regeneration. However, astrogliosis can also contribute to disease pathogenesis by exacerbating inflammation and perturbing the normal physiological functions of astrocytes. The IKK/NF-κB signaling system is a master regulator of inflammation, cell survival and differentiation, which also controls astrocyte functions, in particular their responses to pathological conditions. Activation of IKK/NF-κB signaling in astrocytes is a key driver of neuroinflammation and astrogliosis, which can interfere with normal brain development and homeostasis and can aggravate various central nervous system (CNS) pathologies. Besides IKK/NF-κB signaling, several other signaling pathways regulate pathophysiological responses of astrocytes, in particular hypertrophy, proliferation and the reactivation of neural stem cell-like properties of astrocytes. Further dissection of the role of these signaling pathways in the control of physiological functions and pathophysiological plasticity of astrocytes will reveal new insights into the pathogenesis of neurological diseases and might indicate new neuroprotective and regenerative therapeutic approaches.",signatures:"Michael Lattke and Thomas Wirth",downloadPdfUrl:"/chapter/pdf-download/58019",previewPdfUrl:"/chapter/pdf-preview/58019",authors:[{id:"211692",title:"Dr.",name:"Michael",surname:"Lattke",slug:"michael-lattke",fullName:"Michael Lattke"},{id:"211693",title:"Dr.",name:"Thomas",surname:"Wirth",slug:"thomas-wirth",fullName:"Thomas Wirth"}],corrections:null},{id:"59145",title:"Evidence that Astroglia Influence Dendrite Morphogenesis and Synaptogenesis Independently in the Vertebrate Central Nervous System",doi:"10.5772/intechopen.73891",slug:"evidence-that-astroglia-influence-dendrite-morphogenesis-and-synaptogenesis-independently-in-the-ver",totalDownloads:1237,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"In the absence of external spatial cues, dendritic arbors of neurons grown in vitro approximate those observed in situ. Absent, however, from these culture models is patterned orientation of dendritic trunks, and variation of branch geometry that provide identifiable characteristics of the cytoarchitecture of the intact brain. Although astroglia are present during key stages of dendritic development in vivo, little is known about whether local interactions with glia shape dendritic growth. Astroglial cells are good candidates for this kind of regulation because they can exert control over the formation of synapses, an event correlated with the maturational state of the dendrite. The present review highlights some key findings from vertebrate model systems offering evidence that astroglia can contribute to the shape, and growth, of the dendritic arbor. Drawing from our recent work using a co-culture system composed of neurons growing in differential contact with astroglia, we discuss findings that suggest: 1) growth of dendrites, and addition of synapses, can be independent; further, while astroglia promote synapse formation, they inhibit dendritic growth; 2) astroglia mediate dendrite growth through both paracrine, and contact-dependent mechanisms; and 3) astroglia appear to impose pattern by constraining the growth of dendrites within their zones of influence.",signatures:"Christopher S. Wallace and Ginger S. Withers",downloadPdfUrl:"/chapter/pdf-download/59145",previewPdfUrl:"/chapter/pdf-preview/59145",authors:[{id:"218643",title:"Prof.",name:"Ginger",surname:"Withers",slug:"ginger-withers",fullName:"Ginger Withers"},{id:"221013",title:"Prof.",name:"Christopher",surname:"Wallace",slug:"christopher-wallace",fullName:"Christopher Wallace"}],corrections:null},{id:"58786",title:"NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule",doi:"10.5772/intechopen.72975",slug:"nmda-receptors-in-astroglia-chronology-controversies-and-contradictions-from-a-complex-molecule",totalDownloads:1601,totalCrossrefCites:0,totalDimensionsCites:5,hasAltmetrics:1,abstract:"The neurocentric theory dismissed for decades the role of glia in information handling within the central nervous system (CNS). Nevertheless, almost 3 decades ago, this started to change and today astrocytes are considered relevant players for this function. Astrocytes “listen” to neuronal communication, regulate it, and respond at the cellular and synctitial level. Ionotropic glutamate NMDA receptor (NMDAR) is critical in CNS. It mediates synaptic neuronal communication and it is involved in different mechanisms. However, NMDAR is also expressed by astrocytes, but its functional role in these cells has not been deeply investigated and has been a matter of debate in the last decades. In this chapter, we briefly outline NMDAR intracellular transduction pathways initiated by Ca2+ flux. Then, we review chronologically NMDAR expression and function in astrocytes that have been a source of controversies and apparent contradictions. Finally, some insights are presented regarding NMDAR in astrocytes in the context of the tripartite synapse concept and the recently described Ca2+ flux–independent metabotropic-like NMDAR function in astrocytes. Given the complex molecular nature of NMDAR, its critical role, and the relevance of astrocytes, the study of astrocytic NMDAR promises to provide further understanding of CNS physiology and pathology.",signatures:"Pavel Montes de Oca Balderas and José Roberto González\nHernández",downloadPdfUrl:"/chapter/pdf-download/58786",previewPdfUrl:"/chapter/pdf-preview/58786",authors:[{id:"211726",title:"Dr.",name:"Pavel",surname:"Montes De Oca Balderas",slug:"pavel-montes-de-oca-balderas",fullName:"Pavel Montes De Oca Balderas"},{id:"211733",title:"Mr.",name:"José Roberto",surname:"González-Hernández",slug:"jose-roberto-gonzalez-hernandez",fullName:"José Roberto González-Hernández"}],corrections:null},{id:"58434",title:"Astrocytes in Pathogenesis of ALS Disease and Potential Translation into Clinic",doi:"10.5772/intechopen.72862",slug:"astrocytes-in-pathogenesis-of-als-disease-and-potential-translation-into-clinic",totalDownloads:1493,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Astrocytes are the major cell population in the central nervous system (CNS) and play pivotal role in CNS homeostasis and functionality. Malfunction of astrocytes were implicated in multiple neurodegenerative diseases and disorders, including amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), brain stroke, Parkinson’s disease (PD), and Alzheimer disease (AD). These new insights led to the rationale that transplantation of healthy and functional human astrocytes could support survival of neurons and be of therapeutic value in treating neurodegenerative diseases. Here, we will mainly focus on the role of astrocytes in ALS disease, the major cell sources for generation of human astrocytes, or astrocyte like cells and show how multiple preclinical studies demonstrate the efficacy of these cells in animal models. In addition, we will cover immerging early stage clinical trials that are currently being conducted using human astrocytes or human astrocyte like cell population.",signatures:"Izrael Michal, Slutsky Shalom Guy, Joseph Itskovitz-Eldor and Revel\nMichel",downloadPdfUrl:"/chapter/pdf-download/58434",previewPdfUrl:"/chapter/pdf-preview/58434",authors:[{id:"215025",title:"Ph.D.",name:"Michal",surname:"Izrael",slug:"michal-izrael",fullName:"Michal Izrael"},{id:"215048",title:"Dr.",name:"Shalom Guy",surname:"Slutsky",slug:"shalom-guy-slutsky",fullName:"Shalom Guy Slutsky"},{id:"225933",title:"Prof.",name:"Michel",surname:"Revel",slug:"michel-revel",fullName:"Michel Revel"},{id:"225934",title:"Prof.",name:"Joseph",surname:"Itskovitz-Eldor",slug:"joseph-itskovitz-eldor",fullName:"Joseph Itskovitz-Eldor"}],corrections:null},{id:"58732",title:"Astrocytes’ Role in Alzheimer’s Disease Neurodegeneration",doi:"10.5772/intechopen.72974",slug:"astrocytes-role-in-alzheimer-s-disease-neurodegeneration",totalDownloads:1357,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Central nervous system (CNS) astrocytes are glial cells performing crucial tasks encompassing energy metabolism, neurotransmission, ion and water stable levels, and immune defense and control local blood flow/oxygen levels. Arising from neural stem cells, astrocytes differentiate into subtypes that vary according to animal species. Human cerebral cortex astrocytes are sturdier and cytologically and functionally more complex, control wider domains, and spread calcium signals more quickly than their rodents’ counterparts. They actively partake in CNS homeostasis maintenance and functioning by teaming up with their client neurons, other glial cell types, and cerebrovascular cells. Alterations of astrocytes’ activities deeply impact on age-related chronic ailments like Alzheimer’s disease (AD), the commonest senile dementia; AD involves the growing accumulation of amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins the astrocytes, and neurons supply following the interaction of their calcium-sensing receptors (CaSRs) with exogenous Aβs. The activated Aβ∙CaSR signaling triggers a self-propagating mechanism that spreads the neuropathology among adjacent and far away astrocytes and their neuronal clients causing neurons’ death. CaSR antagonists or calcilytics suppress these noxious effects in vitro. Hence, calcilytics are potential therapeutics that could halt the spread of AD neuropathology and safeguard the patients’ neuronal viability, cognition, memory, and ultimately life.",signatures:"Ilaria Dal Prà, Ubaldo Armato and Anna Chiarini",downloadPdfUrl:"/chapter/pdf-download/58732",previewPdfUrl:"/chapter/pdf-preview/58732",authors:[{id:"211390",title:"Dr.",name:"Ilaria P",surname:"Dal Pra",slug:"ilaria-p-dal-pra",fullName:"Ilaria P Dal Pra"},{id:"222536",title:"Dr.",name:"Anna",surname:"Chiarini",slug:"anna-chiarini",fullName:"Anna Chiarini"},{id:"222537",title:"Prof.",name:"Ubaldo",surname:"Armato",slug:"ubaldo-armato",fullName:"Ubaldo Armato"}],corrections:null},{id:"58306",title:"Mitochondrial Function in Alzheimer’s Disease: Focus on Astrocytes",doi:"10.5772/intechopen.71825",slug:"mitochondrial-function-in-alzheimer-s-disease-focus-on-astrocytes",totalDownloads:1502,totalCrossrefCites:2,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The brain is one of the most energy-requiring organs in the human body. Mitochondria not only generate this energy, but are centrally involved critical cellular functions including maintenance of calcium homeostasis, synthesis of biomolecules, and cell signaling. Even though neurons and astrocytes preferentially use different energy substrates and metabolic pathways, these two cell types are intricately linked in their energy metabolism. Recently it has become clear that astrocytes have a key role in the regulation and support of the neuronal mitochondrial quality control, yet several questions remain unanswered to fully understand the mechanisms of mitochondrial function, transport, turnover and degradation in astrocytes. Alzheimer’s disease is the most common neurodegenerative disorder, the exact mechanisms of which remain incompletely understood. The fact that astrocytic mitochondrial dysfunction is an early event in the pathogenesis of Alzheimer’s disease suggests that more research on mitochondrial function and impairment is required in the hopes of disease alleviation in the future.",signatures:"Riikka Lampinen, Irina Belaya, Isabella Boccuni, Tarja Malm and\nKatja M. Kanninen",downloadPdfUrl:"/chapter/pdf-download/58306",previewPdfUrl:"/chapter/pdf-preview/58306",authors:[{id:"210655",title:"Dr.",name:"Katja",surname:"Kanninen",slug:"katja-kanninen",fullName:"Katja Kanninen"},{id:"210656",title:"MSc.",name:"Riikka",surname:"Lampinen",slug:"riikka-lampinen",fullName:"Riikka Lampinen"},{id:"210658",title:"Ph.D. Student",name:"Irina",surname:"Belaya",slug:"irina-belaya",fullName:"Irina Belaya"},{id:"210660",title:"Ms.",name:"Isabella",surname:"Boccuni",slug:"isabella-boccuni",fullName:"Isabella Boccuni"},{id:"210661",title:"Dr.",name:"Tarja",surname:"Malm",slug:"tarja-malm",fullName:"Tarja Malm"}],corrections:null},{id:"58761",title:"The Role of Astrocytes in Tumor Growth and Progression",doi:"10.5772/intechopen.72720",slug:"the-role-of-astrocytes-in-tumor-growth-and-progression",totalDownloads:1561,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Current research is continually implicating the importance of astrocytes as active participants in neurological injury, disease, and tumor progression. This chapter will discuss some of these emerging concepts, especially as they relate to tumor biology. Astrocytes themselves can become tumorigenic, such as the case in gliomas, which often have aberrant signaling in key regulating genes of astrocyte development. Astrocytes secrete factors that maintain the tight junctions of the blood brain barrier (BBB), which in turn regulates the success or failure of metastatic cells extravasating into the brain. This astrocytic association with the brain vasculature also promotes brain tumor stem cell characteristics, which are known to be necessary for tumor initiation. Tumor cells within the brain make direct contacts with astrocytes through gap junctions, which subsequently lead to increased chemoresistance of the tumor cells. Astrocytes have also been shown to effect tumors cells via secretion of degradative enzymes, cytokines, chemokines, and growth factors, all of which have been shown to promote tumor cell proliferation, survival, and invasion. Thus, research in astrocyte biology and the role of astrocytes in the tumor microenvironment has and will likely continue to reveal novel targets for cancer intervention.",signatures:"Emily Gronseth, Ling Wang, David R. Harder and Ramani\nRamchandran",downloadPdfUrl:"/chapter/pdf-download/58761",previewPdfUrl:"/chapter/pdf-preview/58761",authors:[{id:"164836",title:"Dr.",name:"Ramani",surname:"Ramchandran",slug:"ramani-ramchandran",fullName:"Ramani Ramchandran"},{id:"211372",title:"Ms.",name:"Emily",surname:"Gronseth",slug:"emily-gronseth",fullName:"Emily Gronseth"},{id:"211373",title:"Dr.",name:"Ling",surname:"Wang",slug:"ling-wang",fullName:"Ling Wang"},{id:"211374",title:"Prof.",name:"David",surname:"Harder",slug:"david-harder",fullName:"David Harder"}],corrections:null},{id:"57646",title:"Astrocytes in Aceruloplasminemia",doi:"10.5772/intechopen.71831",slug:"astrocytes-in-aceruloplasminemia",totalDownloads:1028,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In neurons, iron plays an important role in the signal transduction related to synaptic plasticity. The neuronal iron supply is tightly controlled and depends not only on transferrin-bound iron but also on non-transferrin-bound iron (NTBI). Ceruloplasmin is bound to the cell membranes of astrocytes, where it plays a role in iron efflux from astrocytes due to the activity of ferroxidase, which oxidizes ferrous iron after its transfer to the cell surface via ferroportin, and which delivers ferric iron to extracellular transferrin, which is transported to neurons. Aceruloplasminemia is an autosomal recessive neurodegenerative disorder in which iron accumulates in the brain due to the complete lack of ceruloplasmin ferroxidase activity. Redox-active iron accumulation was found to be more prominent in astrocytes than in neurons. Neurons take up iron from alternative sources of NTBI because astrocytes without ceruloplasmin cannot transport iron to transferrin. Neuronal cell loss may result from iron starvation in the early stage of aceruloplasminemia and may result from iron-mediated oxidation in the late stage of the condition. The excess iron in astrocytes can result in oxidative damage to these cells, thereby disrupting the neuronal cell protection offered by astrocytes in patients with aceruloplasminemia.",signatures:"Hiroaki Miyajima",downloadPdfUrl:"/chapter/pdf-download/57646",previewPdfUrl:"/chapter/pdf-preview/57646",authors:[{id:"210055",title:"Prof.",name:"Hiroaki",surname:"Miyajima",slug:"hiroaki-miyajima",fullName:"Hiroaki Miyajima"}],corrections:null},{id:"58516",title:"Astrocyte Pathophysiology in Liver Disease",doi:"10.5772/intechopen.72506",slug:"astrocyte-pathophysiology-in-liver-disease",totalDownloads:1201,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Liver disease is one of the major chronic disabilities around the world. It is known that global casualties are increasing because of virus C infection, alcohol consumption, or non-alcoholic circumstances. One of the main derived comorbidities of liver disease is the hepatic encephalopathy (HE), a severe neuropsychological syndrome derived from the acute or chronic liver disease. A key feature accounting for HE symptoms in cirrhotic patients is brain edema, which is triggered by hyperammonemia. In basal conditions, ammonia can be metabolized in the central nervous system (CNS) by astrocytes, which synthetize glutamine using ammonia and glutamate as substrates. In hyperammonemic conditions, astrocytes synthetize large amounts of glutamine generating a hyperosmotic condition, inducing these cells to become swollen in shape, invoking the characteristic symptom clinically manifested in patients with HE, as brain edema; this condition is regulated by water channels called aquaporins (AQPs) and by other molecules such as myoinositol. Experimental evidence suggests that some small non-coding RNAs may regulate AQPs expression both in vivo an in vitro and that some pharmacological interventions improve cognitive impairment in cirrhotic patients. It is undeniable that astrocytes and the different signaling pathways beneath its plasma membrane play a crucial role in liver disease-derived HE and represent some of the novel pharmacological targets to treat comorbidities of the liver disease.",signatures:"Carlos Pérez-Monter and Aldo Torre-Delgadillo",downloadPdfUrl:"/chapter/pdf-download/58516",previewPdfUrl:"/chapter/pdf-preview/58516",authors:[{id:"211176",title:"Prof.",name:"Carlos",surname:"Pérez-Monter",slug:"carlos-perez-monter",fullName:"Carlos Pérez-Monter"},{id:"211276",title:"Dr.",name:"Aldo",surname:"Torre-Delgadillo",slug:"aldo-torre-delgadillo",fullName:"Aldo Torre-Delgadillo"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8751",title:"Somatosensory and Motor Research",subtitle:null,isOpenForSubmission:!1,hash:"86191c18f06e524e0f97a5534fdb2b4c",slug:"somatosensory-and-motor-research",bookSignature:"Toshiaki Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/8751.jpg",editedByType:"Edited by",editors:[{id:"70872",title:"Prof.",name:"Toshiaki",surname:"Suzuki",slug:"toshiaki-suzuki",fullName:"Toshiaki Suzuki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6331",title:"Hypothalamus in Health and Diseases",subtitle:null,isOpenForSubmission:!1,hash:"d8943dda86e7f5eea7bb5afc1ff70cfe",slug:"hypothalamus-in-health-and-diseases",bookSignature:"Stavros J. 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There is a persistent need of upgrading the information related to heterocyclic compounds, which play a significant role in biochemical reactions in living cells. There is a whole range of heterocycles/fused heterocycles with one/two heteroatoms with diverse applications. The momentum gained for the synthesis of new heterocycles testifies to their significance. The challenges in synthesizing new heterocycles and also its properties that increase their applications stimulate research in heterocycles. In this book, we will be discussing chemical strategies for the synthesis of the spectrum of heterocycles and their relevant applications in pharmaceuticals, agriculture, and material science. The green synthetic approach is an eco-friendly method conferring a unique way of looking into the chemistry involved in synthesis to minimize/eliminate waste, decrease consumption of energy, and usage of green solvents. 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",isbn:"978-1-83768-242-3",printIsbn:"978-1-83768-241-6",pdfIsbn:"978-1-83768-243-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"bc4022af925c0883636e0819008971ee",bookSignature:"Dr. Premlata Kumari and Dr. Amit B Patel",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12079.jpg",keywords:"Green Synthesis, One-Pot Synthesis, Pyrazole, Thiazole, Oxazole, Imidazole, Benzopyrazole, Quinoline, Isoquinoline, Coumarine, Quinazoline, Pyrimidine",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 27th 2022",dateEndSecondStepPublish:"July 29th 2022",dateEndThirdStepPublish:"September 27th 2022",dateEndFourthStepPublish:"December 16th 2022",dateEndFifthStepPublish:"February 14th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Premlata Kumari has 15 plus years of teaching and research experience. 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The majority of her works deal with the Organic synthesis of reaction intermediates and bioactive compounds against various diseases like tuberculosis, malaria, cancer, etc., extraction of natural products from various medicinally important plants, and development of HPLC methods for chemical markers of medicinal plants.\r\nCitations: 1433\r\nh-index: 21",institutionString:"Sardar Vallabhbhai National Institute of Technology Surat",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Sardar Vallabhbhai National Institute of Technology Surat",institutionURL:null,country:{name:"India"}}}],coeditorOne:{id:"183416",title:"Dr.",name:"Amit",middleName:"B",surname:"Patel",slug:"amit-patel",fullName:"Amit Patel",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Dr. Amit B. Patel is presently working as an Assistant Professor in the Department of Chemistry, Government College, Daman, India. Dr. Patel received his Ph.D. degree from Applied Chemistry Department, Sardar Vallabhbhai National Institute of Technology (SVNIT), Surat in 2015. He has done his Master's degree in Organic Chemistry from B.K.M. Science College, Valsad, India. He secured a Gold Medal in his Master's. He has published 18 research papers in Scopus/Web of Science/UGC care list National and International Journals. He has also published 6 books/book chapters. He is serving as a reviewer for many reputed journals. He has been selected as an Assistant Professor at Government College, Daman, India through the Union Service Public Service Commission of India. He has a total of 7 years of teaching experience at the Undergraduate as well as Postgraduate levels. Dr. Patel is a recognized Ph.D. supervisor of Veer Narmad South Gujarat University, Surat, India. 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Tetrazoles easily react with acidic materials and strong oxidizers (acidic chloride, anhydrides, and strong acids) to liberate corrosive and toxic gases and heat. It undergoes reaction with few active metals and produces new compounds which are explosives to shocks. It involves exothermic reactions with reducing agents. On heating or burning, it releases carbon monoxide, carbon dioxide, and harmful nitrogen oxide. Tetrazole dissolves in water, acetonitrile, etc. Generally, dilute 1
The presence of free N-H causes the acidic nature of tetrazoles and forms both aliphatic and aromatic heterocyclic compounds. Heterocycles of tetrazoles can stabilize the negative charge by delocalization and show corresponding carboxylic acid pKa values. Tetrazole nitrogen electron density results in the formation of so many stable metallic compounds and molecular complexes. This compound shows strong negative inductive effect (−I electron withdrawing) and weak positive mesomeric effect (+M electron releasing).
\nThe tetrazole is a five-membered aza compound with 6π electrons, and 5-substituted tetrazole reactivity is similar to aromatic compounds. The Huckel 6π electrons are satisfied by four π electrons of ring and one loan pair of electrons of nitrogen. The acidic nature of tetrazole is similar to corresponding carboxylic acids, but there is a difference in annular tautomerism of ring tetrazoles to carboxylic acids. The acidic nature of tetrazole is mainly affected by substitution compound nature at C-5 position. 5-Phenyltetrazole anion shows high acidic nature like benzoate due to resonance stabilization. A simple method to produce tetrazole anion is the reaction of tetrazole with metal hydroxides and can be stable in aqueous and alcoholic solution at high temperature.
\nClick chemistry is called as tagging in synthesis of chemicals. It is in the category of non-harmful reactions, proposed initially to unite the base materials of choice with certain bimolecular substance. It also can be termed as a non-peculiar reactive process. Indeed it explains a way of generating products that follow examples in nature. At the same time, it can produce the variety of materials by consolidating small compatible units. Usually, click reactions join a biomolecule and a reporter molecule. Click chemistry is not limited to the state of survival. It is the concept of a “click” reaction that has been used in pharmacological and various biomedical applications. It also can be described as non-single specific reaction etic application. Nevertheless, it is observed to be highly functional in the diagnosis of localization and qualification of bimolecular material.
\nClick reactions occur in one pot and generally make an evidence of being uninterrupted by water. They produce negligible and innocuous corollary and are spring-loaded. In addition to this, they are distinguished by a high thermodynamic driving force that pushes them rapidly and irrevocably to supply a single reaction product, with high reaction specificity. In few cases, they are created with both regio- and stereospecificity. These click reactions are specifically adaptable in the case of segregating and navigating the molecules in composite biological environments. In such conditions, items in like manner should be physiologically steady, and any side effects should be nonlethal.
\nResearchers have opened up the likelihood of hitting specific focuses in complex cell lysates, by developing specific and controllable bio-orthogonal reactions. Recently, they have adjusted snap science for use in live cells, for instance, utilizing little atom tests that find and append to their objectives by click reactions. In spite of difficulties of cell porousness, bio-orthogonality, foundation naming, and response effectiveness, click responses have officially demonstrated valuable in another era of pull-down tests and fluorescence spectrometry. All the more as of late, novel strategies have been utilized to fuse click response accomplices onto and into biomolecules, including the joining of unnatural amino acids containing receptive gatherings into proteins and the change of nucleotides. These strategies speak to a piece of the field of compound science, in which click science assumes a central part by deliberately and particularly coupling secluded units to different finishes.
\nThis refresh outlines the developing use of “click” science in various zones, for example, bioconjugation, sedate disclosure, materials science, and radiochemistry. It additionally talks about snap science responses that continue quickly with high selectivity, specificity, and yield. Two essential qualities make click science so appealing for collecting mixes, reagents, and biomolecules for preclinical and clinical applications. To begin with, click reactions are bio-orthogonal. First of all, they are neither reciprocal nor their functional gatherings of different products connect with functionalized biomolecules. Secondly, the responses continue effortlessly under gentle nontoxic conditions. Example is their reaction at the room temperature and, for the most part, in water. The copper-catalyzed Huisgen cycloaddition, azide-alkyne [3+2] dipolar cycloaddition, Staudinger ligation, and azide-phosphine ligation all have these interesting qualities. These responses can be utilized to change one cell part while leaving others unharmed or untouched.
\nClick chemistry has discovered expanding applications in all parts of medication revelation in restorative science, for example, for producing lead mixes through combinatorial strategies. Through bioconjugation click chemistry is thoroughly utilized in proteomics and nucleic exploration. In radiochemistry, specific radiolabeling of biomolecules in cells and living creatures for imaging and treatment has been acknowledged by this innovation. Bifunctional chelating operators for a few radionuclides are valuable for positron discharge tomography and single-photon emanation processed tomography. They have additionally been set up by click chemistry. This survey reasons that click chemistry is not the ideal conjugation, and gathering innovation for all applications, however, gives a capable, appealing another option to ordinary science. This science has turned out to be prevalent in fulfilling numerous criteria, e.g., biocompatibility, selectivity, yield, stereospecificity, etc. In this way, one can expect that it will subsequently turn into a more normal procedure soon for an extensive variety of uses.
\nLock and key models for Ligand-Target fitting.
MD research depends mostly on computationally simulating the molecular recognition process by decreasing the free energy of overall system. Basic awareness on the preferred orientation in turn may be used to predict the binding affinity between two molecules used. Molecular docking is an invaluable tool in the field of molecular biology, computational structural biology, computer-aided drug designing, and pharmacogenomics.
\nThere are two ways of docking approaches, namely, the first matching methodology which explains ligand-enzyme as complementary surfaces and the other simulated docking methodology of protein and ligand pairwise interaction energies. The application of docking in a targeted drug-delivery system is a huge benefit. One can study the size, shape, charge distribution, polarity, hydrogen bonding, and hydrophobic interactions of both ligand (drug) and receptor (target site).
\nThe investigation of tetrazoles centers the most imperative organic exercises like antihypertensive, against inflammatory, antibacterial, antifungal, anticancer, antidiabetic, and hypoglycemic activity. Different strategies for synthesis and characterization techniques were discussed.
\nThroughout the previous couple of years, investigation of tetrazole chemistry has been rapidly expanded in view of its huge applications, for the most part because of the pretended by this heterocyclic usefulness in restorative chemistry. This provides more support to pharma field and metabolically stable swap for carboxylic acid functionalities, particularly, joining of the tetrazole exercises into angiotensin II rival structures, sartans (2–4) [1, 2, 3, 4].
\nIrbesartan (5), one of the essential tetrazole subsidiaries, has a place with the sort of medication called angiotensin II receptor enemy antihypertensives. This medication is utilized for the treatment of high blood pressure (hypertension) and for kidney issues because of Type 2 diabetes (noninsulin-dependent).
\nTetrazolo quinoline has an imminent and empowering new structure for the novel against the anti-inflammatory (6) and antibacterial (7) agents [3, 4].
\nPiperidine-substituted tetrazoles (
Tetrazole derivatives (
The 2,4 thiazolidinedione by-products (
The in vivo hypoglycemic action of tetrazole bears
Powerful drugs in opposition to hypertension, cancer, and bacterial and fungal infections have to fulfill a number of requirements like toxicity to tumor cells and are capable of being dissolved for efficient delivery. This makes necessary full-fledged characterization of drug position, comprising achieved synthetic strategies. In this chapter we directed on tetrazole biological activities. As a consequence, the need of synthetic routes to prepare tetrazole derivatives that are selective toward specific malfunctioning enzyme connects with illness. The study of good approaches of tetrazoles and medicinal applications will definitely allow to propose more useful drugs.
\nSince 1901, regular synthesis of 5-switched-1
Tetrazoles as a gathering of heterocyclic compounds are accounted for having an expansive range of organic exercises, for example, antibacterial, antifungal, antiviral, pain-relieving, mitigating, antiulcer, and antihypertensive exercises. Likewise, 5-substituted-1
A facile method to synthesize Cu(II), Zn(II), Pb(II), and Cd(II) complexes with di-anionic tetrazole-5-carboxylate (ttzCOO2−) ligands (18), involving an in situ hydrolysis of 1
5-Phenyl tetrazole (
Reagent conditions: (i) DMF/ammonium chloride; (ii) acetic anhydride, 20 min; (iii) R-CHO, 50% KOH, ethanol; (iv) isonicotinic acid hydrazide/GAA.
\n5-Phenyl, 1
Tetrazoles (
N1-substituted tetrazoles (
To synthesize tetrazole-containing complexes with anionic ligands (29), tetrazole reacts with another ligand in a coordination compound [24, 25].
\nThe synthetic protocol involves reaction of inorganic azides and organic nitriles in the presence of Zn(II) salts under hydrothermal conditions to afford 5-substituted-1
To union of 5-thio replaced tetrazole subordinates and assessment of their antibacterial and antifungal properties, industrially accessible benzyl isothiocyanate (
The tetrazoles (35, 37) were orchestrated in outstanding reactiveness by the response of sodium azide and triethyl orthoformate with relating amines, viz., 1-[3-(2-amino ethyl)-1
To prepare tetrazole-containing 1,2,3-thiadiazole derivative (
Reagents and conditions: (a) NaBH4 (2.0 equiv.), EtOH, 0°C for 1 h, r.t. for 6 h; (b) pyridinium chlorochromate (2.0 equiv.), CH2Cl2, r.t. for 8 h; (c) (i) R-NH2 (1.0 equiv.), CH3OH, r.t. for 0.5–1 h; and (ii) cyclohexyl isocyanide (1.2 equiv.), TMSN3 (1.5 equiv.), r.t. for 12–24 h.
\n10 mmol of 3-(1,3
A mixture of 1-(2-trifluoromethane phenyl)-5-phenyl-1
A blend of chosen amine (
The above experiments yield very good result in the presence of various catalysts especially with silica sulfuric acid.
\nThe readiness of 1,5-disubstituted-1
A progression of novel 5-phenyl-1-acyl-1,2,3,4-tetrazoles (
A blend of carbonyl compound, malononitrile, and sodium azide in the presence of H2O was mixed at 50°C for proper time to outfit the required tetrazole [34, 60, 61, 62, 63].
\n3-Nitro benzaldehyde (
Aryl dicarbonyl compound (
2,4,6-Trioxo derivative-5-yl compound (
Azidation of benzonitrile (
A mixture of indole-3-carbaldehyde (
To this mixture, aniline, EtOH, and three drops of acidic corrosive are included and after that a warmed steam shower for 5–6 h to obtain the compound (
Cuttlebone has a characteristic minimal effort heterogeneous impetus with high porosity. It carries high flexural firmness, high compressive quality, and high thermal solidness. Cuttlebone was taken out from cuttlefish (
SEM image of cuttlebone.
An advantageous, fast, and metal-free synthesis of 5-substituted-1
Figure 3 describes the system for the synthesis of 5-substituted-1
Synthesis of 5-substituted-1
There are several literature reports pertaining to molecular docking studies of divergent tetrazole derivatives. We are citing a few for basic understanding of the readers who can explore this field a lot.
\nVery recently, Jonnalagadda et al. have synthesized some tetrazole-linked benzochromene derivatives and had their molecular docking study as well [76]. 5-Substituted 5-styryl terazolo[1,5-c]quinazoline derivatives were studied for their cytotoxicity and molecular docking by Parbhoo et al. [77]. In a similar fashion, several tetrazole derivatives were synthesized and subject to molecular docking in recent years [78, 79, 80, 81, 82].
\nThe synthesis of tetrazole derivatives can be approached in various methods like ecofriendly, water solvent, moderate conditions, nontoxic, easy extractions, easy setup, low cost, etc. with good to excellent yields. The structural analysis was done by thermal and spectroscopic methods. Tetrazole and its derivatives play very important role in medicinal and pharmaceutical applications. Molecular docking studies play a vital role to decide the synthesis of pharmacologically relevant tetrazole derivatives in the near future. This facilitates, in fact, for new researchers to choose this topic as an apt and relevant research topic to explore.
\nDr. Ravi Varala thanks honorable Vice Chancellor, Sri Dr. A. Ashok, IAS, RGUKT Basar, and T. N. Venkata Swamy, administrative officer, for his kind support and encouragement.
\nCancer or tumor cells express neoantigens that the immune system can identify from healthy neighboring cells due to genetic mutations. These changes typically result in a tumor-reactive T cell response, most notably CD8+ T cells. However, this mechanism is frequently ineffective at eradicating cancer cells [1]. One cause for this failure is the suppression of invading T cells by a wide range of immunosuppressive mechanisms found in the tumor microenvironment (TME), such as regulatory T cells (Tregs) or immunosuppressive cytokines [2, 3].
Furthermore, binding of the T cell receptor (TCR) to the antigenic peptide bound to the major histocompatibility complex (MHC) of the antigen-presenting cell (APC) is not adequate to yield an immune response, particularly to eradicate cancer cells. Thus, the additional stimulatory co-signal produced by co-receptors is required. These co-receptors play an essential role in modulating T cell responsiveness and balancing co-stimulatory and inhibitory (i.e., immune checkpoint) signals [4]. Extended TCR signals generated from T cells exposure to their cognate antigen result in enhanced and persistent expression of inhibitory co-receptors like cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death protein 1 (PD-1), or many other immune checkpoints. At this moment, T cells enter a state of dysfunction or exhaustion, allowing cancer cells to grow unchecked [5, 6]. Therefore, blockage to these immune checkpoints can reinvigorate the anti-tumor function of immune cells. This chapter aimed to elaborate on the involvement of immune checkpoints in cancer development. It includes the explanation of the normal trafficking and inhibitory signaling of each checkpoint, followed by discussions about how immune checkpoint contributes to cancer growth.
Immune checkpoints serve as the immune system’s gatekeepers and are required for sustaining self-tolerance, thus protecting the host from tissue damage. These immunological checkpoint molecules have modulated T cell responses to self-proteins, persistent infections, and tumor antigens. A few of them, including but are not limited to PD-1, CTLA-4, Lymphocyte activation gene 3 (LAG3; or known as cluster of differentiation 223 [CD223]), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoreceptor with immunoglobulin and ITIM—immunoreceptor tyrosine-based inhibitory motif—domain (TIGIT), and B and T lymphocyte attenuator (BTLA; or known as CD272), have been discovered and investigated as targets in cancer immunotherapy. In general, immune checkpoints are membrane proteins expressed in the endoplasmic reticulum (ER) and subsequently transported to the cell surface to perform their inhibitory roles, which requires the protein sorting system to transport them sequentially through the Golgi apparatus secretory vesicles. Glycosylation acts as quality control during surface delivery, ensuring that only mature and functional immunological checkpoints reach the cell surface. Immune checkpoints are internalized and recycled when they reach the cell surface, providing a quick regulatory pathway to control their surface levels. Immune checkpoints can be ubiquitinated and sorted to the proteasome or lysosome for destruction, another critical method for controlling protein levels. The surface level of immunological checkpoints is determined by several biological mechanisms, which affect cell signaling [7]. This section elaborates on the normal regulations and signaling of each immune checkpoints molecules before discussing its involvement in cancer development.
PD-1 trafficking in the membrane is regulated by the core fucosyltransferase 8 (fut8) in ER. Upon Tcell activation, PD-1 is internalized, then ubiquitinated by F-box protein 38 (FBXO38) for proteasome degradation or recycled back to the surface with the help of thymocyte selection-associated high mobility group box protein (Tox), thus prolonged PD-1 activity. Additionally, Tox expression induces Tcell depletion in hepatocellular cancer [7, 8]. Besides, another extension of PD-1 activity is caused by FBXO38’s low transcriptional level in the TME. Hence, the FBXO38-mediated PD-1 degradation pathway is defective. TCR signaling was the source of FBXO38 downregulation in the absence of concurrent CD28-CD80/86 signaling. CD28-CD80/86 binding provides critical signals for T cell activation in the presence of TCR stimulation. Persistent tumor antigen binding and low CD80/86 expression on cancerous cells might explain the lower FBXO38 expression in tumor-infiltrating lymphocytes (TILs) [7, 9].
Similar to PD-1, its first functionally identified ligand of PD-L1 (also known as B7 homolog 1 [B7-H1] or CD274) is constantly internalized, recycled, or degraded. Regulation of PD-L1 recycling is managed by CKLF-like MARVEL transmembrane domain containing 6 (CMTM6). Meanwhile, ubiquitination and degradation are regulated by multiple proteins such as cyclin D–CDK4 and the cullin 3–SPOP [10], β-TrCP [11], COP9 signalosome 5 (CSN5] [12], Huntingtin-interacting protein 1-related (HIP1R) [13], and others. Each protein is a drugable target to inhibit PD-L1 accumulation, thereby increasing T cell-mediated cytotoxicity.
Regarding the inhibitory signals following the binding of PD1 to PD-L1 or other ligands, it blocks kinases that play a role in activating T cells through the phosphatase SHP2. Besides, since PD1 inhibition blocks the TCR ‘stop signal’, this pathway can alter the length of T cell–APC or T cell–target cell interaction [14]. In detail, PD-1 is phosphorylated through immune receptor tyrosine-based switch motif (ITSM) and ITIM. Then, PD-1 binds the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2) or SHP1, which initiate its inhibitory effect by suppressing both TCR and CD28 co-stimulatory signaling [7, 15, 16, 17]. Moreover, PD-1 signaling also reduces cytokine production (interleukin [IL]-2, interferon [IFN]- α, tumor necrosis factor [TNF]-α), cell cycle progression, and pro-survival Bcl-xL gene expression by interfering with early TCR/CD28 signaling. PD-1/PD-L1 interaction is associated with IL-2-dependent positive feedback and transcription factors involved in effector functions such as GATA-3, T-bet, and Eomes. As signal transduction can only occur during TCR-dependent signaling, PD-1 activity is thus only relevant during simultaneous T cell activation. Mice without the receptor appear healthy at first. Still, they acquire autoimmune disorders such as lupus-like proliferative glomerulonephritis and arthritis, as well as enhanced inflammation after infections at a later age. In humans, genetic variations in the PD-1 region are more likely to suffer autoimmune disorders [18, 19].
Unlike PD-1/PD-L1, which is constitutively expressed on the membrane, CTLA-4 is primarily stored inside the cytoplasm of resting naïve T lymphocytes. The T cell receptor-interacting molecule (TRIM)/LAX/Rab8 complex and phospholipase D (PLD)/ADP ribosylation factor-1 (ARF1)-dependent exocytosis are required for CTLA-4 trafficking from trans Golgi network (TGN) to the cell surface [20]. Exocytosis of CTLA-4-containing vesicles causes upregulation of CTLA-4 on the cell surface due to stimulatory signals originating from TCR and CD28-B7 interaction. More robust TCR signaling causes more CTLA-4 to be translocated to the cell surface, and this process works in a graded feedback loop. CTLA-4 on the surface is rapidly internalized during normal physiologic conditions, resulting in relatively low expression. The clathrin-associated adaptor complex (AP-2) interaction to the unphosphorylated YVKM motif promotes rapid CTLA-4 internalization, which is then either destroyed in the lysosome or returned to the cell surface through LPS responsive beige-like anchor protein (LRBA). Besides, CTLA-4 in TGN may also be transported to the lysosome for destruction through AP-1 binding [7, 21, 22].
The intrinsic signaling of CTLA-4 that dampens T cell immune response has been widely contested with no agreement [23]. However, both CTLA-4 and CD28 interact with the identical ligands, CD80 (B7–1) and CD86 (B7–2). Because CTLA-4 has a 20-fold higher binding affinity than CD28, the intrinsic inhibitory signal rises once CTLA-4 outcompetes CD28, even if CTLA-4 is activated later [24, 25]. In addition to T cell response intrinsic inhibition, CTLA-4 is hypothesized to decrease extrinsic T cell signaling. For example, CTLA-4 suppresses CD80/86 expression on APCs via trans-endocytosis or by increasing tumor growth factor β (TGFβ), which in turn suppresses CD80/86 expression [26]. CTLA-4 is phosphorylated when it binds to its ligands, activating phosphoinositide 3-kinase (PI3K) pathways leading to dephosphorylation of the CD3 chain, decreasing the TCR’s signaling potential. CTLA-4 also prevents T cells from proliferating by inhibiting IL-2 transcription. Additionally, CTLA-4 stimulates the production of indoleamine 2,3-dioxygenase (IDO) in dendritic cells via CD80/86 ligation, resulting in T cell suppression [27].
TIM-3 is expressed on both T cells and innate immune cells. Four ligands have been identified: carcinoembryonic antigen cell adhesion molecule 1 (Ceacam1), C-type lectin galectin9 (Galectin9), high-mobility group box 1 (HMGB1), and non-protein ligand phosphatidylserine (PtdSer). Ceacam1 is a transmembrane protein that interacts in
TIM-3 is more related to co-stimulatory proteins induced in activated T cells than to a dominant inhibitory protein like PD-1; thus, TIM-3 signaling remains a matter of debate. As checkpoint proteins, TIM-3 is a repressor of IFN-γ-secreting CD4+ Th1 and CD8+ T cells. These findings confirmed that inhibiting TIM-3 might correct the defective phenotype of T cells in vivo. In contrast, TIM-3 lacks a conventional ITIM or ITSM in its intracellular domain and lacks structural features that facilitate the recruitment of inhibitory phosphatases. Rather than that, both murine and human TIM-3 cytoplasmic tails include five conserved tyrosine residues, two of which, Y256 and Y263 in mice (Y265, Y272 in humans), have been demonstrated to be crucial for coupling to downstream signaling pathways. Y256 and Y263 in TIM-3’s C-terminal tail interact with Bat3 in the absence of ligand-mediated TIM-3 signaling. Bat3 binds the catalytically active form of Lck in this state, resulting in the formation of an intracellular molecular complex with TIM-3 that retains and maybe enhances T cell signaling while repressing TIM-3-mediated cell death and exhaustion [31, 32]. TIM-3 activation on exhausted effector T cells is closely attributed to PD-1 expression, confirming the functional relationship between TIM-3 and PD-1 throughout the development of T cell exhaustion [33]. Concomitant therapy of anti-TIM-3 and anti-PD-1 is significantly more successful in these models, resulting in more significant tumor regression than either TIM-3 or PD-1 inhibition alone. TIM-3 inhibition in the setting of adaptive resistance to PD-1 treatment may be a useful way to treat individuals who develop resistance to anti-PD-1 therapy. This therapy regimen may be particularly beneficial for malignancies with resistance and immune escape from PD-1 inhibition [34, 35].
Like CTLA-4 and CD28, TIGIT and CD226 can interact with identical ligands, CD112 and CD155. TIGIT is a co-inhibitory receptor, while CD226 is a co-stimulatory receptor. Nevertheless, TIGIT possesses a higher affinity to its ligands than CD226; thus, TIGIT can inhibit co-stimulation signals by outcompeting CD226 ligands binding. TIGIT can bind directly to CD226 in
TIGIT’s signaling is mostly studied in natural killer (NK) cells and activated CD4 and CD8 T cells. The cytoplasmic region of TIGIT comprises an ITIM motif and an immunoglobulin tail tyrosine (ITT)-like motif. Several studies demonstrate that tyrosine (Tyr225) phosphorylation in either the ITIM or ITT-like motif is required for TIGIT’s inhibitory action in human NK cells. According to Liu et al. (2013), the ITT-like motif recruits Src homology domain-containing inositol phosphatases (SHIP1) via cytosolic adaptor proteins Grb2. Recruited SHIP1 then suppresses phosphatidyl-inositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signal to abolish NK cell function. Furthermore, TIGIT signaling can modulate the IFN-γ production of NK cells via the NF-κB pathway. In this context, β-arrestin 2, another TIGIT adaptor, is involved in phosphorylating TIGIT and then inhibits TNF receptor-associated factor 6 (TRAF6) autoubiquitination, hence inhibiting NF-κB activation and suppressing IFN-γ production [38, 39, 40].
LAG3 inhibits CD4-dependent T cell activity by binding to MHC-II due to being structurally homologous with four extracellular immunoglobulin superfamily-like domains. Other investigations demonstrated that LAG3’s inhibitory activity is not dependent on CD4 competition, but rather LAG-3 inhibited T cells responding to stable peptide-MHC-II by transducing inhibitory signals via its intracellular domain. Thus, LAG-3 may act more selectively, allowing tolerance to dominant autoantigens to persist [41, 42]. Alternatively, LAG3 can interact with another ligand like Galectin3 in TME and mediate the suppression of CD8 T cells [43]. Besides, liver sinusoidal endothelial cell lectin (LSECtin) can bind to LAG3 in human melanoma, causing tumor growth by abolishing IFN-γ production and proliferation of tumor-specific T cells [44]. Lastly, fibrinogen-like protein 1 (FGL1) was recently discovered as a novel LAG3 ligand. FGL1 is typically produced in trace amounts into the bloodstream by the liver. However, overexpression of FGL1 has been observed in some human malignancies. Inhibiting the interaction between FGL1 and LAG3 by monoclonal antibodies improves T cells’ anticancer activity [45].
The signal transduction mechanism of LAG3 is regulated by two transmembranes, a disintegrin and metalloproteinase domain-containing protein 10 and 17 (ADAM10 and ADAM17)-mediated cleavage. TCR signaling enhances ADAM10 and ADAM17 cleavage activity, releasing sLAG3. The function of sLAG3 remains controversial as some studies consider this does not have a biological process, while the others state that sLAG3 allows effective T cell proliferation and function [46]. Besides, sLAG3 affects monocyte differentiation into macrophages and DCs, which have decreased immunostimulatory capacity [47].
BTLA and CD160 inhibit T cell activity via the same ligand, herpesvirus entry mediator (HVEM). BTLA-HVEM is an example of crosstalk between two superfamilies in which the ligand is a member of the TNF/TNFR superfamily. However, HVEM interaction with members of the TNF superfamily LIGHT (Lymphotoxins, Inducible, competes with herpes simplex virus (HSV) Glycoprotein D for HVEM, expressed by T cells) produces a co-stimulatory signal on B and T cells. Hence, HVEM may be considered as a molecular switch that enables co-signaling between stimulatory and inhibitory T cells. Additionally, signaling between HVEM and its ligands appears to interact bidirectionally. The cis interaction between BTLA and HVEM inhibits the trans-ligation of HVEM by LIGHT and thus inhibits HVEM stimulatory signaling triggered by LIGHT binding [7, 48, 49].
Regarding the inhibitory signaling of BTLA, it follows the mechanism of PD-1/PD-L1 involving ITIM and ITSM to recruit SHP1/SHP2 [50]. In B-chronic lymphocytic leukemia (B-CLL), both HVEM and BTLA are overexpressed. This co-expression of HVEM and BTLA in CLL cells implies that an unsuccessful autocrine inhibitory loop is triggered. In addition, BTLA is typically downregulated during the development of human CD8+ T cells to effector cells. However, BTLA expression was more significant in melanoma-specific CD8+ T lymphocytes specialized for tumor antigens (TA). Despite effector differentiation, BTLA expression remained persistent, confounding T cell proliferation and IFN-y production. Thus, BTLA may function similarly to PD1 as a T-cell inhibitory receptor in TME [51].
Recent studies have established that immune checkpoint molecules drive cancer growth via various anticancer strategies. The first one is the overexpression of immune checkpoints in cancer cells, immune cells, or the surrounding environment leading to incapabilities of the tumor-specific immune response. Subsequently, immune checkpoints can interfere with metabolic pathways and deplete nutrients needed by immune cells. Lastly, immune checkpoints cripple cancer-specific immune responses by collaborating with regulatory T cells. This section deliberates each strategy thoroughly to get insight into how to combat those actions.
Accumulating evidence showed that several immune checkpoint molecules are overexpressed not only on the surface of cancer cells but also in T cells, Tregs, or even in TME. Here, we thoroughly describe how the immune checkpoint is upregulated and then inhibits antitumor activity. PD-1/PD-L1 are overexpressed on the surface of many cancer cells. Several proinflammatory mediators, which are secreted by activated T cells (types I and II IFN-γ, TNF-α, IL-10, and IL-4) or produced in TME (GM-CSF and VEGF), upregulate PD-L1 expression in the cancer cells resulting in suppression of PD1+ T cells activity. Moreover, cancer cells commonly carry altered PTEN (phosphatase and tension homolog deleted on chromosome ten)—PD-L1 suppressor gene—which may activate the S6K1 gene, resulting in a significant increase in PD-L1 mRNA to polysomes, which promotes PD-L1 mRNA translation and plasma membrane expression [6]. In pancreatic cancer cells, PTEN gene deletion influences PD-L1 expression at the translational level by activating the PI3K/AKT downstream mTOR-S6K1 signaling pathway, thereby increasing PD-L1 production and T lymphocyte apoptosis [52, 53].
Furthermore, amplification and translocation of CD274 on chromosome 9p24.1 have been associated with elevated expression of PD-L1 in Hodgkin’s lymphoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lymphoma, Epstein-Barr virus (EBV)-positive gastric cancer, and oral squamous cell carcinoma (OSCC). In SCLC, chromosomal rearrangements produce CD274 amplification without changing the open reading frame. It is found in various organs, but it is most commonly found in activated T and B lymphocyte cells, dendritic cells, monocytes, and other types of TCs. The CD274/PD-L1 gene is highly conserved, with homologs discovered across the vertebrate lineage (from
PD-L1 induction has also been associated with inflammatory stimuli such as IL-1b, IL-4, IL-6, IL-10, IL-12, IL-17, IL-27, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β). Among the several soluble inflammatory agents, IFN-ϒ is the most important in promoting PD-L1 expression. IFN-ϒ is a proinflammatory cytokine primarily generated by T and NK cells. IFN-ϒ attaches to its receptor, the interferon-gamma receptor (IFNGR), activating the JAK-STAT signaling pathway via STAT1. As a result, it increases the expression of transcription factors, particularly interferon-responsive factors (IRFs). IRF1 is a critical downstream signaling molecule of STAT1 that causes IFN-induced PD-L1. Other proinflammatory agents, IL-4 and TNF-α, have a synergistic impact on the activation of PD-L1 in renal cell carcinoma (RCC) via activating signaling molecules such as NF-κB, IκB, and STAT6. In dendritic cells and monocytes, blocking PD-L1 was associated with decreased IL-10 levels. Furthermore, IL-10 levels on Tyro3, Axl, and Mer (TAM) were closely connected to PD-L1 expression. In monocyte-derived macrophages, IL-12 upregulates PD-L1 expression, but in THP-1-derived macrophages, it downregulates PD-L1 expression. In monocytes, IL-17 is involved in the induction of PD-L1. IL-17 and TNF-α activate NF-κB signaling in prostate cancer and NF-κB and ERK1/2 in colon cancer, respectively, and upregulate PD-L1 expression. PD-L1 expression in dendritic cells is upregulated by IL-1b and IL-27. Furthermore, IL-27 activates phospho-STAT1 and phospho-STAT3 to enhance PD-L1 expression [54, 56].
Meanwhile, CTLA-4 is often constitutively overexpressed on Tregs and has been demonstrated to alter Tregs-mediated immune control. In multiple myeloma patients, FOXP3 and CTLA-4 genes from bone marrow samples were considerably overexpressed [57]. Another sample from peripheral blood mononuclear cells (PBMC) of breast cancer patients showed significantly higher mRNA expression of FOXP3 and CTLA-4 than healthy individuals [58]. Taken together, these results indicated the pivotal role of CTLA-4 in the accumulation of immunosuppressive Tregs in TME, leading to repression of anti-tumor immunity.
Regarding TIM-3 overexpression, it is induced by cytokine stimulation, especially in NK cells. TIM-3 is also extensively expressed on tumor-infiltrating lymphocytes. Similar to its expression pattern during persistent viral infection, TIM-3 is generally co-expressed with PD-1 and represents the most dysfunctional T cell subgroup. TIM-3 overexpression in human malignancies, particularly on immune cells, might be a predictive biomarker for a range of cancers. TIM-3 expression on CD4+ and CD8+ T lymphocytes was enhanced in individuals with hepatitis B virus-related hepatocellular carcinoma (HCC). TIM-3+T cells were replicative senescent and exhibited senescence-related surface and genomic markers. Furthermore, the quantity of tumor-infiltrating cells in TIM-3+ was inversely linked with HCC patient survival [59].
Furthermore, LAG3 is mainly expressed in activated T and natural killer (NK) cells, and it has been identified as a marker for CD4+ and CD8+ T cell activation. Increased LAG3 expression on T cells was observed in combination with other inhibitory receptors such as PD-1, TIGIT, TIM-3, CD160, and 2B4 under pathological conditions such as chronic inflammation or in TME, resulting in T cell exhaustion and reduced cytokine release. In melanoma and colon cancer, LAG3 expression was identified in tissue-infiltrating lymphocytes and peripheral Tregs, tumor-involved lymph nodes, and inside the tumor tissue itself. LAG3 was found on tumor-infiltrating Tregs in patients with head and neck squamous cell carcinoma and non-small cell lung cancer [60].
Similar to other checkpoint molecules, TIGIT is also significantly expressed on Tregs taken from PBMC of cancer patients, and it is further elevated in the TME. Increased TIGIT expression in Tregs is coupled with hypomethylation and FOXP3 binding at the TIGIT gene, distinguishing Tregs from activated effector CD4+ T cells. Furthermore, the Fap2 protein from
Due to cancer cells’ resource intake and vascularization defects, TME is typically deficient in nutrients and oxygen. Cancer cells’ increased need for glucose promotes competition in the TME, which has a detrimental effect on surrounding cells, such as immune cells. Immune checkpoint proteins have been shown to modulate the metabolic energetics of tumor cells, TME, and the tumor-specific immune response, resulting in metabolic reprogramming of both cancerous and immune cells. For instance, CD80 (B7–1) activated the mTOR kinase in naïve CD8+ T cells via the PI3K and STAT4 pathways in solid tumors. mTOR signaling is required to promote glycolysis via hypoxia-inducible factor-1α (HIF-1α) and protein synthesis for supporting cancer cell growth. This activation shifts nutrition balance, and cancerous cells outcompete the immune cells, then evading immune surveillance [62, 63].
Because amino acids are the building blocks of proteins, their availability is critical for tumor development. At the same time, immune cells need amino acids to differentiate and perform their effector activities, hence regulating tumor formation. Given this, a greater knowledge of how each cell species use amino acids in the TME looks critical for successfully stimulating anti-tumor immunity. Tryptophan deficiency impairs CD8+ T cell functions and enhances CD4+ Tregs cell functions, resulting in immunosuppression mediated by the CTLA-4 and PD-1/PD-L1 pathways. The effects are achieved mechanistically by activating the stress response kinase GCN2, which inhibits mTORC2 and its downstream target AKT [64, 65]. The other amino acids, such as glutamine and arginine, are also extensively consumed by the tumors and directly impoverish T cells, leading to the development of immunosuppressive TME [66]. Additionally, tumors may produce and accumulate toxic compounds like aerobic glycolysis byproduct (lactate) in TME, leading to local acidification. Lactate acidosis and hypoxia can activate HIF-1α and then upregulate PD-L1, further inhibiting T-cell responses specific to tumors. Besides, an acidic condition in the surrounding tumors environment suppresses cytokine production (IFN-γ) and limits the activity of T cell cytotoxic, NK cells, and dendritic cells [66, 67].
In contrast to the effector T cells, glucose deprivation may exert a negligible effect on intratumoral Tregs and lactic acid found in the TME may offer nourishment, thus supporting the immunosuppressive function of Tregs [68]. In addition, Tregs differentiation and recruitment is also supported by kynurenine, a metabolite produced from tryptophan through indoleamine 2,3 dioxygenase (IDO)-catabolization in TME [69]. Furthermore, hypoxia and fatty acids production may facilitate Tregs accumulation, thereby favoring its suppressive function [70].
Another immune checkpoint favoring cancer growth strategy is its interaction with Tregs cells either by the expression on Tregs surface or inducing Tregs population and function. Treg cells function in the immune system to regulate and suppress other effector T cells. These cells are responsible for the homeostatic process of the immune system to maintain its unresponsiveness to self-antigens and protect the body from autoimmune reactions or excessive inflammation [71]. However, in this context, the interaction of two immunosuppressive mechanistics is critical in cancer survival from immunosurveillance and progression.
Almost all of the immune checkpoint molecules discussed in this chapter, except BTLA, are expressed in Tregs [72]. CTLA-4 is expressed constitutively on Tregs and induced on effector T cells when activated. CTLA-4 deficiency in Tregs was shown to affect their suppressive effects in animal models. Upon TCR stimulation, CTLA-4 is constitutively recruited on the Tregs cell surface, allowing continuous transendocytosis signaling. Hence, Tregs (CD4+ Foxp3+) can outperformed activated conventional T cells (CD4+ Foxp3−) [73]. Subsequently, downregulation of B7 ligands on APCs leading to diminished CD28 co-stimulation is another way by which Tregs are hypothesized to govern effector T cells [74, 75].
In tumor tissue of non-small cell lung cancer (NSCLC) patients, the PD-L1 expressing CD25+ CD4+ (PD-L1hiTregs) population is higher than in blood or normal tissue. Interestingly, PD-L1hiTregs also correlated with PD-1+ CD8 [76]. In another cancer, highly expressed PD-L1 glioblastoma cells can induce Tregs expansion and maintain its immunosuppressives through PD-1/PD-L1 stimulation. Disrupting the PD-L1/PD-1 axis could target two immunosuppressive mechanisms: inhibition of signaling due to PD-1/PD-L1 ligation and stimulatory proliferation of Tregs cells, which indirectly promotes immunoresistance of high PD-L1 cancers. Thus, Tregs abundance may be a predictive biomarker for patients likely to react to anti-PD-1/anti-PD-L1 therapy or monitor treatment response [77].
Multiple immune checkpoints protein can coexpress and accumulate on the T cell surface, thus increasing dysfunctionality. On CD8+ TILs, it is found that TIGIT is coexpressed with TIM-3, PD-1, and LAG-3 [78]. Although, further investigation is needed to show whether these pathways synergize and whether coblockade is becoming a more efficient immunotherapeutic approach.
Immunological tolerance is normally maintained so that the immune system can recognize and distinguish between self and non-self antigens or neoantigens. Although the immune system is expected to protect the host from exposure to non-self antigens, its robust effector mechanism allows to reverse the attack and disrupt the homeostasis of the immune system. Immune checkpoints, which have gained notoriety as possible cancer therapy targets, are essential immunoregulatory processes found throughout the body. Dysregulation of immune checkpoints promotes tumor cell evasion and plays a significant role in cancer pathogenesis. Therefore, several monoclonal antibodies have been made to block the interaction between ligand and receptor of immune checkpoints, enhancing host immunologic competence against tumors. The list of immune checkpoints inhibitors (ICI), which gained Food and Drug Administration (FDA) approval or are in ongoing clinical trials, is comprehensively summarized in [79]. However, only a tiny proportion of patients respond meaningfully to these therapies due to the signaling complexity and overlapped pathways as mentioned above. Thus, new routes and compounds are being investigated to enhance therapeutic responsiveness and applicability. In clinical practice, the difficulties in treating cancer patients revolve on eliminating the tumor and alleviating symptoms such as pain, fatigue, nausea/vomiting, cough, and diarrhea. Then, concomitant use of medications is negligible and generates new threats for drug interaction such as analgesics [80], steroids [81], antibiotics [82], or many others. Moreover, the use of ICI is often associated with immune-related adverse effects (irAEs). A retrospective study reported that among 1091 patients receiving ICI therapy, 487 (44.63%) patients experienced adverse effects. The most common is fatigue (13.9%), then dermatologic irAEs (12%), endocrine-related irAEs (9.89%), gastrointestinal toxicities (8.4%) and hepatotoxicities (4.94%) [83].
The authors thank our institutions Akademi Farmasi Surabaya and the University of Surabaya, for the support.
The authors declare no conflict of interest.
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