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",isbn:"978-1-80356-336-7",printIsbn:"978-1-80356-335-0",pdfIsbn:"978-1-80356-337-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"c13b60a29b20349f816a6ab71ba35e42",bookSignature:"Prof. Mingzhou Yu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11497.jpg",keywords:"Lab-on-a-Chip, Microfluidics and Nanofluidic Platforms, Micro and Nanoscale Phenomena, Mass and Heat Transport, Multiphase Flow, Nanoparticle-Laden Flows, New Unit-Operation, Theoretical Model, Numerical Method, Experiment, Application, Engineering",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 17th 2022",dateEndSecondStepPublish:"April 21st 2022",dateEndThirdStepPublish:"June 20th 2022",dateEndFourthStepPublish:"September 8th 2022",dateEndFifthStepPublish:"November 7th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher selected for the Alexander von Humboldt research fellowship and previously affiliated with the Karlsruhe Institute of Technology as a postdoc researcher. Dr. Yu is a holder of 90 journal papers, with an h index of 21, is a member of A& WA (USA) and AAAR (USA), and is the holder of 24 registered patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"188972",title:"Prof.",name:"Mingzhou",middleName:null,surname:"Yu",slug:"mingzhou-yu",fullName:"Mingzhou Yu",profilePictureURL:"https://mts.intechopen.com/storage/users/188972/images/system/188972.jpg",biography:"Mingzhou Yu is now a Professor at China Jiliang University and a Guest Professor at Key Laboratory of Aerosol Chemistry and Physics, Chinese Academy of Science. He received his PhD degree from Zhejiang University in 2008 with the major fluid mechanism. During the time period between 2009 and 2012, he moved to Karlsruhe Institute of Technology, Germany, as a Alexander von Humboldt researcher where he worked with Prof. Gerhard Kasper and Dr. Martin Seipenbusch. Since 2013, he joined Prof. Junji Cao's research group as a guest Professor at Key Laboratory of Aerosol Chemistry and Physics, Chinese Academy of Science. During the time period between 2013 and 2016, he worked in The Hongkong Polytechnic University and Universidad Autónoma de Madrid, Spain, as a research associate or postdoc researcher. He is now leading a Aerosol Science and Technology Laboratory supported by Zhejiang Special Provincial Support in CJLU. He has published more than 90 cited articles and five books (or chapters).",institutionString:"China Jiliang University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"China Jiliang University",institutionURL:null,country:{name:"China"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444315",firstName:"Karla",lastName:"Skuliber",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/444315/images/20013_n.jpg",email:"karla@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"73363",title:"Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction",doi:"10.5772/intechopen.93888",slug:"neurological-and-neuropsychiatric-disorders-in-relation-to-olfactory-dysfunction",body:'This chapter provides a cursory description of a well-known phenomenon, namely that a significant percentage of people afflicted with certain prevalent disorders causing degenerative neuropathology, depressive and anxiety disorders, progressive loss of memory and communication function such as Autism Spectrum Disorder (ASD), intellectual challenges, as well as post-traumatic stress disorders present with a range of olfactory deficits. Here, we review our understanding of these deficits and their relation to various clinical manifestations such as neurological and neuropsychiatric diseases and disorders, disorders affecting mood, cognition, communication and memory and finally, olfactory deficits as secondary outcome of therapeutic drugs. At the outset, we will briefly describe the olfactory pathway from olfactory sensory neurons in the nasal epithelium to the olfactory bulb and on to olfactory cortical structures and subcortical structures involved in olfaction such as the amygdala. Then, we shall discuss olfaction in the context of normal age-based decline of physiological functions relating olfactory deficits to the onset of neurodegenerative pathology, decline in cognition, memory, ability to communicate as well as with episodes of depression and anxiety.
The main role of the olfactory system is the detection of odors. This function is critical for food selection by detecting olfactory and gustatory signals. Moreover, our sense of smell plays a role in reproductive and neuroendocrine regulation and is relevant for memory, aggression, emotion, social organization, and recognition of prey and predators [1]. Social chemical stimuli or semiochemical signals are processed by the olfactory system in most mammals. These chemicals differ from general odorants and mediate physiological aspects of mating and aggression. These chemical signals are processed in the accessory olfactory bulb in the brain which is part of the vomeronasal system [1].
The olfactory pathway starts deep in the nasal cavity with an olfactory epithelium that sits on the superior conchae (Figure 1). This pseudostratified ciliated columnar epithelium houses olfactory sensory neurons, supporting cells (sustentacular cells), and basal stem cells. In addition, Bowman’s glands located in the connective tissue under the epithelium (lamina propria) send ducts to the surface of the epithelium and secrete a serous fluid that immerses the cilia of olfactory receptor neurons in a mucous layer to trap odorant molecules. Odorant molecules bind to olfactory receptor proteins in the cilia of olfactory sensory neuron dendrites. The number of cilia that emerges from the dendrite of an olfactory sensory neuron is relatively small, 20 to 30, compared to the ciliated cells that are found in the respiratory epithelium (~300 cilia). Air-borne odorant molecules in the air that we breathe in activate the olfactory receptor proteins in the olfactory cilia. Odorant molecules can find their way to the olfactory sensory neurons either through the nose (orthonasal stimulation) or from the mouth to the nose (retronasal stimulation) [2]. Often this retronasal olfactory stimulation is confused with taste, which takes place in taste buds in the tongue and soft palate of the oral cavity. However, food odors and the consistency of the food (‘crunchiness’) together with tastants contribute to the flavor or aroma of food. The membrane of olfactory sensory neuron cilia houses odorant receptor proteins and thereby activates these neurons in the nasal epithelium. The olfactory receptor proteins form a large gene family (1000 genes in rodents, 350 in humans, [3, 4]). Each olfactory sensory neuron sends an axon through the cribriform plate of the ethmoid bone to the ipsilateral main olfactory bulb in the brain (Figure 1). The axons of olfactory sensory neurons coalesce to form the olfactory nerve (cranial nerve I) and olfactory nerve layer of the main olfactory bulb.
Schematic representation of olfactory pathways. Olfactory sensory neurons in the olfactory epithelium of the nasal cavity send their axons to form synapses with secondary sensory neurons in the olfactory bulb. A small number of neurons from the olfactory bulb participate in olfactory processing as they exchange information with both limbic system components and cortical structures.
The main olfactory bulb is a cortical structure of the cerebrum. However, the main olfactory bulb is not part of the neocortex but part of the allocortex as shown by its fetal development and cytoarchitecture. Neocortical structures undergo a prenatal phase that results in six layers, whereas allocortical structures have three or four layers in the mature brain [5]. While the main olfactory bulb presents itself as a small extension of the brain in humans, in rodents, the main olfactory bulb is a large structure that fills roughly a quarter of the length of the cranial cavity [6] and is dedicated to the processing of odorant information [1, 2, 7].
Several million sensory neurons are present in the olfactory epithelium. A given olfactory receptor protein is expressed by several thousand of them. The olfactory sensory neurons that express the same olfactory receptor protein send their axon to the same one or two glomeruli in the main olfactory bulb to form synaptic contacts (Figure 1). The dendrites of interneurons (juxtaglomerular cells) and output neurons (mitral and tufted neurons) in the olfactory bulb synapse with olfactory sensory neurons. Compared to the large number of olfactory sensory neurons, only relatively few output neurons innervate each glomerulus. These output neurons send their axons to higher order brain centers for brain processing of olfactory signals [8]. The precise sending of olfactory sensory neuron axons to specific glomeruli is critical for the discrimination of odorants [2]. The axons of output neurons leave the main olfactory bulb through the lateral olfactory tract and terminate in various higher order olfactory centers such as the anterior olfactory nucleus (AON), piriform cortex, the anterior parahippocampal cortex (entorhinal cortex), and the cortico-medial amygdala, all of which belong to limbic system (Figure 1) and are on the ipsilateral brain side. In contrast to other sensory modalities, the olfactory pathway routes sensory information directly from the olfactory bulb to cortical centers and bypasses the thalamus [1, 2].
The amygdala is a collection of nuclei in the limbic system [9]. The basolateral nucleus is the largest one and receives input from sensory cortices (vision, hearing) as well as direct auditory signals through a subcortical structure, the medial geniculate nucleus which is part of the thalamus. The olfactory bulb and piriform cortex send sensory information to the cortical and medial nuclei of the amygdala, the cortico-medial nucleus [10, 11]. In addition, the amygdala receives input from other cortical and subcortical brain systems, such as the prefrontal cortex with the anterior cingulate and orbitofrontal cortices. In turn, both piriform cortex and amygdala project to the orbitofrontal cortex to regulate emotion and associative learning. The amygdala is also connected with the entorhinal and hippocampal system for long-term memory [12]. Furthermore, the amygdala is a target for fibers from the hippocampus and rhinal (olfactory) cortices [10, 11]. Functionally, it has been established that odors have the ability to evoke strong emotions and trigger the recall of emotional memories and modulate cognition [11].
Not only does the olfactory bulb send axons to higher order olfactory centers (afferent fibers), an even larger number of centrifugal axons originating in higher olfactory centers innervate the olfactory bulb glomeruli (efferent fibers) [6, 13, 14]. These centrifugal neurons have been shown to provide modulatory feedback to neurons in the different layers of the main olfactory bulb which is important for experience-dependent modulation [13]. The origin of the centrifugal fibers is in the locus coeruleus (noradrenergic), the horizontal limb of the diagonal band of Broca (cholinergic), and the raphe nucleus (serotonergic) [15, 16, 17, 18]. The centrifugal fibers travel mainly through the anterior olfactory nucleus and the anterior commissure, and very little through the lateral olfactory tract [13].
Age-associated impairment in the sense of olfaction has been well documented [19, 20, 21, 22, 23]. Akin to neurodegenerative pathology, a decline in olfactory acuity and olfactory dysfunction are common features of the normal aging process [24, 25, 26, 27] detectable in over 50% individuals ranging in age from 65 to 80 years and almost in 75% of those above 80 years [24, 28, 29, 30]. This decline in olfactory function is detected using different kinds of tests such as psychophysical, psychophysiological and electrophysiological tests that determine odor detection, identification and discrimination, odor related physiological changes in cardiac and respiratory system as well as odor-event related potentials [29]. However, studies analyzing the mechanism of non-pathological, normal chronological age-related decline of olfactory acuity and impaired olfactory function are limited, despite the fact that deficits in the olfactory sense are considered as important symptom for early and differential diagnosis of neurodegenerative disorders [28]. At the anatomical level, the sense of olfaction is affected by age-associated ossification and closure of foramina of the cribriform plate [29, 31]. There is evidence of a quantitative reduction in the olfactory epithelium and its replacement by respiratory epithelium in normal subjects of the aging population which is evident in biopsies of the upper nasal septum [32]. It is now clearly evident that in the course of normal aging, suboptimal olfaction and olfactory dysfunction are associated with a number of anatomical and physiological features such as age-associated thinning of the olfactory neuroepithelium, altered cellular patterns and regional distribution of nuclei of olfactory sensory and sustentacular cells [29], reduction of mucosal metabolizing enzymes and sensory loss of olfactory sensory cells to various odorants along with a cumulative effect of environmental exposure to the olfactory epithelium [30]. An additional causative factor is the parallel loss of olfactory function in direct correlation with a clear age-associated decline in the volume of the olfactory bulb in adults of both genders [33, 34, 35]. Other than the olfactory bulb, a reduction in volume of AON, amygdala, hippocampus and piriform cortex in the limbic system contribute to a loss of olfaction due to their pivotal role in olfactory processing [36]. Testing the sensitivity and response of isolated sensory neurons to odorant mixtures indicates a loss of olfactory sensitivity and specificity in neurons derived from older subjects [37]. In older individuals, there is evidence of decreased beta-event related synchronization in response to certain pleasant odorants and, therefore, these individuals rated such odorants as less pleasant, thereby, denoting a decline in olfactory processing [38]. A change in olfactory perception represents subtle olfactory dysfunction that appears to precede a number neurodegenerative disorders and is presumed due to loss of synaptic function [39, 40]. Subsequent studies have shown that loss in olfactory sensitivity and perception is heterogeneous and appears to be more specific to heavier molecules [41]. Inherent allelic variations of brain derived neurotrophic factor (BDNF) also affect and add to age-dependent olfactory decline [29, 42]. A comparative research study quantifying heritability of odor identification and cognition detected a role of common genes in both olfaction and cognition. However, heritability of odor identification was lower in contrast to that of cognition [43]. Quantitative analysis of olfaction using odor identification (OI) scale in community dwelling subjects of age group 70–79 years reveals association of higher risk of dementia with poor OI score [44] and reduction in OI has been linked to advanced physiological brain aging as well as with a number of neurodegenerative diseases [45]. An aging cortical synapse in limbic structures has been considered as a hallmark of age-associated decline in cognition [46]. However, such studies are still preliminary for the olfactory bulb, despite evidence of growth factor dependent induction of synaptic strength in olfactory bulb cell layers during odor-dependent social transmission of food preference [47]. Chronological age adds to the impact of environmental exposure through living and working conditions on all physiological systems and their functions [48]. Experimental analysis indicates age-dependent accumulation of somatic mutations using both proliferative and non-proliferative cell types from human brain tissue [49]. It further indicates the probability of mutation accumulation in neurons. Genome-wide single somatic nucleotide variant analysis on DNA of 159 single neurons of 15 normal individuals with a wide age range (4 months to 82 years) and 9 individuals diagnosed with early onset of neurodegeneration revealed linear increase in both sets, indicating age-dependent accumulation of somatic mutations as significant factor affecting neurodegeneration [50]. Research studies of classical neurodegenerative disorders have proposed that the observed variability of olfactory dysfunction in diverse neurological and neuropsychiatric diseases could aid in early differential diagnosis of Alzheimer’s disease (AD), Parkinson’s disease (PD), mild cognitive impairment (MCI), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration known as FTLD-TDP43 [51, 52, 53, 54]. A cell biology oriented experimental approach to detect the presence of neurodegeneration-associated proteins used nasal brushing to collect olfactory neurons from olfactory mucosa of normal subjects and detected four different characteristic proteins involved in neurodegenerative pathology: α-synuclein, transactive response DNA-binding protein 43 (TDP-43), hyperphosphorylated tau and β-amyloid proteins [55]. These findings have prompted an analysis of the parallel progression of loss of olfaction with onset of neurodegenerative pathology and/or decline in cognitive abilities as initial symptoms of neurological and neuropsychiatric disorders.
Olfactory deficiencies are evident in a number of neurodegenerative disorders such as AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), MCI, PD and Huntington disease [40, 51, 56, 57, 58, 59]. In an extensive two year study with six-monthly follow up, all MCI patients with lower range of olfaction score but no subjective smelling loss detected by standard UPSIT (University of Pennsylvania Smell Identification Test) developed AD. In contrast, in a control group of higher olfaction score, AD occurrence was nil [60]. A similar association of lower olfaction score with development of AD pathology was evident in a multiethnic community cohort with UPSIT test [61]. In a comparative OI analysis of FTD and AD patients with normal age matched control individuals, OI score of FTD patients differed significantly with control group, however, there was a close resemblance in OI pattern of FTD patients with OI in AD patients [62]. An analysis using Pocket Small Test as indicator of OI performance in AD patients and healthy young and age matched control group of individuals detected reduced OI in an older control group than in a younger control group, and AD patients had even reduced OI compared to their age matched control group [27]. At the cellular level, a characteristic neuropathological feature of AD is the appearance of neurofibrillary tangles consisting of hyperphosphorylated tau protein [63]. In relation to olfactory dysfunction, the two key hallmarks of AD neuropathology are the detection of amyloid-beta (Aβ) and hyperphosphorylated tau protein in the olfactory system; both have been detected together with impaired olfaction much before a clinical presentation of the disease [57]. An analysis assessing OI as indicator of presymptomatic AD pathogenesis in cognitively normal aged individuals shows an association of reduced OI with lower cognitive score and older age as well as increased ratio of total tau protein to phosphorylated tau protein in cerebrospinal fluid [64]. Therefore, at the behavioral level, diminished OI has emerged as a practical and affordable biomarker of AD pathology [64] as well as prodromal symptom of AD [65].
A major factor leading to neurodegenerative PD pathology is the loss of dopaminergic neurons from the substantia nigra, resulting in slow but substantial loss of dopamine that eventually leads to many clinical motor symptoms such as bradykinesia, rigidity, tremor, instability of posture and decline of cognitive function [66]. The olfactory system is a severely affected non-motor system in PD patients with early appearance of olfactory dysfunction that remains independent of progressive PD symptoms, their duration and treatment [67]. Additional research studies have indicated association of olfactory dysfunction with PD for over three decades [25, 68]. Olfactory dysfunction, including hyposmia and decline in olfactory acuity, has been established as one of the earliest features of PD. These are detectable in approximately 90% of early stage PD patients, where they may precede the onset of the motor symptoms by a margin of years [69, 70, 71, 72, 73]. Hyposmia and progressive olfactory decline in PD patients have been attributed to central olfactory processing, since the olfactory epithelium biopsy samples of PD patients were normal [74]. Subsequent MRI studies indicate a varying degree of reduction in olfactory bulb volume and depth of olfactory sulcus in PD patients than in normal control individuals. These studies indicate an association of anatomical changes with altered olfaction in PD patients [75]. Lewy bodies and Lewy neurites comprised of α-synuclein are histological hallmarks of neurodegenerative pathology in PD [76]. The olfactory bulb and lower brainstem have been considered as the induction site for the onset of histopathological features comprising of both Lew bodies and Lewy neurites [73, 77]. Along with the peripheral nervous system, such histological aberrations also begin to appear in gut nerve plexa and the olfactory bulb, thereby indicating participation of olfactory bulb cell layers in the progression of neurodegenerative pathology of PD [78].
Dementia associated with PD, known as Parkinson’s disease dementia (PDD), is one of the most debilitating symptoms of PD and is difficult to predict during early stages of the disease. A research study using OSIT-J (odor stick identification test for Japanese) shows over 18 fold increase in risk of dementia for PD patients with severe hyposmia [79]. Indeed OI has emerged as a reliable tool for providing excellent diagnostic accuracy for PD distinguishing it from PD mimics [80].
In addition to aging, neurodegenerative and psychiatric conditions, olfactory deficits including low OI appear as characteristic feature of mild to severe major depressive disorders [81, 82]. As there is overlap in brain regions involved in AD, depression and olfactory processing, olfactory dysfunction could be the potential early biomarker of both AD and depressive disorders [83]. Similar to research studies using animal models that indicate a strong link between loss of olfaction and depressive behavior, a comparative analysis of age matched control individuals and patients diagnosed with depression showed loss of normal olfaction as marker of depression in humans [84]. Literature reviews of multiple research findings using specific parameters indicate a clear and consistent relation between depression and poor life quality in individuals from both clinical and community setting in age dependent manner [85]. Encoded olfactory stimuli activate emotional memory [86]; olfactory system and brain circuits participating in memory and cognition show a close anatomical link as well as frequent functional alteration in patients with depression [87, 88, 89]. Additional analysis clearly denotes a reciprocal relationship between olfaction and depression; patients with olfactory dysfunction show worsening depressive symptoms while olfactory performance is clearly reduced in depression patients in comparison to normal controls [90]. Moreover,
Declined olfactory acuity and olfactory dysfunction are also evident in individuals suffering with post-traumatic stress disorder (PTSD) and in patients diagnosed with major depressive disorder (MDD). PTSD leads to decreased olfactory bulb volume, thereby leading to decreased olfactory acuity, additional olfactory deficits and dysfunction [35]. MDD indicates decline in both primary and secondary olfactory processing [84, 91]. MDD patients denote lower score for olfactory threshold, odor discrimination in 40-point smell identification test in comparison to normal controls At the same time, patients with olfactory dysfunction show clear symptoms of depression that become acute in comparative analysis of hyposmic to anosmic subjects [90].
ASD adult patients show decline in odor identification ability [92]. Experimental evidence in two different mouse models of ASD indicates weaker and fewer synapses between olfactory sensory nerve terminals and olfactory bulb tufted cell layer; and weaker synapses between olfactory sensory nerve terminals and inhibitory periglomerular cells of the olfactory bulb [93]. Duplication of GABA receptor genes and deletion of TOP3B, topoisomerase involved in relaxation of supercoiled DNA contribute to autism susceptibility and have been assigned to gene families with specific contribution to neurodevelopmental disorders [94]. Out of 102 identified genes that contribute to ASD, most genes are expressed and enriched early in excitatory and inhibitory neuronal lineages and affect synapses [95].
The regenerative ability of olfactory epithelium has made it an attractive target for exploring and evaluating therapeutic strategies to distinguish and treat drug induced olfactory disorders [96]. More than 86% of cancer patients of wide age range display smell and taste disorders that persist even after completion of chemotherapy for cancer [97]. However, not every therapeutic chemotherapy drugs has negative impact on olfactory acuity (personal communication).
The flavonoid Naringenin functions as antidepressant by restoring serotonin and noradrenaline levels in brain tissue [99]. In bulbectomized mice, two weeks of Naringenin treatment ameliorated depression like behavioral alterations, decreased elevated pro-inflammatory cytokines and increased levels of BDNF and serotonin in hippocampus and cortex [100].
Depression with psychomotor agitation (PMA) is a putative psychiatric disorder associated with substance dependence, specifically, opioids. It remains unaffected by drug induced major depressive episodes indicating complex interplay of therapeutic drugs in treating depression [101].
The AON, a key area of the olfactory system, shows accumulation of characteristic neuropathological markers such as hyperphosphorylated tau, α-synuclein and β-amyloid proteins at the earliest stages of AD in a Somatostatin (SST) expressing subpopulation of interneurons. In the limbic system, the same accumulation is evident in same subpopulation of interneurons [102]. However, SST is unequally involved in two predominant neurodegenerative disorders with a very strong involvement in AD pathology but quite weaker participation in PD. In early stages of AD, SST is reduced in olfactory areas whereas it is preserved in non-demented PD cases [102]. Further analysis of SST related olfactory deficiencies will pave the way of SST based therapeutic approaches.
Olfactory dysfunctions unrelated to blocked nasal passages are present in a significant percentage of Covid-19 patients [103, 104, 105]. Altered expression of SARS-CoV-2 entry genes in supporting cells of the olfactory epithelium has been proposed as a mechanism underlying COVID-19-associated anosmia [106, 107].
The mammalian olfactory bulb has been termed the “brain inside the brain”, due to the presence of sensory inputs, neuronal lamination and contribution of new neural elements throughout the lifetime [108]. It plays a pivotal role in olfactory processing [8, 109]. In addition to AD, PD, MCI and depressive disorders, inadequate and/or improper olfactory function together with impaired olfactory processing exist in many other neurodegenerative and neuropsychiatric disorders. For instance, in the case of multiple sclerosis (MS), prevalence of olfactory dysfunction ranges from 20 to 45% of the MS population. However, the mechanism of loss of olfaction remains unknown, except for decreased olfactory bulb and brain volume [110, 111]. In patients with a diagnosis of a behavioral FTD variant, OI and odor discrimination did not show any difference from control cases, but there was a significant difference in the odor association test. It has been attributed to impaired olfactory processing [112]. Within the healthy population, impulsive tendencies exhibit some link to olfactory defects [113]. Narcolepsy is associated with hypocretin deficiency of the limbic system. Despite genetic predisposition, it has been postulated to increase by environmental substances that may access the olfactory bulb, triggering neuroinflammation and induce neurodegeneration [114].
Single cell transcriptome analysis during mouse olfactory neurogenesis in early development reveals that expression of olfactory receptor (OR) genes becomes progressively restricted to one gene per neuron in each mature neuron instead of several receptor genes that express in immature neurons [115, 116]. Expression of a single OR allele in olfactory sensory neurons is the outcome of coalescence of multiple intergenic enhancers to a multi-chromosomal hub that allows the expression of a single OR allele while the remaining OR genes converge into few heterochromatic compartments leading to effective transcriptional silencing [117]. Age associated chromosomal breakage and DNA damage lead to an increase in markers of genome instability [118] and requires many layers of regulatory functions such as inducing senescence [48], reducing accumulation of DNA damage and enhancing DNA repair pathways [119]. Genome protection from DNA damage to minimize aging effects is also an effective strategy to minimize risk factor for neurodegeneration [119]. This is likely to retain olfactory acuity and ability based on the model proposed by Bashkirova and Lomvardas [117].
Single cell RNA sequencing reveals differentially regulated and expressed genes as neuronal markers specific to adult born interneurons that may serve as molecular markers for synapse formation, synapse maintenance, and neural plasticity of adult brain circuits [120]. Research studies analyzing functional mechanisms of these markers and their regulation are likely to facilitate the understanding of decreased OI, olfactory dysfunction and onset of neurodegenerative pathology.
Olfactory ensheathing glial cells help olfactory bulb neurons to connect with both the peripheral and central nervous system, and, therefore, they have been widely used as therapeutic tools for neural repair and olfactory/neural regeneration for injuries and neurodegenerative pathological conditions [121]. Indeed, the olfactory bulb has emerged as an attractive target for many novel therapeutic approaches [122].
Another fast growing research topic addresses the role of microRNAs in regulating genes that participate in cognition and neurodegeneration [123, 124, 125] and olfactory acuity. Such findings would also add to a better understanding of the relationship between olfactory dysfunction and neurodegenerative pathologies.
Targeting synaptic deficits in AD patients and aging individuals by improving synaptic plasticity though alteration of structural deficits in dendritic spines through microRNA mediated regulatory pathways could be an effective and novel therapeutic strategy for AD as well as other neurodegenerative disorders [126].
This work was supported in part by grants from the National Science Foundation (NSF IOS-1355034) and the
The authors declare that there is no conflict of interests regarding the publication of this chapter.
Cutaneous melanoma (CM) is a disease that arises in transition of dermis and epidermis, where the melanocytes are localized. The melanogenesis process starts due to DNA damage secondary to a UV exposition, which can be chronic or acute intermittent exposure. Furthermore, other risk factors are associated with melanoma as frequency of sunbathing, ultraviolet A exposure, low skin phototypes, atypical nevus syndrome, skin sunburn events mostly during childhood and adolescence, a large number of skin moles (congenital or not), familiar or personal history of CM or skin cancer not melanoma. The DNA damage alters the proliferation and cell cycle, culmining in dysregulated apoptosis mechanisms. The CM is characterized by the high invasiveness, a high metastatic capacity, causing a short survival period and high mortality rates due to pharmacological resistance [1, 2].
For the systemic treatment of the patient with high-risk disease to metastasis, pharmacotherapy is used with drugs that can manifest collateral effects, in addition to presenting inefficient mechanisms to guarantee the survival of patients [3]. In this sense, several literatures have indicated biochemical therapy as a promising adjuvant in the CM management [4], even so it is urgent researchers to develop new options for a rise in patients’ survival [1]. Therefore, many research science teams have been engaged to discover melanoma treatment and an interesting alternative to this would be to use natural substances, such as phenolic compounds that can have anticancer effects [5].
An efficient and rapid diagnosis is a priority among the medical and scientific community [6]. Furthermore, correctly and effectively pharmacological therapy promotes better prognosis and better quality of life for the melanoma cutaneous illness. Taking into consideration, the aim of this chapter was to provide an overview of potential modulations of the purinergic system in the treatment of cutaneous melanoma. Thus, initially, the cutaneous melanoma will be characterized based on epidemiology and therapeutics, as well as the purinergic system with its details, and finally, show that some natural compounds have potential in modulating purinergic signaling in melanoma.
Cutaneous melanoma is a disease that has a wide spectrum in relation to the prognosis of the patient who develops this disease. The diagnosis can be made from when the neoplasm is still restricted to the epidermis (
Also, North America and some European countries have high incidence rates of this disease. In the United States alone, 99,780 new cases and 7650 deaths from melanoma are expected in 2022 [9]. In the Scandinavian region, the incidence ranges from 15 to 18 cases/100,000 inhabitants; Northern European countries vary from 12 to 28 cases/100,000 inhabitants [10]. In Asia, Africa, and South America, the number of cases is lower, although there are regional differences as is the case in Brazil, where the South and Southeast regions have the highest number of cases when compared with other areas of the country [11, 12, 13, 14].
Early detection of cutaneous melanoma is a fundamental factor in reducing mortality. Individuals diagnosed in the early stages have a 98% survival rate, while those diagnosed in advanced stages have a significantly decreased survival rate—between 63.8 and 15%. Patients diagnosed with stage III and IV melanoma have survival rates (5 years) of 70% and 30%, respectively. For most human malignancies, the use of chemotherapy for systemic treatment changed the natural history of the disease, and in melanoma the reality, until recently, was different with response rates comparable to the use of placebo [15]. Since the introduction of chemotherapy for adjuvant treatment of malignant neoplasms, numerous therapeutic regimens have been tried in patients with metastatic melanoma [16, 17].
The most widely used treatment for patients with disseminated disease was dacarbazine, but only about 15–20% had some degree of response and 2% were still alive after 5 years of follow-up: a response rate comparable to the placebo-treated group of patients in the early clinical trials [15]. The use of high-dose interleukin-2 (IL-2) was the first treatment that changed the natural history of a small portion of patients with stage IV melanoma, but resulted in severe side effects that often affected survival [18, 19]. In the following years, molecules with direct action on pathways were responsible for controlling cell growth and division emerged, which were called “targeted therapy,” such as BRAF and MEK inhibitors [19, 20]. However, only part of the melanoma patients can benefit from these inhibitors, because it is necessary that the genes involved in these pathways are mutated in order to get a response [21].
With the development of immunotherapy, other molecules called “immune system checkpoint inhibitors”, such as pembrolizumab and nivolumab (programmed cell death protein-1 [PD-1] inhibitors), and ipilimumab (cytotoxic T lymphocyte antigen-4 [CTLA-4] inhibitor), have been routinely used as adjuvant and neoadjuvant treatments in melanoma patients with prognostic factors associated with poor survival [22, 23]. However, only 20% of patients show complete and lasting response with this type of therapy, and no biomarkers have been defined yet that can predict who will benefit from the use of these drugs [23, 24, 25].
The purinergic system is a sophisticated cell-cell communication and ubiquitously expressed in the human body that orchestrates numerous cellular responses in the context of health and disease, displaying several biological processes. Most discussed extracellular signaling molecules include nucleotides such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and the nucleoside adenosine (Ado) [26, 27, 28, 29, 30]. The components belonging to this system are divided between receptors, according to the signaling molecule, as well as in enzymes. Thus, the P2 receptor is sensitized by adenine nucleotides, such as ATP, ADP, and AMP, being subdivided into P2X (1–7) and P2Y (1–12), while the P1 group is signaled Ado molecules and differentiated into A1, A2, A2B, A3 [31]. The levels of signaling molecules are controlled by enzymes known as ectonucleotidases, expressed on the surface of cells. They are nucleoside triphosphate diphosphohydrolase 1 (NTPDase-1/CD39), 5′-nucleotidase (5’-NT/CD73), and adenosine deaminase (ADA) enzymes, which metabolize ATP/ADP into AMP, AMP into adenosine (Ado), and finally this into inosine, respectively [32, 33, 34, 35] (Figure 1).
Purinergic system components and functions. Adenosine triphosphate (ATP), key molecule of the purinergic system, can be released in an extra-cell environment and act as agonist on P2XR and P2YR. Furthermore, the ectonucleotidases presenting on cell surface are capable to hydrolyze the ATP into others nucleotides, such as adenosine monophosphate (AMP), adenosine diphosphate (ADP), and nucleosides, such as adenosine (ado). Between the purinergic receptors, only P1 (P1R) have Ado as agonist. The ectonucleotidase pyrophosphatase/phosphodiesterase (E-NPPS) has potential to break ATP straight to AMP, whereas ectonucleoside triphosphate diphosphohydrolase (E-NTPDase-CD39) can break ATP to ADP or ADP to AMP. In this enzyme orchestra, only one ectoenzyme is capable of hydrolyzing AMP to Ado, the ecto-5′-nucleotidase (E-5’-NT-CD73). In the end of the purinergic cascade, the adenosine deaminase (ADA) converts Ado to inosine (Ino). Source: The authors (2022).
In this context, it is well known that this system is involved in cancer dynamics and has a close relationship with the immune responses, such as in lung cancer [36, 37], leukemia [38], cutaneous melanoma [30, 39], pancreatic cancer [40], and gastric cancer [41]. Likewise, it has been reported that ATP is considered a pivotal molecule, which largely influences immune responses in peripheral and central tissues, can be released from the inflammatory and tumor cells
Thus, yet few studies have been performed to understand the involvement of purinergic signaling in melanoma, some robust evidence showed that this cell pathway plays an important role in this disease. In this sense, a component-system widely reported is the P2X7 receptor, which is expressed by cancer cells, as in melanoma, and is mostly associated with tumor cell killing
Given the pleiotropic actions, the role of P2X7R depends on the nucleotide receptor-interactions, as well as concentration, being that these interactions can promote or inhibit melanoma. Taking account, recently it was reinforced that P2X7 is overexpressed in patients affected by metastatic malignant melanoma and that its expression closely correlates with reduced overall survival. This is because P2X7 stimulation is capable of miRNA-containing microvesicles and exosomes from melanoma cells [54]. Furthermore, it was hypothesized that the Warburg effect is possibly linked to P2X7 modulation by ATP in melanoma. Once activated by ATP, the PI3K-AKT pathway upregulates glycolytic cascade enzymes, which promotes lactate generation and acidification of the TME. Acidification of extracellular microenvironment alters immune response and supporting cancer [5].
Conversely, Hattori et al. [55] by treatment of B16 melanoma cells with oxidized ATP (oxATP) found significantly decreased cell proliferation at concentrations between 300 and 500 mM in low pH conditions. From this, they proposed that the P2X7R is a promising target for treatment of solid tumors. The same way, White et al. [56] after an experimental incubation of melanoma cells with P2X7-agonist 2′–3′-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate found decrease in cell number. In the immunological scenario, P2X7 activity has been associated with tumor-infiltrating T cells (TILs), which leads to senescence and limits tumor suppression, in addition to affected cell cycling of effector T cells and resulting in generation of mitochondrial reactive oxygen species (ROS) and p38 MAPK-dependent upregulation of cyclin-dependent kinase inhibitor 1A [57].
Although the P2X are widely related, other receptors also have been involved in melanoma disease. The P2Y1 receptor was indicated as potential to reduce melanoma cell proliferation; however, P2Y2 usually appears to increase cell numbers [58]. Still, the P2Y12 seems to promote tumor metastasis by platelet activation in melanoma cells [59, 60]. Interestingly, one factor, which leads to skin cancer, UV-B irradiation, seems to have a relationship with purinergic signaling, and severe effects have been associated between irradiation type and reduced P2X1 and P2Y2 receptors, as well as to destruction of P2X7 receptors, with the possibility of contributing to malignant transformation of keratinocytes [61].
From the Ado-stimulated receptor perspective, the A2AR and A3AR seem to lead to melanoma cells’ death
On the other side, ectonucleotidases that control the purinergic chain also are involved in neoplasias. The CD39 decreased activity mitigates ATP hydrolysis, leading to extracellular accumulation of this nucleotide. This was evidenced by Manica et al. [50] that showed that post-surgery CM patients present high ATP levels in microenvironment compared with the healthy controls, suggesting being the cause of poor prognosis [50]. Thus, the ectonucleotidases action seems to play an important role in cancer context as well as in other purinergic components.
Although the CD39 and CD73 dynamics are responsible for forming most Ado extracellular content, another enzyme involved is the E-NPP, which hydrolyzes AMP to Ado. Several studies have evidenced that these ectoenzymes are increased in cancer context [45, 67, 68, 69]. In melanoma, studies suggested high expression of the CD73 in patients [70, 71, 72]. Also, in the melanoma mouse model, a CD73 inhibitor improved T and B cell-mediated antitumor immunity and reduced tumor growth [73]. The hydrolysis CD73 capacity is known and involved in melanoma; however, recently a nonenzymatic action of this enzyme was related, playing a role in cell migration on extracellular matrix through focal adhesion kinase (FAK) [74].
Considering the need for new therapies and therapeutic targets for the treatment of cutaneous melanoma, studies with compounds that modulate the purinergic system and have antitumor effects have been carried out, as is the case with phenolic compounds and vitamin D [75, 76]. Figure 2 represents some possible modulatory mechanisms of natural compounds on the purinergic system in the CM context.
Purinergic system modulation in cutaneous melanoma by means of natural compounds. The literature has been evidenced in the adjuvant therapeutic perspective that several compounds derived from nature can act against carcinogenesis and cutaneous melanoma. Resveratrol, from the grape, has the potential both to increase CD73 expression and modulate P2X7 receptors, which control the growth progression and metastasis. Rosmarinic acid, a phenolic acid from rosemary, can block the P2X7 receptor and inhibits the agonist mechanism by ATP, as well as have antagonism ADP-like on the P2Y12 receptor, leading to a decrease of tumor mass formation. Two important derivatives of coffee, the caffeic acid and caffeine, have been shown as interesting modulators of P1 receptors. These adenosinergic receptors are intimately related to tumor immunity, and these two molecules can act modulating the antitumor immunity. The vitamin D also showed a significant compound with purinergic system modulation, since it is capable of increasing CD73 expression and controlling the adenosine amount, which seems to play a great role in cutaneous melanoma. Source: The authors (2022).
Phenolic compounds are secondary metabolites present in plants, whose function is to participate in their development and protect them from pathogens and UV radiation [77]. More than 8000 compounds have been identified so far, and most of these compounds have some beneficial property to humans [78]. Their therapeutic actions are related to the structure, mainly to the phenolic rings, in which these compounds are classified by the number of rings and structural elements they have, forming four major groups: phenolic acids, stilbenes, lignans, and flavonoids [79]. The most cited group of polyphenols in the literature with therapeutic actions including antitumor effect is flavonoids, which are present in foods consumed daily such as fruits, vegetables, vegetables, red wine, coffee, and green tea [80, 81, 82].
Resveratrol (3,5,4-trihydroxy-trans-stilbene) is found in red wine and in the skin of dark grapes, a polyphenol with antitumor activity, considered a candidate for the treatment of cutaneous melanoma, which has been shown to modulate the expression and activity of CD73, ADA enzyme, and P2X7 and A2A receptors, which are closely related to tumor progression [83, 84, 85, 86]. Tannic acid, a polyphenol, was shown to be able to induce cell death in several types of cancer cells, such as cutaneous melanoma, prostate cancer, glioblastoma [87, 88].
Thus, Bona et al. [89] tested the antitumor effect of this substance in rats with glioblastoma and the interference with ectonucleotidases, in which tannic acid was able to increase the hydrolysis of ATP and AMP nucleotides and decrease the hydrolysis of ADP in platelets of the animals treated compared with untreated. In the lymphocytes of the animals with the disease that received tannic acid, this polyphenol decreased the hydrolysis of ATP and ADP and the degradation of adenosine in relation to the group with the disease that did not receive the substance. When comparing the levels of ectonucleotidases in control mice, those with glioblastoma and those with glioblastoma treated with tannic acid, it was observed that the substance was able to maintain levels similar to those in mice without the disease. Bearing in mind that the purinergic system is able to modulate tumor progression, the aggressiveness of this type of cancer, and the results obtained in the study in question, tannic acid can be considered a promising agent for the treatment of cancer [89].
Regarding purinergic system modulation and the antitumor effect on cutaneous melanoma, Silva et al. [5] proposed the hypothesis that rosmarinic acid, a polyphenol with antitumor effect, would be able to modulate purinergic signaling and prevent tumor progression and metastasis by two-way means: by blocking the P2X7 receptor or by antagonizing the P2Y12 receptor. Interestingly, a paper that focused on Salvia
Coffee (
Quercetin, an abundant flavonoid in plants, also demonstrated antitumor activity in cell lines of bladder cancer, glioblastoma, and hepatocarcinoma and inhibited the activity and expression of ecto-5′- NT/CD73, leaving less Ado available in the TME, consequently preventing immunosuppression [94, 95, 96].
Apigenin (4′,5,7-trihydroxyflavone) is a flavonoid present in significant amounts in parsley, onion, celery, orange, chamomile, oregano, and basil that has shown a beneficial effect in diseases such as cancer, Alzheimer’s, diabetes, and depression [97, 98]. Cutaneous melanoma cells (A375) were treated with these substance and, in addition to the decrease in cell viability, they had an increase in ATPase activity and a concomitant reduction in the ATP/ADP ratio related to the apoptotic process of cancer cells, demonstrating that the present substance has an effect antitumor in addition to acting in purinergic system [99].
The carcinogenesis can be initiated by the overproduction of reactive oxygen species (ROS), since the antioxidant defenses cannot neutralize these molecules. From this, the antioxidant compounds seem to be important against tumor formation, such as the phenolic acids, which can prevent DNA alterations and genome instability. The literature has shown that rosmarinic acid is an example of a powerful antioxidant for the protection of the DNA against UV and H2O2 [100].
Vitamin D, in turn, is a fat-soluble vitamin, in which its deficiency is closely related to carcinogenesis [101]. This vitamin is available in two forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), where it can be obtained through the diet, but 90% of the daily needs are produced by the skin itself and later must be hydroxylated by the liver and kidneys, in order to obtain 1,25-dihydroxyvitamin D, the metabolically active form of vitamin D [102]. In metastatic melanoma cells, SK-Mel-28-treated with 1,25-dihydroxyvitamin D, there was decrease in cell viability, as well as the expression and activity of the CD73 enzyme and the levels of Ado, which has a suppressive function of tumor immunity and is essential for progression tumor, becoming a promising candidate for the adjuvant treatment of cutaneous melanoma [103].
As evidenced, cutaneous melanoma is a malignant neoplasm of great medical importance due to high rates of resistance to treatments and relapses, and for this reason, it is necessary to search for new and effective pharmacological therapies. In this context, the potential of some compounds in modulations of this pathway signaling, such as rosmarinic acid, resveratrol, tannic acid, as well as vitamin D, has been elucidated in this study. Of course, more research needs to be done to open up new horizons in the treatment of melanoma by the purinergic signaling, but the discovery of new ways to improve the anticancer pharmacological perspective has already begun.
The authors declare that there is no conflict of interest.
MDB acknowledges grant support by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, proj. No 310606/2021–7) and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC, proj. No 2021TR1543). GBS, DM, MM, and MDB also thank Fundo de Apoio à Manutenção e ao Desenvolvimento da Educação Superior (FUMDES/UNIEDU) for the graduate scholarships.
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Among them, a deep neuromuscular blockade (NMB) contributes to provide the surgeon with better operating conditions. This chapter discusses the interests and challenges of muscle relaxation during gynecological laparoscopy. The introduction of sugammadex into clinical practice provides the opportunity to modify the management of neuromuscular blockade to improve the surgical conditions during laparoscopy as well as the safety of the patients. The maintenance of a rocuronium-induced deep neuromuscular block from the trocar insertion until the end of laparoscopy is no longer incompatible with rapid recovery and awakening in optimal conditions. Neuromuscular transmission (NMT) monitoring is the key to adequate management and should be used in all cases. Objective measurements allow for excellent intubation and surgical conditions, the definition of thresholds and doses for the administration of reversal agents, and the exclusion of residual blockade prior to the patient extubation.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Christophe Dransart, Laurie Putz, Maria-Laura Marotta and Philippe\nE. Dubois",authors:[{id:"164978",title:"Prof.",name:"Philippe",middleName:"E",surname:"Dubois",slug:"philippe-dubois",fullName:"Philippe Dubois"},{id:"194443",title:"Dr.",name:"Christophe",middleName:null,surname:"Dransart",slug:"christophe-dransart",fullName:"Christophe Dransart"},{id:"194444",title:"Dr.",name:"Laurie",middleName:null,surname:"Putz",slug:"laurie-putz",fullName:"Laurie Putz"},{id:"194445",title:"Dr.",name:"Maria-Laura",middleName:null,surname:"Marotta",slug:"maria-laura-marotta",fullName:"Maria-Laura Marotta"}]},{id:"52300",doi:"10.5772/65296",title:"Endometriosis: When and How We Treat",slug:"endometriosis-when-and-how-we-treat",totalDownloads:1369,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Endometriosis is a chronic, nonmalignant and estrogen‐dependent disease in which endometrial glandular epithelium and stroma are outside the uterine cavity (ovaries, peritoneum, or rectovaginal septum). The prevalence is estimated from 2 to 10% in women of childbearing age and it rises up to 50% in women with infertility. Despite maximal efforts, the therapy of first choice in the management of endometriosis is still unclear. The aim of this chapter is to present an update of its management, emphasizing the benefits and disadvantages of surgical methods. We performed a systematic literature search on the PubMed database of English literature (search terms: endometrioma, surgery, ovarian reserve, assisted reproductive technologies) from 2010 to 2014. For endometrioma, operative laparoscopy proved to be the gold standard. Surgical procedures consist of partial excision of the cyst wall and electro‐coagulation of the rest. Stripping technique may be a better method for reducing the recurrence of pain symptoms, recurrence, and reoperation rates, but it raises concerns about ovarian reserve. For endometriosis, surgery often includes partial rectum or sacrouterine ligament resection. Hysterectomy is not obligatory and refused by the young patients. The approach should be laparoscopic and if necessary vaginal assisted. Good cooperation between various disciplines (gynecology, surgery, urology) is mandatory.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Sidonia Maria Saceanu, Stefan Patrascu, Anca Patrascu and Valeriu\nSurlin",authors:[{id:"158096",title:"Associate Prof.",name:"Valeriu",middleName:null,surname:"Surlin",slug:"valeriu-surlin",fullName:"Valeriu Surlin"},{id:"194539",title:"Dr.",name:"Stefan",middleName:null,surname:"Patrascu",slug:"stefan-patrascu",fullName:"Stefan Patrascu"},{id:"194540",title:"Dr.",name:"Sidonia Maria",middleName:null,surname:"Sandulescu",slug:"sidonia-maria-sandulescu",fullName:"Sidonia Maria Sandulescu"},{id:"194541",title:"Prof.",name:"Anca",middleName:null,surname:"Patrascu",slug:"anca-patrascu",fullName:"Anca Patrascu"}]},{id:"52615",doi:"10.5772/65769",title:"Bowel Dysfunction after Hysterectomy for Benign Conditions: Meta-Analysis and Systematic Review",slug:"bowel-dysfunction-after-hysterectomy-for-benign-conditions-meta-analysis-and-systematic-review",totalDownloads:1531,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The aim of this study was to determine whether hysterectomy for a benign indication can cause functional gastrointestinal disorders (FGIDs). A systematic review was completed with the studies, which used a prospective design and validated quality of life questionnaires. A search strategy using Medline and Embase allowed the relevant studies published between 1950 and October 2010 to be found. Meta-analyses were also performed using the studies, which had similar research objectives. The search revealed 29 potentially suitable articles, of which 5 used a prospective design and validated quality of life questionnaires. The meta-analyses showed that the type of hysterectomy (total or subtotal) did not have an impact on whether a patient is likely to develop gastrointestinal symptoms post-surgery. The prospective studies did not show that hysterectomy for a benign indication causes FGIDs. The belief that hysterectomy can cause gastrointestinal dysfunction is based on the results of retrospective studies.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Constantina Pitsillides and Hany Lashen",authors:[{id:"191199",title:"Mr.",name:"Hany",middleName:null,surname:"Lashen",slug:"hany-lashen",fullName:"Hany Lashen"}]},{id:"52626",doi:"10.5772/65544",title:"Laparoscopic Surgery in the Treatment of Endometriosis",slug:"laparoscopic-surgery-in-the-treatment-of-endometriosis",totalDownloads:1380,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Endometriosis is a benign disease, which affects about 10% of reproductive age women and almost 50% of infertile women. Although every year at least 300 new articles deal with this topic, endometriosis is still a enigmatic disease starting with theories of etiopathogenesis where there is still no consensus about the major cause of endometriosis. Also there is still no consensus about the management of the disease, mainly when there is an infertile patient who is preparing for in vitro fertilization procedure.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Sonja Pop-Trajkovic Dinic, Jasmina Popovic, Radomir Zivadinovic,\nDejan Mitic, Vladimir Antic and Milan Trenkic",authors:[{id:"69225",title:"Dr.",name:"Sonja",middleName:null,surname:"Pop-Trajkovic",slug:"sonja-pop-trajkovic",fullName:"Sonja Pop-Trajkovic"},{id:"194904",title:"Dr.",name:"Vladimir",middleName:null,surname:"Antic",slug:"vladimir-antic",fullName:"Vladimir Antic"},{id:"194905",title:"Prof.",name:"Jasmina",middleName:null,surname:"Popovic",slug:"jasmina-popovic",fullName:"Jasmina Popovic"},{id:"194906",title:"Dr.",name:"Milan",middleName:null,surname:"Trenkic",slug:"milan-trenkic",fullName:"Milan Trenkic"}]}],mostDownloadedChaptersLast30Days:[{id:"53784",title:"Microsurgical Cesarean Section",slug:"microsurgical-cesarean-section",totalDownloads:2355,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Worldwide, not only is cesarean section (CS) the most commonly performed major surgery, but it is also the commonest obstetric operation. CD is associated with some chronic maternal morbidities including pelvic pain, adhesions and adverse reproductive effects. CS carries long‐term sequele which can adversely affect subsequent pregnancies. Why do some women develop bad sequele of CS‐like adhesions, and infertility is well demonstrated in this chapter. Fertility‐oriented step‐by‐step description of CS techniques is extensively described. Some recent controversial issues related to CS like the development of uterine nitche (isthmocele) at the CS scar site, placenta accrete and the role of cesarean myomectomy are discussed in details. At the end of this chapter, the reader will conceive enjoy fertility‐oriented concept of CS.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Atef Darwish",authors:[{id:"29304",title:"Prof.",name:"Atef",middleName:"M.M.",surname:"Darwish",slug:"atef-darwish",fullName:"Atef Darwish"}]},{id:"52615",title:"Bowel Dysfunction after Hysterectomy for Benign Conditions: Meta-Analysis and Systematic Review",slug:"bowel-dysfunction-after-hysterectomy-for-benign-conditions-meta-analysis-and-systematic-review",totalDownloads:1531,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The aim of this study was to determine whether hysterectomy for a benign indication can cause functional gastrointestinal disorders (FGIDs). A systematic review was completed with the studies, which used a prospective design and validated quality of life questionnaires. A search strategy using Medline and Embase allowed the relevant studies published between 1950 and October 2010 to be found. Meta-analyses were also performed using the studies, which had similar research objectives. The search revealed 29 potentially suitable articles, of which 5 used a prospective design and validated quality of life questionnaires. The meta-analyses showed that the type of hysterectomy (total or subtotal) did not have an impact on whether a patient is likely to develop gastrointestinal symptoms post-surgery. The prospective studies did not show that hysterectomy for a benign indication causes FGIDs. The belief that hysterectomy can cause gastrointestinal dysfunction is based on the results of retrospective studies.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Constantina Pitsillides and Hany Lashen",authors:[{id:"191199",title:"Mr.",name:"Hany",middleName:null,surname:"Lashen",slug:"hany-lashen",fullName:"Hany Lashen"}]},{id:"51944",title:"Hysteroscopic Surgery for Submucosal Fibroids",slug:"hysteroscopic-surgery-for-submucosal-fibroids",totalDownloads:17730,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"This chapter presents a contemporary summary of the evidence of the clinical impact of submucosal fibroids and discusses the methods used to investigate and surgically manage this common gynaecological condition.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Rashi Kalra and Roger J Hart",authors:[{id:"187858",title:"Prof.",name:"Roger",middleName:null,surname:"Hart",slug:"roger-hart",fullName:"Roger Hart"},{id:"187861",title:"Dr.",name:"Rashi",middleName:null,surname:"Kalra",slug:"rashi-kalra",fullName:"Rashi Kalra"}]},{id:"52626",title:"Laparoscopic Surgery in the Treatment of Endometriosis",slug:"laparoscopic-surgery-in-the-treatment-of-endometriosis",totalDownloads:1380,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Endometriosis is a benign disease, which affects about 10% of reproductive age women and almost 50% of infertile women. Although every year at least 300 new articles deal with this topic, endometriosis is still a enigmatic disease starting with theories of etiopathogenesis where there is still no consensus about the major cause of endometriosis. Also there is still no consensus about the management of the disease, mainly when there is an infertile patient who is preparing for in vitro fertilization procedure.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Sonja Pop-Trajkovic Dinic, Jasmina Popovic, Radomir Zivadinovic,\nDejan Mitic, Vladimir Antic and Milan Trenkic",authors:[{id:"69225",title:"Dr.",name:"Sonja",middleName:null,surname:"Pop-Trajkovic",slug:"sonja-pop-trajkovic",fullName:"Sonja Pop-Trajkovic"},{id:"194904",title:"Dr.",name:"Vladimir",middleName:null,surname:"Antic",slug:"vladimir-antic",fullName:"Vladimir Antic"},{id:"194905",title:"Prof.",name:"Jasmina",middleName:null,surname:"Popovic",slug:"jasmina-popovic",fullName:"Jasmina Popovic"},{id:"194906",title:"Dr.",name:"Milan",middleName:null,surname:"Trenkic",slug:"milan-trenkic",fullName:"Milan Trenkic"}]},{id:"52107",title:"Deep Neuromuscular Blockade Improves Surgical Conditions During Gynecological Laparoscopy",slug:"deep-neuromuscular-blockade-improves-surgical-conditions-during-gynecological-laparoscopy",totalDownloads:1510,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Obtaining an appropriate laparoscopic workspace depends on several factors related to the patient (i.e., weight and abdominal compliance) and the procedure (i.e., body’s position, depth of anesthesia and intra-abdominal (IA) pressure). Among them, a deep neuromuscular blockade (NMB) contributes to provide the surgeon with better operating conditions. This chapter discusses the interests and challenges of muscle relaxation during gynecological laparoscopy. The introduction of sugammadex into clinical practice provides the opportunity to modify the management of neuromuscular blockade to improve the surgical conditions during laparoscopy as well as the safety of the patients. The maintenance of a rocuronium-induced deep neuromuscular block from the trocar insertion until the end of laparoscopy is no longer incompatible with rapid recovery and awakening in optimal conditions. Neuromuscular transmission (NMT) monitoring is the key to adequate management and should be used in all cases. Objective measurements allow for excellent intubation and surgical conditions, the definition of thresholds and doses for the administration of reversal agents, and the exclusion of residual blockade prior to the patient extubation.",book:{id:"5409",slug:"fertility-oriented-female-reproductive-surgery",title:"Fertility-oriented Female Reproductive Surgery",fullTitle:"Fertility-oriented Female Reproductive Surgery"},signatures:"Christophe Dransart, Laurie Putz, Maria-Laura Marotta and Philippe\nE. 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The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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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). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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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. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null}]},{type:"book",id:"6843",title:"Biomechanics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6843.jpg",slug:"biomechanics",publishedDate:"January 30th 2019",editedByType:"Edited by",bookSignature:"Hadi Mohammadi",hash:"85132976010be1d7f3dbd88662b785e5",volumeInSeries:4,fullTitle:"Biomechanics",editors:[{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"9",type:"subseries",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. 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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.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11405,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. 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