Mechanisms of iron regulation by antioxidants.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
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\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7038",leadTitle:null,fullTitle:"Vitamin D Deficiency",title:"Vitamin D Deficiency",subtitle:null,reviewType:"peer-reviewed",abstract:'Vitamin D is the topic for many discussions in the scientific community. Nowadays, a different interpretation of this secosteroid hormone is needed. Today the term "vitamin" may be considered outdated. This compound may be correctly be called a vitamin only when it is administered to humans or animals that suffer from its deficiency. This book attempts to clarify the role of Vitamin D deficiency in many pathological processes in the whole organism. Chapters in this book cover such issues as the earliest clinical and preclinical investigations of the consequences of Vitamin D deficiency for cognitive, cardiovascular, metabolic, immune, and renal disorders.',isbn:"978-1-83880-776-4",printIsbn:"978-1-83880-775-7",pdfIsbn:"978-1-83880-777-1",doi:"10.5772/intechopen.73799",price:119,priceEur:129,priceUsd:155,slug:"vitamin-d-deficiency",numberOfPages:282,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ba24f0913341357b0779ff9529c4bbfc",bookSignature:"Julia Fedotova",publishedDate:"February 26th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7038.jpg",numberOfDownloads:12858,numberOfWosCitations:4,numberOfCrossrefCitations:13,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:21,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:38,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 16th 2019",dateEndSecondStepPublish:"August 26th 2019",dateEndThirdStepPublish:"October 25th 2019",dateEndFourthStepPublish:"November 18th 2019",dateEndFifthStepPublish:"January 17th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"269070",title:"Prof.",name:"Julia",middleName:null,surname:"Fedotova",slug:"julia-fedotova",fullName:"Julia Fedotova",profilePictureURL:"https://mts.intechopen.com/storage/users/269070/images/system/269070.jfif",biography:"Julia O. Fedotova, MD, PhD habil., Doc. Biol. Sci was born in St. Petersburg (Russia), in 1973. She graduated and received her Diploma of Pharmacist, from Pharmaceutical Faculty, St. Petersburg State Chemical-Pharmaceutical Academy in 1996. She received her\nPh.D. in Experimental and Clinical Pharmacology and\nPhysiology of Humans and Animals in 1999. She attended the Medical\nSchool, Department of Pharmacology, University of Catania in\n2002, and the Institute of Physiology, Medical School, University of Pecs. She graduated from the special doctoral course in neuropharmacology at the Department\nof Neuropharmacology in the Institute for Experimental Medicine of the Russian\nAcademy of Medical Sciences and she received her Doctor of Biological Sciences degree\n(Ph.D. habil.) in 2008. She is currently a professor at the ITMO University and the\nleading researcher at the I.P. Pavlov Institute of Physiology. She has more than 200 publications (mostly in Russian), 2 patents, and 4 journal articles in collaboration, as well as 6 chapters in journals.\nShe is head of the project “The studying of Vitamin D3 role in the development of\naffective-related disorders in women in the climacteric period, the search of ways for\npharmacorrection”, from the prestigious Russian Scientific Foundation.",institutionString:"ITMO University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"ITMO University",institutionURL:null,country:{name:"Russia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"379",title:"Vitaminology",slug:"alimentology-vitaminology"}],chapters:[{id:"68649",title:"Vitamin D and Its Deficiency in Saudi Arabia",doi:"10.5772/intechopen.88745",slug:"vitamin-d-and-its-deficiency-in-saudi-arabia",totalDownloads:1064,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Vitamin D is a hot topic that has attracted attention over the past 10 years, especially since a large proportion of people suffer from this nutrient deficiency. Vitamin D deficiency is estimated to be about 1 billion people all over the world and 50% in Asia and the Middle East. Saudi Arabia has also demonstrated a high prevalence of vitamin D deficiency among healthy Saudi individuals. This chapter provides, in detail, a clear and understandable identification of vitamin D, its function, source, synthesis, metabolism, status, and deficiency. The chapter also focuses on studying vitamin D deficiency in Saudi Arabia based on PubMed’s initial research criteria.",signatures:"Fawzi F. Bokhari and Mai Albaik",downloadPdfUrl:"/chapter/pdf-download/68649",previewPdfUrl:"/chapter/pdf-preview/68649",authors:[null],corrections:null},{id:"69039",title:"Vitamin D Deficiency in Children",doi:"10.5772/intechopen.89208",slug:"vitamin-d-deficiency-in-children",totalDownloads:831,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In addition to its contribution to bone metabolism, vitamin D seems to fulfill a broad spectrum of biological functions which justifies the interest in monitoring its body content. The aim of this study is to analyze the prevalence of hypovitaminosis D and associated factors in schoolchildren and adolescents living in a region of northern Spain. A cross-sectional clinical and analytical study (calcium, phosphorus, calcidiol, and parathyroid hormone) was accomplished in a group of 602 Caucasian individuals (aged 3.1–15.4 years). Gender, age, body mass index, residence, and season of the year were recorded, and their association with vitamin D deficiency was analyzed by multiple regression. Vitamin D status was defined according to the US Endocrine Society criteria. The prevalence of hypovitaminosis D was 60.4% (insufficiency: 44.6%; deficiency: 15.8%). The female sex, adolescence, season of blood sample collection (autumn, winter, and spring), an urban residence, and severe obesity showed an association with an increased risk of hypovitaminosis D.",signatures:"Teodoro Durá-Travé, Fidel Gallinas-Victoriano, María Urretavizcaya-Martinez, Lotfi Ahmed-Mohamed, María Malumbres-Chacón and Paula Moreno-González",downloadPdfUrl:"/chapter/pdf-download/69039",previewPdfUrl:"/chapter/pdf-preview/69039",authors:[{id:"53819",title:"Prof.",name:"Teodoro",surname:"Durá-Travé",slug:"teodoro-dura-trave",fullName:"Teodoro Durá-Travé"}],corrections:null},{id:"70755",title:"Maternal Vitamin D Status among Different Ethnic Groups and Its Potential Contribution to Adverse Pregnancy and Child Outcomes",doi:"10.5772/intechopen.90766",slug:"maternal-vitamin-d-status-among-different-ethnic-groups-and-its-potential-contribution-to-adverse-pr",totalDownloads:818,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Maternal vitamin D deficiency in pregnancy is a widespread public health concern. Race and ethnicity as biological and cultural factors, respectively, can affect vitamin D status through differences in skin color, sunlight exposure, and dietary intake. Low maternal vitamin D status in pregnancy may affect both mother and fetus adversely. Vitamin D deficiency and insufficiency are linked to a wide variety of adverse pregnancy outcomes such as gestational diabetes, preeclampsia, and preterm delivery. Furthermore, maternal vitamin D deficiency has been linked to several adverse health outcomes in infants and children. The examples include, but not limited to, impaired growth, skeletal problems, and autoimmune diseases such as type 1 diabetes and asthma. This chapter reviews the vitamin D status during pregnancy across different ethnic groups, looking into the adverse pregnancy and child outcomes, followed by a discussion on the association between maternal and child vitamin D status and successful interventions. Strong evidence exists about the association between vitamin D and some health outcomes during pregnancy, while more studies are needed to confirm the other claim. The existing body of evidence justifies the need for well-designed policies and systematic interventions to ensure optimal vitamin D status of pregnant women and their offsprings across different ethnic and racial groups.",signatures:"Pardis Keshavarz, Parisa Jandaghi, Mojtaba Shafiee, Naorin Islam and Hassan Vatanparast",downloadPdfUrl:"/chapter/pdf-download/70755",previewPdfUrl:"/chapter/pdf-preview/70755",authors:[null],corrections:null},{id:"69654",title:"Nutritional Considerations of Vitamin D Deficiency and Strategies of Food Fortification",doi:"10.5772/intechopen.89612",slug:"nutritional-considerations-of-vitamin-d-deficiency-and-strategies-of-food-fortification",totalDownloads:773,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Vitamins and minerals are crucial for human health. Any deficiency can lead to major diseases; however, the most prevalent one is the vitamin D deficiency. Due to its high risk in the Middle East and Lebanon, besides its major effects, solutions to decrease this deficiency are taken nowadays. Vitamin D food fortification is the most popular solution taken now. Liposomes showed highest efficiency in vitamin D fortification. However, a study must be done in order to deduce the amounts needed in the targeted population. Therefore, before fortification starts, FDA regulations must be reviewed. Several foods succeeded in fortification with vitamin D and increasing its levels such as milk and cheddar cheese. Stability and flavors showed good results over fortification, while according to the odor, water sources showed more aroma depth than oil sources. The AOAC methods for vitamin D amount in fortified foods must be applied. Dietary 25(OH)D3 was 7.14-fold more effective at raising serum 25(OH)D than dietary vitamin D3.",signatures:"Sami El Khatib and Malak Abou Shahine",downloadPdfUrl:"/chapter/pdf-download/69654",previewPdfUrl:"/chapter/pdf-preview/69654",authors:[null],corrections:null},{id:"70173",title:"An Evidence-Based Review of Efficacy and Safety of Dietary, Natural Supplements and Sunlight in Vitamin D Deficiency",doi:"10.5772/intechopen.89598",slug:"an-evidence-based-review-of-efficacy-and-safety-of-dietary-natural-supplements-and-sunlight-in-vitam",totalDownloads:906,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"There have been recent concerns about the propensity of calcium and vitamin D supplementation to cause cancer. In osteoporotic patients, this has led to increasing recommendations advocating the replacement of calcium supplementation with dietary or other means. Around the world, the problem of vitamin D deficiency remains, being a large contributor of rickets and osteomalacia in the developing world and osteoporosis in post-menopausal women and people dependent on long-term corticosteroid treatment. We review the alternatives of vitamin D supplementation through dietary, other natural supplements as well as sunlight therapy, in an evidence-based manner. We will also review the safety aspect of each modality.",signatures:"Jenson Mak",downloadPdfUrl:"/chapter/pdf-download/70173",previewPdfUrl:"/chapter/pdf-preview/70173",authors:[{id:"60765",title:"Dr.",name:"Jenson",surname:"Mak",slug:"jenson-mak",fullName:"Jenson Mak"}],corrections:null},{id:"70606",title:"Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review",doi:"10.5772/intechopen.90617",slug:"association-of-vitamin-d-deficiency-and-mood-disorders-a-systematic-review",totalDownloads:1005,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:1,abstract:"The cells of our body comprise calcitriol (1,25(OH) vitamin D2), the active form of vitamin D, an integral biological substance that has an impact on a large number of biological processes. While high prevalence of vitamin D deficiency is detected in population worldwide, the reports from sun-soaked countries like India are also alarming to note that the deficiency of vitamin D as high as 70 to 90% is observed leading to several chronic diseases in the majority of people. Deficiency of vitamin D is observed not only because of low levels of vitamin D in the diet, less exposure to sunlight, reduced cutaneous vitamin D synthesis, but also due to consumption of particular medicines, undue alcohol intake, and tobacco smoking. Vitamin D is known to affect estradiol, dopamine, and pro-inflammatory cytokine levels, besides being involved in the regulation of mechanisms pertaining to hormones like glucocorticoids. When vitamin D binds to vitamin D receptors (VDR) present in the central nervous system, it is noted to be responsible for the regulation of brain neuronal functions. Low 25-hydroxy vitamin D levels are found to have a higher incidence of various mood disorders. This review focusses on vitamin D receptors, VDR gene mutations, and pathophysiology causing vitamin D deficiency disorders.",signatures:"Jigna Shah and Sakshi Gurbani",downloadPdfUrl:"/chapter/pdf-download/70606",previewPdfUrl:"/chapter/pdf-preview/70606",authors:[null],corrections:null},{id:"69069",title:"The Effects of Vitamin D Deficiency on Neurodegenerative Diseases",doi:"10.5772/intechopen.89160",slug:"the-effects-of-vitamin-d-deficiency-on-neurodegenerative-diseases",totalDownloads:963,totalCrossrefCites:2,totalDimensionsCites:7,hasAltmetrics:1,abstract:"Approximately 90% of the elderly population in the western countries has at least a mild to moderate vitamin D hypovitaminosis. Besides the well-known function of vitamin D in calcium homeostasis, it has been recently found that several enzymes and receptors involved in its homeostasis are expressed in the nervous system and brain suggesting also an important role in the brain homeostasis. Interestingly, epidemiological and clinical studies found reduced vitamin D level associated with an increased risk of several neurodegenerative disorders. In this chapter, we focus on a potential link between vitamin D and Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, prion disease, and motor neuron disease. Epidemiological studies were summarized, an overview of the known potential underlying pathomolecular mechanisms are given, and results from clinical studies dealing with vitamin D supplementation were presented. As an outlook, recent literature suggesting an impact of vitamin D on autism spectrum disease, depression, and schizophrenia are briefly discussed. In conclusion, the identification of an abundant vitamin D metabolism in the brain and the tight link between the increasing number of several neurological and mental disorders emphasize the need of further research making a clear recommendation of the intake and supplementation of vitamin D in a growing elderly population.",signatures:"Anna A. Lauer, Daniel Janitschke, Tobias Hartmann, Heike S. Grimm and Marcus O.W. Grimm",downloadPdfUrl:"/chapter/pdf-download/69069",previewPdfUrl:"/chapter/pdf-preview/69069",authors:[null],corrections:null},{id:"69594",title:"Vitamin D3 Modulates NF-kB/p65, 17β-Estradiol, and Vitamin D Receptors Expression at Estrogen Deficiency",doi:"10.5772/intechopen.89357",slug:"vitamin-d-sub-3-sub-modulates-nf-kb-p65-17-estradiol-and-vitamin-d-receptors-expression-at-estrogen-",totalDownloads:833,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The aim of the present study was to focus on the effects of Vitamin D3 (VD3) supplementation (5.0 mg/kg, s.c.) on the NF-kB/p65, 17β-estradiol (17β-E2)/VD3 receptors expression in the hippocampus in the long-term ovariectomized (OVX) rats treated with low dose of 17β-E2 (0.5 μg/rat, s.c.) submitted for the chronic unpredictable mild stress (CUMS) for 28 days. Sucrose preference (SPT), forced swimming (FST), and open-field (OFT) tests were conducted to estimate the anhedonia-/depression-like states. NF-kB/p65, 17β-E2/VD3 receptors levels in the hippocampus were evaluated by ELISA and Western blot assays. The findings demonstrated that VD3 at high dose (5.0 mg/kg, s.c.) in a combination with low dose of 17β-E2 decreased anhedonia in the SPT and depression-like behavior in the FST of the long-term OVX rats submitted to CUMS. VD3 (5.0 mg/kg) resulted in significant decreased levels of hippocampal NF-kB/p65 protein expression, as well as to the normalization of hippocampal 17β-E2/VD3 receptors levels in long-term OVX rats treated with 17β-E2 exposed to CUMS. In conclusion, VD3 (5.0 mg/kg, s.c.) in a combination with low dose of 17β-E2 had a synergic antianhedonic- and antidepressant-like effects in the adult female rats following long-term ovariectomy submitted to CUMS.",signatures:"Alexandra Koshkina, Olga Volkova and Julia Fedotova",downloadPdfUrl:"/chapter/pdf-download/69594",previewPdfUrl:"/chapter/pdf-preview/69594",authors:[null],corrections:null},{id:"70127",title:"Vitamin D and Obesity",doi:"10.5772/intechopen.90181",slug:"vitamin-d-and-obesity",totalDownloads:963,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Obesity is a very common issue worldwide, and it is one of the risk factors for mortality. Several studies were done to identify the causes of this issue and to investigate factors that can affect this condition. Vitamin D is claimed to have an impact not only for maintaining bone health but also for having an association between its deficiency and obesity as some studies found that the concentrations of this vitamin are low in obese individuals. The suggested mechanisms and a discussion of the latest findings as well as the possibility of integrating supplementation in the treatment of obesity are covered in this book chapter. It was concluded that vitamin D deficiency is prevalent in many parts of the world and the supplements are an affordable option, but further studies are required to address different confounding factors that will result in clear data interpretation and will contribute to the future planning of health policies and guidelines used by healthcare professionals.",signatures:"Sabrina Ait Gacem and Moyad Jamal Shahwan",downloadPdfUrl:"/chapter/pdf-download/70127",previewPdfUrl:"/chapter/pdf-preview/70127",authors:[null],corrections:null},{id:"69402",title:"Vitamin D Deficiency and Diabetes Mellitus",doi:"10.5772/intechopen.89543",slug:"vitamin-d-deficiency-and-diabetes-mellitus",totalDownloads:1579,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Vitamin D (VD) is a molecule that can be synthesized directly in the humans’ body or enter the organism with food in the form of inactive precursors. To exert its biological action, VD undergoes two-stage hydroxylation (at the 25th and 1st position) catalyzed by cytochromes P450, the presence of which has already been shown in almost all tissues of the human body. The product of hydroxylation is hormone-active form of vitamin D–1,25(OH)2D. 1,25(OH)2D binds to specific vitamin D receptor (VDR) and regulates the expression of genes involved in bone remodeling (classical function) and genes that control immune response, hormone secretion, cell proliferation, and differentiation (nonclassical functions). VD deficiency is prevalent around the globe and may be one of the key factors for diabetes development. The direct association between vitamin D deficiency and type 1 (T1D) and type 2 (T2D) diabetes has been proven. Detection of VDR in pancreas and adipose tissue, skeletal muscles, and immune cells allowed implying the antidiabetic role of vitamin D by enhancing insulin synthesis and exocytosis, increasing the expression of the insulin receptor, and modulating immune cells’ functions. This chapter summarizes data about relationship between VD insufficiency/deficiency and development of T1D and T2D, and their complications.",signatures:"Ihor Shymanskyi, Olha Lisakovska, Anna Mazanova and Mykola Veliky",downloadPdfUrl:"/chapter/pdf-download/69402",previewPdfUrl:"/chapter/pdf-preview/69402",authors:[null],corrections:null},{id:"70095",title:"Vitamin D and Cardiovascular Disease: The Final Chapter?",doi:"10.5772/intechopen.90106",slug:"vitamin-d-and-cardiovascular-disease-the-final-chapter-",totalDownloads:755,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Vitamin D deficiency is globally prevalent and has been associated with the pathogenesis and complications of cardiovascular disease (CVD) and its risk factors. Defining these relationships has been challenging, and the clinical applications of vitamin D screening and supplementation for CVD risk prevention and modification have only recently become clearer. Most of the available evidence includes large observational studies and smaller randomized trials that scarcely evaluate CV outcomes as primary endpoints. Additionally, these studies include methodological inconsistencies, making it difficult to ascertain the benefits of vitamin D supplementation. However, more recently, randomized trials have been conducted which utilize CVD outcomes as primary endpoints, while assessing the effects of high dose vitamin D supplementation on CV health. Despite observational evidence as well as a conventional consensus that vitamin D supplementation improves CV health, these studies suggest that vitamin D supplementation likely has no benefit in this regard, at least in the follow-up period and populations evaluated.",signatures:"Jeremy I. Purow and Seth I. Sokol",downloadPdfUrl:"/chapter/pdf-download/70095",previewPdfUrl:"/chapter/pdf-preview/70095",authors:[null],corrections:null},{id:"69633",title:"Vitamin D and Autoimmune Diseases",doi:"10.5772/intechopen.89707",slug:"vitamin-d-and-autoimmune-diseases",totalDownloads:1279,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Vitamin D has many and profound effects on the immune system. Vitamin D deficiency is known to be related to the development of autoimmune diseases. In particular, vitamin D deficiency is related to the development and the severity of rheumatoid arthritis (RA). RA develops in patients with vitamin D deficiency, and the activity of the disease is related to vitamin D deficiency. Vitamin D deficiency is also related to the development of systemic lupus erythematosus (SLE). SLE develops in patients with vitamin D deficiency, and the activity of the disease is also greater in patients with vitamin D deficiency. Vitamin D deficiency is also related to the development and the severity of multiple sclerosis. Vitamin D should be administered to patients with multiple sclerosis, and this seems to mitigate the symptoms of the disease and to prevent disease progression. Vitamin D deficiency is also observed in patients with inflammatory bowel disease and may be related to disease severity. Low vitamin D levels have also been observed in patients with autoimmune Hashimoto’s thyroiditis. Low vitamin D levels have been observed in patients with systemic sclerosis, especially in the diffuse form of the disease. Optimal vitamin D levels appear to be required for normal immune function and for the prevention and treatment of autoimmune diseases.",signatures:"Ifigenia Kostoglou-Athanassiou, Lambros Athanassiou and Panagiotis Athanassiou",downloadPdfUrl:"/chapter/pdf-download/69633",previewPdfUrl:"/chapter/pdf-preview/69633",authors:[null],corrections:null},{id:"69574",title:"Vitamin D Deficiency in Renal Disease",doi:"10.5772/intechopen.88928",slug:"vitamin-d-deficiency-in-renal-disease",totalDownloads:1090,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Vitamin D deficiency is highly prevalent in patients with renal disease. The abnormal vitamin D (VD) metabolism in chronic kidney disease (CKD) is a key factor for developing CKD-related mineral bone disease (CKD-MBD), which directly influences the survival of the CKD patients. The importance of VD is perhaps of greater value due to its pleiotropic effects that span beyond calcium-phosphorus metabolism (cancer protection, diabetes prevention, and renal protection). The aim of our chapter is to depict the clinical implications of VD deficiency in the setting of CKD, including VD pleiotropy in renal disease, and to propose the most adequate treatment suggested in the literature.",signatures:"Jean Jeanov Filipov and Emil Paskalev Dimitrov",downloadPdfUrl:"/chapter/pdf-download/69574",previewPdfUrl:"/chapter/pdf-preview/69574",authors:[{id:"181956",title:"Dr.",name:"Jean",surname:"Jeanov Filipov",slug:"jean-jeanov-filipov",fullName:"Jean Jeanov Filipov"},{id:"185237",title:"Prof.",name:"Emil",surname:"Paskalev Dimitrov",slug:"emil-paskalev-dimitrov",fullName:"Emil Paskalev Dimitrov"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5940",title:"Vitamin C",subtitle:null,isOpenForSubmission:!1,hash:"e23e79359167bb9d4a53edd78c7b5038",slug:"vitamin-c",bookSignature:"Amal H. 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\r\n\tExpert systems are the branch of artificial intelligence dealing with utilizing human expertise for solving problems. They are defined as computer systems that are capable of solving problems in the same way as a human expert would do when they face the same problem. With the current stream of digital transportation and an enormous amount of interest in intelligent systems, they will be a potential area of research for providing better intelligence to systems. They will also motivate the researchers to generate systems with more and more expertise. In this book, a general introduction to expert systems will be provided after a brief introduction to Artificial Intelligence. Detailed information about Expert Systems will be defined concerning their basic features and architectures as well as main characteristics and basic differences from traditional computer systems. Various applications of expert systems will also be provided. Potential readers will find both theoretical progress as well as practical applications. They will find a great amount of information to ease their research and implementation of intelligent systems.
",isbn:"978-1-83969-422-6",printIsbn:"978-1-83969-421-9",pdfIsbn:"978-1-83969-423-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"514907388f7a2b291f71f9b93b58b795",bookSignature:"Prof. Ercan Oztemel",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11912.jpg",keywords:"Artificial Intelligence, Intelligent Systems, Smart Systems, Computational Intelligence, Knowledge Base, Knowledge Representation, Knowledge Management, Inference Engine, Manufacturing Applications, Finance Applications, Smart Factories, Health Applications",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 22nd 2022",dateEndSecondStepPublish:"June 29th 2022",dateEndThirdStepPublish:"August 28th 2022",dateEndFourthStepPublish:"November 16th 2022",dateEndFifthStepPublish:"January 15th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Prof. Dr. Oztemel graduated from the Istanbul Technical University and received his Ph.D. degree from the Department of Electrical, Electronics and Systems Engineering of the University of Wales, UK. He worked as a Chief Researcher at the Information Technologies Institute of Turkish Science and Technology Council (TUBITAK). He also served as the vice president of the Turkish Measurement and Placement Center of Turkey and as a member of the Executive Board in the TUBITAK Public Research Group.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"306974",title:"Prof.",name:"Ercan",middleName:null,surname:"Oztemel",slug:"ercan-oztemel",fullName:"Ercan Oztemel",profilePictureURL:"https://mts.intechopen.com/storage/users/306974/images/system/306974.png",biography:"Prof. Dr. Ercan Oztemel was born in 1962 in Elazig of Turkey. He graduated from the Department of Industrial Engineering, Sakarya Engineering Faculty of Istanbul Technical University in 1984. He completed his postgraduate studies at Boğaziçi University between 1985-1987, and his doctorate study at the Department of Electrical, Electronics and Systems Engineering of University of Wales between 1988-1992. Between 1993 and 2006, he worked as a lecturer at Sakarya University. In addition to his academic life, he worked as a Chief Researcher at Information Technologies Institute of Turkish Science and Technology Council (TUBITAK), between 1993 and 2011. In this institute, he conducted research on Artificial Intelligence applications, especially in the military domain. He carried out projects that were the first of their kind, such as placing simulation systems on military training aircraft (flying simulator), Artificial combat Pilot, nurse robots, war fare exercises in the virtual world. Between 1997 and 2010, he carried out research in the Western European Union Armament Group, as well as a Member of the Executive Board in the 11th and 15th Groups, and a member of the System Analysis and Simulation (SAS) Panel within NATO between 2001-2006. On the other hand, he supported the creation and execution of many sub-projects as a Member of the Executive Board in the IPROMS (Intelligent Production and Mechanization Systems) Center of Excellence project opened within the scope of the European Union 6th Framework Program. He served as the vice president of Turkish Measurement and Placement Center of Turkey between 2011 and 2015, and as the member of the Executive Board in the TUBITAK Public Research Group between 2012 and 2017. He conducts research in areas such as artificial intelligence, intelligent manufacturing systems, management information systems, simulation and modeling, strategic planning, quality management. He has many articles, papers and books on these subjects. 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It is prevalent in the Mediterranean countries, the Middle East, and Southeast Asia, as well as countries along the Americas, coincidental with the occurrence of malaria. Carriers of β-thalassemia genes are considered relatively protected against malaria parasite. At present, because of vast population migration and intermarriage between different ethnic groups, β-thalassemia is also common in North and South America, Northern Europa, Australia, and the Caribbean. As a consequence of the reduced or absent synthesis of β-globin chains, there is an excess on α-globin chains that are instable and precipitate in red blood cell precursors causing abnormal cell maturation and their premature destruction in the bone marrow (ineffective erythropoiesis). Red blood cells that survive to reach the peripheral circulation are prematurely destroyed in the spleen. The break down products of Hb, heme, and iron catalyze chemical reactions that generate free radicals, including reactive oxygen species (ROS), which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system [1]. More than 300 different point mutations cause β-thalassemia. They are inherited in a multitude of genetic combinations responsible for clinical manifestations extremely diverse, spanning a broad spectrum from the transfusion-dependent state of thalassemia major (TM) to the asymptomatic state of heterozygous carriers for β0 or β+ (thalassemia trait). β-thalassemia intermedia requires only periodic blood transfusion, while β-thalassemia minor does not require a specific treatment. One of the major consequences in this genetic disorder is iron overload due to multiple blood transfusions, ineffective erythropoiesis, and premature hemolysis in the plasma. Cardiomyopathy is the most common cause of death in transfusion-dependent thalassemia patients as a consequence of iron overloading. Thanks to the significant improvement in therapy, patients with β-thalassemia may reach an advanced age. This is associated with clinical symptoms that are the consequence of the disease itself and the treatment modalities. The aim of this chapter is that to give a complete picture of current knowledge on the etiology of iron accumulation, the role of hepcidin in regulating increased iron absorption, and the pathophysiology resulting from excess of “free iron.” It will also be explored whether there are ways to decrease the iron overload and to neutralize its deleterious effects in the tissues other than iron chelation (for an extensive revision, see Refs. [1, 2, 3, 4, 5]).
\nIn β-thalassemia, as well as in other acquired and hereditary hemolytic anemia, iron overload is a common and serious complication and represents a major cause of morbidity and premature mortality in these patients. Hemoglobin instability, frequent blood transfusion, and increased iron absorption from the gastrointestinal tract represent the main causes of iron overload in β-thalassemia. Iron deposition occurs in visceral organs (mainly in the heart, liver, and endocrine glands), causing tissue damage and ultimately organ dysfunction and failure. Iron homeostasis depends on a coordinated regulation of molecules involved in the import of this element and those exporting it out of the cells. In particular, the iron status reflects the balance among iron uptake from the diet, its storage and mobilization, and its utilization [1]. Normally, 1–2 mg of iron is absorbed from the diet per day, with an equivalent amount lost by the turnover of gastrointestinal tract epithelial cells. In β-thalassemia and other transfusion-dependent anemias, iron overload may accumulate in relatively short time because there are no physiologically regulated means of iron excretion. Iron is essential for several vital biological processes. It regulates enzymatic activity and oxidation-reduction reactions playing a pivotal role in proliferation and cell survival. Iron ensures the transport of oxygen and the catalysis of reactions involved in electron transfer, DNA synthesis, and nitrogen fixation. However, it is also highly toxic due to its ability to react with oxygen and catalyze the production of reactive oxygen species (ROS). In solution, iron can exit in two states of oxidation, Fe (II) and Fe (III), and is very poorly soluble at physiological pH, especially when it is in the oxidized form Fe (III). Living organisms have thus developed many proteins to carry iron in biological fluids and transport it through cellular membranes and to store it in a non-toxic and easily mobilizable form [2, 6, 7, 8]. Iron is bound to transferrin in the plasma, but the iron overload in β-thalassemia patients saturates the ability of the transferrin iron transport system, leading to nontransferrin bound iron (NTBI) and labile plasma iron (LPI) starting to circulate in plasma and subsequently becoming deposited inside the susceptible cells [9, 10]. Rather than using the transferrin receptor, NTBI enters cells by nontransferrin pathways [1, 11]. Long-term uptake and accumulation of NTBI and LIP, its redox active component, lead to increate levels of storage iron and labile cellular iron [12]. Tissues susceptible to iron accumulation by this mechanism include the liver, endocrine system, and myocardium [13]. When the magnitude of the cellular LIP exceeds the capacity of the cell to synthesize new ferritin molecule, a critical concentration is reached that can generate reactive oxygen species (ROS). ROS produced by the metabolism of NTBI play a central role in inducing cellular dysfunction, apoptosis, and necrosis [14]. A variety of ROS, most notably hydroxyl radicals, increase lipid peroxidation and organelle damage, leading to cell death and fibrogenesis mediated by transforming growth factor β-1 (TGF-beta-1) [15]. An underappreciated effect of iron overload is increased the infection risk that is a high cause of mortality in β-thalassemia patients [16]. The LIP has been suggested as a low-molecular-weight intermediate or transitory pool between extracellular iron and intracellular firmly bound iron [17]. The intracellular LIP is redox active, catalyzing the Fenton and Haber-Weiss reactions that generate ROS [18]. Excess ROS are cytotoxic through their interaction with cellular components, such as DNA, proteins, and lipids, causing damage to vital organs [19].
\nβ-thalassemia is a significant health problem in various areas of the world due to its frequency and severity. The standard treatment of β-thalassemia is currently based on transfusion therapy, iron chelation, and, in rare cases, splenectomy. This has led to an increased survival and amelioration of the quality of life, although many patients continue to be affected by cardiac disease and other clinical complications, e.g., developed endocrine failure and delayed pubertal maturation. The only approach that may lead to a definitive cure for β-thalassemia is represented by allogenic hemopoietic stem cell transplantation, but the need to control transplant-related complications and the requirement for matched donors make this option not available to most patients. Thus, the main therapeutic option for the majority of patients remains to be supportive care in the form of blood transfusion combined with chelation therapy [2]. The function of iron chelators is that to remove excess iron from the plasma and the cells by binding the labile and chelatable iron, thus facilitating its excretion through the urine and feces. Deferoxamine was the first iron chelator to be used clinically and is given by a slow, continuous, subcutaneous, overnight infusion through a portable pump. Its side effects are minimal, but its mode of administration results in low compliance [1]. Deferasirox presents several side effects [1, 2]. Neutropenia is the main potential complication of deferiprone, the first effective oral iron chelator in removing excess iron from the organs and from the heart. The use of a combination of chelators leads to an improvement in the efficacy of chelation therapy: deferiprone may mobilize iron from tissues into the circulation, while deferoxamine binds and facilitates its excretion in the urine (the “shuttle mechanism”) [1]. An additional potential approach to reduce iron overload is the downregulation of transferrin receptor 1 (TfR1) by administration of exogenous iron-free (apo) transferrin. In addition to free iron, some iron-containing compounds, due to hemolysis, are elevated in the plasma of β-thalassemia patients. They are free hemin and hemoglobin and are of considerable toxicity [1, 2]. These compounds are neutralized by their scavengers: hemopexin for free hemin and haptoglobin for free hemoglobin. These proteins are reduced in β-thalassemia patients, leaving free, un-neutralized hemin, and hemoglobin. The administration of hemopexin and haptoglobin may be suggested to reduce iron toxicity.
\nThe discovery of hepcidin has led to an important advancement in the understanding of iron metabolism. Hepcidin is a key regulator of whole body iron homeostasis originally identified from urine as an antimicrobial peptide produced in the hepatocytes [20]. Mutations in the human HAMP gene or targeted deletion of the HAMP gene in mice result in massive iron overload [21]. Conversely, high levels of hepcidin lead to decreased iron absorption and iron-restricted anemias indicating that hepcidin is a negative regulator of iron transport into plasma. Many experimental data suggested that the hepcidin could be the regulator of iron absorption and recycling acting principally or solely by binding to ferroportin, the only known cellular iron exporter. The systemic iron homeostasis is controlled by hepcidin-ferroportin interaction: hepcidin binds to ferroportin and induces its internalization and degradation, thus regulating the distribution of iron in the body. When hepcidin concentration increases, hepcidin binds to ferroportin, causing its phosphorylation, internalization, ubiquitylation, sorting through the multivesicular body pathway, and degradation in lysosomes, and iron is retained within the cells in cytoplasmic ferritin [22, 23, 24, 25]. The expression of hepcidin is regulated by different stimuli at the transcriptional level: hypoxia, iron deficiency, erythroid expansion, and anemia are all negative regulators of hepcidin expression, while transferrin receptor 2 (TfR2), the membrane isoform of hemojuvelin (HJV), IL-6, iron, and the hemochromatosis protein HFE are all positive regulators of hepcidin transcription [2]. In β-thalassemia, in spite of iron overload, hepcidin production is generally low, and consequently, iron absorption is high. The process of differentiation and maturation of erythroid precursors is markedly altered in β-thalassemia (ineffective erythropoiesis). An excess of free α-globin chains within the red blood cells is the consequence of the reduced or lack synthesis of β-globin chains. Aggregation, denaturation, and degradation of these chains lead to the formation of insoluble precipitates that cause oxidative membrane damage within the red blood cell and developing erythroblasts (Figure 1A) [26]. Ineffective erythropoiesis is accompanied by a massive iron overload, due to an increase in iron absorption by the gastrointestinal tract and to frequent blood transfusions. Nevertheless, iron overload occurs also in patients who have not received transfusions such as patients suffering from thalassemia intermedia [27, 28]. If iron was a dominant regulator, patients with β-thalassemia should express very high levels of hepcidin in serum in order to decrease intestinal iron absorption. By contrast, the levels of hepcidin are very low in these patients, suggesting that the ineffective erythropoiesis alone is able to suppress the synthesis of hepcidin in spite of the presence of a severe iron overload [25, 29, 30, 31]. Transfusions of erythrocyte partially rerelieved suppression of hepcidin, but transfusions add large amounts of exogenous iron and lead to iron overload. Hepcidin mRNA expression in the HepG2 cell line by serum from β-thalassemia patients suggested the existence of a negative erythropoietic regulator of hepcidin expression [32]. The nature of this humoral factor is still uncharacterized but may include growth differentiation factor (GDF-15), twisted gastrulation protein homolog 1 (TWSG1), soluble transferrin receptor, and erythroferrone, which are all overproduced by the proliferating erythroid precursors (Figure 2). Controlling absorption of iron may be beneficial to the administration of synthetic hepcidin or of agents that increase its expression. Hepcidin agonists or stimulators of hepcidin production are being developed for the treatment or prevention of iron overload in hepcidin deficiency states, including hereditary hemochromatosis and β-thalassemia [33]. The rationale for the use of hepcidin agonists is justified by two principal observations: first, the phlebotomy is an expensive and effective treatment for iron overload that is acceptable to must but not all patients affected by hereditary hemochromatosis; second, iron-loading anemias cannot be treated in this way and require iron chelation therapy, which is not well tolerate by many patients. Hepcidin agonists are agents that replace hepcidin activity or stimulate its endogenous production and, in both hereditary hemochromatosis and iron loading anemia, could prevent iron accumulation by redistributing iron from parenchymal tissues to macrophages where iron is less toxic [34, 35].
\n(A) Erythroid expansion and ineffective erythropoiesis represent oxidative events in the bone marrow. (B). Oxidative events in the circulation: (1) hemolysis leads to hemoglobin release in the plasma. Autoxidation of free hemoglobin produces ROS, free heme, and iron; (2) eryptosis and senescence: two different mechanisms of endocytosis of red blood cells (RBCs) by macrophages; and (3) membrane oxidative damage by ROS, free heme, and iron: activation of NF-κB and AP-1 by ROS and heme increases the production of pro-inflammatory cytokines (IL-1, IL-6, and TNFα) and adhesion molecules on the endothelium. Activated leucocytes generate more ROS by their NAPDH oxidase, creating a loop of oxidative stress and inflammation.
Dysregulation of iron homeostasis in β-thalassemia disease. Ineffective erythropoiesis and premature death of red blood cells are the main cause of anemia in β-thalassemia patients. Erythropoietin production induced by anemia causes an increase in erythropoiesis activating secretion of erythroid factors such as GDF15, TWSG1, and ERFE. The suppression of hepcidin expression caused by an excess of eryhtroid factors leads to an increase in intestinal iron absorption, release of iron from the liver, and reticuloendothelial system. All these lead to iron overload. GDF15: Growth differentiation factor 15; TWSG1: Twisted-gastrulation 1; ERFE: Erythroferrone.
TMPRSS6 suppression could be an alternative approach to increase hepatic synthesis of hepcidin. It is a transmembrane serine protease (matriptase-2) that normally suppresses the synthesis of hepcidin by deactivating hemojuvelin (HJV) [36]. Data showed that the deletion of TMPRSS6 gene in mouse model increased hepcidin expression resulting in anemia improvement, ineffective erythropoiesis, and splenomegaly reducing and decreased iron loading [37]. An improvement in anemia and iron overload has been showed in mice and in preclinical studies using antisense oligonucleotides or small interfering RNAs (siRNA9 decreasing TMPRSS6) [38, 39]. The somministration of exogenous transferrin, through the downregulation of TfR1, increased erythroid precursor enucleation and improved terminal erythroid differentiation and maturation in β-thalassemic mice [40, 41]. Recently, a new iron metabolism regulating factor produced in erythroblasts in response to erythropoietin, ERFE (erythroferrone), was identified. In murine models with β-thalassemia intermedia, ERFE is highly expressed and mediates hepcidin suppression and contributes to iron overload. On the contrary, a deficiency of ERFE leads to an increase in hepcidin expression, a significant reduction in iron overload, and a slight improvement of erythropoietic indices [42]. All these data indicate that the inhibition of ERFE may be a future target with therapeutic potential in diseases with ineffective erythropoiesis and iron overload as β-thalassemia. Agents targeting hepcidin expression are more likely to be beneficial to patients with NTDT than those with TDT because transfusional iron overload is not mediated by low hepcidin levels. However, mini-hepcidins and TMRSS6 inhibitors can be evaluated for use in patients with TDT because improvement in erythropoiesis could potentially reduce transfusion requirements [43]. All discussed novel agents merit further evaluation of efficacy and safety in both preclinical and clinical development studies.
\nOxidative stress plays a major role in pathophysiology of β-thalassemia, although it is not the primary etiology of disease. The cell oxidative status depends on the equilibrium between oxidants and anti-oxidants. The reactive oxygen species (ROS) are oxidants produced mainly as byproducts of cellular respiration, while reduced glutathione is an example of anti-oxidants. A balance between oxidants and anti-oxidants is crucial for normal physiology. ROS are utilized from the cells as regulators in many physiological processes, including proliferation and differentiation of the erythroid precursors. Oxidative stress ensues in many pathological processes when the balance between oxidants and anti-oxidants is broken, as it occurs in β-thalassemia. Excess ROS cause cytotoxicity by binding to cell components such as DNA, proteins, and membrane lipids [19]. In β-thalassemia, the main consequence of the unstable Hbs and iron overload is the oxidative stress. It mediates many of symptoms due to oxidative damage to red blood cells, leukocytes (recurrent infections), platelets (hypercoagulable state), as well as in heart, liver, and the endocrine glands (Figures 1A and B) [19, 44, 45, 46]. Endogenous and exogenous antioxidants may ameliorate the oxidative stress in β-thalassemia. They act scavenging and inactivating ROS and correcting their damage to cellular components. We introduce many antioxidants by nutrition. For example, a moderate wine consumption and a “Mediterranean diet” are thought to have a protective effect due to their high contents of antioxidants [47, 48]. Antioxidants can also be taken as food additives, or as crude extracts, such as preparation of papaya fermented and curcumin, either as pure compounds such as vitamins C and E and Q10 [49]. An improvement in many parameters of oxidative stress by using such additives in β-thalassemia was observed, but a clear clinical benefit, such as reducing transfusion dependence, was less successful. A combination of drugs affecting both the oxidative stress and the iron overload can give an effective outcome. Forkhead-box-O3 (Foxo3) is a critical transcription factor that protects the cell from oxidative stress by upregulating antioxidant enzymes during early stages of erythropoiesis [50]. At early stages, Foxo3 is phosphorylated by proteins of the EPOR-P13K/AKT/mTOR signaling pathway and is translocated out of the nucleus, where it remains inactivated. At late stages, Foxo3 is relocated into the nucleus, gets activated, and induces the production of antioxidants that neutralize ROS to allow efficient erythropoiesis [1, 36, 51, 52]. In mice with β-thalassemia intermedia, downregulation of Foxo3, as a result of persistent activation of EPOR-p13K/AKT/mTOR pathway, was observed. Inactivation of Foxo3 leads to oxidative damage in late erythroblasts and plays a significant role in the process of ineffective erythropoiesis [53]. β-thalassemia patients could be beneficial in improving anemia by activation of Foxo3 as a potential inducer of HbF. However, the function of Foxo3 in hemoglobinopathies has yet to be elucidated. A remarkable improvement in erythroid cell maturation, production of β-globin chains, and anemia has been observed following the use of rapamycin, an mTOR inhibition, in mice with β-thalassemia intermedia [53]. In another study, rapamycin increased α-globin expression and HbF production in cultured erythroid precursors from patients with β-thalassemia intermedia [54, 55]. Similar findings were reported with the use of another Foxo3 activating agent, resveratrol (3,5,4′-trihydroxy-trans-stilbene), a non-flavonoid polyphenol that upregulates antioxidant enzymes in mice with β-thalassemia intermedia [56]. Metformin, an approved drug for diabetes type 2 and a Foxo3 inducer, has been investigated as an HbF inducer in an ongoing phase 1 clinical trial in patients with sickle cell anemia and nontransfusion-dependent thalassemia (NTDT; NCT02981329) [57]. All these agents are in preclinical studies and need further evaluation. Then, further laboratory and clinical investigations are required in this field. A factor required for the initiation of translation through the binding of tRNA to the ribosomes is the eukaryotic initiation factor 2 (eIF2). It is regulated by a mechanism involving phosphorylation at its α-subunit by heme-regulated eIF2a kinase (HRI) in the erythroid precursors. Stress, as heme deficiency and oxidative stress during the late stage of erythroid differentiation, activates HRI that coordinates the synthesis of heme and globin. It was demonstrated that the phosphorylated α-subunit of eIF2 turned on the activating transcription factor 4 (ATF4) to diminish oxidative stress in erythroid precursors [58, 59, 60]. A selective inhibitor of eIF2aP dephosphorylation as salubrinal augmented the HRI signaling pathway and reduced the production of hemichromes in β-thalassemia erythroid precursors [59]. In another study, salubrinal increased HbF production with a concomitant decrease of HbA in differentiating human CD34 cells by a post-transcriptional mechanism [61]. Thus, manipulation of the HRI-eIF2aP signaling pathway could represent a new approach for the treatment of β-thalassemia.
\nAn antioxidant protein that scavenges and inactivates ROS is the peroxiredoxin-2 (Prx2), essential during erythropoiesis. The expression of this protein is upregulated both murine and human β-thalassemia indicating that the oxidative stress induces peroxiredoxin-2 as a novel cytoprotective response in β-thalassemic erythropoiesis [62, 63]. Heme oxygenase (HO-1) is an enzyme that catalyzes the degradation of heme in response to stress, such as oxidative stress or hypoxia, both of which occur in β-thalassemia. In EPO-dependent fetal liver erythropoietic cells from β-thalassemic mice, the expression of HO-1 was augmented. The administration of tin protoporphyrin IX, an HO-1 inhibitor, improved ineffective erythropoiesis and Hb levels and decreased spleen size and liver iron [64, 65].
\nVarious antioxidant enzyme systems are activated by the oxidative stress to protect the body tissues from its damaging effects in β-thalassemia patients. These antioxidants include superoxide dismutase (SOD), catalase, glutathione (GSH), thioredoxin (Trx), and ferritin. Superoxide (O2\n−) is the first reactive radical produced, and this radical can be neutralized by SOD. There are three distinct SODs: SOD1 (cu/Zn-SOD) is present in cytoplasm, whereas SOD2 (Mn-SOD) is present in the mitochondria, and SOD3 is almost exclusively extracellular [66, 67]. Each of these distinct SODs performs a specific function in human cells. In β-thalassemia, major patients higher levels of erythrocyte superoxide dismutase and glutathione peroxidase (GPx) as well as higher plasma malondialdehyde (MDA) were observed as compared to healthy controls [68]. Iron overload through repeated blood transfusions and subsequent oxidative stress produced by reactive oxygen species may be the cause of increased levels of MDA. The rise in SOD and glutathione peroxidase may occur as a result of compensatory mechanisms in response to oxidative stress [44]. Neutralization of O2\n− produces H2O2, which can be metabolized into nontoxic products by a catalase and glutathione peroxidase (GPx) in conjunction with glutathione. Location of GPx depends on the subtype, whereas catalase is present in peroxisomes [67]. The stability of the cellular and subcellular membranes depends mainly on glutathione peroxidase, and the protective antioxidant effect of glutathione peroxidase depends on the presence of selenium. In patients with β-thalassemia, major was confirmed the peroxidative status generated by iron overload and the high increase in serum ferritin, iron, plasmatic thiobarbituric acid reactive substances (TBARS), SOD, and glutathione peroxidase activity, while the vitamin E and zinc concentration decreased in these patients [44, 69]. Glutathione (GSH) is present in nearly all cells in the body and is present in high levels in organs with high oxygen consumption and energy production, e.g., the brain [67, 70]. Glutathione, in conjunction with its oxidized form (GSSG), plays a major role in controlling cellular redox state. The ubiquitous thioredoxin system also plays an important role in maintaining the cell’s redox state [67, 71]. Finally, ferritin is considered an endogenous antioxidant as it performs the important function of sequestering potentially toxic labile iron. When endogenous antioxidants are unable to neutralize oxidative stress, as in β-thalassemia, exogenous antioxidants can be used to augment the antioxidant system of the body. Iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Iron overload can affect redox state, and not only this condition can be restored to physiological conditions using iron chelation, but also the addition of antioxidants to these treatment regimens can be a viable therapeutic approach for attenuating tissue damage induced by oxidative stress (Table 1), (Figure 3, [72, 73, 74]). Vitamin A (β-carotene), vitamin C, vitamin E (α-tocopherol), polyphenols, and other bioactive plant-derived compounds are effective exogenous antioxidants that also regulate iron metabolism. At the transcriptional level, antioxidant enzymes are regulated by the transcription factor Nrf2, which binds to the antioxidant response element (ARE) in the target gene’s promoter region. Nrf2 is believed to be phosphorylated by protein kinase C (PKC), which causes the transcription factor to translocate to the nucleus, where it activates ARE-containing genes [67, 75], ultimately leading to the neutralization of free radicals and the attenuation of oxidative damage [76]. Table 1 summarizes the flavonoids and other antioxidants that regulate both iron homeostasis and redox state, in some cases via independent mechanisms. Flavonoids are present in a wide variety of plants and represent the most common class of polyphenols, organic chemicals that protect the plant from ultraviolet radiation, pathogens, and effects of oxidative stress, making them suitable for therapeutic purposes [77, 78]. Examples of flavonoids include quercetin, cathechins, curcumin, and kaempferol, which are abundant in fruits, vegetables, legumes, red wine, and green tea. Curcumin is a potent flavonoid antioxidant that can chelate iron in addition to modulating redox state [79]. A flavonoid-rich extract of orange and bergamot juice has been shown to chelate iron in iron-overload A549 cells and to activate the antioxidant enzyme catalase, leading to a decrease in ROS production and membrane lipid peroxidation [80]. It is a promising candidate for regulating both oxidative stress and iron homeostasis. Quercetin can reduce hepatic iron deposition in mice that were exposed to either ethanol or excess iron and increase BMP6, intranuclear SMAD4, SMAD4 binding to the HAMP promoter, and hepcidin expression, leading to decreased hepatic iron levels and reduced iron-related damage [81]. Another potent antioxidant is genistein. It reduces inflammation induced by ethanol and oxidative stress in mice [82] and, similar to quercetin, increases HAMP promoter activity in both zebrafish and human hepatocytes via Stat3- and Smad4-dependent process [83]. Silymarin, another flavonoid, is present in milk thistle plant extract and may have iron-chelating properties [84]. It is safe, well tolerated, cost-effective alternative to currently available iron chelation therapies for treating patients with β-thalassemia [84]. Ferulic acid is present in a wide variety of plants, and the antioxidant effects are believed to be mediated via the neutralization of free radicals [85]. The antioxidant effects of resveratrol may prevent adverse changes that lead to cardiovascular disease by modulating vascular cell function, low density lipoprotein (LDL) oxidation, and platelet aggregation, thereby reducing myocardial damage [86, 87]. Both vitamin A and vitamin C have well-established antioxidant properties that are mediated via the attenuation of oxidative damage [88]. Vitamin A and β-carotene increase hepcidin and TfR expression and intestinal iron absorption, reduce inflammatory signaling and ferroportin expression, increase intracellular ferritin levels, and release intracellular trapped iron [89, 90, 91]. Vitamin C reduces Fe3+ to Fe2+ and inhibits hepcidin expression [92]. In recent years, research for new therapies based on plant-derived compounds has developed considerably. This is to maximize the benefits of plant phytochemicals and avoid the adverse effects often associated with synthetic pharmaceutical agents [93]. Several plant extracts, such as tucum-do-cerrado, astragalus,
Antioxidant | \nMechanisms of iron regulation | \nSources of antioxidants | \n
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| \nCurcumin is a bright yellow chemical produced by | \n|
\n
| \nVegetables, leaves, grains, red onions, kale, red wine, and tea | \n|
\n
| \nCitrus fruits | \n|
\n
| \nLupin, fava beans, soy beans, kudzu, psoralea, | \n|
\n
| \n\n | \n|
\n
| \nVegetables, popcorn, bamboo shoots, cereals (bran, wheat, and barley grain) | \n|
\n
| \nSkin of grapes, blueberries, raspberries, mulberries, peanuts, and red wine | \n
Mechanisms of iron regulation by antioxidants.
Summary of the mechanisms regulating iron and oxidative stress by antioxidants. BMP6-SMAD-HAMP: Bone morphogenetic factor-mothers against decapentaplegic homolog-hepcidin antimicrobial peptide; GPx: Glutathione peroxidase;Nrf2-ARE: Nuclear factor erythroid 2-related factor 2-antioxidant response element; SOD: Superoxide dismutase.
Alteration in iron homeostasis is associated with oxidative stress and inflammation. Many bioactive antioxidants and plant-derived phytochemicals can regulate iron homeostasis, inflammation, and oxidative stress. Nevertheless, the majority of data collected to date are derived from in vitro and animal experiments, and further studies are needed in order to evaluate the efficacy of these phytochemicals as a natural substitute for pharmaceutical agents. This is very important because many pharmaceutical agents are associated with adverse side effects.
\nPeroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that is activated by ligand binding as well as via ligand-independent activation. PPARγ plays an active role in regulation of glucose and lipid metabolism but more recently has been examined for its role in numerous disease states including: diabetes, cardiovascular disease, cancer, inflammation, angiogenesis and metastasis [1, 2, 3, 4, 5, 6]. Some research also suggests it provides potential for anti-aging activity [7]. Prior to the discovery of the thiazolidinedione (TZD) drugs used for treatment of diabetes, the general consensus was that PPARγ was subject only to ligand-independent activation [8]. It was the discovery of these drugs that suggested that PPARγ was also sensitive to ligand-dependent activation [8, 9, 10, 11]. The goal of the first generation TZDs was to target insulin sensitivity and although the drugs were successful with this they were not without toxicity concerns. The focus more recently has looked to natural methods to accomplish therapeutic level results and PPARγ provides a viable target with multiple mechanisms available for activation and a variety of functional food sources for PPARγ ligands.
PPARγ is a member of the nuclear receptors gene subfamily and is found on chromosome 3. Other members of the gene family include PPARα and PPARβ/δ. In addition due to alternative splicing, there are multiple isoforms of PPARγ, known as PPARγ1 and PPARγ2 [12, 13]. PPARγ1 is expressed at high levels in white and brown adipose tissue, however, lower levels of expression of PPARγ1 are found in all tissues as well as the immune cells. PPARγ2 is expressed only in white and brown adipose tissue [14]. Although disease states are sometimes related to changes in expression of these isoforms and inefficient signaling associated with the pathway, some research has demonstrated that specific variants have been linked to early onset type 2 diabetes. Nearly half of these patients had a variant in PPARγ2 resulting in an amino acid substitution of tyrosine to cysteine in the activation function domain 1 (AF1). Of note is also that of these patients, 83% also had diabetic kidney disease [15]. Another study demonstrated that loss of function mutation of arginine 288 to histidine in the ligand-binding domain (LBD) resulted in significant conformational changes in the protein that lead to blunting of the activation via prostaglandins [16].
Mouse studies have shown that knockout of PPARγ2 results in insulin resistance [13]. In contrast, it was demonstrated that activation of PPARγ in mouse adipocytes improves insulin sensitivity [17]. Together these studies support the effects of PPARγ activity on insulin resistance and type 2 diabetes in addition to its known role in adipocyte differentiation [12, 18]. PPARγ also controls the expression of the skeletal muscle and adipose glucose transporter (GLUT4), and adipose tissue based hormones adiponectin, resistin and leptin [19, 20, 21]. It is clear from these studies that modulation of PPARγ activity plays a significant role in patient wellness considering the effects of activation on glucose homeostasis, lipid metabolism and adipocyte differentiation. These effects strongly suggest that activation of PPARγ in a controlled fashion provide strong potential for improvement of patient quality of life. Nutraceuticals offer this type of low level controlled activation that may benefit the patient even beyond the potential for the synthetic drugs targeting PPARγ activation.
The structure of PPARγ contains multiple protein domains of importance as shown in Figure 1. The individual domains are separated based on function and can themselves be modified in most cases. The activation function domain 1 (AF1) is on the N-terminus and is subject to phosphorylation, and small ubiquitin like modifiers (SUMOylation). In general SUMOylation leads to suppression of transcriptional activity while ubiquitination increase transcriptional activity. Phosphorylation can increase or decrease transcriptional activity depending on the site of phosphorylation and the enzyme catalyzing the phosphorylation event. In general deacetylation by Sirt-1, the histone deacetylase leads to dissociation of the nuclear receptor corepressor (NCoR) and increased transcriptional activity [22]. The next domain is the DNA binding domain (DBD) responsible for interacting with the DNA in conjunction with the retinoid c receptor (RXR). RXR houses a binding site for 9-cis-retinoic acid, which when bound allows RXR to complex with the PPARγ complex and interaction with DNA [23]. The HD domain is a regulatory domain named due to the histidine (H)-aspartate (D) amino acids conserved in the region. The HD domain interacts with either the coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) or the corepressors NCoR and silencing mediator of retinoid and thyroid hormone receptors (SMRT) [24]. On the C-terminal end is the ligand binding domain (LBD) that when ligand bound by an activator, stimulates transcription. When no ligand is bound, and the corepressor is bound, transcription is limited. The LBD is also subject to phosphorylation, ubiquitination, SUMOylation and acetylation. Each of these affect the likelihood of ligand activation. Of interest are the histone deacetylase enzyme (HDAC) which deacetylate the ligand binding domain. Inhibition of this HDAC, limits deacetylation of the LBD and leads towards PPARγ activation via the ligand independent pathway [25].
The structure of PPARγ. AF-1 is the activated function 1 domain. A/B houses a SUMOylation (S) and phosphorylation (P) site. DBD is the DNA binding domain. HD is the conserved protein domain with histidine and aspartate that interacts with the coactivator PGC-1α. The ligand binding domain (LBD) is attached via a hinge region and houses a SUMOylation, phosphorylation, ubiquitination (Ub) and two acetylation (Ac) sites. AF-2 is the activated function.
The PPARγ pathway involves several overlapping cellular functions. Activation of PPARγ, either ligand-independent or ligand dependent, leads to change in the immune system, metabolic organs including skeletal muscle and adipose tissue [26, 27, 28]. For example in the immune system macrophages and regular T cells, activation of PPARγ in general will decrease inflammation. Inflammation is decreased in the heart and brain but lipid storage is increased in the heart as well as growth. In white adipose tissue lipid metabolism and glucose homeostasis is improved with activation. Of particular interest is the fact that activation of PPARγ increases remodeling and browning of white adipose tissue, a benefit that will likely lead to better ability for patients to manage weight (ref). It is clear that there are strong benefits to PPARγ activation, but potential side effects such as lipid storage in the heart, sodium and fluid retention and increased desire for food can also result in unwanted effects [22].
It is important to consider how PPARγ activation can be achieved while minimizing the potentially harmful side effects. A benefit also exists to activate PPARγ in a ligand dependent fashion versus the ligand independent activation. Endogenous ligands to PPARγ are typically fairly weak agonists while the TZDs are strong agonists [8, 29]. The first generation TZD troglitazone was pulled from the market in the US approximately 3 years after first becoming available because it resulted in severe or fatal hepatotoxicity in numerous cases [30, 31, 32, 33, 34]. Other TZDs were taken off the European market and restricted in the US markets due to potentially dangerous side effects including myocardial infarction, heart failure, hepatic failure [35, 36, 37, 38]. It is still currently believed that these side effects resulted in part to the full PPARγ activation rather than the moderate activation offered by the weaker ligand agonists [29]. Gene expression, especially expression of genes involved in metabolic process that are sensitive to endogenous ligands as well, should be tightly controlled with an effective regulatory method that allows frequent adjustment of expression levels in response to the environment. Altering expression of genes fully by fully activating PPARγ poses several concerns, especially since there is so much overlap within the PPARγ activation pathway. Thus, an increased emphasis on natural and less specific activators is warranted. Natural ligands are particularly useful in this situation because the full and permanent activation is not desired. Given the range of disease state linked to PPARγ signaling, exploring the potential natural food based ligands is an essential tool in moving patient wellness forward.
Several herbs and foods have been used medicinally for centuries, although mechanism of action was not known and in some cases remains unclear. Many of the compounds found in common herbs and foods have been discovered to be ligands of the nuclear receptors such as PPARγ. A variety of studies presented summarize the compound identified to harbor therapeutic potential as a PPARγ ligand resulting in partial activation of the transcription factor and expression of a variety of metabolic and growth genes. Many of these compounds are found in overlapping herbs or spices. For example, cinnamon contains numerous compounds that are demonstrated ligands including: 2-hydroxychalcone, cinnamaldehyde, catechin, eugenol, ethylcinnamate, epicatechin, and cinnaminc acid. As expected, cinnamon has been used medicinally to treat digestive disorders and metabolic problems for decades.
Given the large number of compounds that function as PPARγ ligands, detailed discussion of each is warranted, but an overall summary is also important. Table 1 identifies several of the compounds of interest, their food sources and conveniently lists references that pertain to the studies. Apigenin acts as a partial agonist for PPARγ, inducing an effect of agonism in the absence of a full agonist, and antagonism in the presence of a full agonist. This is due to the low binding affinity that apigenin has for PPARγ itself [6, 39]. However, even with this low binding affinity, it has shown to still produce beneficial effects through this pathway. Due to its interactions with PPARγ, apigenin has anti-inflammatory effects, and has been used for treatment of colitis, or inflammation of the intestines. However, beyond its interactions with PPARγ, apigenin has also been shown to decrease food-intake, and help with weight loss [39]. Apigenin has a lot of potential clinical use and application, and can be found in marjoram, sage, thyme, holy basil, parsley, and alfalfa [6, 39].
PPAR𝛾 agonists | Food Sources | References |
---|---|---|
Apigenin | Marjoram, sage, thyme, holy basil, parsley, alfalfa | [6, 39] |
2-Hydroxychalcone | Cinnamon | [6, 39] |
Luteolin | Marjoram, sage, rosemary, tarragon, thyme, parsley, alfalfa | [6, 39] |
Rosmarinic Acid | Marjoram, sage, rosemary, lavender, thyme, oregano | [6, 39] |
Cinnamaldehyde, Cinnamic Acid | Cinnamon, clove | [6, 39] |
Resveratrol | Bilberries (European blueberries), peanuts, grapes, wine | [5, 6, 32] |
Quercetin | Dill, bay leaves, oregano, pomegranate fruit, apples, tarragon, parsley, chive, lovage | [6, 39] |
Catechin | Apples, marjoram, sage, rosemary, cinnamon, pomegranate fruit, cacao, green tea, grapes, apricots, cherries | [4, 6, 40, 41] |
Eugenol | Cinnamon, clove | [6, 39] |
Epicatechin | Cacao, tea, cinnamon, thyme, apples, grapes | [6, 42, 43] |
Select compounds that function as PPARγ agonists and the food sources.
2-Hydroxychalcone is another example of a partial agonist for PPARγ. Similar to apigenin, this partial agonism of PPARγ leads to anti-inflammatory effects induced by 2-Hydroxychalcone. Although the pathways for these effects are not yet understood in the case of 2-Hydroxychalcone, it is an example of a PPARγ ligand that has shown anti-inflammatory effects [4, 6, 39]. As for food sources of 2-Hydroxychalcone, it is primarily found in cinnamon [6, 39].
Luteolin acts as a partial agonist for PPARγ, thus affecting PPARγ-dependent gene expression and causing agonism, or an increase in gene expression in the absence of a full agonist, and causing antagonism, or a decrease in gene expression in the presence of a full agonist. However, luteolin uniquely acts as a full agonist for the gene expression of insulin dependent glucose transporters (GLUT-4) in the 3 T3-L1 mouse cell model [4]. Currently it is unclear if this effect is also seen in humans, however it is a potential target for future research. Luteolin also has an effect on inflammation through its effect on proinflammatory cytokines such as interleukin-8 (IL-8) [4]. Although the clinical implications are still unclear for luteolin, recent studies have started to uncover some of the potential beneficial effects it may have. In an in vitro study in human intestinal cells, luteolin has shown to prevent the damage caused by chemotherapeutic treatment. As for the sources of luteolin, luteolin has been shown to be present in marjoram, sage, rosemary, tarragon, thyme, parsley, and alfalfa [6, 39].
Similar to luteolin, rosmarinic acid also acts as a partial agonist for PPARγ, allowing for weak agonism in the absence of a full agonist, and antagonism in the presence of a full agonist [6]. Rosmarinic acid has shown to have anti-inflammatory activity in cell culture assays, however its clinical applications should still be further explored and elaborated on. Rosmarinic acid does however have a poor bioavailability, so its application in humans may be limited regardless of its ability to bind to PPARγ [39]. It still has shown activity as a PPARγ ligand though, so it may be worth further investigation. As far as where rosmarinic acid can be found, it is seen in marjoram, oregano, rosemary, sage, thyme, and lavender [6, 39].
Cinnamic acid and cinnamaldehyde work very similarly. Cinnamaldehyde acts as a partial agonist for PPARγ, allowing for weak agonism in the absence of a full agonist, and antagonism in the presence of a full agonist. Cinnamic acid functions in a similar way, but with a much higher binding affinity for PPARγ [6, 44]. They have both shown a plethora of beneficial effects related to its effect on PPARγ. These include, but are not limited to reducing amyloid-β plaques in Alzheimer’s disease, anti-inflammatory effects, as well as improving glucose and lipid levels as well as insulin sensitivity in Diabetes [39, 44, 45]. Although not all of these effects have been shown in humans yet, some have, and there is great potential for clinical application of cinnamaldehyde. As far as the sources of cinnamaldehyde and cinnamic acid, they can both be found in cinnamon as well as clove [6, 39].
Similar to luteolin, resveratrol also acts as a partial agonist for PPARγ-dependent gene expression, which leads to slight agonism in the absence of a full agonist, and antagonism in the presence of a full agonist. Resveratrol affects both glucose and lipid metabolism, and can also have an effect on inflammation in animal models. Resveratrol has also been shown to improve insulin sensitivity in human patients, which is a contributing factor for Type 2 Diabetes, and can help in control of that disease state beyond metabolism of foods consumed. These mechanisms indicate Resveratrol as potentially beneficial in patients with Type 2 Diabetes, as it can help with glucose metabolism, insulin action, and the storage of fat, potentially lowering their risk of cardiovascular events associated with fats [4]. As for the sources of resveratrol, resveratrol has been shown to be present in foods such as bilberries (European blueberries), grapes, wines, and peanuts [5, 6].
Quercetin acts as a partial agonist for PPARγ-dependent gene expression, causing agonism, or an increase in gene expression in the absence of a full agonist, and causing antagonism, or a decrease in gene expression in the presence of a full agonist [4, 6]. Quercetin has also been shown in a mouse fibroblast cell model (3 T3-L1), that it promotes glucose uptake through insulin-dependent glucose transporters (GLUT-4), however does not affect the production of lipid stores through adipogenesis [4]. Additionally quercetin has shown anti-inflammatory effects in vivo, and is very similar in this regard to resveratrol [4, 39, 46, 47]. Quercetin is also fairly abundant in food sources, and can be found in dill, bay leaves, oregano, pomegranate fruit, apples, tarragon, parsley, chive, and lovage [6, 39].
Catechin too binds to PPARγ, however unlike the previous compounds mentioned, catechin acts as a full agonist for PPARγ-dependent gene expression, and as such does not provide antagonism [4]. This being said, the effects of catechin are expected to differ from the other compounds mentioned previously. One of these differences seen is that the negative enantiomer of catechin promotes the differentiation of mesenchymal stem cells into adipocytes, or fat cells [40]. Alternatively, the positive enantiomer of catechin has anti-inflammatory properties, similar to those previously mentioned [41]. Altogether, both enantiomers of catechin appear to have beneficial effects in terms of health, and both appear to affect the PPARγ pathways. Additionally, the sources of catechin are plentiful, as it can be found in apples, marjoram, sage, rosemary, cinnamon, pomegranate fruit, cacao, green tea, grapes, apricots, and cherries [4, 6, 40, 41].
Although the activities of eugenol through PPARγ are not yet well-defined, it is known to bind to PPARγ with a greater affinity than that of catechin, which acts as a full agonist [4, 6]. Eugenol is also a compound that has been demonstrated to increase insulin sensitivity, and has seen use in essential oils for that purpose [39]. Eugenol has also shown anti-inflammatory effects, like all of the other compounds discussed in this chapter [39]. As for where eugenol is found though, it is seen mostly in clove and cinnamon [6, 39].
Ethyl cinnamate is very similar to cinnamic acid and cinnamaldehyde. It too works similarly in terms of agonism, but has a binding affinity more similar to that of cinnamic acid as opposed to cinnamaldehyde [6]. Additionally, as a PPARγ agonist, it shows the same anti-inflammatory effects that all of the other compounds previously mentioned exhibit [39]. In terms of food sources for ethyl cinnamate though, it is seen in mainly cinnamon and clove [6, 39].
Epicatechin is very similar to the compound discussed earlier, catechin. They both have great binding affinities for PPARγ, and have very similar effects [6]. Like catechin, epicatechin has anti-inflammatory properties. However unlike catechin, epicatechin has also been shown to inhibit PPARγ signaling as well as adipogenesis, or the development of fat stores. Altogether, epicatechin has many positive effects, whether related to its actions on PPARγ, or it’s other bioactivities, and has great promise for medicinal application [42, 43]. In terms of sources of epicatechin, it can be found most prominently in cacao, but also in tea, cinnamon, thyme, apples, grapes, and many other fruits and vegetables [6, 42, 43].
As presented there are several natural sources of PPARγ ligands found in spices and food that are commonly consumed. The degree of activation varies on whether the ligand acts as a full agonist or simply as a partial agonist. Molecules that demonstrate a low binding affinity, less than 100 μM, include apigenin, 2-hydoxylchalcone, luteolin, rosmarinic acid, cinnamaldehyde and cinnamic acid, resveratrol and quercetin. Those with moderate binding affinities of 100 to 500 μM, are catechin and eugenol. Those with higher binding affinities include ethylcinnamate and epicatechin. It is important to note that many of these compounds have also been shown to interact in other signaling pathways in the body that could lead to an altered therapeutic response. Together these provide a variety of sources to treat diseases related to PPARγ activity such as inflammation, diabetes, and heart disease.
The authors declare no conflict of interest.
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However, conventional fuzzy inference systems may suffer from either too sparse, too complex or imbalanced rule bases, given that the data may be unevenly distributed in the problem space regardless of its volume. Fuzzy interpolation addresses this. It enables fuzzy inferences with sparse rule bases when the sparse rule base does not cover a given input, and it simplifies very dense rule bases by approximating certain rules with their neighbouring ones. This chapter systematically reviews different types of fuzzy interpolation approaches and their variations, in terms of both the interpolation mechanism (inference engine) and sparse rule base generation. Representative applications of fuzzy interpolation in the field of control are also revisited in this chapter, which not only validate fuzzy interpolation approaches but also demonstrate its efficacy and potential for wider applications.",book:{id:"5883",slug:"modern-fuzzy-control-systems-and-its-applications",title:"Modern Fuzzy Control Systems and Its Applications",fullTitle:"Modern Fuzzy Control Systems and Its Applications"},signatures:"Longzhi Yang, Zheming Zuo, Fei Chao and Yanpeng Qu",authors:[{id:"167084",title:"Dr.",name:"Fei",middleName:null,surname:"Chao",slug:"fei-chao",fullName:"Fei Chao"},{id:"198988",title:"Dr.",name:"Longzhi",middleName:null,surname:"Yang",slug:"longzhi-yang",fullName:"Longzhi Yang"},{id:"200974",title:"Dr.",name:"Yanpeng",middleName:null,surname:"Qu",slug:"yanpeng-qu",fullName:"Yanpeng Qu"},{id:"200975",title:"Mr.",name:"Zheming",middleName:null,surname:"Zuo",slug:"zheming-zuo",fullName:"Zheming Zuo"}]},{id:"54790",doi:"10.5772/67989",title:"A Model for Evaluating Soil Vulnerability to Erosion Using Remote Sensing Data and A Fuzzy Logic System",slug:"a-model-for-evaluating-soil-vulnerability-to-erosion-using-remote-sensing-data-and-a-fuzzy-logic-sys",totalDownloads:1835,totalCrossrefCites:4,totalDimensionsCites:6,abstract:"Soil vulnerability is the capacity of one or more of the ecological functions of the soil system to be harmed. 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This spectral index provides relevance and is updated for each scene, evidences about the biomass and soil productivity, and vegetation density cover or vegetation stress (e.g., forest fires, droughts). Modeled output maps are suitable for temporal change analysis, which allows the identification of the effect of land management practices, soil and vegetation regeneration, or climate effects.",book:{id:"5883",slug:"modern-fuzzy-control-systems-and-its-applications",title:"Modern Fuzzy Control Systems and Its Applications",fullTitle:"Modern Fuzzy Control Systems and Its Applications"},signatures:"Ignacio Meléndez-Pastor, Jose Navarro Pedreño, Ignacio Gómez\nLucas and Antonis A. 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However, the underlying rule sets for OBIA are usually too complex to be directly applied on a variety of image data without any adaptations or human interactions. Thus, recent research projects investigate the potential for integrating the agent-based paradigm with OBIA. Agent-based systems are highly adaptive and therefore robust, even under varying environmental conditions. In the context of image analysis, this means that even if the image data to be analyzed varies slightly (e.g., due to seasonal effects, different locations, atmospheric conditions, or even a slightly different sensor), agent-based methods allow to autonomously adapt existing analysis rules or segmentation results according to changing imaging situations. The basis for individual software agents’ behavior is a so-called believe-desire-intention (BDI) model. Basically, the BDI describes for each individual agent its goal(s), its assumed current situation, and some action rules potentially supporting each agent to achieve its goals. The chapter introduces a believe-desire-intention (BDI) model based on fuzzy rules in the context of agent-based image analysis, which extends the classic OBIA paradigm by the agent-based paradigm.",book:{id:"5883",slug:"modern-fuzzy-control-systems-and-its-applications",title:"Modern Fuzzy Control Systems and Its Applications",fullTitle:"Modern Fuzzy Control Systems and Its Applications"},signatures:"Peter Hofmann",authors:[{id:"199778",title:"Dr.",name:"Peter",middleName:null,surname:"Hofmann",slug:"peter-hofmann",fullName:"Peter Hofmann"}]},{id:"56033",doi:"10.5772/68126",title:"A Fuzzy Logic Approach for Separation Assurance and Collision Avoidance for Unmanned Aerial Systems",slug:"a-fuzzy-logic-approach-for-separation-assurance-and-collision-avoidance-for-unmanned-aerial-systems",totalDownloads:1398,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"In the coming years, operations in low altitude airspace will vastly increase as the capabilities and applications of small unmanned aerial systems (sUAS) continue to multiply. Therefore, finding solutions to managing sUAS in highly congested airspace will facilitate sUAS operations. In this study, a fuzzy logic-based approach was used to help mitigate the risk of collisions between aircraft using separation assurance and collision avoidance techniques. The system was evaluated for its effectiveness at mitigating the risk of mid-air collisions between aircraft. This system utilizes only current state information and can resolve potential conflicts without knowledge of intruder intent. The avoidance logic was verified using formal methods and shown to select the correct action in all instances. Additionally, the fuzzy logic controllers were shown to always turn the vehicles in the correct direction. Numerical testing demonstrated that the avoidance system was able to prevent a mid-air collision between two sUAS in all tested cases. Simulations were also performed in a three-dimensional environment with a heterogeneous fleet of sUAS performing a variety of realistic missions. Simulations showed that the system was 99.98% effective at preventing mid-air collisions when separation assurance was disabled (unmitigated case) and 100% effective when enabled (mitigated case).",book:{id:"5883",slug:"modern-fuzzy-control-systems-and-its-applications",title:"Modern Fuzzy Control Systems and Its Applications",fullTitle:"Modern Fuzzy Control Systems and Its Applications"},signatures:"Brandon Cook, Tim Arnett and Kelly Cohen",authors:[{id:"200830",title:"Mr.",name:"Brandon",middleName:"Matthew",surname:"Cook",slug:"brandon-cook",fullName:"Brandon Cook"},{id:"200833",title:"Mr.",name:"Timothy",middleName:null,surname:"Arnett",slug:"timothy-arnett",fullName:"Timothy Arnett"},{id:"200834",title:"Dr.",name:"Kelly",middleName:null,surname:"Cohen",slug:"kelly-cohen",fullName:"Kelly Cohen"}]}],mostDownloadedChaptersLast30Days:[{id:"54537",title:"Fuzzy Logic Application, Control and Monitoring of Critical Machine Parameters in a Processing Company",slug:"fuzzy-logic-application-control-and-monitoring-of-critical-machine-parameters-in-a-processing-compan",totalDownloads:1846,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The processing company under study found out that the boiler was the key machine and needs artificial intelligence monitoring and control. It was simulated under Matlab software and oil level, and pressure and temperature were to be modelled and controlled using the programmable logic controller (PLC) with a fuzzy logic controller as the main brain of control. The company is for processing of fruits to produce juice.",book:{id:"5883",slug:"modern-fuzzy-control-systems-and-its-applications",title:"Modern Fuzzy Control Systems and Its Applications",fullTitle:"Modern Fuzzy Control Systems and Its Applications"},signatures:"Tawanda Mushiri",authors:[{id:"198749",title:"Dr.",name:"Tawanda",middleName:null,surname:"Mushiri",slug:"tawanda-mushiri",fullName:"Tawanda Mushiri"}]},{id:"65167",title:"Functional Safety of FPGA Fuzzy Logic Controller",slug:"functional-safety-of-fpga-fuzzy-logic-controller",totalDownloads:799,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this paper we describe a methodology to implement a fuzzy logic controller in FPGA. The implementation of fuzzy logic controller (FLC) in FPGA requires a qualitative and a quantitative analysis to define the system safety integrity level (SIL). This level can be defined by the quantification of the probability of failure on demand (PFDavg). We propose to analyze the implementation advance safety architecture of fuzzy logic controllers with 1-out-of-2 controllers (1oo2) in FPGA using the reliability block diagram (RBD) and the Markov model. We demonstrate how from hardware characteristics parameters, such as rate of dangerous detected failure and undetected failure, the diagnostic coverage, proof test interval and other parameters to evaluate the PFDavg.",book:{id:"7656",slug:"fuzzy-logic",title:"Fuzzy Logic",fullTitle:"Fuzzy Logic"},signatures:"Mohammed Bsiss and Amami Benaissa",authors:[{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss"},{id:"286059",title:"Prof.",name:"Benaissa",middleName:null,surname:"Amami",slug:"benaissa-amami",fullName:"Benaissa Amami"}]},{id:"67797",title:"The Fuzzy Logic Methodology for Evaluating the Causality of Factors in Organization Management",slug:"the-fuzzy-logic-methodology-for-evaluating-the-causality-of-factors-in-organization-management",totalDownloads:773,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The paper is concerned with solving the problem of factor causality using the tools of the fuzzy set theory. The paper formulates the problem of causal relations in a broad sense and analyzes the methods for its solution with an emphasis on the socioeconomic aspects. For this purpose, the system approach, comparative experiment, economic and mathematical modeling, and other general scientific methods are used. The authors suggest that the causality of factors be studied based on the theory of fuzzy binary relations using the mathematical tools of Goguen’s fuzzy implication. As an example, the paper describes the effect of organizational culture indicators under the Denison’s model on the key performance indicators of an organization.",book:{id:"7656",slug:"fuzzy-logic",title:"Fuzzy Logic",fullTitle:"Fuzzy Logic"},signatures:"Nazarov Dmitry Mikhailovich",authors:[{id:"278819",title:"Dr.",name:"Dmitrii",middleName:null,surname:"Nazarov",slug:"dmitrii-nazarov",fullName:"Dmitrii Nazarov"}]},{id:"55096",title:"EMG-Controlled Prosthetic Hand with Fuzzy Logic Classification Algorithm",slug:"emg-controlled-prosthetic-hand-with-fuzzy-logic-classification-algorithm",totalDownloads:1871,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"In recent years, researchers have conducted many studies on the design and control of prosthesis devices that take the place of a missing limb. Functional ability of prosthesis hands that mimic biological hand functions increases depending on the number of independent finger movements possible. From this perspective, in this study, six different finger movements were given to a prosthesis hand via bioelectrical signals, and the functionality of the prosthesis hand was increased. Bioelectrical signals were recorded by surface electromyography for four muscles with the help of surface electrodes. The recorded bioelectrical signals were subjected to a series of preprocessing and feature extraction processes. In order to create meaningful patterns of motion and an effective cognitive interaction network between the human and the prosthetic hand, fuzzy logic classification algorithms were developed. A five-fingered and 15-jointed prosthetic hand was designed via SolidWorks, and a prosthetic prototype was produced by a 3D printer. In addition, prosthetic hand simulator was designed in Matlab/SimMechanics. Pattern control of both the simulator and the prototype hand in real time was achieved. Position control of motors connected to each joint of the prosthetic hand was provided by a PID controller. Thus, an effective cognitive communication network established between the user, and the real-time pattern control of the prosthesis was provided by bioelectrical signals.",book:{id:"5883",slug:"modern-fuzzy-control-systems-and-its-applications",title:"Modern Fuzzy Control Systems and Its Applications",fullTitle:"Modern Fuzzy Control Systems and Its Applications"},signatures:"Beyda Taşar and Arif Gülten",authors:[{id:"198982",title:"Ph.D. Student",name:"Beyda",middleName:null,surname:"Tasar",slug:"beyda-tasar",fullName:"Beyda Tasar"},{id:"201773",title:"Dr.",name:"Arif",middleName:null,surname:"Gulten",slug:"arif-gulten",fullName:"Arif Gulten"}]},{id:"64740",title:"Some Topological Properties of Intuitionistic Fuzzy Normed Spaces",slug:"some-topological-properties-of-intuitionistic-fuzzy-normed-spaces",totalDownloads:847,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In 1986, Atanassov introduced the concept of intuitionistic fuzzy set theory which is based on the extensions of definitions of fuzzy set theory given by Zadeh. This theory provides a variable model to elaborate uncertainty and vagueness involved in decision making problems. In this chapter, we concentrate our study on the ideal convergence of sequence spaces with respect to intuitionistic fuzzy norm and discussed their topological and algebraic properties.",book:{id:"7656",slug:"fuzzy-logic",title:"Fuzzy Logic",fullTitle:"Fuzzy Logic"},signatures:"Vakeel Ahmad Khan, Hira Fatima and Mobeen Ahmad",authors:[{id:"276104",title:"Dr.",name:"Vakeel A.",middleName:null,surname:"Khan",slug:"vakeel-a.-khan",fullName:"Vakeel A. Khan"},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima"},{id:"276129",title:"Mr.",name:"Mobeen",middleName:null,surname:"Ahmad",slug:"mobeen-ahmad",fullName:"Mobeen Ahmad"}]}],onlineFirstChaptersFilter:{topicId:"164",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"June 20th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:13,paginationItems:[{id:"38",title:"Pollution",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",slug:"meng-chuan-ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",slug:"olga-anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",slug:"jose-navarro-pedreno",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",biography:"Full professor at University Miguel Hernández of Elche, Spain, previously working at the University of Alicante, Autonomous University of Madrid and Polytechnic University of Valencia. Graduate in Sciences (Chemist), graduate in Geography and History (Geography), master in Water Management, Treatment, master in Fertilizers and Environment and master in Environmental Management; Ph.D. in Environmental Sciences. His research is focused on soil-water and waste-environment relations, mainly on soil-water and soil-waste interactions under different management and waste reuse. His work is reflected in more than 230 communications presented in national and international conferences and congresses, 29 invited lectures from universities, associations and government agencies. Prof. Navarro-Pedreño is also a director of the Ph.D. Program Environment and Sustainability (2012-present) and a member of several societies among which are the Spanish Society of Soil Science, International Union of Soil Sciences, European Society for Soil Conservation, DessertNet and the Spanish Royal Society of Chemistry.",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",slug:"elke-jurandy-bran-nogueira-cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"147289",title:"Prof.",name:"Francisco",middleName:null,surname:"Guevara-Hernández",slug:"francisco-guevara-hernandez",fullName:"Francisco Guevara-Hernández",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRCgVQAW/Profile_Picture_2022-06-27T11:25:21.png",institutionString:null,institution:{name:"Autonomous University of Chiapas",institutionURL:null,country:{name:"Mexico"}}},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",slug:"sandra-ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",slug:"salustiano-mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",biography:"Salustiano Mato de la Iglesia (Santiago de Compostela, 1960) is a doctor in biology from the University of Santiago and a Professor of zoology at the Department of Ecology and Animal Biology at the University of Vigo. He has developed his research activity in the fields of fauna and soil ecology, and in the treatment of organic waste, having been the founder and principal investigator of the Environmental Biotechnology Group of the University of Vigo.\r\nHis research activity in the field of Environmental Biotechnology has been focused on the development of novel organic waste treatment systems through composting. The result of this line of work are three invention patents and various scientific and technical publications in prestigious international journals.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",slug:"josefina-garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",biography:"Josefina Garrido González (Paradela de Abeleda, Ourense 1959), is a doctor in biology from the University of León and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. She has focused her research activity on the taxonomy, fauna and ecology of aquatic beetles, in addition to other lines of research such as the conservation of biodiversity in freshwater ecosystems; conservation of protected areas (Red Natura 2000) and assessment of the effectiveness of wetlands as priority areas for the conservation of aquatic invertebrates; studies of water quality in freshwater ecosystems through biological indicators and physicochemical parameters; surveillance and research of vector arthropods and invasive alien species.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",slug:"francisco-ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",biography:"Fran Ramil Blanco (Porto de Espasante, A Coruña, 1960), is a doctor in biology from the University of Santiago de Compostela and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. His research activity is linked to the taxonomy, fauna and ecology of marine benthic invertebrates and especially the Cnidarian group. Since 2004, he has been part of the EcoAfrik project, aimed at the study, protection and conservation of biodiversity and benthic habitats in West Africa. He also participated in the study of vulnerable marine ecosystems associated with seamounts in the South Atlantic and is involved in training young African researchers in the field of marine research.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorialBoard:[{id:"220987",title:"Dr.",name:"António",middleName:"Onofre",surname:"Soares",slug:"antonio-soares",fullName:"António Soares",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNtzQAG/Profile_Picture_1644499672340",institutionString:null,institution:{name:"University of the Azores",institutionURL:null,country:{name:"Portugal"}}}]},{id:"41",title:"Water Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",slug:"yizi-shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",biography:"Prof. Dr. Yizi Shang is a pioneering researcher in hydrology and water resources who has devoted his research career to promoting the conservation and protection of water resources for sustainable development. 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Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8018",title:"Extracellular Matrix",subtitle:"Developments and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/8018.jpg",slug:"extracellular-matrix-developments-and-therapeutics",publishedDate:"October 27th 2021",editedByType:"Edited by",bookSignature:"Rama Sashank Madhurapantula, Joseph Orgel P.R.O. and Zvi Loewy",hash:"c85e82851e80b40282ff9be99ddf2046",volumeInSeries:23,fullTitle:"Extracellular Matrix - Developments and Therapeutics",editors:[{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula",profilePictureURL:"https://mts.intechopen.com/storage/users/212416/images/system/212416.jpg",institutionString:"Illinois Institute of Technology",institution:{name:"Illinois Institute of Technology",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9759",title:"Vitamin E in Health and Disease",subtitle:"Interactions, Diseases and Health Aspects",coverURL:"https://cdn.intechopen.com/books/images_new/9759.jpg",slug:"vitamin-e-in-health-and-disease-interactions-diseases-and-health-aspects",publishedDate:"October 6th 2021",editedByType:"Edited by",bookSignature:"Pınar Erkekoglu and Júlia Scherer Santos",hash:"6c3ddcc13626110de289b57f2516ac8f",volumeInSeries:22,fullTitle:"Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoğlu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoğlu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.jpg",institutionString:"Hacettepe University",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:4},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:9},{group:"subseries",caption:"Chemical Biology",value:15,count:13}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:8},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. 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:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{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. 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