Medicinal plants effective against T1DM and T2DM.
\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\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:"8728",leadTitle:null,fullTitle:"Update on Critical Issues on Infant and Neonatal Care",title:"Update on Critical Issues on Infant and Neonatal Care",subtitle:null,reviewType:"peer-reviewed",abstract:"Infant and neonatal health is one of the areas of greatest development and evolution within pediatrics. This edited volume Update on Critical Issues in Infant and Neonatal Care is a collection of reviewed and relevant research chapters offering a comprehensive overview of recent developments in six topics about common newborn and infant health problems. In 6 chapters that address relevant issues about infant and neonatal care, the book seeks to contribute to the clinical work of the health teams of critical care units. Specialists in the field of pediatrics from different countries have developed these chapters and through them they hope to share part of their experience.",isbn:"978-1-78985-362-9",printIsbn:"978-1-78985-361-2",pdfIsbn:"978-1-83880-085-7",doi:"10.5772/intechopen.80145",price:100,priceEur:109,priceUsd:129,slug:"update-on-critical-issues-on-infant-and-neonatal-care",numberOfPages:94,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"52c4dbe7c0deb54899657dc4323238d6",bookSignature:"René Mauricio Barría",publishedDate:"April 22nd 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8728.jpg",numberOfDownloads:4734,numberOfWosCitations:1,numberOfCrossrefCitations:3,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:8,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:12,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 22nd 2019",dateEndSecondStepPublish:"April 23rd 2019",dateEndThirdStepPublish:"June 22nd 2019",dateEndFourthStepPublish:"September 10th 2019",dateEndFifthStepPublish:"November 9th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"88861",title:"Dr.",name:"R. 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He is currently the director of the Institute of Nursing, Faculty of Medicine, Universidad Austral de Chile.",institutionString:"Austral University of Chile",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Austral University of Chile",institutionURL:null,country:{name:"Chile"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1108",title:"Neonatology",slug:"neonatology"}],chapters:[{id:"67757",title:"Neonatal Hyperbilirubinemia in Newborns of the Republic of North Macedonia",doi:"10.5772/intechopen.87045",slug:"neonatal-hyperbilirubinemia-in-newborns-of-the-republic-of-north-macedonia",totalDownloads:804,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Neonatal indirect hyperbilirubinemia is one of the most frequent neonatal problems that affect almost two thirds of term infants. Although etiology of jaundice has been widely studied, identification of pathological causes presents constant clinical challenge. Our study group performed an extensive retrospective study of etiology of neonatal hyperbilirubinemia and showed high frequency (44.37%) of jaundice of undefined etiology. The group included exaggerated physiological jaundice, early- and late-onset breast-milk jaundice, and no identifiable etiology. Other etiologies were neonatal infection, prematurity, birth trauma, and hemolysis represented with 15%. We described hematological parameters in both non-hemolytic and hemolytic type of jaundice; a significant correlation of relevant laboratory findings with etiology was established. In this chapter we will present our own data and perform a data-relevant literature review. Furthermore, investigation and management plan of neonatal indirect hyperbilirubinemia will be presented in accordance with own data and available literature.",signatures:"Anet Papazovska Cherepnalkovski, Natasha Najdanovska Aluloska, Nikolina Zdraveska, Katica Piperkova and Vjekoslav Krzelj",downloadPdfUrl:"/chapter/pdf-download/67757",previewPdfUrl:"/chapter/pdf-preview/67757",authors:[null],corrections:null},{id:"70806",title:"Neonatal Respiratory Distress Syndrome: Things to Consider and Ways to Manage",doi:"10.5772/intechopen.90885",slug:"neonatal-respiratory-distress-syndrome-things-to-consider-and-ways-to-manage",totalDownloads:893,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Involving more commonly the premature (less than 37 weeks of gestational age) infants, neonatal respiratory distress syndrome is an important clinical syndrome responsible for a high rate of mortality and morbidity. The main progress in respiratory distress syndrome (RDS) management is attributable to prescription of surfactant for fastening pulmonary maturation. Respiratory protection, such as mechanical ventilation and nasal continuous positive airway pressure, and surfactant are building blocks of disease treatment. In this chapter, we are going to have a rapid review on epidemiology, diagnosis and treatments of RDS.",signatures:"Bita Najafian and Mohammad Hossein Khosravi",downloadPdfUrl:"/chapter/pdf-download/70806",previewPdfUrl:"/chapter/pdf-preview/70806",authors:[{id:"214323",title:"Dr.",name:"Mohammad Hossein",surname:"Khosravi",slug:"mohammad-hossein-khosravi",fullName:"Mohammad Hossein Khosravi"},{id:"308156",title:"Dr.",name:"Bita",surname:"Najafian",slug:"bita-najafian",fullName:"Bita Najafian"}],corrections:null},{id:"69313",title:"One of the Main Problems of Infants: Bronchiolitis",doi:"10.5772/intechopen.89417",slug:"one-of-the-main-problems-of-infants-bronchiolitis",totalDownloads:665,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Acute bronchiolitis, which is the most common acute lower respiratory system disease, is resulting in significant morbidity and mortality in children less than 2 years. Respiratory syncytial virus (RSV) is the most common causative pathogen for over 30 million new acute lower respiratory infection episodes in children under 5 years of age. Rhinovirus, adenovirus, influenza virus, parainfluenza, and other respiratory viruses also cause acute bronchiolitis as the sole pathogen or as coinfection with or without RSV. Cardiovascular disease, chronic pulmonary disease, immunodeficiency, and premature birth are important risk factors for hospitalization and increase the risk of acute bronchiolitis-associated respiratory failure or even death. Bronchiolitis is a clinical diagnosis that varies from mild illness to severe respiratory failure. The severity of bronchiolitis is evaluated with several parameters including wheezing, retraction, respiratory rate, and general situation. However, the most important clinical finding is the presence or absence of hypoxemia and whether the patient can tolerate respiratory distress. Fluid support and oxygen supplementation by nasal cannula, face mask, or head box are critical for the treatment of bronchiolitis. Commonly used bronchodilators, corticosteroids, ribavirin, and antibiotics have not been shown to be effective in improving the clinical course of the bronchiolitis.",signatures:"Şule Gökçe",downloadPdfUrl:"/chapter/pdf-download/69313",previewPdfUrl:"/chapter/pdf-preview/69313",authors:[{id:"269379",title:"M.D.",name:"Şule",surname:"Gökçe",slug:"sule-gokce",fullName:"Şule Gökçe"}],corrections:null},{id:"68793",title:"PDA Closure in ELBW Infants: If, When, and How to Do It",doi:"10.5772/intechopen.88857",slug:"pda-closure-in-elbw-infants-if-when-and-how-to-do-it",totalDownloads:938,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Patent ductus arteriosus (PDA) is the most common cardiovascular condition afflicting premature neonates especially those born extremely low birth weight (ELBW). Despite five decades of scientific inquiry which has produced thousands of publications including over 65 randomized controlled trials, cardiologists, neonatologists, and surgeons still cannot answer simple questions such as if, when and how to close to the PDA in ELBW infants. This chapter will examine current evidence in order to answer these fundamental questions. The chapter will specifically focus on transcatheter PDA closure (TCPC), which albeit a new therapy, has displayed great potential to be the best therapeutic option in the future. It is about time that physicians from all sub-specialties come together and integrate the evidence to develop a management algorithm for ELBW infants with hemodynamically significant PDA.",signatures:"Stephanie Whiting and Shyam Sathanandam",downloadPdfUrl:"/chapter/pdf-download/68793",previewPdfUrl:"/chapter/pdf-preview/68793",authors:[null],corrections:null},{id:"69364",title:"Universal Screening for Congenital CMV Infection",doi:"10.5772/intechopen.89611",slug:"universal-screening-for-congenital-cmv-infection",totalDownloads:872,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Congenital cytomegalovirus (CMV) infection is an important public health problem. It is a leading cause of disability in children. Congenitally infected neonates often appear asymptomatic at birth or have nonspecific symptoms. An early diagnosis and subsequent early antiviral therapy associated to nonpharmacological therapy (e.g., hearing rehabilitation, speech-language therapy, and cochlear implants) can reduce long-term disability. Much research has been done in this field, but further studies are still necessary. Looking back at the most recent papers, we will draw a review on this topic trying to answer to the question: could universal CMV screening be a useful and cost-effective diagnostic tool?",signatures:"Sara Lunardi, Francesca Lorenzoni and Paolo Ghirri",downloadPdfUrl:"/chapter/pdf-download/69364",previewPdfUrl:"/chapter/pdf-preview/69364",authors:[null],corrections:null},{id:"68922",title:"VANEDELA’s Test Screening, Comparison Low, Middle, and High Risk in Mexican Population",doi:"10.5772/intechopen.88729",slug:"vanedela-s-test-screening-comparison-low-middle-and-high-risk-in-mexican-population",totalDownloads:562,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The neurodevelopment screening test Valoración Neuroconductual del Lactante (VANEDELA’s) allows the professional to follow the rapid and economic application development in which high- and moderate-risk children who do not reach their optimum development potential during the first 2 years of life can be detected in a timely manner. It also provides a tracking tool to follow-up the recommendations and interventions of children who had developmental delays to see how adaptive strategies work.",signatures:"Rosa Ivone Martínez-Vázquez, Blásquez-Martínez Jorge Ulises, Morales Ramírez Aline and Gerardo Alberto Alvarado-Ruiz",downloadPdfUrl:"/chapter/pdf-download/68922",previewPdfUrl:"/chapter/pdf-preview/68922",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5821",title:"Selected Topics in Neonatal Care",subtitle:null,isOpenForSubmission:!1,hash:"711594f833d5470b73524758472f4d96",slug:"selected-topics-in-neonatal-care",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/5821.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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Imran",slug:"muhammad-babar-imran",email:"muhammadbabarimran@yahoo.com",position:null,institution:null}]},book:{id:"7769",title:"Medical Isotopes",subtitle:null,fullTitle:"Medical Isotopes",slug:"medical-isotopes",publishedDate:"January 7th 2021",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"7183",leadTitle:null,title:"Functional Foods",subtitle:null,reviewType:"peer-reviewed",abstract:'"Let food be thy medicine and medicine be thy food" said Hippocrates, the father of medicine approximately 2500 years ago. Is food also medicine? Are products that intend to cure diseases medicinal products and not food? Do we know the combination of foods or food components with functional properties that can help promote the well-being or reduce the risk of chronic diseases? In general terms, all foods are functional because they provide the nutrients necessary for a healthy diet. So what are the components that functional foods have beyond their nutrition value? What is the definition of functional foods? What scientific research is needed to validate health claims for functional foods? This book will provide answers to all of these questions. It is important for scientists to have the opportunities to study the relationship between a food type or a food active component and the improved state of health or reduction of diseases. The communication of health benefits to consumers is of critical importance so that they have the knowledge to make informed choices about the foods they eat and enjoy.',isbn:"978-1-83881-150-1",printIsbn:"978-1-83881-149-5",pdfIsbn:"978-1-83881-151-8",doi:"10.5772/intechopen.73983",price:119,priceEur:129,priceUsd:155,slug:"functional-foods",numberOfPages:132,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"8023d990ea5254d039f9c438b66899c6",bookSignature:"Vasiliki Lagouri",publishedDate:"October 23rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7183.jpg",keywords:null,numberOfDownloads:10046,numberOfWosCitations:12,numberOfCrossrefCitations:16,numberOfDimensionsCitations:39,numberOfTotalCitations:67,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 28th 2018",dateEndSecondStepPublish:"May 2nd 2018",dateEndThirdStepPublish:"July 1st 2018",dateEndFourthStepPublish:"September 19th 2018",dateEndFifthStepPublish:"November 18th 2018",remainingDaysToSecondStep:"4 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"232589",title:"Dr.",name:"Vasiliki",middleName:null,surname:"Lagouri",slug:"vasiliki-lagouri",fullName:"Vasiliki Lagouri",profilePictureURL:"https://mts.intechopen.com/storage/users/232589/images/system/232589.jpeg",biography:"Vasiliki Lagouri BA MSc PhD received her three degrees from Aristotle University of Thessaloniki and National and Kapodistrian University of Athens, Greece. She has research and academic experience (1992-2019) at the Chemistry Department of Aristotle University of Thessaloniki, Food Technology Department in Technological Educational Institute of Thessaloniki, Post doc positions in the Department of Organic Chemistry, Faculty of Chemistry and Department of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, School of Health Sciences at National and Kapodistrian University of Athens. Her current position is Project Manager in National Hellenic Research Foundation (NHRF), Institute of Chemical Biology (ICB). \r\nShe has over 30 of publications in International Journals, Conference Proceedings and 3 Book authorships and editorships in food chemistry, natural antioxidants, and olive oil and olives as functional foods (number of citations more than 400). She has research experience on experimental designs and applications of different methods to study the chemistry of natural sources, the isolation, identification and quantification of biologically active polar and non-polar compounds. She offered her services as a reviewer for the Journals: International Journal of Food properties, Journal of the Science of Food and Agriculture, Central European Journal of Chemistry, Separation Science and Technology, Natural Products Research, Nutrients, Molecules. She is a member of the American Chemical Society, Society Free-Radical Research-Europe (SFRR-E), Oxygen Club of California (OCC), ISEKI-Food Association: European Association for Integrating Food Science and Engineering Knowledge Into the Food Chain and the Greek Chemist’s Union and she is included in Who’s Who of America.",institutionString:"National Hellenic Research Foundation",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"National Hellenic Research Foundation",institutionURL:null,country:{name:"Greece"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"323",title:"Food and Nutrition",slug:"food-and-nutrition"}],chapters:[{id:"64524",title:"Introductory Chapter: Functional Foods",slug:"introductory-chapter-functional-foods",totalDownloads:1020,totalCrossrefCites:2,authors:[{id:"232589",title:"Dr.",name:"Vasiliki",surname:"Lagouri",slug:"vasiliki-lagouri",fullName:"Vasiliki Lagouri"}]},{id:"63575",title:"Olive Oil: Antioxidant Compounds and Their Potential Effects over Health",slug:"olive-oil-antioxidant-compounds-and-their-potential-effects-over-health",totalDownloads:2153,totalCrossrefCites:2,authors:[{id:"248097",title:"Ph.D.",name:"Seray",surname:"Kabaran",slug:"seray-kabaran",fullName:"Seray Kabaran"}]},{id:"64324",title:"Olive Oil Phenols",slug:"olive-oil-phenols",totalDownloads:1399,totalCrossrefCites:4,authors:[{id:"258502",title:"Ph.D.",name:"Christos",surname:"Papanikolaou",slug:"christos-papanikolaou",fullName:"Christos Papanikolaou"},{id:"267135",title:"Prof.",name:"Prokopios",surname:"Magiatis",slug:"prokopios-magiatis",fullName:"Prokopios Magiatis"},{id:"267136",title:"Dr.",name:"Eleni",surname:"Melliou",slug:"eleni-melliou",fullName:"Eleni Melliou"}]},{id:"63677",title:"Functional Properties of Snack Bars",slug:"functional-properties-of-snack-bars",totalDownloads:2133,totalCrossrefCites:2,authors:[{id:"252951",title:"Dr.",name:"Daniela",surname:"Istrati",slug:"daniela-istrati",fullName:"Daniela Istrati"},{id:"253109",title:"Associate Prof.",name:"Oana",surname:"Constantin",slug:"oana-constantin",fullName:"Oana Constantin"}]},{id:"63516",title:"Fermented Functional Beverages",slug:"fermented-functional-beverages",totalDownloads:1207,totalCrossrefCites:1,authors:[{id:"252951",title:"Dr.",name:"Daniela",surname:"Istrati",slug:"daniela-istrati",fullName:"Daniela Istrati"},{id:"252503",title:"Prof.",name:"Camelia",surname:"Vizireanu",slug:"camelia-vizireanu",fullName:"Camelia Vizireanu"},{id:"253118",title:"Dr.",name:"Eugenia",surname:"Pricop",slug:"eugenia-pricop",fullName:"Eugenia Pricop"},{id:"253119",title:"Dr.",name:"Alina",surname:"Profir",slug:"alina-profir",fullName:"Alina Profir"}]},{id:"65354",title:"Fish as an Important Functional Food for Quality Life",slug:"fish-as-an-important-functional-food-for-quality-life",totalDownloads:1243,totalCrossrefCites:5,authors:[{id:"253367",title:"Dr.",name:"Dr",surname:"Hei",slug:"dr-hei",fullName:"Dr Hei"},{id:"258615",title:"Prof.",name:"Ch",surname:"Sarojnalini",slug:"ch-sarojnalini",fullName:"Ch Sarojnalini"}]},{id:"64935",title:"Instant Controlled Pressure-Drop DIC as a Strategic Technology for Different Types of Natural Functional Foods",slug:"instant-controlled-pressure-drop-dic-as-a-strategic-technology-for-different-types-of-natural-functi",totalDownloads:892,totalCrossrefCites:0,authors:[{id:"22910",title:"Prof.",name:"Abdul Karim Salim",surname:"Allaf",slug:"abdul-karim-salim-allaf",fullName:"Abdul Karim Salim Allaf"},{id:"22911",title:"Ms.",name:"Tamara",surname:"Allaf",slug:"tamara-allaf",fullName:"Tamara Allaf"},{id:"24143",title:"Ms.",name:"Colette",surname:"Besombes",slug:"colette-besombes",fullName:"Colette Besombes"},{id:"258593",title:"Dr.",name:"Sabah",surname:"Mounir",slug:"sabah-mounir",fullName:"Sabah Mounir"},{id:"258680",title:"Dr.",name:"Carmen",surname:"Tellez-Perez",slug:"carmen-tellez-perez",fullName:"Carmen Tellez-Perez"},{id:"258758",title:"Dr.",name:"Maritza",surname:"Alonzo-Macías",slug:"maritza-alonzo-macias",fullName:"Maritza Alonzo-Macías"},{id:"268755",title:"Dr.",name:"Ezzeddine",surname:"Amami",slug:"ezzeddine-amami",fullName:"Ezzeddine Amami"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"220812",firstName:"Lada",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/220812/images/6021_n.jpg",email:"lada@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Renal artery stenosis (RAS) is a common condition in patients suffering from atherosclerosis and fibromuscular dysplasia [1, 2, 3, 4, 5, 6], with an overall prevalence disease rate of 15.4% [4]. Progression to severe stenosis is well documented and leads to hypertension and kidney damage [7, 8, 9]. Clinically, renovascular hypertension is one the most important causes of secondary hypertension and kidney damage. In patients with RAS, 65% are hypertensive and 26.5% suffer kidney failure [4, 6]. Advancement to end stage renal disease is known to increase cardiovascular events [10]. The clinical trials Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) [11], and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) [12] targeted renal vascularization to improve disease outcomes but failed to show any improvement in renal function, cardiovascular events or mortality [11, 12]. Furthermore, prospective studies in ASTRAL and CORAL concluded that 15-22% of patients suffering from renovascular disease will progress to renal “end point” within 3 to 4 years [13]. The NHLBI Cardiovascular Health Study used a non-invasive screen and found that 6.8% elderly patients (both African American and white) had more than 60% RASten or renal artery occlusion [14, 15]. The renin angiotensin aldosterone system (RAAS) plays a key role in hypertension, with renin recognized as the driver of renovascular hypertension (Figure 1). In humans, plasma renin activity (PRA) is used as biomarker for the activation of RAAS in hypertension and in patients with atherosclerotic RAS, high PRA is associated with increased risk for cardiovascular events and high mortality [16]. These suggest an important function for RAAS in renovascular hypertension onset and the need to target different components of RAAS for therapy.
Renin Angiotensin Aldosterone System (RAAS) key role in renal artery stenosis (RAS) induction of renovascular hypertension and kidney damage. Deterioration of renal perfusion in the stenosed kidney cause a decrease in renal pressure which in turn stimulates RAAS. This stimulation triggers a series of events starting with renin release leading to angiotensin II production; decrease in sodium excretion, increase sympathetic tone; ending in hypertension.
Renal artery stenosis causes a decrease in renal perfusion in the stenosed kidney which in turn stimulates RAAS. This stimulation triggers a series of events starting with renin release leading to angiotensin II (Ang II) production, decrease in sodium excretion, increase sympathetic tone; all contributing to the development of hypertension (Figure 1) [17, 18]. When there is a need for renin expression and release, the number of renin expressing cells increase a process known as Juxtaglomerular (JG) cell recruitment [19, 20, 21, 22, 23, 24] involving the trans differentiation of vascular smooth muscle cells into renin expressing cells along the afferent arteriole [20, 21, 23]. JG cell recruitment is well documented in this model [25, 26, 27]. Activation of the renal baroreceptor in RAS causes renovascular hypertension through RAAS activation [28]. In uni- and bi-lateral RAS aldosterone levels are upregulated [29, 30, 31, 32]. Moreover, in renovascular hypertension prostaglandins mediate renin release in the stenosed kidney [33, 34, 35, 36], and catecholamines mediated by an increase in cAMP and activation of protein kinase A (PKA) [37, 38, 39]. Decrease renal perfusion cause a decline in renal function and increase kidney injury [40, 41]. This decrease in renal function starts with endothelial damage, decrease in nitric oxide and increase in vasoconstrictors and oxidative species [42]. Reactive oxidative stress (ROS) increase renal vascular tone, tubuloglomerular feedback, and endothelial disfunction decreasing glomerular filtration rate [43].
Successful treatments for hypertension such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) alleviate hypertension, but need close examining for kidney failure and hyperkalemia [4]. Aliskiren, a direct renin inhibitor, may still be a potential option for the treatment of high blood pressure in some forms of hypertension such as chronic kidney disease (CKD) and renovascular hypertension [44]. In a clinical study, aliskiren combined with olmesartan reduced proteinuria by about 40% from baseline in patients with CKD with persistent proteinuria [45]. In non-diabetic CKD patients, aliskiren combined with ARBs, safely reduced proteinuria and attenuated the decline in glomerular filtration rate (GFR) [46]. These results indicate that a complete treatment of renal artery stenosis induced renovascular hypertension and kidney damage may need targeting both the angiotensin II-dependent and the Ang II-independent arms of RAAS.
Renal artery stenosis is common in diabetic patients placing them at higher risk of end organ damage causing end stage renal disease [9, 47, 48, 49]. In older patients, RAS is the most common problem of end stage renal failure [50]. In RAS renin is recognized as the disease driver [6, 16, 51, 52, 53, 54]. RAS is common in atherosclerotic patients and caused hypertension, oxidative stress, and kidney damage [7, 9]. Increased oxidative stress has been reported in humans as well as in two kidney one clip (2K1C) animal model and other hypertensive animal models [24, 55, 56, 57, 58, 59, 60]. Changes in renal perfusion activate RAAS and increase the sympathetic activity of the afferent renal nerves contributing to renovascular hypertension and end-stage renal disease during RAS [61]. In the 2K1C model renal denervation decreases hypertension [62, 63]. Clinical trials (Renal Denervation in Patients With Refractory Hypertension (HTN-1) (Symplicity HTN-1), Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2), The Renal Denervation for Hypertension (DENERHTN), and Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL)) report that using renal denervation as therapy for hypertension has good outcomes [64, 65, 66, 67]. The therapeutic effects of renal denervation have been attributed to removal of sympathetic efferent and/or afferent fibers [68]. Renin secretion is stimulated by renal efferent nerves, which also stimulate tubular sodium reabsorption [62] without perturbations to glomerular filtration rate or albumin urinary secretion [69]. These indicates that initially, renal artery stenosis induces RAAS and in later stages other organs involved in blood pressure homeostasis are involved in the induction of renovascular hypertension such as renal nerves and adrenal gland.
Different experimental models of hypertension showed the crucial role play by the central nervous system (CNS) in this disease. Specifically, sympathetic efferent outflow augments during hypertension. It has been shown that both Ang II and aldosterone actions are mediated by the CNS [70, 71]. In experimental models of hypertension, ablation of the forebrain surrounding the anteroventral third cerebral ventricle (AV3V) inhibited hypertension [72, 73]. In the CNS the AV3V contains the median preoptic eminence, the organum vasculosum of the lateral terminalis, and the preoptic periventricular nucleus [74]. This forebrain region is responsible for cardiovascular regulation, and includes the subfornical organ, the organum vasculosum of the lamina terminalis, which are circumventricular organs lacking a blood-brain barrier [75]. Production of ROS in these brain regions strongly influences blood pressure [76]. Several reports showed that actions on these brain regions are responsible for Ang II hypertension and increase oxidative stress with NADPH oxidase playing a key role [77, 78, 79, 80]. Renal vasculature and tubular segments are controlled by the efferent sympathetic renal nerves and promote arteriolar vasoconstriction and renin release and increases sodium reabsorption [81]. In the afferent arterioles Ang II activates the alpha1 adrenergic receptor, which increases oxidative stress and constriction of the afferent arterioles, reducing renal blood flow [82]. Contrary, activation of the b1-adrenergic receptor activation inhibits ROS generation promoting vasodilation [83]. In different hypertension animal models renal denervation inhibit the induction of hypertension, showing that ablation of renal efferent induction of ROS is important in hypertension development [84, 85]. These data indicate that oxidative stress control efferent and afferent renal nerve actions in the development of hypertension.
Renal artery stenosis activates RAAS and increases the activity of the afferent renal nerves resulting in hypertension and end-stage renal disease [61]. It is known that in the 2K1C model renal denervation decreases hypertension [62, 63]. Removal of sympathetic efferent and/or afferent fibers controls hypertension [68], and the renal efferent nerves stimulate renin secretion and tubular sodium reabsorption [62]. During renal artery stenosis, there is an increase in Neutrophil Oxidase Factor p47 (p47phox) and p67phox [86, 87, 88]. Furthermore, in renal artery stenosis generation of ROS induced renal damage [88, 89], with the main source of ROS being NADPH oxidase [90, 91].
In the induction of renovascular hypertension, the renal nerves as well as the renin angiotensin aldosterone system activation cause the increase in blood pressure and dysregulation of sodium secretion, with renal denervation alleviating the central nerve system input decreasing blood pressure.
Oxidative stress in the kidney and vasculature contribute to hypertension development. NADPH oxidase is a major source of oxidative stress in mammalian cells [75]. Most of the renal cells express NADPH oxidase and there are several stimuli that cause its activation leading to organ injury and hypertension development [75, 92, 93]. Reactive oxygen species (ROS) produced by NADPH oxidase in the kidney cause vasoconstriction and organ injury. Specifically, increase of superoxide reduces nitric oxide (NO) in the afferent arteriole increasing vasoconstriction and a marked decrease in GFR. In rabbits, Ang II-induced hypertension increase the p22phox subunit of NADPH oxidase causing endothelial dysfunction in the afferent arteriole [94]. Moreover, in spontaneous hypertensive rats, superoxide is generated in the afferent arteriole in response to endothelin-1 (ET-1) [95, 96]. Podocytes are important components of the renal filtration system. Dahl salt-sensitive rats had increase glomerular expression of p22phos and NOX2 that increases oxidative stress causing podocyte injury, glomerular sclerosis and proteinuria, with the antioxidant tempol (4-Hydroxy-TEMPO) correcting this glomerular injury [97, 98]. Plasminogen causes podocyte injury through stimulation of NOX2 and NOX4 expression [99], Ang II stimulates ROS generation in the mitochondria stimulating autophagy [100], Ang II-induced ROS production caused glomerulosclerosis [101], and oxidative stress disrupts nephrin – caveolin-1 crosstalk in podocytes disrupting of glomerular filtration barrier [102]. In the vasculature, increased oxidative stress causes hypertension in different animal models [103, 104, 105, 106, 107, 108]. During renal artery stenosis, generation of ROS is recognized as the main mechanism of renal damage [88, 89, 109, 110] with the activation of NADPH oxidase as the source of ROS [90, 91], and associated with an increase in p47phox and p67phox [19, 86, 87, 88].
It is important to recognize that renal artery stenosis increase the production of reactive oxygen species leading to renal damage. ROS production influences not only organ damage but also contributes to the increase in blood pressure. In the therapy of this disease multiple molecules are involved leading to increases in oxidative stress, blood pressure and renal injury and all start with the activation of the renin angiotensin aldosterone system.
In renal artery stenosis induction of renovascular hypertension, renin is recognized a key molecule, and as such in the therapy of renovascular hypertension Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor blockers (ARBs) are used [4]. Moreover, sympathetic nervous systems action in the kidney promotes renin secretion through renal efferent nerves, which also stimulate tubular sodium reabsorption [62], and in the 2K1C model denervation inhibit the onset of hypertension [62, 63]. Renal artery stenosis causes renovascular hypertension, which is associated with deterioration of kidney function [20]. Reduction in renal flow is recognize as a source of hypoxia during renovascular hypertension [21]. Arterial stenosis causes thrombosis, and ischemia in renovascular hypertension [22]. During renal artery stenosis generation of ROS is recognized as the main mechanism of renal damage [88, 89], causing increased in vasoconstrictors, cell death and decrease in the activity of nitric oxide [109, 110]. A swine model of renal artery stenosis presented an increase in ROS, renal and cardiac damage [23, 86, 87, 88, 89, 111, 112, 113]. In renal artery stenosis activation of RAAS increase ROS generating by the activation of NADPH oxidase [90, 91], associated with is an increase in p47phox and p67phox [86, 87, 88]. Phosphorylation of p47phox by PKC is a key step in NADPH oxidase activation [114, 115, 116, 117, 118]. Hypertension is associated with PKC activation and increase oxidative stress [119], which caused endothelial nitric oxide synthase (eNOS) disfunction and uncoupling producing ROS instead of NO. This uncoupling is a key mechanism for endothelial dysfunction in angiotensin II-induced hypertension [120, 121, 122]. Increase in NOX2 activity requires increase NOX2 expression and p47phox association and activation of NOX2 [19]. Furthermore, increase in oxidative stress is well documented in 2K1C model [55, 56, 57, 58, 59, 123, 124]. All the actions mentioned above are Ang II mediated.
New evidence places (pro)renin receptor (PRR) as an effector molecule in the Ang II-independent RAAS [125]. PRR binds both renin and prorenin [125, 126, 127, 128, 129]. There is an association of PRR with different pathophysiology of diseases [130, 131, 132, 133, 134, 135]. PRR binds renin causing an increase in Ang I [125] and it can activate prorenin by promoting a conformational change [125, 126, 127, 128, 129]. PRR mRNA is expressed in different organs such as kidney, heart, brain, eye, adipose tissue and vascular SMCs [125, 134], It has been proposed that PRR activates the Ang II-independent RAAS with tissue specificity [136]. My laboratory and others are uncovering new functions of the Ang II independent pathway in blood pressure, oxidative stress and organ damage. New studies will define the relevance of this arm of RAAS and possible define new molecular targets for therapy.
In the definition of the molecular pathways involved in the development of renovascular hypertension, the Goldblatt two kidney one clip animal model has been critical. This animal mode has been extensively used with different animals all showing that renal artery stenosis strongly stimulates renin overexpression and release promoting renovascular hypertensions and kidney injury. In renovascular hypertension renin is key and promotes the increase in Ang II leading to hypertension. Renin being the rate limiting step in the production of Ang II in RAAS, has been investigated as a possible target for the therapy. However, the main therapies used are angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Direct renin inhibition by aliskiren, is potential therapy for hypertension in chronic kidney disease (CKD) and renovascular hypertension. Combination of aliskiren with olmesartan in the clinic, reduced proteinuria in patients with CKD with persistent proteinuria. In non-diabetic CKD patients, aliskiren combined with ARBs, reduced proteinuria and protected from the decline in glomerular filtration rate. We have shown here clinical and research data that indicates the during renal artery stenosis induced renovascular hypertension RAAS is activated and play a critical role in this pathology. It is important that a complete treatment of renovascular hypertension may need targeting both the angiotensin II-dependent and the Ang II-independent arms of RAAS.
We apologize to colleagues whose work has not been included in this chapter due to space limitations. This work was supported by NIH Grants: NHLBI Research Scientist Development Grant (1K01HL135461).
Diabetes mellitus (DM), simply called diabetes, are metabolic disorders characterized by varying or persistent hyperglycemia (high levels of sugar in the blood) over an extended time period. The most common symptoms of DM usually include increased appetite, increased thirst, and frequent urination. If not treated or when poorly managed, DM can result in several complications. While acute complications of DM often include hyperosmolar hyperglycemic state, diabetic ketoacidosis, or even death, severe chronic complications include cognitive impairment, damage to the eyes, damage to the nerves, foot ulcers, chronic kidney disease, stroke, and cardiovascular disease [1]. Diabetes mellitus (DM) manifest by hyperglycemia, defects in insulin secretion, glucose intolerance, and/or failure of insulin activity to boost uptake of glucose. Diabetes mellitus (DM) causes global burden as a result of its high morbidity/mortality rates, as well as the capital intensity required for its treatment and management. About 463 million people have DM worldwide, while estimates project 700 million people by 2045 [2].
Globally, epidemiological studies showed that diabetes is more prevalent in middle- and low-income countries with about 50 percent of cases unreported and undiagnosed [2, 3]. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are the most common types of DM. Over 90 to 95% of DM cases are T2DM [2, 4], while the remain 5 to 10% are other types of DM, including T1DM, the gestational diabetes, and other minor specific types rarely encountered. Worldwide, there has been serious search for cost effective and potent drug against T1DM and T2DM in order to reduce the annual death rate [5]. Various antidiabetic therapeutics and treatments that make use of conventional medications are often laborious as they are not single-dose treatment regimen; some are taken throughout lifetime. In recent years, medicinal plants, bioactive compounds, and dietary measures have been found to be effective in the treatment of T1DM and T2DM.
The increasing awareness of the safety and efficacies of medicinal plants, dietary therapy, and bioactive compounds in treatment of various metabolic diseases is gradually reshaping treatment measures for many metabolic diseases [6, 7, 8], including DM. Medicinal plants and their bioactive constituents play important role in regulating metabolisms in humans, usually resulting in improved health and general wellbeing. They can be largely found in fruits and vegetables, medicinal plants [9, 10, 11, 12, 13, 14, 15, 16], whole grains [11], etc., and could be consumed every day. The health benefits of bioactive compounds are commonly reported in animal and cell studies, which often include regulating cell signaling pathway, scavenging free radicals, and decreasing inflammation [17, 18]. Natural materials containing bioactive compounds have been traditionally employed in the treatment of diabetes mellitus (DM). Due to their safety, availability, and tolerable side effects, bioactive compounds applications have been suggested for reducing incidences or delaying progression of many diseases, such as T1DM and T2DM, constipation, Alzheimer’s disease, etc. [19, 20]. This chapter provides detailed descriptions and efficacies of the medicinal plants, bioactive compounds, and dietary nutrients shown to be effective in treating T1DM and T2DM. Although the medicinal plants, bioactive compounds, and dietary nutrients discussed in this chapter are mainly focused on T1DM and T2DM, they could also be effective against the less common types of DM such as the gestational diabetes and other minor specific types rarely encountered.
Type 1 diabetes mellitus (T1DM) is caused by the loss of beta cells of pancreatic islets that produce insulin, resulting in the deficiency of insulin. T1DM can be additionally classified as idiopathic or immune-mediated. Most T1DM has the nature of the immune mediation, where an autoimmune attack mediated by T-cell results in loss of beta cells and consequently insulin [21]. The majority of the affected individuals are otherwise mostly healthy, with healthy weight during the onset occurrence. Responsiveness and sensitivity to insulin are often normal, particularly in initial stages. Though T1DM is often referred to as “juvenile diabetes” due because of the regular onset in children, most people with T1DM are currently adults. T1DM could be accompanied by unpredictable, irregular high levels of blood sugar, and potentials for serious low levels of blood sugar or diabetic ketoacidosis. Other T1DM complications are endocrinopathies (such as Addison’s disease), gastroparesis (that results in irregular dietary carbohydrates absorption), infection, and impairment in the counterregulatory responses to low levels of blood sugar. These usually occur in 1–2% of those with T1DM [22]. T1DM is in part hereditary, with several genes, such as some HLA genotypes, having influence on T1DM risks. In those with genetic susceptibility, the onset of DM could be caused by at least environmental factors, including diet, stress, or viral infection [23]. Although many viruses have been reported, however, no reliable evidence has supported their potentials to cause DM in humans [23, 24]. Among dietary factors, it has been reported that gliadin (a gluten protein) can be a factor in the development of T1DM, although the mechanism has not been established, at least not entirely. T1DM occurs at any stage of life; significant percentage has been detected in adulthood. Latent autoimmune diabetes of adults (LADA) is a term used when T1DM occurs in adulthood, and has slower onset than T1DM in children. Due to this difference, few people make use of the unofficial term “type 1.5 diabetes” in place of T1DM in adults. Adults with latent autoimmune diabetes of adults are often misdiagnosed as having T2DM initially, due to age instead of cause [25].
On the other hand, type 2 diabetes mellitus (T2DM), which constitutes over 90 to 95% of all DM cases, is caused by insulin resistance, and could combine relative reduction in the secretion of insulin. The defects in body tissues response to insulin is considered to be related the insulin receptors. Cases of DM with known defects are categorized separately. Many individuals with T2DM present clinical prediabetes evidence (such as impaired glucose tolerance and/or impaired fasting glucose) prior to developing T2DM [26]. Prediabetes progression to overt T2DM could be reversed or slowed by lifestyle medications/changes, which enhance sensitivity to insulin or decrease the production of glucose in the liver [27]. T2DM is mostly because of lifestyle and environmental factors, as well as genetics [28]. Some lifestyle factors result in T2DM development, such as obesity (body mass index ≥30), urbanization, stress, poor diet, and lack of physical activities. Dietary factors, including sugar-sweetened drinks, have been correlated with increased risks of T2DM. Fat types in the food are also significant; trans fats and saturated fat increase the risks, while monounsaturated and polyunsaturated fat reduce the risks [28]. Excessive consumption of carbohydrates dense foods such as white rice may increase risks of DM [29]. Lack or insufficient physical activities can increase risks of DM in some individuals. Adverse childhood experiences (ACEs), such as neglect, abuse, and household challenges, increase possibility of T2DM by 32% later in life, with neglect reported to have the most significant effects [30].
Several medicinal plants have been shown to be effective in treating and managing DM.
Scientific name of plant | Common name | Parts used | Effectiveness and mechanisms against T1DM and T2DM | Type of study | Reference |
---|---|---|---|---|---|
Garlic | Bulb | Antihyperlipidemic and antihyperglycemic effects. Lowers FBG, improves glycemic control via increased secretion of insulin and improved sensitivity to insulin | In vivo | [32] | |
Aloe vera | Leaves | Prevents changes in insulin levels. Diabetic kidney shows distinctive changes resulting in kidney failure or renal insufficiency. Major alteration was mostly reported in kidney tissue proximal tubules in diabetic animal models | In vitro | [33] | |
Brazilian orchid tree | Leaves | After treatment for 31 days using decoction, in T2DM group, urinary glucose and plasma glucose levels reduced significantly | In vitro | [31] | |
Gray Nicker | Seeds | The 50% ethanolic and aqueous extracts of seeds of | In vitro | [31] | |
Safflower | Flower | The hydroalcoholic extracts from flower of | In vivo | [34] | |
Cinnamon | Whole plant | In vivo | [32] | ||
Kinkeliba, geza’ | Leaves | Hypoglycemic properties of | In vitro | [31, 35] | |
Asafoetida | Gum | With the presence of antioxidants, gum of | In vivo | [35] | |
Ginseng | Root, berries, stalk, leaves | Ginseng significantly reduced fasting blood glucose (FBG) and insulin resistance in patients with T2DM. Amongst 30 T2DM patients treated using Renshen tangtai (injection containing Ginseng polysaccharides and polypeptide), 86.7% presented significant effects on symptoms of T1DM and T2DM | In vivo and in vitro | [31, 32] | |
Cowplant | Leaf | The crude extracts of | In vitro | [35] | |
Monkey grass | Leaves | Aqueous extracts of | In vitro | [35] | |
Mango | Leaves | Extracts of mango leaves have hypoglycemic properties, possibly because of decrease in intestinal glucose absorption | In vitro | [31] | |
Bitter melon | Fruit | In vivo | [32] | ||
S. spinosum | Root | In vitro | [35] | ||
Swertia | Whole plant | Mechanism | In vitro | [35] | |
Fenugreek | Seed | Powdered fenugreek (15 g) administered to T2DM patients decreased Darqndkhvn sense | In vivo | [36] | |
Stinging nettle | Leaves | In vivo | [37] | ||
Bitter ginger | Root | Ethanol extracts of bitter ginger rhizome were administered to streptozotocin-induced diabetic rats. After 3 months of diabetic conditions, weight gain in streptozotocin-induced diabetic rats was significantly less in comparison with healthy rats, while the glucose levels in the blood were significantly higher. Body weight reduction was unnoticeable in streptozotocin-induced diabetic rats receiving ethanol extracts of bitter ginger rhizome during study period | In vitro | [38] |
Medicinal plants effective against T1DM and T2DM.
Many dietary nutrients and bioactive compounds have effectiveness in the treatment of T1DM and T2DM. This section discusses the most common bioactive compounds and dietary nutrients for treating DM, with more focus on type 1 and type 2 DM. Figure 1 shows the complex mechanisms of cell signaling targeted by T1DM and T2DM therapeutic strategies and bioactive compounds of plants.
Few complex mechanisms of cell signaling targeted by T1DM and T2DM therapeutic strategies and bioactive compounds of plants.
Vitamins are bioactive organic compounds which are essential micronutrients organisms required in small quantities, usually within micrograms to milligrams, for the proper functioning of body metabolisms [39]. Here are some vitamins for treating T1DM and T2DM.
Vitamin A has been known to be important in treating DM. it is a group of unsaturated organic compounds essential to organisms, e.g. retinol, retinal, as well as many provitamin A carotenoids [39]. Retinol (or Vitamin A) is essential nutrient required for vision, normal growth, and reproduction. Retinoic acid (RA) is a metabolite of vitamin A with physiological importance. Retinol is converted intracellularly to 9-cis-retinoic acid or retinal all-trans-RA [40]. Mechanisms by which vitamin A influence T1DM and T2DM include adipose and obese biology regulation, increasing insulin sensitivity,
Vitamin E is a significant constituent of antioxidant systems in every body tissue.
The most important forms of Vitamin Ds in humans are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Vitamin D is a group of fat soluble secosteroids responsible for various biological functions, including intestinal absorption of calcium, phosphate, magnesium, and other biological functions. Vitamin D3 is obtained from diets and also synthetically made in skin from 7-dehydrocholesterol when exposed to radiation of solar UVB. It is converted in the kidney to the active vitamin D, 1,25-(OH)2 VD3 [46]. Vitamin Ds are mediated by vitamin D receptor (VDR), their nuclear receptor. Vitamin D plays significant roles in modulating T1DM and T2DM risks through having influence on inflammation, insulin sensitivity, and
Lycopene, a natural occurring carotenoid, is commonly found in tomatoes, pink grapefruit, etc.; it gives the red color. Several in vivo examinations indicated the health benefits of lycopene on T1DM and T2DM, and its accompanying complications [52, 53]. The antioxidant and anti-inflammatory properties of lycopene may be connected with its antidiabetic functions. Ali and Agha [54] carried out study with diabetic rats where lycopene supplementation resulted in a dose-dependent reduction of hydrogen peroxide (H2O2), lipid peroxidation, and NO, and also increased antioxidant enzymes activities, which led to decreased levels of glucose, increased levels of insulin, and enhanced profiles of serum lipids. Lycopene antioxidant properties have also indicated to solve diabetic endothelial dysfunctions in rats with induced diabetes [52]. Lycopene was evaluated for its capability to reduce cognitive decline associated with T2DM. Kuhad [55] showed dose-dependent responses to chronic treatments using lycopene, which eased cognitive impairments, decreased TNF-
Table 2 shows bioactive compounds, dietary nutrients, and their sources for T1DM and T2DM treatment.
Plants and sources of the compounds | Bioactive Compound | Phytochemical class | T1DM and T2DM properties | References |
---|---|---|---|---|
Asparagus, buckwheat, figs, apples, etc. | Rutin | Polyphenol (flavonoid) | Rutin reduced levels of blood glucose in insulin-resistant mouse by improving GLUT4 translocation and activities of insulin-dependent receptor kinase | [59] |
Vitamin D3 (Cholecalciferol) is obtained from diets (fatty fishes, cooked egg yolk, liver, fungi) or synthetically made in skin when exposed to solar UVB. | Vitamin D | Vitamin | Treating streptozotocin-induced diabetic rat using diet with vitamin D supplements decreased fasting blood glucose levels, increased levels of insulin, as well as restored pancreatic islets injured by STZ | [48] |
Citrus fruits, such as lemons, oranges, etc., and few plants | Hesperidin | Polyphenol (flavonoid glycoside) | It has protective effects in diabetic nephropathy, often through inhibiting transforming growth factor- | [60, 61] |
Cod liver oil, carrots, broccoli leaf, liver (fish, pork, beef), sweet potato, spinach, etc. | Vitamin A, including provitamin A compounds | Vitamin | Increases levels of insulin mRNA and secretion of insulin in cultured islets, through raising pancreatic glucokinase by activating glucokinase promoter. Retinol and retinoic acid are uncoupling protein 1 (UCP-1) positive regulators; UCP-1 overexpression could enhance insulin resistance and glucose transport | [41] |
Fruits, flowers, vegetables, etc. | Anthocyanin | Polyphenol (flavonoid) | In STZ-induced diabetic rats, pelargonidin (an anthocyanin) injection improved glucose tolerance, normalized elevated levels of blood glucose, and improved serum insulin level | [62] |
Grapefruit, pumelo, tomatoes, grapefruit juices, etc. | Naringin | Polyphenol (flavonoid) | Naringin protects cells against high glucose-induced destruction. Naringin inhibits high inflammatory reaction induced by glucose through mediating oligomerization and nucleotide-binding domain-related receptors family of inflammasome of pyrin domain-containing 3 in mesangial cells of rat | [63] |
Grapefruit, oranges, lemon, tomatoes, etc. | Naringenin | Polyphenol (flavonoid) | Naringenin ameliorated structural changes and renal damages, including glomerulosclerosis in STZ-induced diabetic rats, possibly via downregulating IL-1 and TGF- | [64] |
Green tea, black tea, white tea, onions, apple skin, plums, etc. | Epigallocatechin gallate | Polyphenol (Catechin) | Epigallocatechin gallate supplementations have influence on expression of the genes involved in metabolism of lipid and glucose in liver, such as through increasing glucose kinase by mRNA expression and reducing mRNA expressions of G6Pase, fatty acid synthases, as well as PEPCK | [65] |
Turmeric plant ( | Curcumin | Polyphenol | Curcumin oral administration reduced blood glucose levels, increased levels of plasma insulin, and reduced body weight | [66] |
Red onions, apples, tea, broccoli, etc. | Quercetin | Polyphenol (flavonoid) | Quercetin increased glucose uptakes in cultured skeletal muscle cell by stimulating GLUT4 translocation through 5’ AMP-activated protein kinase activation. Quercetin has activities on homeostasis of glucose in skeletal muscle and liver. | [67] |
Red wines, grape skins, seeds, groundnut skins, etc. | Resveratrol | Polyphenol | In insulin-secreting cell, treatment with resveratrol improved mitochondrial activity, improved insulin secretion stimulated by glucose, and enhanced glucose metabolism. | [68] |
Soybeans, fava beans, chickpeas, etc. | Genistein | Polyphenol (isoflavone) | Supplementation with genistein alleviated hyperglycemia induced by streptozotocin and improved insulin levels and glucose tolerance | [69] |
Tomatoes, pink grapefruit, etc. | Lycopene | Carotenoid | Lycopene antioxidant activities have demonstrated to solve diabetic endothelial dysfunctions in diabetic rats | [52] |
Wheat germ oil, sunflower oil, rapeseed/canola oil, almonds, g hazelnut oil, etc. | Vitamin E | Vitamin | After vitamin E supplementation, rats with streptozotocin-induced DM, in vivo, were shown to present significant reduction in glucose level and improved antioxidant enzyme activities, such as catalase, glutathione peroxidase, and glutathione reductase. | [44] |
Medicinal plants, bioactive compounds, nutrients with effectiveness against T1DM and T2DM.
Several polyphenols have been directly linked to treatment of T1DM and T2DM, including resveratrol, epigallocatechin-3-gallate (EGCG), quercetin, genistein, hesperidin, naringin, anthocyanins, curcumin, rutin, naringenin, etc.
This polyphenol occurs naturally in red wines, seeds, grape skins, and groundnut (peanut) skins. In insulin-secreting cell, treatment with resveratrol improved insulin secretion stimulated by glucose, improved mitochondrial activity, and enhanced glucose metabolism [68]. The effects depend on active Sirtuin 1-induced key genes upregulation for
Epigallocatechin-3-gallate, a polyphenol, is obtained from numerous plants, especially green teas, black tea, white tea, and apple skin. Studies have been done on green tea health benefits, with the benefits associated with epigallocatechin-3-gallate, which is most abundant constituent. EGCG has strong antioxidant activities. Han [74] reported that epigallocatechin-3-gallate protected cells of RINn5F against
Quercetin is a flavonoid which occurs naturally in many foods such as red onions, tea, apples, etc. A study indicated that treatment with quercetin enhanced lipid and glucose metabolism, as well as eased hepatic histomorphological damage in rats with STZ-induced DM, which possibly connected to the SIRT1 activity upregulation by quercetin and its impacts on Akt signaling pathways [76]. Vascular complications have been associated with most mortality and morbidity in T1DM and T2DM patients [77]. Youl et al. [78] carried out research and reported that quercetin improved secretion of glucose-induced insulin and protected
Genistein, a naturally occurring compound, structurally belongs to a group of compounds known as isoflavone. Genistein is found in many plants such as soybeans, chickpeas, etc. [79]. Evidence support genistein as a therapeutic potential and preventive treatment for T1DM and T2DM [69, 80, 81]. Genistein dietary supplementation enhanced mass of
Hesperidin, a flavonoid glycoside, is commonly found in citrus fruits, e.g. lemons and oranges, in rich quantity. Hesperidin oral administration significantly decreased HbA1c and glucose levels and raised serum insulin, vitamin E, and vitamin C levels in rats with HFD/STZ-induced diabetes [83]. The effects were most likely as a result of decline in producing oxidants and proinflammatory cytokines, including IL-6 and TNF-
Naringin, also a flavonoid, is commonly seen in some grapefruits and citrus species. It is known for its antihyperglycemic, antioxidant, and anti-inflammatory properties [86]. Numerous studies recently conducted demonstrated that naringin may improve T1DM and T2DM and ameliorate the severity of their associated health complications; their mechanism is understood [63, 86]. In vitro studies showed that naringin protects cells against high glucose-induced destruction. A typical example is the work done by [63], which showed that naringin inhibits high inflammatory reaction induced by glucose through mediating the oligomerization and nucleotide-binding domain-related receptors family of inflammasome of pyrin domain-containing 3 (NLRP3) in mesangial cells of rat. Sharma et al. [87] showed that naringin ameliorated kidney damage and hepatic steatosis, and attenuated
Anthocyanins (ANTs) are flavonoids mostly responsible for purple, blue, and red colors of fruits, flowers, and vegetables [91]. Most anthocyanins have strong antioxidant properties which may play role in their antidiabetic activities against T1DM and T2DM. In rats with STZ-induced diabetes, pelargonidin (an anthocyanin) injection improved serum insulin level, improved glucose tolerance, and normalized elevated levels of blood glucose [62]. Yan et al. [92] reported that anthocyanins pre-treatment attenuated
Curcumin, a polyphenol, is extracted from dried root of turmeric plant (
Rutin is a flavonoid commonly found in several fruits and vegetables, including asparagus, buckwheat, figs, and apples. Rutin is known to have many biological properties such as antioxidant, neuroprotective, antihyperglycemic, and anti-inflammatory properties [99], and all support its potential applications in the prevention and treatment of T1DM and T2DM and their associated health complications. Rutin reduced glycogen phosphorylase and G6Pase activities and increased hepatic hexokinase activities [47]. To this effect, rutin might decrease output of hepatic glucose. In rats with nicotinamide-STZ-induced diabetes, rutin administration decreased serum glucose levels, ameliorated glucose tolerance significantly, ameliorated oxidative stress, and also improved serum lipid variables, including serum total lipids, triglycerides, VLDL-cholesterol, and LDL-cholesterol. Rutin antihyperglycemic effects could be accomplished through increasing the uptake of glucose by peripheral tissue, stimulating secretion of insulin, suppressing gluconeogenesis in liver, and improving insulin resistance. Hsu et al. [59] showed that rutin decreased levels of blood glucose in insulin-resistant mouse by improving GLUT4 translocation and activities of IRK (insulin-dependent receptor kinase).
Naringenin, another flavonoid, naturally occur in citrus fruits, including oranges, tomatoes, grapefruits, and lemons [100]. Due to its beneficial effects in treating T1DM and T2DM and their associated health complications, naringenin has recently gained more attention. Several studies have evaluated naringenin role in complications associated with T1DM and T2DM, including vascular disease, neuropathy, hepatotoxicity, cardiac hypertrophy, and nephropathy [101, 102]. Kapoor and Kakkar [101] showed that increased apoptotic proteins expression, mitochondria dysfunction, increased ROS generation, altered antioxidant status, and altered activities of kidney and liver enzymes; may induce diabetic hepatopathy and liver damage in rats with T2DM; all the effects were completely rescued after treatment with naringenin. Consequently, naringenin has promising potentials for diabetic hepatopathy treatment. Naringenin functioned as cholinesterase inhibitor and as antioxidant, ameliorating diabetes-induced dysfunctions in memory of rats [103]. Roy et al. [64] reported that naringenin ameliorated renal damage and structural changes, including glomerulosclerosis in rats with STZ-induced diabetes, likely via downregulating IL-1 and TGF-
Epigenetic modification is heritable and persistent changes in DNA which regulate how the expression of genes are done, with no effects on the sequence of the nucleotide itself. Epigenetic modification includes DNA methylation, microRNA regulation, and histone modification. It has been generally acknowledged that epigenetic and genetic factors predispose to T1DM and T2DM. The main genes which regulate the differentiation of β-cell, including GLP1 receptor, PDX1, and PAX4, are epigenetically regulated. To prevent or alleviate symptoms of hyperglycemia, preventive strategies using nonpharmacological measures have been employed. Weight loss, regular exercise, and healthy diet can help manage glucose serum level and also enhance normal metabolism of glucose. Pancreatic islets can be transplanted [105]. Epigenetic modification encourages insulin resistance via having pro-inflammatory effects on numerous biological factors, such as osteopontin, NF-kB, and Toll-like receptors [106, 107]. Some of the bioactive compounds and dietary nutrients associated with the epigenetic modification in T1DM and T2DM are shown in Table 3.
Plants and natural sources of the compounds | Bioactive compound | Phytochemical group | Epigenetic modification effect | Reference |
---|---|---|---|---|
Apples, black tea, grapes, blackberries, etc. | Epigallocatechin gallate | Polyphenol (flavonoids) | Chromatin remodelling, histone acetylation, DNA methylation | [108, 109] |
Broccoli, cabbages, Brussels sprouts, etc. | Sulforaphane | Isothiocyanate | DNA methylation | [110] |
Cod liver oil, liver, carrots, broccoli leaf, sweet potato, spinach, etc. | Vitamin A | Vitamin | Changes chromatin structure | [111] |
Fatty fishes, liver, fungi, cooked egg yolk. Synthetically made in skin when exposed to solar UVB | Vitamin D | Vitamin | Changes chromatin structure | [112] |
Grapes, chocolate, grape skins, red wines, seeds, peanut skins, etc. | Resveratrol | Polyphenol | miRNA levels modifications, chromatin remodelling, histone modifications | [113] |
Turmeric plant ( | Curcumin | Polyphenol | miRNA levels modifications, chromatin remodelling, histone modifications | [114] |
Red onions, broccoli, apples, tea, etc | Quercetin | Polyphenol (flavonoid) | Histone modifications | [67] |
Rice, fat fraction of bran, rice bran oil, etc. | ϒ-oryzanol | Lipid | DNA methylation | [115] |
Soybeans, chickpeas, beans, fava, etc. | Genistein | Polyphenol (isoflavone) | Histone modifications, DNA methylation | [116] |
Soybeans, chickpeas, fava, etc. | Genistein | Polyphenol (isoflavone) | DNA methylation | [116] |
Tomatoes, pink grapefruit, etc. | Lycopene | Carotenoid | DNA methylation | [117] |
Medicinal plants, nutrients, and bioactive compounds in epigenetic modification in T1DM and T2DM.
Bioactive compounds, including EGCG, resveratrol, curcumin, sulforaphane, lycopene, etc., have been reported to modify epigenetic mechanisms, which could result in increased cells sensitivity to conventional agents [118]. Quercetin is a bioactive compound in buckwheat and citrus fruits. The bioactive compound functions as DNMT1 inhibitor through repressing TNF-induced NFkappa transcription factor and also encourages Fas ligand associated apoptosis through histone H3 acetylation, in addition to potential inhibition of HDAC [119]. Quercetin has been reported to take part in glucose uptake stimulation via MAPK insulin-dependent mechanisms. This is achieved in muscles through translocating GLUT4 transporters and in the liver through downregulating key enzymes of gluconeogenesis [67]. Resveratrol is a polyphenol which naturally occurs in grapes, chocolate, etc. Resveratrol activates a NAD-dependent HDAC, called sirtuin 1 (SIRT1); administration of SIRT1 to animals with insulin resistance regulates insulin sensitivity and improves glucose homeostasis [113]. Curcumin inhibits DNMTs, HDACs, and HATs. It inhibits or activates many miRNAs [120]. Epigallocatechin gallate (EGCG), an abundant catechin in green tea, is known to affect T1DM and T2DM. Epigenetic action mechanism of EGCG involves DNA methylation, histone acetylation, and deacetylation. Epigallocatechin gallate upregulates activities of anti-inflammation of regulatory T cell [108]. Genistein, a polyphenol obtained from soybean, induces active histone modifications and reverses hypermethylation [121]. Genistein appears to modulate on T1DM and T2DM through having direct effects on protection against apoptosis, glucose-stimulated insulin secretion, and β-cell proliferation. These have been reported to modulate through epigenetic mechanisms and to involve cascades of cAMP/PKA signaling [116]. Sulforaphane obtained from broccoli is a bioactive compound with epigenetic effects. Sulforaphane was reported to inhibit HDACs, decrease promoter methylation, and inhibit expression of DNMT1 in T2DM [122].
Diabetes mellitus (DM), simply called diabetes, are metabolic disorders characterized by varying or persistent hyperglycemia (high levels of sugar in the blood) over an extended time period. About 463 million people have diabetes worldwide; estimates project 700 million people by 2045. Over 90 to 95% of DM cases are T2DM, while the remain 5 to 10% are other types of DM, including T1DM, the gestational diabetes, and other minor specific types rarely encountered. Medicinal plants, bioactive compounds, and dietary measures have been found to be effective in the treatment of T1DM and T2DM. While T1DM is caused by the loss of beta cells of pancreatic islets that produce insulin, resulting in the deficiency of insulin, T2DM is caused by insulin resistance, and could combine relative reduction in the secretion of insulin.
The author acknowledge the effort of his colleagues at School of Natural and Applied Sciences, Kampala International University, Uganda, for helping through one way or the other.
The author declares no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nYuekun Lai
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nPrevious years (alphabetically by surname)
\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
\\n\\nFrede Blaabjerg 2015-18
\\n\\nGang Chen 2016-18
\\n\\nJunhong Chen 2017, 2018
\\n\\nZhigang Chen 2016, 2018
\\n\\nMyung-Haing Cho 2016, 2018
\\n\\nMark Connors 2015-18
\\n\\nCyrus Cooper 2017, 2018
\\n\\nLiming Dai 2015-18
\\n\\nWeihua Deng 2017, 2018
\\n\\nVincenzo Fogliano 2017, 2018
\\n\\nRon de Graaf 2014-18
\\n\\nHarald Haas 2017, 2018
\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
\\n"}]'},components:[{type:"htmlEditorComponent",content:'New for 2018 (alphabetically by surname).
\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
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\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
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\n\nCyrus Cooper 2017, 2018
\n\nLiming Dai 2015-18
\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
\n\nRon de Graaf 2014-18
\n\nHarald Haas 2017, 2018
\n\nFrancisco Herrera 2017, 2018
\n\nJaakko Kangasjärvi 2015-18
\n\nHamid Reza Karimi 2016-18
\n\nJunji Kido 2014-18
\n\nJose Luiszamorano 2015-18
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\n\nAndrea Natale 2017, 2018
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\n\nMohamed Oukka 2016-18
\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
\n\nYulong Yin 2015, 2017, 2018
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