Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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They play a very important role in human health and have significant biological activities, including anticancer, antimicrobial, anti-inflammatory, and antioxidant effects. This book provides an overview and highlights recent research in the phytochemical and biological understanding of terpenes and terpenoids, examining the most essential functions of these kinds of secondary metabolites.",isbn:"978-1-83881-917-0",printIsbn:"978-1-83881-916-3",pdfIsbn:"978-1-83881-918-7",doi:"10.5772/intechopen.87558",price:119,priceEur:129,priceUsd:155,slug:"terpenes-and-terpenoids-recent-advances",numberOfPages:142,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"575689df13c78bf0e6c1be40804cd010",bookSignature:"Shagufta Perveen and Areej Mohammad Al-Taweel",publishedDate:"July 28th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9753.jpg",numberOfDownloads:3479,numberOfWosCitations:2,numberOfCrossrefCitations:11,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:20,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:33,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 1st 2020",dateEndSecondStepPublish:"September 14th 2020",dateEndThirdStepPublish:"November 13th 2020",dateEndFourthStepPublish:"February 1st 2021",dateEndFifthStepPublish:"April 2nd 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"408197",title:"Prof.",name:"Areej",middleName:"Mohammad",surname:"Al-Taweel",slug:"areej-al-taweel",fullName:"Areej Al-Taweel",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Prof. Areej Al-Taweel obtained her Ph.D. in Pharmacognosy from King Saud University, Riyadh, Saudi Arabia. Her research focuses on different Saudi Arabian medicinal plants and she has isolated many bioactive natural products. Dr. Al-Taweel has published more than fifty-five papers in ISI-ranking journals.",institutionString:null,position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"494",title:"Bioorganic Chemistry",slug:"organic-chemistry-bioorganic-chemistry"}],chapters:[{id:"77011",title:"Introductory Chapter: Terpenes and Terpenoids",doi:"10.5772/intechopen.98261",slug:"introductory-chapter-terpenes-and-terpenoids-1",totalDownloads:292,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Shagufta Perveen",downloadPdfUrl:"/chapter/pdf-download/77011",previewPdfUrl:"/chapter/pdf-preview/77011",authors:[{id:"192992",title:"Prof.",name:"Shagufta",surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen"}],corrections:null},{id:"73536",title:"Terpenes in Essential Oils: Bioactivity and Applications",doi:"10.5772/intechopen.93792",slug:"terpenes-in-essential-oils-bioactivity-and-applications",totalDownloads:727,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Secondary metabolites from plant organisms have always been excellent options for the pharmaceutical, cosmetic, and food industries. Essential oils are a type of metabolites found in vegetables, and their chemical composition is diverse; however, monoterpenes and sesquiterpenes are inside the most abundant molecules. These terpenes have a diverse chemical composition that range from a simple molecule with carbon and hydrogen to more complex molecules with oxygenated organic groups, such as alcohols, aldehydes, ketones, and ethers. Many of these molecules with 10 and 15 carbon atoms have an especially important biological activity, being important the antimicrobial, antifungal, antioxidant, anti-inflammatory, insecticide, analgesic, anticancer, cytotoxic, among others. Some of these substances are potentially toxic, and hence, they should be handled with caution, especially when they are pure. They are easily obtained by different methods, and their industrial value grows every year, with a market of several million dollars. This chapter seeks to provide a better understanding of this type of bioactive molecules, with an emphasis in those whose information is remarkable in the scientific literature and whose value for health and human well-being makes them extremely important.",signatures:"Paco Noriega",downloadPdfUrl:"/chapter/pdf-download/73536",previewPdfUrl:"/chapter/pdf-preview/73536",authors:[{id:"323588",title:"Dr.",name:"Paco",surname:"Noriega",slug:"paco-noriega",fullName:"Paco Noriega"}],corrections:null},{id:"75305",title:"Terpene Compounds of New Tunisian Extra-Virgin Olive Oil: Effect of Ripening Stage",doi:"10.5772/intechopen.96254",slug:"terpene-compounds-of-new-tunisian-extra-virgin-olive-oil-effect-of-ripening-stage",totalDownloads:185,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The volatile profiles of Tunisian virgin olive oils were established by solid phase micro-extraction (SPME) and gas chromatography (GC), using flame ionisation and mass spectrometer detectors. Terpenes compounds were identified and characterized. Limonene, the main terpene compound extracted by SPME, characterized the studied olive oil. Significant differences in the proportions of terpenes constituents from oils of different maturity index were detected. The results demonstrated that the accumulation of the terpenes compounds in the studied oils obtained from different ripeness stage was strictly connected with the ripeness stage.",signatures:"Bechir Baccouri and Imene Rajhi",downloadPdfUrl:"/chapter/pdf-download/75305",previewPdfUrl:"/chapter/pdf-preview/75305",authors:[{id:"326893",title:"Associate Prof.",name:"Bechir",surname:"Baccouri",slug:"bechir-baccouri",fullName:"Bechir Baccouri"},{id:"335283",title:"Dr.",name:"Rajhi",surname:"Imen",slug:"rajhi-imen",fullName:"Rajhi Imen"}],corrections:null},{id:"75634",title:"Sacha Inchi Seed (Plukenetia volubilis L.) Oil: Terpenoids",doi:"10.5772/intechopen.96690",slug:"sacha-inchi-seed-em-plukenetia-volubilis-em-l-oil-terpenoids",totalDownloads:480,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sacha inchi oil is a product obtained from oilseed (Plukenetia volubilis L.) and is an excellent source of bioactive compounds, especially in polyunsaturated fatty acids, tocopherols, and sterols. These compounds are causally related to their positive impact on human health. In this study summarizes some monoterpenes, sesquiterpenes, and triterpenes reported in Sacha inchi oil seeds and reviews their sensory properties. The terpenoids that characterize Sacha inchi seed oil are: α-pinene, sabinene, limonene, aristolene, cycloartenol, 24-methylene cycloartenol, lanosterol, β-sitosterol, stigmasterol, campesterol and phytol. The sensory properties of this oil are due to a set of volatile compounds including terpenoids, the odor descriptors of monoterpenes, sesquiterpenes and diterpenes are: flower, pine, turpentine, pepper, wood, lemon, orange, and sweet. These compounds were characterized by gas chromatography with different detectors.",signatures:"Alexandra Valencia, Frank L. Romero-Orejon, Adriana Viñas-Ospino, Dayana Barriga-Rodriguez, Ana María Muñoz and Fernando Ramos-Escudero",downloadPdfUrl:"/chapter/pdf-download/75634",previewPdfUrl:"/chapter/pdf-preview/75634",authors:[{id:"324039",title:"Dr.",name:"Fernando",surname:"Ramos",slug:"fernando-ramos",fullName:"Fernando Ramos"},{id:"348838",title:"MSc.",name:"Alexandra",surname:"Valencia",slug:"alexandra-valencia",fullName:"Alexandra Valencia"},{id:"348840",title:"MSc.",name:"Frank",surname:"Romero-Orejon",slug:"frank-romero-orejon",fullName:"Frank Romero-Orejon"},{id:"348841",title:"Dr.",name:"Adriana",surname:"Viñas-Ospino",slug:"adriana-vinas-ospino",fullName:"Adriana Viñas-Ospino"},{id:"348842",title:"Dr.",name:"Dayana",surname:"Barriga-Rodriguez",slug:"dayana-barriga-rodriguez",fullName:"Dayana Barriga-Rodriguez"},{id:"348843",title:"Dr.",name:"Ana Maria",surname:"Muñoz",slug:"ana-maria-munoz",fullName:"Ana Maria Muñoz"}],corrections:null},{id:"75827",title:"Potential Antioxidant Activity of Terpenes",doi:"10.5772/intechopen.96638",slug:"potential-antioxidant-activity-of-terpenes",totalDownloads:255,totalCrossrefCites:4,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Terpenes play a key part in the metabolic processes of a wide variety of animals, plants and microorganisms in which they are produced. In nature, terpenoids serve a variety of purposes including defense, signaling and as key agents in metabolic processes. Terpenes have been used in perfumery, cosmetics and medicine for thousands of years and are still extracted from natural sources for these uses. Terpenes antioxidant activities may sometimes explain their capacity to adjust inflammation, immunological effects and neural signal transmission. They offer pertinent protection under oxidative stress situations including renal, liver, cancer, cardiovascular diseases, neurodegenerative and diabetes as well as in ageing mechanisms.",signatures:"Bechir Baccouri and Imen Rajhi",downloadPdfUrl:"/chapter/pdf-download/75827",previewPdfUrl:"/chapter/pdf-preview/75827",authors:[{id:"326893",title:"Associate Prof.",name:"Bechir",surname:"Baccouri",slug:"bechir-baccouri",fullName:"Bechir Baccouri"},{id:"332936",title:"Dr.",name:"Rajhi",surname:"Imen",slug:"rajhi-imen",fullName:"Rajhi Imen"}],corrections:null},{id:"74101",title:"Algal Terpenoids: A Potential Source of Antioxidants for Cancer Therapy",doi:"10.5772/intechopen.94122",slug:"algal-terpenoids-a-potential-source-of-antioxidants-for-cancer-therapy",totalDownloads:502,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:1,abstract:"In cancer treatment, increase in drug resistance and decrease in new chemotherapeutic drugs have become a pressing problem. Hence, searching for novel anticancer agents with less toxicity and high sensitivity is expanding gradually. Many preclinical and clinical studies indicate that natural antioxidants can help combating carcinogenicity and reduce the adverse effects on cancer therapy, when used alone or as adjuvant in chemotherapy. Consequently, marine algae pave the way for exploring more potential antioxidant compounds which have pharmaceutical importance. Algal terpenoids comprise a large group of bioactive compounds that have excellent antioxidative property and can be used as source of antioxidant in cancer therapy. This chapter summarizes the potential role of terpenoids from algal sources in inhibiting cancer cells, blocking cell cycle, hindering angiogenesis and metastasis as well as in inducing apoptosis.",signatures:"Umme Tamanna Ferdous and Zetty Norhana Balia Yusof",downloadPdfUrl:"/chapter/pdf-download/74101",previewPdfUrl:"/chapter/pdf-preview/74101",authors:[{id:"240031",title:"Dr.",name:"Zetty-Norhana Balia",surname:"Yusof",slug:"zetty-norhana-balia-yusof",fullName:"Zetty-Norhana Balia Yusof"},{id:"329649",title:"MSc.",name:"Umme Tamanna",surname:"Ferdous",slug:"umme-tamanna-ferdous",fullName:"Umme Tamanna Ferdous"}],corrections:null},{id:"73578",title:"Sesquiterpene from Myanmar Medicinal Plant (Curcuma comosa)",doi:"10.5772/intechopen.93794",slug:"sesquiterpene-from-myanmar-medicinal-plant-em-curcuma-comosa-em-",totalDownloads:389,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Curcuma comosa (Zingiberaceae) is widely grown in tropical and subtropical areas of Asia, like Thailand, Indonesia, Malaysia, and Myanmar. In Myanmar, the rhizome of Curcuma comosa is called Sa-nwin-ga, and local people had used it as a traditional medicine for stomach ache, diabetes mellitus, and hypertension. This species produces secondary metabolites of phenolic and nonphenolic groups. Phenolic groups like diarylheptanoids and flavonoids. While nonphenolics are terpenoids, especially sesqui- and monoterpenes. In this chapter, the group of sesquiterpene compounds from Curcuma comosa starts from the isolation technique, followed by the elucidation of the molecular structure, and their activity tests have been discussed.",signatures:"Khun Nay Win Tun, Nanik Siti Aminah, Alfinda Novi Kristanti, Hnin Thanda Aung and Yoshiaki Takaya",downloadPdfUrl:"/chapter/pdf-download/73578",previewPdfUrl:"/chapter/pdf-preview/73578",authors:[{id:"323446",title:"Dr.",name:"Nanik Siti Aminah",surname:"Aminah",slug:"nanik-siti-aminah-aminah",fullName:"Nanik Siti Aminah Aminah"}],corrections:null},{id:"74134",title:"Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth Muscle and on Systemic Blood Pressure: Pharmacological Studies and Perspective of Therapeutic Use",doi:"10.5772/intechopen.94194",slug:"effects-of-terpenes-and-terpenoids-of-natural-occurrence-in-essential-oils-on-vascular-smooth-muscle",totalDownloads:322,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Terpenes are a class of chemical compounds with carbon and hydrogen atoms in their structure. They can be classified into several classes according to the quantity of isoprene units present in its structure. Terpenes can have their structure modified by the addition of various chemical radicals. When these molecules are modified by the addition of atoms other than carbon and hydrogen, they become terpenoids. Terpenes and terpenoids come from the secondary metabolism of several plants. They can be found in the leaves, fruits, stem, flowers, and roots. The concentration of terpenes and terpenoids in these organs can vary according to several factors such as the season, collection method, and time of the day. Several biological activities and physiological actions are attributed to terpenes and terpenoids. Studies in the literature demonstrate that these molecules have antioxidant, anticarcinogenic, anti-inflammatory, antinociceptive, antispasmodic, and antidiabetogenic activities. Additionally, repellent and gastroprotective activity is reported. Among the most prominent activities of monoterpenes and monoterpenoids are those on the cardiovascular system. Reports on literature reveal the potential effect of monoterpenes and monoterpenoids on systemic blood pressure. Studies show that these substances have a hypotensive and bradycardic effect. In addition, the inotropic activity, both positive and negative, of these compounds has been reported. Studies also have shown that some monoterpenes and monoterpenoids also have a vasorelaxing activity on several vascular beds. These effects are attributed, in many cases to the blocking of ion channels, such as voltage-gated calcium channels. It can also be observed that monoterpenes and monoterpenoids can have their effects modulated by the action of the vascular endothelium. In addition, it has been shown that the molecular structure and the presence of chemical groups influence the potency and efficacy of these compounds on vascular beds. Here, the effect of several monoterpenes and monoterpenoids on systemic blood pressure and vascular smooth muscle will be reported.",signatures:"Ana Carolina Cardoso-Teixeira, Klausen Oliveira-Abreu, Levy Gabriel de Freitas Brito, Andrelina Noronha Coelho-de-Souza and José Henrique Leal-Cardoso",downloadPdfUrl:"/chapter/pdf-download/74134",previewPdfUrl:"/chapter/pdf-preview/74134",authors:[{id:"284195",title:"Emeritus Prof.",name:"Jose Henrique",surname:"Leal Cardoso",slug:"jose-henrique-leal-cardoso",fullName:"Jose Henrique Leal Cardoso"},{id:"331789",title:"Dr.",name:"Ana Carolina",surname:"Cardoso-Teixeira",slug:"ana-carolina-cardoso-teixeira",fullName:"Ana Carolina Cardoso-Teixeira"},{id:"331836",title:"Dr.",name:"Klausen",surname:"Oliveira-Abreu",slug:"klausen-oliveira-abreu",fullName:"Klausen Oliveira-Abreu"},{id:"331837",title:"Dr.",name:"Andrelina Noronha",surname:"Coelho-De-Souza",slug:"andrelina-noronha-coelho-de-souza",fullName:"Andrelina Noronha Coelho-De-Souza"},{id:"331838",title:"Mr.",name:"Levy Gabriel De Freitas",surname:"Brito",slug:"levy-gabriel-de-freitas-brito",fullName:"Levy Gabriel De Freitas Brito"}],corrections:null},{id:"76165",title:"Terpenoids: Lycopene in Tomatoes",doi:"10.5772/intechopen.97126",slug:"terpenoids-lycopene-in-tomatoes",totalDownloads:330,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Terpenoids are compounds that only contain carbon and hydrogen, or carbon, hydrogen and oxygen that are aromatic, some terpenoids contain carbon atoms whose number is a multiple of five called isoprene units. There are many terpenoids in tomatoes, one of which is a tretrapenoid. A type of tetrapenoid, the carotenoids. Lycopene is a terpenoid found in tomatoes. Lycopene is the most carotenoid group in tomatoes. Lycopene plays a very important role in maintaining human health, including its role in the risk of chronic diseases such as cancer, heart disease, and others. The lycopene content in tomatoes depends on genetic factors, in this case the tomato variety, the environment where the tomatoes grow and the fruit storage environment, and the age of the tomatoes. The genetic factor of tomato fruit that greatly affects lycopene content in tomatoes is the color of the fruit. Color is generally an accurate indicator of lycopene content, with yellow cultivars containing less lycopene than red cultivars, and two out of three red cultivars contain more than orange cultivars. Shade tomato plants can increase the lycopene content in tomatoes. Aside from the lack of light in the tomato plant environment, the humidity and air temperature around the tomato plants also greatly affect the lycopene content in the fruit.",signatures:"Dwi Setyorini",downloadPdfUrl:"/chapter/pdf-download/76165",previewPdfUrl:"/chapter/pdf-preview/76165",authors:[{id:"330555",title:"Dr.",name:"Dwi",surname:"Setyorini",slug:"dwi-setyorini",fullName:"Dwi Setyorini"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:{id:"15",series:{id:"11",title:"Biochemistry",issn:"2632-0983",editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}}},tags:null},relatedBooks:[{type:"book",id:"8290",title:"Pharmacognosy",subtitle:"Medicinal Plants",isOpenForSubmission:!1,hash:"0288b7ddce8b6d3ff07a3d78db289282",slug:"pharmacognosy-medicinal-plants",bookSignature:"Shagufta Perveen and Areej Al-Taweel",coverURL:"https://cdn.intechopen.com/books/images_new/8290.jpg",editedByType:"Edited by",editors:[{id:"192992",title:"Prof.",name:"Shagufta",surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6530",title:"Terpenes and Terpenoids",subtitle:null,isOpenForSubmission:!1,hash:"104f235908f326361a3ab16891949b70",slug:"terpenes-and-terpenoids",bookSignature:"Shagufta Perveen and Areej Al-Taweel",coverURL:"https://cdn.intechopen.com/books/images_new/6530.jpg",editedByType:"Edited by",editors:[{id:"192992",title:"Prof.",name:"Shagufta",surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2326",title:"Cellulose",subtitle:"Fundamental Aspects",isOpenForSubmission:!1,hash:"de85a5810169999b1c069d863593e56a",slug:"cellulose-fundamental-aspects",bookSignature:"Theo van de Ven and Louis Godbout",coverURL:"https://cdn.intechopen.com/books/images_new/2326.jpg",editedByType:"Edited by",editors:[{id:"130492",title:"Dr.",name:"Theo G.M.",surname:"Van De Ven",slug:"theo-g.m.-van-de-ven",fullName:"Theo G.M. 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\r\n\tThe goal of this book is to give the reader an overview of a field related to various applications in chemistry, chemical engineering, and nanotechnology. This book aims to provide information about the design of ion exchangers, their application in environmental technologies, and in biotechnology and pharmaceutical applications. This book will be written by authors in the field of experimental methods and critical reviews from multi-disciplines such as chemistry, membranes, and materials science. Among others, some of the topics covered will be Structure of ion exchangers, Synthesis of ion exchangers, Synthesis of inorganic ion exchangers, Properties of ion exchangers, Ion exchange voltammetry, Ion exchange as a separations method, Ion exchange in analytical chemistry, Ion exchange and extraction, Ion exchange membranes, Preparation of organic-inorganic hybrid ion exchangers, Application in environmental technologies, Application in biotechnology and pharmaceutical applications.
\r\n
\r\n\tIn this book, the authors will focus on recent studies, applications, and new technological developments on the fundamental properties of ion exchangers.
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\n
1. Introduction
\n
Cardiovascular diseases resulting from atherosclerosis have become the most important cause of mortality and morbidity in the general population [1]. Although atherosclerosis develops as a consequence of multiple risk factors such as hypertension, dyslipidemia, diabetes, aging and smoking, the common pathway for its development is endothelial dysfunction and vascular inflammation [2]. In the last two decades, the role of advanced glycation end products (AGEs) in the development of endothelial dysfunction has gained increasing interest [3, 4, 5], initially as a possible molecular mechanism of diabetic cardiovascular complications [3], and, in the last years, as an independent risk factor of vascular injury [6].
\n
AGEs are products of non-enzymatic molecular modifications of proteins and lipids that affect the structure and function of the target molecule. They are produced endogenously by spontaneous reactions, but pathophysiological conditions may accelerate their formation and they also contribute to disease by different mechanisms.
\n
AGEs comprise a heterogeneous group: the most studied are pentosidine and Nε-carboxymethyl-lysine (CML) and quantitatively, the most important in the tissues are the hydroimidazolones like CML [7]. AGEs are formed by a combination of glycation, oxidation, and/or carbonylation reactions both in the extra- and in the intracellular space. Other processes involving lipid peroxidations in the cell membranes lead to the formation of advanced lipid end products, as for example, malondialdehyde [8]. The classical mechanism of AGE formation is the slow Maillard reaction between glucose or reducing sugars and proteins [9]. The interaction between the carbonyl groups of reducing sugars and amino groups of proteins results in the formation of a Schiff base within a few hours. Intramolecular rearrangement of the Schiff base results in more stable Amadori products [9]. An example of these types of products is glycated hemoglobin or glycated albumin, the former is widely used in clinical practice for diagnosis and follow-up of diabetes mellitus and the last could be regarded as a smart alternative to modified hemoglobin for the same purposes, with less dependence on hematological diseases and intracellular conditions. Finally, the process of oxidation of the Amadori products leads to reactive carbonyl compounds and subsequently to the formation of AGEs within weeks to months. AGEs can also be formed intracellularly. Glucose is altered into reactive carbonyl compounds during glycolysis pathway, of which the best-known is methylglyoxal. The chemical reaction between these carbonyl compounds and proteins can result in AGEs [10].
\n
Absorption of exogenous AGEs also contributes to their accumulation in tissues. Tobacco smoke contains highly reactive glycation products which rapidly form AGEs in vitro and in vivo and therefore, increase the serum AGEs levels in smokers compared to non-smokers [11]. The content of AGEs in food depends on the temperature at which food products are prepared, with oven frying being the most severe inducer [12]. Approximately 10% of the ingested AGEs are absorbed from the gastrointestinal tract into the blood [13]. The final level of AGEs accumulation depends on their clearance and the metabolic mechanisms by the kidney and liver, respectively. Increased level of AGEs can be found in patients with either renal [13] or liver failure [14].
\n
The role of AGEs in cardiovascular diseases is a matter of interest in the last years [15], and the strong association between the axis of action of AGEs and their receptor (RAGE) and atherosclerosis or cardiovascular ischemic disease [3, 16, 17] has attracted increased attention. The aim of this chapter is to review the results of our laboratory and others on the molecular mechanisms triggered by AGEs in the endothelium that could participate in the atherosclerotic process. These mechanisms and molecular pathways could help in the development of new therapeutic targets against atherosclerosis or vascular disease.
\n
\n
\n
2. Molecular mechanisms triggered by AGEs in the endothelium
\n
It is generally accepted that AGEs target cells by three main mechanisms. First, proteins modified by AGEs have altered biological function, either enzymatic activity, binding properties or structural conformation. Second, extracellular matrix components modified by AGEs interact abnormally with other matrix components and with matrix receptors, such as integrins. This includes also the formation of new links or the alteration of those previously existing, between proteins, which may alter the physical properties of extracellular matrix and cell environment. Third, plasma proteins modified by AGEs bind to cell surface receptors, of which the receptor for AGEs (RAGE) is acknowledged to be the most important, activating intracellular signaling pathways and various cellular responses.
\n
Binding of AGEs to RAGE is responsible for the generation of reactive oxygen species (ROS) and the activation of transcription factors such as nuclear factor-κB (NF-κB), with subsequent changes in the expression of many genes involved in vascular inflammation and endothelial dysfunction [18, 19, 20]. Besides from the involvement of AGEs-RAGE axis, the precursors of AGEs, like Amadori products or early glycated products also have a role in the global response of non-enzymatic glycation of proteins, so we will also discuss their effects on endothelial cells.
\n
\n
2.1. AGEs-induced ROS production in the endothelium
\n
One of the first and best studied actions of AGEs on endothelial cells is the induction of ROS. The suggested mechanisms for this action are several and range from the activation of ROS-producing enzymes to the reduction of ROS-neutralizing enzymes. In the first group of enzymes or enzyme complexes are nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [21] and mitochondria [22], whereas in the second, there are endothelial nitric oxide (NO) synthase (eNOS) [23], superoxide dismutase (SOD) and glutathione peroxidase [24, 25]. The molecular mechanisms of these actions have been related to the activation of NF-κB via RAGE [26, 27].
\n
ROS production in endothelial cells has important consequences on endothelial activation. In brain microvascular endothelial cells, AGEs-induced ROS production enhances vascular endothelial growth factor (VEGF) expression, which mediates an increase in cell permeability [28], and platelet tissue factor up-regulation [29]. Other mechanisms of AGEs on endothelial cells promoting endothelial activation or dysfunction are the generation of asymmetric dimethylarginine (ADMA, a metabolic by-product of natural protein modification processes in the cytoplasm of cells, that acts as a competitive inhibitor of NOS) [30], or impaired calcium signaling [31].
\n
It is important to note that the effects of AGEs’ precursors (i.e. Amadori products or glycated proteins) on endothelial cells, differ from the effects of AGEs themselves. Several works have focused on this issue (see, for a review, [32]). Amadori products modify eNOS activity and gene expression, promoting apoptosis of endothelial cells [33, 34]. A recent study performed by our group has highlighted the important molecular and functional differences between early glycated human serum albumin (gHSA) and advanced glycated albumin (AGE-HSA), obtained commercially or by glucose incubation during 4 weeks at 37°C in aseptic conditions, respectively [35]. The respective control molecules of these treatments were unmodified commercial HSA and HSA incubated for the same time than AGE-HSA, but without glucose (Ct-HSA). Molecular characterization of the early and advanced glycation products formed on each modified albumin (gHSA and AGE-HSA) were studied by matrix assisted laser desorption/ionization—time of flight (MALDI-TOF)-mass spectrometry. Once characterized, the effects on ROS production of human umbilical vein endothelial cells (HUVECs) under the stimuli of gHSA or AGE-HSA were compared [35]. Low concentrations of gHSA enhanced long-lasting ROS production in HUVECs, whereas AGE-HSA induced extracellular ROS production after short time of incubation and at lower concentrations than gHSA. Extracellular ROS production of HUVEC was measured by the cytochrome C reduction method, whereas intracellular ROS production of HUVEC was measured by 5(6)-carboxy-2′,7′-dichlorofluorescein diacetate (cDCF-DA; Sigma-Aldrich), an intracellular dye for that purpose [36].
\n
Treatment of HUVECs with gHSA (25–100 μg/mL) for different times (4–12 h) induced significant increments of extracellular ROS production with respect to treatment with the same concentration of un-modified albumin (HSA, used as control) [36]. The maximal response (i.e. the quantity of ROS) was obtained with 25 μg/mL gHSA after 4 h of treatment (Figure 1a). The effects of AGE-HSA were studied under the same conditions. AGE-HSA increased the extracellular ROS production at lower concentrations (12 μg/mL) and after shorter time of exposure than gHSA (2 h). Another important difference is that, at long incubation periods, the ROS-inducing effects of gHSA were maintained, whereas no significant increases on ROS production were observed with AGE-HSA at 4–8 h (Figure 1b).
\n
Figure 1.
Extracellular ROS production in HUVECs after treatment with different concentrations of (a) gHSA (12–50 mg/mL) or (b) AGE-HSA (12–50 mg/mL), for periods of time indicated on each graph. Columns represent the ratio of ROS produced by treatment/HSA and are expressed as mean ± S.E.M. (vertical bars) of at least three independent experiments. *p < 0.05 with respect to the control values (Student’s t test).
\n
Similar experiments were designed to measure the intracellular ROS production by using cDCF-DA after 4 h of treatment the HUVECs with gHSA or AGE-HSA (12–50 μg/mL). Interestingly, at 25 μg/mL, gHSA significantly enhanced the intracellular ROS production, whereas AGE-HSA only showed a trend to slightly increase it (Figure 2).
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Figure 2.
Intracellular ROS production in HUVECs after 4 h of treatment with different concentrations of gHSA (white columns) and AGE-HSA (black columns), as indicated in the x-axis. Results are shown as the ratio modified HSA/control HSA, expressed as mean, in columns, ± S.E.M. (vertical bars) of at least four independent experiments. Comparisons were made between each ratio level and the unit (*p < 0.05; Student’s t test).
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Therefore, differences in the induction of ROS production were observed between gHSA (a low glycated product) and AGE-HSA (a high glycated product). Although the effects of AGE-HSA are accepted to be mediated by RAGE, the receptor that mediates the effects of gHSA has not been revealed yet [37], since, the effects of gHSA are not mediated by RAGE [38].
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2.2. Expression of adhesion molecules mediating leukocyte adhesion to endothelium
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RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF-κB as well as increased expression of cytokines, chemokines, and adhesion molecules [39]. Expression of inducible adhesion molecules is a final common pathway in the development of vascular inflammation and pathology, rendering the vasculature a selective target for circulating peripheral blood cells [27, 40].
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A number of studies have demonstrated induction of vascular cell adhesion molecule-1 (VCAM-1) expression in a RAGE-dependent manner when endothelial cells are exposed to AGEs [18]. Moreover, engagement of RAGE by AGEs results in enhanced expression of other adhesion molecules, such as E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) [40, 41, 42]. High expression of adhesion molecules in endothelial cells may promote adhesive interactions of circulating monocytes with the endothelial surface, resulting, eventually, in transendothelial migration [43].
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We confirmed that AGE-HSA up-regulated ICAM-1 and VCAM-1 expression more than gHSA, in terms of mRNA quantitative changes, measured by total messenger RNA retro-transcription and quantitative real-time polymerase chain reaction (qPCR) [35]. Even while the effects of gHSA seemed to be limited to 4 h- treatment, AGE-HSA up-regulated VCAM-1 and ICAM-1 expression for longer periods of time (from 2 to 6 h). Differences on the active concentrations of both glycation products were also observed: whereas gHSA was only active at 25 μg/mL, AGE-HSA was also effective at 12 and 100 μg/mL (Figure 3).
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Figure 3.
The expression levels of mRNA of VCAM-1 (a and c) and ICAM-1 (b and d) after treatment with gHSA or AGE-HSA at the concentrations and times indicated on HUVEC cultures. Results are shown as the ratio treatment/respective control, expressed as mean (columns) ± S.E.M. (vertical bars) of at least four independent experiments. Comparisons were made between each ratio level and the unit (*p < 0.05; Student’s t test) and between AGE-HSA and gHSA treated experiments ate the same time of incubation (a and b) or concentration (c and d; #p < 0.05; Student’s t test).
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To further confirm the increase in the expression of these adhesion molecules, protein levels of VCAM-1 and ICAM-1 were analyzed by western blot analysis after the treatment of HUVECs with two relevant concentrations of gHSA and AGE-HSA: 25 and 100 μg/mL, in comparison with the same concentrations of unmodified HSA and Ct-HSA, respectively. There was a significant elevation of VCAM-1 and ICAM-1 levels caused by the effect of both AGE-HSA concentrations tested. On the other hand, only the concentration of 25 μg/mL gHSA (but not 100 μg/mL) enhanced the ICAM-1 protein levels (Figure 4).
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Figure 4.
The expression levels of VCAM-1 and ICAM-1 measured by western blot in HUVEC protein extracts obtained after 4 h of treatment with gHSA or AGE-HSA (25 or 100 μg/mL, as indicated). TNF-α (10 ng/mL) was used as a positive inducer control. (a) Representative blots for VCAM-1, ICAM-1 and β-actin. Columns represent the fold change of protein expression for (b) VCAM-1 and (c) ICAM-1 calculated by optical densitometry with respect to β-actin and expressed as mean values (columns) ± S.E.M. (vertical bars) of at least three independent experiments. *p < 0.05 with respect to unmodified HSA or Ct-HSA for gHSA and AGE-HSA, respectively (Student’s t test).
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The functional translation of VCAM-1 and ICAM-1 up-regulation was analyzed by the adhesion of peripheral blood mononuclear cells (PBMCs) to HUVEC monolayers after treatment with both types of modified albumins for 4 h (Figure 5). After these treatments, the adhesion of calcein-AM-stained PBMCs to HUVEC monolayers after 1 h of incubation and washing of non-adhered PBMCs was quantified by fluorescence. In these conditions, gHSA (25 μg/mL) induced no significant effect in PBMCs adhesion in comparison with the control HSA. However, AGE-HSA (25 μg/mL) induced a significant increase in the adhesion of PBMC to HUVEC monolayers.
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Figure 5.
Quantification of the adhesion of PBMCs to a HUVEC monolayer, after treatment of HUVECs during 4 h with gHSA (25 μg/mL) or AGE-HSA (25 μg/mL), compared with HSA (25 μg/mL) or ct-HSA (25 μg/mL), respectively. The graph represents the mean percentage of adhesion (columns) ± S.E.M. (vertical bars) of at least three independent experiments. *p < 0.05 between the columns indicated (ANOVA followed by Tukey’s test).
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The effects of gHSA and AGE-HSA on PBMCs transmigration through HUVEC monolayers were studied in comparison to the ICAM-1 and VCAM-1 changes of expression. For these experiments HUVEC with transfected green fluorescent protein were grown until confluence onto transwells with 5 μm of pore size (Millipore). After treatment with AGE-HSA (25 and 100 μg/mL) for 4 h PBMCs were layered over the HUVECs and incubated at 37°C. TNF-α (10 ng/mL) was used as a positive control because it induces endothelial cell activation and promotes PBMCs transmigration through the endothelial monolayer. The number of transmigrated PBMCs were estimated by quantification of nuclei acids content with CyQUANT® GR dye (Molecular probes, Invitrogen) at the end of the experiment. Unless for the case of TNF-α, no changes were observed for any of the stimuli after 3 h of treatment. However, after 24 h of HUVEC incubation with 25 μg/mL AGE-HSA, a significant increase in the migration of PBMCs was observed as compared to control (Figure 6). On the contrary, higher concentration of AGE-HSA (100 μg/mL), showed no effect in the transmigration of PBMCs. The positive control with TNF-α increased the migration of PBMCs even more than after 3 h (Figure 6).
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Figure 6.
Transmigration of PBMCs through HUVEC monolayers after 3 h (white columns) or 24 h (black columns). Columns represent the mean (columns) ± S.E.M. (in vertical bars) of the increase of PBMCs transmigration after treatment compared to untreated control. *p < 0.05 with respect to untreated control (Student’s t test).
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Given the results obtained in the adhesion molecules expression in HUVECs, another approach was performed repeating the study with in vivo glycated albumin obtained from healthy volunteers and from cardiovascular patients, which donated their blood after signing informed consent. The whole study and protocols were approved by the Ethics Committee for Human Studies at Galicia (Spanish region) in accordance to the 1975 Declaration of Helsinki. Particularly, we analyzed the effect of HSAs categorized in healthy or nonglycated (from healthy volunteers), low-AGE or high-AGE (from cardiovascular patients), according to their content in AGE adducts. Glycation level was estimated by the molecular weight increment of isolated HSAs, due to the incorporation of different glycation products to the molecule. This was measured by mass spectrometry with a 4800 MALDI-TOF/TOF analyzer (Applied Biosystems). On this basis, attending to the increase of HSA molecular weight with respect to non-modified HSA, three stocks of HSA were prepared and categorized as healthy-nonglycated HSA, low-, and high-AGE HSA (molecular weights of 66,481, 66,665 and 66,778 Da for healthy, low-, and high-AGE HSA, respectively). HUVECs were incubated with a range of concentrations of these types of HSAs (12–200 μg/mL) for 4 h. In these conditions, the treatment with high-AGE HSA significantly increased the mRNA expression of ICAM-1 at concentrations of 12.5 and 25 μg/mL with respect to healthy-nonglycated HSA (Figure 7a; p < 0.001). An increase was also observed at 100 μg/mL concentration with respect to healthy HSA (p = 0.046). Moreover, high-AGE HSA was able to induce a significant increase with respect to low-AGE HSA at 12.5 and 25 μg/mL (Figure 7a; p < 0.05).
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Figure 7.
The expression of mRNA for ICAM-1 (a) and VCAM-1 (b) after the treatment of HUVECs with HSA isolated from healthy volunteers (healthy HSA) or with low-AGE HSA and high-AGE HSA from cardiovascular patients for 4 h. Columns represent the fold increase of mRNA expression for each gene and are expressed as mean values (columns) ± S.E.M. (vertical bars) of at least three independent experiments. *p < 0.05 with respect to healthy HSA. #p < 0.05 with respect to low-AGE HSA (Student’s t test).
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In the case of VCAM-1 expression, high-AGE HSA only induced an increase in the mRNA expression at 12.5 μg/mL with respect to healthy HSA and low-AGE HSA (Figure 7b; p < 0.05). At this concentration, low-AGE HSA also induced an increase in the expression of VCAM-1 with respect to healthy HSA (Figure 7b; p < 0.05). Finally, at a concentration of 50 μg/mL, high-AGE HAS induced a reduction in the expression of VCAM-1 with respect to healthy HSA (p < 0.05). This reduction in the expression of VCAM-1 was only transient as the mRNA levels recovered again at higher concentrations. Altogether, these results suggest that in vivo glycation of albumin could have a pro-inflammatory effect in endothelial cells, which would trigger chronic endothelial dysfunction.
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PBMCs adhesion to HUVECs was also studied with in vivo glycated albumins at 12.5, 25 and 100 μg/mL. HUVECs were treated with these concentrations for 24 h. After that, HUVECs were incubated with PBMCs for 1 h. A slight but significant increase in PBMCs adhesion (measured as explained above) was observed with high-AGE HSA with respect to low-AGE HSA at 12.5 μg/mL (p < 0.05), but not with respect to healthy HSA (Figure 8; p < 0.05). A trend toward an increase in PBMCs adhesion was also observed after treatment with high-AGE HSA with respect to low-AGE HSA at 25 μg/mL (p = 0.06). This suggests that in vivo glycated albumin needs more time to induce PBMCs adhesion than highly in vitro glycated albumin (AGE-HSA).
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Figure 8.
PBMCs adhesion to HUVEC monolayers treated with albumin from healthy volunteers (healthy HSA) or low-AGE HSA and high-AGE HSA from cardiovascular patients for 24 h. Columns represent the fold change of percentage of PBMCs adhered with respect to commercial HSA, expressed as mean values (columns) ± S.E.M. (vertical bars) of at least three independent experiments. #p < 0.05 with respect to low-AGE HSA (Student’s t test).
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3. Potential implications for pharmacological modulation of AGE-RAGE axis activity
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In an attempt to counteract the inflammatory effects of AGE-HSA, we selected three RAGE inhibitors: a soluble form of RAGE (sRAGE; R&D systems), used at 0.25, 0.5 and 1 ng/mL; a monoclonal antibody against RAGE (anti-RAGE; R&D systems), used at 5, 10 and 20 μg/mL; and the RAGE antagonist FPS-ZM1 (Calbiochem, Merck Millipore), used at 125, 250, 500 and 1000 nM. HUVECs were pre-treated with different concentrations of these inhibitors and 50 min later treated with 25 μg/mL AGE-HSA. The inhibitory effect of these agents on the expression of VCAM-1 and ICAM-1 in HUVECs was studied.
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However, contrary to what we expected, blockade of RAGE by using sRAGE, anti-RAGE antibody and FPS-ZM1 was not sufficient to counteract the AGE-induced VCAM-1 and ICAM-1 up-regulation at any of the concentrations tested under our experimental conditions. Our results may suggest that on endothelium, other RAGE-independent mechanisms may also be acting to increase adhesion molecule expression and induce inflammation. Other possible explanation for these results is that the pharmacological tools actually available to block RAGE activity are not able to block the effects of AGEs at the endothelial level. However, the results obtained on in vivo models of disease are promising, as we comment below.
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To investigate the effects of RAGE blockade in pathological conditions, many studies have used soluble forms of RAGE or anti-RAGE antibodies, which can antagonize RAGE-ligand interaction to competitively inhibit the activation of RAGE signaling [39, 44, 45]. Evidence from these studies has shown that RAGE blockade protected against various disease challenges. Soluble RAGE, which competes with cellular RAGE for ligand binding, has been able to reduce inflammatory responses in several models tested. Streptozotocin-induced diabetic apoE−/− mice treated with once daily injections of murine sRAGE showed suppressed acceleration of atherosclerotic lesions in a dose-dependent manner [46]. In parallel with decreased atherosclerotic lesion area and the complexity of the atheroma plaque composition, the levels of tissue factor, VCAM-1, AGEs, and nuclear translocation of NF-kB were decreased in the aortas of sRAGE-treated mice [42, 46]. In other work, sRAGE-treated mice displayed significant stabilization of the lesion area at the aortic root. Compared with diabetic mice receiving albumin (placebo), those receiving sRAGE had significantly diminished activity of monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2), VCAM-1 and matrix metalloprotease 9 (MMP-9) within aortic tissue [47]. Similarly, administration of sRAGE resulted in a highly significant decrease in atherosclerotic lesion area in parallel with decreased vascular expression of pro-inflammatory RAGE ligand S100/calgranulins and VCAM-1 and MMPs [48]. Moreover, sRAGE-treated non-diabetic mice displayed significantly decreased atherosclerosis and vascular inflammation [47, 48].
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Further studies using anti-RAGE IgG fragments to block ligand binding to RAGE have confirmed these results, especially at the highest dose (up to 10 μg/mL) tested [49]. Exposure of HUVECs to AGE-bovine serum albumin induced expression of VCAM-1 and increased adhesiveness of the monolayer for T lymphoblast of the Molt-4 cell line, which was inhibited by addition of anti-RAGE IgG or sRAGE [40]. Activation of signaling pathway on endothelial cells by advanced oxidation products resulted in overexpression of VCAM-1 and ICAM-1 at both, gene and protein levels, something that was prevented by blocking RAGE with either anti-RAGE IgG or excess sRAGE [27]. Administration of anti-RAGE IgG or sRAGE strongly blocked the increase in vascular permeability in diabetic rats injected with human diabetic red blood cells [50]. Mice treated with sRAGE or anti-RAGE F(ab’)2 fragments displayed significantly lower intima/media ratio (a marker of negative vascular remodeling after injury) compared to vehicle-treated animal models of femoral artery injury [51]. However, despite the fact that both, sRAGE and anti-RAGE IgG were able to reduce inflammatory responses in all models tested so far [42, 46, 50, 52], no significant decrease in ICAM-1 and VCAM-1 expression was observed after pre-treatment with soluble RAGE or anti-RAGE antibody, under our experimental conditions.
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A recently developed high-affinity RAGE-specific inhibitor: FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide; Calbiochem, Merck Millipore) [53] was also studied. This inhibitor was developed to interact with the ligand-binding domain of the receptor and block RAGE signaling. In our in vitro experimental conditions this approach was also unable to inhibit AGE-induced VCAM-1 and ICAM-1 up-regulation.
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It is worth mentioning that, most of the above-mentioned works did not elucidate the precise AGE(s) that trigger signal transduction mechanisms upon interacting with RAGE. Kislinger et al. [54] studied the effect of CML-adducts and showed that CML-mediated VCAM-1 expression on HUVECs was also suppressed in the presence of excess sRAGE or anti-RAGE IgG. Nevertheless, they suggest that the findings presented in their work do not rule out other specific AGE products of glycation or oxidation, such as pentosidine, pyralline, methylglyoxal, and imidazolone [55, 56, 57], which are present in our modified albumins. Additionally, they also specified that their findings do not rule out either the presence of other receptors or cellular interaction sites for CML adducts, being possible that other receptors for AGE [58, 59, 60] may also engage CML- and AGE-modified adducts. These situations might explain why no reduction in the up-regulation of adhesion molecules is observed after pre-treatment with sRAGE and anti-RAGE antibody under our experimental conditions.
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Additionally, Amadori-modified albumin stimulates adhesion of monocytes to endothelial cells through enhanced transcription of the cell surface adhesion molecules E-selectin, VCAM-1 and ICAM-1 [61], implicating an initial endothelial cell activation occurring at atherosclerosis-prone vascular sites [62, 63]. However, Amadori products do not compete with AGE-albumin for binding to AGE receptors such as RAGE [64]. Aortic endothelial cells express specific receptors for Amadori-modified albumin [37, 65]. Although less information is available for the receptor for Amadori products and signaling through Amadori-modified albumin receptors remains obscure, calnexin [66] and nucleophosmin [67, 68] have been reported to be the fructosyl-lysine specific binding proteins [66, 67, 68]. Binding of Amadori-modified albumin to calnexin-like receptors may participate in degradation and/or activation of signal transduction processes involved in mediating the biologic activities of Amadori-modified albumin [66]. The E-selectin expression induced by Amadori-modified albumin was 10 or 20 times higher than that induced with three types of AGEs-HSAs and was not suppressed by anti-RAGE antibody [69]. This would explain why RAGE antagonism would not counteract the increase in adhesion molecules expression.
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In agreement with this hypothesis, Esposito et al. [70] found that anti-RAGE antibody completely prevented leukocyte adhesion to endothelial cells grown for 8 weeks in high-glucose-containing media, but it did not reduce the adhesion at 24 h. These results demonstrate that AGEs are important mediators of high-glucose-induced endothelial dysfunction after long-term exposure, whereas the same changes in acute exposure occur with the action of mediators other than AGEs. As the formation of Amadori products is highly probable after 24 h incubation in high glucose medium, but not the formation of AGEs, the effects on the inflammation parameters observed by Esposito et al. [70], and not prevented by anti-RAGE antibodies, might be due to the effect of the early glycated products, and not AGEs.
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Besides from directly blocking RAGE, alternative pharmacological approaches might turn out to be more promising. Namely, it has been shown that both RAGE and sRAGE can be regulated by currently available pharmacological agents [71]. Other drugs currently in use for diabetic complications have been shown to have an effect on AGE accumulation. These include the antihypertensive angiotensin-converting enzyme inhibitor (ACEI) ramipril [72] and the glucose-lowering drug metformin [73], which both reduce AGE. Forbes et al. [74] demonstrated that compared with placebo, the ACEI perindopril increased human plasma sRAGE levels and reduced plasma AGE concentrations, suggesting an additional mechanistic effect of ACE inhibition in the treatment and prevention of vascular disease. The inhibition of ACE in rats increased the renal expression of sRAGE and decreased the expression of renal full-length RAGE protein [74]. These investigators also showed that plasma sRAGE levels were significantly increased by inhibition of ACE in both diabetic rats and human subjects with type 1 diabetes [74]. Olmesartan, an angiotensin II type 1 receptor blocker, inhibited the AGE-evoked ROS generation and reduced the expression levels of monocyte chemoattractant protein 1 and ICAM-1 in endothelial cells, subsequently blocking T-cell adhesion to endothelial cells [75].
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Other potential agents that may affect circulating sRAGE include the thiazolidinediones [76, 77] and statins [78, 79, 80], both of which are known to modulate AGE-RAGE axis. Marx et al. [76] investigated the effects of the two thiazolidinediones available, rosiglitazone and pioglitazone, on RAGE expression in HUVECs. Exposure of HUVECs to thiazolidinedione resulted in a similar reduction in RAGE mRNA expression, via inhibition of NF-κB activation, and in RAGE cell surface expression, demonstrating how these drugs may influence RAGE expression and its deleterious inflammatory activity in subjects with DM [76]. Blockade of the interaction of S100A12 (an endogenous ligand of RAGE) with RAGE by statins at an early stage may prevent inflammation in atherosclerosis and counteract the harmful effects mediated by C reactive protein [81].
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Finally, recent results testing new potential drugs have been reported. Curcumin, a polyphenolic natural compound is able to trap methylglyoxal, an important precursor of AGEs [82]. Added on endothelial cell cultures curcumin reduced the intracellular ROS levels and improved cell viability compared with the treatment of methylglyoxal alone. There was also a significant reduction in the expression levels of ICAM-1 [82]. Liquiritin, the 4’-O-glucoside of the flavanone liquiritigenin, reduced AGEs-induced apoptosis and ROS generation in HUVECs and also significantly increased AGEs-reduced SOD activity [83]. It even down-regulated the RAGE protein expression and significantly blocked NF-κB activation [83].
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4. Conclusions
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Oxidative stress induction by AGEs at endothelium triggers molecular signaling pathways that produce an inflammatory response or even endothelial dysfunction. Adhesion molecules expression at the membrane surface of endothelial cells as a consequence of this response or induced by AGEs by other mechanisms mediates the adhesion of leukocytes to endothelium. This adhesion is a key step in the atherogenesis process and the possible involvement of AGE-RAGE axis in it should be considered as potential therapeutic target. Finally, possible pharmacological modulation of AGE-RAGE axis activity at the endothelium is suggested, but specific pharmacological tools available nowadays are not efficient enough; momentarily, drugs used for cardiovascular and metabolic problems could be helpful in modulating the AGE-RAGE axis.
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Acknowledgments
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This study was supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016 and the Instituto de Salud Carlos III (grant number PI14/01140), co-financed by European Regional Development Fund. Axudas para a consolidación e estructuración de unidades de investigación competitivas, Xunta de Galicia (grant number ED431B 2016/022). The work of Beatriz Paradela-Dobarro was supported by Instituto de Salud Carlos III (grant number FI11/00325).
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\n',keywords:"advanced glycation end products, atherosclerosis, endothelial dysfunction, oxidative stress, receptor for advanced glycation end products, vascular adhesion molecules, vascular inflammation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/58939.pdf",chapterXML:"https://mts.intechopen.com/source/xml/58939.xml",downloadPdfUrl:"/chapter/pdf-download/58939",previewPdfUrl:"/chapter/pdf-preview/58939",totalDownloads:1343,totalViews:222,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:77,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"April 27th 2017",dateReviewed:"December 8th 2017",datePrePublished:null,datePublished:"October 24th 2018",dateFinished:"January 23rd 2018",readingETA:"0",abstract:"The role of advanced glycation end products (AGEs) in cardiovascular diseases is a matter of interest in the last years and the strong association between the action of AGEs on their receptor (RAGE) and atherosclerosis has attracted increased attention. The aim of this chapter is to review the results of our laboratory and others on the molecular mechanisms triggered by AGEs in the endothelium that could participate in the atherosclerotic process. These mechanisms and molecular pathways could be the source of new therapeutic targets against atherosclerosis or vascular disease. Oxidative stress in endothelium induced by AGEs triggers molecular signaling pathways that produce an inflammatory response or even endothelial dysfunction. Adhesion molecules expression at the membranes of endothelial cells as a consequence of this response or induced by other mechanisms involving AGEs mediates the adhesion of leukocytes to endothelium. This adhesion is a key step in the atherogenesis process and the possible involvement of AGE-RAGE axis in this process should be considered as a potential therapeutic target. Finally, potential pharmacological modulation of AGE-RAGE axis activity at the endothelium is suggested, but the specific pharmacological tools available nowadays are missing; respectively, drugs used for the treatment of cardiovascular and metabolic diseases could be helpful for AGE-RAGE axis modulation, thus also affecting endothelial (dys)function.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/58939",risUrl:"/chapter/ris/58939",book:{id:"6209",slug:"endothelial-dysfunction-old-concepts-and-new-challenges"},signatures:"Ezequiel Alvarez, Beatriz Paradela-Dobarro, Mercedes González-\nPeteiro and José Ramón González-Juanatey",authors:[{id:"200771",title:"Dr.",name:"Ezequiel",middleName:null,surname:"Álvarez",fullName:"Ezequiel Álvarez",slug:"ezequiel-alvarez",email:"ezequiel.alvarez.castro@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"220873",title:"Ms.",name:"Beatriz",middleName:null,surname:"Paradela-Dobarro",fullName:"Beatriz Paradela-Dobarro",slug:"beatriz-paradela-dobarro",email:"bea_paradela@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"220875",title:"Dr.",name:"Mercedes",middleName:null,surname:"González-Peteiro",fullName:"Mercedes González-Peteiro",slug:"mercedes-gonzalez-peteiro",email:"mmercedes.gonzalez@usc.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Santiago de Compostela",institutionURL:null,country:{name:"Spain"}}},{id:"220876",title:"Prof.",name:"José R.",middleName:null,surname:"González-Juanatey",fullName:"José R. González-Juanatey",slug:"jose-r.-gonzalez-juanatey",email:"Jose.Ramon.Gonzalez.Juanatey@sergas.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Servicio Gallego de Salud",institutionURL:null,country:{name:"Spain"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Molecular mechanisms triggered by AGEs in the endothelium",level:"1"},{id:"sec_2_2",title:"2.1. AGEs-induced ROS production in the endothelium",level:"2"},{id:"sec_3_2",title:"2.2. Expression of adhesion molecules mediating leukocyte adhesion to endothelium",level:"2"},{id:"sec_5",title:"3. Potential implications for pharmacological modulation of AGE-RAGE axis activity",level:"1"},{id:"sec_6",title:"4. Conclusions",level:"1"},{id:"sec_7",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459-1544\n'},{id:"B2",body:'Cahill PA, Redmond EM. Vascular endothelium—Gatekeeper of vessel health. Atherosclerosis. 2016;248:97-109\n'},{id:"B3",body:'Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: Implications for accelerated atherosclerosis in diabetes. Cardiovascular Research. 2004;63(4):582-592\n'},{id:"B4",body:'Sena CM, Pereira AM, Seica R. Endothelial dysfunction—A major mediator of diabetic vascular disease. Biochimica et Biophysica Acta. 2013;1832(12):2216-2231\n'},{id:"B5",body:'Wautier JL, Schmidt AM. Protein glycation: A firm link to endothelial cell dysfunction. 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Tobacco smoke is a source of toxic reactive glycation products. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(25):13915-13920\n'},{id:"B12",body:'Goldberg T et al. Advanced glycoxidation end products in commonly consumed foods. Journal of the American Dietetic Association. 2004;104(8):1287-1291\n'},{id:"B13",body:'Koschinsky T et al. Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(12):6474-6479\n'},{id:"B14",body:'Yagmur E et al. Elevation of nepsilon-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis. Clinical Biochemistry. 2006;39(1):39-45\n'},{id:"B15",body:'Prasad A, Bekker P, Tsimikas S. Advanced glycation end products and diabetic cardiovascular disease. Cardiology in Review. 2012;20(4):177-183\n'},{id:"B16",body:'Fukami K, Yamagishi S, Okuda S. Role of AGEs-RAGE system in cardiovascular disease. Current Pharmaceutical Design. 2014;20(14):2395-2402\n'},{id:"B17",body:'Chiang KH et al. Plasma levels of soluble receptor for advanced glycation end products are associated with endothelial function and predict cardiovascular events in nondiabetic patients. Coronary Artery Disease. 2009;20(4):267-273\n'},{id:"B18",body:'Basta G et al. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: A mechanism for amplification of inflammatory responses. Circulation. 2002;105(7):816-822\n'},{id:"B19",body:'Wautier MP et al. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. American Journal of Physiology. Endocrinology and Metabolism. 2001;280(5):E685-E694\n'},{id:"B20",body:'Yan SF, Ramasamy R, Schmidt AM. The RAGE Axis: A fundamental mechanism signaling danger to the vulnerable vasculature. Circulation Research. 2010;106(5):842-853\n'},{id:"B21",body:'Lubrano V, Balzan S. Roles of LOX-1 in microvascular dysfunction. Microvascular Research. 2016;105:132-140\n'},{id:"B22",body:'Shen GX. Mitochondrial dysfunction, oxidative stress and diabetic cardiovascular disorders. Cardiovascular & Hematological Disorders Drug Targets. 2012;12(2):106-112\n'},{id:"B23",body:'Ren X et al. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovascular Diabetology. 2017;16(1):52\n'},{id:"B24",body:'Liu GD et al. The augmentation of O-GlcNAcylation reduces glyoxal-induced cell injury by attenuating oxidative stress in human retinal microvascular endothelial cells. International Journal of Molecular Medicine. 2015;36(4):1019-1027\n'},{id:"B25",body:'Chen J et al. C-reactive protein upregulates receptor for advanced glycation end products expression and alters antioxidant defenses in rat endothelial progenitor cells. Journal of Cardiovascular Pharmacology. 2009;53(5):359-367\n'},{id:"B26",body:'Morita M et al. Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cells. Journal of Diabetes and its Complications. 2013;27(1):11-15\n'},{id:"B27",body:'Guo ZJ et al. Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxidants & Redox Signaling. 2008;10(10):1699-1712\n'},{id:"B28",body:'Niiya Y et al. Advanced glycation end products increase permeability of brain microvascular endothelial cells through reactive oxygen species-induced vascular endothelial growth factor expression. Journal of Stroke and Cerebrovascular Diseases. 2012;21(4):293-298\n'},{id:"B29",body:'Niiya Y et al. Susceptibility of brain microvascular endothelial cells to advanced glycation end products-induced tissue factor upregulation is associated with intracellular reactive oxygen species. Brain Research. 2006;1108(1):179-187\n'},{id:"B30",body:'Ando R et al. Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction. Diabetes & Vascular Disease Research. 2013;10(5):436-441\n'},{id:"B31",body:'Naser N et al. Advanced glycation end products acutely impair Ca(2+) signaling in bovine aortic endothelial cells. Frontiers in Physiology. 2013;4:38\n'},{id:"B32",body:'Schalkwijk CG, Miyata T. Early- and advanced non-enzymatic glycation in diabetic vascular complications: The search for therapeutics. Amino Acids. 2012;42(4):1193-1204\n'},{id:"B33",body:'Amore A et al. Amadori-configurated albumin induces nitric oxide-dependent apoptosis of endothelial cells: A possible mechanism of diabetic vasculopathy. 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Biochemical and Biophysical Research Communications. 1993;193(3):1131-1136\n'},{id:"B38",body:'Zhang M et al. Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: Involvement of Nox2 (gp91phox)-containing NADPH oxidase. Circulation. 2006;113(9):1235-1243\n'},{id:"B39",body:'Chuah YK et al. Receptor for advanced glycation end products and its involvement in inflammatory diseases. International Journal of Inflammation. 2013;2013:403460\n'},{id:"B40",body:'Schmidt AM et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. The Journal of Clinical Investigation. 1995;96(3):1395-1403\n'},{id:"B41",body:'Boulanger E et al. AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression. Kidney International. 2002;61(1):148-156\n'},{id:"B42",body:'Kislinger T et al. Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21(6):905-910\n'},{id:"B43",body:'Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: Molecular mecha-nisms. Cardiovascular Diabetology. 2002;1:1\n'},{id:"B44",body:'Chen Y et al. Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products. Journal of Immunology. 2004;173(2):1399-1405\n'},{id:"B45",body:'Zeng S et al. Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice. Hepatology. 2004;39(2):422-432\n'},{id:"B46",body:'Park L et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nature Medicine. 1998;4(9):1025-1031\n'},{id:"B47",body:'Bucciarelli LG et al. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation. 2002;106(22):2827-2835\n'},{id:"B48",body:'Wendt T et al. Receptor for advanced glycation endproducts (RAGE) and vascular inflammation: Insights into the pathogenesis of macrovascular complications in diabetes. Current Atherosclerosis Reports. 2002;4(3):228-237\n'},{id:"B49",body:'Liliensiek B et al. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. The Journal of Clinical Investigation. 2004;113(11):1641-1650\n'},{id:"B50",body:'Wautier JL et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. The Journal of Clinical Investigation. 1996;97(1):238-243\n'},{id:"B51",body:'Sakaguchi T et al. Central role of RAGE-dependent neointimal expansion in arterial restenosis. The Journal of Clinical Investigation. 2003;111(7):959-972\n'},{id:"B52",body:'Goova MT et al. Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. The American Journal of Pathology. 2001;159(2):513-525\n'},{id:"B53",body:'Deane R et al. A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. The Journal of Clinical Investigation. 2012;122(4):1377-1392\n'},{id:"B54",body:'Kislinger T et al. N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. The Journal of Biological Chemistry. 1999;274(44):31740-31749\n'},{id:"B55",body:'Sell DR, Monnier VM. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. The Journal of Biological Chemistry. 1989;264(36):21597-21602\n'},{id:"B56",body:'Njoroge FG, Sayre LM, Monnier VM. Detection of d-glucose-derived pyrrole compounds during Maillard reaction under physiological conditions. Carbohydrate Research. 1987;167:211-220\n'},{id:"B57",body:'Westwood ME, Thornalley PJ. Molecular characteristics of methylglyoxal-modified bovine and human serum albumins. Comparison with glucose-derived advanced glycation endproduct-modified serum albumins. Journal of Protein Chemistry. 1995;14(5):359-372\n'},{id:"B58",body:'Vlassara H, Bucala R. Recent progress in advanced glycation and diabetic vascular disease: Role of advanced glycation end product receptors. Diabetes. 1996;45(Suppl 3):S65-S66\n'},{id:"B59",body:'Araki N et al. Macrophage scavenger receptor mediates the endocytic uptake and degradation of advanced glycation end products of the Maillard reaction. European Journal of Biochemistry. 1995;230(2):408-415\n'},{id:"B60",body:'el Khoury J et al. Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors. The Journal of Biological Chemistry. 1994;269(14):10197-10200\n'},{id:"B61",body:'Desfaits AC, Serri O, Renier G. Gliclazide reduces the induction of human monocyte adhesion to endothelial cells by glycated albumin. Diabetes, Obesity & Metabolism. 1999;1(2):113-120\n'},{id:"B62",body:'Dai G et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(41):14871-14876\n'},{id:"B63",body:'Nakashima Y et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18(5):842-851\n'},{id:"B64",body:'Schmidt AM et al. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. The Journal of Biological Chemistry. 1992;267(21):14987-14997\n'},{id:"B65",body:'Wu VY, Cohen MP. Receptors specific for Amadori-modified glycated albumin on murine endothelial cells. Biochemical and Biophysical Research Communications. 1994;198(2):734-739\n'},{id:"B66",body:'Wu VY, Shearman CW, Cohen MP. Identification of calnexin as a binding protein for Amadori-modified glycated albumin. Biochemical and Biophysical Research Communications. 2001;284(3):602-606\n'},{id:"B67",body:'Krantz S et al. Purification and partial amino acid sequencing of a fructosyllysine-specific binding protein from cell membranes of the monocyte-like cell line U937. Biochimica et Biophysica Acta. 1995;1266(1):109-112\n'},{id:"B68",body:'Brandt R et al. Nucleophosmin is a component of the fructoselysine-specific receptor in cell membranes of Mono Mac 6 and U937 monocyte-like cells. Biochimica et Biophysica Acta. 2004;1670(2):132-136\n'},{id:"B69",body:'Higai K, Shimamura A, Matsumoto K. Amadori-modified glycated albumin predominantly induces E-selectin expression on human umbilical vein endothelial cells through NADPH oxidase activation. Clinica Chimica Acta. 2006;367(1-2):137-143\n'},{id:"B70",body:'Esposito C et al. Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC. Kidney International. 2001;59(5):1842-1849\n'},{id:"B71",body:'Koyama H, Yamamoto H, Nishizawa Y. RAGE and soluble RAGE: Potential therapeutic targets for cardiovascular diseases. Molecular Medicine. 2007;13(11-12):625-635\n'},{id:"B72",body:'Forbes JM et al. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes. 2002;51(11):3274-3282\n'},{id:"B73",body:'Sena CM et al. Metformin restores endothelial function in aorta of diabetic rats. British Journal of Pharmacology. 2011;163(2):424-437\n'},{id:"B74",body:'Forbes JM et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. Journal of the American Society of Nephrology. 2005;16(8):2363-2372\n'},{id:"B75",body:'Yamagishi S et al. Olmesartan blocks inflammatory reactions in endothelial cells evoked by advanced glycation end products by suppressing generation of reactive oxygen species. Ophthalmic Research. 2008;40(1):10-15\n'},{id:"B76",body:'Marx N et al. Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products. Diabetes. 2004;53(10):2662-2668\n'},{id:"B77",body:'Tan KC et al. Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes. Diabetologia. 2007;50(9):1819-1825\n'},{id:"B78",body:'Paradela-Dobarro B et al. Statins modulate feedback regulation mechanisms between advanced glycation end-products and C-reactive protein: Evidence in patients with acute myocardial infarction. European Journal of Pharmaceutical Sciences. 2013;49(4):512-518\n'},{id:"B79",body:'Okamoto T et al. Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. The FASEB Journal. 2002;16(14):1928-1930\n'},{id:"B80",body:'Cuccurullo C et al. Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26(12):2716-2723\n'},{id:"B81",body:'Mahajan N, Bahl A, Dhawan V. C-reactive protein (CRP) up-regulates expression of receptor for advanced glycation end products (RAGE) and its inflammatory ligand EN-RAGE in THP-1 cells: Inhibitory effects of atorvastatin. International Journal of Cardiology. 2010;142(3):273-278\n'},{id:"B82",body:'Sun YP et al. Curcumin inhibits advanced glycation end product-induced oxidative stress and inflammatory responses in endothelial cell damage via trapping methylglyoxal. Molecular Medicine Reports. 2016;13(2):1475-1486\n'},{id:"B83",body:'Zhang X et al. Liquiritin attenuates advanced glycation end products-induced endothelial dysfunction via RAGE/NF-kappaB pathway in human umbilical vein endothelial cells. Molecular and Cellular Biochemistry. 2013;374(1-2):191-201\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ezequiel Alvarez",address:"ezequiel.alvarez.castro@gmail.com",affiliation:'
Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain
CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Servicio de Cardiología y Unidad de Hemodinámica, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain
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1. Introduction
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When the UN has adopted Agenda 2030 in 2015 for sustainable development, it committed itself and the member states to work on achieving a social, environmental, and economically sustainable world by the year 2030 [1]. According to Agenda, by 2030 everyone will have access to safe green areas and public places. Unfortunately, not all green areas and public places are perceived as safe. According to the Swedish National Council for Crime Prevention (Brå) due to the fear of being exposed to crime, people change their pattern of movement [2]. Almost a quarter of the population in Sweden takes a different route or a different mode of transport than desired due to the fear of crime [2]. According to the Swedish security survey [2], those areas that have exposure to crime generated a higher level of concern for the respondents to be exposed to crime themselves. This worry left people with a limited choice in terms of when and where they move within the city [2]. It has been argued that sustainability as a whole cannot be achieved unless all of the residents feel safe [3].
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The feeling of being unsafe can be problematic both at a personal level and at the level of society. Several empirical studies have sought that there is not always a connection between feeling unsafe and being actually in danger, conversely, it is quite possible to feel unsafe in an environment that looks completely safe. Safety is a concept that is based on subjective experiences, which means that it can be defined differently. According to UN-Habitat [4], security is defined as the statistical risk to be exposed to criminal acts in one place. If the risk is low, security is high. Whether you are in danger or not, it is the subjective feeling of insecurity that creates a problem in society because it affects human behavior and freedom [5] and makes it difficult to achieve social sustainability. Social sustainability is a concept that contains several factors where the safety aspect is included. Safety is one concept that can vary depending on the context in which the research is presented. Subjective safety reflects the perception of social safety and encompasses fear or anxieties caused by real or presumed fears [6]. Research that exists on safety is most often associated with crime preventative measures and it is therefore important to distinguish between crimes that have taken place and perceived fear of crimes. There is a willingness on the part of actors to work actively with issues of safety in urban planning, but most often there is little or no natural cooperation between them. More knowledge, clearer guidelines, and better coordination can help actors to work more on these issues together [7] to promote smooth urban transition and achieve resilience as a whole. Resilience is mostly defined as ecosystems and climate change. However, this is not the only dimension that is connected to resilience. The demand for safe and secure places continues to upsurge [4]. The challenge for providing such places in developing and third world countries is another serious issue to demonstrate that design can meet the needs of the residents around the world. In this book chapter, the term safety is used as it is explained by Iqbal [8] “the risk of being a victim of crime, the perception of risk of being a victim of crime, and the expression of fear/anxieties of crime”. The term “urban safety is considered to be the quality of the environment and is defined for a person or group in an urban area” [8].
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This book chapter aims to highlight the connection between public spaces regarding crime and fear of crime by (1) showing links between parks and public spaces, and crime and fear of crime, (2) highlighting how different land uses and people’s activities in the built environment can affect people’s perception, (3) understanding socio-technical perspectives i.e., how technological systems and equipment’s (such as lighting sensors, security alarms, security electronic devices, closed-circuit television (CCTV), smartphones or other technological instruments) are influencing safety/security and sustainability, (4) demonstrating the issues and challenges found in Sweden, and, (5) providing recommendations on how these places can be planned and designed to become more sustainable. This book chapter presents a synthesis of earlier work on fear of crime, perceived safety and parks by the author [8, 9, 10, 11, 12, 13]. The book chapter begins with a discussion of factors that influence fear of crime and perceived safety in parks and public spaces. Second, a review of the recent literature about perceived safety associated with the physical design perspective of the built environment. Third, how technological systems and equipment (such as lighting sensors, security alarms, security electronic devices, CCTV, smartphones or other technological instruments) are influencing safety/security and sustainability is outlined. Fourth, the issues and challenges found in Stockholm, Sweden will be demonstrated. The context of the empirical studies was the city of Stockholm, therefore, the policy and design recommendations for being safe in the public space discussed in the last section are applicable to other major cities of Sweden or the cities similar to those as Stockholm.
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2. Fear of crime and perceived safety in public spaces
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Public space is characterized as an open space that is accessible to people. In other words, public spaces are the places that provide opportunities for social interactions within the communities. Parks, public squares and streets are some examples of public spaces. To create an inclusive public space, it is important that the various groups of people feel safe and can freely participate in society. Due to its blurred nature of definition boundaries the terms public place and public space are used in this book chapter interchangeably (i.e., for discussion, see [14, 15]. Several studies have shown the positive impact of parks and public spaces on human health and well-being [16] while, others have shown that such places can be a reason for stress and anxiety [5, 17] and affect human life negatively. According to Iqbal and Wilhelmsson [11], not all parks and public spaces have equal amenity value and some may be valued as disamenities. For example, noise around parks, high beam lights from sports arenas, and traffic congestion around parks, street parking near parks, garbage, vandalism, and the gathering of undesirable groups (such as alcoholics, drug addicts, etc.) in public spaces affect individuals negatively [8]. Poor maintenance and criminogenic conditions of the park and public spaces are highlighted by several researchers [9, 11, 18]. A small number of studies have also shown that potential buyers may avoid buying properties located near parks and public spaces with high crime rates [10, 11, 19].
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According to UN-Habitat [4] “crime is defined as an antisocial act that violates a law and for which a punishment can be imposed by the state or in the state’s name”. while fear of crime refers to the “fear of being a victim of a crime instead of the actual possibility of being a victim of crime” [20]. Fear of crime or feeling unsafe is a concept that is complex and based on subjective experiences attached to various other contexts such as age, gender, socioeconomic status and emotional responses to worry or anxiety [5]. According to Ceccato [21], safety is a concept that is shaped by an individual’s actions and interventions in everyday life. Safety is affected by many different factors. These factors can be more easily understood in their context if they support personal, social and physical attributes. For example, there are several strands of literature analyzing the personal and social attributes such as age, gender and socioeconomic status that affect the perceived safety of public spaces [22, 23].
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According to Furedi [24] social and cultural processes guide people on how to respond to threats to their safety [24]. Several researchers highlighted the fear of crime in parks as the most important factor that keeps women out of public spaces [25, 26]. Fear of crime also encourages the separation of women from men in public space [12]. For instance, the creation of safe places for female social interactions and activities to accommodate their outdoor space needs [12, 27]. The international literature shows that some women are mainly fearful of sexual assault [25]. According to Hilinski et al. [28], young age women are targeted for sexual assault and rape [28] then old age women [29]. Following this, there are many places in the world, where the openness in public space is not open for all [12]. In those places, public space is considered as a place where men have more rights than women and where women are often left out because of the fear of harassment [30]. Marginalized groups tend to be more fearful in society because of their vulnerability and feel segregated. Exclusion and loneliness are some of the social attributes in society that enhance the fear of crime. Social integration is essential to reduce the fear of crime and increasing perceived safety. A neighborhood is perceived as safe when it has a social network that includes both regular communication and offered help to all groups. According to Olsson [31], the socially defined space applies when there are social ties between the inhabitants and it is easy to understand and use the public space. It is important to the public space feels open and welcoming for people to make them stay. If the connection with space is missing and identities become unclear, the social control becomes more difficult which resulted in an unsafe place. A socially sustainable, cohesive and resilient public spaces can be achieved by promoting social inclusion and by empowering all groups of people.
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3. Fear of crime and perceived safety: physical design perspective
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In this book chapter, physical design perspective refers to the design attributes of the physical environment of public spaces such as design layouts, mixed land use, street patterns, street furniture (garbage bins and seating arrangements), barriers (actual and symbolic), lighting, accessibility, landscape design and maintenance. Previous research about fear of crime and safety in the urban environment has dealt with situational crime prevention measures [32, 33] and how the physical environment should be designed safely [34, 35, 36]. Situational crime prevention measures are applied when a criminal is motivated to commit a crime and the design of the place makes it difficult to carry out the crime. Situational crime prevention methods deal with the physical, social, and psychological aspects of the place to counteract crimes [37]. The role of the physical environment in promoting safety highlighted by several researchers [34, 35]. Crime prevention through environmental design (CPTED) is a concept that explains the relationship between environmental features and crime occurrence through the principles of surveillance, territoriality, access control, target hardening, activity support, and image/maintenance. CPTED is a method that is about how proper development of physical environments can be designed to prevent crime and increase the sense of safety in the built environment. The importance of using CPTED principles is highlighted by many researchers as an inventory in public spaces such as parks [9, 38].
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The best-known theory that explains environmental preferences from an architectural, interior and urban planning perspective and its impact on people is “Prospect-refuge theory”. This theory seeks to describe why certain environments feel secure and thereby meet basic human psychological needs. It is a strategic assessment of how different potential environments enable the ability to observe (prospect) without being seen themselves (refuge). By emphasizing subjective references such as experiences, behaviors and relationships more than architecture, Appleton [39] claims that people evaluate environments functionally and search for strategic opportunities that environments can provide. According to Dosen & Ostwald [40] the physical elements in the planning that creates a perception of spatial arrangements of different components affect human perception and thus the perception of safety. Components that provide the opportunity to move and explore in an environment and whether the effect of shadow and sun is taken into account affects the human perception and experience of safety [40].
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In her seminal work, ‘The life and death of the great American cities’ Jane Jacobs [36] argue how the safety aspect is an important part of a livable urban environment. Jacobs [36] brings forward the idea of mixed land uses of buildings and people by analyzing the uses of different urban elements, such as sidewalks, neighborhood parks, and city neighborhoods. According to Jacobs [36], three requirements should be fulfilled to create perceived safety in the streets. First, a clear division of the public and private space is important. Second, businesses along the street should have large windows facing towards the street. This can create more “eyes upon the streets” that can perceive what takes place in the street space and can help to intervene in potential crime events. The third and the last is to create a continuous flow of people passing by. This increases the number of eyes while encouraging people in the surrounding buildings to look out at the street and observe the events happening in street space. Jacobs believes that no one is interested to look out on an empty street, on the contrary, many people feel entertained when observing a living street [36]. To create the flow of people that makes the street space come alive, Jacobs mentions the importance of having a mixed type of activities that attract people at all hours of the day and provide guardianship. The concept of guardianship is mainly highlighted by Cohen and Felson [41] in routine activity theory. According to them, “in order to take place a crime event, the presence of a motivated offender, the presence of a suitable target, and the absence of a capable guardian is required” [41]. Capable guardians can be provided with the help of planning a mixed type of activities and mixed land use.
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The role of mixed land use in the built environment is highlighted by various researchers, architects and urban planners. It has been argued that mixed land use activities lead to an active day for a longer period, which contributes to natural surveillance and leads to an increase in the feeling of safety [42]. In a study of parks and crime, Groff and McCord [43] found that mixed land use reduces crime. Larger parks that generate more activities have lower crime levels, which in turn are connected to greater numbers of people using these parks [43]. Contrary to this Iqbal and Ceccato [9] found that large parks can have safety issues due to the big area of the park. Parks can attract criminal activities and in turn have a high number of crimes in certain areas. For instance, cafes, restaurants and sports arenas in summers can also have an increasing number of crimes in parks, such as mishandling incidence, pickpocketing and vandalism [9]. When explaining the fear of crime in parks, overgrown trees and vegetation has an important role in association with fear of crime and disorder and affect perceived safety negatively. The major proposition is given to the idea that trees and vegetation can block the view and can create hiding places [44, 45]. Proper maintenance can help to avoid hiding places and in turn deter the incidents of crimes. Vegetation is also a physical element that is used to define demarcation or create symbolic barriers that question the accessibility of public places. Gehl [46] emphasized the need to eliminate such barriers (both physical and mental) to increase space accessibility (Figure 1).
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Figure 1.
(a) Presence of dark tunnels often limits the prospects and provides refuge for a criminal. (b) Padlocks can increase fear of crime. (Source: Iqbal, A*) *All photographs were taken by the author.
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Accessibility in public places has an important role from the physical design perspective. A public place should feel accessible and open to everyone. Accessibility can be seen from two perspectives. It could be either actual or symbolic barriers that prevent visitors from visiting or staying at a place. Within the physical aspect, accessibility can sometimes be associated with the lack of obstacles and barriers. The perceived accessibility is instead about whether the place is perceived as inclusive for all. It is also very important to understand the dilemma of “public spaces as a public good” — that nobody feels the responsibility of being in charge of publically owned spaces [9, 43] however, at the same time everyone wants to get benefit from it. While explaining accessibility in the public urban space, Olsson [31] argued that an accessible and well-planned public space must be identified as open and attractive. In order to create attractiveness, the presence of other people is identified as the crucial element [31, 46, 47] and a prerequisite for a well-functioning city [31]. Urban events such as cultural events and sports were criticized by Olsson [31] as they are not sustainable solutions to create accessibility and attractiveness in the city.
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Another important physical element that helps to feel safe in an urban environment is the use of street furniture such as the placement of garbage bins and seating arrangements in a public space. In order to investigate how people use the spaces and interact in public places such as squares and parks in New York, William Whyte [47] stated an essential prerequisite for attracting people to squares and parks in the presence of other people as well as access to the seating. Food sales, the presence of water, movable chairs and access to the sun were identified as other significant elements [47]. Public spaces that provide seating with a natural overview mainly allow for social interaction and automatically generates perceived safety. Saville & Cleveland [48] found that park furniture can create natural surveillance if place adequately. The placement of park furniture can work as a source of creating eyes on the street on the other hand they are a major source of creating a social connection among park users. At the same time, they can be part of the noise and other problems in parks [48]. A park or public space with well-groomed trees and vegetation, good lighting, and cleanliness increase the perceived safety.
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Perceived safety is also associated with the disorder in the surroundings. The disorder is mainly affected by physical attributes such as graffiti, poorly maintained landscapes, debris (garbage), vandalism, and poor lighting. According to Broken Windows Theory, physical and social deterioration can affect residents’ perceived safety and may result in a higher fear of crime [23]. The relationship between perceived safety and disorder is recurring. An increase in disorder decreases people’s perceived safety which in turn leads to place avoidance. On the other hand place avoidance leads to further disorder [49].
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When emphasizing crime preventative measures, several researchers found street lighting as an important part of physical features that helps in feeling safe in public spaces [14, 50] However, there are mixed trend results in research that show both positive and negative effects of lighting. In a recent systematic literature study, Ceccato and Nalla [14] mentioned that 72 percent of studies (from their sample research papers) show that good lighting affects positively by reducing crime and/or fear of crime however, the impact on the safety of other security technologies, are inconclusive [51]. According to Rezvani and Sadra [5], lighting and visual accessibility of public places lead to strengthening the sense of feeling safe in the neighborhoods. Physical design affects perceived safety, but it is not just physical planning that administers how safe a public space can be. Sreetheran & van den Bosch [52] argues that physical attributes can be apparent like vandalism or sometimes even more prevailing factors such as lighting or maintenance of an area. Physical factors that indicate disorder in society generate fear and can be perceived as a warning sign of an unsafe place. It is important to keep in mind that the personal, social and physical attributes are interdependent to achieve perceived safety. Investigating negative aspects of light pollution on ecological systems and health, Chepesiuk [53] shows that lighting also has divergent effects on both flora and fauna. It has also been highlighted that light pollution in cities shown a negative effect on people’s sleeping habits [53].
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4. Fear of crime and perceived safety: a socio-technical perspective
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Our cities have developed a lot and access to modern technology such as smartphones, laptops, the internet, etc. has most likely had an impact on how public places are used and how people interact with each other. Since this new era of smartphones and location-based services has started an increasing trend of debate is taking place between various actors in society on the role of socio-technical perspective to design cities that can help to reduce crimes. Cities are comprised of people, infrastructure, physical forms, services, ecosystems and communications. The interaction between society’s complex infrastructures and human behavior has a great role in interconnecting all three forms of sustainability that are, social, physical and ecological. However, it is inappropriate to expect that the sustainability challenges that our cities are facing can be solved by only traditional disciplinary methods of research. Cities require a socio-technical approach rather than a purely technological one because societal functions are achieved by a combination of technology, infrastructure, production systems, policy and legislation, user practices and cultural meaning [54]. When it comes to explaining socio-technical perspectives about crime and fear of crime the most important element is how the use of technological systems and equipment (such as lighting sensors, security alarms, security electronic devices, CCTV, smartphones or other technological instruments) are influencing safety/security and sustainability. So what makes a public place inclusive, safe and resilient from the socio-technological perspective?
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Video surveillance cameras are a common part of the modern world today. The implementation of CCTV cameras has been considered a supplemental tool for surveillance and a potential means of facilitating social control [55]. However, still there are some significant legal and social limitations associated with it [56]. Besides the subjective nature of feeling safe, some people feel that the presence of CCTV makes them feel more confident and safe while others feel it reduces their confidence [57]. To identify the crime prevention effects of CCTV and street lighting Welsh and Farrington [58] found that “CCTV and improved lighting were more effective in reducing property crimes than in reducing violent crimes, with CCTV being significantly more effective than street lighting in reducing property crime” [58]. More focus was given to parking lots and/or garages and little is known about the effectiveness of these crime prevention effects in other public spaces. One example of research on the effectiveness of urban video surveillance in public spaces was assessed by Socha & Kogut [56]. The authors found that the installation of smart surveillance and analysis system in public space supports the use of monitoring systems to prevent and reduce crime and improve safety in public space [56]. Similarly, McCormick and Holland [59] found that CCTV cameras can decrease criminal activities in urban parks. Contrary to this, Surette and Stephenson [60] investigated the relationship between safety and video surveillance camera. The results show that the surveillance cameras had an insignificant effect on the disorder in parks. Ratcliffe [61] identified installation of video surveillance cameras as a tool that increases the risk of facilitating the arrest of the offenders. However, the same study also demonstrated that in general cameras can serve to reduce criminal activity, some locations do not get any benefit from camera installations [61]. In another study, Welsh and Farrington [58] suggest that CCTV works better in well-defined conditions (especially in car parks) than in public places and has the greatest impact on car crime, without having any impact on violent crimes.
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The age of new technology has also contributed to the development of methodological, and ethical challenges. For example, Ceccato [62] emphasized on what happens in public space is getting new expressions, for example, the role of guardians in surveillance has been redefined. “Eyes on the streets” by Jane Jacob [36] is complemented by “apps on streets” [62]. Ceccato explored the concept of surveillance and related terms by evaluating the nature of the data captured by users of an incident-reporting app. Results from this study suggest that the app is often used to report a crime, mostly in residential areas (as opposed to inner-city areas). Findings also indicate that data from a survey of app users can rarely represent the actual population of those using the tool, or the population residing and working in these areas [62]. While exploring spatial patterns of guardianship through civic technology platforms at the level of neighborhood units in England, Solymosi [63] found that it is possible to make use of civic tech data to explore people’s engagement in guardianship and map their guardianship capacity in physical space by using digital traces of behavior available online, however, there are limitations associated with crowdsourced data as they are characterized by bias sample self-selection as well as participation inequality [62] also highlighted technological, legal, institutional, ethical, and cultural—that limits the use of apps/smartphones for planning purposes. The author emphasized that the issues of data privacy, the responsibility of actions (e.g., intervening) and accountability should be addressed before data of this kind is used [62]. So what makes a public place inclusive, safe and resilient from the socio-technological perspective? Beginning from the installation of appropriate street lighting sensors, alarms to CCTV, using smart mobile phones to location-based services, and reporting crimes digitally to crowdsource data reporting various surveillance techniques can work in both ways as they increase the sense of security, and at the same time creates certain worries among people.
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5. Fear of crime and perceived safety in Stockholm, Sweden
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Stockholm the capital of Sweden, is one of the green and also one of the safest cities in Europe and the world. Stockholm is chosen as the case study area for several reasons. First, Stockholm is built in between and around plenty of parks and natural green open spaces (Figure 2 shows 1,046 parks and green spaces in Stockholm For more detail, see [64]). Second, little research has been done to know the relation between crimes in parks and public spaces in Stockholm [9, 10, 11].
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Figure 2.
Public green areas in Stockholm. Source: [2].
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According to the Swedish National Council for Crime Prevention [2], a total of 31 percent of the population (aged 16–84) state that they feel very unsafe or quite unsafe when outdoors alone at night or that they avoid going out alone at night due to the feeling of being unsafe in Stockholm. In particular, Women (42%), complained of feeling unsafe than men (20%). In 2020, 28 percent of the population (aged 16–84) state that they often have chosen another route or another mode of transport as a result of concern about being a victim of crime, while 15 percent have avoided doing an activity often as a result of this concern. Lastly, 10 percent state that their quality of life is affected as a result of being concerned about being a victim of crime in Stockholm [2].
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At a macro scale, field survey observations in a pilot study in 2011 were conducted by the author at twenty-five parks in Stockholm [13]. The main aim behind the fieldwork was to understand the nature of parks and to categorize them as either ‘amenities’ or ‘disamenities’ according to the attributes that exist in the park. During the study, the author investigated activities/functions, aesthetical features, location and management (crime, the safety and security situation) as the main categories. All parks were inspected at two different periods of the year (winter and the summer of 2011. See [10]). The result of the study shows that Stockholm’s central areas are targeted by different types of crimes, with some parks becoming crime attractors [13, 18]. By investigating the incidence of crime in parks, we found that more serious crimes including violence, drugs, assault and graffiti occurred within Hilly Park and Inner City Parks in Stockholm, however, not all parks have high crimes [10]. Some parks, especially parks with Play Grounds, Parks with Squares and Neighborhood Parks had comparatively low crime rates. Several reasons can justify these trends. For instance, no one can deny the existence of students, coaches and parents —who work as capable guardians and have an important role in perceived safety in such public spaces [10]. These findings are in line with the routine activity theory [41] where such guardians assume personal responsibility to react at such places. However, there have been studies that highlight the fact that capable guardians are not always present [65]. Findings also suggest that easy access to a neat, well-managed, and relatively safe Neighborhood Park is valued more in Stockholm. In addition to this park’s location plays a crucial role. The crime and safety situation of a park is directly linked to the management and design of park, without taking into account park location in the city. For instance, parks located at or near the city center are valued positively as compared with parks located in the city’s periphery [10].
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At a micro-scale, Iqbal and Ceccato [9] studied the nature of a park with high crime rates in Stockholm—‘Tantolunden’. Tantolunden is located in the southern part of central Stockholm, Sweden. Tantolunden was nominated as one of the most dangerous parks, with the topmost violent reported crimes in Stockholm [66]. Regarding the effectiveness of CPTED in parks and public spaces, a detailed inventory was developed based on CPTED principles [9]. Sweden like its other neighboring Scandinavian countries was quite late to adopt such an initiative that incorporates the CPTED principle [67]. New sustainable housing was built by using CPTED principles in design and planning [67]. Stockholm police with the National housing board in Stockholm launched the most famous strategical document BoTryggt05 in 2005 that was about the inclusion of CPTED measures in housing construction guidelines. In 2017 Stockholm has adopted a strategy for “Greener Stockholm” that provides guidelines for planning, implementation and management of the city’s parks and nature areas in Stockholm. The main agenda is to highlight the importance of a safe and equal urban environment to promote perceived safety and social cohesion among all groups of people in Stockholm. Well-designed and illuminated squares, streets, sidewalks, parks and playgrounds were highlighted as important measures for the increased experience of safety in the document. However, still, these principles are not being used as the standards in Sweden. For instance, while implying these guidelines, Stockholm park plan documents for individual districts in Stockholm mainly show concern about missing lights and overgrown bushes and trees. No more information at a deeper level has been provided (for details see park plan of each specific area [68]). Recently, BoTryggt 2030 has been launched — that claimed as a tool for building safer cities that covers not only housing but also neighborhoods, public space, commercial places and more to respond to today’s holistic approach in urban planning [69]. To understand authorities’ point of view on the use of CPTED principles and collaborative planning in this large nature area park, a questionnaire was sent by e-mail to the park manager and a crime prevention coordinator working in Stockholm municipality. Findings from the questionnaire suggest that safety guidelines that are used in Stockholm are not categorized under the CPTED umbrella yet. These results are in line with the previous findings that CPTED has not been used in its full capacity as it is used in other parts of the world [66]. A policy recommendation on incorporating CPTED principles could be derived from these results.
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A great deal of CPTED is mainly about increasing natural surveillance, protecting targets, access control and creating environments that encourage activities that can help to limit crimes. CPTED also helps to focus on criminal activity patterns. If compared to the other similar Hilly Parks in Stockholm such as Vitabergsparken, Kronobergsparken and Vanadislunden, Tantolunden still stays at the topmost reported crimes [70]. According to police statistics [70], vandalism is still the topmost reported crime in Tantoulnden between 2017 and 2019 following narcotics and theft that happens mostly in the afternoon and evenings (see Figure 3). The authors found that parks that have large nature areas may have in-between spaces that transform into desolate spaces and, as a consequence, have the potential to attract litter and graffiti that may affect inhabitants negatively [10]. These desolate spaces are also perceived as obstacles to access to other parts of the city. Some of these large-area nature parks are not easy to maintain, and they adopt an atmosphere of disorder and affect negatively [9]. These results are in line with the previous findings of the cyclic relationship between perceived safety and disorder [23, 49]. It has been suggested that a well-maintained park with a sense of belonging among residents and park users can create a positive image [8].
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Figure 3.
Reported crimes per crime hour in Tantolunden Park (2017–2020). (Source: [70]).
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Results from the interview showed how residents feel about the safety conditions of this large area nature park [9]. A total of four interviews were conducted with park users (two males and two females aged 18–40 years). All of the interviewees showed concern for the presence of the so-called “illegitimate” park users [18] such as homeless individuals, alcoholics/drug users). All of them pointed out that public toilets in the park are frequently being used by illegitimate users [9]. This study also concludes that crime in parks must be considered in perspective with crimes in the neighboring areas because any park with high crime rates is usually associated with high crime rates in the surrounding area [11].
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Regarding the socio-technical perspective, neither CCTV cameras nor security guards were found in this large nature area park at the time of field inspection (for instance., see details [9]). This can be associated with the Swedish government policies that require authorization to install CCTV cameras. That also put a limitation on the general use of CCTV cameras in parks and other public spaces. Several researchers found that implementation of technical systems and tools such as CCTV cameras can affect criminal activities in urban parks [59], however, it has been also suggested that “none of these measures could reduce all crimes but each may work for a specific offense category and cumulatively lead to an overall crime reduction” [71].
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6. Conclusions and recommendation
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Fear of crime has been regarded as a significant social problem in urban areas. As Rezvani and Sadra [5] stated, “the presence of fear of crime in urban environment shows troubles of communities in the modern age” [5]. The ability to be in a park or public space without being fearful is regarded as an individual right and important for the quality of life in a city. The previous discussion shows being safe in a city is such a broad concept that it is not just associated with the actual crimes, many dimensions of the perceived safety that are linked to the built environment should be considered in planning and designing such places to reduce the fear of crime and increase safety. But then which policy or design solutions can create a sense of safety? Which physical attributes discourage crimes in public spaces? Based on the previous discussion, this section provides some of the general policy and design recommendations for being safe in the public space that should be applicable to other major cities of Sweden or cities similar to those as Stockholm.
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This book chapter has mainly focused on safety and the influencing physical factors however, other social conditions and factors also play a role in the origin of the crime, and sometimes it is a combination of several factors [52]. Findings suggest that no one can deny the importance of the physical design layout of the parks and public spaces that have an impact on perceived safety. Small area parks and public open spaces with playgrounds are more “preferred” than large nature area parks. Working with the large nature area park’s design can help to remove unused in-between spaces, to reduce criminal activities in parks and public spaces. This can be done by splitting park areas into two or more parts according to the design and its requirement. Introducing new activities also encourages mixed land use or mixed activities/functions that can create the flow of people at different hours of the day. This can also help in providing activity support in terms of new guardianship with more eyes on the streets [36]. In contrast, other environmental characteristics in parks, such as maintenance and management of trees and bushes, access control, installation of CCTV cameras can help to create a positive image of the park. Perception of safety also differs according to the time of the day and the presence of more street lights can contribute to the feeling of being safe in a public space.
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A way forward, for the implementation of safety and security guidelines in public spaces in Stockholm, is the creation of programs that highlights the implementation of CPTED principles guidelines in public space. Such practices should be encouraged as good practices designed with people not for people and should be showcase as successful and appropriate approaches. Another important issue is to think about the implementation of CPTED’s appropriateness to ensure safety on a global scale for instance, in other continents. What CPTED can do to create safer cities must also be complemented by other social sustainability measures. CPTED provides tools and good conditions for reducing crime, however, the active participation of community members in the process can help to implement safe public spaces in Stockholm and to maintain them in the longer term. This way public space can work to empower people and a prospect to create social capital.
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Creating safe and sustainable cities requires inclusive and collaborative planning between different actors both at the national and the local level [54]. We can create long-term safe and sustainable cities with the help of strategic planning by including social sustainability besides the economic one [72]. For achieving socially sustainable cities and thus also safe cities, the role at the municipal level is extremely important. As per discussion in the previous section, there are many legal and social restrictions associated with such socio-technological systems that put limitations to their use (such as the need for approval to install CCTV cameras in public places). To improve the image of the park or public space an interface between all stakeholders can create a sense of attachment. Following this, it is also important to understand that new solutions demand new forms of policy formation and collaboration. For instance, about the use of technological systems and equipment. It has long been suggested that risks are attached to human activities and managing and controlling these risks has been built on the experience of generation [73]. Similarly, using these technological systems in creating safe cities is not free from risks, for example, techno trash, pollution, malware, and hacking and privacy issues. It is high time to think of other solutions for producing circular and resilient places.
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Public spaces have played an important role in building resilience in the cities. Can we promote a positive urban transition where we design our public spaces in a way that supports better resilience and thus creating sustainable cities? In quest of finding an answer to the above question, this book chapter suggests that despite their intangible and immaterial nature overall, parks and public spaces affect positively and investing in the safety of public spaces does not only affects the quality of a place but also increases the quality of life as a whole because safety is an important indicator of overall social health [5] and quality of life [2]. However, the outcomes of this investment depend on the types of public space and the types of crime that are committed at or near the place. It is important to remember that if these physical designs and improvements will be implemented in public spaces, it does not mean that the crimes will disappear completely. Continuous work with all stakeholders involved and getting to the depth of what causes these crimes is equally important. These findings are important for different groups of people: individual citizens who use such public places in their daily life, police and other safety experts who work with these issues in the city, researchers and practitioners who are involved in the process of creating the safe, sustainable and resilient cities.
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Acknowledgments
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Part of this research was undertaken under the supervision of Prof. Vania Ceccato while the author was a student at the School of Architecture and the Built Environment, KTH Royal Institute of Technology, Sweden. The author would like to express her thanks to Mikael Blomgren from Stockholm police for providing the current dataset used in this analysis. Special thanks go to Roya Bamzar and the editors of this book for their valuable feedback.
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\n',keywords:"Public spaces, perceived safety, fear of crime, sustainable cities",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76318.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76318.xml",downloadPdfUrl:"/chapter/pdf-download/76318",previewPdfUrl:"/chapter/pdf-preview/76318",totalDownloads:343,totalViews:0,totalCrossrefCites:3,dateSubmitted:"November 25th 2020",dateReviewed:"March 22nd 2021",datePrePublished:"April 16th 2021",datePublished:null,dateFinished:"April 16th 2021",readingETA:"0",abstract:"The rapid urbanization process of cities is majorly coupled with extreme climate change, housing shortage and urban safety issues. These issues are raising new challenges to address the capability of urban resilience. Enhancing Urban Safety and Security is one of the major principles addressed by UN-Habitat in Sustainable Development Goal number 11. Making cities safe and sustainable means ensuring access to safe and affordable public spaces for all. This book chapter aims to highlight how do the city’s public spaces are linked and affected by crime and fear of crime? How do crime and fear of crime interconnect to the built environment in cities while promoting positive urban transitions in terms of safe and sustainable cities? This book chapter explores answers to these questions through the parks and public spaces of the city as a case study. In other words, the book chapter deals with the issue of safety and security by (1) showing links between parks and public spaces, and crime and fear of crime, (2) highlighting how different attributes in the built environment can affect people’s perception of safety, (3) understanding socio-technical perspectives i.e., how technological systems and equipment’s (such as lighting sensors, security alarms, security electronic devices, closed-circuit television (CCTV), smartphones or other technological instruments) are influencing safety/security and sustainability, (4) demonstrating the issues and challenges found in Stockholm, Sweden, and, (5) providing recommendations on how these places can be planned and designed to become more sustainable.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76318",risUrl:"/chapter/ris/76318",signatures:"Asifa Iqbal",book:{id:"10811",type:"book",title:"Urban Transition - Perspectives on Urban Systems and Environments",subtitle:null,fullTitle:"Urban Transition - Perspectives on Urban Systems and Environments",slug:null,publishedDate:null,bookSignature:"Ph.D. Marita Wallhagen and Dr. Mathias Cehlin",coverURL:"https://cdn.intechopen.com/books/images_new/10811.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83962-413-1",printIsbn:"978-1-83962-412-4",pdfIsbn:"978-1-83962-414-8",isAvailableForWebshopOrdering:!0,editors:[{id:"337569",title:"Ph.D.",name:"Marita",middleName:null,surname:"Wallhagen",slug:"marita-wallhagen",fullName:"Marita Wallhagen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Fear of crime and perceived safety in public spaces",level:"1"},{id:"sec_3",title:"3. Fear of crime and perceived safety: physical design perspective",level:"1"},{id:"sec_4",title:"4. Fear of crime and perceived safety: a socio-technical perspective",level:"1"},{id:"sec_5",title:"5. Fear of crime and perceived safety in Stockholm, Sweden",level:"1"},{id:"sec_6",title:"6. Conclusions and recommendation",level:"1"},{id:"sec_7",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\nUN. Transforming our world: the 2030 Agenda for Sustainable Development. A/RES/70/1 2015 [cited 2021 25 January]; Available from: https://www.refworld.org/docid/57b6e3e44.html\n\n'},{id:"B2",body:'\nThe Swedish National Council for Crime Prevention, B. National Security Survey 2020 [Swedish Crime Survey 2020]. 2020 [cited 2021 10 Feb-]; Available from: https://www.bra.se/ntu-skapa-din-tabell.\n'},{id:"B3",body:'\nDu Plessis, C., The links between crime prevention and sustainable development. Open House International, 1999. 24: p. 33-40.\n'},{id:"B4",body:'\nUN-Habitat, Enhancing urban safety and security: Global report on human settlements 2007. 2012: Routledge.\n'},{id:"B5",body:'\nRezvani, M. and Y. Sadra, Sociological Explanation of Fear of Crime in Public Spaces Case Study Mashhad. 2017.\n'},{id:"B6",body:'\nRuijsbroek, A., et al., Social safety, general health and physical activity: changes in neighbourhood safety and the role of social cohesionAnnemarie Ruijsbroek. European Journal of Public Health, 2014. 24(suppl_2).\n'},{id:"B7",body:'\nCeccato, V. and R. Peterson, Trygg stadsmiljö i praktiken: Visioner, exempel & tips. 2019, KTH Royal Institute of Technology.\n'},{id:"B8",body:'\nIqbal, A., Park Matters: Studies on Safety and Property Values. 2017, KTH Royal Institute of Technology.\n'},{id:"B9",body:'\nIqbal, A. and V. Ceccato, Is CPTED useful to guide the inventory of safety in parks? A study case in Stockholm, Sweden. International criminal justice review, 2016. 26(2): p. 150-168.\n'},{id:"B10",body:'\nIqbal, A. and V. Ceccato, Does crime in parks affect apartment prices? Journal of Scandinavian Studies in Criminology and Crime Prevention, 2015. 16(1): p. 97-121.\n'},{id:"B11",body:'\nIqbal, A. and M. Wilhelmsson, Park proximity, crime and apartment prices. International Journal of Housing Markets and Analysis, 2018.\n'},{id:"B12",body:'\nIqbal, A., How safe are women-only parks perceived to be? Security Journal, 2018. 31(4): p. 859-881.\n'},{id:"B13",body:'\nIqbal, A., Property values, parks and crime: A hedonic analysis in Stockholm, Sweden, in Department of Urban Planning and Environment, Division of Urban and Regional Studies. 2012, The Royal Institute of Technology: Stockholm.\n'},{id:"B14",body:'\nCeccato, V. and M.K. Nalla, Crime and fear in public places: an introduction to the special issue. 2020, Taylor & Francis.\n'},{id:"B15",body:'\nCostamagna, F., R. Lind, and O. Stjernström, Livability of urban public spaces in northern Swedish cities: The case of Umeå. Planning Practice & Research, 2019. 34(2): p. 131-148.\n'},{id:"B16",body:'\nChiesura, A., The role of urban parks for the sustainable city. Landscape and urban planning, 2004. 68(1): p. 129-138.\n'},{id:"B17",body:'\nTandogan, O. and B.S. Ilhan, Fear of crime in public spaces: From the view of women living in cities. Procedia Engineering, 2016. 161: p. 2011-2018.\n'},{id:"B18",body:'\nKnutsson, J., Restoring public order in a city park. Policing for prevention: Reducing crime, public intoxication and injury, 1997. 7: p. 133-151.\n'},{id:"B19",body:'\nTroy, A. and J.M. Grove, Property values, parks, and crime: A hedonic analysis in Baltimore, MD. Landscape and urban planning, 2008. 87(3): p. 233-245.\n'},{id:"B20",body:'\nFarrall, S., E. Gray, and J. Jackson, Theorising the fear of crime: The cultural and social significance of insecurities about crime. Experience & expression in the fear of crime working paper, 2007(5).\n'},{id:"B21",body:'\nCeccato, V., The urban fabric of crime and fear, in The urban fabric of crime and fear. 2011, Springer. p. 1-33.\n'},{id:"B22",body:'\nShaw, C.R. and H.D. McKay, Juvenile delinquency and urban areas. 1942: University of Chicago Press.\n'},{id:"B23",body:'\nWilson, J.Q. and G.L. Kelling, Broken windows. Atlantic monthly, 1982. 249(3): p. 29-38.\n'},{id:"B24",body:'\nFuredi, F., The changing meaning of disaster. Area, 2007. 39(4): p. 482-489.\n'},{id:"B25",body:'\nMadge, C., Public parks and the geography of fear. Tijdschrift voor economische en sociale geografie, 1997. 88(3): p. 237-250.\n'},{id:"B26",body:'\nBell, W., Women and community safety. Safer Communities: Strategic Direction in Urban Planning, 1998: p. 10-11.\n'},{id:"B27",body:'\nArjmand, R., Public urban space, gender and segregation: Women-only urban parks in Iran. 2016: Taylor & Francis.\n'},{id:"B28",body:'\nHilinski, C.M., K.E. Pentecost Neeson, and H. Andrews, Explaining the Fear of Crime Among College Women, in their own Words. Southwest Journal of Criminal Justice, 2011. 8(1).\n'},{id:"B29",body:'\nMadriz, E.I., Images of criminals and victims: A study on women\'s fear and social control. Gender & Society, 1997. 11(3): p. 342-356.\n'},{id:"B30",body:'\nGardner, C.B., Passing by: Gender and public harassment. 1995: Univ of California Press.\n'},{id:"B31",body:'\nOlsson, S., Stadens attraktivitet och det offentliga stadslivet. 2000.\n'},{id:"B32",body:'\nClarke, R.V.G., Situational crime prevention: Successful case studies. 1992.\n'},{id:"B33",body:'\nEkblom, P., Crime prevention, security and community safety using the 5Is framework. 2010: Springer.\n'},{id:"B34",body:'\nJeffery, C.R., Crime prevention through environmental design. American Behavioral Scientist, 1971. 14(4): p. 598-598.\n'},{id:"B35",body:'\nNewman, O., Defensible space. 1972: Macmillan New York.\n'},{id:"B36",body:'\nJacobs, J., The Death and Life of Great American Cities. 1961, New York: Vintage Books.\n'},{id:"B37",body:'\nCarmona, M., et al., Public places, urban spaces: the dimensions of urban design. 2010: Routledge.\n'},{id:"B38",body:'\nThani, S.K.S.O., N.H.M. Hashim, and W.H.W. Ismail, Surveillance by Design: Assessment using principles of Crime Prevention through Environmental Design (CPTED) in urban parks. Procedia-social and behavioral sciences, 2016. 234: p. 506-514.\n'},{id:"B39",body:'\nAppleton, J., Prospects and refuges re-visited. Landscape Journal, 1984. 3(2): p. 91-103.\n'},{id:"B40",body:'\nDosen, A.S. and M.J. Ostwald, Evidence for prospect-refuge theory: a meta-analysis of the findings of environmental preference research. City, territory and architecture, 2016. 3(1): p. 1-14.\n'},{id:"B41",body:'\nCohen, L.E. and M. Felson, Social change and crime rate trends: A routine activity approach. American sociological review, 1979: p. 588-608.\n'},{id:"B42",body:'\nSohn, D.-W., Residential crimes and neighbourhood built environment: Assessing the effectiveness of crime prevention through environmental design (CPTED). Cities, 2016. 52: p. 86-93.\n'},{id:"B43",body:'\nGroff, E. and E.S. McCord, The role of neighborhood parks as crime generators. Security journal, 2012. 25(1): p. 1-24.\n'},{id:"B44",body:'\nMichael, S.E., R.B. Hull, and D.L. Zahm, Environmental factors influencing auto burglary: A case study. Environment and Behavior, 2001. 33(3): p. 368-388.\n'},{id:"B45",body:'\nBogacka, E., The case of Poznań, Poland. Crime and Fear in Public Places: Towards Safe, Inclusive and Sustainable Cities, 2020: p. 108.\n'},{id:"B46",body:'\nGehl, J., Life Between Buildings Skive. 2006, The Danish Architectural Press.\n'},{id:"B47",body:'\nWhyte, W., The design of spaces. Richard T. LeGates and Frederic Stout (1996) The city reader,(2nd ed). New York: Routledge, 1988.\n'},{id:"B48",body:'\nSaville, G. and G. Cleveland, Second-generation CPTED. 21st century security and CPTED: Designing for critical infrastructure protection and crime prevention, 2008. 79.\n'},{id:"B49",body:'\nFoster, S., B. Giles-Corti, and M. Knuiman, Does fear of crime discourage walkers? A social-ecological exploration of fear as a deterrent to walking. Environment and Behavior, 2014. 46(6): p. 698-717.\n'},{id:"B50",body:'\nGreen, J., et al., Reduced street lighting at night and health: a rapid appraisal of public views in England and Wales. Health & place, 2015. 34: p. 171-180.\n'},{id:"B51",body:'\nLorenc, T., et al., Fear of crime and the environment: systematic review of UK qualitative evidence. BMC public health, 2013. 13(1): p. 1-8.\n'},{id:"B52",body:'\nSreetheran, M. and C.C.K. Van Den Bosch, A socio-ecological exploration of fear of crime in urban green spaces–A systematic review. Urban Forestry & Urban Greening, 2014. 13(1): p. 1-18.\n'},{id:"B53",body:'\nChepesiuk R., Missing the dark: health effects of light pollution. Environmental health perspectives, 2009. 117(1): p. A20-A27.\n'},{id:"B54",body:'\nAnthony, I., Secure Cities: Inclusivity, Resilience and Safety. 2017.\n'},{id:"B55",body:'\nReynald, D.M., Guardianship and informal social control, in Oxford research encyclopedia of criminology and criminal justice. 2018.\n'},{id:"B56",body:'\nSocha, R. and B. Kogut, Urban Video Surveillance as a Tool to Improve Security in Public Spaces. Sustainability, 2020. 12(15): p. 6210.\n'},{id:"B57",body:'\nKoskela, H., Video surveillance, gender, and the safety of public urban space:" Peeping Tom" goes high tech? Urban Geography, 2002. 23(3): p. 257-278.\n'},{id:"B58",body:'\nWelsh, B.C. and D.P. Farrington, Evidence-based crime prevention: The effectiveness of CCTV. Crime Prevention and Community Safety, 2004. 6(2): p. 21-33.\n'},{id:"B59",body:'\nMcCormick, J.G. and S.M. Holland, Strategies in use to reduce incivilities, provide security and reduce crime in urban parks. Security Journal, 2015. 28(4): p. 374-391.\n'},{id:"B60",body:'\nSurette, R. and M. Stephenson, Expectations versus effects regarding police surveillance cameras in a municipal park. Crime Prevention and Community Safety, 2019. 21(1): p. 22-41.\n'},{id:"B61",body:'\nRatcliffe, J., Video surveillance of public places. 2006: Citeseer.\n'},{id:"B62",body:'\nCeccato, V., Eyes and apps on the streets: From surveillance to sousveillance using smartphones. Criminal Justice Review, 2019. 44(1): p. 25-41.\n'},{id:"B63",body:'\nSolymosi, R., Exploring spatial patterns of guardianship through civic technology platforms. Criminal Justice Review, 2019. 44(1): p. 42-59.\n'},{id:"B64",body:'\nCity, S., Stockholms parkprogram-Stockholm: Kommunfullmäktige (City of Stockholm, Stockholm park programs—Stockholm: City Council). Retrieved June, 2006. 10: p. 2011.\n'},{id:"B65",body:'\nPiza, E. and D. Kennedy, Transit stops, robbery, and routine activities: Examining street robbery in the Newark, NJ subway environment. Crime Mapping, Dr. Kennedy, 2003.\n'},{id:"B66",body:'\nJennicshe, A., Tantolunden stans farligaste park, in Mitt i Södermalm. 2011: Stockholm.\n'},{id:"B67",body:'\nGrönlund, B., Is hammarby sjöstad a model case? Crime prevention through environmental design in Stockholm, Sweden, in The urban fabric of crime and fear. 2011, Springer. p. 283-310.\n'},{id:"B68",body:'\nStockholm, C.o. Natur, parker och grönområden. 2020 [cited 2020 25th January]; Available from: https://start.stockholm/om-stockholms-stad/sa-arbetar-staden/natur-parker-och-gronomraden/.\n'},{id:"B69",body:'\nBoTryggt2030. BoTryggt2030 – handboken för planering av säkra och trygga. 2020 [cited 2021 1st Feb.]; Available from: https://botryggt.se/english/.\n'},{id:"B70",body:'\nstatistics, P., Crime statistics. Retrieved from Stockholm police headquarters Web site. 2020.\n'},{id:"B71",body:'\nTilley, N., Community, security and distributive justice, in The urban fabric of crime and fear. 2011, Springer. p. 267-282.\n'},{id:"B72",body:'\nUNDP, Human Development Report 2015. 2015: New York.\n'},{id:"B73",body:'\nSjöberg, L. and T. Thedéen, Reflections on risks and technology, in Risks in technological systems. 2010, Springer. p. 7-17.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Asifa Iqbal",address:"asifa.iqbal@hig.se",affiliation:'
University of Gävle, Gävle, Sweden
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
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This is an emerging area of research that is of high relevance to researchers and clinicians interested in body image and appearance concerns.",book:{id:"5925",slug:"perception-of-beauty",title:"Perception of Beauty",fullTitle:"Perception of Beauty"},signatures:"Jennifer S. Mills, Amy Shannon and Jacqueline Hogue",authors:[{id:"202110",title:"Dr.",name:"Jennifer S.",middleName:null,surname:"Mills",slug:"jennifer-s.-mills",fullName:"Jennifer S. Mills"}]},{id:"59227",doi:"10.5772/intechopen.73385",title:"Differentiating Normal Cognitive Aging from Cognitive Impairment No Dementia: A Focus on Constructive and Visuospatial Abilities",slug:"differentiating-normal-cognitive-aging-from-cognitive-impairment-no-dementia-a-focus-on-constructive",totalDownloads:1353,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Constructive and visuospatial abilities in normal and in pathological aging (cognitive impairment, no dementia, CIND) are investigated. The sample includes 188 participants over 60 years of age, divided in 2 groups: healthy subjects (MMSE ≥28), without cognitive complaints, and individuals with CIND (MMSE between 24 and 27 and subjective cognitive complains). Drawing of cube and drawing of house, Benton Visual Retention Test (BVRT), and Block design are used to test the hypothesis that short visuoconstructive and visuospatial tests can distinguish normal from pathological cognitive aging in its very early stages. Results proved the discriminative sensitivity of BVRT general assessment criteria and of omissions and distortions in CIND. The diagnostic sensitivity of a modification of Moore and Wike [1984] scoring system for house and cube drawing tasks was confirmed as well. Drawing of cube and house could be used for quick screening of CIND in subjects over 60. Principal component analysis with oblimin rotation was performed to explore the different dimensions in the visuospatial and visuoconstructive abilities in old age. A four-factor structure was established, all four factors explaining 71% of the variance.",book:{id:"6381",slug:"gerontology",title:"Gerontology",fullTitle:"Gerontology"},signatures:"Radka Ivanova Massaldjieva",authors:[{id:"75907",title:"Associate Prof.",name:"Radka Ivanova",middleName:null,surname:"Massaldjieva",slug:"radka-ivanova-massaldjieva",fullName:"Radka Ivanova Massaldjieva"}]},{id:"59658",doi:"10.5772/intechopen.74748",title:"Ageing Better in the Netherlands",slug:"ageing-better-in-the-netherlands",totalDownloads:1193,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"The Dutch National Care for the Elderly Programme was an initiative organized by the Netherlands Organisation for Health Research and Development (ZonMw) between 2008 and 2016. The aim of the programme was to collect knowledge about frail elderly, to assess their needs and to provide person-centred and integrated care better suited to their needs. The budget of EUR 88 million was provided by the Dutch Ministry of Health, Welfare and Sports. Putting the needs of elderly people at the heart of the programme and ensuring their active participation were key to the programme’s success. The programme outcomes included the establishment of eight geriatric networks around the medical universities with 650 organisations and the completion of 218 projects. These projects, involving 43,000 elderly people and 8500 central caregivers, resulted in the completion of 45 PhD theses and the publication of more than 400 articles and the development of 300 practice toolkits, one database and a website, www.beteroud.nl. The Dutch National Care for the Elderly Programme has since developed into a movement and continues under the consortium Ageing Better, made up of eight organisations. Through the use of ambassadors, Ageing Better promotes the message that ageing is not a disease but a new phase of life.",book:{id:"6381",slug:"gerontology",title:"Gerontology",fullTitle:"Gerontology"},signatures:"Betty Meyboom-de Jong, Klaske Wynia and Anjo Geluk-Bleumink",authors:[{id:"224997",title:"Emeritus Prof.",name:"Betty",middleName:null,surname:"Meyboom-De Jong",slug:"betty-meyboom-de-jong",fullName:"Betty Meyboom-De Jong"},{id:"232900",title:"Dr.",name:"Klaske",middleName:null,surname:"Wynia",slug:"klaske-wynia",fullName:"Klaske Wynia"},{id:"232901",title:"Mrs.",name:"Anjo",middleName:null,surname:"Geluk-Bleumink",slug:"anjo-geluk-bleumink",fullName:"Anjo Geluk-Bleumink"}]},{id:"55890",doi:"10.5772/intechopen.69529",title:"Mindfulness Meditation and the Perception of Beauty: Implications for an Ecological Well-Being",slug:"mindfulness-meditation-and-the-perception-of-beauty-implications-for-an-ecological-well-being",totalDownloads:1428,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Meditation is a first-person method for contemplating ourselves and the world, with more than 2500 years of history, rooted in the philosophical and contemplative traditions of the east. The present chapter aims to explore this worldview in order to demonstrate its relevance to our capacity for the appreciation of beauty. To this end, the aesthetic experience, the contemplative experience and their relationship with the practice of mindfulness are analysed. We suggest that the contemplative meditative experience bestows a state of consciousness and acceptance of life which places the practitioner in a progressive encounter with a self-concept that begins to detach from a static sense of the self and from the categories that define it, so that it may be experienced as an ongoing mental event, removed from cultural ideals of beauty or positivity. The result of this de-identification from the static self is a greater degree of psychological flexibility and a more genuine way of seeing the world, leading to a new perception of the self that is connected to an experience of freedom, and contributes to one’s own well-being, as well as to that of others and of the environment.",book:{id:"5925",slug:"perception-of-beauty",title:"Perception of Beauty",fullTitle:"Perception of Beauty"},signatures:"Álvaro I. Langer, Carlos Schmidt and Edwin Krogh",authors:[{id:"199843",title:"Dr.",name:"Álvaro",middleName:null,surname:"Langer",slug:"alvaro-langer",fullName:"Álvaro Langer"},{id:"201865",title:"MSc.",name:"Carlos",middleName:null,surname:"Schmidt",slug:"carlos-schmidt",fullName:"Carlos Schmidt"},{id:"201866",title:"Dr.",name:"Edwin",middleName:null,surname:"Krogh",slug:"edwin-krogh",fullName:"Edwin Krogh"}]}],mostDownloadedChaptersLast30Days:[{id:"60564",title:"Ageing Process and Physiological Changes",slug:"ageing-process-and-physiological-changes",totalDownloads:6996,totalCrossrefCites:19,totalDimensionsCites:34,abstract:"Ageing is a natural process. Everyone must undergo this phase of life at his or her own time and pace. In the broader sense, ageing reflects all the changes taking place over the course of life. These changes start from birth—one grows, develops and attains maturity. To the young, ageing is exciting. Middle age is the time when people notice the age-related changes like greying of hair, wrinkled skin and a fair amount of physical decline. Even the healthiest, aesthetically fit cannot escape these changes. Slow and steady physical impairment and functional disability are noticed resulting in increased dependency in the period of old age. According to World Health Organization, ageing is a course of biological reality which starts at conception and ends with death. It has its own dynamics, much beyond human control. However, this process of ageing is also subject to the constructions by which each society makes sense of old age. In most of the developed countries, the age of 60 is considered equivalent to retirement age and it is said to be the beginning of old age. In this chapter, you understand the details of ageing processes and associated physiological changes.",book:{id:"6381",slug:"gerontology",title:"Gerontology",fullTitle:"Gerontology"},signatures:"Shilpa Amarya, Kalyani Singh and Manisha Sabharwal",authors:[{id:"226573",title:"Ph.D.",name:"Shilpa",middleName:null,surname:"Amarya",slug:"shilpa-amarya",fullName:"Shilpa Amarya"},{id:"226593",title:"Dr.",name:"Kalyani",middleName:null,surname:"Singh",slug:"kalyani-singh",fullName:"Kalyani Singh"},{id:"243264",title:"Dr.",name:"Manisha",middleName:null,surname:"Sabharwal",slug:"manisha-sabharwal",fullName:"Manisha Sabharwal"}]},{id:"55388",title:"Beauty, Body Image, and the Media",slug:"beauty-body-image-and-the-media",totalDownloads:7764,totalCrossrefCites:5,totalDimensionsCites:12,abstract:"This chapter analyses the role of the mass media in people’s perceptions of beauty. We summarize the research literature on the mass media, both traditional media and online social media, and how they appear to interact with psychological factors to impact appearance concerns and body image disturbances. There is a strong support for the idea that traditional forms of media (e.g. magazines and music videos) affect perceptions of beauty and appearance concerns by leading women to internalize a very slender body type as ideal or beautiful. Rather than simply being passive recipients of unrealistic beauty ideals communicated to them via the media, a great number of individuals actually seek out idealized images in the media. Finally, we review what is known about the role of social media in impacting society’s perception of beauty and notions of idealized physical forms. Social media are more interactive than traditional media and the effects of self‐presentation strategies on perceptions of beauty have just begun to be studied. This is an emerging area of research that is of high relevance to researchers and clinicians interested in body image and appearance concerns.",book:{id:"5925",slug:"perception-of-beauty",title:"Perception of Beauty",fullTitle:"Perception of Beauty"},signatures:"Jennifer S. Mills, Amy Shannon and Jacqueline Hogue",authors:[{id:"202110",title:"Dr.",name:"Jennifer S.",middleName:null,surname:"Mills",slug:"jennifer-s.-mills",fullName:"Jennifer S. Mills"}]},{id:"56505",title:"Aesthetics of the Naked Human Body: From Pornography (Sexualised Lust Object) to Iconography (Aesthetics of Human Nobility and Wisdom) in an Anthropology of Physical Beauty",slug:"aesthetics-of-the-naked-human-body-from-pornography-sexualised-lust-object-to-iconography-aesthetics",totalDownloads:2100,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In many religious circles and philosophies of life, the human body is excluded from the realm of spirituality and meaning. Due to a dualistic approach, nudity is viewed as merely a physical and corporeal category. In social media, there is the real danger that the naked human body is exploited for commercial gain. Advertisements often leave the impression that the body, very specifically the genitals, is designed merely for physical desire and corporeal chemistry. They become easily objects for lust, excluded from the beauty of graceful existence and noble courage. It is argued that the naked human body is not designed for pornographic exploitation and promiscuous sensuality but for compassionate intimacy and nurturing care in order to instil a humane dimension in human and sexual encounters. In this regard, antiquity and the Michelangelesque perspective can contribute to a paradigm shift from abusive exploitation to the beauty of vulnerable sensitivity. In order to foster an integrative approach to theory formation in anthropology, the methodology of stereometric thinking is proposed.",book:{id:"5925",slug:"perception-of-beauty",title:"Perception of Beauty",fullTitle:"Perception of Beauty"},signatures:"Daniel J Louw",authors:[{id:"200645",title:"Prof.",name:"Daniel",middleName:"Johannes",surname:"Louw",slug:"daniel-louw",fullName:"Daniel Louw"}]},{id:"56059",title:"A Plastic Surgeon’s Perspective on Stereotyping and the Perception of Beauty",slug:"a-plastic-surgeon-s-perspective-on-stereotyping-and-the-perception-of-beauty",totalDownloads:1918,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"In the world of plastic surgery, misconceptions may lead to irrational requests or outcomes not appreciated by patients. Those who manage aesthetics should always listen and recognize the variability of cultural identities, desires, attitudes, anxieties and uncertainties of the patient. Emerging from a diversity of cultures and its transforming trends, the scope of cosmetic surgery and its practice reflect not only the individual’s personality, but also the culture as a whole. When counseling an individual, one has to recognize that even in groups of seemingly identical social or cultural standards; there are subtle differences in expectations. To illustrate the potential for inaccuracy of ethnic profiling in the field of plastic surgery authors quote their own work on Asian subjects and facial beauty and resort to experience of others. To reaffirm their opinion and to exemplify how sometimes “fine” differences in the perception of beauty exist, an original study that evaluates the preferences among selected groups of Latina women in respect to buttock aesthetics has been included. This dissertation will focus on how cultural factors influence beauty perception; strengthen the fact that beauty is in the eye of the beholder and how variable differences exist even between small subgroups.",book:{id:"5925",slug:"perception-of-beauty",title:"Perception of Beauty",fullTitle:"Perception of Beauty"},signatures:"Johanna D’Agostino and Marek Dobke",authors:[{id:"17590",title:"Dr.",name:"Marek K.",middleName:null,surname:"Dobke",slug:"marek-k.-dobke",fullName:"Marek K. Dobke"},{id:"201244",title:"Dr.",name:"Johanna",middleName:null,surname:"D'Agostino",slug:"johanna-d'agostino",fullName:"Johanna D'Agostino"}]},{id:"80326",title:"Anti-Senescence Therapy",slug:"anti-senescence-therapy",totalDownloads:110,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The development of therapeutic strategies aimed at the aging process of cells has attracted increasing attention in recent decades due to the involvement of this process in the development of many chronic and age-related diseases. Interestingly, preclinical studies have shown the success of a number of anti-aging approaches in the treatment of a range of chronic diseases. These approaches are directed against aging processes such as oxidative stress, telomerase shortening, inflammation, and deficient autophagy. Many strategies has been shown to be effective in delaying aging, including antiaging strategies based on establishing healthy lifestyle habits and pharmacological interventions aimed at disrupting senescent cells and senescent-associated secretory phenotype. Caloric restriction and intermittent fasting were reported to activate autophagy and reduce inflammation. In turn, immune-based strategies, senolytic agents, and senomorphics mediate their effects either by eliminating senescent cells through inducing apoptosis or by disrupting pathways by which senescent cells mediate their detrimental effects. In addition, given the association of the decline in the regenerative potential of stem cells with aging, many experimental and clinical studies indicate the effectiveness of stem cell transplantation in preventing or slowing the progress of age-related diseases by enhancing the repairing mechanisms and the secretion of many growth factors and cytokines.",book:{id:"10935",slug:null,title:"Mechanisms and Management of Senescence",fullTitle:"Mechanisms and Management of Senescence"},signatures:"Raghad Alshadidi",authors:null}],onlineFirstChaptersFilter:{topicId:"235",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82112",title:"Comparative Senescence and Lifespan",slug:"comparative-senescence-and-lifespan",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.105137",abstract:"The word senescence is derived from the Latin word “senex” (meaning old). In biology, senescence is a process by which a cell ages and permanently stops dividing. Senescence is a natural universal phenomenon affecting all living organisms (e.g., humans, animals, and plants). It is the process of growing old (aging). The underlying mechanisms of senescence and aging at the cellular level are not fully understood. Senescence is a multifactorial process that can be induced by several stimuli including cellular stress, DNA damage, telomere shortening, and oncogene activation. The most popular theory to explain aging is the free radical theory. Senescence plays a role in the development of several age-related chronic diseases in humans (e.g., ischemic heart disease, osteoporosis, and cancer). Lifespan is a biological characteristic of every species. The lifespan of living organisms ranges from few hours (with mayfly) to potential eternity (with jellyfish and hydra). The maximum theoretical lifespan in humans is around 120 years. The lifespan in humans is influenced by multiple factors including genetic, epigenetic, lifestyle, environmental, metabolic, and endocrine factors. There are several ways to potentially extend the lifespan of humans and eventually surpass the maximum theoretical lifespan of 120 years. The tools that can be proposed include lifestyle, reduction of several life-threatening diseases and disabilities, hormonal replacement, antioxidants, autophagy inducers, senolytic drugs, stem cell therapy, and gene therapy.",book:{id:"10935",title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg"},signatures:"Hassan M. Heshmati"},{id:"81638",title:"Aging and Neuropsychiatric Disease: A General Overview of Prevalence and Trends",slug:"aging-and-neuropsychiatric-disease-a-general-overview-of-prevalence-and-trends",totalDownloads:30,totalDimensionsCites:0,doi:"10.5772/intechopen.103102",abstract:"The increasing trend of life-expectancy is becoming a significant demographic, societal and economic challenge. Currently, global number of people above sixty years of age is 900 million, while United Nations expect this number to rise to over 1.4 billion in 2030 and over 2.5 billion by 2050. Concordant to this trend, numerous physiological changes are associated with aging and brain-related ones are associated with neuropsychiatric diseases. The main goal of this chapter is to identify the most important neuropsychiatric diseases to assess in older patients to help to promote health and prevent diseases and complications associated with chronic illness, as these changes are progressive and require important psychological and setting-related social adjustments. Findings identify several health-aspects highly present in elderly: stroke, white matter lesions, dementia rise with age, changes in levels of neurotransmitters and hormones, depression as well as the bereavement following loss of the loved one, and the most common neurodegenerative disease—Alzheimer’s disease and Parkinson’s. In conclusion, studying the aging process should include all developmental, circumstantial, and individual aspects of aging. This offers opportunities to improve the health of elderly by using a wide range of skills and knowledge. Thus, further studies are necessary to elucidate what can be done do to improve the aging process and health of elderly in the future.",book:{id:"10935",title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg"},signatures:"Jelena Milić"},{id:"80326",title:"Anti-Senescence Therapy",slug:"anti-senescence-therapy",totalDownloads:110,totalDimensionsCites:0,doi:"10.5772/intechopen.101585",abstract:"The development of therapeutic strategies aimed at the aging process of cells has attracted increasing attention in recent decades due to the involvement of this process in the development of many chronic and age-related diseases. Interestingly, preclinical studies have shown the success of a number of anti-aging approaches in the treatment of a range of chronic diseases. These approaches are directed against aging processes such as oxidative stress, telomerase shortening, inflammation, and deficient autophagy. Many strategies has been shown to be effective in delaying aging, including antiaging strategies based on establishing healthy lifestyle habits and pharmacological interventions aimed at disrupting senescent cells and senescent-associated secretory phenotype. Caloric restriction and intermittent fasting were reported to activate autophagy and reduce inflammation. In turn, immune-based strategies, senolytic agents, and senomorphics mediate their effects either by eliminating senescent cells through inducing apoptosis or by disrupting pathways by which senescent cells mediate their detrimental effects. In addition, given the association of the decline in the regenerative potential of stem cells with aging, many experimental and clinical studies indicate the effectiveness of stem cell transplantation in preventing or slowing the progress of age-related diseases by enhancing the repairing mechanisms and the secretion of many growth factors and cytokines.",book:{id:"10935",title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg"},signatures:"Raghad Alshadidi"},{id:"79828",title:"Cellular Senescence in Bone",slug:"cellular-senescence-in-bone",totalDownloads:119,totalDimensionsCites:0,doi:"10.5772/intechopen.101803",abstract:"Senescence is an irreversible cell-cycle arrest process induced by environmental, genetic, and epigenetic factors. An accumulation of senescent cells in bone results in age-related disorders, and one of the common problems is osteoporosis. Deciphering the basic mechanisms contributing to the chronic ailments of aging may uncover new avenues for targeted treatment. This review focuses on the mechanisms and the most relevant research advancements in skeletal cellular senescence. To identify new options for the treatment or prevention of age-related chronic diseases, researchers have targeted hallmarks of aging, including telomere attrition, genomic instability, cellular senescence, and epigenetic alterations. First, this chapter provides an overview of the fundamentals of bone tissue, the causes of skeletal involution, and the role of cellular senescence in bone and bone diseases such as osteoporosis. Next, this review will discuss the utilization of pharmacological interventions in aging tissues and, more specifically, highlight the role of senescent cells to identify the most effective and safe strategies.",book:{id:"10935",title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg"},signatures:"Danielle Wang and Haitao Wang"},{id:"79668",title:"Identification of RNA Species That Bind to the hnRNP A1 in Normal and Senescent Human Fibroblasts",slug:"identification-of-rna-species-that-bind-to-the-hnrnp-a1-in-normal-and-senescent-human-fibroblasts",totalDownloads:81,totalDimensionsCites:0,doi:"10.5772/intechopen.101525",abstract:"hnRNP A1 is a member of the hnRNPs (heterogeneous nuclear ribonucleoproteins) family of proteins that play a central role in regulating genes responsible for cell proliferation, DNA repair, apoptosis, and telomere biogenesis. Previous studies have shown that hnRNPA1 had reduced protein levels and increased cytoplasmic accumulation in senescent human diploid fibroblasts. The consequence of reduced protein expression and altered cellular localization may account for the alterations in gene expression observed during senescence. There is limited information for gene targets of hnRNP A1 as well as its in vivo function. In these studies, we performed RNA co-immunoprecipitation experiments using hnRNP A1 as the target protein to identify potential mRNA species in ribonucleoprotein (RNP) complexes. Using this approach, we identified the human double minute 2 (HDM2) mRNA as a binding target for hnRNP A1 in young and senescent human diploid fibroblasts cells. It was also observed that alterations of hnRNP A1 expression modulate HDM2 mRNA levels in young IMR-90 cells. We also demonstrated that the levels of HDM2 mRNA increased with the downregulation of hnRNP A1 and decrease with the overexpression of hnRNP A1. Although we did not observe a significant decrease in HDM2 protein level, a concomitant increase in p53 protein level was detected with the overexpression of hnRNP A1. Our studies also show that hnRNP A1 directly interacts with HDM2 mRNA at a region corresponding to its 3′ UTR (untranslated region of a gene). The results from this study demonstrate that hnRNP A1 has a novel role in participating in the regulation of HDM2 gene expression.",book:{id:"10935",title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg"},signatures:"Heriberto Moran, Shanaz A. Ghandhi, Naoko Shimada and Karen Hubbard"},{id:"79295",title:"Genetic and Epigenetic Influences on Cutaneous Cellular Senescence",slug:"genetic-and-epigenetic-influences-on-cutaneous-cellular-senescence",totalDownloads:136,totalDimensionsCites:0,doi:"10.5772/intechopen.101152",abstract:"Skin is the largest human organ system, and its protective function is critical to survival. The epithelial, dermal, and subcutaneous compartments are heterogeneous mixtures of cell types, yet they all display age-related skin dysfunction through the accumulation of an altered phenotypic cellular state called senescence. Cellular senescence is triggered by complex and dynamic genetic and epigenetic processes. A senescence steady state is achieved in different cell types under various and overlapping conditions of chronological age, toxic injury, oxidative stress, replicative exhaustion, DNA damage, metabolic dysfunction, and chromosomal structural changes. These inputs lead to outputs of cell-cycle withdrawal and the appearance of a senescence-associated secretory phenotype, both of which accumulate as tissue pathology observed clinically in aged skin. This review details the influence of genetic and epigenetic factors that converge on normal cutaneous cellular processes to create the senescent state, thereby dictating the response of the skin to the forces of both intrinsic and extrinsic aging. From this work, it is clear that no single biomarker or process leads to senescence, but that it is a convergence of factors resulting in an overt aging phenotype.",book:{id:"10935",title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg"},signatures:"Tapash Jay Sarkar, Maiko Hermsmeier, Jessica L. Ross and G. Scott Herron"}],onlineFirstChaptersTotal:6},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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"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"}}}},{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"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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