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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"6258",leadTitle:null,fullTitle:"Cognitive Behavioral Therapy and Clinical Applications",title:"Cognitive Behavioral Therapy and Clinical Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"The main purpose of this book is to be useful in daily practice to clinicians, including less-discussed subjects that are frequently encountered in practice. 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\r\n\tIn textbooks and manuals, diplomacy is often defined as "the science of foreign relations" and "the art of negotiation." This certainly makes a lot of sense. A balanced analysis of the global situation and the correct consideration of the balance of power in the international arena are essential for the development of truly scientific, deeply grounded recommendations in the field of foreign policy. It is necessary to carefully study historical trends, fully take into account the different directions and trends in international relations, to be able to seek and attract allies to desired side, to achieve the isolation of the most aggressive and hostile circles. One can really expect success only if diplomacy acts in principle and, at the same time, pragmatically and flexibly, avoids dogmatism and sectarianism, and is not afraid of compromises that ultimately benefit national interests. Hence, the importance of mastering a number of sciences: history of individual countries and international relations, international law, complex sciences related to the study of the world economy and the economies of individual countries, comparative political science and law, philosophy, psychology, and etc. In short, diplomacy should rely on the laws of social life and consider the findings of the relevant sciences.
\r\n\r\n\tThis book intends to provide the reader with a comprehensive understanding of the real essence of public diplomacy. Public diplomacy and related concepts such as ""strategic communication"" and ""national branding"" are a part of increasingly common public administration practices. It also represents an area of research with significant growth potential. The nation states have in various contexts recognized the need to communicate with foreign communities and to develop networks through various forms of interaction, including international communication, exchange programmes and cultural diplomacy. As a result, public diplomacy has become an effective tool of purposeful communication with the foreign public to promote short-term political goals, to develop long-term relations, and to address pressing issues of transnational politics. Nevertheless, there are big problems that lie behind the popularization of modern public diplomacy initiatives which will also be discussed in the book.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"ca82945156946b18f4e457ce91ac6643",bookSignature:"Dr. Galina V. Timofeeva and Ms. Alexandra Baranova",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8535.jpg",keywords:"Diplomatic Service, Cultural Diplomacy, Negotiation, Tools, Mechanisms, Actors, Official Diplomacy, Digital Diplomacy, Conflict Resolution, Intergovernmental Organizations, Cooperation",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 13th 2019",dateEndSecondStepPublish:"March 27th 2020",dateEndThirdStepPublish:"May 26th 2020",dateEndFourthStepPublish:"August 14th 2020",dateEndFifthStepPublish:"October 13th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"311522",title:"Dr.",name:"Galina",middleName:"V.",surname:"Timofeeva",slug:"galina-timofeeva",fullName:"Galina Timofeeva",profilePictureURL:"https://mts.intechopen.com/storage/users/311522/images/system/311522.jpg",biography:"Galina V. Timofeeva, PhD is a Professor at the Department of Economics and Public Diplomacy at the Institute of Public Service and Management of the Russian Presidential Academy of National Economy and Public Administration (RANEPA). Professor Timofeeva is an expert of the Higher Attestation Commission of the Ministry of Education and Science of the Russian Federation. She is also an expert and a scientific editor of the strategy of socio-economic development of the Republic of Abkhazia-2025, as well as the specialist at the Russian Foundation for Basic Research.",institutionString:"Russian Presidential Academy of National Economy and Public Administration",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Russian Presidential Academy of National Economy and Public Administration",institutionURL:null,country:{name:"Russia"}}}],coeditorOne:{id:"312195",title:"Ms.",name:"Alexandra",middleName:null,surname:"Baranova",slug:"alexandra-baranova",fullName:"Alexandra Baranova",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:"Dr. Alexandra Baranova is a lecturer at the Russian Academy of National Economy and Public Administration. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41812",title:"Natural Compounds, Antioxidant and Antiandrogens in the Prevention of Prostate Cancer: In vivo Evidences from Murine Models and Human Clinical Studies",doi:"10.5772/52292",slug:"natural-compounds-antioxidant-and-antiandrogens-in-the-prevention-of-prostate-cancer-in-vivo-evidenc",body:'Prostate cancer (PCa)is the most frequent malignant neoplasia in men. The number of cases has continuously increased over the past decades, partly due to the higher life expectancy. Additional factors are the high caloric diet and lack of physical exercise, typically seen in the Western countries. Notably, up to 40% of cancer incidents are preventable by consuming a healthy diet, regular physical activity, and maintenance of optimum body weight, and more than 20% by consuming vegetables and fruits. PCa represents an ideal candidate disease for chemoprevention. It is typically diagnosed in elderly men and even a modest delay in the neoplastic development could result in substantial reduction in the incidence of the clinically detectable disease.In this chapter we will review the history, the development, and the applications of some of the most common animal models of PCa,and we will discuss of the role of animal models in translational research.
Prostate cancer (PCa) is the most common non-cutaneous malignant neoplasm in men in Western countries, responsible for the deaths of approximately 30,000 and 85,000 men per year in the United States and Europe, respectively [1,2].The number of cases is increasing rapidly in step with the growing number of men >50 worldwide, strategies for the prevention of PCa and its progression are urgently required. Since studies of chemopreventive agents in humans are hampered by the long latency period and challenging epidemiological problems, reliable preclinical models can be useful to overcome these problems. Early prostate tumorigenesis is apparently characterised by dysplasia that starts with proliferative inflammatory atrophy as the prelude to low-grade Prostatic Intraepithelial Neoplasia (PIN), high-grade PIN, primary cancer, metastatic cancer, and hormone-refractory cancer. During this progression, genetic damage accumulates within cancer cells [3,4]. Animal modelling has made a significant contribution to the study of prostate development and disease. Identification of the molecular features of PCa pathogenesis and progression could be greatly facilitated by laboratory and clinical models. However, a prerequisite for the elaboration of useful models is a better understanding of the molecular characteristics of human PCa. This puzzle, in addition to the well-known inter- and intra-individual heterogeneity of the disease itself and its multi-faceted nature, has necessitated the development of several complementary model systems. The most effective animal models will be those that most closely mimic the phenotypic and genetic changes accompanying the progression of the human disease. Systems shown to be promising include the dog, the rat, the human xenograft, and the genetically manipulated mouse. They have been widely employed to test preventive regimens, combinations of chemopreventive agents and/or drugs, cancer vaccines, and targeted treatments [5-12].This paper reviews the history, development, and applications of some of the most common animal models, and discusses their pros and cons in translational research.
The dog is the animal known to commonly develop high-grade PIN and PCa spontaneously in a human-like manner [13]. The many similarities between the canine and the human form include the morphologic and phenotypic heterogeneity of the tumoral lesions, the age-dependency of tumor occurrence, and the propensity to metastasize to bones in an osteoblastic manner [14,15]. Androgen-dependency, on the other hand, is ruled out by a similar incidence in castrated animals [15], while a relatively long latency, the low incidence of spontaneous disease, the impracticability of genetic manipulation, and the high expense of maintaining dog colonies [16,17] are other limitations of canine systems.
Spontaneous PCa is sometimes observed in some strains of rats [18]. The Dunning model [19] is the most popular. The original R-3327 tumor arose spontaneously in an inbred Copenhagen rat, and was translated into a syngenic Copenhagen x Fisher F1 rat. It is a slow growing, well differentiated and non-metastatic form. Several sublines with different characteristics mimicking some aspects of the human disease have since been developed [20-23]. Copenhagen and Wistar rats also develop a wide range of PCa phenotypes [24,25]. This variability, however, coupled with the rarity and long latency of these tumors, and their lack of metastases, bar the realistic employment of such models [12], though the recent elaboration of knockout methods [26-28] indicates that greater use could be made of genetically engineered rats in the future [29].
In immunodeficient nude mice tumors grow after injection of cancer cells or xenograft implantation with no evidence of a graft-versus-host response. In function of the number of cells injected, or the size of the xenograft, the tumor will develop over 1–8 weeks, 1–4 months, or longer, and its response to treatment can be studied [30]. By comparison with in vitro studies, this approach offers several advantages, especially a 3D structure complete with tumor-induced angiogenesis, hormonal, paracrine/autocrine factors, and metastasis [12]. Xenografting of human PCa began in the 1970s [31]. Thereafter several cell lines that displayed different PCa phenotypes when injected into athymic nude mice have been developed [32,33]. This model has been used to show the ability of tumor xenografts to metastasize to the lymph node and bone, the two most common human sites [34].
Mice with an autosomal recessive Severe Combined Immuno Deficiency mutation (SCID mice) were identified in 1983 [35]. This mutation results in a lack of T- and B-lymphocyte function. However, normal natural killer (NK) cells and myeloid function are present, and in some SCID mice, some B and T cells are still present [36]. In this model subcutaneous injection of HER2/neu overexpressing human CLNCaP cells has shown that HER2/neu induces androgen-independent tumor growth through modulation of the androgen receptor signalling pathway[37].
In 1995, the features of this model were improved by crossing SCID mice with nonobese diabetic (NOD) mice, which lack in NK cells, antigen-presenting cells, and circulating complement [38]. NOD-SCID mice accepted foreign tissue more successfully and were more immunodeficient than SCID mice. This strain has been used to elaborate a model for orthotopic implantation of PC-3 and DU145 cells with a tumor take efficacy of >80% for both lines [39]. Some xenograft models result in metastasis to bone after intracardiac injection of bone cells that probably survive in a niche whose microenvironment is optimal for their seeding and growth. However intracardiac injection is not an ideal procedure and attention has thus been focused on xenografts to orthotopic sites such as the prostate. The success rates depend on the host strain and the use of hormones or Matrigel to provide adequate growth factors and a scaffold for cell growth [40-42].
The immunodeficiency mouse model has been further improved by crossing NOD-SCID mice with interleukin-2 receptor gamma null mice (NOG/NSG mice). These long-living mice (median 90 weeks) totally lack B, T, and NK cell activities, and cytokine signaling, together with no age-related “leakiness”. They have a higher xenograft success rate and are more effective than other models, particularly in long-term studies involving prostate and non prostate cancer cells [43-45].
For preclinical prostate studies, most laboratories employ human PCa cell lines xenografted in mice. Many excellent reviews of the characteristics of these lines have been published [46-50]. The most widely used, each with thousands of studies published according to PubMed, are the classic three lines PC-3, LNCaP, and DU145, while each of the other lines has less than 200 citations [8]. These cell lines do not represent the steps of PCa progression. For example, almost all cell lines, including the most popular, were obtained from metastatic deposits: PC-3 from bone, LNCaP from lymph node, and DU145 from dural metastasis. In addition, PC-3 and DU145 are androgen receptor (AR) negative and LNCaP expresses a mutated AR. Again, cell lines, and their sublines in particular, are not fully genetically, functionally and phenotypically characterized, nor is there a method for standardization [8,46-48].
The last ten years have witnessed a remarkable shift in animal-based cancer research from xenograftedtumor to transgenic models since it is believed that they will recapitulate the complete course of carcinogenesis more accurately[48].This assumption stems from the recognition of several advantages that transgenic models offer when compared to xenograft systems. Among these are that the process of carcinogenesis begins with normal cells, progresses through distinct genetic and histological stages, occurs in an immuno-competent host and in its own cellular microenvironment, and that metastasis can occur along routes and to sites relevant to the clinical disease. A perhaps unrecognized attribute lies in the fact that, because the disease is not initiated by human action but by a genetic program that passes through the germline, the disease process is ‘‘reset’’ each generation. Statistically, the progression of a transgenic model of cancer should therefore be precisely recapitulated across time and between colonies. Given appropriate record keeping and data analysis, this feature should allow epidemiological- style investigations of great statistical power, free from both the mathematical noise of genetic and environmental variation, and from many of the economic and ethical constraints of human medicine.
Genetically engineered mouse (GEM) models have been utilized to identify pathways involved in carcinogenesis and investigate the role of particular gene mutations/deletions, and validate key genes as therapeutic targets. These models have been widely employed to test preventive regimens, combinations of chemopreventive agents and/or drugs, cancer vaccines, and targeted PCa treatments [5-12]. To mimic the human disease, GEMs could be generated through several mechanisms, such as overexpression or activation of oncogenes, elimination of target suppressor genes (Knock-outs), or generating dominant negative proteins that disrupt the function of regulatory genes.
The methods initially reported for genetic mouse modification involved the introduction of DNA constructs designed to induce the expression of proteins under the control of strong tissue-specific promoters, such as probasin and PSA. Simian virus 40 (SV40) large T antigens (Tag) were widely used because of their transforming ability. They interact with and suppress the tumor suppressor protein p53 and retinoblastoma [51,52]. In addition, the small t antigen interacts with the serine/threonine-specific protein phosphatase 2α to induce transformation [53].
The first model involving the expression of SV40 tumor antigens to develop PCa in the mouse was the C3(1)-Tag model[54].Targeting the Tag expression to the prostate was achieved by using a region of the C3 (1) gene, the rat prostatic steroid binding protein gene. Most C3(1)-Tag mice developed PIN after about eight weeks of age. Invasive adenocarcinomas followed after 28 weeks in about 40%. These tumors rarely metastasized (<4%), and always to the lungs. However, SV 40 expression was also detected in the mammary and salivary gland, while all females develop mammary intraepithelial neoplasia that may progress to mammary carcinomas[55].More effective prostate targeting was obtained in later models. Relatively few studies have used the C3 (1)/Tag model.
The transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse [56,57] is the best known and most widely used PCa model because it closely mimics the human disease.In this model, expression of both large and small SV40 early genes (T and t antigen, Tag) are driven by the prostate-specific promoter probasin that leads to cell transformation within the prostate. In this model, Tag are under the control of the minimal rat probasin –426/+C28 fragment. All male TRAMP mice develop PCa spontaneously: as in humans, they develop PIN, and well- or moderately- differentiated adenocarcinomas (between 10 and 20 weeks of age) and undifferentiated carcinomas (expressing or not AR) as well as phyllode tumors in the seminal vesicles [58,59]. Most adenocarcinomas arose in the dorsolateral lobe, which is considered most analogous to the peripheral zone where the human disease originates [10]. TRAMP was the first mouse model to display distant organ metastases, albeit rarely to the skeleton. Metastatic progression can be observed after 28 weeks of age, when almost all mice display lymphatic and >60% lung metastases from AR-, poorly differentiated (PD) tumors that constitute the main “lethal phenotype” in the TRAMP mouse on account of their fast growth and consequent acute renal damage due to compression, and also because they are the source of distant metastases and systemic cachexia [60]. These phenomena can also occur in the absence of other physiologic sequelae of metastatic disease [61]. An issue with the TRAMP model is that its most frequent lethal and metastatic malignancy (i.e. the PD tumor), has been reported to be of neuroendocrine nature and origin, while the simultaneous loss of p53 and Rb could increase susceptibility to neuroendocrine cancer [62-64].
The TRAMP mouse has become a popular preclinical model for studying chemoprevention/treatment of PCa, and elucidation of the antitumorigenic effects of many classes of chemopreventive/therapeutic regimens, including anti-androgen, anti-estrogen, anti-angiogenic, ornithine decarboxylase inhibitors, green tea polyphenols, COX-2 inhibitors, phytoestrogens, retinoic acid, grape seed extract, flavonolignans, etc (Table 1).This model enables comparison of the efficacy of treatments. A significant decrease of incidence and a delay of tumor progression was observed following anti angiogenic treatment (endostatin and angiostatin gene therapy), and lycopene and tomato supplementation. Other promising anti-oxidant agents include green tea, soy, resveratrol, crucifers, curcumin, tocotrienols, triterpenoids and methyl-selenium.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Anti-androgen | \n\t\t\tFlutamide | \n\t\t\t108 | \n\t\t\t2000 | \n\t\t
Ornithine decarboxylase inhibition | \n\t\t\talpha-difluoromethylornithine | \n\t\t\t109 | \n\t\t\t2000 | \n\t\t
Green tea | \n\t\t\tPolyphenolic extract | \n\t\t\t110 | \n\t\t\t2001 | \n\t\t
Soy | \n\t\t\tGenistein | \n\t\t\t111 | \n\t\t\t2001 | \n\t\t
Anti-estrogen | \n\t\t\tToremifene | \n\t\t\t112 | \n\t\t\t2002 | \n\t\t
Anti-inflammatory | \n\t\t\tCelecoxib | \n\t\t\t113 | \n\t\t\t2004 | \n\t\t
Anti-inflammatory | \n\t\t\tCelecoxib, exisulind | \n\t\t\t114 | \n\t\t\t2004 | \n\t\t
Soy | \n\t\t\tGenistein | \n\t\t\t115 | \n\t\t\t2004 | \n\t\t
Differentiative, antiangiogenic | \n\t\t\tRetinoic acid | \n\t\t\t116 | \n\t\t\t2004 | \n\t\t
Green tea | \n\t\t\tPolyphenolic extract | \n\t\t\t117 | \n\t\t\t2004 | \n\t\t
Green tea | \n\t\t\tEpigallocatechin-3-gallate (EGCG) | \n\t\t\t118 | \n\t\t\t2004 | \n\t\t
Green tea | \n\t\t\tPolyphenolic extract | \n\t\t\t119 | \n\t\t\t2004 | \n\t\t
Green tea | \n\t\t\tPolyphenolic extract | \n\t\t\t120 | \n\t\t\t2005 | \n\t\t
Anti-inflammatory | \n\t\t\tEtodolac | \n\t\t\t121 | \n\t\t\t2005 | \n\t\t
Block of the α1-adrenergic receptors | \n\t\t\tDoxazosin | \n\t\t\t122 | \n\t\t\t2005 | \n\t\t
Rye | \n\t\t\tBran | \n\t\t\t123 | \n\t\t\t2005 | \n\t\t
Soy | \n\t\t\tGenistein | \n\t\t\t124 | \n\t\t\t2005 | \n\t\t
Anti-inflammatory | \n\t\t\tCelecoxib | \n\t\t\t125 | \n\t\t\t2006 | \n\t\t
Anti-oxidative | \n\t\t\tSpinach extract, EGCG, acetylcysteine | \n\t\t\t126 | \n\t\t\t2006 | \n\t\t
DNA methyltransferase inhibition | \n\t\t\t5-aza-2’-deoxycytidine | \n\t\t\t127 | \n\t\t\t2006 | \n\t\t
Estrogen metabolite | \n\t\t\t2-Methoxyestradiol | \n\t\t\t128 | \n\t\t\t2006 | \n\t\t
Grape seeds | \n\t\t\tPolyphenolicextracy | \n\t\t\t129 | \n\t\t\t2007 | \n\t\t
Anti-β-Catenin | \n\t\t\tApigenin | \n\t\t\t130 | \n\t\t\t2007 | \n\t\t
Soy | \n\t\t\tGenistein | \n\t\t\t131 | \n\t\t\t2007 | \n\t\t
Anti-angiogenic | \n\t\t\tEndostatin and angiostatin gene therapy | \n\t\t\t132 | \n\t\t\t2007 | \n\t\t
Green tea | \n\t\t\tEpigallocatechin-3-gallate (EGCG) | \n\t\t\t133 | \n\t\t\t2007 | \n\t\t
Milk thistle(Silybummarianum) seeds | \n\t\t\tSilibin | \n\t\t\t134 | \n\t\t\t2007 | \n\t\t
Combined immunoprophylaxis | \n\t\t\tAllogeneic cells and recombinant IL-12 | \n\t\t\t135 | \n\t\t\t2007 | \n\t\t
Saw palmetto | \n\t\t\tLiposterolic extract | \n\t\t\t136 | \n\t\t\t2007 | \n\t\t
Grape | \n\t\t\tResveratrol | \n\t\t\t137 | \n\t\t\t2007 | \n\t\t
Plant flavonoid | \n\t\t\tApigenin | \n\t\t\t138 | \n\t\t\t2007 | \n\t\t
Milk thistle(Silybummarianum) seeds | \n\t\t\tSilibin | \n\t\t\t139 | \n\t\t\t2008 | \n\t\t
Milk thistle(Silybummarianum) seeds | \n\t\t\tSilibin | \n\t\t\t140 | \n\t\t\t2008 | \n\t\t
Cruciferous vegetables | \n\t\t\tSulphoraphane | \n\t\t\t141 | \n\t\t\t2009 | \n\t\t
Green tea | \n\t\t\tPolyphenolic extract | \n\t\t\t142 | \n\t\t\t2009 | \n\t\t
Milk thistle(Silybummarianum) seeds | \n\t\t\tSilibin | \n\t\t\t143 | \n\t\t\t2009 | \n\t\t
Anti-oxidative | \n\t\t\tγ-Tocopherol | \n\t\t\t144 | \n\t\t\t2009 | \n\t\t
Systemic buffers | \n\t\t\t\n\t\t\t | 145 | \n\t\t\t2012 | \n\t\t
Anti-oxidative | \n\t\t\tγ-Tocopherol | \n\t\t\t146 | \n\t\t\t2012 | \n\t\t
Anti-inflammatory | \n\t\t\tUrsolic acid | \n\t\t\t147 | \n\t\t\t2012 | \n\t\t
High-fat diet | \n\t\t\tWhole walnuts | \n\t\t\t148 | \n\t\t\t2012 | \n\t\t
Pomegranate | \n\t\t\tFruit exctract | \n\t\t\t149 | \n\t\t\t2012 | \n\t\t
Plant flavonoid | \n\t\t\tApigenin | \n\t\t\t150 | \n\t\t\t2012 | \n\t\t
Cancer therapy | \n\t\t\tDocetaxel, Dexametasone, Octeotride | \n\t\t\t151 | \n\t\t\t2012 | \n\t\t
Bitter melon | \n\t\t\tFruit exctract | \n\t\t\t152 | \n\t\t\t2011 | \n\t\t
Diet | \n\t\t\tFolate deficiency | \n\t\t\t153 | \n\t\t\t2011 | \n\t\t
Anti-inflammatory | \n\t\t\tUrsolic acid | \n\t\t\t154 | \n\t\t\t2011 | \n\t\t
Anti-inflammatory + anti-hormonal | \n\t\t\tCelecoxib, Hormone ablation | \n\t\t\t155 | \n\t\t\t2011 | \n\t\t
Garlic | \n\t\t\tDiallyltrisulfide | \n\t\t\t156 | \n\t\t\t2011 | \n\t\t
Anti-oxidative | \n\t\t\tIndolole-3-carbinole | \n\t\t\t157 | \n\t\t\t2011 | \n\t\t
Anti-oxidative | \n\t\t\tWhole tomatoes | \n\t\t\t158 | \n\t\t\t2010 | \n\t\t
Anti-oxidative | \n\t\t\tLycopene beadlet, tomato paste | \n\t\t\t159 | \n\t\t\t2010 | \n\t\t
Diet | \n\t\t\tWestern diet | \n\t\t\t160 | \n\t\t\t2010 | \n\t\t
Anti-oxidative | \n\t\t\tSeleniun | \n\t\t\t161 | \n\t\t\t2011 | \n\t\t
Triterpenoids | \n\t\t\tSynthetic CDDO | \n\t\t\t162 | \n\t\t\t2011 | \n\t\t
Mitocondrial Hsp90 inhibition | \n\t\t\t\n\t\t\t | 163 | \n\t\t\t2011 | \n\t\t
Arginine metabolism | \n\t\t\tModulators | \n\t\t\t164 | \n\t\t\t2011 | \n\t\t
Anti-oxidative | \n\t\t\tMethyl-seleniun | \n\t\t\t165 | \n\t\t\t2009 | \n\t\t
Hormonal | \n\t\t\tMethoxyestradiol | \n\t\t\t166 | \n\t\t\t2009 | \n\t\t
Interferon-alpha | \n\t\t\t\n\t\t\t | 167 | \n\t\t\t2009 | \n\t\t
3,3’-Diindolylmethane | \n\t\t\t\n\t\t\t | 168 | \n\t\t\t2010 | \n\t\t
Anti-oxidative | \n\t\t\tMixed tocotrienols | \n\t\t\t169 | \n\t\t\t2010 | \n\t\t
Diet | \n\t\t\tZinc | \n\t\t\t170 | \n\t\t\t2010 | \n\t\t
Cancer therapy | \n\t\t\tTreatment targeting HIF-a and Stat3 | \n\t\t\t171 | \n\t\t\t2011 | \n\t\t
Crucifers | \n\t\t\tIndole-3-carbinol | \n\t\t\t172 | \n\t\t\t2011 | \n\t\t
Preventive/Therapeutic Regimens Tested in the TRAMP Model of Prostate Cancer
To increase the transgene expression beyond that obtained with the minima probasin promoter, as in the TRAMP mouse, an 11.5 kb 5’ flanking fragment of the prostate-specific probasin promoter (large probasin) has since been isolated [65], and used to direct large T-antigen expression to the dorsolateral and ventral prostate (Lady mouse model). The second key difference in this model is that the large probasin promoter was linked to a deletion mutant of the SV40 T-antigen that expressed only the large T-antigen [66,67]. The Lady model is advantageous because expression is high, but the PCa progression is less aggressive, beginning with low to high-grade PIN and proceeding to carcinoma with neuroendocrine features. However, metastatic progression was not seen [5,67]. Several other trangenic mouse models have been developed with or without the involvement of SV40 antigens and with different strategies (reviewed in ref. [12]). In summary, while T antigen expression generally induces castration-resistant, aggressive and metastatic PCas, often with a neuroendocrine phenotype, the specific expression of other oncogenes in the prostate results in a mild phenotype that rarely progresses to adenocarcinoma.
The roles of genes significant in prostate carcinogenesis can also be studied in, whole-body knockout models. Here, however, the gene involved is knocked out ubiquitously, and its specific role in a given organ cannot be readily determined. Estrogen receptor b knockout mice display hyperplastic foci in the prostate or even no pathological changes [68]. Deletion of retinoic acid receptor γ determines squamous metaplasia of prostate and seminal vesicles, but not carcinomas [69]. p27knockout mouse display prostatic hyperplasia histologically similar to that observed in human BPH, but not PIN, and a pathogenetic role of p27 loss in BPH development in both mice and humans has been suggested [70]. Inactivation of T (phosphatase and tensin homolog deleted on chromosome 10) prevents activation of AKT and apoptosis resulting in embryonic lethality. However, haploinsufficiency leads to early stages (PIN) of prostatic carcinogenesis [71]. Double-knockout models in which loss of PTEN is associated with loss of other tumor suppressors (p27, Nkx3.1, and p53), are characterized by more aggressive tumor phenotype.The highest stage of tumor progression was adenocarcinoma (PTEN x p27 mouse) [72], lymph node metastases (PTEN x Nkx3.1 mouse) [73], and high grade PIN (PTEN x p53 mouse) [74]. In addition, several mouse models with up to 5 genetic hits demonstrated, as expected, the complexity of the events required for a complete progression of prostatic tumors from low-grade PIN to metastatic disease (see review [75]).
The “old” (1979) [76] Cre-loxP system was used to produce mice with prostate-specific alterations. Cre is a recombinase that promotes specific genetic recombination in trans at loxP sites. The Cre-loxP system was developed and used for genetic recombination first in yeast and later in mice [77,78]. Many genes knocked out with the whole body strategy were also knocked out by using a conditional approach that results in higher prostate tumor severity. As an example, tissue-specific deletion indicated that homozygous loss of prostatic PTEN led to most stages of prostate tumor progression (metastatic disease) when compared to whole-body haploinsufficiecy, where only PIN was present [79]. At present, the Cre-lox system is diffusely employed to generate mouse models characterized by cell-type-specific and tissue-specific genetic modification (see recent review in ref. [12]). The probasin and the prostate specific antigen (PSA) promoters were extensively utilized to induce targeted Cre expression in the prostate. PB-Cre and PSA-Cre mice have been employed to delete the intraprostatic expression of PTEN, Rb, p53, APC, IGF1 and PTEN, Nkx3, respectively.
E-Resources for mouse models of human cancer, including PCa, are also available online (http://emice.nci.nih.gov/,http://cancermodels.nci.nih.gov/,andhttp://cancerimages.nci.nih.gov/).
Mouse models have significantly contributed to our understanding of PCa biology through their identification of new cancer genes and biomarkers, and their illustration of the molecular and cellular mechanisms underlying tumor initiation and progression. They have also been employed in a preclinical setting to test novel preventive and/or therapeutic strategies [5,6,8-12,80]. Mice, in fact, offer several advantages. They are small, relatively inexpensive, and reproduce rapidly with large litters. More importantly, technical advances have facilitated the generation of defined genetic modifications that can also be spatially controlled, to mimic human prostate carcinogenesis. In general, and perhaps not surprisingly, a variety of phenotypes are obtained depending on the specific genetically engineered mouse model, but none exactly mimics the human disease. Although preclinical studies and the epidemiological evidence suggest that specific dietary components or nutritional supplements influence overall mortality and/or reduce the risk of PCa, randomized, controlled clinical trials provide high-quality evidence of benefit, no effect, or even harm. Examples of ongoing clinical trials are reported in Table 2. In the last ten years, several primary prevention trials have been reported (reviewed in ref. [11,81]). Preventive strategies in a clinical setting have focused on two approaches: antioxidant regimens to reduce DNA damage and suppression of androgenic stimulation [82]. Since a wealth of preclinical and epidemiologic data indicated that selenium and vitamin E reduce PCa, these compounds were evaluated in humans. The Nutritional Prevention of Cancer (NPC) trial found a 63% reduction of PCa incidence (secondary endpoint) following the administration of selenized yeast [83]. The Alpha-Tocopherol Beta-Carotene Cancer prevention study (ATBC), one of the first large studies (14,569 subjects enrolled), investigated the prevention of lung cancer among male smokers. The results indicated that beta carotene supplements increased the risk of lung cancer, rather than preventing it, and that vitamin E had no effect [84-86]. However, a significantly lower risk of PCa was observed for participants receiving vitamin E alone. The NPC and ATBC findings underpinned the NCI-sponsored selenium and vitamin E cancer prevention trial (SELECT). This randomized 35,533 men into four groups: (1) selenium/placebo, (2) vitamin E/placebo, (3) both agents, and (4) placebo alone [87]. At a mean of 5.5 years neither agent reduced risk of PCa. However, at a mean of 7 years and with an additional person-year of follow-up, men receiving vitamin E alone had a significantly increased the risk of PCa (Hazard Ratio 1.17, 99% CI 1.004– 1.36,
The most promising agents for preventing PCa are probably the 5-alpha reductase inhibitors (5-ARIs). Five-alpha reductase catalyzes the conversion of testosterone to the more active dihydrotestosterone. The Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial evaluated the activities of two 5-ARIs, finasteride and dutasteride, respectively (reviewed in ref. [81,91]). 5-ARI use for 4-7 years reduced the overall risk of biopsy-detectable PCa by 23-25%. All the prevented cases are either low-grade (PCPT) or GS ≤3 + 4 = 7 prostatic carcinoma (REDUCE). It is unclear whether the slightly increased risk of high-grade cancers in both trials is real or an artifact. In addition to the risk of androgen-independent tumors, the side effects of 5-ARI such as neurodegeneration, osteoporosis, cardiovascular diseases, genitourinary dysfunctions, and hormonal disarrangement limit their use as primary chemopreventive drugs [92-94].
Clinical translation has thus proved to be a general failure when viewed against the optimism aroused by preventive treatments (antioxidant, anti-hormonal, anti-inflammatory, anti-angiogenic etc agents) in the preclinical setting. It has been proposed that species-specific differences, and differences in time of treatment intervention age, trial design enrolment criteria, genetic variation, and the choice, dose, and bioavailability of preventive/therapeutic agents are lie behind for the discrepancy [11]. The most substantial challenge posed by mouse models of PCa, as for other tumors, is their species-specific differences. The lifespan of a mouse is 25-50 times shorter than that of humans, and mice are 3000 times smaller, with consequent differences in pharmacokinetics [95,96]. Anatomically, the human prostate is a single alobular organ with a central, a transitional, and a peripheral zone, whereas the murine prostate comprises four paired lobes located around the urethra, namely the anterior (or coagulating gland), dorsal, lateral, and ventral prostate. The dorsal and lateral lobes are treated as one (the dorsolateral lobe) as they share a ductal system. This lobe has been described as the most similar to the human peripheral zone where most carcinomas arise [97,98]. According to the Bar Harbor Pathology Panel consensus opinion, however, there is no direct relationship between any mouse lobe and any of the human zones [58]. Histologically, the mouse and the human prostate display similar cell types (secretory, basal and neuroendocrine), but their ratio varies from one species to another [99,100]. Mice have fewer basal cells and a discontinuous layer on the basal membrane, whereas in humans, this layer is continuous between secretory cells and the basal membrane. Neuroendocrine cells, rare in humans, are even more rare in mice. The human prostate is characterized by an abundant fibromuscular stoma, whereas the murine gland has a small stromal component. Mice are susceptible to malignancies. By comparison with humans, however, they tend to have more sarcomas and lymphomas and very few epithelial tumors, probably due to differences in relative telomere activity [101-103]. Telomerase, mostly inactive in cells from adult humans, is present in mouse cells, which can thus be transformed/immortalized more easily than their human counterparts, and fewer genetic hits are required to bring about neoplastic transformation in mice than in men. Inactivation of telomerase in the mouse model may be necessary to more accurately recapitulate human cancer phenotypes [80,104].
Most primary PCa prevention studies used mice with an average age of 4-8 weeks, by which time they are considered to have attained sexual maturity and are unlikely to have sustained hormone-induced oxidative stress. In the mouse, a delay in the start of treatment results in a reduced or even no effect. Most human PCa prevention trials were conducted on men aged 50 or more. In addition, the agent dose in animals is 50-80% of the maximally tolerated dose, whereas in humans lower doses may be required for bioethical reasons. The excellent review of Pienta et al. (Prostate Cancer Model Working Group) offers a list of limitations of preclinical models that have hampered the translation of their findings to human clinical trials [8].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Green tea | \n\t\t\tNCT00685516 | \n\t\t\tTherapy | \n\t\t\tJonsson Comprehensive Cancer Center | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t
NCT00253643 | \n\t\t\tPrevention | \n\t\t\tOregon Health and Science University | \n\t\t\t\n\t\t\t | Recruiting | \n\t\t|
NCT00003367 | \n\t\t\tTherapy | \n\t\t\tMemorial Sloan-Kettering Cancer Center | \n\t\t\tIII | \n\t\t\tActive | \n\t\t|
NCT00676780 | \n\t\t\tBasic science | \n\t\t\tLouisiana State University Active | \n\t\t\tII | \n\t\t\tActive | \n\t\t|
NCT00744549 | \n\t\t\tTherapy | \n\t\t\tUniversity Health Network, Toronto | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
Genistein | \n\t\t\tNCT00546039 | \n\t\t\tBasic science | \n\t\t\tUniversity Hospital, Aker Active | \n\t\t\tII | \n\t\t\t\n\t\t |
NCT00005827 | \n\t\t\tTherapy | \n\t\t\tNorth Carolina University LinebergerCenter | \n\t\t\tI | \n\t\t\tCompleted | \n\t\t|
NCT00058266 | \n\t\t\tTherapy | \n\t\t\tRobert H. Lurie Cancer Center | \n\t\t\tII | \n\t\t\tActive | \n\t\t|
NCT00584532 | \n\t\t\tTherapy | \n\t\t\tUniversity of California, Davis | \n\t\t\tII/III | \n\t\t\tCompleted | \n\t\t|
NCT00376948 | \n\t\t\tTherapy | \n\t\t\tBarbara Ann Karmanos Cancer Institute | \n\t\t\tII | \n\t\t\tSuspended | \n\t\t|
NCT00499408 | \n\t\t\tTherapy | \n\t\t\tWake Forest University | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
Pomegranate | \n\t\t\tNCT00413530 | \n\t\t\tTherapy | \n\t\t\tM. D. Anderson Cancer Center | \n\t\t\t\n\t\t\t | Recruiting | \n\t\t
NCT00719030 | \n\t\t\tPrevention | \n\t\t\tUniversity of California, Los Angeles | \n\t\t\t\n\t\t\t | Recruiting | \n\t\t|
NCT00732043 | \n\t\t\tPrevention | \n\t\t\tRadiant Research | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
NCT00731848 | \n\t\t\tTherapy | \n\t\t\tRadiant Research | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
NCT00336934 | \n\t\t\tTherapy | \n\t\t\tRoll International Corporation | \n\t\t\tIII | \n\t\t\tRecruiting | \n\t\t|
NCT00060086 | \n\t\t\tTherapy | \n\t\t\tJonsson Comprehensive Cancer Center | \n\t\t\tII | \n\t\t\tActive | \n\t\t|
NCT00433797 | \n\t\t\tTherapy | \n\t\t\tUniversity of Oslo | \n\t\t\tI/II | \n\t\t\tRecruiting | \n\t\t|
Lycopene | \n\t\t\tNCT00042731 | \n\t\t\tTherapy | \n\t\t\tH. Lee Moffitt Cancer Center | \n\t\t\t\n\t\t\t | Completed | \n\t\t
NCT00416325 | \n\t\t\tPrevention | \n\t\t\tUniversity of Illinois | \n\t\t\tI | \n\t\t\tCompleted | \n\t\t|
NCT00178113 | \n\t\t\tPIN Prevention | \n\t\t\tUniversity of Pittsburgh | \n\t\t\tI | \n\t\t\tCompleted | \n\t\t|
NCT00093561 | \n\t\t\tPrevention | \n\t\t\tUniversity of Illinois Completed | \n\t\t\tI | \n\t\t\tCompleted | \n\t\t|
NCT00450749 | \n\t\t\tTherapy | \n\t\t\tM. D. Anderson Cancer Center | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
NCT00006078 | \n\t\t\tPrevention | \n\t\t\tUniversity of Illinois | \n\t\t\tI | \n\t\t\tCompleted | \n\t\t|
NCT00322114 | \n\t\t\tPrevention | \n\t\t\tUniversity of Illinois | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
NCT00402285 | \n\t\t\tTherapy | \n\t\t\tUniversity of California San Francisco | \n\t\t\t\n\t\t\t | Active | \n\t\t|
NCT00450957 | \n\t\t\tPrevention | \n\t\t\tUniversity of Illinois | \n\t\t\tI | \n\t\t\tActive | \n\t\t|
NCT00068731 | \n\t\t\tTherapy | \n\t\t\tNorth Central Cancer Treatment Group | \n\t\t\tII | \n\t\t\tActive | \n\t\t|
NCT00744549 | \n\t\t\tTherapy | \n\t\t\tUniversity Health Network, Toronto | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
NCT00669656 | \n\t\t\tTherapy | \n\t\t\tNorris Comprehensive Cancer Center | \n\t\t\tII | \n\t\t\tRecruiting | \n\t\t|
n-3 poly | \n\t\t\tNCT00458549 | \n\t\t\tTherapy | \n\t\t\tDana-Farber Cancer Institute | \n\t\t\t\n\t\t\t | Recruiting | \n\t\t
unsaturated fatty acids | \n\t\t\tNCT00402285 | \n\t\t\tTherapy | \n\t\t\tCalifornia San Francisco Helen Diller Center | \n\t\t\t\n\t\t\t | Active | \n\t\t
Clinical Trials of Preventive/Therapeutic Regimens for Prostate Cancer
* Data from ref. [105]
Genetically engineered mouse models of PCa have paved the way to many important discoveries and helped to define the molecular events of prostate tumorigenesis. However, no single model precisely recapitulates all the molecular or cellular features of the progression of PCa from the normal gland to metastatic, hormone-refractory carcinoma, especially since its early stages are not those of single-cell-type disease, but must be viewed as a complex system of epithelial cells that display dysregulated growth within both a microenvironment composed of many cells which support such growth, and the host macroenvironment with its unique genotype and immune system. Further research is needed to better define these interactions, many of which are potential therapeutic targets. Several in vivo models can be utilized to study specific components of tumor initiation and progression. Meaningful interpretation of their results, however, demands a full understanding of the properties and limits of each model, along with employment of the model most consonant with the subject to be studied. Preclinical models have been poorly predictive of results in human studies because of both their inadequacy and their inappropriate use leading to the designing of clinical trials that do not mirror the preclinical model testing [106]. However, the chemoprevention field is particularly challenging since discrepancies have also been found between initial findings in several trials, secondary analyses and epidemiologic data, and subsequent randomized studies in humans [107]. These inconsistencies may reasonably be supposed to stem from the fact that dietary agents may act long before the scheduled commencement of a chemoprevention trial. Since such trials need to find outcomes (cancers), they invariably start with populations at higher risk of developing clinically detectable cancer, namely middle-aged and older subjects. However, dietary elements may either have a lifelong effect in their changes to the baseline risk for cancer or act at key points by priming the pump for its future development. In either case, dietary chemoprevention might be possible, but its indisputable demonstration in a trial would be highly unlikely. Do these discrepancies mean that all the preclinical and epidemiologic studies are wrong? It must primarily be considered that the timing of such interventions is unclear. Their employment in very high risk subjects, indeed, may actually be too late to significantly prevent cancer formation. Future studies will require both the use of other models founded on our increased understanding of human cancer proteomic genetics and epigenetics to define the very first steps in the progression of the disease and the ability of agents to impair or retard it, and a better “translational approach” achieved through preclinical studies that utilize the appropriate agent doses, and pharmacokinetic and pharmacodynamic parameters to take into account the differences in metabolism between mice and humans, together with clinical trials whose design takes account of how the preclinical testing was accomplished.
We wish to thank Prof. John Iliffe for reading the manuscript and critical suggestions. The work of the authors is supported by the Italian Ministry for the Universities and Research.
Overeating leads to obesity, which heightens the risk of several chronic illnesses including hypertension, diabetes, high blood triglycerides, heart disease, stroke, kidney problems and cancer. One of the causes of overeating is palatability of foods, especially those containing sweet and fatty substances, which often promote ingestion over homeostatic repletion [1, 2, 3]. It is suggested that the palatability-induced ingestion is based on a sequential release of brain substances such as β-endorphin, dopamine and orexigenic neuropeptides, corresponding to palatability (liking), motivation (wanting), and actual intake (eating), respectively [3, 4, 5, 6, 7]. Any attempts to suppress actions of one or more of these brain substances could be an effective approach to prevent from overeating.
Odors produce various physiological, psychoemotional, and behavioral reactions depending on their qualities and hedonic tones [8, 9, 10, 11, 12, 13, 14, 15]. Concerning food intake behavior, it is our common experience that odors associated with pleasant foods enhance appetite, but repellent odors reduce appetite. Interestingly, some fragrant odors attenuate ingestive behavior and body weight gain. Studies using rats have demonstrated that grapefruit odor inhibits food intake, leading to a reduction in body weight gain. It is plausible that this effect is mainly caused by activation of sympathetic nerve activity, which enhances energy consumption and suppresses appetite [16, 17]. Another example is the odor of
OSM is an evergreen shrub that has been grown in Eastern Asia, especially in China, for more than 2500 years [20]. It produces small clusters of flowers in the late summer and autumn. The flowers are small, pale yellow, yellow, or orange-yellow and have a strong fragrant scent of ripe peaches or apricots. Because of its favorable fragrance, tea, wine, and jam with OSM flowers are traditionally very popular and are enjoyed on a daily basis in far-east Asia, especially in Taiwan and China. Since it has been traditionally believed to exert good effects on physical and mental health, the OSM plant has also been utilized as a Chinese herbal medicine. Among the volatile compounds of the scent of OSM, the essential ones are γ-decalactone, β-ionone, dihydro-β-ionone, linalool oxides [18, 21].
Although both grapefruit and OSM odors suppress appetite, food intake and body weight gain, the underlying causative mechanisms appear to differ to those described above. However, there are a lack of comparative data on the possible effects of grapefruit odor on feeding-related neuropeptides and effects of OSM odor on autonomic nerve activity. The present study, therefore, was designed to examine possible effects of grapefruit odor on the expression of orexigenic and anorexigenic neuropeptides in rats. We also examined effects of OSM odor, together with odors of lavender, jasmine, and milk on the autonomic nervous activity in humans. Finally, we examined how OSM odor affects appetitive reactions in humans.
A total of 18 Wistar male rats were used. They were randomly divided into experimental and control groups (n = 9 each). Rats were individually housed in plastic cages, with freely available food and water, in a temperature- and humidity-controlled room (23°C, 60%). All animals were handled in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals (National Institute of Health Guide), and this study was approved by the institutional committee on animal research (Animal Research Committee of Kio University).
The experimental rats received grapefruit essential oil as an olfactory stimulus with the same method as described in our previous paper [18]. Briefly, a drop (100 μl) of the oil was put on a filter paper, which was inserted between two metal mesh plates, and placed on the floor of the cage. The control rats were exposed to a filter paper containing a drop of water instead of the olfactory stimulus. The brains were removed 60 min after the onset of stimulation and the hypothalamus was removed, and preserved at −80 degrees. To examine the changes in the expression of mRNAs for prepro-orexin, MCH, AgRP, NPY, CART, and POMC, we used the same quantitative real time (RT)-PCR technique as that in the previous study [18].
We used the essential oils of lavender, jasmine, milk (these three are products of Takasago International Corp. Japan), and
The technical procedures and physiological interpretation of the HRV analysis have been reported by a number of researchers [24, 25, 26, 27, 28, 29] with a useful guideline for HRV measurement and physiological interpretation [30]. The heart rate data were transferred to a personal computer, and the frequency domain measurements of HRV were determined by spectral analysis using fast Fourier transformation. The power spectrum was decomposed into its frequency components and quantified in terms of the relative power of each component. We used three frequency domain variables as an index of HRV. These frequency domain variables included low-frequency (LF: 0.04─0.15 Hz), high-frequency (HF: 0.15─0.40 Hz) and the ratio of LF to HF (LF/HF). The LF component reflects both parasympathetic and sympathetic nervous activities, the HF component reflects parasympathetic nervous activity, and the LF/HF ratio is considered an index of sympathetic nervous activity.
We used two odor stimuli (lavender and OSM), which were the same as those described in the previous section, and an odorless control stimulus (distilled water). To examine the effects of odors on feeding behavior, another cohort of 66 university students (20─21 years old, 60 females and six males) who belonged to one class of a nutritional course from Kio University were used. Experiments were conducted every Wednesday in three consecutive weeks.
The time schedule of an experimental day is shown in Figure 1. The experiment started at 12:00. After checking the physical condition, the subjects were randomly divided into three groups of 22 subjects. Each subject was served with a box lunch and a bottle of water and ate the lunch between 12:15 and 12:50 (Figure 2). Then, each subject wore a mask with a small pocked inside in which a filter paper (one cm x five cm) was inserted (Figure 3). The filter papers were infiltrated with a few drops of 2.5% OSM, 2.5% lavender oil, or non-odor distilled water. Each group received either OSM odor, lavender odor, or no odor-containing filter papers during a lecture on the first experimental day. Similarly, on the second and third experimental days, each group received a different stimulus (of the three stimuli). Thus, every subject received all three stimuli throughout the three experimental days. Subjects attended two lectures with a 20-minute intermission from 13:00-to-15:40. They took off their masks during the intermission and wore the masks again with new filter papers just before the second lecture. After stimulation, each subject was given a package of snacks, containing 16 pieces of small cookies (Bourbon Petit with French Butter flavor, Bourbon Co. Niigata, Japan), and they were allowed to eat them freely, as much as they desired (Figure 4). The numbers of leftover cookies were counted and compared among the three odor groups.
Time schedule of the conducted experiments on Wednesday. Subjects participated in the experiment with different odor stimuli on another two Wednesdays for three consecutive weeks.
A box of lunch and a bottle of water served on the first experimental day. A different box of lunch was served on the second and third experimental days.
A mask with a filter paper in an inside pocket. The filter paper was soaked with 2.5%
A commercially available package of 16 small cookies served as snack after taking off mask.
The following sensory tests were assessed in each subject. To evaluate intensity and pleasantness of odors (sensory test 1 in Figure 1), the subjects were asked to select the score from one of five values ranging from 1 (very weak), 2 (weak), 3 (neutral), 4 (strong) to 5 (very strong) soon after putting masks and soon after taking off masks. To evaluate the level of hunger (sensory test 2), the subjects selected the score from one of five values from 1 (not hungry), 2 (slightly hungry), 3 (medium), 4 (moderately hungry) to 5 (very hungry). To evaluate the sweetness and pleasantness of the cookies (sensory test 3), the subjects selected scores from one of five values, ranging from 1 (very weak) to 5 (very strong), soon after eating the cookies.
To examine mood changes before and after odor stimulation, we administered the Profile of Mood States (POMS), a short-form questionnaire translated into Japanese (Kaneko Shobo Co. Ltd. Tokyo, Japan), after finishing lunch (or before odor stimulation) and after taking off the mask (or after odor stimulation). The POMS test consisted of 35 questions about the current mood state. The 35 questions were classified into six subscales: T─A (tension and anxiety), D (depression and dejection), A─H (anger and hostility), V (vigor), F (fatigue), and C (confusion). The subjects selected the score from one of five values from 0 (not at all) to 4 (extremely). Total mood disturbance (TMD) was calculated by subtracting V from the sum of the other five subscale scores in each subject. Lower TMD scores were indicative of an improved mood.
For the experiments in humans (as described above), the study protocol was approved in advance by the Ethics Committee of Kio University and was performed in accordance with the Declaration of Helsinki of the World Medical Association. All subjects received an explanation of the nature of the research and agreed with the study protocol. We did not tell subjects about the names of the odors used in the experiments. All subjects signed written informed consent.
A two-way analysis of variance (ANOVA) was used to compare the expression of the feeding-related neuropeptides between grapefruit odor and non-odor conditions. To examine the effects of the four odors on the autonomic nerve activity in humans, a two-tailed paired
The expression of mRNAs for the hypothalamic orexigenic neuropeptides, such as AgRP, MCH, NPY and orexin, and anorexigenic neuropeptides, such as CART and POMC, was measured using a real-time polymerase chain reaction (RT-PCR) on the rat hypothalamic specimens taken 60 minutes after the onset of grapefruit odor stimulation. The results were compared to those of similar samples taken from non-odor control rats. Figure 5 shows the expression of mRNAs for four orexigenic and two anorexigenic neuropeptides in the control and experimental groups. A two-way analysis of variance (ANOVA) with peptide (gene expression of six peptides) and odor (water and grapefruit) revealed a statistically significant main effect of peptide [F (5;96) = 8.76,
Effects of grapefruit odor on the expression of mRNAs for feeding-related neuropeptides in the hypothalamus of rats. Values are means ± SE. No difference was detected between the grapefruit odor group and the non-odor control group (two-way ANOVA,
The effects of four kinds of odors (lavender, jasmine, OSM, and milk) on autonomic nerve activity, in terms of frequency analysis, are graphically summarized in Figure 6. The mean high frequency (HF) component of R-R variation (variability of the time interval between R waves), an indicator of the parasympathetic activity, was statistically significantly (
Effects of odors on autonomic nerve activity. Odors are lavender (L), jasmine (J), OSM (O) and milk (M). C, non-odor control; HF, high-frequency component; LF, low-frequency component. Values are means ± SE. Asterisks denote that the autonomic activity in the presence of the odor is significantly different from that in non-odor condition (two-tailed paired
Five minutes after wearing masks with OSM odor, lavender odor or non-odor distilled water, the intensity score for the odors was 3.8 ± 0.9 (mean ± standard deviation [SD], n = 66) and 4.3 ± 0.7 (n = 66) for OSM and lavender groups, respectively. Soon after taking off the masks, the intensity score was significantly (Mann–Whitney
Before and after eating cookies, we asked subjects how they evaluated their hunger status. The number of subjects was counted at each level, ranging from no-hunger (1), slightly hungry (2), medium hunger (3), moderately hungry (4), and very hungry (5). Since the numbers of subjects belonging to the no-hunger and very hungry groups were so small, we categorized the subjects into three groups: not hungry (1 + 2), medium hunger (3) and hungry (4 + 5), and the results for OSM, lavender, and control groups are shown in Figure 7-A. The proportion among the three levels was significantly (
Proportion of hunger status. The numbers of subjects in the OSM, lavender, and non-odor control groups are expressed in three categories of hunger status (1, no-hunger; 2, slightly hungry; 3, medium hunger; 4, moderately hungry; 5, very hungry) before and after eating snacks. The hunger status before snack eating was different between OSM and control groups (Friedman test,
After offering a snack package to each subject, which contained 16 pieces of small cookies that could be consumed at will, we counted the remaining cookies. The number of leftover cookies varied greatly among the subjects. To examine any difference of odor effects on cookie eating, the subjects were divided into three subgroups: a high-eating group (with leftovers ranging from zero-to-four cookies), a moderate-eating group (leftovers ranging from five-to-nine cookies), and a low-eating group (leftovers ranging from 10-to-16 cookies). The number of subjects belonging to each subgroup is shown for the three odor conditions in Figure 8. The graphical representation suggests that the subjects in OSM group ate less than those in control group, and this difference was statistically significant (Friedman test and
The numbers of leftover cookies in the three groups. The numbers of subjects who left a small number (zero-to-four) of cookies, a moderate (five-to-nine) number of cookies, and many (10─16) cookies are shown for the OSM, lavender, and non-odor control groups. The OSM group ate fewer cookies compared with the control group (Friedman test,
The palatability score for the cookies was 4.1 ± 0.7 (n = 66), 4.1 ± 0.6 (n = 66), and 4.2 ± 0.6 (n = 66) (mean ± SD) for OSM, lavender, and non-odor control groups, respectively. The sweetness score for the cookies was 3.5 ± 0.8, 3.6 ± 0.7 and 3.6 ± 0.7, respectively. No statistically significant difference in sweetness or palatability was observed among the three groups.
Total mood disturbance (TMD) scores of the Profile of Mood States (POMS) test are shown in Figure 9. The basal mood after lunch (or before putting on the odor mask) varied among the three groups: in the two odor (OSM and lavender) groups and the non-odor control group, the mean TMD scores were standardized to one. The rates of change in mood soon after taking off the mask (or before eating the cookie snack) were compared among the three groups. Statistically significantly (two-tailed paired
Total mood disturbance (TMD) scores before and after odor stimulation. The relative TMD score is shown after odor stimulation when the score before odor stimulation was set at unity. A statistically significant difference was apparent for OSM odor between the pre- and post-odor stimulation scores (two-tailed paired
Previous studies in our laboratory have demonstrated that the odor of OSM attenuates food intake in rodents [18]. The present study was designed to confirm this effect in humans and also to compare the underlying causative mechanisms, in terms of autonomic nerve activity and expression of mRNA for feeding-related neuropeptides, between the OSM odor and grapefruit odor, which also attenuates food intake and body weight gain [16, 17, 31].
It is well established that feeding-related neuropeptides in the hypothalamus play important roles in the elicitation, maintenance, and cessation of appetite and food intake [3, 32, 33]. Previously, our research group revealed that the neural information of OSM odor decreased mRNA expression of orexigenic neuropeptides (AgRP, NPY, MCH, and orexin) and increased expression of anorexigenic neuropeptides (CART and POMC) [18]. These findings are suggested to be, at least in part, the causative mechanisms underlying the effects of OSM odor on the decreased motivation to eat, sluggish masticatory movements, and the resulting reduction in body weight [18, 19]. Since comparative data are not available for the grapefruit odor, the present study examined the expression of feeding-related neuropeptides following exactly the same method we have previously used for the OSM odor. Consequently, we could not detect any difference in the expression of feeding-related neuropeptides between the grapefruit odor group and non-odor control group, indicating that grapefruit odor essentially had no effect on the expression of hypothalamic feeding-related neuropeptides.
Fragrant odors are known to affect the autonomic nerve activity. For example, the odors of rose flowers [13, 15], lavender [34, 35, 36], and yuzu [37] activate parasympathetic neurons, whereas those of lemon [38], jasmine [39] and grapefruit [13, 17, 38, 40] activate sympathetic nerve activity. To our knowledge, there is only one previously published study that suggests that the OSM odor stimulates parasympathetic activity in humans [41]; therefore, more research is required to confirm these findings.
To examine how the OSM odor affects autonomic nerve activity in humans, we used the fingertip photoplethysmogram (PPG) to monitor autonomic nervous activation. Analysis of fingertip PPG signals is an important tool for assessing pulse wave components and their relation to vascular health. Several studies have demonstrated that the PPG waveform can provide clinical information on the dynamics of the autonomic nervous system, as well as the activity of the left ventricle, vascular aging, and arterial stiffness [42, 43, 44]. Although PPG is easy to set up, convenient, simple, and inexpensive, with only a single fingertip sensor, it has been proven that electrocardiogram and PPG signal recordings can be interchanged for heart rate variation (HRV) analysis including the time and frequency domains [45]. The PPG technique is also utilized for the assessment of arterial wall stiffening during aging [46] and for the assessment of the index of the periodontal condition [47].
The present HRV analysis on the basis of PPG has revealed that lavender odor significantly stimulates parasympathetic nerve activity, which is in agreement with previous results [34, 35, 36]. Jasmine odor tended to be a sympathetic activator, but the effect was not significant, which may have reflected an inter-individual difference in the preference for this odor, as suggested by Inoue
The differences in the physiological actions between the OSM and grapefruit odors (as mentioned above) should be derived from the difference in volatile compounds in these odors. There are more than 10 active compounds detected in OSM odor, including major volatiles (such as ocimene, ionone, linalool, capraldehyde, and decalactone) [21, 50]. The major active volatile compound in grapefruit odor is limonene; additional compounds include myrcene, pinene, and linalool [51, 52]. It is noted that not only the major volatiles but some volatiles with low content also contribute to aroma [50]. Further study is required to elucidate the specific role of each compound.
To confirm our previous findings in rodents that the OSM odor attenuates appetite and food intake, we elaborated on an experimental design in which the effect of OSM odor on snack eating behavior was examined in university students. Since OSM odor activates parasympathetic nerve activity (as described above), we selected lavender odor which also stimulates parasympathetic nerve activity for a comparable stimulus. Although sweetness and palatability of cookies were not different after exposure to OSM or lavender odors and in non-odor control group, we found that the hunger level, TMD score, and the numbers of cookies eaten significantly changed in the OSM group, compared with lavender and control groups. After exposure to the odors, subjects in the OSM group felt less hungry than those exposed to lavender or subjects in the control group, suggesting that appetite is reduced after exposure to OSM odor. Consequently, the consumption of cookies after OSM odor was less than that after lavender or non-odor conditions. Such effects in feeding behavior are not due to disagreeable feelings to OSM odor because pleasantness of OSM odor after exposure was not statistically significantly different from that of lavender odor. Moreover, mood states were significantly improved after exposure to OSM odor compared with lavender odor or non-odor conditions, as shown by the POMS data. Thus, the previous finding that the odor of OSM decreases food intake in rodents was modestly confirmed in humans through the present experimental paradigm.
How could the findings of this present study be utilized in our daily life? As it is expected that appetite and meal size could be reduced under the presence of OSM odor, you will be more satisfied (satiated) with a smaller meal size that otherwise would not fulfill your appetite (Figure 10). Repeating this procedure at every meal, you could adjust yourself to eating smaller meals, which could possibly lead to a reduction in body weight. To examine this possibility, we performed a pilot study [53] where five females were exposed to OSM odor daily from the hour of rising to bedtime for 12 days. For delivery of the odor, each subject hung a small case containing a filter paper soaked in OSM essential oils around their neck. At the end of the experiment, the subjects showed a reduction in total body fat and body weight, compared with five females in the non-odor control group. For a practical use, it is necessary to elucidate the most effective and convenient method of odor exposure, or exposure duration. A proper use of the OSM odor as well as grapefruit odor could be an attractive and promising tool to promote ecological eating and to improve and promote good health.
A model showing that a less amount attains the same satiation level after exposure to the
A limitation of our study pertains to the selection of subjects and the duration of odor stimulation. The number of subjects was not enough to analyze the results in terms of sex differences because the number of male subjects was too small to be compared with female subjects. Subjects wore masks with odor continuously for 70 minutes and another 70 minutes, separated by a 20-minute-intermission without masks. Adaptation to odors is a well-known phenomenon: repeated or prolonged exposure to an odorant leads to decreases in olfactory sensitivity to that odorant [54, 55, 56]. According to Inoue
The present human experiments have shown that OSM odor is agreeable and elicits sedative effects, improves mood, attenuates hunger, and reduces food intake. Grapefruit odor, which has also been shown to attenuate food intake, activates sympathetic nerve activity and had no effects on expression of feeding-related neuropeptides in rats, which is contrary to the results obtained for OSM odor, indicating the difference of causative neural mechanisms between the two odors. Exposure to OSM odor before eating and that to grapefruit odor after eating may be recommended as the effective practical use for preventing from overeating and obesity.
The essential oils of odors were supplied by Ryouichi Komaki of the Seisyo Aroma Institute, Kanagawa, Japan. We are grateful to Ryouichi Komaki, Masao Kubota, Satomi Kunieda, and Yuji Minematsu for their contributions (preparing, executing, and analysis the data) to the human feeding behavior experiment. This work was supported by JSPS KAKENHI (Grant Number 17 k00835 to T.Y.) and a grant for Project Research from Kio University.
TY and KU designed the study, KU and TI performed the experiments on humans and animals, respectively, HM performed the data analyses, TY wrote the manuscript, and all authors reviewed and approved the paper.
The authors declare no competing interests.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
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\n\nIn no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
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