Role of antioxidants in the protection against free radical damage
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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.
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\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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The book consists of 23 closely related thematic contributions, which fall into 4 separate sections: Interactions between Economy and Entrepreneurship; Innovation in Entrepreneurship and Economic Growth; Current Trends in Family Business, Social Entrepreneurship and Responsibility; and The Role of Human Resource Management, Education and Gender in Entrepreneurship. Authors-contributors have submitted the results of their recent research and presented essential findings about the decision-making process of entrepreneurs in order to maintain their businesses competitive. The reader can get an insight into the selection of the best scientific contributions that have been reviewed and ready for debate. Our piece of work, Entrepreneurship: Development Tendencies and Empirical Approach, has interdisciplinary features. This work by authors from different countries - Finland, Germany, Czech Republic, Slovakia, Italy, Spain, Turkey and Malaysia - is dedicated to readers providing up-to-date research data and background for further research as well as implementation techniques in business practice.",isbn:"978-953-51-3761-0",printIsbn:"978-953-51-3760-3",pdfIsbn:"978-953-51-4050-4",doi:"10.5772/intechopen.68372",price:139,priceEur:155,priceUsd:179,slug:"entrepreneurship-development-tendencies-and-empirical-approach",numberOfPages:472,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"a486ac3894ef64c8dad75e45a948d9d1",bookSignature:"Ladislav Mura",publishedDate:"January 24th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6165.jpg",numberOfDownloads:30846,numberOfWosCitations:17,numberOfCrossrefCitations:21,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:38,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:76,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 16th 2017",dateEndSecondStepPublish:"April 6th 2017",dateEndThirdStepPublish:"July 20th 2017",dateEndFourthStepPublish:"October 1st 2017",dateEndFifthStepPublish:"December 20th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",middleName:null,surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura",profilePictureURL:"https://mts.intechopen.com/storage/users/85474/images/system/85474.jpg",biography:"Prof. Mura is an associate professor at the Faculty of Economics and Business, Pan-European University in Bratislava, Slovakia. He is a supervisor for master and doctoral students as well as an author of a number of national and international journal articles. His research interests include small and medium enterprises, family business, business innovation, the impact of internationalization on business activities, human resource management.",institutionString:"Pan-European University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Pan-European University",institutionURL:null,country:{name:"Slovakia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"453",title:"Entrepreneurial Economics",slug:"entrepreneurial-economics"}],chapters:[{id:"57488",title:"Entrepreneurs and Growth: An Option, Obligation or Obsession",doi:"10.5772/intechopen.70527",slug:"entrepreneurs-and-growth-an-option-obligation-or-obsession",totalDownloads:1968,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"“Growth” as a word carries a positive tone in it; human beings grow and mature, gaining new knowledge and resources, and so do companies. Growth, however, has never been for all. In competitive markets, some grow and others do not—or grow at slower pace than others. Furthermore, growth is a process that strains the capabilities and resources of an individual, company, and its acting entrepreneurs to their extreme. Growth means also learning and leaving behind something learned of possessed before. Growth disrupts the history and path of a single company and its entrepreneur. The text synthetizes the scattered literature in growth and entrepreneurship. A case study shows how growth is viewed in an entrepreneurial company. The author shows how companies can be categorized to different sub-segments based on their growth opportunities, urge to grow, and growth aspirations. The typical enablers and hindrances of growth hindrances get introduced. The chapter underlines that for some companies, growth is one of the strategic options, whereas to some, it is more of an internal and external obligation. Despite the existence of multiple stage-based models, growth is an individual path and no model should be taken in a law-like manner.",signatures:"Juha Saukkonen",downloadPdfUrl:"/chapter/pdf-download/57488",previewPdfUrl:"/chapter/pdf-preview/57488",authors:[{id:"207054",title:"M.Sc.",name:"Juha",surname:"Saukkonen",slug:"juha-saukkonen",fullName:"Juha Saukkonen"}],corrections:null},{id:"57418",title:"Entrepreneurship and Creative Economy: Mental Models of Cultural Entrepreneurs in Belo Horizonte, Brazil",doi:"10.5772/intechopen.70770",slug:"entrepreneurship-and-creative-economy-mental-models-of-cultural-entrepreneurs-in-belo-horizonte-braz",totalDownloads:1054,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This study aims to analyze the common elements in the mental models of cultural entrepreneurs in Belo Horizonte, Brazil, as well as to contribute to the expansion of public policies that enable the development of such enterprises. The theoretical framework of this study addresses entrepreneurship and the mental models of entrepreneurs in the creative economy sector. The Brazilian government has showed concern with the development of the creative economy sector, considering its importance in the national and international scenario. There is a lack of information and data that describes the specific characteristics and issues of the creative economy. Thus, it is important not only to present a statistical data on the sector, but also qualitative data that can broaden and deepen the knowledge of the sector and its professionals.",signatures:"Anna G.M. Oliveira and Marlene C.O.L. Melo",downloadPdfUrl:"/chapter/pdf-download/57418",previewPdfUrl:"/chapter/pdf-preview/57418",authors:[{id:"207393",title:"M.Sc.",name:"Anna",surname:"Oliveira",slug:"anna-oliveira",fullName:"Anna Oliveira"},{id:"217914",title:"Dr.",name:"Marlene",surname:"Melo",slug:"marlene-melo",fullName:"Marlene Melo"}],corrections:null},{id:"56784",title:"Economic Transition and the Corporate Governance Implementation",doi:"10.5772/intechopen.70533",slug:"economic-transition-and-the-corporate-governance-implementation",totalDownloads:1192,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In Slovakia, the privatization of the state property in the beginning of the 1990s created a need for the corporate governance implementation. The aim of this chapter is to evaluate the level of implementation of corporate governance in Slovakia after more than 25 years since starting the transition from a centrally planned to a market economy, including a legal framework for its implementation. To support our analysis, we explored a relationship between the level of the corporate governance implementation and economic results of corporations. For this purpose, we reviewed annual reports for year 2015 by 27 corporations listed on the Bratislava Stock Exchange. The average profit of the evaluated corporations was approaching 21 million EUR, and the average assets value was at 1.2 billion EUR. Using the scoring method devised by us for this purpose, the average score of the annual report evaluation reached 2.59 points out of maximum 5 points. Finally, we tested a hypothesis that improving the level of corporate governance implementation may contribute to profitability and assets value of corporations.",signatures:"Zuzana Kittová, Dušan Steinhauser and Viera Ružeková",downloadPdfUrl:"/chapter/pdf-download/56784",previewPdfUrl:"/chapter/pdf-preview/56784",authors:[{id:"207431",title:"Associate Prof.",name:"Zuzana",surname:"Kittova",slug:"zuzana-kittova",fullName:"Zuzana Kittova"},{id:"208363",title:"Mr.",name:"Dušan",surname:"Steinhauser",slug:"dusan-steinhauser",fullName:"Dušan Steinhauser"},{id:"216786",title:"Mrs.",name:"Viera",surname:"Ružeková",slug:"viera-ruzekova",fullName:"Viera Ružeková"}],corrections:null},{id:"57461",title:"The Roll of the Entrepreneur in the Establishment of Economic Equilibria",doi:"10.5772/intechopen.70674",slug:"the-roll-of-the-entrepreneur-in-the-establishment-of-economic-equilibria",totalDownloads:1016,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In this chapter, a simple market model is presented to illustrate how random entrepreneurial activity can be responsible for the establishment of economic equilibria without the assumption of perfect knowledge. In this model it is assumed that the entrepreneurs (both traders and producers) have no information regarding the other entrepreneurs’ preferences, wealth, or production skills. The only information they have is the past transaction prices, and yet this information is sufficient for the market to reach equilibrium price. Equilibrium is not a stationary process on the microscopic level. It is a process, which consists of interactions between entrepreneurs, who act randomly without insight. Consequently, the market price continuously oscillates randomly around the equilibrium values. The higher the risk the producers are willing to take, the more stable is the equilibrium. When entrepreneurial actions are depressed, the market may drift from its optimal point. This model also investigates the more realistic scenario, in which, due to specialization, the production boundary frontiers are convex (instead of linear). It is shown that in this case, the drifts are suppressed and the optimal equilibrium is more stable. Moreover, the amount of risk aversion has a clear effect on the production growth of the economy. The lower the risk aversion is, the higher is the growth rate of the economy.",signatures:"Er’el Granot",downloadPdfUrl:"/chapter/pdf-download/57461",previewPdfUrl:"/chapter/pdf-preview/57461",authors:[{id:"181601",title:"Prof.",name:"Er'El",surname:"Granot",slug:"er'el-granot",fullName:"Er'El Granot"}],corrections:[{id:"65667",title:"Erratum - The Roll of the Entrepreneur in the Establishment of Economic Equilibria",doi:null,slug:"erratum-the-roll-of-the-entrepreneur-in-the-establishment-of-economic-equilibria",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]},{id:"57750",title:"Determinants of Established Entrepreneurs’ Innovative Activity in Northern and Western Europe",doi:"10.5772/intechopen.71843",slug:"determinants-of-established-entrepreneurs-innovative-activity-in-northern-and-western-europe",totalDownloads:1005,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"For established entrepreneurs from Western European economies (WEEs) and Northern European economies (NEEs), we estimated relationships between firms’ innovative activity and their owner-managers’ educational level, the firms’ international orientation, and their growth aspirations. International orientation proved to be positively and significantly related to innovative activity in both groups, but associations were stronger in NEEs. Established entrepreneurs with higher educational levels are more innovative than those with less education, with an exception for NEEs, where more innovative are entrepreneurs with a secondary instead of a postsecondary degree. Established entrepreneurs with growth aspirations are more innovative only for the NEEs. The empirical results confirm our two hypotheses for both groups of economies, whereas the third hypothesis which suggests that established entrepreneurs with aspirations for growing their firms are expected to be more innovative is confirmed only for the NEEs.",signatures:"Karin Širec and Dijana Močnik",downloadPdfUrl:"/chapter/pdf-download/57750",previewPdfUrl:"/chapter/pdf-preview/57750",authors:[{id:"208473",title:"Prof.",name:"Karin",surname:"Širec",slug:"karin-sirec",fullName:"Karin Širec"},{id:"221122",title:"Prof.",name:"Dijana",surname:"Močnik",slug:"dijana-mocnik",fullName:"Dijana Močnik"}],corrections:null},{id:"57068",title:"Business Intelligence: An Innovative Technological Way to Influence Corporate Entrepreneurship",doi:"10.5772/intechopen.70538",slug:"business-intelligence-an-innovative-technological-way-to-influence-corporate-entrepreneurship",totalDownloads:1853,totalCrossrefCites:7,totalDimensionsCites:7,hasAltmetrics:1,abstract:"Adaptation to dynamism and complex environments in today’s Knowledge Society is key for firms to survive and improve their positions. This paper applies business intelligence (BI) to the firm to shape its organizational design and improve its performance. The paper also relates business intelligence to organizational performance management through organizational learning (OL), knowledge management (KM) and the technological competencies of the company’s employees and managers. Theoretical study of the main current research serves as the basis for the development of several propositions to fill the gaps in knowledge of business intelligence. Finally, the paper presents conclusions about application of business intelligence in firms.",signatures:"Reyes Giménez-Figueroa, Rodrigo Martín-Rojas and Víctor Jesús\nGarcía-Morales",downloadPdfUrl:"/chapter/pdf-download/57068",previewPdfUrl:"/chapter/pdf-preview/57068",authors:[{id:"208170",title:"Associate Prof.",name:"Rodrigo",surname:"Martin-Rojas",slug:"rodrigo-martin-rojas",fullName:"Rodrigo Martin-Rojas"},{id:"208171",title:"Ms.",name:"Reyes",surname:"Giménez-Figueroa",slug:"reyes-gimenez-figueroa",fullName:"Reyes Giménez-Figueroa"},{id:"208172",title:"Prof.",name:"Victor Jesus",surname:"Garcia-Morales",slug:"victor-jesus-garcia-morales",fullName:"Victor Jesus Garcia-Morales"}],corrections:null},{id:"56990",title:"Entrepreneurship and Sustainability as Key Elements for Innovation: A Brazilian Dilemma",doi:"10.5772/intechopen.70771",slug:"entrepreneurship-and-sustainability-as-key-elements-for-innovation-a-brazilian-dilemma",totalDownloads:1356,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Considering the socio-economic reality of Brazil and from the relevance of the issues related to entrepreneurship and organizational innovation in the country, the importance of sustainability for the organizations could become a solution for the integration of entrepreneurship with innovation. The objective of this research is to highlight the relevance of sustainability for organizations as a way to trigger the integration of entrepreneurship toward innovation in the Brazilian context. Various exploratory and descriptive researches on the dynamics of entrepreneurship, innovation and sustainability in the main organizations of the Serra Gaúcha (RS), Brazil were carried out through the Multidisciplinary Research Group on Innovation and Competitiveness, in partnership with a research Nucleus on Innovation, Entrepreneurship and Sustainability. The main results indicate that the key sectors of this Brazilian regional economy present less “innovation intensity,” which are mainly characterized by internal organizational activities of innovation, preventing them to become “regional systems of innovation,” and which presupposes the lack of sustainability. Those limitations can be characterized as “innovation ghettos.” In that logic, the researchers have also demonstrated the presence of “ghettos of sustainability, ghettos of innovation, and therefore, ghettos of sustainability and innovation” in the sectors of this Brazilian regional economy, but in differentiated and restricted perspectives",signatures:"Eric Charles Henri Dorion, Pelayo Munhoz Olea, François Coallier,\nCleber Cristiano Prodanov, Eliana Andrea Severo, Julio Cesar Ferro\nGuimarães, Cristine Hermann Nodari, Ana Cristina Fachinelli, Vânia\nBeatriz Merlotti Heredia, Fernando Fantoni Bencke, Nilson Varella\nRubenich, Paula Patricia Ganzer, Claudio Baltazar Corrêa De Mello,\nAdrieli Alves Pereira Radaelli, Cassiane Chais, Oberdan Teles Da\nSilva, Luana Folchini Da Costa, Vanessa Machado, Joel Tshibamba\nMukendi and Vandoir Welchen",downloadPdfUrl:"/chapter/pdf-download/56990",previewPdfUrl:"/chapter/pdf-preview/56990",authors:[{id:"22626",title:"Dr.",name:"Eric",surname:"Dorion",slug:"eric-dorion",fullName:"Eric Dorion"},{id:"114255",title:"Dr.",name:"Eliana Andrea",surname:"Severo",slug:"eliana-andrea-severo",fullName:"Eliana Andrea Severo"},{id:"137241",title:"Dr.",name:"Pelayo Munhoz",surname:"Olea",slug:"pelayo-munhoz-olea",fullName:"Pelayo Munhoz Olea"},{id:"137242",title:"Dr.",name:"Cristine Hermann",surname:"Nodari",slug:"cristine-hermann-nodari",fullName:"Cristine Hermann Nodari"},{id:"204862",title:"Dr.",name:"Paula Patricia",surname:"Ganzer",slug:"paula-patricia-ganzer",fullName:"Paula Patricia Ganzer"},{id:"204863",title:"Dr.",name:"Claudio Baltazar",surname:"Corrêa de Mello",slug:"claudio-baltazar-correa-de-mello",fullName:"Claudio Baltazar Corrêa de Mello"},{id:"209651",title:"Dr.",name:"Vânia Beatriz Merlotti",surname:"Heredia",slug:"vania-beatriz-merlotti-heredia",fullName:"Vânia Beatriz Merlotti Heredia"},{id:"209653",title:"Dr.",name:"François",surname:"Coallier",slug:"francois-coallier",fullName:"François Coallier"},{id:"209654",title:"Dr.",name:"Cleber Cristiano",surname:"Prodanov",slug:"cleber-cristiano-prodanov",fullName:"Cleber Cristiano Prodanov"},{id:"209655",title:"MSc.",name:"Adrieli Alves",surname:"Pereira Radaelli",slug:"adrieli-alves-pereira-radaelli",fullName:"Adrieli Alves Pereira Radaelli"},{id:"209656",title:"MSc.",name:"Oberdan",surname:"Teles Da Silva",slug:"oberdan-teles-da-silva",fullName:"Oberdan Teles Da Silva"},{id:"209657",title:"BSc.",name:"Luana",surname:"Folchini Da Costa",slug:"luana-folchini-da-costa",fullName:"Luana Folchini Da Costa"},{id:"209658",title:"BSc.",name:"Vanessa",surname:"Machado",slug:"vanessa-machado",fullName:"Vanessa Machado"},{id:"209659",title:"BSc.",name:"Joel",surname:"Tshibamba Mukendi",slug:"joel-tshibamba-mukendi",fullName:"Joel Tshibamba Mukendi"},{id:"209660",title:"BSc.",name:"Vandoir",surname:"Welchen",slug:"vandoir-welchen",fullName:"Vandoir Welchen"},{id:"209712",title:"M.Sc.",name:"Cassiane",surname:"Chais",slug:"cassiane-chais",fullName:"Cassiane Chais"},{id:"209728",title:"Dr.",name:"Julio Cesar Ferro",surname:"Guimarães",slug:"julio-cesar-ferro-guimaraes",fullName:"Julio Cesar Ferro Guimarães"},{id:"209844",title:"Dr.",name:"Fernando Fantoni",surname:"Bencke",slug:"fernando-fantoni-bencke",fullName:"Fernando Fantoni Bencke"},{id:"209845",title:"Dr.",name:"Nilson Varella",surname:"Rubenich",slug:"nilson-varella-rubenich",fullName:"Nilson Varella Rubenich"},{id:"209852",title:"Dr.",name:"Ana Cristina",surname:"Fachinelli",slug:"ana-cristina-fachinelli",fullName:"Ana Cristina Fachinelli"}],corrections:null},{id:"57588",title:"Entrepreneurship and Consulting",doi:"10.5772/intechopen.70673",slug:"entrepreneurship-and-consulting",totalDownloads:1341,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"For entrepreneurs, counselling means one of the ways how to overcome the challenges of developing markets and the environment through flexibility and creative innovation potential. It brings effects in the form of problem solving with the help of a counsellor and by adjusting the business entity to the change that this solution brings. All changes, suggested or implemented by counsellors, should contribute directly or indirectly to improving business performance and improving overall business performance. Therefore, the task and the aim of counselling are to find new solutions and optimize the entire corporate system, which is reflected in the savings and economic growth of a business as a measurable effect.",signatures:"Eva Hanuláková and Ferdinand Daňo",downloadPdfUrl:"/chapter/pdf-download/57588",previewPdfUrl:"/chapter/pdf-preview/57588",authors:[{id:"207780",title:"Prof.",name:"Eva",surname:"Hanulakova",slug:"eva-hanulakova",fullName:"Eva Hanulakova"},{id:"207781",title:"Prof.",name:"Ferdinand",surname:"Dano",slug:"ferdinand-dano",fullName:"Ferdinand Dano"}],corrections:null},{id:"57541",title:"Family Business: Experience from the Czech Republic",doi:"10.5772/intechopen.71020",slug:"family-business-experience-from-the-czech-republic",totalDownloads:1014,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The chapter deals with problems of small family-owned companies in the Czech Republic. The main aim of the chapter is to describe a family business in the Czech Republic. The partial aims of the chapter are as follows: presentation of family business definition used in investigation of Czech family businesses and model of successful transfer of power to the next generation called “relay.” This chapter uses a research methodology of the secondary as well as primary data collection. In the frame of secondary data collection, the data were obtained from the company’s websites as well as from the official Amadeus database and those by the Czech Statistical Office. The collection method of primary data was based on interviews with the company’s founder and his children and on the questionnaire survey. So gained interview results were transformed into the paper form and then transcribed. The research case study was analysed and focused on the case. This chapter states the results of qualitative research regarding a small family-owned company, called Kaláb—Building Company, Ltd. The concerning research part has the form of a case study. Two models are given in discussion of research results: (1) strategy of small family-owned enterprise and (2) power delegation in a family-owned enterprise.",signatures:"Vojtěch Koráb and Anastasia Murinova",downloadPdfUrl:"/chapter/pdf-download/57541",previewPdfUrl:"/chapter/pdf-preview/57541",authors:[{id:"207366",title:"Prof.",name:"Vojtěch",surname:"Koráb",slug:"vojtech-korab",fullName:"Vojtěch Koráb"},{id:"207367",title:"Ph.D. Student",name:"Anastasia",surname:"Murinova",slug:"anastasia-murinova",fullName:"Anastasia Murinova"}],corrections:null},{id:"57899",title:"Investment in Microenterprises for Scaling up Business Growth: Evidence from Social Business Project",doi:"10.5772/intechopen.72126",slug:"investment-in-microenterprises-for-scaling-up-business-growth-evidence-from-social-business-project",totalDownloads:1277,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Promoting entrepreneurship among the youth and women is an emerging global trend for inclusive sustainable development. This study aims to unlock the potential of social business investments in microenterprises for turning unemployment into entrepreneurship and scaling up business growth. According to Prof Yunus, “social business is selfless business to solve social problems” based on seven principles. The study has selected 264 enterprises of Nobin Udyokta (NU) meaning new entrepreneurs under Nobin Udyokta Project (NUP) of Grameen Telecom Trust (GTT). NUs and GTT have co-investments under equity participation for at least one or more than 1 year. NUs are basically emerging micro entrepreneurs, who are often disproportionately burdened with multi-dimensions of poverty and lack of working capital, which inhibits business growth. Findings of regression analysis show that social business fund can significantly influence the growth of NU enterprises and increased investment can also create more employments. Therefore, this study is having value to the promoter, advocates, investors in social enterprises, and policy makers seeking strategy for reducing poverty and unemployment through entrepreneurship for sustainable development leaving no one behind.",signatures:"Farhana Ferdousi and Parveen Mahmud",downloadPdfUrl:"/chapter/pdf-download/57899",previewPdfUrl:"/chapter/pdf-preview/57899",authors:[{id:"198685",title:"Dr.",name:"Farhana",surname:"Ferdousi",slug:"farhana-ferdousi",fullName:"Farhana Ferdousi"},{id:"208422",title:"Mrs.",name:"Parveen",surname:"Mahmud",slug:"parveen-mahmud",fullName:"Parveen Mahmud"}],corrections:null},{id:"57218",title:"Social Entrepreneurship in an Inclusive Business Model: A New Business Model for Sustainable Agroforestry",doi:"10.5772/intechopen.70295",slug:"social-entrepreneurship-in-an-inclusive-business-model-a-new-business-model-for-sustainable-agrofore",totalDownloads:1597,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Business’s role in society is expanding; they are held accountable not only for their (traditional) business conduct but also for institutional development that leads to alleviation of poverty as well as institutional development. The aim of the case study is to identify critical factors for the implementation of an inclusive business model. These factors are contextualized at a regional and local level as a part of an ongoing agro-food project. The forestry company’s operations in Lao PDR, offers an understanding of challenges related to political, social and financial sourcing conditions in needs of an inclusive business model. Creating the shared values relates to creating job opportunities, embracing gender aspects and engaging in institutional development in marginalized communities. A key factor in the development is a social entrepreneur, who re-creates a new community of practice by coordinating corporate strategies with local and regional needs. This case study offers a narrative of the development of a new context bound business model that positively influences the development of a multinational enterprise, an industry, a local community and academic understanding of what might become a dominant discourse for industrial upgrade and sustainable development.",signatures:"Cecilia Mark-Herbert and Brita Prejer",downloadPdfUrl:"/chapter/pdf-download/57218",previewPdfUrl:"/chapter/pdf-preview/57218",authors:[{id:"121344",title:"Dr.",name:"Cecilia",surname:"Mark-Herbert",slug:"cecilia-mark-herbert",fullName:"Cecilia Mark-Herbert"},{id:"215924",title:"MSc.",name:"Brita",surname:"Prejer",slug:"brita-prejer",fullName:"Brita Prejer"}],corrections:null},{id:"56866",title:"Entrepreneurship with Social Responsibility",doi:"10.5772/intechopen.70609",slug:"entrepreneurship-with-social-responsibility",totalDownloads:1728,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Since the second half of the twentieth century, the society’s thinking about the behavior of companies has gradually begun to change. Companies are expected to use their power and finances to influence life around themselves, especially their quality. The corporate social responsibility (CSR) concept is a very progressive management approach that focuses on long-term goals and long-term returns. CSR seeks to harmonize relationships with stakeholders, which the company identifies and implements activities that go beyond legal and ethical standards. A socially responsible company performs something extra volunteer, conducts dialog with its stakeholders, and invests in improving relationships. The Department of Economics of the University of Žilina conducted a marketing survey entitled “Perceptions of Corporate Social Responsibility and its Communication by Companies”. The survey was conducted to find out how companies in Slovakia use the CSR concept and what is the level of their communication about this concept in relation to the external environment. Anonymous questionnaire method was used to obtain this data. The method of induction and deduction was used to process the obtained data and the phenomena investigated and to generalize and produce conclusions. Mathematical and statistical methods were used to evaluate survey data, and the synthesis method was used to create recommendations for companies.",signatures:"Anna Križanová, Katarína Moravčíková and Jana Klieštiková",downloadPdfUrl:"/chapter/pdf-download/56866",previewPdfUrl:"/chapter/pdf-preview/56866",authors:[{id:"207368",title:"Ph.D. Student",name:"Katarína",surname:"Moravčíková",slug:"katarina-moravcikova",fullName:"Katarína Moravčíková"},{id:"217839",title:"Prof.",name:"Anna",surname:"Križanová",slug:"anna-krizanova",fullName:"Anna Križanová"},{id:"218210",title:"Dr.",name:"Jana",surname:"Klieštiková",slug:"jana-kliestikova",fullName:"Jana Klieštiková"}],corrections:null},{id:"56823",title:"Importance of Corporate Governance in Socially Responsible Behaviour of Enterprises",doi:"10.5772/intechopen.70536",slug:"importance-of-corporate-governance-in-socially-responsible-behaviour-of-enterprises",totalDownloads:1340,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Many organisations have already realised that if they want to be successful, they must have a sense of responsibility not only for their business activities, but also for the whole society. That approach is entirely consistent with the basic idea of the concept of corporate social responsibility (CSR). In the economic area of the CSR concept, corporate governance plays an important role. Based on the OECD definition, corporate governance (CG) is a system by which business corporations are directed and controlled. The chapter provides the first comprehensive survey of corporate governance, the way to estimate the level of CG to individual companies on the Slovak capital market through our own corporate governance index. In analytical part of this chapter, we investigate disclosure of corporate governance in selected enterprises in Slovakia for the period 2011?2015 and on the basis of this information we prepare a corporate governance index. The corporate governance index helps assess the level of compliance with CG principles in companies whose securities are listed on the Bratislava Stock Exchange. The chapter fulfils a need for advancing knowledge on corporate governance and provides a practical framework for responsible behaviour of shareholders and managers in socially responsible enterprises.",signatures:"Hussam Musa, Zdenka Musová and Lenka Debnárová",downloadPdfUrl:"/chapter/pdf-download/56823",previewPdfUrl:"/chapter/pdf-preview/56823",authors:[{id:"208526",title:"Associate Prof.",name:"Hussam",surname:"Musa",slug:"hussam-musa",fullName:"Hussam Musa"},{id:"208548",title:"Prof.",name:"Zdenka",surname:"Musová",slug:"zdenka-musova",fullName:"Zdenka Musová"},{id:"208596",title:"Dr.",name:"Lenka",surname:"Debnárová",slug:"lenka-debnarova",fullName:"Lenka Debnárová"}],corrections:null},{id:"57585",title:"Management of Human Resource in Small and Medium-Sized Enterprises: Case Study",doi:"10.5772/intechopen.70294",slug:"management-of-human-resource-in-small-and-medium-sized-enterprises-case-study",totalDownloads:1712,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Strategic management is a current direction of management types. It is applied in all types of businesses, including small and medium-sized enterprises. However, the use of its principles is limited in SMEs. The limits are caused by the size of these enterprises related to greater focus on operational management. For SMEs, cumulating of functions is also typical; oral communication is more common than written, etc. Despite those limitations, implementation of strategic principles in the management of SMEs is able to increase their competitiveness, reduce costs, improve decision-making, facilitate the introduction of employee motivation, shorten delivery times, provide better customer care, etc. The paper discusses whether and to what extent SMEs implement the principles of strategic management and whether its use is effective. The basic principle of strategic management is the formulation and selection of a strategy. Most of the SMEs in the sample formulated a strategy. However, a written strategy was designed mostly by enterprises with more than 25 employees; enterprises with fewer employees designed a written strategy only exceptionally. Classified by the type of activity, a strategy is seen less frequently in wood-work enterprises. On the other hand, enterprises operating in trade and services, including transport, designed a strategy, or even a written strategy, the most often. Quality and stabilisation were the most monitored characteristics, regardless of the number of employees or business type. Profit was the least monitored strategy in the sample. Positive effects after the introduction of strategic management principles were rated as significant by 27% of the subjects analysed and by 36% as moderate, and 38% of enterprises had no positive effects. The most striking positive effect, after the introduction of strategic management principles, was achieved by 44% in decision-making and costs. The smallest number of enterprises, only 8%, had a positive effect of the introduction of strategic management principles in the area of internal communication. The results show that the introduction of strategic management has a positive impact on small and medium enterprises, and it is highly desirable that its principles were introduced into these entities.",signatures:"Darja Holátová and Monika Březinová",downloadPdfUrl:"/chapter/pdf-download/57585",previewPdfUrl:"/chapter/pdf-preview/57585",authors:[{id:"208227",title:"Ph.D.",name:"Monika",surname:"Březinová",slug:"monika-brezinova",fullName:"Monika Březinová"},{id:"208275",title:"Dr.",name:"Monika",surname:"Březinová",slug:"monika-brezinova",fullName:"Monika Březinová"}],corrections:null},{id:"57679",title:"Understanding the Motivation that Shapes Entrepreneurship Career Intention",doi:"10.5772/intechopen.70786",slug:"understanding-the-motivation-that-shapes-entrepreneurship-career-intention",totalDownloads:1345,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Entrepreneurship intention for graduate students like many other job and work career options depends on other considerations. Individuals who pursue their intentions are most likely to implement their intention. Interest in entrepreneurship as career appears to be growing. Reviews show the need in investigating the determinants of entrepreneurship as a career intention of students and it has remains the focus of most of the recent studies. This is due to the facts that entrepreneurs are creating jobs and driving economic development of a nation. In this study, the Theory of Planned Behaviour is applied to investigate students’ entrepreneurial motivation and entrepreneurship intention. A total of 413 sets of completed questionnaire collected using the structured sampling methodology from the various faculties, races and student seniority at a University located in Batu Pahat, Johor, Malaysia were used in the analyses. The factors of entrepreneurial motivation affecting career entrepreneurship intention were found to be behavioural control, subjective norm, and attitude towards entrepreneurship. Behavioural control is found to be at a very good level while subjective norm and attitude towards entrepreneurship are both at a good level. Multiple regression analyses indicated that subjective norm and attitude of self-employment are both significantly related to student immediate and future entrepreneurship intentions. The behavioural control entrepreneurial motivation indicated significant relationship with student immediate career intention. However it was found that it is not related to entrepreneurship career intention. This study implies that young aspirant entrepreneur can be identified and targeted for development via the Planned Behaviour model for entrepreneurial interventions initiatives.",signatures:"Ng Kim-Soon, Abdul Rahman Ahmad and Nurul Nadia Ibrahim",downloadPdfUrl:"/chapter/pdf-download/57679",previewPdfUrl:"/chapter/pdf-preview/57679",authors:[{id:"109304",title:"Prof.",name:"Kim-Soon",surname:"Ng",slug:"kim-soon-ng",fullName:"Kim-Soon Ng"}],corrections:null},{id:"57560",title:"Entrepreneurship, Leadership and Charisma: Which Are the Links with Business Models Sustainability?",doi:"10.5772/intechopen.70535",slug:"entrepreneurship-leadership-and-charisma-which-are-the-links-with-business-models-sustainability-",totalDownloads:1435,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Leadership ethics tend to emphasise the benefits of implementing ethical practices within organisations, focussing on the importance of a leader’s values and virtues and the positive effects of a leader’s behaviour on employees’ satisfaction, the organisational culture and stakeholders’ relationships. Drawing from this premise, the work addresses entrepreneurial and managerial leadership model, such as charismatic and virtues-based leadership, and its contribution in developing sustainability-oriented strategy. Using a methodological approach which merges the inductive and deductive perspective, a critical review of leadership approaches is followed by the empirical analysis based on a case study relative to a large Italian public company—Brunello Cucinelli Spa—driving attention to the effectiveness of sustainable business models which require managers and entrepreneurs to govern the internal and external complexity and actively contribute to both the sustainability of the company and the local and global environment.",signatures:"Mara Del Baldo",downloadPdfUrl:"/chapter/pdf-download/57560",previewPdfUrl:"/chapter/pdf-preview/57560",authors:[{id:"208657",title:"Dr.",name:"Mara",surname:"Del Baldo",slug:"mara-del-baldo",fullName:"Mara Del Baldo"}],corrections:null},{id:"57811",title:"Entrepreneurship in Higher Education: The Effect of Academy, Motivation, Resources, Incentives, and Self-Efficacy in the Entrepreneurship Potential",doi:"10.5772/intechopen.71695",slug:"entrepreneurship-in-higher-education-the-effect-of-academy-motivation-resources-incentives-and-self-",totalDownloads:1085,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Entrepreneurship in higher education is a current and relevant topic. The objective of this study is to analyze to what extent the entrepreneurial potential of polytechnic higher education students can be predicted from entrepreneurial motivations, opportunities, and resources to undertake, incentives to entrepreneurship, and self-perception of student efficacy, controlling for academic preparation and desire to undertake. Body—Research methods: Through the analysis of the reasons that encourage higher education students to undertake, a survey was carried out to 6532 students of Portuguese Polytechnic Institutes, who answered to the following measures: scale of opportunities and resources to undertake, scale of entrepreneurial motivations, scale of incentives to entrepreneurship, entrepreneurial potential, academic preparation to undertake, and desire to undertake. Conclusion—Key results: Hierarchical multiple regression analysis showed that academic preparation to undertake explained R2 = 5% of entrepreneurial potential, followed by motivations to undertake (ΔR2 = 11.5%), opportunities and resources to undertake (ΔR2 = 1.4%), incentives to undertake (ΔR2 = 0.7%), and self-efficacy (ΔR2 = 3.6%). The results are discussed taking into account the models of entrepreneurship and the importance of the academic preparation to undertake.",signatures:"Pedro Miguel Dinis Santos Parreira, Lisete dos Santos Mónico, Carla\nMaria Santos de Carvalho and Alexandra Cristina Riscado da Silva",downloadPdfUrl:"/chapter/pdf-download/57811",previewPdfUrl:"/chapter/pdf-preview/57811",authors:[{id:"208247",title:"Ph.D.",name:"Pedro",surname:"Parreira",slug:"pedro-parreira",fullName:"Pedro Parreira"},{id:"208268",title:"Prof.",name:"Carla",surname:"Carvalho",slug:"carla-carvalho",fullName:"Carla Carvalho"},{id:"208269",title:"Prof.",name:"Lisete",surname:"Mónico",slug:"lisete-monico",fullName:"Lisete Mónico"},{id:"208271",title:"MSc.",name:"Alexandra",surname:"Silva",slug:"alexandra-silva",fullName:"Alexandra Silva"}],corrections:null},{id:"57170",title:"Higher Education, Entrepreneurship and Learning by Practice: Collaborative Work from the Stakeholders’ Point of View",doi:"10.5772/intechopen.70539",slug:"higher-education-entrepreneurship-and-learning-by-practice-collaborative-work-from-the-stakeholders-",totalDownloads:1040,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The involvement of different stakeholders has created a positive dynamics in the context of higher education, on the one hand by the reinforcement of entrepreneurship linked to innovation, the transference of technology, and the creation of companies and on the other hand by offering extracurricular activities in the formal curricular plans involving different academic stakeholders. Although there are countless initiatives and entrepreneurship programmes, in Portugal there are no (or, at least, no known) studies that analyse the non-formal and informal apprenticeships conceived and implemented by the stakeholders in order to clarify the potential development of entrepreneurial competences. Our results gathered from the research project: “Entrepreneurial learnings, cooperation and labour market: good practices in higher education (POAT-FSE)” show which are the main stakeholders or interface institutions between the university and the surrounding community in the process of technological and knowledge transfer. Our analysis proceeds to a report of the profiles, fields of work, advantages and factors of marked obstacles. By highlighting the contributions of these results, used for the innovation and revitalisation of the partnership networks in the field of science, technology and knowledge transfer, we intend to anchor the discussion about the relevance of the stakeholders in European Higher Education governance.",signatures:"Ana Paula Marques",downloadPdfUrl:"/chapter/pdf-download/57170",previewPdfUrl:"/chapter/pdf-preview/57170",authors:[{id:"208274",title:"Prof.",name:"Ana Paula",surname:"Marques",slug:"ana-paula-marques",fullName:"Ana Paula Marques"}],corrections:null},{id:"57253",title:"The Entrepreneurship in Communication as an Educational- Learning Method: University Teaching and Educommunication",doi:"10.5772/intechopen.71369",slug:"the-entrepreneurship-in-communication-as-an-educational-learning-method-university-teaching-and-educ",totalDownloads:1041,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This text is based on a study that was done with the aim of analysing the development of university training processes through real entrepreneurship projects. The research was carried out using the study case modality, and it was focused on observing the teaching methodology variations according to the implementation—or not—of a real entrepreneurship project as a method in a certain subject, collecting data of both the faculty and the students. Departing from the current situation of economic crisis and unemployment in Spain and from the despondency and discouragement situation of the students in their latest years of university studies, the self-employment is set up as a new job opportunity for the training projects of these university students. This study departs from the inclusion of an entrepreneurship plan as a method of evaluation and teaching in several subjects belonging to Advertising and Public Relations studies. With this entrepreneurship model, we study the formative consequences for the students and the impact on the society. Results showed a common methodological pattern regardless of the training model of the subject—obligatory entrepreneurship versus optional entrepreneurship—and a faculty interest in alternating several methodologies.",signatures:"Gloria Jiménez-Marín, Rodrigo Elías Zambrano and Elena Bellido-\nPérez",downloadPdfUrl:"/chapter/pdf-download/57253",previewPdfUrl:"/chapter/pdf-preview/57253",authors:[{id:"213908",title:"Dr.",name:"Gloria",surname:"Jiménez-Marín",slug:"gloria-jimenez-marin",fullName:"Gloria Jiménez-Marín"},{id:"216693",title:"Dr.",name:"Rodrigo",surname:"Elías Zambrano",slug:"rodrigo-elias-zambrano",fullName:"Rodrigo Elías Zambrano"},{id:"216694",title:"MSc.",name:"Elena",surname:"Bellido Pérez",slug:"elena-bellido-perez",fullName:"Elena Bellido Pérez"}],corrections:null},{id:"58157",title:"Business Plan: In or Out? A Holistic View of the Combination of Planning and Learning Processes when Evaluating Business Opportunities",doi:"10.5772/intechopen.71844",slug:"business-plan-in-or-out-a-holistic-view-of-the-combination-of-planning-and-learning-processes-when-e",totalDownloads:1758,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Entrepreneurship is an important driver of innovation that is a critical factor to boost the competitiveness of modern economies. However, the rate of failure of start-ups tends to be quite significant. This chapter offers a new understanding of entrepreneurship inasmuch as a particular attention is given to different insights on the business plan in the creation of start-ups. In this context, we propose a broader understanding of the business plan integrating it in a holistic understanding of the business planning process. This investigation project results from the merits associated with the concomitant approach that combines planning and learning when creating new businesses. We support the adoption of this approach by developing a scheme that combines two processes that seem to be opposite. One focuses on the business planning and the other on the information collected from customers and other stakeholders. This scheme is likely to guide entrepreneurs and managers when they choose the concomitant approach that combines planning and learning over the other approaches previously studied. Furthermore, we also establish the foundation for future scientific research to develop a framework that can be used to help decrease the number of new businesses that do not survive in the market.",signatures:"Sandra Filipa Moreira Fernandes, Amélia Maria Pinto da Cunha\nBrandão and Carlos Henrique Figueiredo e Melo de Brito",downloadPdfUrl:"/chapter/pdf-download/58157",previewPdfUrl:"/chapter/pdf-preview/58157",authors:[{id:"143325",title:"Prof.",name:"Carlos",surname:"Brito",slug:"carlos-brito",fullName:"Carlos Brito"},{id:"217805",title:"M.Sc.",name:"Sandra",surname:"Fernandes",slug:"sandra-fernandes",fullName:"Sandra Fernandes"},{id:"222064",title:"Prof.",name:"Amélia",surname:"Brandão",slug:"amelia-brandao",fullName:"Amélia Brandão"}],corrections:null},{id:"57198",title:"Does Gender Matter in Strategies Adopted to Face the Economic Crisis? A Comparison Between Men and Women Entrepreneurs",doi:"10.5772/intechopen.70292",slug:"does-gender-matter-in-strategies-adopted-to-face-the-economic-crisis-a-comparison-between-men-and-wo",totalDownloads:1182,totalCrossrefCites:5,totalDimensionsCites:12,hasAltmetrics:0,abstract:"The purpose of this paper is to understand how Italian micro-entrepreneurs responded to the economic crisis and strategies they adopted to deal with it. A comparison between male and female entrepreneurs is presented, in order to understand if they adopted similar or different strategies. The paper also aims to understand if variables, other than gender, influenced strategies adopted to face the economic crisis. Drawing from a telephone questionnaire survey involving a sample of 300 (150 male and 150 female) owners of Italian micro-enterprises, located in Marche Region, findings suggest that entrepreneurs mostly dealt with the crisis through a defensive approach (restructuring and resizing strategies). Compared to men, female entrepreneurs had a lower propensity towards offensive strategies (innovation, development and growth). Differences in the approach towards the crisis were also identified with respect to company’s age, industry and impact of the crisis. These findings contribute to the debate on gender-based differences in behaviors, attitudes and preferences. Moreover, they can help to identify economic policy measures useful to help men and women entrepreneurs to address the crisis. Policy-makers who want to support female entrepreneurship should consider these aspects, in order to identify tools and policies that can help female firms to resist the crisis more effectively in the short-term and to seize new market opportunities in the recovery phase. The sample is restricted to sole proprietors and to a limited geographical context. So further analysis should involve companies of different sizes and located in different geographical contexts, both in Italy and abroad.",signatures:"Andrea Buratti, Francesca Maria Cesaroni and Annalisa Sentuti",downloadPdfUrl:"/chapter/pdf-download/57198",previewPdfUrl:"/chapter/pdf-preview/57198",authors:[{id:"207476",title:"Associate Prof.",name:"Francesca Maria",surname:"Cesaroni",slug:"francesca-maria-cesaroni",fullName:"Francesca Maria Cesaroni"},{id:"207528",title:"Dr.",name:"Annalisa",surname:"Sentuti",slug:"annalisa-sentuti",fullName:"Annalisa Sentuti"},{id:"207529",title:"Dr.",name:"Andrea",surname:"Buratti",slug:"andrea-buratti",fullName:"Andrea Buratti"}],corrections:null},{id:"57829",title:"Testing Gender Productivity Difference with Informal Enterprises Data: A Case Study of Burkina Faso",doi:"10.5772/intechopen.71696",slug:"testing-gender-productivity-difference-with-informal-enterprises-data-a-case-study-of-burkina-faso",totalDownloads:955,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In the literature, we have seen results stating that women are less efficient than men in entrepreneurship. In this chapter, we have used data of informal enterprises in Burkina Faso to test gender productivity difference. Our data support the assumption that men’s enterprises employ and carry out more income than women’s enterprises. Nevertheless, women’s enterprises are technically more efficient and stable than men’s enterprises. We have also found out that to succeed in entrepreneurship, it is profitable for women to be young. However, men need to get more experiences in order to become efficient in informal entrepreneurship.",signatures:"Akouwerabou Babikigalaga Dénis, Legala-Keud Genesquin Guibert\nand Bayala Balibié Auguste Serge",downloadPdfUrl:"/chapter/pdf-download/57829",previewPdfUrl:"/chapter/pdf-preview/57829",authors:[{id:"213761",title:"Dr.",name:"Denis",surname:"Akouwerabou",slug:"denis-akouwerabou",fullName:"Denis Akouwerabou"},{id:"213862",title:"Mr.",name:"Keudem",surname:"Legala",slug:"keudem-legala",fullName:"Keudem Legala"},{id:"220637",title:"Prof.",name:"Serge",surname:"Bayala",slug:"serge-bayala",fullName:"Serge Bayala"}],corrections:null},{id:"56997",title:"Deinstitutionalization through Business Model Evolution: Women Entrepreneurs in the Middle East and North Africa",doi:"10.5772/intechopen.70834",slug:"deinstitutionalization-through-business-model-evolution-women-entrepreneurs-in-the-middle-east-and-n",totalDownloads:1562,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:1,abstract:"This chapter is among the first to examine the interplay between deinstitutionalization and the rollout of novel business models by women entrepreneurs in developing countries. Much of the existing literature has examined the ways in which policy directives by formal institutions are the key drivers of entrepreneurial activity among women. Implicitly, this orientation suggests that the fate of women entrepreneurs is tied to, and cascades from, macro-level deinstitutionalization efforts, arising through changes in policies, laws and regulations championed at the highest levels. While this top-down view may intuitively be attractive, there are empirical reasons to doubt that the “institutional cascading” model accurately captures the underlying mechanisms of entrepreneurial activity among women. Taking a radically different tack, we develop and test an alternative, market-based perspective in which novel business models developed by women drive deinstitutionalization in bottom-up fashion. The context for our study involves detailed case histories of 95 women who started new businesses in the Middle East and North Africa (MENA), 1960–2012. Using a question-driven research design, our findings indicate that deinstitutionalization is strongly associated with the timing and substance of entrepreneurial action taken by MENA women.",signatures:"Richard A. Hunt and Lauren L. Ortiz-Hunt",downloadPdfUrl:"/chapter/pdf-download/56997",previewPdfUrl:"/chapter/pdf-preview/56997",authors:[{id:"207571",title:"Dr.",name:"Richard",surname:"Hunt",slug:"richard-hunt",fullName:"Richard Hunt"},{id:"216029",title:"Ms.",name:"Lauren",surname:"Ortiz-Hunt",slug:"lauren-ortiz-hunt",fullName:"Lauren Ortiz-Hunt"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5826",title:"Issues of Human Resource Management",subtitle:null,isOpenForSubmission:!1,hash:"82f12348a5b3544c8caae7b1d1731f9b",slug:"issues-of-human-resource-management",bookSignature:"Ladislav Mura",coverURL:"https://cdn.intechopen.com/books/images_new/5826.jpg",editedByType:"Edited by",editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2261",title:"Entrepreneurship",subtitle:"Born, Made and Educated",isOpenForSubmission:!1,hash:"6b9d8745c32f3c93df38a88c74594d07",slug:"entrepreneurship-born-made-and-educated",bookSignature:"Thierry Burger-Helmchen",coverURL:"https://cdn.intechopen.com/books/images_new/2261.jpg",editedByType:"Edited by",editors:[{id:"105866",title:"Prof.",name:"Thierry",surname:"Burger-Helmchen",slug:"thierry-burger-helmchen",fullName:"Thierry Burger-Helmchen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2262",title:"Entrepreneurship",subtitle:"Creativity and Innovative Business 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\r\n\tDrilling technology has progressed tremendously over the last decade. Because of advancements in drilling technology, it is now possible for drilling engineers to drill for energy resources from previously unreachable locations. Complex wells can only be designed and planned with the use of interdisciplinary information, which is becoming more important as technology advances.
\r\n\r\n\tThis book aims to discuss current breakthroughs, fresh views, and applications in drilling for conventional and renewable energies. This book will address this requirement by providing a comprehensive guide and case studies to drilling procedures, performance, tools, and well design. Several drilling technologies will be presented in detail, beginning with rotary drilling and directional drilling. This book will focus on the challenging topic of sustainability as well, which is a vital topic. The role of drilling in the energy transition will cover drilling for carbon sequestration and geothermal energy, drilling and the environment, and sustainable drilling fluids. This book intends to provide the reader with a comprehensive overview of the current state-of-the-art in drilling engineering and technology, featuring several environmental and energy transition aspects in this critically important area.
\r\n\t
Diabetes mellitus is a group of disorders of multiple aetiologies resulting from a defect in insulin secretion, insulin action, or both. Insulin deficiency in turn leads to chronic hyperglycemia (very high blood glucose levels) with disturbances in carbohydrate, fat and protein metabolism [1]. The two major types of diabetes mellitus (DM) are insulin dependent (IDDM) - type 1 and non -insulin dependent (NIDDM) -type 2. Type 1 DM is characterized by a specific destruction of the pancreatic β cells commonly associated with immune-mediated damage [2]. Individuals with type 2 DM display a gradual change in glucose homeostasis due to insulin resistance and/or decreased insulin secretion [3].
\nSustained hyperglycemia leads to the progressive development of long-term microvascular and macrovascular complications which causes morbidity and mortality among those affected [4, 5]. Although glycemic control has long been the mainstay for preventing the progression of diabetic complications, there is far less evidence that these interventions reverse diabetic complications [6]. Also, limitations in intensive glycemic treatment such as difficulty in achieving and/or maintaining tight glycemic control [7], incidence of hypoglycemia and increased mortality [8, 9] suggest an urgent need for alternative and/or complementary therapies to this disorder.
\nHyperglycemia-induced oxidative stress is now recognized as the driving force for the development of diabetic complications [10]. Oxidative stress in diabetes results in stimulation of the polyol pathway, formation of advanced glycation end products (AGE), activation of protein kinase C (PKC) and subsequent formation of reactive oxygen radicals [11, 12]. Hyperglycemia, not only generates more reactive oxygen species (ROS), but also attenuates antioxidative mechanisms by scavenging enzymes and substances [13].
\nThe injurious effects of hyperglycemia are separated into microvascular (involving small vessels such as capillaries) and macrovascular complications (involving large vessels, such as arteries and veins). Microvascular complications include diabetic nephropathy, neuropathy and retinopathy while macrovascular complications include coronary artery disease, peripheral arterial disease and stroke [5].
\nDiabetic nephropathy is a major cause of end-stage renal disease worldwide. It is a progressive decline in the glomerular filtration rate, characterized by glomerular hyperfiltration, glomerular and tubular epithelial hypertrophy, increased urinary albumin excretion, increased basement membrane thickness and mesangial expansion with the accumulation of extracellular matrix proteins (ECM) [14]. Alteration of the permeability characteristics of the glomerular capillary wall manifests clinically as abnormal albuminuria [15]. Microalbuminuria progresses to end-stage renal disease through a number of stages including normoalbuminuria, microalbuminuria and macroalbuminuria [16].
\nDiabetic retinopathy results from the damage of the small vasculature of the retina, multi cellular and the light sensitive tissue at the back of the eye. It is a major cause of visual impairment worldwide [17, 18]. The retina capillaries are lined with endothelial cells responsible for maintaining the blood retinal barrier, and are surrounded by smooth muscle cells, pericytes, which provide tone to the vessels [18]. The vascular lesions that are identified at the early stage of diabetic retinopathy include pericytes disappearance from capillaries resulting in pericyte ghosts, obliteration of capillaries and small arterioles, gradual thickening of vascular basement membrane, increased permeability of endothelial cells, and formation of microaneurysms (i.e. weakening of vessel walls that results in the projection of a balloonlike sac), vessel leakage, exudate, and hemorrhage [19, 20].
\nNeuropathies are characterized by a progressive loss of nerve fiber function. A widely accepted definition of diabetic neuropathy is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with mellitus after exclusion of other causes” [21]. In the peripheral nervous system, diabetes causes a progressive deterioration of sensory nerves and damage to motor nerves [22]. Diabetic neuropathy is ultimately the leading cause of lower extremity amputation [23]. Peripheral neuropathy is thought to develop because of cellular damage to endothelial cells, affecting nerve blood flow and also damage to the neurons affecting conductivity of impulses [23]. Signs and symptoms of diabetic neuropathy include decrease or no sweating, numbness, or tingling, and some sort of burning sensation, weakness and loss of reflexes [24].
\nBoth type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease [25, 26, 27]. Diabetics have a 2- to 4-fold higher risk for cardiovascular events [28] and nearly 80% of diabetes-associated deaths are caused by cardiovascular disease (CVD) [29]. Atherosclerosis, (excessive accumulation of lipids, cholesterol, inflammatory cells, and connective tissue in the vessel wall) accounts for more than 80% of the CVD-associated death and disability [30, 31]. Formation of atherosclerotic plaques can result in occlusion of vessel lumen and a rapid cessation in blood flow to target tissue [32]. Hyperglycemia, increased free fatty acids, and insulin resistance induce a large number of alterations at the cellular level that contribute to vascular dysfunction and accelerate the atherosclerotic process. These include increased oxidative stress, decreased bioavailability of NO, disturbances of intracellular signal transduction and increased production of several prothrombotic factors [32, 33].
\nReactive oxygen species (ROS) and reactive nitrogen species (RNS) are the terms collectively describing free radicals and other non-radical reactive derivatives also called oxidants. Biological free radicals are highly unstable molecules which are products of normal cellular metabolism. They have electrons available to react with various organic substrates such as lipids, proteins and deoxyribonucleic acid (DNA). Free radicals are well recognized for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems [34]. At low or moderate levels free radicals (ROS and RNS) exerts beneficial effects such as defence against infectious agents, induction of a mitogenic response and the maturation process of cellular structures [35-37]. ROS include superoxide anion (O2\n .-), hydroxyl (.OH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) while RNS include nitric oxide (.NO), nitrogen dioxide (NO2\n\n .-) and peroxynitrite (OONO−) [38, 39]. High concentrations of free radicals on the other hand result in deleterious processes that can damage cell structures due to oxidative stress [40, 41].
\nFree radicals produced under physiological conditions are maintained at steady state levels by endogenous or exogenous antioxidants (externally supplied through foods or supplements) which act as free radical scavengers. However, oxidative stress occurs when the production of free radicals overwhelms the detoxification capacity of cellular antioxidant system causing biological damage [42-44]. The endogenous antioxidants (Table 1) comprise of the enzymatic antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and non-enzymatic antioxidants including glutathione (GSH), α lipoic acid, vitamins C and E [39, 45, 46]. On the other hand, the exogenous antioxidants include micronutrients and other exogenously administered compounds such as vitamin E, vitamin C, trace metals (selenium, manganese, zinc), carotenoids and flavonoids [39, 44, 47].
\n\n | \n \n | \n \n | \n \n | \n
\n | \n \n | \n | \n |
(A) Catalase | \nPeroxisomes | \nDecomposition of H2O2to water and oxygen | \n[48] | \n
(B) Glutathione peroxidase | \nCytoplasm, mitochondria, and nucleus | \nDetoxifies H2O2 and lipid peroxides with simultaneous oxidation of GSH and generation of GSSG | \n[49] | \n
(C) Glutathione reductase | \nCytoplasm, mitochondria, and nucleus | \nRecycles Glutathione disulfide back to glutathione using the cofactor NADPH | \n[50] | \n
(D) Superoxide dismutase | \nCytoplasm, nucleus lysosomes, mitochondria | \nConversion of superoxide radical to H2O2\n | \n[51] | \n
\n | \n |||
(A) GSH | \nCytoplasm, mitochondria and nucleus | \nActs as a cofactor for antioxidant enzymes (GPx, GST), regenerates other antioxidants such as Vitamins C and E to their active forms | \n[52] | \n
(B) Vitamin-E | \nMembrane | \nDirectly scavenge singlet oxygen, peroxyl and superoxide radicals , protects against peroxidation of membrane lipids | \n[34] | \n
(C) Vitamin-C | \nCytosol | \nActs synergistically with vitamin E to terminate radical inducedlipid peroxidation | \n[34, 53] | \n
(D) α-Lipoic acid | \nCell membrane and cytoplasm | \nIncreases glutathione and vitamin C levels | \n[54] | \n
Role of antioxidants in the protection against free radical damage
Numerous experimental evidences have highlighted a direct link between oxidative stress and diabetes through the measurement of oxidative stress biomarkers in both diabetic patient and rodents. As shown in Table 2, a hyperglycemic state can lead to an increase in the levels of oxidative DNA damage markers such as 8-hydroxy-2’-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydro-2\'-deoxyguanosine (8-oxodG); lipid-peroxidation products measured as thiobarbituric acid-reactive substances (TBARS); protein oxidation products such as nitrotyrosine and carbonyl levels and also lower the activity of antioxidant enzymes. Cell culture studies using pancreatic beta cells, aortic smooth muscle cells and endothelial cells have also provided evidence for an increase in ROS production in diabetes [55, 56].
\nDue to their ability to directly oxidize and damage DNA, proteins, and lipids, free radicals are believed to play a key role in the onset and progression of late-diabetic complications [57]. In the absence of an appropriate condensation by antioxidant defense network, increased oxidative stress leads to activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to late diabetic complications [58-61].
\n\n | \n | \n \n | \n \n | \n \n | \n
\n | \n Enzymatic antioxidants | \n\n | \n Liver, Pancreas, Liver, kidney | \n[62-64] | \n
Non-enzymatic antioxidant | \n\n | \n Liver, kidney | \n[64] | \n|
\n | \n Kidney, hippocampus. Retina, Heart | \n [65] [66] [67] [68] | \n ||
Lipids | \n\n | \n Kidney | \n[69-70] | \n|
DNA | \n\n | \n Plasma, Liver, Kidney | \n[71-72] | \n|
Protein | \n\n | \n kidney Retina | \n [73] [67] | \n |
Reactive oxygen species | \n\n | \n Hippocampus | \n[66] | \n|
\n | \n Enzymatic antioxidants | \n\n | \n Erythrocyte | \n[74] | \n
Non enzymatic antioxidants | \n\n | \n Erythrocyte | \n[75] | \n|
Lipid | \n\n \n | \n Urine Erythrocyte | \n [76] [77] | \n |
DNA | \n\n | \n Urine | \n[78-79] | \n|
Protein | \n\n Protein carbonyl | \n Plasma | \n[80, 81] | \n
Experimental evidence supporting the involvement of oxidative stress
In diabetes, ROS is thought to be generated through increased polyol pathway [82], increased formation of advanced-glycation end products (AGEs) [83] and protein kinase C (PKC) activation [84].
\nAldose reductase is the rate limiting enzyme of the polyol pathway. The nicotinamide adenine dinucleotide phosphate (NAD(P)H)-requiring aldose reductase, catalyses the reduction of glucose to sorbitol followed by the oxidation of sorbitol to fructose by NAD+ dependent sorbitol dehydrogenase. At normal blood glucose concentration (5.5 mM), aldose reductase catalyzed reaction represents less than 3% of total glucose utilization [85]. However, hyperglycemia results in saturation of hexokinase and more than 30% of glucose is directed into the polyol pathway [86]. In a diabetic state, polyol pathway increases in tissues that do not require insulin for cellular glucose uptake, such as retina, kidney, peripheral nerves and blood vessels [87].
\nThe overall reaction of the polyol pathway leads to a shortage of intracellular NAD(P)H and a surplus of NADH, i.e, a reductive imbalance. Increased NADH generation during conversion of sorbitol to fructose provides substrate for NADH oxidase to generate ROS [88]. NADH serves as a source of electrons in complex 1 of the electron transport chain resulting in increased mitochondrial generation of superoxide radical. In diabetic cells, oxidative phosphorylation in mitochondria is enhanced due to increase flux of electron donors into the electron transport chain. This drives the inner mitochondrial membrane potential upward causing blockage of electron transfer inside complex III [89]. Electrons back up to coenzyme Q results and electrons are transferred one at a time to molecular oxygen, generating superoxide. DNA damage by superoxide and peroxynitrite results in the activation of poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme. PARP reduces the activity of glyceraldehyde-3- phosphate dehydrogenase (GAPDH) (an enzyme of the glycolytic pathway which catalyses the conversion of glyceraldehydes -3 phosphate to 1, 3 biphosphoglycerate) by ADP- ribosylation [90, 91]. A consequence of GAPDH inhibition by PARP is an increase in triose phosphate pool, upstream of GAPDH and increase flux of intermediates into the damaging pathways of diabetic complications.
\nThe polyol pathway also results in reduction in the bioavailability of NAD(P)H. The reduced bioavailability of NAD(P)H negatively affects the antioxidant defence system by depleting glutathione (GSH) a very important antioxidant. This is because the activity of GSH reductase, an antioxidant enzyme that generates GSH from its oxidized form (GSSH) depends on NAD(P)H. Depletion of NAD(P)H also decreases the synthesis of nitric oxide (NO), a vaculoprotective agent. NAD(P)H serves as a cofactor for nitric oxide synthase (NOS) which synthesizes NO from L-arginine. If endothelial nitric oxide synthase (eNOS) lack its substrate, L-arginine or one of its co-factor, it may produce superoxide radical (.O2\n\n -) instead of NO and this is referred to as ‘‘uncoupled state of nitric oxide’’[92]. Nitric oxide performs several physiological roles such as inhibition of platelet activation, vascular relaxation [93] and acts as an anti-inflammatory agent by reducing platelet aggregation and adhesion [94]. These properties inhibit atherogenesis and protect the blood vessel. Reduced bioavailability of NO level will therefore increase inflammation, enhance thrombosis and disrupt the integrity of endothelial cells. Reduction in NO has been documented in diabetes subjects with nephropathy [95]. Superoxide anion directly quenches NO by forming highly reactive peroxynitrite (ONOO-) which initiates lipid peroxidation, oxidizes sulfhydryl group in protein and nitrates amino acids such as tyrosine, thereby affecting many signal transduction pathways. The polyol pathway serves as a main source of ROS generation in the retina [96]. In addition, sorbitol accumulation has been implicated in osmotic swelling of the eye lens and cataractogenesis [97].
\nGlucose can react spontaneously with free amino groups of protein to form Schiff bases. These Schiff bases through complex reactions such as amadori rearrangement, dehydration and condensation forms cross-linked heterogeneous fluorescent derivatives called advanced glycation end products (AGEs). Advanced glycation end products constitute a heterogeneous group of molecules formed by non-enzymatic reactions of reducing sugars, ascorbate and other carbohydrates with amino acids, lipids and nucleic acids [98, 99]. Glycation end product’s adducts such as pyraline, pentosidine and N- Carboxy- methyl lysine (CML) are found to be elevated in diabetic tissues [100 - 102].
\nOnce formed, AGEs can cause tissue damage by two main pathways which are: (1) formation of cross links that alter protein structure and function and, (2) interaction of AGE with AGE-cell surface receptors on the surfaces of various cells such as endothelial cells, macrophages, neurons, and smooth-muscle cells resulting in activation of cell signaling and gene expression that induces oxidative stress and inflammation [98, 99; 102-105]. Oxidative stress can accelerate AGE formation while AGE formation can also amplify the production of more ROS resulting in a vicious cycle of AGE formation and oxidative stress.
\nAGE’s mediate some of their effect via interaction with some receptors that have been shown to bind to these chemical moieties. Among these receptors, Receptor for Advanced Glycation End products (RAGE) is the most extensively studied [106]. Evidence from numerous studies suggest that AGE’s are involved in a vicious cycle of inflammation, generation of ROS and increased production of AGE’s. Ligand RAGE interaction results in activation of pathways such as p21ras, erk1/2 (p44/p42), MAP kinases, p38 and SAPK/JNK MAP kinases [107-109]. A consequence of the activation of these pathways is the nuclear translocation of transcription factor, Nuclear Factor Kappa B (NF-КB). Translocation of NF-КB to the nucleus increases the transcription of a number of proteins such as, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) and pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, 1L-18 and tumour necrosis factor (TNF)-α which are centrally involved in the endothelial recruitment of neutrophil and subsequent development or progression of atherosclerotic plaque [109-112].
\nThe gene regions of NF-КB are located at the promoter region of RAGE. Moreover, binding of NF-КB to the promoter region of RAGE results in up-regulation of RAGE itsel. Interaction of AGE with RAGE generates more oxidative stress and this further potentiates the formation of AGE’s [109, 113]. Generation of ROS by ligand stimulated RAGE activation is mediated at least in part via activation of NADPH oxidase [114]. Other mechanisms by which AGE’s may be linked to increased generation of ROS is by reducing the activities of enzymatic antioxidant such as SOD and CAT, lowering of glutathione stores, and activation of PKC [107, 115, 116].
\nIncreased renal AGE in diabetic animals and patients have been linked to structural abnormality observed in diabetic nephropathy such as mesangial expansion, glomerular basement membrane thickening and tubulointerstitial fibrosis [117]. Advanced Glycation End Product’s level is increased with decreased renal function in type 1 diabetic patients [118]. Evidence from clinical studies indicates a correlation between progression of diabetic retinopathy and the level of AGE in serum and retinal blood vessels of diabetic patients [100, 119]. In diabetes, increased AGE’s are observed within retinal capillary cells and causes pericyte loss in diabetic retinopathy [120]. AGE’s induce toxic effects on retinal pericytes by causing oxidative stress and subsequent apoptosis [121].
\nHigh levels of serum AGE’s have been documented in patients with type 2 diabetes mellitus and coronary heart disease [122]. Glycation increases susceptibility of low density lipoprotein (LDL) to oxidative modification which is considered a critical step in its atherogenicity [123]. Glycation end products can also enhance atherosclerosis by trapping LDL in the subendothelium and decrease the recognition of AGE-modified LDL by LDL receptor [124]. Modification of LDL and its increased localization in vessels increases foam cell production and accelerates atherosclerosis development [125]. Oxidative stress induces AGE’s formation on collagen leading to cross-linking which is considered to play a role in diabetic cardiomyopathy [126]. The intermolecular collagen cross-linking caused by AGE increases vascular stiffness and interferes with arterial blood flow [127, 128] and this partly explains the diastolic dysfunction and systolic hypertension seen in diabetic subjects.
\nPKC activation is related to vasoconstriction, proliferation and overgrowth of smooth muscle cells as well as accelerated synthesis of extracellular matrix proteins, and thus plays significant roles in the onset and progression of vascular cell dysfunction in diabetes mellitus [129-131]. Two major pathways have been implicated in the activation of PKC in hyperglycemia. Persistent and excessive activation of several PKC isoforms result primarily from enhanced
PKC likely regulates diabetic complications on multiple levels such as activation of eNOS, NAD(P)H oxidase, phospholipase A2 (PLA2), endothelin-1 (ET-1), Vascular endothelial growth factor (VEGF), Transforming growth factor-β (TGF-β), and by activating NF-KB. Diacylglycerol activated PKC alters the gene expression of key proteins leading to decrease blood flow, capillary occlusion, inflammation, free radicals generation and damage to cellular macromolecule [130-132, 136, 137].
\nHigh glucose levels can stimulate ROS production via a PKC-dependent activation of NAD(P)H oxidase in cultured aortic endothelial cells, smooth muscle cells, and renal mesangial cells [84]. Nicotinamide adenine dinucleotide phosphate oxidase, which is primarily found in phagocytic cells, is the main source of ROS in non-phagocytic cells such as mesangial cells, endothelial cells [138], fibroblasts [139], podocytes [140] and smooth muscle cells [141]. The expression of NAD(P)H oxidase components is up-regulated in vascular tissues from animal models of diabetes and in patients with diabetes and coronary artery disease [142-144]. Experimental evidence indicates that NAD(P)H oxidase-dependent production of ROS may cause DNA damage in diabetic renal tissues leading to the development of nephropathy [145]. Increased activity of the NAD(P)H oxidase has also been reported in the retina of diabetic rats suggesting its involvement in the development of diabetic retinopathy [146].
\nDespite efforts to control blood glucose, tissue and organ damage are cumulative over many years in most diabetic patients. Varying degrees of hyperglycemia are virtually unavoidable in subjects with diabetes mellitus and glycemic memory has been used to describe the development of diabetes-related complications in diabetic patients even after normoglycemia has been restored and initial glycemic environment is remembered in the target organs [105,147]. It is noteworthy that ROS has been implicated as a major cause of the metabolic memory after glucose normalization due to the chains of reactions leading to cell damage and loss of cellular function. Due to the implication of hyperglycemia-induced oxidative stress in diabetes, these patients should in theory benefit from antioxidant supplementation. The beneficial effect of antioxidants has been reported in animal models of diabetes and in diabetic patients [50, 148]
\nVitamin E is a fat-soluble vitamin. It has been shown that plasma α-tocopherol concentrations are lower in diabetics compared to controls [58] and appear to be even lower in diabetics with complications such as microangiopathy than in diabetics without complications [81]. Administration of Vitamin E has proven to be beneficial in preventing cellular damage by inhibition of lipid peroxidation, protein oxidation, protein glycations and platelet aggregation [149-151] Vitamin E supplementation for two weeks (600 mg/day) lowered urinary F2-isoprostanes (a marker of lipid oxidation) in type 2 diabetics [152]. It was shown in a study that a decrease in plasma F2-isoprostanes was seen in type 2 diabetic patients after six weeks supplementation with Vitamin E [153].
\nOxidative stress in the kidney of diabetics is usually associated with tissue damage that interferes with proper organ function, causing an increase in urinary protein excretion and blood urea nitrogen (BUN) [154]. Vitamin E supplementation (1000 IU/kg diet) to diabetic rats for 4 weeks significantly reduced urinary protein excretion and BUN suggesting a beneficial effect on kidney function [154]. Inhibitory effect of Vitamin E on glycation of hemoglobin in type I and type 2 diabetic rats has been documented [151, 155]. The ability of vitamin E to inhibit AGE’s might be due to its antioxidant effect on the autoxidative pathways of AGE formation [156]. Vitamin E administration has also reduced oxidation of low density lipoprotein (LDL) and development of atherosclerosis [157].
\nNumerous studies have shown that vitamin E normalized parameters of oxidative stress and inhibited vascular abnormalities caused by hyperglycemia-induced production of DAG and PKC activation in the retina, glomerulus and macrophages [158-160]. Supplementation with vitamin E reduced basement membrane thickening in diabetic rat retina and reduced vascular endothelial growth factor (VEGF) and aldose reductase activity, the abnormalities associated with diabetic retinopathy [161]. Dietary supplementation of vitamin E (2000 IU/kg) to diabetic rats for 8 weeks had cardioprotective effects which was simultaneously associated with an ability of vitamin E to blunt diabetes-induced amplification of myocardial 8-
Vitamin C is an antioxidant vitamin which plays an important role in protecting free radical-induced damage and a decrease in basal vitamin C levels has been documented in type 2 DM. Treatment of diabetic rats with vitamin C significantly decreased renal malondialdehyde, albuminuria, proteinuria, glomerular and tubulointerstitial sclerosis, suggesting the role of vitamin C in suppressing the progression of renal injury in diabetic rats [167]. Vitamin C also improved diabetes-induced endothelial dysfunction in a rat model by enhancing NO bioavailability [168].
\nThe beneficial effects of vitamin C supplementation in humans are controversial. A study reported that vitamin C may improve glycemic control, lowering both fasting blood glucose and glycated haemoglobin (HbA1c) [169]. Chronic oral administration of vitamin C to patients with type 2 diabetes causes a decline in plasma free radicals that is associated with improved whole body glucose disposal [170,171] and improved endothelial function [172]. Recently, another study reported a reduction in the malondialdehyde (MDA) level, a major product of oxidative damage in both fasting and postprandial states of type 2 diabetic patients after vitamin C (1000 mg day-1) supplementation for 6 weeks although no effect was observed on lipid profiles [173]. Some studies have indicated that the intra-arterial infusion of vitamin c restores endothelium-dependent vasodilation in patients with type 1 or type 2 diabetes [174, 175] suggesting that hyperglycemia-induced oxidative stress mediates endothelial dysfunction in diabetic patients.
\nHowever, in contrast to these promising results, other studies showed no beneficial effect with vitamin C treatment. Chen and colleagues [176] concluded that a high oral dose of vitamin C therapy was ineffective at improving endothelial dysfunction and insulin resistance in type 2 DM. It is important to note that complete replenishment of vitamin C levels was not achieved in the subjects. This is crucial since high concentrations of vitamin C (>80 μM) has been documented as a requirement for the preservation of NO-dependent endothelial function as vitamin C only competes with NO for superoxide anion at these high concentrations [177-178]. Also, in another study, no beneficial effects of oral vitamin C supplementation (1.5 g daily for 3 weeks) was observed on blood pressure, oxidative stress, and endothelial function in type 2 diabetes [179].
\nFlavonoids (bioflavonoids) are a diverse group of polyphenols (phenyl benzopyrans) which function as phytochemicals [180]. Flavonoids are well-known for their multi-directional biological activities including anti-diabetic efficacy. Experimental evidence has shown that flavonoids exhibits anti-inflammatory [181], anticarcinogenic [182], antiviral [183] and antiallergic properties. These effects are generally associated with free radical scavenging activity of flavonoids. The antioxidant effects of flavonoids are enhanced by the number and position of hydroxyl groups in the molecule. The catechol structure, presence of unsaturation and 4-oxo function in the C-ring also contributes to their radical scavenging activity [184, 185]. Flavonoids may be capable of binding the transition metal ions, which play a role in glycoxidation, thus preventing metal-catalysed formation of hydroxyl radicals or related species from H2O2 [186].
\nClasses of flavonoids [
The potential beneficial effects of flavonoids in the prevention of diabetes mellitus and its associated complications have been investigated both
Flavonoids, in addition to their antioxidant effect, possess inhibitory activity on aldose reductase pathway and can serve as a potential multifunctional agent in the prevention of diabetic retinopathy. Goodarzi
Activation of PKC contributes to the loss of capillary pericytes and thickening of vascular basement membrane (BM) in diabetic retinopathy [194]. Also PKC mediated alterations in vascular permeability, blood flow, formation and response to angiogenic growth factors contribute to retinal leakage, ischemia, and neovascularisation [195]. Therefore, PKC inhibitors can be targeted for the treatment of diabetic retinopathy. Hesperetin (Hsp), a flavanone found in citrus fruits and a potent antioxidant has retina vasculo-protective properties due to its strong anti-angiogenic effect via inhibiting VEGF and PKC-β pathways [196]. Modulation of endogenous biomarkers and inhibition of diabetes induced neuropathic pain was observed in diabetic rats after naringin (4′,5,7-trihydroxy flavonone 7-rhamnoglucoside) administration [197]. In the same study, a dose dependent decrease in the levels of oxidative-nitrosative stress, inflammatory mediators as well as apoptosis was documented in neural cells. The antioxidant properties of naringin may be a factor in the inhibition of neurodegeneration.
\nThe soy isoflavone genistein (3 and 6mg/kg), administered by a subcutaneous injection to diabetic mice relieved peripheral painful neuropathy by reverting the proinflammatory cytokine and ROS overproduction. It also restored the inducible nitric oxide synthase (iNOS) and eNOS content and increased NO production in thoracic aorta although treatment had no effect on hyperglycemia [198]. The flavonoid luteolin (200 mg/kg), when administered to rats orally, protected against the progression of diabetes-induced cardiac dysfunction by attenuation of myocardial oxidative stress probably through its antioxidant properties [199].
\nIn a double blind placebo-controlled study, the effects of daflon 500 (made up of flavonoids diosmin (90%) and hesperidin (10%)) was investigated in a group of 28 type 1 diabetic patients. Treatment with these flavonoids resulted in a decrease in HbA1C which is associated with an increase in the level and activities of thiol-containing antioxidants such as glutathione peroxidase [200]. The
The treatment of diabetic rats with rutin decreased fasting plasma glucose, glycosylated haemoglobin, thiobarbituric acid reactive substances and lipid hydroperoxides while levels of non-enzymatic antioxidants were increased [202]. In another study, rutin supplementation (500 mg tablets) to diabetic patients for 60 days decreased the levels of fasting blood glucose, blood pressure and improved lipid profiles in the diabetic subjects [203]. Rutin reduced blood glucose, ameliorated oxidative stress and inhibited the accumulation of extracellular matrix (ECM) component and glomerular basement membrane thickening in the renal cortex of diabetic rats suggesting its renoprotective effect in experimental diabetic nephropathy [204]. The inhibitory effect of rutin on AGE formation in STZ-induced rats has also been shown [205].
\nDiosmin (DS) (diosmetin 7-
\n | \n \n | \n \n | \n \n | \n \n | \n
Flavonols (Brussel sprouts, apples, onion, curly kale, leek, beans, cherries, Citrus fruits, Cranberries) | \n Morin | \nLiver | \nDecreased MDA levels , Increased activity of SOD and GSH concentration. | \n [210] | \n
Hepatocytes | \nDecreased ROS production, DNA damage and apoptosis. Modulation of antioxidant enzymes; GSH, CAT, SOD and GPX. | \n[211] | \n||
Rutin | \nKidney, serum, urine | \n Lowered blood glucose and improved renal function. Increased total antioxidant capability activities of SOD, CAT and GPX. Lowered ECM accumulation and AGE formation. Decreased renal expression of TGF-β. | \n[204] | \n|
Quercetin | \nPancreas, serum, erythrocyte. | \nLowered MDA and NO level, increased antioxidant enzyme activity and preservation of islet cells integrity. | \n[212] | \n|
Kidney , serum, urine | \nLowered blood glucose and improved renal function. Reduced renal lipid peroxides and increased activity of anti-oxidative enzymes; SOD and CAT and non-enzymatic antioxidant GSH. | \n[213] | \n||
Flavanones (Citus peel, Orange juice, grape fruit juice, lemon juice) | \n Hesperidin & Naringin | \nLiver, serum | \nBoost antioxidant system by increasing activities of SOD, GR, GPx, CAT and levels of non-enzymatic antioxidants; GSH, VIT-C and VIT-E. Decreased lipid peroxidation product, MDA and proinflammatory markers, TNF-α, IL-6. | \n [214] | \n
Hesperidin | \nRetina, plasma | \nDecreased aldose reductase activity and levels of AGE’s, VEGF, ICAM-1, TNF-α, IL-1β and MDA while increasing SOD activity. | \n[215] | \n|
Naringenin | \nPancreas, heamoglobin, serum, plasma | \nLowered fasting blood glucose, decreased hyperglycemia, glycated haemoglobin, MDA and markers of hepatic damage. Increased levels of insulin and enzymatic and non-enzymatic antioxidants. | \n [216] | \n|
Kidney, liver serum, urine, | \nImproved glycemic control and elevated insulin level, reduced plasma levels of kidney dysfunction markers. Lowered renal activity and expression of NF-KB and pro-inflammatory cytokine and chemokine, suppression of PKC activity. | \n[217] | \n||
Flavanolols (Milk thistle, red onion, Siberian larch tree) | \n Silymarin | \nKidney | \nIncreased expression and activity of SOD, GPX, CAT. Decreased high blood glucose | \n[218] | \n
Flavones (Parsley, pepper celery, broccoli capsicum) | \n Luteolin | \nKidney | \nDecreased activity of SOD, MDA content and expression of Heme Oxygenase-1 (HO-1) protein. | \n[219] | \n
Aortic ring | \nAortic Vasorelaxation, decrease in ROS production, increased activity of SOD, NOS and level of NO. | \n[220] | \n||
Diosmin | \nLiver and kidney | \nDecreased TBARS and hydroperoxides. Increased activity of enzymatic antioxidants ;SOD, CAT, GPx, GST and GR and non-enzymatic antioxidants; GSH, Vitamin C and Vitamin E. | \n [207] | \n|
Flavones | \nChrysin and luteolin | \nSerum and aorta | \nAortic relaxation, decreased blood pressure, decreased lipidemia and serum AGE’s. Increased .NO generation | \n [221] | \n
Apigenin | \nSerum and liver | \nIncreased insulin levels and decreased hyperglycemia. Normalized LPO and endogeneous antioxidants, CAT, SOD, GSH in the liver. | \n[222] | \n|
Flavan-3-ols (Red wine and red grapes, green and black tea) | \nCatechin | \nThoracic aorta | \nDecreased hyperglycemia NADPH oxidase activity and ROS production. Increased insulin level, lowered blood pressure and improved aortic relaxation. | \n[223] | \n
Epicatechin | \nPancreatic Islets, plasma, haemoglobin | \nIncreased anti-inflammatory cytokines, IL-10, IL-12. Improved glucose tolerance and insulin levels and lowered HbA1C. | \n [224] | \n|
Isoflavones (Soy foods and legumes) | \n Genistein | \nKidney | \nDecreased MDA level and expression of PKC and pro-inflammatory proteins such as NF-KB, MCP-1 and Cox-2. Activation of antioxidant enzymes and defense against oxidative damage via increase expression of Nrf2, a transactivator of antioxidant genes. | \n [225] | \n
Daidzein | \nAorta | \nMaintenance of endothelium dependent relaxation and attenuation of oxidative stress via decrease MDA levels and increase SOD activity | \n[226] | \n
Beneficial effects of some flavonoids in diabetes mellitus
Abbreviations: Find all citations in this journal (defECM: Extracellular matrix, MDA: Malondialdehyde, NO: Nitric oxide, NOS: Nitric oxide synthase, NADPH; nicotinamide adenine dinucleotide phosphate, LPO: Lipid peroxidation, Nrf2: NF-E2-related factor-2, Cox-2: Cyclooxygenase-2, TAOC: Total antioxidative capability
The inherent antioxidative properties of some common antidiabetic drugs such as aminoguanidine, statins, thiazolidinediones, glibenclamide and repaglinide also provides an additional support to the involvement of oxidative stress in diabetes and therefore suggest that the use of antioxidants as therapeutic agents in diabetes is a promising approach [227-231].
\nIncreased ROS production has been suggested as a common pathway linking diverse pathogenic mechanisms of diabetic vascular complications. There are numerous evidences from animal studies on the beneficial effect of antioxidant vitamins supplementation in diabetes mellitus, but results from clinical studies are inconclusive. The antioxidant activity of some anti-diabetic drugs has also been shown to contribute significantly to their therapeutic effect. Biflavonoids as antioxidants are promising and attractive natural substances to enrich the current therapy options against diabetes. The overall positive results from animal studies suggest that the role of antioxidants cannot be underestimated in the quest to find effective therapies for diabetic complications. A multi-therapeutic approach to the treatment of diabetic complications might increase the chance of successful therapeutic intervention. In addition to maintaining glycemic control, blockage of pathways involved in the formation of free radicals with antioxidants is a promising approach to the treatment of hyperglycemia-mediated complications in humans. The bioactivity of flavonoids
Epilepsy is one of the chronic brain disorders characterized by recurrent seizures due to abnormal excessive electrical discharges of cerebral neurons [1]. It is believed that genetic factors play a crucial role in the etiopathogenesis of epilepsy. So far ~1000 genes have been proved to be associated with epilepsy, among which genes encoding VGIC predominate [2].
VGICs are pore-forming membrane proteins. Their functions include establishing APs and maintaining homeostasis by gating the ionic flow traversing the cell membrane, managing the ionic flow across cells and regulating Ca2+ signal transduction, which are essential to the neuroexcitability, so VGICs are potentially involved in epileptogenesis [2]. The association of VGIC genes and epilepsy might provide insights into the etiopathogenesis underlying epilepsy. Pathophysiological studies illuminated that two key defects are (i) a neuronal disinhibition induced by loss-of-function of VGIC gene expressed specifically in inhibitory interneurons (for example, Nav1.1 and P/Q VGCCs) or (ii) dysfunction of axon initial segments, the neuronal structure in which APs are generated and many VGICs (such as Nav1.2 and Kv7) are mainly localized (Figure 1). Moreover, clinically originated studies identified novel genes, defined their neuronal functions, and sometimes established novel physiological principles [2].
Neuronal localization of some relevant voltage-gated ion channels. A schematic view of an excitatory pyramidal (orange), an inhibitory (green) neuron, and their synaptic connections is shown. Distinctive intracellular compartments are targeted by different populations of VGICs. Examples of which as mentioned in this chapter are shown here: in the somatodendritic compartment, Nav, Cav (L- and T-type), TRP, BK, and Kv channels; at axon initial segments (AIS) and nodes of Ranvier in pyramidal neurons, Nav1.2, Kv7 channels; at AIS of inhibitory neurons, Nav1.1; in the somatodendritic compartment of inhibitory neurons, BK and Nav1.6; in the presynaptic terminals, Cav P/Q type. GOF represents the gain-of-function mutation of VGICs-induced human epilepsy. LOF represents the loss-of-function mutation of VGICs.
In this chapter, we summarize the epilepsy-associated VGIC genes, the mutations, corresponding phenotypes, and functional changes, aiming to provide clues for evaluating the relationship between VGIC genes and epileptogenesis.
VGSCs play a critical role in the generation and propagation of APs in neurons, genetic alterations in VGSC genes are considered to be associated with epileptogenesis. Mammalian VGSC is composed of a large pseudotetrameric pore-forming α subunit with a molecular weight of 260 KDa, and one or more auxiliary β subunits (30–40 KDa) [3, 4, 5] (Figure 2). Nine subtypes of VGSC α subunits have been found in humans, including Nav1.1-Nav1.9, encoded by the genes SCN1A-SCN5A, SCN8A-SCN11A, respectively.
Structure of voltage-gated sodium channels. Schematic representation of VGSC subunits. The α subunit of the VGSC is illustrated together with β1 and β2 subunits; extracellular domains of the β subunits are shown as immunoglobulin-like folds, interacting with the loops in α subunits. Roman numerals indicate the domains of the α subunit; segments 5 and 6 (shown in green) are the pore-lining segments, and S4 helices (red) make up the voltage sensors. The red circle in the intracellular loop of domains III and IV indicates the inactivation gate IFM motif; Ψ, probable N-linked glycosylation site. The circles in reentrant loops in each domain represent the residues that form the ion selectivity filter.
Nav1.1 is mainly distributed in the inhibitory GABAergic neurons of cerebellum and hippocampus. The Nav1.1 gene SCN1A is the clinically most relevant SCN gene for epilepsy. More than 1200 mutants have been identified to be associated with epilepsy; most of them are febrile seizures [6]. M145T mutation, a well-conserved amino acid in the first transmembrane segment of domain I of the Nav1.1 α-subunit, caused a reduction in peak sodium currents and a positive shift in the voltage dependence of activation [7], which provided the first evidence that the mild loss-of-function mutations in Nav1.1 may cause a significant portion of febrile seizures. Complete loss-of-function mutations in Nav1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravet’s syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. Besides, homozygous null Nav1.1−/− mice developed ataxia and died on half a month of postnatal and did not change the voltage-dependent activity of VGSCs in hippocampal neurons. However, heterozygous Nav1.1+/− mice exhibited spontaneous seizures and sporadic deaths after 3 weeks, and the sodium current density was substantially reduced in inhibitory interneurons, except in excitatory pyramidal neurons [8]. So loss-of-function mutations in Nav1.1 can severely impair sodium currents and AP firing in hippocampal GABAergic inhibitory neurons. The functional downregulation in inhibitory neurons might cause the hyperexcitability of dentate granule or pyramidal neurons, which could lead to epilepsy in patients with SMEI. Experiments in mice have demonstrated that haploinsufficiency of Nav1.1 channels is sufficient to allow induction of seizures by elevated body temperature, supporting that haploinsufficiency of SCN1A is pathogenic in human SMEI which has striking temperature and age dependence of onset and progression of epilepsy [9]. What is more, SCN1A mutations were mostly missense mutations in GEFS+ patients, which are typically well controlled by treatment with antiepileptic drugs and no cognitive impairment is observed. The R1648H channels showed the reduced function in both excitatory and inhibitory neurons although the biophysical mechanisms were different, reducing peak sodium currents and enhancing slow inactivation in inhibitory neurons versus negatively shifted voltage dependence of fast inactivation in excitatory neurons [10]. The similar conclusion had been drawn when the R1648H mutation has been inserted into the mouse genome under the native promoter [11]. In light of these results, GEFS+ and SMEI may be caused by a continuum of mutational effects that selectively impair firing of GABAergic inhibitory neurons, which lead to increase in the excitability of the neural network [12].
The mutation of the Nav1.2 gene SCN2A is associated with various epilepsies, such as benign familial neonatal seizures (BFNIS), hereditary epilepsy with febrile seizures plus (GEFS+), Dravet’s syndrome (DS), and other stubborn childhood epilepsy encephalopathy. Nav1.2 subunit is mainly distributed in the axon-initiating segment (AIS) and node of Ranvier. SCN2A mutations cause changes in VGSC function and expression and result in abnormal neuronal discharge. Because Nav1.2 plays an important role in the AIS area during the development, it is more common for infants to show SCN2A mutant-induced epilepsy encephalopathy [13]. BFNIS is the most common phenotype caused by gain-of-function missense mutations in SCN2A [14]. Up to now, at least 10 SCN2A mutations associated with BFNIS have been identified. SCN2A mutations are also found to result in the reduced expression of Nav1.2 on the surface of neurons [15]. Therefore, SCN2A mutants will lead to the decrease of sodium current density at node of Ranvier and AIS, seriously affecting the excitability of neurons [16]. For missense mutation of SCN2A, p.Tyr1589Cys causes a depolarizing shift of steady-state inactivation, increased persistent Na+ current, a slowing of fast inactivation, and an acceleration of its recovery, which contribute to neuronal hyperexcitability and familial epilepsy [17]. Due to the SCN2A mutation, early infantile epileptic encephalopathy (EIEE) patients with burst suppression and tonic-clonic migrating partial seizures showed a specific dose-dependent efficacy of VGSC blockers [18]. It is mainly caused by the dysfunction of VGSC [19]. By replacing neonatal Nav1.2 with adult Nav1.2 in mice, it has been suggested that neonatal Nav1.2 reduced neuronal excitability and had a significant impact on seizure susceptibility and behavior.
The SCN3A gene, clustered on human chromosome 2q24, encodes the Nav1.3 subtype [20], which is usually located in the soma of neurons. It is important in the integration of synaptic signals, determination of the depolarization threshold, and AP transmission [21]. In contrast to the rodent gene which is transiently expressed during development, human SCN3A is widely expressed in adult brain [22]. The first epilepsy-associated mutation (K354Q) in SCN3A was found in 2008. K354Q mutation decreased inactivation rate and increased INaP [23]. The mutation is not sensitive to antiepilepsy drug carbamazepine or oxcarbazepine. K354Q mutation causes neuronal abnormal spontaneous discharge and membrane potential paroxysmal depolarization [24]. In 2014, four more missense variants were identified in SCN3A, which are R357Q, D766N, E1111K, and M1323V [25]. Compared to wild-type channels, R357Q caused smaller currents, slower activation, and depolarized voltage dependences of activation and inactivation. The E1111K mutation evoked a significantly greater level of persistent sodium current. All four mutants increase current activation in response to depolarizing voltage ramps. These findings support for a contribution of Nav 1.3 to childhood epilepsy. Recently, a novel SCN3A variant (L247P) was identified by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium currents in a heterologous expression system. To further test the possible clinical consequences of reduced SCN3A activity, they investigated the effect of a hypomorphic Scn3a allele (Scn3a Hyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous SCN3A mutant mice (SCN3A+/Hyp) neither exhibit spontaneous seizures nor hyperthermia-induced seizures, but they displayed increased susceptibility to electroconvulsive- and chemiconvulsive-induced seizures, which provide evidence that loss-of-function of SCN3A may contribute to increased seizure susceptibility [26].
Nav1.6, mainly distributed to the soma and synaptic origin, is important for APs generation and propagation [27]. In the development process, Nav1.2 is gradually replaced by Nav1.6 in the mature node of Ranvier [28]. The first heterozygous missense mutation (p.Asn1768Asp) in the Nav1.6 gene SCN8A was identified in 2012 by whole-genome sequencing (WGS) in a patient with severe epileptic encephalopathy who exhibited early-onset seizures, autistic features, intellectual disability, ataxia, and sudden unexpected death in epilepsy (SUDEP) [29]. Since this initial discovery, more than 100 pathogenic SCN8A variants have been identified in patients with epilepsy [30]. Most of the SCN8A variants have been detected in individuals with EIEE.
Different mutations in the SCN8A gene encoding Nav1.6 have different effects on epilepsy. For the missense mutation V929F, an evolutionarily conserved residue in the pore loop of domain II of Nav1.6, it was found that heterozygous mutations produced well-defined spike-wave discharges and are associated to absence epilepsy in mice [31]. However, missense mutations in Scn8amed−jo were able to improve the epilepsy symptoms of SCN1A+/− heterozygotes. The mechanism might be the decrease in Nav1.6 expression of excitatory neurons compensating for the loss of Nav1.1 in inhibitory neurons [32]. Recently, more and more de novo and inherited SCN8A epilepsy mutations were detected by gene panel analysis [33]. For example, loss-of-function mutants [34], underlying the complex seizure phenotype, were identified using specific mouse line. It was suggested that decreasing Scn8a expression in cortical excitatory neurons could reduce seizures. On the contrary, the decreasing expression of SCN8A in the thalamic reticular nucleus (RT) leads to absence seizures. Loss of Scn8a will impair tonic firing mode behavior and impair desynchronizing recurrent RT-RT synaptic inhibition in the thalamic reticular nucleus, which suggested that Scn8a-mediated hypofunction in cortical circuits, conferring convulsive seizure resistance, while hypofunction in the thalamus is sufficient to generate absence seizures.
The SCN9A gene encodes the Nav1.7 subtype, which was initially identified in the peripheral nervous system, sympathetic ganglion, and olfactory sensory neurons [35, 36, 37, 38]. Nav1.7 is also found expressed in the central nervous system such as in the cerebral cortex and hippocampus [39]. A missense mutation of SCN9A (N641Y), at a conserved amino acid residue located at the intracellular loop between domain I and II, is associated with a family of febrile seizures (FS, N641Y). Mice carrying N641Y mutations were more susceptible to electrical stimulation-induced clonic and tonic seizures [40]. However, it is still unclear how SCN9A gene mutation caused epilepsy in the CNS.
K+ channels control the resting membrane potential and enable rapid repolarization of the AP by producing outward K+ currents, thus limiting neuronal excitability. K+ channels are composed of four pore forming a subunits and modulatory b subunits. Kv channels are the largest ion channel group (Kv1–Kv12) that are expressed substantially in the CNS. Dysfunction of Kv channels including Ca2+-activated K+ channels, are associated with epilepsy [2].
Large conductance calcium-activated potassium (BK) channels, consisting of functional α subunit and the tissue-specific regulatory subunits (β1–4 and γ1–4), are widely distributed in the CNS. BK channels are usually considered as vital players in the development of epilepsy (Figure 3), with the evidence including the K+ derangement and regulating AP shape and duration [41, 42].
Yin and Yang of BK channels in epilepsy. For epilepsy suppression, BK (α) channels act as negative feedback regulators on calcium rise and transmitter release in most synapses. Activation of mitoBK channel subtypes (α or α+β4) may contribute to suppressing seizure as well as conferring neuroprotection via the inhibition of ROS synthesis [
Gain-of-function mutation of BK, promoting the high-frequency neuron firing, is associated with spontaneous epileptic seizures paradoxically in both humans and rodents [43]. In fact, patients suffering from generalized epilepsy were detected a site mutation D434G at the RCK1 domain of BK α subunit. D434G increased the opening time of BK, through the enhancement of Ca2+ sensitivity [43]. In terms of functionality, the enhanced membrane excitability is associated with the increased BK activity and fAHP consequent [43, 44]. The augment seems to be induced by an increased recovery rate, underlying fast currents of VGSCs with a APs’ reduced refractory period and/or through disinhibiting thalamocortical circuits by blocking brain GABAergic interneurons [43, 45, 46].
The knockout mice of BK channel β4 subunit exhibit temporal lobe epilepsy (TLE) seizure associated with a gain-of-function phenotype of BK, which not only sharpens APs but also induces a higher neuronal firing frequency in hippocampus DG granule cells [47].It is worth mentioned that epileptic seizures themselves also could induce a gain-of-function effect to BK. Picrotoxin and pentylenetetrazol (PTZ) caused generalized tonic-clonic epileptic seizures, with giving rise to a gain-of-function effect on BK channels, presenting increased BK currents and neuron firing in the neocortex [48]. It is of interest that BK-specific inhibitors attenuated generalized tonic-clonic epileptic seizures in picrotoxin or PTZ-induced epilepsy models, which suppressed the increase of neuron firing [48, 49].
Loss-of-function phenotype of BK might also contribute to the pathological process of clinical TLE. It was reported that two siblings suffered from the severe cerebellar atrophy and developmental delay, who adopted the exome analysis that identified a homozygous frameshift duplication in BK gene
Kv7 is its seventh member of Kv channel family (Kv1–Kv12). The Kv7.1 mutation mediates type 1 long QT syndrome (long-QT syndrome type 1, LQT1) and is therefore named KCNQ1 (K, potassium; CN, channel; Q, LQT). KCNQ has five subtypes of KCNQ1–KCNQ5, which play crucial roles in physiological functions. Dysfunction of KCNQ is associated with many diseases.
KCNQ1 is mainly distributed in the heart, which mediates cardiac delayed-rectifier K+ current and maintains the normal repolarization process of cardiomyocytes [55]. KCNQ2–KCNQ5 are mainly distributed in central and peripheral neuronal tissues, of which KCNQ2 and KCNQ3 are distributed in brain regions [56]. KCNQ2 and KCNQ3 form functional heterotetramers, which are the main molecular bases for the formation of M currents that can be inhibited by acetylcholine M1 receptor activation [57]. Abundant KCNQ2 and KCNQ3 mutations could induce abnormal M currents, causing similarities in neonatal seizures and other nervous system diseases.
Benign familial neonatal seizure (BFNS) is an autosomal dominant idiopathic epilepsy syndrome that occurs on the 2nd to 8th day after birth and stops spontaneously after a few weeks. Whereas 15% of patients in later life may have recurrence of epilepsy [58]. With the study of pathogenic genes in epilepsy, 60–70% of patients with BFNS were found to be associated with KCNQ2 and KCNQ3 mutations. More than 80 different mutations have been reported on KCNQ2, and multiple mutations on KCNQ3 are associated with BFNS. Soldovieri et al. [58] studied the genes of 17 BFNS clinical patients. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, 3 insertions/deletions, and 3 large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. Borgatti studied a BFNS family with four affected members: two of them exhibit BFNS only, while the other two, in addition to BFNS, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation. All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tridimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression. The KCNQ2 K526N mutation might affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus [59, 60]. KCNQ2 or KCNQ3 mutations cause M current to be downregulated, and the frequency of neuronal firing increases, leading to epilepsy.
Inward-rectifier potassium channels (Kir, IRK) are a specific subset of potassium channels. To date, seven subfamilies have been identified, which are associated with a variety of diseases [61]. The G-protein-coupled Kir (GIRK) channels belong to the subfamily of Kir3 (GIRKs) which are activated by ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs, interacting with GIRK channels, facilitate their activation, resulting in hyperpolarization of the cell membrane [61].
GIRK channels have four identified subunits (GIRK1–4, encoded by KCNJ3, KCNJ6, KCNJ9, and KCNJ5, respectively) in mammals, existing in vivo both as homotetramers and heterotetramers with unique biophysical properties, regulation, and distribution [61, 62]. GIRK 1, 2, 3, and 4 subunits are expressed in the brain, localized in certain axons, postsynaptic, and presynaptic regions [63]. GIRK channels may be involved not only in slow inhibitory postsynaptic potentials but also in the presynaptic modulation of neuronal activity [61].
GIRK in the CNS is a heterotetramer composed of GIRK1 and GIRK2 subunits [63], which is responsible for maintaining the resting membrane potential and excitability of the neuron [64]. GIRK1 and GIRK2 subunits are found in the dendritic areas of neurons highly [63] correlate with the large concentration of GABAB receptors. Once the GABAB receptors are activated by their ligands, they can in turn activate IRK, mediating a significant part of the GABA postsynaptic inhibition [63].
Alterations in GIRK function have been associated with pathophysiology of severe brain disorders, including epilepsy. In this regard, a GIRK2 knockout mouse model resulted to be more susceptible to develop both spontaneous and induced seizures in respect to wild-type mice [65]. In particular, mice carrying a p Gly156Ser mutation displayed an epileptic phenotype [66]. Indeed, this mutation has been found to alter the putative ion-permeable, pore-forming domain of the channel, inducing Ca2+ overload in cells and reducing channel availability, leading thus to neurodegeneration and seizure susceptibility [67].
An increased expression of GIRK was observed in rat brain after an electroconvulsive shock, probably altering the excitability of granule cells and the functions of neurotransmitter receptors which are coupled to these channels [68]. Another evidence in support of a role of GIRK in epilepsy was provided by the demonstration that ML297, a potent and selective activator of GIRK, showed epileptogenic properties in mice [69]. On the other hand, the inhibition of GIRK activity by drugs causes seizures [70]. All these considerations imply that changes in Kir3 channel activity may alter the susceptibility to seizures.
As an important second messenger, Ca2+ plays a vital role in normal brain function and in the pathophysiological process of different neurodegenerative diseases. Ca2+ entry via VGCCs conveys the electric signals to intracellular transduction cascades in a wide variety of cells [71]. VGCCs were first identified by Fatt and Katz [72] and shown to consist of several subunits [73, 74]. VGCCs were divided into low-voltage-activated (LVA) and high-voltage-activated (HVA), based on electrophysiological and pharmacological properties. HVA channels, composed of α1, β, α2δ, γ subunit, are further divided into L, N, P, and Q types, which have an activation threshold at membrane voltage positive to −20 mV [75]. LVA channels, also called T type, consist only of the α1 subunit, activated at a membrane voltage positive to −70 mV. It is composed of transmembrane topology with four homologous transmembrane domains, each containing six transmembrane segments and a pore region between segments S5 and S6.
The L-type VGCC family has four members, Cav1.1–1.4, of which α subunits present tissue-specific expression, such as the α1D subunit in the brain. The L-type VGCC family shapes neuronal firing and activates Ca2+-dependent pathways involved in regulation of gene expression [76]. Cav1.2 channels appear to contribute critically to the generation of febrile seizures, which was proved by testing the excitability of hippocampal pyramidal cells in rat brain slices [77]. The Wistar Albino Glaxo/Rij (WAG/Rij) model experiments suggest that L-type calcium channels play a positive role in the frequency and duration of epileptic spikes [78]. Verapamil, an L-type VGCC blocker, could significantly reduce TLE seizure, enhancing the expression of the α subunit of γ-GABAAR [79].
P/Q-, N-, and R-type are corresponding to Cav2.1, Cav2.2, and Cav2.3, respectively, which initiate rapid synaptic transmission, regulated primarily by direct interaction with G proteins and SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) and secondarily by protein phosphorylation. The loss function of P/Q VGCC could lead to epileptic spikes, paroxysmal dystonia and ataxia. If P/Q VGCCs were blocked, it could disrupt the triggering synaptic neurotransmitter release [80]. Spikes of Cacna1aNtsr−/− mice are increased in layer VI corticothalamic neurons compared with control group, suggesting that Cav P/Q deletion generates absence epilepsy [81]. Cacna1a LOF from parvalbumin (PV)(+) and somatostatin (SST)(+) interneurons results in severe generalized epilepsy. It might be the mechanism for severe generalized epilepsy that the loss of Cav2.1 channel function from cortical PV(+) interneurons inhibits GABA release from these cells, which impairs their ability to constrain cortical pyramidal cell excitability [82]. When knocking out the cerebellar Cav2.1 channel in mice, cortical function is changeable, which caused movement disorders and epilepsy [83]. In two families with idiopathic epilepsy, the loss of function mutation in γ4 subunits, auxiliary subunit of Cav2.1 channels, could also cause seizures, and maybe aggravate seizures [84]. Downregulation of α2δ2 subunits in rats will generate 5–7 Hz epileptic wave accompanied by ataxia [85]. N-type calcium channels are mainly distributed in the nucleus of different neurons and glial cells. In the pilocarpine model, Cav2.2 expression decreased in the granule layer of the dentate gyrus and the pyramidal cells of the CA3 region during the acute phase of seizure. However, the expression of N-type calcium channels increased in the subsequent chronic phase, which demonstrated that the increase of N-type calcium channels might be associated with recurrent status epilepticus [86]. R-type calcium channel, Cav2.3, is mainly distributed in the presynaptic membrane, such as hippocampal mossy fibers, globus pallidus, and neuromuscular junctions. Knocking out R-type calcium channels could increase the susceptibility of seizures, with altering the seizure form [87]. The lack of Cav2.3 resulted in a marked decrease in the sensitivity of the animal to γ-butyrolactone-induced absence epilepsy and change thalamocortical network oscillations [88]. Administration of kainic acid revealed alteration in behavioral seizure architecture, dramatic resistance to limbic seizures and excitotoxic effects in Cav2.3−/− mice compared with controls. It indicated that the Cav2.3 plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration after excitotoxic events [89].
T-type channels, widely distributed in the thalamus, are important for the repetitive firing of APs in rhythmically firing cells, which could be activated and inactivated more rapidly at more negative membrane potentials than other VGCCs [90]. Three subtypes of T-type channels have been identified, designated as Cav3.1, Cav3.2, and Cav3.3; they correspond to complexes containing the pore-forming α1 subunits, α1G, α1H, and α1I, respectively [91]. It has long been suggested that generalized absence seizures are accompanied by hyperexcitable oscillatory activities in the thalamocortical network [92]. The evidence that succinimide and related anticonvulsants could block thalamic T-type channels make researchers speculate that T-type Ca2+ channels might be related to the pathogenesis of spike-and-wave discharges (SWDs) in generalized absence seizures [93]. In the kainate epilepsy model, Cav3.1−/− mice display significantly reduced duration of seizures compared to wild type, but the frequency of seizures increased slightly [94]. In the WAG/Rij model, the expression of Cav3.1 may be related to age, and blocking Cav3.1 can reduce the onset of epilepsy [94, 95] which suggested that decrease in Cav3.1 channel expression and Ca2+ current component that they carry in thalamocortical relay neurons serves as a protective measure against early onset of SWD and absence seizures [96]. Notably, Cav3.1−/− mice are resistant to SWD seizures specifically induced by γ-GABABR agonists. Simultaneously, the γ-GABABR agonists induced only very weak and intermittent SWDs in Cav3.1−/− mice [97]. Cav3.2 single nucleotide mutation has been reported in patients with childhood absence epilepsy and other types of idiopathic generalized epilepsies [98, 99]. Gain-of-function mutations (C456S) in Cav3.2 channels increase seizure susceptibility by directly altering neuronal electrical properties and indirectly by changing gene expression [100].
Transient receptor potential (TRP) channels, which could induce a transient voltage changes to continuous light mutations of
TRPC channels are the closet homolog to Drosophila TRP channels. Based on the functional comparisons and sequence alignments, four subsets of mammalian TRPCs (TRPC1, TRPC2, TRPC3/6/7, and TRPC4/5) have been generated [101]. These channels form receptor-modulated currents in the mammalian brain and important to SE-induced neuronal cell death. These channels could play a critical role in the generation of spontaneous seizures. TRPC1 and TRPC4 are expressed in CA1 pyramidal neurons. The amplitude of the plateau and the number of spikes were significantly reduced in mice without TRPC1 and TRPC4 [102]. TRPC3 channels are found to be responsible for pilocarpine-induced status epilepticus (SE) in mice. The reduction on SE in TRPC3 KO mice is caused by a selective attenuation of pilocarpine-induced theta wave activity [103]. TRPC7 can be detected in CA3 pyramidal neurons largely. The spontaneous seizures in CA3 pyramidal neurons and the pilocarpine-induced increase in gamma wave activities during the latent period could be significantly reduced by ablating the gene TRPC7 [104].
TRPV1 is one subfamily of TRP channels, expressing in most neurons. The expression of TRPV1 protein in epileptic brain areas was increased [105], but the epileptic activity in hippocampal slices was decreased by iodoresiniferatoxin (IRTX), a selective TRPV1 channel antagonist [106]. It is well known that glutamate could be released when the TRPV1 channel was activated [107], and the glutamate neurotransmitters are related to the etiology of epilepsy. Thus, focusing the TRPV1 channels activity may be important for the modulating neuronal excitability in epilepsy [106]. Recent studies showed that the high expression of TRPV1 channels could induce the temporal lobe epilepsy [105]. Cytosolic calcium elevation through activation of TRPV1 channels plays a physiologically relevant role in the regulation of epileptic seizures [108], decreasing the calcium accumulation by inhibiting the TRPV1 channels, could play a neuronal protective role against epilepsy-induced Ca2+ entry in hippocampal neurons. As mentioned above, the TRPV1 could be activated by hyperthermia; the hyperthermia-induced TRPV1 might be an effective candidate therapeutic target in heat-induced hyperexcitation [109, 110]. The activation of TRPV1 promotes glutamate release by increasing the excitability of neurons and synaptic terminals [111]. Whereas the activities would be reduced in hippocampus slices of rats after given the CPZ and ITRX, which were the TRPV1 channel blockers.
At present, the treatment of epilepsy is still dominated by drugs. More than 35% of marketed antiepileptic drugs target VGICs, such as phenytoin, carbamazepine, oxcarbazepine, and ethosuximide. Phenytoin and carbamazepine are broad-spectrum antiepileptic drugs blocking VGSCs as their primary mechanism of action. For example, phenytoin is a more effective inhibitor of SCN8A-I1327V than other drugs [112], which could be used in treating patients with gain-of-function mutations of SCN8A. Different types of VGCCs play different roles in the pathological process of epilepsy. Decreased expression of P/Q type could induce epilepsy, whereas increased expression of N-type and T-type calcium channels could lead to epilepsy. Calcium blockers including ethosuximide have been widely accepted for the treatment of absence epilepsy [71]. Gain-of-function BK channels contribute to epileptogenesis and seizure generation. BK-blocking agents, like paxilline [49], might be used as potential therapeutic drugs.
In the future, novel techniques might contribute to develop reasonable therapies for treating inherited or acquired epileptic syndromes. For instance, induced pluripotent stem cells (IPS) and genetically engineering animal models could be used for accurate treatments of epilepsy. Single-nucleotide polymorphisms (SNPs) of VGIC genes from hereditary epilepsy patients could be detected by
We systemically summarized the mutations and phenotype information of 21 epilepsy-associated VGIC genes. The dysfunctional VGICs are like the blasting fuse for neuronal hyperexcitability. We have good reason to believe that epilepsy-associated mutations of VGICs could be considered as a biomarker, which is possible to be one of the molecular bases underlying the classification of epilepsy syndromes identified by modern medicine. VGICs are the important targets for many antiepileptic drugs. Novel VGIC modulators are potentially effective strategy for the development of novel antiepileptic drugs. Individualized precise treatment using matching VGIC drugs will provide novel research directions and antiepileptic strategies.
This work was supported by National Science Foundation of China (Nos. 81603410 and 31771191), Innovation Fund of Putuo District Health System (No. 17-PT-10), Shanghai Municipal Commission of Health and Family Planning Fund (Nos. 20184Y0086, 2016JP007, and 2018JQ003), Project within budget of Shanghai University of Traditional Chinese Medicine (No. 18TS086), the Key Speciality Program (No. 2016102A) and Research Project (No. 2016208A) of Putuo Hospital, Shanghai University of Traditional Chinese Medicine.
The authors confirm that this article content has no conflict of interest.
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