\r\n\t• Role of technological innovation and corporate risk management \r\n\t• Challenges for corporate governance while launching corporate environmental management among emerging economies \r\n\t• Demonstrating the relationship between environmental risk management and sustainable management \r\n\t• Contemplating strategic corporate environmental responsibility under the influence of cultural barriers \r\n\t• Risk management in different countries – the international management dimension \r\n\t• Global Standardization vs local adaptation of corporate environmental risk management in multinational corporations. \r\n\t• Is there a transnational approach to environmental risk management? \r\n\t• Approaches towards Risk management strategies in the short-term and long-term.
",isbn:"978-1-83968-906-2",printIsbn:"978-1-83968-905-5",pdfIsbn:"978-1-83968-907-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"9b65afaff43ec930bc6ee52c4aa1f78f",bookSignature:"Dr. Muddassar Sarfraz and Prof. Larisa Ivascu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10226.jpg",keywords:"Global Risk Management, Risk Assessment, Climate Risk, Environmental Management, International Business, Business Sustainability, Corporate Governance, Financial Market, Financial Risks, Sustainable Economic Environment, Business Valuation, Organizational Behavior",numberOfDownloads:131,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 24th 2020",dateEndSecondStepPublish:"October 22nd 2020",dateEndThirdStepPublish:"December 21st 2020",dateEndFourthStepPublish:"March 11th 2021",dateEndFifthStepPublish:"May 10th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Muddassar Sarfraz focuses on corporate social responsibility, human resource management, strategic management, and business management. 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He is an Editorial Board Member of the International Journal of Human Resource as well as a member of the British Academy of Management (UK), Chinese Economists Society (USA), World Economic Association (UK), American Economic Association (USA), and an Ambassador of the International MBA program of Chongqing University, PR China, for Pakistan. \nHis research focuses on corporate social responsibility, human resource management, strategic management, and business management.",institutionString:"Binjiang College, Nanjing University of Information Science &Technology, Wuxi, Jiangsu",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],coeditorOne:{id:"288698",title:"Prof.",name:"Larisa",middleName:null,surname:"Ivascu",slug:"larisa-ivascu",fullName:"Larisa Ivascu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRfMOQA0/Profile_Picture_1594716735521",biography:"Dr Larisa IVAȘCU is currently an associate professor at the Politehnica University of Timisoara. 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1. Introduction
One of the greatest challenges in the current chemical industry is the development of high-efficient processes with increased selectivity and reduced generation of by-products. This has motivated extensive research in the last years focused on the use of alternative renewable feedstocks and on the development of less energetic reaction pathways or radically new chemical processes [1]. Catalysis plays an important role in defining new eco-efficient processes, where improvements in catalyst design and in catalytic reactor engineering are key elements that have to be linked to each other. The rational development of catalysts with enhanced catalytic performance relays on a fundamental knowledge of the catalytic process encompassing the reaction mechanism, rate-limiting reaction step, and the nature of active sites of the catalyst, where spectroscopy and theoretical studies are key aspects [2, 3]. Among the different types of spectroscopies, infrared (IR) spectroscopy is one of the most powerful techniques for the characterization of catalytic systems. This is easily demonstrated by the high number of studies found in the literature focused on the characterization of catalysts involved in industrial relevant processes [4, 5, 6, 7, 8]. In recent years, thanks to the technological advances allowing enhanced spectral (signal/noise level), temporal (rapid scan and step scan), and spatial (IR microscopy) resolution, with cutting-edge values in the μs and μm range, respectively, and by the development of new catalytic IR cells enabling transient studies in the μs range [9], a lot of interest has emerged in studying the catalyst under conditions resembling those encountered in catalysis, i.e., under “in situ” or “operando” conditions [10, 11]. In addition, extensive effort is being placed in coupling IR spectroscopy to other spectroscopies (UV–Vis, EXAFS, AP-XPS) [12, 13], expanding the information obtained for a given catalytic system. In the present chapter, the application of IR spectroscopy in catalysis is described providing interesting examples to illustrate how IR spectroscopy allows accurate characterization of catalyst surface sites and the identification of active sites in working catalysts enabling to establish structure-activity correlations, being this key point in the design of new catalysts. Moreover, the analysis of the reaction mechanism and rate-determining reaction steps by means of time- and temperature-resolved IR spectroscopy will also be discussed. Some examples related to relevant industrial processes like Fischer-Tropsch synthesis, ethylene oligomerization, dehydration of aldoxime compounds to their corresponding nitriles, and hydrogenation of nitrobenzene to aniline or azobenzene will be provided in order to illustrate the great potential of IR spectroscopy in the field of catalysis.
2. IR spectroscopy in catalyst characterization
IR spectroscopy provides detailed molecular information of the nature of adsorbed species on a catalyst surface, their interaction strength, and evolution under controlled atmospheres and temperatures. Using specific probe molecules, it allows to extract relevant information of the nature of surface sites on a catalyst, such as acid, base, and redox sites, surface defects, and the dynamic behavior of those sites under reaction conditions. Moreover, thermodynamic data such as entropy and enthalpy of molecular adsorption on a specific surface site [14, 15] and kinetic data can be accurately obtained. Altogether and comparing the IR data with macro-kinetic catalytic data, it assists in defining precise structure-activity correlations on a working catalyst, which is crucial in new catalyst designs. On the other hand, IR spectroscopy can be applied under a diverse set of environments: in air, in vacuum or in the presence of reactants under controlled low pressure, at cryogenic or high temperatures, and under more relevant catalytic conditions, including gases at atmospheric or even at higher pressures (20–30 bar) and liquids, allowing catalyst research to be performed under a wide range of reaction conditions. In the following sections, the application of IR spectroscopy in catalysis, especially in unraveling the nature of surface sites, discerning those who acts as active sites, and determining the reaction mechanism and rate-limiting step, will be discussed through selected illustrative examples.
2.1 Determination of the nature of surface sites
The surface of industrial catalysts is quite complex, comprising sites of different natures such as Brønsted (H+) acid sites, Lewis acid and base sites, transition metals with redox properties, and surface defects. Due to this huge number of sites, it is sometimes hard to get information about the intrinsic properties of the surface sites present in a working catalyst and, more importantly, to identify those who are involved in the catalytic process, called active sites. In this direction, IR spectroscopy with the aid of probe molecules has been proven as a very powerful characterization technique. Such probe molecules interact with specific surface sites resulting in a shift of their characteristic vibrational mode providing information about the chemical properties of the surface site (i.e., oxidation state, coordination, and chemical environment) and in the case that the adsorption coefficient of the corresponding IR mode is known, allowing their quantification. Many probe molecules are reported in the literature enabling information of specific aspects of the catalyst surface [16, 17, 18]. The choice of an appropriate molecule is a crucial point in the surface characterization, and often the combined use of several molecules is required for a comprehensive knowledge of the catalyst surface sites. Perhaps, the most widely known application of probe molecules in IR spectroscopy is related to the identification and quantification of acid sites (Lewis and Brønsted) in a catalyst [19, 20]. Several base molecules have been used for that purpose, where weak bases like H2, N2, CO, and NO have been proven as very sensitive to the local environment and oxidation state of the surface site [21, 22], while strong bases, like pyridine and ammonia, are less sensitive but very specific to the presence of Brønsted acid sites [23, 24]. The use of other probe molecules, like acetonitrile, alcohols, and thiols, has also been reported [25]. In this direction, an interesting example with important industrial repercussion is the search of efficient catalysts for the elimination of NOx emissions, where the selective catalytic reduction (SCR) of NOx with ammonia (NH3-SCR) or hydrocarbons (HC-SCR) is today one of the most efficient technologies. In this context, Cu-exchanged zeolites have shown interesting catalytic performance, where the identification of the nature of copper species is clue but highly challenging due to the coexistence of many different species such as isolated Cu2+,Cu+,Cu(OH)+, dimeric [Cu-O-Cu], sub-nanometric CuxOy clusters, and/or CuO and Cu2O aggregates [26, 27, 28]. Despite the massive number of investigations on these systems, there is still controversy about the nature of active sites, mainly due to the wide range of catalysts explored in the literature containing a mixture of multiple copper sites. Therefore, one way to overcome the complexity of many industrial catalysts is to try to design catalysts containing well-defined uniform sites and use them as model systems in both catalytic and spectroscopic studies. Following this hint, Cu-exchanged zeolites with uniform isolated sites (Cu-SAPO-34 and Cu-SSZ-13) have been prepared in our group by a hydrothermal synthetic approach [29, 30, 31]. Both catalysts show high activity and stability in the NH3-SCR reaction, making them interesting candidates for the investigation of active sites in the SCR reaction. IR spectroscopy of CO and NO adsorption as probe molecules, combined with theoretical modeling of the vibrational frequencies, has allowed precise identification of Cu2+/Cu+ species located either in the 8-ring or 6-ring of the zeolite structure, as well as the identification of Cu-O-Cu dimeric species, resolving some of the controversy in the assignation of IR band frequencies present in the literature and establishing the role of isolated Cu2+/Cu+ ions as active sites in the NH3-SCR [32].
Among the different types of industrial catalysts, metal-based catalysts containing noble metals like Pt, Pd, and Rh and non-noble metals like Ni, Co, and Ru are used in many industrial processes. The catalytic activity and selectivity of this class of catalysts are strongly influenced by their particle size and morphology, electronic state of surface metal atoms, and metal interfaces or heterojunctions in the metal particle, where a comprehensive knowledge of these parameters is essential in understanding their catalytic performance. To achieve that, the combination of several spectroscopic tools is strongly required, being IR of CO as probe molecule of great interest. Based on the shift of the ν(C≡O) frequency, metal particles exhibiting different facets like the (111) (100) (110) crystallographic planes, as well as the presence of undercoordinated metal atoms located in steps and corners of the metal particle, can be easily detected [33, 34]. For example, by combining IR of CO as probe molecule with theoretical vibrational simulations obtained by the density functional theory (DFT) method, gold atoms of different natures have been investigated in supported gold nanoparticle catalysts. Specifically, gold atoms with different coordination degrees (for instance, in the edge and corners of the particle), electron density (for instance, Auδ+ atoms located in the perimeter of the gold particle in close contact with the support), and oxidation state (Au3+, Au+ and Au0) have been accurately defined [35].
Finally, the characterization of surface base sites in a catalyst using IR spectroscopy of probe molecules (like CO2, trichloromethane, acetylene, and pyrrole) is less studied, mainly due to the complexity of some of the probe molecules when adsorbed on the catalyst surface [17, 36]. For example, CO2 adsorption on basic surface sites leads to several types of carbonate species which hinder accurate identification of surface base properties [37].
2.2 Determination of the nature of active sites: structure-activity correlation
The main challenge in spectroscopy, and specifically in IR spectroscopy, is to differentiate the catalytic active sites which are directly involved in the reaction mechanism, from the rest of sites normally present on the surface of working catalysts. Only in this case, it is possible to define accurate structure-activity correlations, which allows to direct the synthesis of new catalysts. Identification of active sites is not always straightforward and requires a multidisciplinary approach, combining surface characterization with catalytic data and, if possible, with theoretical calculations. In the following subsections, we will provide some examples of our work where active sites have been accurately identified.
2.2.1 Nature of active sites in the dehydration of aldoximes to nitriles on heterogeneous ceria catalysts
Nitriles are precursors for a wide range of organic products like carboxylic acids, amines, ketones, and amides. The most efficient route for the synthesis of nitriles is the dehydration of aldoximes that can easily be obtained from the corresponding aldehydes. Homogeneous catalytic systems such as Pd(II) complexes with a phosphino-oxime ligand [38], Co(II)Cl2 [39], Ga(OTf)3 [40], and Fe(ClO4)3 [41] are employed with interesting performance but presenting important limitations such as catalyst recovery, use of hazardous organic solvents, and long reaction time. Therefore, a lot of attention is paid in developing alternative heterogeneous catalysts. Among the different heterogeneous catalysts reported in the literature [42, 43], nanocrystalline ceria (nCeO2) stands as a very promising catalyst in the dehydration of a variety of aldoximes (including alkyl and cycloalkyl aldoximes) to the corresponding nitriles at moderate temperature (149°C) with yields around 80–97% [44]. The catalyst shows good stability and recyclability after several uses. While both acid and basic sites are discussed in the literature for aldoxime dehydration, there is no clear understanding about the role of each of them in the reaction mechanism. In order to shed light into the participation of acid and base sites in the reaction mechanism, we performed a detailed IR study on nCeO2 compared with other catalysts (CeO2, MgO, Al2O3, and TiO2). The different catalysts are studied in the dehydration of 4-methoxybenzaldehyde oxime, where the initial reaction rate follows the order nCeO2 > MgO > Al2O3 > CeO2 > TiO2. Surface characterization is done using CO and CHCl3 as probe molecules. Based on the IR spectra of CO adsorption (Figure 1A), the acid strength of the different catalysts (being proportional to the red ν(C≡O) shift) can be ranked in the order Al2O3 > TiO2 > MgO > nCeO2 > CeO2, while the number of surface acid sites (peak area normalized by the catalyst surface area), called surface acid density, follows a different order CeO2 > TiO2 > nCeO2 > Al2O3 > MgO. In the same way, based on the IR spectra of CHCl3 adsorption (Figure 1B), the basic strength (being proportional to the blue ν(C-H) shift) can be ranked in the order MgO > nCeO2 > CeO2 > TiO2 > Al2O3. The same order can be applied for the surface base density.
Figure 1.
(A) IR spectra of CO adsorption at saturation coverage on the different catalysts. (B) IR spectra of CHCl3 adsorption at saturation coverage on the same catalysts. All spectra are normalized to sample weight.
Once the catalyst acid and base sites are established, the “in situ” dehydration of propionaldehyde oxime is studied by IR spectroscopy in order to understand how the presence of those sites influences the reactivity of the samples. The observed IR red shift of both νC=N (from 1640 cm−1 in the gas phase to 1646 cm−1 on nCeO2 and 1667 cm−1 on Al2O3) and νN-OH vibrations (1028 cm−1 in the gas phase to 1037 cm−1 on nCeO2 and 1051 cm−1 on Al2O3), suggests a mechanism for which the activation of propionaldehyde oxime involves an N-bond complex to a surface Lewis acid site increasing in that way the C=N and N-OH bond strength [45], followed by N-OH bond elimination and C-H cleavage with subsequent water and nitrile formation (Scheme 1). This differs to the conventional oxidative dehydration mechanism (i.e., interaction of the oxygen of the oxime with Lewis acid sites) for which a blue shift of both vibrations would be expected [45].
Scheme 1.
Proposed mechanism for the dehydrogenation of aldoximes to nitriles on metal oxide heterogeneous catalysts.
In addition, notice that in general the shift in the IR vibration of an adsorbed molecule reflects the degree of bond activation which is proportional to their catalytic reactivity. However, such a correlation is not found in this case, where the observed shift of the N-OH vibration is proportional to the sample acid strength, but doesn’t match to the catalyst activity. Thus, Lewis acid sites, while being involved in the reaction mechanism, seems not to be a determinant factor for the catalytic activity. On the contrary, considering that both nCeO2 and MgO samples, with the highest basic strength, are the most active catalysts, surface basicity should play a decisive role in the reaction mechanism. Basic sites are involved in the C-H bond cleavage, which from the IR and catalytic studies can be proposed as the rate-limiting step of the reaction. In conclusion, both Lewis acid sites and basic sites are involved in the reaction mechanism, being Lewis acid sites involved in the adsorption of the oxime, while strong basic sites are required for C-H activation.
In this way, combining IR data with catalytic data, the highest catalytic activity of the nCeO2 can be ascribed to an appropriate number of surface acid sites enabling the activation of the oxime and strong basic sites favoring C-H cleavage. While similar strong basic sites are present on MgO, the lower surface density of acid sites explains its lower activity than nCeO2. Moreover, owing to the basic character of both nCeO2 and MgO, desorption of the nitrile from the catalyst surface is favored avoiding secondary reactions and enhancing catalyst stability.
2.2.2 Nature of active sites in ethylene oligomerization reaction
Ethylene oligomerization is an interesting chemical route of industrial importance for the production of linear and branched higher olefins. Those olefins, depending on their carbon number, show several applications, for example, comonomers in polyethylene industry (C4–C6), as plasticizer alcohols (C8–C10), as synthetic lubricants (C10–C12), in the detergent industry (C12–C16), and as lube oil components or in surfactant manufacture (C16–C18). Industrially, the process takes place in liquid phase using homogeneous transition metal complexes as catalysts and alkyl aluminum compounds as activators [46]. Owing to the limitations of the actual industrial process, such as difficulty to separate the catalyst from oligomers, increase of operational cost, and broad carbon number distribution of products, the search of alternative heterogeneous solid catalysts is very interesting from both economic and environmental points of view. In this sense, nickel loaded on acidic aluminosilicates such as zeolites and amorphous mesoporous supports has attracted great attention as efficient and environmentally friendly heterogeneous catalysts for ethylene oligomerization, although they suffered from catalyst deactivation with time of stream (TOS) [47]. Recently, our group developed a bifunctional catalyst comprised of Ni loaded on nanocrystalline zeolite HBeta (Ni-HBeta) with high catalytic activity and stability during the oligomerization process [48]. Ethylene conversions of ∼90% at 2.5 wt% Ni loading in the Ni-HBeta catalyst under conventional reaction conditions (T = 120°C, Ptot = 35 bar, PC2H4 = 26 bar, WHSV = 2.1 h−1) are obtained without apparent signs of deactivation within 1–9 h TOS. Despite the high promising features displayed by Ni-based catalysts, the nature of active sites (isolated Ni+ and/or Ni2+) remained under debate, being subject of intense research studies in the last years [49, 50, 51, 52]. To this aim, catalytic studies with high temporal resolution in the earliest stage of the reaction monitored by a combined gas chromatograph (GC) and mass spectrometry (MS) analysis technique and coupled with “in situ” IR-CO surface titration spectroscopic studies are performed in our group in order to identify the nature of the active Ni sites for ethylene oligomerization in the Ni-HBeta catalyst [53]. Catalysts with different nickel loadings (1, 2.5, 5, and 10 wt%) are studied. Specification of the nature of nickel sites monitored by IR of CO as probe molecule shows in all samples isolated Ni2+ cations in ion exchange positions of the zeolite and isolated Ni2+ interacting with silanol groups of internal defects (hydroxyl nests) or stacking faults of the nanocrystalline beta zeolite. Indeed, the IR-CO spectra of the activated 5wt%Ni-HBeta catalyst show IR bands at 2214 and 2207 cm−1 assigned to carbonyls of isolated Ni2+ ion exchange cations [51, 54] and an IR band at 2196 cm−1 attributed to isolated Ni2+ interacting with silanol groups [55], in addition to IR bands at 2175, 2164, 2156, and 2143, 2131 cm−1 attributed to CO interacting with Brønsted acid sites, aluminols, silanols, and physically adsorbed CO, respectively (Figure 2).
Figure 2.
IR spectra of CO adsorption at saturation coverage and at −175°C on the 5wt%Ni-HBeta sample activated in N2 flow (20 ml/min) at 300°C for 3 h.
Interestingly, independent of the nickel loading in the Ni-HBeta sample, the time-resolved GC–MS catalytic studies performed in a low-dead-volume catalytic setup, working at 1 bar, 120°C, and WHSV of 33 h−1 (Figure 3A), show a significant loss of ethylene conversion in parallel to a decrease in the butene concentration at the very early reaction stage (first 10 min) before achieving pseudo-steady-state activity at TOS of 30 min. The short time frame where the initial loss of activity occurs prevents their detection in a conventional high-pressure reactor setup, where all catalysts are shown to remain stable up to 9 h TOS. Coupled to the catalytic studies, IR studies at the same experimental conditions are performed using a low-volume IR catalytic cell. The “in situ” IR ethylene oligomerization reaction is stopped at different stages of the reaction (10 s, 8 min, 30 min, and 70 min) and the nature of Ni sites titrated by IR of CO as probe molecule. Since all catalysts displayed similar trends, the 5wt%Ni-HBeta catalyst is taken as representative in the following discussion. After “in situ” reaction with ethylene in the IR catalytic cell, a sharp reduction in the intensity of the IR bands related to the isolated Ni2+ ions is noticed even after only 10s of reaction (Figure 3B). The decrease in intensity is particularly significant for the higher frequency bands at 2214 and 2207 cm−1 related to the ion exchanged Ni2+ ions with stronger Lewis acid character, while that at 2196 cm−1 of less acidic isolated Ni2+ interacting with silanol groups is much less affected; meanwhile, Brønsted acid sites at 2175 cm−1 are also considerably reduced in intensity. In addition, dicarbonyl Ni+ bands at 2138 and 2095 cm−1 [56] are clearly detected at low CO coverage since the very early reaction stage, increasing in intensity during the course of the reaction (spectra not shown).
Figure 3.
(A) Time-resolved GC–MS analysis in the ethylene oligomerization reaction performed at 1 bar and 120°C on the 5wt%Ni-HBeta sample. The arrows correspond to the reaction stages where surface titration by IR-CO is performed. (B) IR spectra of CO adsorption at −175°C and at saturation coverage on the 5wt%Ni-HBeta sample stopped at selected reaction times. (C) Evolution in the concentration of the different nickel sites in the working 5wt%Ni-HBeta sample and their correlation with catalytic data (conversion). (D) The “in situ” IR spectra under ethylene oligomerization reaction at 1 bar and 120°C and at different TOS highlighting hydrocarbon formation.
Linking the IR and GC–MS data (Figure 3C), Ni+ ions cannot be considered as active site since the intensity of the IR bands of Ni+ ions increases with reaction time, while the catalytic activity decreases. Despite this, a clear parallelism between the reduction in intensity of the IR bands of isolated Ni2+ ions and the initial decline in ethylene conversion rate is observed, implying that the two phenomena should be closely related. Significantly, while isolated ion exchange Ni2+ ions (IR bands at 2214 and 2207 cm−1) become almost totally blocked in the first seconds of the reaction, Ni2+ ions interacting with silanol groups (IR band at 2196 cm−1) remain accessible under reaction conditions and can accordingly be considered as the true catalytic active sites under steady-state conditions. The blocking of the most acid Ni2+ and Brønsted acid sites under reaction conditions is due to irreversibly adsorbed hydrocarbons formed from the very early stages of reaction as detected in the “in situ” IR spectra (Figure 3D). In conclusion, these results highlight the importance of nickel sites of intermediate Lewis acid strength in order to design efficient ethylene oligomerization catalysts.
2.2.3 Nature of active sites in the Fischer-Tropsch reaction
The Fischer-Tropsch (FT) reaction has gained renewed interest in the last years as an alternative route to produce high-quality liquid fuels from alternative sources to petroleum, such as natural gas, coal, and biomass [57]. In the FT process, cobalt-based catalysts have preferentially been employed due to their high stability, low activity for the competitive reverse water gas shift reaction (WGSR), and high selectivity to long-chain n-paraffins compared to alternative catalysts based on iron [58]. Due to the interest in this process, a lot of research has been devoted to prepare novel catalysts with improved catalytic behavior. One conventional way to improve the catalytic activity is increasing the metal dispersion (i.e., decreasing particle size), but unexpectedly a low reaction rate and a low selectivity to the desired long-chain hydrocarbons have been observed in the FT process when decreasing the cobalt particle size below 8–9 nm [59, 60]. This trend differs from the classical structure sensitivity behavior, and the reason behind has been a long-lasting debate in the literature. Particularly, the presence of unreduced Co species due to the lower reducibility of small Co nanoparticles and the reoxidation of Co sites under reaction conditions in highly dispersed catalysts [60, 61, 62, 63, 64] have been the most widely discussed issues. In order to understand this nonclassical particle size-dependent activity, cobalt nanoparticles with a homogenous particle size distribution from 5.6 to 10.4 nm are prepared in our laboratory using a reverse micellar synthesis procedure and deposited onto a surface-silylated ITQ-2 delaminated pure silica zeolite [65]. As reference, a Co/SiO2 catalyst with Co particle size of 141 nm is also studied. The metal loading in all samples is 10 wt%. The high reducibility of the catalysts and their homogeneous particle size distribution make them ideal candidates as model systems for investigating the aforementioned catalytic behavior. Spectroscopic studies combined with catalytic studies under FT conditions (P = 20 bar and T = 220°C) are performed. In the catalytic studies, the intrinsic catalytic activity (TOF) decrease with decreasing Co particle size from 10.4 to 5.6 nm remains constant for particle sizes above 10.4 nm, according to the literature. The evolution of the cobalt sites under FT reaction conditions is nicely followed in the “in situ” IR studies performed at ambient pressure under syngas flow and at increasing temperatures (25–220°C) (Figure 4). All samples show similar trend, where at 25°C two IR bands at 2048 cm−1 associated with linearly CO adsorbed on fcc Co0 sites [66] and at 1625 cm−1 due to adsorbed water are observed. Increasing the temperature to 150 and 200°C, there are no bands observed in the Co-carbonyl region, probably due to a complete blockage of the surface sites and due to CO dissociation and the growth of adsorbed HxC intermediate species. Indeed, a band at 612 cm−1 is observed in the low-frequency range, associated with adsorbed oxygen atoms (i.e., Co-O) [67]. Finally, increasing the temperature to 220°C, Co-carbonyls are rapidly restored, due to desorption of reaction intermediate species leaving free cobalt metal sites for CO adsorption. Concomitantly, a progressive shift in the Co-carbonyl IR band is observed from 2048 cm−1 to 2024 and 2000 cm−1 with increasing reaction time at 220°C, where the 2024 and 2000 cm−1 IR bands are related to unsaturated or low coordinated cobalt surface sites located in defect sites or on more open crystallographic cobalt planes [68, 69]. Being this shift in the IR bands irreversible, it is ascribed to cobalt surface reconstruction from an fcc structure to a more open crystallographic structure, the last one behaving as the true active site under working conditions [65]. Notice the parallel appearance of an IR band at 642 cm−1 ascribed to cobalt-carbon species [70, 71] which provides the first experimental evidence for the role of carbon atoms in promoting surface reconstruction of the cobalt particle under FT conditions, in agreement to previous DFT calculations [72].
Figure 4.
FTIR spectra of the Co/ITQ-2 sample with 10.4 nm Co particle size under FT reaction conditions at 1 bar and at 25, 150, 200, and 220°C. Each spectrum is recorded after 45 min at each temperature. At 220°C the IR spectra are recorded at 120, 210, and 240 min time on stream (TOS).
Notoriously, on the sample with the smallest Co particle size (5.6 nm) and lower catalytic activity (Figure 5A), a band at 2060 cm−1, not observed on the other samples, is detected in the “in situ” IR spectra (Figure 5B). This band, already observed in their reduced state prior to FT reaction, increases in intensity under FT conditions and has been ascribed to Coδ+ sites in the cobalt-support interface [73]. While those interface sites are mayoritary in particles of small size, their increase under FT reaction conditions results from morphological changes in the small cobalt nanoparticle, as already detected by HRTEM, where a flattening of the cobalt particle is observed after FT reaction, enhancing the amount of metal interface sites. Since the electropositive character of the Coδ+ sites inhibits CO dissociation, a higher amount of these sites turn out in a lower FT activity, explaining in that way the lower FT catalytic activity observed at small Co particle sizes. This result is interesting from a fundamental point of view explaining the nonclassical particle size-dependent FT activity and more importantly from a scientific point of view, highlighting the dynamism of catalysts under reaction condition and their impact on their catalytic performance, which has been underestimated in many studies. In this context, thanks to the recent development of advances of the spectroscopic tools with “in situ” capabilities, a lot of progress has been done in this direction, not only in the FT reaction but also in other catalytic processes, revealing a highly dynamic behavior of the catalysts at working conditions [74, 75].
Figure 5.
(A) Variation of the turnover frequency (TOF) in FT at 220°C and 20 bar with the cobalt particle size. (B) IR spectra after 4 h on stream in FT (220°C, 1 bar) for (a) Co-ITQ-2 with 10.4 nm Co particle size, (b) Co/SiO2 with 141 nm Co particle size, and (c) Co-ITQ-2 with 5.6 nm Co particle size samples. In the inset the deconvolution of the Co-carbonyl region highlighting the presence of the 2060 cm−1 IR band.
2.3 Determination of reaction mechanism and rate-limiting reaction step
Besides the characterization of catalyst surface sites, the identification of reaction intermediate species and reaction mechanism in a catalytic process is of great interest. It allows to define the rate-limiting reaction step, which coupled to a fundamental knowledge of the nature of active sites involved in each elementary step, enables a rational design of industrial catalysts. However, due to the transient nature of reaction intermediates, differentiating them from other species present in the catalyst but not being involved in the catalytic process (called as spectators) is often difficult. Ways to do it are following the evolution of surface species during time- and temperature-resolved IR experiments and combining the IR data with catalytic data obtained either “in situ” in coupled GC–MS analysis or in “ex situ” studies. The same can be done performing pressure-dependent IR studies. Next, an example will be presented that is supported by temperature-resolved IR studies, and different reaction mechanisms are established depending on the catalyst properties.
2.3.1 Hydrogenation of nitroaromatics on supported gold catalysts
Experiments performed in our laboratory have shown that under the same reaction conditions (T = 120°C, P = 4 bar H2, [Au] = 1%mol, Nitrobenzene = 0.25 M), Au nanoparticles of 2.5–3.5 nm particle size deposited on ceria (Au/CeO2) and on titania (Au/TiO2) display different selectivities in the hydrogenation of nitrobenzene. Thus, aniline is predominately formed on Au/TiO2 (∼90% selectivity at 97% conversion), while azobenzene (∼99% selectivity at 100% conversion) is formed on the Au/CeO2 catalyst [76]. Both aniline and azobenzene are valuable intermediates in the industrial production of pharmaceuticals, agrochemicals, pigments, dyes, and food additives, conferring high interest in the possibility to tune in a rational way the selectivity to the desired product by modifying the nature of the catalyst. If one considers the general reaction scheme proposed by Haber to reduce nitroaromatics (Scheme 2), it seems that the different catalytic performance of both Au/TiO2 and Au/CeO2 catalysts has to be related to a different reaction route (direct route versus condensation route), but the question is why both catalysts follow different reaction paths, and why in the case of the condensation route aniline is not formed as the final product. In order to answer this question, IR studies combined with micro-kinetic studies have been performed on both catalysts.
Scheme 2.
Reaction pathways in the hydrogenation of nitrocompounds to anilines. NC = nitrocompound, NSC = nitrosocompound, AHA = aromatic hydroxylamine, AN = aniline, AOC = azoxycompound, AC = azocompound, HAC = hydrazocompound [76].
2.3.1.1 IR studies of the hydrogenation of nitrobenzene on Au/TiO2 catalysts
The hydrogenation of nitrobenzene is followed by IR on the Au/TiO2 catalysts performing temperature-dependent studies. In the IR spectra (Figure 6A), simultaneous to the consumption of nitrobenzene (IR bands at 1523 cm−1), nitrosobenzene (1483, 1475 cm−1), phenylhydroxylamine (1489 cm−1), and aniline (1495 cm−1) are formed [77, 78]. The micro-kinetic data IR displayed in Figure 6B shows a low surface concentration of nitrosobenzene and a high amount of phenylhydroxylamine. Being phenylhydroxylamine an intermediate compound (see Scheme 2), its high surface concentration indicates a low hydrogenation rate to aniline and the coexistence of an additional parallel direct reaction path of phenylhydroxylamine formation starting from nitrobenzene in which nitrosobenzene formation is circumvented (Figure 6C). These results and the absence of IR bands of azoxy and/or azocompounds help to propose a direct hydrogenation route. Moreover, it is shown that the low surface concentration of nitrosobenzene during nitrobenzene hydrogenation is clue in this reaction path. This is confirmed by additional IR experiments where the surface coverage of nitrosobenzene on the Au/TiO2 catalyst is modified and the evolution of surface species under hydrogenation conditions monitored. Thus, at low surface coverage, a fast hydrogenation of nitrosobenzene to phenylhydroxylamine is observed, followed by further hydrogenation to aniline, whereas at high nitrosobenzene coverage, azoxybenzene is mainly formed [76].
Figure 6.
(A) IR spectra in the hydrogenation of nitrobenzene on Au/TiO2 catalyst at (a) 25°C, (b) 70°C, (c) 85°C, (d) 100°C, and (e) 120°C (0.5 mbar NB and 8 mbar H2). (B) Evolution of the IR surface reaction intermediates species with temperature. (C) Proposed reaction path.
2.3.1.2 IR studies of the hydrogenation of nitrobenzene on Au/CeO2 catalysts
In the temperature-dependent nitrobenzene hydrogenation IR studies performed on the Au/CeO2 catalyst, nitrobenzene (IR bands at 1509 and 1343 cm−1) disappears slowly, followed by nitrosobenzene formation (1540, 1491, and 1398 cm−1) (Figure 7A). Nitrosobenzene is stabilized on the catalyst surface until 100°C, temperature at which azoxybenzene (IR bands at 1546, 1372, and 1357 cm−1) is formed. Increasing temperature to 120°C azobenzene (IR bands at 1303 and 1566 cm−1) is formed, showing a maximum at 21 min of reaction and then starting to decrease. This is associated to desorption of azobenzene to the gas phase, avoiding in that way a progressive hydrogenation to aniline and explaining the high selectivity to azobenzene displayed by the Au/CeO2 catalyst [76]. These results are in line with a condensation route favored by an accumulation of nitrosobenzene on the catalyst surface. Moreover, previous IR results show a very fast reactivity of nitrosobenzene with phenylhydroxylamine, even at 25°C, giving azoxybenzene. Based on it, the surface accumulation of nitrosobenzene in the hydrogenation of nitrobenzene on the Au/CeO2 catalyst, the absence of phenylhydroxylamine in the IR spectra, and the onset of azoxybenzene formation at 100°C indicate that the hydrogenation rate of nitrosobenzene to phenylhydroxylamine is low, being this the rate-limiting step. In conclusion, from these results, the different reaction pattern observed on the Au/CeO2 catalysts is related to the stabilization of nitrosobenzene on the CeO2 surface, which is ascribed to their basic properties compared to the TiO2 as support.
Figure 7.
(A) IR spectra in the hydrogenation of nitrobenzene on Au/CeO2 catalyst at (a) 25°C, (b) 70°C, (c) 85°C, (d) 100°C 10 min, (e) 100°C 30 min, (f) 120°C 7 min, (g) 120°C 17 min, (h)120°C 21 min, (i) 120°C 26 min, and (j)120°C 46 min (0.5 mbar NB and 8 mbar H2). (B) Evolution of the IR surface reaction intermediates species with temperature. (C) Proposed reaction path.
Accordingly, these results show that it is possible to modulate the selectivity in the one-step nitroaromatic hydrogenation by adjusting the catalyst properties modulating in that way the concentration of nitrosobenzene on the catalyst surface.
3. Conclusion
IR spectroscopy has been shown as a very powerful technique in the field of catalysis, enabling important information difficult to obtain with other techniques. Thus, surface sites and active species can be properly analyzed, which combined with the analysis of the reaction mechanism and the rate-limiting step are key points to direct the synthesis of catalysts with improved selectivity. Moreover, the dynamism of catalyst surfaces under reaction conditions monitored by IR spectroscopy has been highlighted, a fact usually underestimated but with strong repercussion on the catalytic performance.
Acknowledgments
PC thanks the financial support of the Spanish government “Severo Ochoa Program” (SEV-2016-0683).
Conflict of interest
There is no conflict of interest in this publication.
\n',keywords:"catalysis, Fischer-Tropsch, ethylene, nitrobenzene, aldoximes, CO",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/63268.pdf",chapterXML:"https://mts.intechopen.com/source/xml/63268.xml",downloadPdfUrl:"/chapter/pdf-download/63268",previewPdfUrl:"/chapter/pdf-preview/63268",totalDownloads:893,totalViews:309,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"April 26th 2018",dateReviewed:"July 26th 2018",datePrePublished:"November 5th 2018",datePublished:"March 6th 2019",dateFinished:null,readingETA:"0",abstract:"Catalysis plays an important role in sustainable chemistry, enabling the development of more efficient processes by minimizing the consumption of energy and reducing the generation of by-products. The design of efficient catalysts is a key point in this respect, where spectroscopy confers fundamental knowledge at the molecular scale. Among the different spectroscopies, infrared (IR) spectroscopy is of great interest, enabling information about the nature of active species and the reaction mechanism, leading to precise structure-activity correlations, which are a key point in the design of new catalysts. Moreover, the dynamic behavior of the catalysts under working conditions can be also monitored by IR spectroscopy, where structural modifications of working catalysts have strong repercussion in catalysis. In this chapter, interesting examples will be discussed, related to industrial relevant processes, like Fischer-Tropsch synthesis, ethylene oligomerization, synthesis of aniline from nitrocompounds, and the dehydration of aldoximes to nitriles.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/63268",risUrl:"/chapter/ris/63268",book:{slug:"infrared-spectroscopy-principles-advances-and-applications"},signatures:"Patricia Concepción",authors:[{id:"256501",title:"Dr.",name:"Patricia",middleName:null,surname:"Concepcion",fullName:"Patricia Concepcion",slug:"patricia-concepcion",email:"pconcepc@upvnet.upv.es",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. IR spectroscopy in catalyst characterization",level:"1"},{id:"sec_2_2",title:"2.1 Determination of the nature of surface sites",level:"2"},{id:"sec_3_2",title:"2.2 Determination of the nature of active sites: structure-activity correlation",level:"2"},{id:"sec_3_3",title:"2.2.1 Nature of active sites in the dehydration of aldoximes to nitriles on heterogeneous ceria catalysts",level:"3"},{id:"sec_4_3",title:"2.2.2 Nature of active sites in ethylene oligomerization reaction",level:"3"},{id:"sec_5_3",title:"2.2.3 Nature of active sites in the Fischer-Tropsch reaction",level:"3"},{id:"sec_7_2",title:"2.3 Determination of reaction mechanism and rate-limiting reaction step",level:"2"},{id:"sec_7_3",title:"2.3.1 Hydrogenation of nitroaromatics on supported gold catalysts",level:"3"},{id:"sec_7_4",title:"2.3.1.1 IR studies of the hydrogenation of nitrobenzene on Au/TiO2 catalysts",level:"4"},{id:"sec_8_4",title:"2.3.1.2 IR studies of the hydrogenation of nitrobenzene on Au/CeO2 catalysts",level:"4"},{id:"sec_12",title:"3. 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Bari",slug:"dindar-s.-bari"}]},{id:"71012",title:"Experimental and Theoretical Study of the Adsorption Behavior of Nitrate Ions by Layered Double Hydroxide Using Impedance Spectroscopy",slug:"experimental-and-theoretical-study-of-the-adsorption-behavior-of-nitrate-ions-by-layered-double-hydr",signatures:"Abderrahmane Elmelouky, Abdelhadi Mortadi, Elghaouti Chahid and Reddad Elmoznine",authors:[{id:"313846",title:"Ph.D.",name:"Elmelouky",middleName:null,surname:"Abderrahmane",fullName:"Elmelouky Abderrahmane",slug:"elmelouky-abderrahmane"}]},{id:"72014",title:"Electrochemical Impedance Spectroscopy (EIS) in Food, Water, and Drug Analyses: Recent Advances and Applications",slug:"electrochemical-impedance-spectroscopy-eis-in-food-water-and-drug-analyses-recent-advances-and-appli",signatures:"Marwa El-Azazy",authors:[{id:"198210",title:"Dr.",name:"Marwa",middleName:"S.",surname:"El-Azazy",fullName:"Marwa El-Azazy",slug:"marwa-el-azazy"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"70943",title:"Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease",doi:"10.5772/intechopen.91028",slug:"neuroprotective-potentials-of-natural-vitamin-e-for-cerebral-small-vessel-disease",body:'\n
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1. Introduction
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The recognition of vitamin E for its nutritive value was first linked to reproductive health in laboratory rats, then coined as factor X [1]. While alpha-tocopherol was the first vitamin E isomer to be recognized, there are now eight chemically distinct isomers known, consisting of alpha (α), beta (β), gamma (γ), and delta (δ)-isoforms of tocopherols and tocotrienols [2]. Current recommendations for adequate intake values are established based on α-tocopherol alone, whereas other forms of vitamin E need to meet other criteria [3]. Nature affords tocopherols in abundance, particularly in plants such as peanuts, sunflower seeds, and sesame seeds. The major dietary source of tocopherol is largely from corn and soybean oil consumption [4]. In contrast, the less ubiquitous tocotrienols are found in certain cereals and vegetables such as palm oil and annatto. A non-food source of tocotrienols is also recognized, namely, the latex of the rubber plant [2].
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The well-established bioactivity of vitamin E is its antioxidant property by means of lipid peroxidation of cellular membranes [2]. As such, this property lends vitamin E the roles in promoting vascular health in arterial compliance studies and endothelial dysfunction biomarker. Pertinent to this, vitamin E involvement is the vascular endothelium, which lines the intraluminal surface of blood vessels and is involved in the regulation of vascular tone, platelet activity, thrombosis, and the overriding pathogenesis of atherosclerosis [5, 6]. Vitamin E engages with the production of nitric oxide (NO) that relaxes the vascular smooth muscle while limiting free radicals to maintain arterial compliance [7]. More recently, vitamin E has been linked with anti-atherogenic effects that decrease low-density lipoprotein (LDL) oxidation and downstream inhibition of protein kinase C (PKC), adhesion molecules, monocyte transmigration, and vascular smooth muscle cell proliferation [8].
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Therefore, the foregoing facts on vascular health and vitamin E profiles offer interrelated perspectives for a largely unexplored neurological condition termed cerebral small vessel diseases (CSVD). CSVD variable manifestations inflict small blood vessels or microcirculation at the subcortical and deeper parts of the brain. It has been widely reported to cause cerebral ischemic stroke or lacunar stroke that accounts for nearly a third of all stroke subtypes worldwide [9, 10, 11, 12]. The pathological consequences of small vessel disease on the brain parenchyma rather than the underlying diseases of the vessels is frequently viewed as the basis of CSVD [13]. Notably, CSVD lesions can be silent, and the affected individual may not have any apparent clinical symptoms. This silent (subclinical) lesion, with higher numbers (single or multiple), poses as a risk for vascular cognitive impairment, dementia, Alzheimer’s disease, and full-blown stroke [14, 15].
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Furthermore, aging and chronic hypertension are known to accelerate CSVD, as the two conditions (physiological and pathological, respectively) may result in less efficient ability to self-regulate cerebral blood flow (cBF) from the concurrent varying systemic blood pressure levels and increased arterial stiffness which increases the speed and flow pulsatility in cerebral arterioles [16]. These hemodynamic changes are postulated to cause variable degrees of endothelial damage in the blood-brain barrier (BBB) and alter its permeability through an increase of the shear stress [17]. Hence, the BBB breakdown is an important etiopathogenesis feature of CSVD [17, 18, 19].
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In addition, there is an elevated production of reactive oxygen species (ROS) in CSVD that ultimately leads to endothelium dysfunctions [20, 21]. This is mainly due to the cumulative reactions and processes (i.e., high blood pressure, very low density of lipoproteins, diabetes mellitus, homocysteinemia, and smoking) that trigger and escalate the inflammatory responses and oxidative stress [20, 21]. This, in turn, heightens the release of adhesion molecules and recruits leukocytes, causing higher leukocyte-endothelial cell (EC) adhesion and reduced cBF. Accordingly, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases intensify the oxidative stress (a major source of ROS in vessel wall) and the consequent destructive impact on EC-dependent NO signaling [22, 23].
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Collectively, this chapter focuses on highlighting the contemporary evidence on vitamin E, especially α-tocopherol and α-tocotrienol, their neuroprotective potential in relation to the heterogenous spectrum of CSVD manifestations, in promoting health as we age, and in mitigating disease.
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2. Natural sources of vitamin E
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2.1 Forms and structure
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Vitamin E was first discovered in 1922 by Herbert Evans and Katherine Bishop at the University of California in Berkeley when they studied nutritive dependencies in reproduction [1]. They observed that rats fed with a purified diet of casein 18%, cornstarch 54%, lard 15%, butterfat 9%, and salts 4% and adequate vitamin A (as cod liver oil), vitamin B (as yeast), and vitamin C (as orange juice) did not reproduce. They observed in females defective placental function, whereas the ovaries, ovulation, and implantation were unimpaired; and in males, there was a complete atrophy of the seminiferous epithelium [24, 25]. The addition of lettuce to the diet prevented embryo resorption during rodent gestation, and healthy pups were born again, thus, leading to the discovery of an anti-sterility factor, then termed as factor X. Wheat germ oil was later found to be a rich source of factor X. It was not until some 10 years later that Evans successfully isolated the components of vitamin E family and named them tocopherols (Greek: toc (child), phero (to bring forth), and –ol because it behaves chemically like an alcohol) [25, 26].
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Meanwhile, tocotrienol was named by Bunyan and colleagues, when they identified the unsaturated derivatives of tocols, isolated from the latex of the rubber plant (Hevea brasiliensis) [27]. The structure of tocotrienols was further described by Pennock and colleagues, who found that palm oil was a rich source of this “new tocopherol” [28]. Palm oil derived from Elaeis guineensis (African oil palm) now represents the richest source of the lesser characterized vitamin E, α-tocotrienol.
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α-Tocopherol is currently the only form of vitamin E recognized to meet human requirements, and recommended adequate intake values are established based on α-tocopherol alone. Other forms of vitamin E must fulfill the following to be recognized as vitamin E: (1) converted to α-tocopherol in humans and (2) recognized by the α-tocopherol transfer protein. Plasma α-tocopherol concentrations in humans range from 11 to 37 μmol/L, whereas γ-tocopherol concentrations are roughly 2–5 μmol/L, and tocotrienol concentrations are less than 1 μmol/L in non-supplemented humans [3].
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Tocopherols are widely found in nature, predominantly in plant seeds such as peanuts, sunflower seeds, almonds, walnuts, and sesame seeds. The major dietary source of tocopherol comes from the widespread use of corn and soybean oil [4]. Tocotrienols, which are less ubiquitous, are found in certain cereals and vegetables such as palm oil, rice bran oil, and annatto. Lower levels of tocotrienols can be found in grapefruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flaxseed oil, poppy seed oil, and sunflower oil [3]. A non-food source of tocotrienols is the latex of the rubber plant. While it has been shown that the different vitamin E forms are interconvertible by plants, there has been no convincing evidence that the same is true for animals [29].
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While alpha-tocopherol was the first vitamin E isomer to be recognized, there are now eight chemically distinct isomers known, consisting of alpha (α), beta (β), gamma (γ), and delta (δ)-isoforms of tocopherols and tocotrienols [2], as shown in Figure 1. The molecular structure of vitamin E is based on a chromanol ring with a side chain at the C2 position. While the lipophilic tail of tocopherols is completely saturated, tocotrienols have three double bonds, at the 3′, 7′, and 11′ positions. Plants synthesize eight different forms of vitamin E, tocopherols and tocotrienols, which include α, β, γ, and δ forms that differ in the number of methyl groups on the chromanol ring [29]. The slight difference in structure between isoforms translates into striking variations in activity. Compared with tocopherols, tocotrienols are more efficiently incorporated into membranes and cultured cells [30], thus giving rise to more potent antioxidant activities.
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Figure 1.
Chemical structures of (A) tocopherol and (B) tocotrienol. Note the three double bonds in the tocotrienol side chain. Note: Isoforms—α (R′ = CH3, R″ = CH3); β (R′ = CH3, R″ = H); γ (R′ = H, R″ = CH3); δ (R′ = H, R″ = H).
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2.2 Mechanism and regulation of metabolism
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Upon oral administration, vitamin E, a lipid-soluble vitamin, requires biliary and pancreatic secretions in order to form micelles for the subsequent uptake by intestinal epithelial cells [3]. Therefore, the absorption of vitamin E is enhanced if taken with food which contributes fat, thereby triggering the secretion of enzymes that facilitate the formation of micelles required for absorption. Despite many years since its discovery, there is still a lack of understanding of the mechanism of absorption, liver trafficking, and disposition of vitamin E isoforms [31].
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The general understanding of vitamin E absorption and trafficking is that orally administered vitamin E undergoes intestinal luminal processing, where it accumulates in lipid droplets, which then coalesce with nascent chylomicrons [32]. The vitamin E isoforms are not discriminated during the intestinal absorption or incorporation into chylomicrons. Chylomicrons then transport vitamin E from the intestine through circulation to the liver, which metabolizes or resecretes vitamin E back into the plasma for trafficking to tissues via enriched lipoproteins.
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After the liver takes up chylomicron remnants, vitamin E isoforms with greater affinity to α-tocopherol transport protein (αTTP) are preferentially bound for transport to tissues, thereby avoiding catabolism. αTTP expressed in the liver is required to facilitate vitamin E transport from the liver to other tissues and organs. The discrimination of vitamin E isoforms occurs in the liver as a result of differing affinity of isoforms to αTTP. αTTP has the ability to bind to both α-tocotrienol and α-tocopherol, but αTTP binds to α-tocotrienol with approximately 10 fold lower affinity than that for α-tocopherol [33]. All lipoproteins are involved in the trafficking of α-tocopherol to the tissues, although very low-density lipoprotein apparently leaves the liver preferentially enriched in α-tocopherol compared with LDL or high-density lipoprotein (HDL) [29]. Discrimination between dietary forms of vitamin E is dependent upon the hepatic αTTP to maintain circulating α-tocopherol [34]. α-tocopherol is also most retained in tissues due to preferential binding by αTT, facilitating secretion into plasma [2] and trafficking to tissues, whereas large portions of other forms of vitamin E are catabolized through general xenobiotic processes [4].
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Interestingly, a study using αTTP knockout mice showed that orally administered α-tocotrienol was absorbed and delivered to vital organs, despite being deficient of αTTP [35]. In organs such as adipose tissue, skin, skeletal muscle, and the heart, α-tocotrienol levels were many folds higher than α-tocopherol in supplemented αTTP knockout mice. Oral supplementation of the female mice with α-tocotrienol also restored fertility, suggesting that it can be successfully delivered to the relevant tissues and that α-tocotrienol supported reproductive function under conditions of α-tocopherol deficiency. These findings suggest TTP-independent mechanisms for the tissue delivery of oral α-tocotrienol. While αTTP may contribute to tocotrienol trafficking, αTTP does not represent a major or sole mechanism of α-tocotrienol transport in the body [35].
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Vitamin E is metabolized by ω-hydroxylation by cytochrome P450 (CYP), followed by β-oxidation and conjugation to generate carboxychromanols and conjugated counterparts [2, 29]. The tail of vitamin E isoforms is ω-hydroxylated by CYP 4F2 and subjected to several rounds of β-oxidation, which ultimately results in the formation of carboxyethyl hydroxy chromanol (CEHC) (Figure 2). Thus, the tail-shortened, water-soluble metabolite, CEHC, is synthesized and excreted in the urine [36]. Conjugation such as sulfation and glucuronidation of the phenolic on the chromanol may also take place in parallel with β-oxidation when there is a high intake of vitamin E forms [4]. Although α-tocopherol largely escapes catabolism and ends up in the blood circulation, α-CEHC is synthesized endogenously when the quantity of hepatic α-tocopherol exceeds the capacity of αTTP to facilitate α-tocopherol secretion from the liver into the circulation [31].
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Figure 2.
Tocol structures. The chromanol head group is identical in the alpha-forms of synthetic (A) all-racemic α-tocopherol [2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl) chroman-6-ol], (B) natural (RRR) α-tocopherols [(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl) chroman-6-ol], (C) α-tocotrienol [2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl) chroman-6-ol], and (D) the metabolite of all three isoforms, α-carboxyethyl hydroxychromanol (CEHC) [3-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) propanoic acid]. CEHC results from the ω-hydroxylation, followed by β-oxidation of the side chain (as well as conjugation with glucuronide, sulfate, or other compounds), yielding a water-soluble molecule that is largely excreted in urine [34].
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Traber and colleagues established that urinary α-CEHC might be useful to noninvasively assess α-tocopherol adequacy, especially in populations with metabolic syndrome-associated hepatic dysfunction that likely impairs α-tocopherol trafficking. Their finding also suggests that people with metabolic syndrome may have a higher requirement for vitamin E due to poorer trafficking leading to lower apparent α-tocopherol bioavailability. However, it is still unknown whether urinary α-CEHC excretion reflects α-tocopherol intake from a single meal or whether its changes reflect long-term vitamin E status [31].
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Recently, Traber and colleagues, which lead as one of the most prolific research groups in vitamin E tocopherol, suggested novel approaches to assess α-tocopherol absorption and trafficking in order to establish human vitamin E requirements [32]. Their study observed that the absorption of α-tocopherol is not necessarily limited by the absence of fat or fasting and that the absorption is highly dependent on chylomicron assembly processes. The transport of α-tocopherol across the intestines may be prolonged during fasting and potentiated by eating. However, the authors recognized the conclusion derived from the study has several limitations, including small sample size, lack of randomization or blinding, and compliance issues, leading to an imbalance with attendant potential for baseline and residual confounding. Nevertheless, if proven in a larger trial, this observation changes the conventional thinking that vitamin E needs to be taken with or immediately after meal to enhance absorption and also reflects that there is still much to learn on the absorption and transport of vitamin E in humans.
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2.3 Antioxidant activities
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The most established bioactivity of vitamin E is its antioxidant property, primarily against lipid peroxidation in biological membranes [2]. By quenching the lipid radicals, vitamin E, as chain-breaking antioxidant, terminates the chain reaction of the oxidation of polyunsaturated fatty acids (PUFAs) [3]. This function is critical to ensure the integrity of cellular membranes and systems which rely on the abundance of PUFAs, such as the nervous system. Hence, neurological symptoms such as progressive ataxia and hyporeflexia are manifestations of vitamin E deficiency as a result of malabsorption.
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Tocopherols and tocotrienols are potent antioxidants that scavenge lipid peroxyl radicals by donating hydrogen from the phenolic group on the chromanol ring [4]. A synergistic antioxidant system made up of vitamin C and other hydrogen donors such as thiol antioxidants, namely, glutathione and lipoic acid, reacts with the resulting tocotrienoxyl or tocopheroxyl radicals to regenerate vitamin E [37], returning it to its reduced state for further use (Figure 3). There is very little evidence in vivo for more advanced vitamin E oxidation products [34].
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Figure 3.
The antioxidant network showing the interaction among vitamin E, vitamin C, and thiol redox cycles [37]. Notes: *thiol transferase (glutaredoxin), protein disulfide isomerase, glutathione (GSH)-dependent dehydroascorbate reductase, thioredoxin (TRX) reductase.
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Packer and colleagues noted that the substituents on the chromanol nucleus and properties of side chain (saturated vs. unsaturated) were critical to the effectiveness of the different vitamin E homologs [37]. Preferential distribution of α-tocopherol to the tissues in vivo may have contributed to its greater impact compared with other homologs, but the structural differences between α-tocopherol and α-tocotrienol have given rise to differences in reactivity observed in in vitro and in vivo studies.
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Tocotrienols were suggested to be more effective scavengers of peroxyl radicals due to more even distribution in the phospholipid bilayer, more effective interaction with lipid peroxyl radicals [4], stronger disordering of membrane lipids, and greater recycling of chromanoxyl radical due to closer location to the membrane surface [37]. The chromanoxyl radical of α-tocotrienol was found to be recycled in membranes and lipoproteins more quickly than the corresponding α-tocopheroxyl radical [38].
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The antioxidant activity of vitamin E is critical to a healthy nervous system, as evident from the consequences of neurological function under deficient condition. The vitamin E protection of PUFAs leads to neuroprotective effects under pathologic and high oxidative stress conditions. Due to the early discovery of α-tocopherol as an essential vitamer and its ubiquitous nature, most research in vitamin E, concerning the mechanisms of action and physiological implications of deficiency, has centered on tocopherols. Tocotrienols, without having any apparent consequence of deficiency and being not inherently detectable in non-supplemented humans or animals, were not the focus of vitamin E-related research until much later. Since the discovery of rich sources of tocotrienols and subsequent availability as an active ingredient, there is growing evidence that tocotrienols have superior potency in terms of antioxidant activity and modulation of impaired biochemical pathways resulting in physiologically beneficial effects.
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Arachidonic acid (AA), one of the most abundant PUFAs of the central nervous system, is highly susceptible to oxidative metabolism under pathologic conditions. [39]. A number of neurodegenerative conditions in the human brain are associated with disturbed PUFA metabolism of AA, including acute ischemic stroke [40]. Cleaved from the membrane phospholipid bilayer by cytosolic phospholipase A2 (cPLA2), AA is metabolized by both enzymatic and nonenzymatic pathways into neurotoxic metabolites. Palm oil-derived α-tocotrienol at nanomolar concentrations has been shown to attenuate both enzymatic and nonenzymatic mediators of AA metabolism and neurodegeneration [39] (Figure 4).
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Figure 4.
The arachidonic acid (AA) cascade and potential target sites for α-tocopherols (αTOC) and α-tocotrienols (αTCT) [39]. cPLA2, cytosolic phospholipase A2; 12-LOX, 12-lipoxygenase; c-Src, proto-oncogene tyrosine-protein kinase or simply c-Src (cellular sarcoma); 12-HPETE, 12-hydroperoxyeicosatetraenoic acid; COX, cyclooxygenase.
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2.4 Benefits in vascular health
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Vitamin E has also been associated with improved vascular health in studies measuring arterial compliance and endothelial dysfunction as biomarkers. Vascular endothelium, which lines the blood luminal surface of vessels, is involved in the regulation of vascular tone, platelet activity, and thrombosis and intimately involved in the pathogenesis of atherosclerosis [5, 6]. The endothelium is an integral part of the vasculature and is involved in promoting an atheroprotective environment via the complementary actions of endothelial cell-derived vasoactive factors [41]. Vasomotor tone is modulated through the release of endothelium-derived relaxing factors (EDRFs) such as NO [6]. Impaired vascular homeostasis can lead to endothelial dysfunction, which contributes to atherosclerosis [41]. Intact endothelium is also needed for normal arterial compliance, a predictor of cardiovascular events. Arterial compliance, which can be assessed by pulse wave velocity (PWV) and augmentation index (AI), can be improved in healthy subjects even with dietary interventions [7].
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In a randomized controlled trial, subjects with the following risk factors, hypercholesterolemia (13 subjects), smokers (14 subjects), or both (15 subjects), were supplemented with placebo or vitamin E for 4 months. The authors hypothesized that long-term supplementation with vitamin E would improve endothelium-dependent relaxation in hypercholesterolemic patients and/or chronic smoking, two risk factors that have been associated with increased radical formation, impaired endothelial vasodilator function, and increased plasma levels of autoantibodies against oxidized LDL [6]. The study found the most severe endothelial vasodilator dysfunction in patients with both risk factors present. Vitamin E significantly improved endothelium-dependent relaxation in forearm resistance vessels of hypercholesterolemic smokers. There was a significant relationship between improvement in acetylcholine-induced vasodilation and the change in autoantibody titer against oxidized LDL (r = −0.59; p = 0.002) [6].
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Moreover, in a randomized controlled trial, 36 healthy male volunteers were supplemented with placebo or tocotrienol-rich vitamin (50, 100, 200 mg/day) with self-emulsifying formula for 2 months [7]. Arterial compliance was assessed using carotid-femoral PWV and AI, at baseline and after 2 months of supplementation. Subjects treated with tocotrienols at doses of 100 and 200 mg/day showed significant improvement in arterial compliance with PWV reductions of 0.77 m/s (p = 0.007) and 0.65 m/s (p = 0.002), respectively. The placebo group did not show a reduction in PWV and AI compared with baseline. The treatment had no effect on blood pressure, serum total cholesterol, and LDL-C [7], which are potential confounding factors to the observed improvement in arterial compliance. The improvement in vascular function can be achieved through mechanisms involving enhanced NO production by the endothelium and inhibition of free radicals that inactivate EDRF. Vitamin E can potentially increase the production of NO, which relaxes the vascular smooth muscle cells, while also neutralizing free radicals which preserve the action of EDRF to maintain arterial compliance [7].
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In addition to promoting vascular health, vitamin E is also postulated to exert anti-atherogenic effects via its ability to decrease LDL oxidation, quench free radicals, inhibit protein kinase C (PKC), inhibit expression of adhesion molecules and monocyte transmigration, and impair vascular smooth muscle cell proliferation [8].
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3. Cerebral small vessel disease
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The general ischemia implicated in CSVD of small blood vessels (i.e., arterial tree occlusion in particular) involving the subcortical and deeper parts of the brain has been widely reported to cause cerebral ischemic stroke or lacunar stroke and accounts for nearly 30% of all stroke subtypes worldwide [9, 10, 11, 12].
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3.1 Characteristic and classification
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The complexity and overlapping pathophysiological mechanism of the disease make the interpretation of CSVD debatable. However, it is a widely accepted view that pathological consequences of small vessel disease (SVD) on the brain parenchyma rather than the underlying diseases of the vessels serve as the basis of CSVD [13]. Hence, the injury in the brain parenchyma that is linked with leptomeningeal and intracerebral vessel pathology that vascularizes with poor collaterals in the deep white matter and subcortical gray matter is the main diagnostic landmark of CSVD. Moreover, CSVD is generally due to several vasculo-pathological processes that affect and cause occlusion to the small perforating cerebral arterioles, capillaries, and venules (of sizes 50–400 mm), which are small arteries (chiefly of middle cerebral artery tributaries) that penetrate and supply the brain subcortical region, resulting in various lesions in the brain [42, 43, 44, 45, 46].
\n
Several manifestations of CSVD can be seen through clinical, radiological (i.e., neuroimaging such as CT or MRI), or pathological phenomena with various etiologies [46, 47, 48, 49]. Recent advancement in neuroimaging techniques had enabled the imaging-based (such as MRI) identification and characterization of multiple manifestation of CSVD including white matter hyperintensities (WMHs) of presumed vascular origin or leukoaraiosis, lacunes of presumed vascular origin (i.e., small subcortical infarcts and silent brain infarcts, SBI), perivascular spaces, microinfarcts, and cerebral microbleeds (CMBs) [46, 50, 51]. Alarmingly, the aforementioned lesions can be silent, and the affected individual may not have any clinical symptoms. More importantly, this silent lesion with higher number of single or multiple, is associated with higher risk of mild cognitive impairment, dementia, Alzheimer’s disease, and full-blown stroke [14, 15].
\n
There are several etiopathogenic classifications of CSVD. However, the most prevalent forms of CSVD are amyloidal CSVD (sporadic and hereditary cerebral amyloid angiopathy [CAA]) and non-amyloidal CSVD (arteriolosclerosis, age-related, vascular risk-factor-related SVD, i.e., microatheroma, lipohyalinosis, fibrinoid necrosis, and segmental arterial disorganization) [42, 52, 53]. Other less common forms of CSVD include inherited or genetic CSVD that is recognizably different from CAA (i.e., Fabry’s disease and cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leukoencephalopathy [CADASIL]), inflammatory and immunologically mediated CSVD (i.e., rheumatoid vasculitis, lupus erythematosus, and CNS vasculitis secondary to infection), venous collagenosis, and other CSVD (i.e., non-amyloid microvessel degeneration in AD and postradiation angiopathy) [42, 52, 53].
\n
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3.2 Neuroepidemiology and health burden
\n
Different manifestations of CSVD based on neuroimaging findings result in different and overlapping health burden and epidemiology [54]. Increasing age has been reported to elevate the finding of WMHs, lacunes, perivascular spaces, and CMBs in healthy populations [54, 55, 56]. However, increased vascular risk factors are consistent with the prevalence of CMBs but not in other imaging findings [56, 57]. Race, ethnicity, and gender with adjusted age also explain the variability of these imaging findings, whereby some findings had reported that higher WMH grade and volume were found in ethnic or racial minorities than non-Hispanic white [58] and WMHs were much higher in women than men, although no definite mechanism was reported for this gender difference [59]. In addition, previous study had reported stroke-free elderly Hispanic and/or Latino had SBI (16%), especially in subcortical region (82.9%) [60] and perivascular spaces (48%) [61].
\n
In other ethnic groups, previous study had reported that the prevalence of WMHs in South Asians and Europeans is similar, although South Asian elderly individuals with known vascular risk are more likely to be associated with higher WMHs [62]. Meanwhile, data in three Asian countries (Singapore, Hong Kong, and Korea) have shown that elderly Asians with higher SVD burden are associated with cognitive decline [63]. This was further supported by the Taizhou Imaging Study, whereby the authors found increased incidental findings of WMHs (10.68%), lacunes (26.69%), CMBs (18.51%), and perivascular spaces (27.76%) in elderly Chinese with vascular risk [64]. However in the Japanese population, most are having moderate to mild dilated perivascular spaces, especially in the centrum semiovale and basal ganglia [65]. Thus, it is apparent that more data are required to understand the role of racial and/or ethnic contributions for the presence of different CSVD manifestations.
\n
The effects of several manifestations of CSVD on cognition seem to be invariably influenced by the location of the lesion(s). The damaged and reduced white matter integrity in the frontal lobe and its dysfunction are associated with reduced transmission of information to other parts of the brain in the presence of WMHs [54], lacunes (deep nuclear [78.2%], posterior fossa [10.1%]) [66], and perivascular spaces [65, 67]. In contrast, temporal lobe lesion is more associated with the findings of lobar and deep CMBs [68, 69]. Several studies have reported that an increase in WMHs is associated with worse general and specific domain of cognitive performance, especially in executive function, processing speed, and episodic memory [70, 71, 72, 73]. Intriguingly, an increase in WMHs with reduced cognitive performance is similar to the individual with amyloid load, mild parkinsonism, and functional impairments [70].
\n
Furthermore, reduced cognitive ability has been reported in elderly and non-demented people with the presence of lacunes of presumed vascular origin [54, 72, 74]. Memory declines have also been associated with thalamic infarcts, whereas decreased psychomotor speed is associated with non-thalamic infarcts [75]. In contrast, the presence of a lesion in the perivascular spaces reduces the individual processing speed [76] and, in others, reported no effect on the cognitive performance [67]. Meanwhile, a decrease in global cognitive performance and domain specific has been linked with the location of CMBs [77].
\n
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3.3 Pathomechanism
\n
Despite the growing insights from histopathological, epidemiological, and physiological studies in the past two decades, the underlying pathomechanism of CSVD remains contentious [46, 53]. In general, it is recognized that advanced age and the presence of chronic hypertension may reduce the ability to self-regulate cBF in response to various systemic blood pressure levels and increased arterial stiffness, hence the increased speed and flow pulsatility in cerebral arterioles [16]. These hemodynamic changes are postulated to inflict a certain degree of endothelial damage in the BBB and alter its permeability through an increase of the shear stress [17]. Hence, the BBB breakdown is an important etiopathogenesis feature of CSVD [17, 18, 19].
\n
Another key factor thought to contribute to the pathogenesis of CSVD is endothelial dysfunction, with elevated biomarkers as the surrogates [78, 79]. The endothelial dysfunction involvement is also associated with metabolic syndrome [80, 81] and hence a strong link with CSVD. Furthermore, this dysfunction is also implicated for a higher risk of aging-related disease [82, 83]. In addition to the endothelium, cross-talk among cellular components of the BBB, such as pericytes, astrocytes, and oligodendrocyte precursor cells (OPCs), may be involved in the microvascular damage as precursors for the onset and progression of CSVD [84, 85]. In relation to this, reduced white matter integrity due to changes in oligodendrocytes has been shown in CSVD, whereby the EC-OPC signaling became compromised and altered the ECs’ ability to secrete the releasing factor crucial for the growth and survival of OPCs to eventually cause oligodendrocytes prone to damage [86]. Therefore, the interaction of multiple BBB components may play a crucial role in the discovery and development of new prevention steps and therapies for CSVD.
\n
In parallel, an increased activity of matrix metalloproteinase-2 (MPP2) from endothelial cell membrane (ECM) also caused tight junctions (TJs) to dissemble. TJ damage eventually leads to basement membrane degradation and endothelial damage and, hence, endothelial dysfunction. This results in BBB damage, making it vulnerable to the infiltration of neutrophils, monocytes, and blood components into the ECM [53]. Activated neutrophils induce the activation of ROS, proteolytic enzymes, and cytokines, thus causing higher leukocyte-EC adhesion and reduced cBF (Figure 5). Meanwhile, activated monocytes will be induced by cytokine and neopterin to cause inflammation in the ECs. Cumulatively, the increased shear and oxidative stress from the system also lead to the activation of blood components and increased production of microparticles, reduced tissue factor pathway inhibitor, and increased fibrinogen accumulation that result in lumen narrowing and consequent cBF reduction [53].
\n
Figure 5.
General pathomechanism and role of ROS in CSVD. ECs, endothelial cells; BBB, blood–brain barrier; ECM, extracellular matrix; cBF, cerebral blood flow; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; COX, cyclooxygenase; NADPH, nicotinamide adenine dinucleotide phosphate; MPs, microparticles; TNF-alpha, tumor necrosis factor-alpha; WMHs, white matter hyperintensities; CMBs, cerebral microbleeds; AD, Alzheimer’s disease.
\n
Understandably, the role of hypoperfusion or reduced cBF in endothelial dysfunction for CSVD has been hypothesized [87]. Generally, the regulation of cBF is mediated by NO signaling; thus, NO serves as a marker for endothelial dysfunction [88]. Since endothelial dysfunction is associated with increased BBB permeability, this would worsen brain parenchyma and white matter lesions given the reduced integrity of ECs [89]. In addition, the increased expression of the mutated NOTCH3 gene (a genetic determinant of CADASIL) in pericytes was found to contribute to CSVD pathogenesis due to abnormal cross-talk between ECs and pericytes [87]. Therefore, one can posit that increased BBB permeability, reduced cBF, and impaired cerebral autoregulation serve as three main interrelated underlying pathogenesis precursors to the development and progression of CSVD, notwithstanding the role of other potential and novel factors.
\n
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\n
3.4 Role of reactive oxygen species
\n
Multiple studies have reported that the early detection of cognitive and motor decline in neurodegenerative disease has been linked with protein, lipids, sugar, and nucleic acid oxidation [90, 91]. Therefore, it can be postulated that changes or damage to the cerebral vasculature, BBB, and cBF is due to localized oxidative stress, hence initiating the neurodegenerative changes in the brain tissue.
\n
Generally, overproduction of oxidants by NADPH oxidases and malfunction or reduced activities of antioxidant enzymes may result in oxidative stress [52]. The imbalance between antioxidants and prooxidants in aging and age-related neurological disease is regarded to be mainly due to ROS [92] which is a large group of oxygen radicals (i.e., superoxide anion radical, hydroxyl radical, peroxyl radical, and alkoxyl radical) and non-radicals (i.e., hydrogen peroxide, organic hydroperoxide, singlet molecular oxygen, electronically excited carbonyls, and ozone) [52, 64]. NADPH oxidase- and superoxide dismutase-mediated enzymatic conversion of molecular oxygen to superoxide initiates the production of ROS; however, the production of ROS can also be mediated by spontaneous transformation of non-radical hydrogen peroxide [93].
\n
There are multiple oxidative markers used to correlate with neurodegenerative disease including CSVD, for example, thioredoxins (positively correlate with severity of acute ischemic stroke and infarct volume) [94], thioredoxin reductase (reduced thioredoxin reductase attenuates the capacity of endothelium-dependent vasodilatory) [95], and peroxiredoxins (higher during stroke onset and traumatic brain injury) [96]. Moreover, reduced plasma levels of uric acid and vitamins E, A, and C have been used as antioxidant biomarkers for Alzheimer’s disease and also Parkinson’s disease [97, 98, 99, 100]. Similarly, coenzyme Q10 (i.e., ubiquinone Q10) is another antioxidant that has been shown to provide potential protective effects for a spectrum of CSVD and cerebral metabolic syndrome [82].
\n
In CSVD, the elevated production of ROS is mainly due to reactions and process (i.e., high blood pressure, very low density of lipoproteins, diabetes, and homocysteinemia and smoking) that lead to inflammatory mechanism and oxidative stress hence causing endothelium dysfunction [20, 21]. Induction of oxidative stress further enhanced the releasing of adhesion molecules and recruiting of leukocytes causing higher leukocyte-EC adhesion and reduced cBF (Figure 5). NADPH oxidases induce oxidative stress (major source of ROS in vessel wall), and its destructive impact on EC-dependent NO signaling has been widely studied [22, 23]. The NADPH oxidases can be stimulated by mechanical forces and vasoactive agonists (i.e., thrombin, platelet-derived growth factor, and tumor necrosis factor-alpha) hence enhancing the production of ROS through superoxide anion radical synthesis [101, 102, 103].
\n
Another two key enzymes that facilitate the production of ROS include cyclooxygenase (COX) and enzymatic cascade in mitochondria (i.e., oxidative phosphorylation). COX is an important enzyme that produces superoxide in cerebral blood vessels through prostaglandin H2 synthesis mediated by AA [104, 105]. Superoxide can also be synthesized after endothelial nitric oxide synthase dysfunction that halts the NO production. This eventually reduces the bioavailability of NO and, in turn, facilitates the production of reactive nitrogen species (RNS) to cause reduced anti-inflammatory, reduced vasodilating, increased platelet aggregation, disinhibition of leukocyte adhesion, and reduced antiproliferative effects of NO [52, 106]. Hence, biomarkers of oxidative stress can be used to study the redox imbalance in individuals with WMHs while it draws a plausible therapeutic avenue with targeted dietary supplements to reduced ROS and RNS that would be neuroprotective against CSVD onset and/or manifestations [107].
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4. Prospects of vitamin E for CSVD neuroprotection
\n
As remarked in the previous sections, increasing body of evidence indicated that oxidative stress might play a pivotal role in the largely elusive pathomechanism of CSVD and other neurodegenerative disease, including cognitive impairment. Moreover, targeting oxidative stress, as a therapeutic approach of vascular-related disease, has been an area of continuing interest given its significance on the aging world population and the rising trend of noncommunicable disease burden, typically cardio-cerebrovascular disorders which include CSVD. However, informative and converging data on vitamin E and its neuroprotective potential for CSVD are scarce.
\n
Central to this proposition of vitamin E potential in CSVD is the involvement of ROS in the physiological role for normal regulation of cerebral vascular event. Hence, a balance between mitigating oxidative stress and normal physiological role should be considered in this ROS-centric approach for natural vitamin E in CSVD neuroprotective potentials. Nonetheless, the idea of attaining or sustaining certain levels of antioxidants to mitigate vascular oxidative stress remains a contentious issue. For instance, antioxidants such as vitamin E have been proven beneficial for vascular function in small clinical and experimental trials [108], whereby vitamin E supplementation had been shown to reduce the onset of WMHs in small clinical trials [109]. Moreover, natural vitamin E also had been shown favorable to lessen cognitive impairments in CSVD animal models [110, 111]. Notwithstanding, a larger-scale clinical trial had shown less convincing beneficial outcomes on stroke and vascular disease prevention with antioxidant (i.e., vitamin E) supplementation [112].
\n
Moreover, utilizing other antioxidants such as coenzyme Q10 has been reported to have potential neuroprotective effects in treating oxidative stress-induced metabolic syndrome with CSVD-related deterioration with reduced plasma level of coenzyme Q10 in experimental animal model with metabolic syndrome [82]. Nonetheless, recent studies on oxidative stress-induced diet reported weak or no apparent association in modifying the cardiovascular risk in an animal model (normotensive wild-type mice, C57BL/6 J), at least in its impact on systemic blood pressure [113].
\n
The inconsistency in the reports of the potential neuroprotective effects of antioxidant (natural vitamin E) in cerebrovascular disease is partly due to the apparent lack of optimization in terms of concentrations/doses of the vitamin E used. This is despite the supportive data on supra(optimal)-physiological concentration of vitamin E (especially α-tocotrienol) that can interrupt the superoxide and NO reaction [108] to reduce the activation of ROS and endpoint BBB disintegration in CSVD. Hence, we are tempted to posit that appropriate nutritive consumptions of vitamin E could prove advantageous to attenuate BBB damages that underlie CSVD heterogenous manifestations, i.e., by halting the leukocyte-EC adhesion that can further degrade the BBB damages with WMHs. Biomarkers of oxidative stress can serve to monitor the redox imbalance in individuals with WMHs while exploring the putative therapeutic avenue with targeted dietary supplements as neuroprotective potentials against CSVD onset and/or disease manifestations. As such, the vitamin E neuroprotective merits could prevent a comprising reduction of cBF in cerebral ischemia in numerous CSVD manifestations, be it silent or symptomatic, from the ROS-centric targeting (Figure 6).
Although data on therapeutic regimes had shown promising increased plasma levels of antioxidants, whether this translates to increased levels in the vasculature remains unknown. Even if sufficient levels of antioxidants were achieved in vascular cells, the antioxidants might in fact exert prooxidant effects as a result of their conversion to radical species following their reactions with superoxide [114, 115]. Either way, a single approach of conventional antioxidant supplementation would be suboptimal in combating oxidative stress in CSVD [108].
\n
Corroboratively, with multiple studies having successfully linked the potential therapeutic and neuroprotective potentials of vitamin E in vascular health domains, a multicenter and adequately powered clinical trial is much needed for CSVD. Such data would further strengthen the nutritive value of vitamin E for CSVD neuroprotective supplements. In addition, opportunities exist to examine the connectivity of white matter tracts to exhibit vitamin E role in protection of small vessel collateral circulation as well as an increased expression of proarteriogenic (new blood vessel formation) genes in future research.
\n
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\n
6. Conclusion
\n
CSVD, as the commonest neurological condition as we age, could benefit from the potency of vitamin E antioxidant neuroprotective potentials through oxidative stress and BBB integrity modulation. This chapter converges contemporary evidence to shed plausible insights on the neuroprotective potentials of natural vitamin E in addressing the heterogenous CSVD spectrum, in health and disease.
\n
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Acknowledgments
\n
Authors thank MIGHT Newton-Ungku Omar Fund, grant number Universiti Sains Malaysia (USM) 304.PPSP.6150151.N118. The authors would like to thank Enago (www.enago.com) for the English language review.
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Conflict of interest
The authors acknowledge that there is no conflict of interests in this work.
\n',keywords:"cerebral small vessel diseases, vitamin E, antioxidants, dementia, aging",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70943.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70943.xml",downloadPdfUrl:"/chapter/pdf-download/70943",previewPdfUrl:"/chapter/pdf-preview/70943",totalDownloads:235,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 11th 2019",dateReviewed:"January 7th 2020",datePrePublished:"February 17th 2020",datePublished:"November 26th 2020",dateFinished:null,readingETA:"0",abstract:"Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and neuroimaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. It is the commonest neurological problem that results in significant disability, but awareness of it remains poor. It affects over half of people over 65 years old and inflicts up to third of acute strokes, over 40% of dementia, and a significant decline in physical ability in otherwise asymptomatic, aging individuals. Moreover, the unifying theory for the pathomechanism of the disease remains elusive and hence the apparent ineffective therapeutic approaches. Given the growing literature for natural vitamin E (tocopherols and tocotrienols) as a potent antioxidant, this chapter attempts to consolidate the contemporary evidence to shed plausible insights on the neuroprotective potentials of natural vitamin E in addressing the heterogenous CSVD spectrum, in health and in disease.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70943",risUrl:"/chapter/ris/70943",signatures:"Muzaimi Mustapha, Che Mohd Nasril Che Mohd Nassir, Yuen Kah Hay, Fung Wai Yee and Hafizah Abdul Hamid",book:{id:"8087",title:"Neuroprotection",subtitle:"New Approaches and Prospects",fullTitle:"Neuroprotection - New Approaches and Prospects",slug:"neuroprotection-new-approaches-and-prospects",publishedDate:"November 26th 2020",bookSignature:"Matilde Otero-Losada, Francisco Capani and Santiago Perez Lloret",coverURL:"https://cdn.intechopen.com/books/images_new/8087.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193560",title:"Dr.",name:"Matilde",middleName:null,surname:"Otero-Losada",slug:"matilde-otero-losada",fullName:"Matilde Otero-Losada"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"180412",title:"Associate Prof.",name:"Mustapha",middleName:null,surname:"Muzaimi",fullName:"Mustapha Muzaimi",slug:"mustapha-muzaimi",email:"mmuzaimi@usm.my",position:null,institution:null},{id:"313133",title:"Dr.",name:"Che Mohd Nasril",middleName:null,surname:"Che Mohd Nassir",fullName:"Che Mohd Nasril Che Mohd Nassir",slug:"che-mohd-nasril-che-mohd-nassir",email:"nasrilche123@gmail.com",position:null,institution:{name:"Universiti Sains Malaysia",institutionURL:null,country:{name:"Malaysia"}}},{id:"316151",title:"Prof.",name:"Kah Hay",middleName:null,surname:"Yuen",fullName:"Kah Hay Yuen",slug:"kah-hay-yuen",email:"khyuen@usm.my",position:null,institution:{name:"Universiti Sains Malaysia",institutionURL:null,country:{name:"Malaysia"}}},{id:"316152",title:"Dr.",name:"Wai Yee",middleName:null,surname:"Fung",fullName:"Wai Yee Fung",slug:"wai-yee-fung",email:"waiyeefung.85@gmail.com",position:null,institution:{name:"Universiti Sains Malaysia",institutionURL:null,country:{name:"Malaysia"}}},{id:"316153",title:"Dr.",name:"Hafizah",middleName:null,surname:"Abdul Hamid",fullName:"Hafizah Abdul Hamid",slug:"hafizah-abdul-hamid",email:"a_hafizah@upm.edu.my",position:null,institution:{name:"Universiti Putra Malaysia",institutionURL:null,country:{name:"Malaysia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Natural sources of vitamin E",level:"1"},{id:"sec_2_2",title:"2.1 Forms and structure",level:"2"},{id:"sec_3_2",title:"2.2 Mechanism and regulation of metabolism",level:"2"},{id:"sec_4_2",title:"2.3 Antioxidant activities",level:"2"},{id:"sec_5_2",title:"2.4 Benefits in vascular health",level:"2"},{id:"sec_7",title:"3. Cerebral small vessel disease",level:"1"},{id:"sec_7_2",title:"3.1 Characteristic and classification",level:"2"},{id:"sec_8_2",title:"3.2 Neuroepidemiology and health burden",level:"2"},{id:"sec_9_2",title:"3.3 Pathomechanism",level:"2"},{id:"sec_10_2",title:"3.4 Role of reactive oxygen species",level:"2"},{id:"sec_12",title:"4. Prospects of vitamin E for CSVD neuroprotection",level:"1"},{id:"sec_13",title:"5. Challenge and future direction",level:"1"},{id:"sec_14",title:"6. 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The American Journal of Clinical Nutrition. 2019;110(5):1148-1167\n'},{id:"B33",body:'\nHosomi A, Arita M, Sato Y, Kiyose C, Ueda T, Igarashi O, et al. Affinity for α-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Letters. 1997;409(1):105-108\n'},{id:"B34",body:'\nNiki E, Traber MG. A history of vitamin E. Annals of Nutrition and Metabolism. 2012;61(3):207-212\n'},{id:"B35",body:'\nKhanna S, Patel V, Rink C, Roy S, Sen CK. Delivery of orally supplemented αtocotrienol to vital organs of rats and tocopherol-transport protein deficient mice. Free Radical Biology and Medicine. 2005;39(10):1310-1319\n'},{id:"B36",body:'\nSchultz M, Leist M, Petrzika M, Gassmann B, Brigelius-Flohé R. Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2′-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply? The American Journal of Clinical Nutrition. 1995;62(6):1527S-1534S\n'},{id:"B37",body:'\nPacker L, Weber SU, Rimbach G. Molecular aspects of α-tocotrienol antioxidant action and cell signaling. The Journal of Nutrition. 2001;131(2):369S-373S\n'},{id:"B38",body:'\nSerbinova E, Kagan V, Han D, Packer L. Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Free Radical Biology and Medicine. 1991;10(5):263-275\n'},{id:"B39",body:'\nSen CK, Rink C, Khanna S. Palm oil–derived natural vitamin E α-tocotrienol in brain health and disease. Journal of the American College of Nutrition. 2010;29(Suppl 3):314S-323S\n'},{id:"B40",body:'\nRink C, Christoforidis G, Khanna S, Peterson L, Patel Y, Khanna S, et al. Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis. Journal of Cerebral Blood Flow and Metabolism. 2011;31(11):2218-2230\n'},{id:"B41",body:'\nSandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. The Open Cardiovascular Medicine Journal. 2010;4:302\n'},{id:"B42",body:'\nPantoni L. Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges. The Lancet Neurology. 2010;9(7):689-701\n'},{id:"B43",body:'\nNovakovic V. Cardiovascular risk factors, white matter abnormalities and diffusion tensor magnetic resonance imaging. Biological Psychiatry and Psychopharmacology. 2010;12:103\n'},{id:"B44",body:'\nHinman JD, Lee MD, Tung S, Vinters HV, Carmichael ST. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain. 2015;138(3):736-745\n'},{id:"B45",body:'\nBenjamin P, Zeestraten E, Lambert C, Ster IC, Williams OA, Lawrence AJ, et al. Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials. Journal of Cerebral Blood Flow & Metabolism. 2015;36(1):228-240\n'},{id:"B46",body:'\nWardlaw JM, Smith C, Dichgans M. Small vessel disease: Mechanisms and clinical implications. The Lancet Neurology. 2019;18(7):684-696\n'},{id:"B47",body:'\nOgata J, Yamanishi H, Ishibashi-Ueda H. Pathology of cerebral small vessel disease. In: Pantoni L, Gorelick P, editors. Cerebral Small Vessel Disease. Cambridge: Cambridge University Press; 2014. pp. 4-15\n'},{id:"B48",body:'\nSorond FA, Cruz-Almeida Y, Clark DJ, Viswanathan A, Scherzer CR, Jager PD, et al. Aging, the central nervous system, and mobility in older adults: Neural mechanisms of mobility impairment. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2015;70(12):1526-1532\n'},{id:"B49",body:'\nYakushiji Y, Charidimou A, Noguchi T, Nishihara M, Eriguchi M, Nanri Y, et al. Total small vessel disease score in neurologically healthy Japanese adults in the Kashima scan study. Internal Medicine. 2018;57(2):189-196\n'},{id:"B50",body:'\nWardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. The Lancet Neurology. 2013;12(8):822-838\n'},{id:"B51",body:'\nVeluw SJV, Shih AY, Smith EE, Chen C, Schneider JA, Wardlaw JM, et al. Detection, risk factors, and functional consequences of cerebral microinfarcts. The Lancet Neurology. 2017;16(9):730-740\n'},{id:"B52",body:'\nGrochowski C, Litak J, Kamieniak P, Maciejewski R. Oxidative stress in cerebral small vessel disease. Role of reactive species. Free Radical Research. 2017Nov;52(1):1-13\n'},{id:"B53",body:'\nMustapha M, Nassir CMNCM, Aminuddin N, Safri AA, Ghazali MM. Cerebral small vessel disease (CSVD)—lessons from the animal models. Frontiers in Physiology. 2019;10:1317\n'},{id:"B54",body:'\nCaunca MR, Leon-Benedetti AD, Latour L, Leigh R, Wright CB. Neuroimaging of cerebral small vessel disease and age-related cognitive changes. Frontiers in Aging Neuroscience. 2019;11:145\n'},{id:"B55",body:'\nChowdhury MH, Nagai A, Bokura H, Nakamura E, Kobayashi S, Yamaguchi S. Age-related changes in white matter lesions, hippocampal atrophy, and cerebral microbleeds in healthy subjects without major cerebrovascular risk factors. Journal of Stroke and Cerebrovascular Diseases. 2011;20(4):302-309\n'},{id:"B56",body:'\nAkoudad S, Portegies ML, Koudstaal PJ, Hofman A, Lugt AVD, Ikram MA, et al. Cerebral microbleeds are associated with an increased risk of stroke. Circulation. 2015;132(6):509-516\n'},{id:"B57",body:'\nAkoudad S, Wolters FJ, Viswanathan A, Bruijn RFD, Lugt AVD, Hofman A, et al. Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurology. 2016;73(8):934\n'},{id:"B58",body:'\nKnopman DS, Penman AD, Catellier DJ, Coker LH, Shibata DK, Sharrett AR, et al. Vascular risk factors and longitudinal changes on brain MRI: The ARIC study. Neurology. 2011;76(22):1879-1885\n'},{id:"B59",body:'\nDijk EJV, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences. Stroke. 2008;39(10):2712-2719\n'},{id:"B60",body:'\nWright CB, Dong C, Perez EJ, Rosa JD, Yoshita M, Rundek T, et al. Subclinical cerebrovascular disease increases the risk of incident stroke and mortality: The northern Manhattan study. Journal of the American Heart Association. 2017;6(9):e004069\n'},{id:"B61",body:'\nGutierrez J, Rundek T, Ekind M, Sacco R, Wright C. Perivascular spaces are associated with atherosclerosis: An insight from the northern Manhattan study. American Journal of Neuroradiology. 2013;34(9):1711-1716\n'},{id:"B62",body:'\nSudre CH, Smith L, Atkinson D, Chaturvedi N, Ourselin S, Barkhof F, et al. Cardiovascular risk factors and white matter hyperintensities: Difference in susceptibility in south Asians compared with Europeans. Journal of the American Heart Association. 2018;7(21):e010533\n'},{id:"B63",body:'\nHilal S, Mok V, Youn YC, Wong A, Ikram MK, CL-H C. Prevalence, risk factors and consequences of cerebral small vessel diseases: Data from three Asian countries. Journal of Neurology, Neurosurgery & Psychiatry. 2017;88(8):669-674\n'},{id:"B64",body:'\nLi S, Fang F, Cui M, Jiang Y, Wang Y, Kong X, et al. Incidental findings on brain MRI among Chinese at the age of 55-65 years: The Taizhou imaging study. Scientific Reports. 2019;9(1):464\n'},{id:"B65",body:'\nYakushiji Y, Charidimou A, Hara M, Noguchi T, Nishihara M, Eriguchi M, et al. Topography and associations of perivascular spaces in healthy adults: The Kashima scan study. Neurology. 2014;83(23):2116-2123\n'},{id:"B66",body:'\nBryan RN, Wells SW, Miller TJ, Elster AD, Jungreis CA, Poirier VC, et al. Infarctlike lesions in the brain: Prevalence and anatomic characteristics at MR imaging of the elderly—data from the cardiovascular health study. Radiology. 1997;202(1):47-54\n'},{id:"B67",body:'\nYao M, Zhu Y-C, Soumaré A, Dufouil C, Mazoyer B, Tzourio C, et al. Hippocampal perivascular spaces are related to aging and blood pressure but not to cognition. Neurobiology of Aging. 2014;35(9):2118-2125\n'},{id:"B68",body:'\nGraff-Radford J, Simino J, Kantarci K, Mosley TH, Griswold ME, Windham BG, et al. Neuroimaging correlates of cerebral microbleeds. Stroke. 2017;48(11):2964-2972\n'},{id:"B69",body:'\nMesker DJ, Poels MMF, Ikram MA, Vernooij MW, Hofman A, Vrooman HA, et al. Lobar distribution of cerebral microbleeds. Archives of Neurology. 2011;68(5):656-659\n'},{id:"B70",body:'\nVemuri P, Lesnick TG, Przybelski SA, Knopman DS, Preboske GM, Kantarci K, et al. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain. 2015;138(3):761-771\n'},{id:"B71",body:'\nLampe L, Kharabian-Masouleh S, Kynast J, Arelin K, Steele CJ, Löffler M, et al. Lesion location matters: The relationships between white matter hyperintensities on cognition in the healthy elderly. Journal of Cerebral Blood Flow & Metabolism. 2017;39(1):36-43\n'},{id:"B72",body:'\nKnopman DS, Griswold ME, Lirette ST, Gottesman RF, Kantarci K, Sharrett AR, et al. Vascular imaging abnormalities and cognition. Stroke. 2015;46(2):433-440\n'},{id:"B73",body:'\nAu R, Massaro JM, Wolf PA, Young ME, Beiser A, Seshadri S, et al. Association of white matter hyperintensity volume with decreased cognitive functioning. Archives of Neurology. 2006;63(2):246\n'},{id:"B74",body:'\nKoga H, Takashima Y, Murakawa R, Uchino A, Yuzuriha T, Yao H. Cognitive consequences of multiple lacunes and leukoaraiosis as vascular cognitive impairment in community-dwelling elderly individuals. Journal of Stroke and Cerebrovascular Diseases. 2009;18(1):32-37\n'},{id:"B75",body:'\nVermeer SE, Prins ND, Heijer TD, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. New England Journal of Medicine. 2003;348(13):1215-1222\n'},{id:"B76",body:'\nDing J, Sigurðsson S, Jónsson PV, Eiriksdottir G, Charidimou A, Lopez OL, et al. Large perivascular spaces visible on magnetic resonance imaging, cerebral small vessel disease progression, and risk of dementia. JAMA Neurology. 2017;74(9):1105\n'},{id:"B77",body:'\nDing J, Sigurðsson S, Jónsson PV, Eiriksdottir G, Meirelles O, Kjartansson O, et al. Space and location of cerebral microbleeds, cognitive decline, and dementia in the community. Neurology. 2017;88(22):2089-2097\n'},{id:"B78",body:'\nFarrall AJ, Wardlaw JM. Blood–brain barrier: Ageing and microvascular disease – systematic review and meta-analysis. Neurobiology of Aging. 2009;30(3):337-352\n'},{id:"B79",body:'\nPoggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. Journal of Cerebral Blood Flow & Metabolism. 2015;36(1):72-94\n'},{id:"B80",body:'\nOtero-Losada ME, Loughlin SM, Rodríguez-Granillo G, Müller A, Ottaviano G, Moriondo M, et al. Metabolic disturbances and worsening of atherosclerotic lesions in ApoE−/− mice after cola beverages drinking. Cardiovascular Diabetology. 2013;12(1):57\n'},{id:"B81",body:'\nOtero-Losada M, Cao G, Loughlin SM, Rodríguez-Granillo G, Ottaviano G, Milei J. Rate of atherosclerosis progression in ApoE−/− mice long after discontinuation of cola beverage drinking. PLoS One. 2014;9(3):e89838\n'},{id:"B82",body:'\nOtero-Losada ME, Grana DR, Müller A, Ottaviano G, Ambrosio G, Milei J. Lipid profile and plasma antioxidant status in sweet carbonated beverage-induced metabolic syndrome in rat. International Journal of Cardiology. 2011;146(1):106-109\n'},{id:"B83",body:'\nOtero-Losada M, González J, Müller A, Ottaviano G, Cao G, Azzato F, et al. Exercise ameliorates endocrine pancreas damage induced by chronic cola drinking in rats. PLoS One. 2016;11(5):e0155630\n'},{id:"B84",body:'\nIhara M, Yamamoto Y. Emerging evidence for pathogenesis of sporadic cerebral small vessel disease. Stroke. 2016;47(2):554-560\n'},{id:"B85",body:'\nRajani RM, Williams A. Endothelial cell–oligodendrocyte interactions in small vessel disease and aging. Clinical Science. 2017;131(5):369-379\n'},{id:"B86",body:'\nRajashekhar G, Willuweit A, Patterson CE, Sun P, Hilbig A, Breier G, et al. Continuous endothelial cell activation increases angiogenesis: Evidence for the direct role of endothelium linking angiogenesis and inflammation. Journal of Vascular Research. 2006;43(2):193-204\n'},{id:"B87",body:'\nArmulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circulation Research. 2005;97(6):512-523\n'},{id:"B88",body:'\nDeplanque D, Lavallee PC, Labreuche J, Gongora-Rivera F, Jaramillo A, Brenner D, et al. Cerebral and extracerebral vasoreactivity in symptomatic lacunar stroke patients: A case-control study. International Journal of Stroke. 2012;8(6):413-421\n'},{id:"B89",body:'\nYoung VG, Halliday GM, Kril JJ. Neuropathologic correlates of white matter hyperintensities. Neurology. 2008;71(11):804-811\n'},{id:"B90",body:'\nHalliwell B. Role of free radicals in the neurodegenerative diseases. Drugs & Aging. 2001;18(9):685-716\n'},{id:"B91",body:'\nHalliwell B. Antioxidant defence mechanisms: From the beginning to the end (of the beginning). Free Radical Research. 1999;31(4):261-272\n'},{id:"B92",body:'\nMariani E, Polidori M, Cherubini A, Mecocci P. Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview. Journal of Chromatography B. 2005;827(1):65-75\n'},{id:"B93",body:'\nDel Río LA. ROS and RNS in plant physiology: An overview. Journal of Experimental Botany. 2015;66:2827-2837\n'},{id:"B94",body:'\nQi AQ , Li Y, Liu Q , Si J-Z, Tang X-M, Zhang Z-Q , et al. Thioredoxin is a novel diagnostic and prognostic marker in patients with ischemic stroke. Free Radical Biology & Medicine. 2015;80:129-135\n'},{id:"B95",body:'\nChoi H, Tostes RC, Webb RC. Thioredoxin reductase inhibition reduces relaxation by increasing oxidative stress and s-nitrosylation in mouse aorta. Journal of Cardiovascular Pharmacology. 2011;58:522-527\n'},{id:"B96",body:'\nRichard S, Lapierre V, Girerd N, Bonnerot M, Burkhard PR, Lagerstedt L, et al. Diagnostic performance of peroxiredoxin 1 to determine time-of-onset of acute cerebral infarction. Scientific Reports. 2016;6:38300\n'},{id:"B97",body:'\nKim TS, Pae CU, Yoon SJ, Jang W-Y, Lee NJ, Kim J-J, et al. Decreased plasma antioxidants in patients with Alzheimer’s disease. International Journal of Geriatric Psychiatry. 2006;21:344-348\n'},{id:"B98",body:'\nIuliano L, Monticolo R, Straface G, Spoletini I, Gianni W, Caltagirone C, et al. Vitamin E and enzymatic/oxidative stress-driven oxysterols in amnestic mild cognitive impairment subtypes and Alzheimer’s disease. Journal of Alzheimer\'s Disease. 2010;21:1383-1392\n'},{id:"B99",body:'\nCristalli DO, Arnal N, Marra FA, de Alaniz MJT, Marra CA. Peripheral markers in neurodegenerative patients and their first-degree relatives. Journal of the Neurological Sciences. 2012;314:48-56\n'},{id:"B100",body:'\nPaganoni S, Schwarzschild MA. Urate as a marker of risk and progression of neurodegenerative disease. Neurotherapeutics. 2017;14:148-153\n'},{id:"B101",body:'\nPatterson C, Ruef J, Madamanchi NR, Barry-Lane P, Hu Z, Horaist C, et al. Stimulation of a vascular smooth muscle cell NAD(P)H oxidase by thrombin. Evidence that p47(phox) may participate in forming this oxidase in vitro and in vivo. The Journal of Biological Chemistry. 1999;274:19814-19822\n'},{id:"B102",body:'\nMarumo T, Schini-Kerth VB, Fisslthaler B, Busse R. Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation. 1997;96:2361-2367\n'},{id:"B103",body:'\nSundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science. 1995;270:296-299\n'},{id:"B104",body:'\nBusija DW, Katakam PV. Mitochondrial mechanisms in cerebral vascular control: Shared signaling pathways with preconditioning. Journal of Vascular Research. 2014;51:175-189\n'},{id:"B105",body:'\nSanthanam AV, d’Uscio LV, Katusic ZS. Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling. Journal of Neurochemistry. 2014;131:521-529\n'},{id:"B106",body:'\nXie H, Ray PE, Short BL. NF-kappaB activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/reoxygenation. Stroke. 2005;36:1047-1052\n'},{id:"B107",body:'\nUlivi L, Maccarrone M, Giannini N, Ferrari E, Caselli M, Montano V, et al. Oxidative stress in cerebral small vessel disease dizziness patients, basally and after polyphenol compound supplementation. Current Molecular Medicine. 2018;18(3):160-165\n'},{id:"B108",body:'\nDrummond GR, Selemidis S, Griendling KK, Sobey CG. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nature Reviews Drug Discovery. 2011;10(6):453-471\n'},{id:"B109",body:'\nGopalan Y, Shuaib IL, Magosso E, Ansari MA, Bakar MRA, Wong JW, et al. Clinical investigation of the protective effects of palm vitamin E tocotrienols on brain white matter. Stroke. 2014;45(5):1422-1428\n'},{id:"B110",body:'\nMurad LB, Guimarães MRM, Paganelli A, Oliveira CABD, Vianna LM. Alpha-tocopherol in the brain tissue preservation of stroke-prone spontaneously hypertensive rats. Journal of Physiology and Biochemistry. 2013;70(1):49-60\n'},{id:"B111",body:'\nUeno Y, Koike M, Shimada Y, Shimura H, Hira K, Tanaka R, et al. L-Carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. Journal of Cerebral Blood Flow & Metabolism. 2015;35(3):382-391\n'},{id:"B112",body:'\nHeart Protection Study Collaborative Group. MRC/BHF heart protection study of antioxidant vitamin supplementation in 20 536 high-risk individuals: A randomised placebo-controlled trial. The Lancet. 2002;360(9326):23-33\n'},{id:"B113",body:'\nGraneri L, Dalonzo Z, Lam V, Mamo J, Dhaliwal S, Takechi R. Chronic consumption of a commercial energy drink reduces blood pressure in normotensive wild-type mice. Frontiers in Nutrition. 2019;6:111\n'},{id:"B114",body:'\nWitting PK, Upston JM, Stocker R. Role of α-tocopheroxyl radical in the initiation of lipid peroxidation in human low-density lipoprotein exposed to horse radish peroxidase. Biochemistry. 1997;36(6):1251-1258\n'},{id:"B115",body:'\nWitting PK, Willhite CA, Davies MJ, Stocker R. Lipid oxidation in human low-density lipoprotein induced by metmyoglobin/H2O2: Involvement of α-tocopheroxyl and phosphatidylcholine alkoxyl radicals. Chemical Research in Toxicology. 1999;12(12):1173-1181\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Muzaimi Mustapha",address:"mmuzaimi@usm.my",affiliation:'
Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Malaysia
'},{corresp:null,contributorFullName:"Che Mohd Nasril Che Mohd Nassir",address:null,affiliation:'
Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Malaysia
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Malaysia
'},{corresp:null,contributorFullName:"Hafizah Abdul Hamid",address:null,affiliation:'
Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Malaysia
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Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.
",metaTitle:"What Does It Cost?",metaDescription:"Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"
We are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
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European Commission
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Bill and Melinda Gates Foundation
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Wellcome Trust
\\n\\t
National Institute of Health (NIH)
\\n\\t
National Science Foundation (NSF)
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National Institute of Standards and Technology (NIST)
We are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
\n\n
All of our IntechOpen sponsors are in good company! The research in past IntechOpen books and chapters have been funded by:
\n\n
\n\t
European Commission
\n\t
Bill and Melinda Gates Foundation
\n\t
Wellcome Trust
\n\t
National Institute of Health (NIH)
\n\t
National Science Foundation (NSF)
\n\t
National Institute of Standards and Technology (NIST)
\n\t
Research Councils United Kingdom (RCUK)
\n\t
Foundation for Science and Technology (FCT)
\n\t
Chinese Academy of Sciences
\n\t
Natural Science Foundation of China (NSFC)
\n\t
German Research Foundation (DFG)
\n\t
Max Planck Institute
\n\t
Austrian Science Fund (FWF)
\n\t
Australian Research Council (ARC)
\n
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