\r\n\tAn update on clinical manifestations, their assessment, monitoring, and imagiology, including peripheral arthritis, enthesopathy, and extra-articular findings, and, the differential diagnosis with other diseases which evolves with axial and peripheral calcifications will be provided.
\r\n
\r\n\t \r\n\tAn important component of this book must be dedicated to the more recent treatments namely with biologic therapies but focusing also on new small molecule inhibitors and experimental therapies.
",isbn:"978-1-80356-243-8",printIsbn:"978-1-80356-242-1",pdfIsbn:"978-1-80356-244-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"e07e8cf78550507643fbcf71a6a9d48b",bookSignature:"Dr. Jacome Bruges Armas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11273.jpg",keywords:"Diagnostic Criteria, Occurrence, Peripheral Involvement, Extra-Articular Manifestations, Axial Imaging, MRI, Disease Activity, Physical Function, Potential Pathways, MHC, Drug Treatment, New Small Molecules",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 9th 2022",dateEndSecondStepPublish:"May 6th 2022",dateEndThirdStepPublish:"July 5th 2022",dateEndFourthStepPublish:"September 23rd 2022",dateEndFifthStepPublish:"November 22nd 2022",remainingDaysToSecondStep:"17 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Senior Specialist in Internal Medicine and Specialist in Oncology. 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Member of the Comprehensive Health Research Center (CHRC), Nova medical School, University of Lisbon, and Director of the Oncology Service and Director of the Epidemiology and Molecular Biology Service (SEEBMO) at the Hospital de Santo Espirito de Angra do Heroísmo, Terceira Island, Azores, Portugal. Main research interests are the epidemiology and molecular genetics of Spondyloarthritis (SpA), Diffuse Idiopathic Skeletal Hyperostosis (DISH), and Chondrocalcinosis (CC). 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1. Introduction
Considering the nature of contaminants, chlorinated hydrocarbons and other groups of organic compounds belong to the group of chemicals that have widely been used in the past due to their environmental persistence and toxicity their use has been prohibited and became greatly controlled [1, 2, 3, 4, 5, 6, 7]. They can be decomposed by many chemical oxidation processes among which Advanced oxidation processes (AOPs) prevail. AOPs represent a group of methods of chemical oxidation in liquid phase which are employed to destroy organic compounds. AOPs were developed in order to oxidize organic compounds that can be resistant or which are able to deactivate traditionally used biological stage at sewage disposal plants (these compounds are non-biodegradable) including also pharmaceutical residues [8, 9]. If the final results of chemical oxidation are just inorganic products, such as CO2, H2O and other harmless inorganic compounds, we talk about complete mineralization or total oxidation. AOPs are employed to replace standard oxidation technologies, such as oxidation with KMnO4, K2Cr2O7 and Na2S2O8 because they can oxidize many organic compounds only partially [10]. Those oxidants can also serve as secondary source of pollution, e.g. hexavalent chromium ions are environmentally non-friendly. Some of the AOPs can also be based on sulphate chemistry combined with UV irradiation or photochemical processes combined with electrochemical processes [11, 12]. The effectiveness of oxidation agents is given by their standard oxidation potentials that were listed in Table 1 in Section 2.1.3. AOPs comprise several common features that can be briefly described as follows: [13, 14, 15, 16, 17].
Hydroxyl radicals OH• are employed as reactive oxidizing agent without any restrictions to reaction mechanisms.
OH• attack is very fast; Rate constant reaches values of 109 mol−1 dm3 s−1.
OH• attack reveals very low selectivity; It gives very high assumption for wide utilization of AOPs for water treatment containing non-biodegradable organic compounds.
AOPs can effectively work at ambient pressure and temperature; It brings savings in process cost.
OH• can be generated by various methods; It gives flexibility to utilization of AOPs for solving of various practical problem.
Oxidative species
Reaction
E°[V]
Fluorine
F2 + 2H+ + 2e ̄⇌ 2 HF (aq)
3.03
Hydroxyl radical
OH• + H+ + e ̄⇌ H2O
2.8
Singlet oxygen
1O2 + 2H+ + 2e ̄⇌ H2O
2.42
Ozone
O3 + 2H+ + 2e ̄⇌ H2O + O2
2.07
Sodium persulfate
S2O82− + 2e ̄⇌ 2 SO42 ̄
2.01
Hydrogen peroxide
H2O2 + 2 H+ + 2 e ̄⇌ 2 H2O + O2
1.78
Hydro peroxide radical
2 HO2• + 2 H+ + 2 e ̄⇌ 2 H2O + O2
1.7
Potassium manganite
MnO4− + 8H+ + 5e ̄⇌ Mn2+ + 4H2O
1.68
Chloride (IV) oxide
ClO2 + 4H+ + 5e ̄⇌ Cl ̄ + 2H2O
1.57
Potassium dichromate
Cr2O72− + 14H+ + 6e ̄⇌ 2 Cr3+ + 7 H2O
1.38
Chlorine
Cl2 + 2e ̄⇌ 2 Cl ̄
1.36
Dissolved oxygen
O2 (g) + 4H+ + 4e ̄⇌ 2 H2O
1.22
Table 1.
Standard redox potentials of some typical oxidative species [13].
The main disadvantages of AOPs are relatively high treatment costs and special safety requirements because of the use of very reactive chemicals (ozone, hydrogen peroxide), etc. and high-energy sources (UV lamps, electron beams, etc.). Attention is also paid to low energy sources, such as UV LED [18]. Among AOPs the following processes can be categorized: Fenton oxidation (Fe2+/H2O2); Fenton-like oxidation (Fe3+/H2O2); photo assisted Fenton (Fe2+/3+/H2O2/UV); photocatalysis (TiO2/hv/O2); ozone systems (O3/H2O2, O3/UV), UV photolysis (UV/H2O2). It is favorable to treat wastewaters with maximum content of COD = 10 to 15 g/L (chemical oxygen demand) [19]. For higher values of COD, other oxidation methods are usually applied as can be seen in Figure 1.
Figure 1.
Suitability of water treatment technologies according to COD contents [12].
Significance of the AOPs’ usage in water treatment is supported by existing registered trademarks like ULTROX®, RAYOX®, UVOX®, ECOCLEAR®. Trademarks ULTROX®, RAYOX®, UVOX® are ex-situ water remediation technologies utilizing ultraviolet irradiation and ozone used by company Ultrox International in California, US [20]. ECOCLEAR® is a heterogeneous catalytic ozonation process [21].
A brief summary of oxidative species used for chemical oxidation is briefly given in Table 1. The oxidative species are arranged according to their standard redox potentials. Standard redox potential describes capability of certain oxidizing agents for oxidation reaction. The higher the redox potential is revealed, the stronger the oxidizing agent is.
2. Fenton oxidation
Fenton oxidation is the most traditional method of AOPs. It was invented by Henry John Horstman Fenton in 1890 [22]. He discovered oxidation with reagent containing Fe2+ and hydrogen peroxide. The OH• production occurs by means of H2O2 addition to the solution containing Fe2+ salts:
Fe2++H2O2→Fe3++OH̄+OH•E1
This is a very simple way of producing OH• requiring neither special reactants nor special reaction apparatus. Iron is naturally very abundant and non-toxic element to the environment. Hydrogen peroxide is also environment friendly chemical and easy to store and handle. It was pointed recently that at low values of pH = 2,5–3 Fe3+ salts are reduced to Fe2+ and reaction becomes Fenton-like [23]. It is described by Eqs. (2) and (3):
Fe3++H2O2⇌H++FeOOH2+E2
FeOOH2+→HO2•+Fe2+E3
Fenton oxidation also exists in several modifications. One of them is the photo assisted Fenton reaction. It is the classical Fenton reaction enhanced by presence of UV–VIS irradiation [24, 25]. It utilizes a product yielding from reaction (2) and upon irradiation it yields Fe2+ ions and OH• as described by reaction (4).
FeOH2++hν→Fe2++OH•E4
There are also other modifications of Fenton-like reactions, e.g. electro-Fenton, nano-Fenton utilizing graphene oxide wrapped nanoparticels of Fe3O4 [26, 27] and various modifications.
3. Photocatalytic processes
Photocatalytic processes employing semiconductor metal oxides have been the target of research interest for more than 30 years [28]. Many types of catalysts were tested and TiO2 revealed many interesting properties (high stability, good performance and low cost) for organic compounds degradation [29, 30]. Triggering mechanism of TiO2 photocatalysis is ultraviolet light absorption resulting in formation of electron–hole pairs.
TiO2+hν→ē+h+E5
Electrons are capable of interaction with dissolved oxygen yielding superoxide radicals, and the holes are capable of oxidizing water molecules or hydroxyl anions adsorbed on the TiO2 surface to reactive OH• radicals.
TiO2h++H2O→TiO2+OH•+H+E6
TiO2h++OH̄→TiO2+OH•E7
Reactions 6 and 7 are of great importance in oxidative degradation of processes due to high concentration of H2O and OH ̄ adsorbed on the catalyst surface. Great interest is also put on the exploitation of solar spectrum with TiO2 but overlap between TiO2 absorption spectra and solar spectrum is quite low [31, 32]. The emphasis is also laid on doping of TiO2 with various metals [33, 34]. TiO2 phtoocatalysis is also combined with SiO2 or Al2O3 for enhancing photodegradability of organic compounds utilizing adsorption as synergistic effect [35, 36].
4. Ozone water system
Ozone utilization for water purification is another well-known technology [37]. Ozone is understood as one of the most efficient oxidizing agents. As can be seen in Table 1, it is on the fourth position right after fluorine, hydroxyl radical and singlet oxygen. Ozone utilization can be intensified by addition of hydrogen peroxide and/or exploiting UV irradiation. Ozone water systems with H2O2 and/or UV require alkaline environment [14, 16].
O3+H2O+hν→O2+H2O2E8
2O3+H2O2→2OH•+3O2E9
Another oxidation process utilizing ozone is Mn2+/(COOH)2/O3 that is capable of hydroxyl radical production under gently acidic conditions (at pH > 4). Under acidic conditions Mn(III) dioxalate and Mn(III) trioxalate are formed. Hydroxyl radicals are produced by reaction between manganese complexes and ozone [16, 38]. The decomposition of ozone is accompanied with hydroxyl radical generation and this decomposition is initiated by the presence of OH ̄.
5. Hydrogen peroxide photolysis
Hydrogen peroxide photolysis by ultraviolet light (UV-C/H2O2) is one of the most effective AOPs. The UV-C/H2O2 system is based on the decomposition of hydrogen peroxide towards hydroxyl radicals using ultraviolet irradiation with wavelengths below 280 nm [39]. The mechanism of hydroxyl radical formation is understood as homolytic cleavage of hydrogen peroxide molecule yielding two radicals from one hydrogen peroxide molecule. On the contrary hydrogen peroxide has a small absorption coefficient (18.6 M−1 cm−1 at 254 nm) and consequently the utilization of UV-C light source is decreased when organic compounds act as optical filters8. The cage effect of water molecules also decreases the efficiency of hydroxyl radical generation [15, 16]. There are also studies reporting on hydrogen peroxide photolysis upon 308–465 nm [40].
5.1 Hydrogen peroxide
It is a colorless, odorless, weakly acidic liquid similar to water having higher density and viscosity. It is miscible with water in all proportions. Hydrogen peroxide is a versatile oxidant that is effective over the whole pH range with relatively high oxidation potential (E0 = 1.763 V at pH = 0, E0 = 0.878 V at pH = 14) and water is the only co-product. [41].
Hydrogen peroxide can oxidize a broad variety of inorganic and organic substrates in liquid-phase reactions under mild reaction conditions. In industry H2O2 is used as an efficient bleaching agent in place of chlorine containing agents. Owing to its low molecular weight hydrogen peroxide is a more efficient oxidizing agent than other oxidants, such as nitric acid and sodium hypochlorite. H2O2 is an environment friendly compound since it decomposes towards water and oxygen (10). That makes it one of the cleanest and most versatile chemical oxidants available [42]. Hydrogen peroxide decomposition towards oxygen and water is intensified by increasing the temperature. Decomposition also occurs when hydrogen peroxide is exposed to metals.
2H2O2→2H2O+O2E10
The first historical preparation of hydrogen peroxide was performed by Luis Jacques Thenard in July, 1818 [43]. In the 1950’s production of hydrogen peroxide in industrial scale started to be performed by anthraquinone way [44]. The main stages of the process are (Figure 2):
Hydrogenation of anthraquinone.
Oxidation of the resulting anthraquinol.
Extraction of hydrogen peroxide solution.
Purification and concentration of hydrogen peroxide.
Figure 2.
Anthraquinone and 2-ethylanthraquinone.
The 2-ethyl derivate of anthraquinone is generally used in the process. A solution of the 2-ethylanthraquinone in a multi-compound mixed solvent system containing a non-polar hydrocarbons and polar solvents is hydrogenated using hydrogen. A suspension of a nickel or palladium based catalyst on a solid support is used. The reaction yields 2-ethylanthraquinol. Level of hydrogen feeding must be carefully controlled otherwise hydrogenation of aromatic rings occurs and undesired products are obtained. The catalyst is separated from the reaction mixture by filtration and it is recycled. The solution of 2-ethylanthraquinol is then oxidized by air to hydroperoxide, which reacts in water to reform 2-ethylanthraquinone and it produces a dilute solution of hydrogen peroxide. Thus the overall equation of hydrogen peroxide production is very simple:
H2+O2→H2O2E11
The demonstrative reaction scheme for anthraquinone process is shown in Figure 3: Illustrative reaction scheme of hydrogen peroxide production:
Figure 3.
Illustrative reaction scheme of hydrogen peroxide production from anthraquinone process [45].
Water is added to extract the peroxide as an aqueous solution containing 35% w/w solution of hydrogen peroxide. The organic solvent layer is recycled to the hydrogenation unit for further reaction. The aqueous hydrogen peroxide solution is treated with organic solvents and by air being pumped through to remove residual 2-ethylanthraquinone and solvents and produce the standard 35% product. Some applications require higher concentration product which is produced by vacuum concentration or distillation to concentrations of up to 70%.
Hydrogen peroxide in its purest form is inherently stable. However, if brought into contact with certain contaminants (mainly heavy metals) it can decompose according to Eq. (10). Typical additives enhancing stability of produced H2O2 are sodium compounds like stannate (IV) (which hydrolyzes to tin(IV) hydroxide), sodium citrate, sodium dihydrophosphate and various phosphates [46]. They act by complexing with any traces of transition metal ions present which would otherwise catalyze the decomposition of hydrogen peroxide. Acetone hydrogenation yielding propan-2-ol is an alternative to the use of 2-ethylanthraquinone. Oxidation of propan-2-ol yields hydrogen peroxide and acetone that is brought back to the beginning of the process.
5.2 Mechanism of hydrogen peroxide photolysis
The simplified mechanism of hydrogen peroxide decomposition is described as follows: [47].
H2O2+hν→2OH•E12
OH•+H2O2→HO2•+H2OE13
HO2•+H2O2→OH•+H2O+O2E14
2HO2•→H2O2+O2E15
HO2•→O2•̄+H+E16
1/2O2•̄+H2O→H2O2E17
1/2O2•̄+H2O→2OH•E18
The homolytic cleavage of hydrogen peroxide molecule yielding two hydroxyl radicals is described by Eq. (12). A certain part of hydroxyl radicals reacts with the hydrogen peroxide molecule yielding hydroperoxide radicals (Eq. 13). Hydroperoxide radical then reacts with hydrogen peroxide yielding the desired hydroxyl radicals (Eq. 14). Eq. (15) shows radical recombination that can lead back to the hydrogen peroxide. Also superoxide radicals can be produced from hydroperoxide radicals. Superoxide radicals can be then transformed into hydrogen peroxide or hydroxyl radicals in water environment (Eqs. 17 and 18). However, superoxide radicals appear in the reaction system utilizing hydrogen peroxide decomposition in much lower extent [48, 49].
Hydroxyl radicals produced by reactions (12) to (14) can attack organic molecules and decompose them through various reaction intermediates towards inorganic products, such as CO2, H2O and relevant mineral acids. The formation of hydroxyl radicals increases when more alkaline conditions are used. Presence of hydroxyl anions causes formation of peroxide anion which reveals the molar absorption coefficient of 240 M−1 cm−1. Photolysis of HO2 ̄ anions leads to additional formation of hydroxyl radicals [50].
H2O2+OH̄→H2O+HO2̄E19
2HO2̄+hν→2OH•+O2E20
5.3 Reaction mechanism of hydroxyl radicals with organic molecules
The hydroxyl radical is a particle with very low lifetime period but very high reactivity. Mechanism of organic molecule attack is dependent on the type of organic molecule. In general, there are three possible simplified mechanisms: [13].
Attack accompanied with hydrogen abstraction.
Attack accompanied with electron transfer.
Attack in terms of electrophilic addition.
The hydroxyl radical generated by direct hydrogen peroxide photolysis reacts with aliphatic organic compounds to produce an organic radical (R•). These radicals react quickly with dissolved oxygen yielding the organic peroxyl radical (RO2•) initiating subsequent thermal oxidation reactions.
RH+OH•→H2O+R•TiO2+hν→ē+h+E21
R•+O2→RO2•E22
Subsequent thermal reactions are of three types: [13, 51].
Heterolysis and generation of organic cations as well as superoxide anion.
1,3-Hydrogen shift and homolysis into hydroxyl radicals and carbonyl compounds.
Back reaction to R• and O2.
The second mechanism of reaction is accompanied by electron transfer. Reduction of hydroxyl radicals to hydroxide anions by an organic compound is of particular interest in the decomposition of halogenated hydrocarbons.
RX+OH•→RX•++OH̄E23
The third possible mechanism is employed when organic molecules with multiple bounds react with hydroxyl radicals. This mechanism works either with aliphatic or aromatic hydrocarbons and runs similarly as electrophilic addition (Figure 4).
Figure 4.
Reaction scheme of electrophilic addition.
Electrophilic addition is of particular interest for an interpretation of the rapid dechlorination of chlorinated phenols yielding chloride ions. One possible pathway could in fact consist of an electrophilic addition of the hydroxyl radical to the aromatic ring and of subsequent fragmentation of the chlorohydrol intermediate followed by the ring opening (Figure 5).
Figure 5.
Example of 4-chlorophenol attack with hydroxyl radical.
5.4 Advantages and limits
The use of hydrogen peroxide as an oxidant brings a number of advantages in comparison to other methods of chemical or photochemical water treatment: [14, 15, 16].
Infinite solubility in water.
No mass transfer problems associated with gases (for example ozonation).
Two hydroxyl radicals are formed for each molecule of H2O2 photolyzed.
Peroxyl radicals are generated after HO• attack on most organic substrates, leading to subsequent oxidation reactions.
Minimal capital investment, very cost-effective source of hydroxyl radicals, and simple operation procedure.
UV irradiation is capable of photolytic degradation of some compounds; Only addition of hydrogen peroxide leads to total oxidation.
There are, however, also obstacles encountered with the UV-C/H2O2 process: [52, 53].
The rate of chemical oxidation of the contaminant is limited by the rate of formation of hydroxyl radicals.
Molar absorption coefficient of H2O2 at 254 nm is only 18,6 l·mol−1·cm−1. It causes decrease of irradiation in cases where organic substrates act as inner filters.
Higher rates of HO• radical formation may, nevertheless, be realized by the use of Xe-doped Hg lamps having a strong emission spectra in the region of 210–240 nm, where H2O2 reveals a higher molar absorption coefficient.
Post-treatment of residual H2O2 might be required.
UV light penetration is negatively affected by increasing turbidity.
The main disadvantage of oxidative processes using hydroxyl radicals as an oxidizing agents can be found in efficient trapping of HO• radicals by HCO3 ̄ and CO3 ̄ ions [54]. Hydroxyl radical is nonselective and, thus, can be exhausted by the presence of organic or inorganic compounds other than the contaminants of the main concern.
HO•+HCO3̄→H2O+CO3•̄E24
HO•+CO32̄→HŌ+CO3•̄E25
Carbonate and hydrocarbonate ions act then as scavengers of hydroxyl radicals. Similar observations were also made for ammonia [55]. Although, the generated carbonate radical anion has been shown to be an oxidant itself. Its oxidation potential is, however, significantly lower than that of the HO• radical [56].
5.5 Reactors for UV-C/H2O2 oxidations
Most conventional UV reactors are often available in tubular arrangements and can either be an open channel or a closed vessel [57]. For large scale operation of these reactors, multistage arrangement (reactors in series) is recommended [58]. Ideal characteristic features of the tubular reactor arrangements are uniform flow through the inside of the reactor, high length-to-width ratio, flow from the bottom to the top48. Production of UV irradiation requires energy to supply UV lamps. Low and medium pressure mercury vapor lamps are considered to be the suitable option [59]. Another possible option is to use pulsed UV xenon arc lamps [60]. Low pressure lamps emit their maximum energy photons at wavelength of 254 nm, while medium pressure lamps emit photons with wavelengths ranging from 180 to 1370 nm with maximum between 200 and 400 nm [61].
Typically, low-pressure lamps are closed in a quartz sleeve to separate the water stream from the lamp surface or alternatively the treated water can flow through the quartz tube surrounded by UV lamps [62, 63]. Although Teflon sleeves are also an alternative to quartz sleeves, quartz sleeves absorb only 5% of the UV radiation, while Teflon sleeves absorb 35% [59]. The UV lamps can be arranged in different ways in the reactor, depending on the required scale. A system designed for large scales (water flows over 1000 m3/h), would typically consist of one single reactor vessel equipped with several UV lamps arranged perpendicularly or parallel to the water flow [64]. The more water needs to be treated, the more lamps and possibly more reactors in series are recommended. Generally, no or simple cooling system is required for systems handling large volumes of effluent, since heat transfers from the lamps are usually low (<1°C) [65].
Hydrogen peroxide introduction into the treated water is one of the most critical points of the oxidation process. It must not come to the contact with any metallic parts otherwise undesired decomposition of H2O2 is initiated. The reaction rate between hydrogen peroxide and organic compound determines the point of the H2O2 addition [66]. A good homogenization of reaction mixture must be ensured. The simplest method of hydrogen peroxide dosing is the gravity feed through mixing valve but this method is rather difficult to control the rate of dosing. Another easy option is the pump feeding which is very easy to maintain and to control the rate of hydrogen peroxide dosing. For water treatment 30–50% H2O2 solutions are recommended. Higher concentrations (≈ 70%) would increase the reaction rates, but these are not already safe because they can produce detonable mixtures upon storage [67].
5.6 Perspectives of AOPs
Many AOP processes use UV radiation, but alone UV/O2 photooxidation is generally effective when using ionizing (energy>5 eV) or polychromatic UV radiation. The energy of UV-A and UV-B radiation is for degradation of most organic substances by direct photolysis insufficient. The low-pressure mercury lamp is a source of UV-C radiation with a wavelength of 253.7 nm, which is itself for removal most organic pollutants only partially effective. Therefore, this source is often combined with H2O2, O3 and also with catalysts Fe2+, Fe3+ Mn2+ or TiO2 in practice. The use of photolysis in application of polychromatic radiation, such as available medium-pressure mercury lamp (emitting radiation in the area 254–400 nm) can also be applied. This approach reveals advantages of both generations of radicals OH•, as well as for the direct excitation of organic molecules absorbing in UV region, such as benzene, toluene, xylene, dinitrotoluene or chlorophenols. However, the oxidation reaction rate of the pollutant tends to increase with increasing concentration of hydrogen peroxide, which is a source of OH radical. The H2O2 concentration must be carefully optimized because reaction system overdosed with H2O2 will result in undesired decomposition towards H2O and O2. Also, natural presence of scavenging ions may decrease applicability of the process.
6. Phthalocyanines
Phthalocyanines are macro-cyclic compounds that are derived from the group of heterocyclic compounds containing four pyrrol structures connected mainly with methionine groups (–CH=). A typical structure of metallic phthalocyanine is shown in Figure 6. Unlike porphyrines, phthalocyanines contain four benzene rings bounded on basic pyrrol structures. Phthalocyanines are, due to their photochemical properties, often labeled as photosensitizers [68]. Photosensitizers are compounds containing chromophores. Chromophore is a part of molecule responsible for light absorption. Absorption of light photon causes excitation to higher energy layer and reaction with molecular oxygen yields singlet oxygen species [69].
Figure 6.
Basic structure of the phthalocyanine molecule.
It must be reminded that solubility of phthalocyanine in water is very low. Modification by halogenation, chlorine methylation, sulphonation or sulphochlorination influences their solubility in both polar and non-polar solvents [70].
There are two major methods of phthalocyanine productions. The first is based on reaction of phthaloimide with relevant metal, metal chloride or metal alkoxide in quinoline solvent. Presence of urea enhances the reaction pathway with use of metal chlorides because it blocks chlorination of phthalocyanine structure [71]. Second method is based on the reaction of urea and phthalanhydride yielding di-iminophthaloimide. Di-iminophthaloimide then reacts with relevant metal chloride with sodium molybdate as catalyst [72]. First method is mostly performed as batch process; the second is carried out continuously.
Phthalocyanine produced by both batch and continuous methods reveals similar structure to the one showed in Figure 6. A characteristic metallic atom is bounded in the center of phthalocyanine molecule. However, as mentioned before, this raw phthalocyanine is insoluble in water. To enhance the solubility, benzene rings are modified by sulphonation or sulphochlorination [70]. The main area of phthalocyanine utilization covers dyes and pigments. Their share on the market is 30% of all produced organic dyes.
6.1 Mechanisms of singlet oxygen generation
It is known that phthalocyanines are capable to generate singlet oxygen when interact with visible light [73]. Singlet oxygen is a form of oxygen molecule in its excited state where all electrons are coupled. Singlet oxygen evinces high lifetime period. Stability of singlet oxygen species is dependent on reaction environment [74].
The general mechanism of the phthalocyanine interaction with light is usually described by two types of reaction mechanisms [75, 76, 77]. For both mechanisms, interaction of phthalocyanine with visible light photons occurs, mostly at wavelength of 670 nm. Figure 7 depicts absorption spectra of zinc phthalocyanine (ZnPC). Strong absorption area in visible part of spectra enables photon absorption followed by excitation. The double peak in visible area indicates a presence of both mono- and disulphonated forms of ZnPC. Absorption of photons at 670 nm causes excitation of phthalocyanine molecule towards the excited singlet state.
Figure 7.
Absorption spectra of ZnPC.
It starts with its absorption of photon(s) followed by intersystem crossing from the excited singlet state to the low-lying triplet state.
PC+hν→1PC∗isc→3PC∗E26
The triplet state of phthalocyanine transfers its energy to an oxygen molecule. The first mechanism involves hydrogen-atom abstraction or electron-transfer between the excited phthalocyanine and another molecule (e.g. solvent, air oxygen), forming free radicals and ion-radicals [78, 79]. These radicals can then react with ground-state oxygen to form an active species such as the superoxide radical anion.
3PC∗+O2→PC•+O2•̄E27
PC•̄+O2→PC+O2•̄E28
½O2•̄+H2O→H2O2E29
½O2•̄+H2O→2OH•E30
O2•̄→1O2E31
This mechanism causes an electron transfer from phthalocyanine to oxygen molecule yielding superoxide anion-radical (Eqs. 27 and 28). Superoxide anion-radical tends to hydrogen peroxide formation in water environment and further produces hydroxyl radicals as active species (Eqs. 29 and 30) or it can be transferred towards singlet oxygen (Eq. 31) [80].
The second mechanism comprises interaction of triplet phthalocyanine state with molecular oxygen. Energy from triplet phthalocyanine transfers to the oxygen and the upcoming release of energy causes formation of singlet oxygen and basic state of phthalocyanine [81].
3PC∗+O2→PC+1O2E32
6.2 Mechanisms of singlet oxygen interactions with organic molecules
As already mentioned singlet oxygen is a particle of long lifetime depending on the environment where it currently exists. And also the reaction mechanism depends on type of organic molecule which enters the reaction with singlet oxygen. It is supposed that singlet oxygen interacts with organic compounds upon yielding endoperoxides and superoxide radicals or hydrogen peroxide via mechanisms resulting in one- or two-electron transfer [82].
In case of substituted aromatic hydrocarbon (e.g. 4-chlorophenol) chlorine cleavage can be observed yielding either p-benzoquinone or p-hydroquinone. Following reactions with singlet oxygen lead to aromatic ring opening (Figure 8).
Figure 8.
Simplified reaction scheme of 4-chlorophenol attack by singlet oxygen.
6.3 Advantages and limits
The use of phthalocyanines as catalysts producing singlet oxygen reveals several advantages to other methods of chemical or photochemical water treatment: [83, 84, 85, 86].
Thermal stability of the phthalocyanines.
Solubility in water is possible to enhance by substitution of aromatic rings.
No mass transfer problems.
Possibility of artificial visible light utilization.
Difficulties related with the processes utilizing phthalocyanines as photosensitizers can also be found: [87].
The rate of chemical oxidation of the contaminant is limited by the rate of formation of singlet oxygen.
Crude form of phthalocyanine is insoluble in water thus modification has to be performed.
Too high concentrations cause dark color of the treated water and light photons cannot reach the entire irradiated volume.
Phthalocyanine catalyzed oxidations have been widely described in the laboratory in cuvette arranged on optical bench [88, 89, 90]. Also performance of such catalyzed reaction in micro reactor arrangement is coming to the fore [91, 92]. Immobilization of phthalocyanines on various supports is also well known process but it does not work sufficiently [93, 94]. All these processes and many others are performed only at laboratory scale. First quarter scale experiments performed with phthalocyanines acting as photosensitizers have been described recently [95]. However, if the phthalocyanines successfully mineralize all organic contaminants in water, phthalocyanine removal needs to be applied as in treated water it would act as coloring contaminats. For such purposes, activated carbon might be effective.
7. Summary
Advanced oxidation processes for hydroxyl radicals and singlet oxygen species were introduced and discussed according to their mechanisms and applicability for water treatment. The emphasis was put on hydrogen peroxide photolysis in UV-C region but other AOPs were also introduced. Phthalocyanine utilization as photosensitizer for generation of singlet oxygen, as another strong oxidizing agent was also discussed. It has been demonstrated that applicability potential of such technologies exists. AOPs based on hydroxyl radicals’ generation reveal higher potential for application because they usually don’t require addition of coloring chemicals (as phthalocyanines).
Acknowledgments
Financial support of Technology Agency of the Czech Republic (Project No. SS02030008) and Ministry of Education, Youth and Sports of the Czech Republic (Project No. CZ.02.1.01/0.0/0.0/17_048/0007435) is gratefully acknowledged. Part of the work was provided by research infrastructure NanoEnviCz (Project No. LM2018124).
Conflict of interest
The author declares no conflict of interest.
\n',keywords:"hydroxyl radicals, singlet oxygen, advanced oxidation processes, photosensitization, oxidation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76950.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76950.xml",downloadPdfUrl:"/chapter/pdf-download/76950",previewPdfUrl:"/chapter/pdf-preview/76950",totalDownloads:232,totalViews:0,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:68,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"March 30th 2021",dateReviewed:"April 28th 2021",datePrePublished:"June 8th 2021",datePublished:"April 28th 2022",dateFinished:"May 29th 2021",readingETA:"0",abstract:"Considering the nature of organic contaminants in water, methods of their oxidative decomposition seem to be most appropriate for their removal from contaminated water. There are a lot of methods of chemical oxidation, however, Advanced Oxidation Processes (AOPs) seem to be the most suitable technologies for organic contaminants removal. AOPs belong to a group of processes that efficiently oxidize organic compounds towards harmless inorganic products such as water or carbon dioxide. The processes have shown great potential in treatment of pollutants of low or high concentrations and have found applications for various types of contamination. The hydroxyl radical (•OH) is oxidizing agent used at AOPs to drive contaminant decomposition. It is a powerful, non-selective chemical oxidant, which reacts very rapidly with most organic compounds. Another strong oxidizing agent, singlet oxygen, can be generated by photosensitization of phthalocyanines. Phthalocyanines are molecules based on pyrrol structures connected mainly with methionine groups (–CH=) having a metallic central atom. Illumination upon specific wavelengths initiates formation of singlet oxygen that attack organic contaminants.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76950",risUrl:"/chapter/ris/76950",book:{id:"10803",slug:"reactive-oxygen-species"},signatures:"Pavel Krystynik",authors:[{id:"214522",title:"Dr.",name:"Pavel",middleName:null,surname:"Krystynik",fullName:"Pavel Krystynik",slug:"pavel-krystynik",email:"krystynik@icpf.cas.cz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Institute of Chemical Process Fundamentals",institutionURL:null,country:{name:"Czech Republic"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Fenton oxidation",level:"1"},{id:"sec_3",title:"3. Photocatalytic processes",level:"1"},{id:"sec_4",title:"4. Ozone water system",level:"1"},{id:"sec_5",title:"5. Hydrogen peroxide photolysis",level:"1"},{id:"sec_5_2",title:"5.1 Hydrogen peroxide",level:"2"},{id:"sec_6_2",title:"5.2 Mechanism of hydrogen peroxide photolysis",level:"2"},{id:"sec_7_2",title:"5.3 Reaction mechanism of hydroxyl radicals with organic molecules",level:"2"},{id:"sec_8_2",title:"5.4 Advantages and limits",level:"2"},{id:"sec_9_2",title:"5.5 Reactors for UV-C/H2O2 oxidations",level:"2"},{id:"sec_10_2",title:"5.6 Perspectives of AOPs",level:"2"},{id:"sec_12",title:"6. Phthalocyanines",level:"1"},{id:"sec_12_2",title:"6.1 Mechanisms of singlet oxygen generation",level:"2"},{id:"sec_13_2",title:"6.2 Mechanisms of singlet oxygen interactions with organic molecules",level:"2"},{id:"sec_14_2",title:"6.3 Advantages and limits",level:"2"},{id:"sec_16",title:"7. Summary",level:"1"},{id:"sec_17",title:"Acknowledgments",level:"1"},{id:"sec_20",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'A. 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A: Gen. 2008, 340, 16-24'},{id:"B95",body:'Krystynik, P.; Kluson, P.; Hejda, S.; Buzek, D.; Masin, P.; Tito, D. N. Appl. Catal. B: Environ. 2014, 160, 506-513'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Pavel Krystynik",address:"krystynik@icpf.cas.cz",affiliation:'
Faculty of Environment, University of J.E. Purkyne, Czech Republic
Institute of Chemical Process Fundamentals, Academy of Sciences of the Czech Republic, Czech Republic
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1. Introduction
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide. It affects about 30% of the population in the United States [1, 2] and 10% of adolescents and children [3, 4]. NAFLD is a spectrum of metabolic disorders starting with simple steatosis characterized with excessive accumulation of triglycerides in the hepatocytes, progressing to nonalcoholic steatohepatitis (NASH) characterized with inflammation, to fibrosis and cirrhosis, and eventually to liver failure and hepatocellular carcinoma (HCC) [5, 6, 7]. Obesity and insulin resistance or diabetes are the most prevalent risk factors for development of NAFLD [8, 9, 10, 11, 12, 13].
Bile acids are the metabolites of cholesterol and synthesized in the liver. It is well known that bile acids act as biological detergents to solubilize cholesterol and lipids in the bile and intestine, play important roles in cholesterol and lipid absorption and transport. Recent studies have revealed that bile acids can serve as hormone-like signaling molecules to activate several nuclear receptors, notably the farnesoid X receptor (FXR) [14, 15]. The bile acids/FXR signaling plays critical roles in regulating a myriad of metabolic homeostasis including bile acids, cholesterol, lipids, and glucose [16, 17, 18, 19], as well as inflammation/immunity [20, 21, 22, 23, 24] and liver regeneration [25, 26, 27].
Under physiological condition, bile acid homeostasis is maintained through multiple negative feedback loops for bile acid synthesis [18, 28, 29, 30] and a tightly regulated enterohepatic circulation of bile acids [31, 32, 33, 34]. Since liver is the organ for bile acid synthesis and metabolism and biliary excretion of bile acids is the limiting step for the enterohepatic circulation [35, 36], impairment of liver function as a result of various liver disorders leads to dysregulation of bile acids. Indeed, the measurement of bile acids is considered a biomarker of liver function and serves as an indicator of hepatobiliary impairment or diseases [37, 38, 39, 40, 41]. On the other hand, excessive accumulation of bile acids in the liver causes liver damages by multiple mechanisms including disrupting the integrity of cell membranes through their detergent property [42, 43, 44], causing mitochondrial stress and promoting the generation of reactive oxygen species [45, 46, 47, 48], and inducing endoplasmic reticulum stress [49, 50, 51] and inflammatory responses [52, 53, 54], resulting in cell death via apoptosis and/or necrosis [55, 56, 57, 58].
Because of the reciprocal effects between liver damage and bile acid dysregulation, it is often difficult, if not impossible, to determine the cause-and-effect relation between liver damage and bile acid dysregulation for many liver disorders. In one hand, liver damage causes bile acid dysregulation. On the other hand, bile acid dysregulation potentially causes liver damage. The connection between NAFLD and bile acid dysregulation has long been recognized and reported [59, 60, 61, 62, 63, 64, 65, 66, 67]. It is well established that liver function is compromised in patients with NAFLD, especially advanced stages of NAFLD, such as NASH and NASH-associated fibrosis and cirrhosis, due to pathological and structural damages to the liver. Research interests and emphasis are recently condensed on investigating the contribution of bile acid dysregulation to the pathogenesis of NAFLD and developing therapeutic interventions for NAFLD by manipulating the bile acid signaling pathway [66, 67, 68, 69, 70, 71, 72, 73]. However, the outcomes of clinical trials targeting bile acid signaling using ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) to treat NASH patients are not very encouraging [74, 75, 76, 77, 78, 79], indicating that our understanding on the relationship between bile acids and NAFLD is not complete or even may be misinterpreted.
Taken together, the link between bile acids and NAFLD has been firmly established. However, certain fundamental questions remain to be answered. How bile acid homeostasis is disrupted in patients with NAFLD? Whether dysregulation of bile acids is one of the manifestations of NAFLD or actually contributes to the development and/or progression of NAFLD? It only becomes possible to develop rationalized approaches to treat patients with NAFLD until those fundamental questions are fully addressed. In this chapter, the effects of NAFLD on bile acid homeostasis are reviewed and discussed.
2. Altered bile acid profiles in subjects with NAFLD
In human, cholic acids (CAs) and chenodeoxycholic acid (CDCA) are two primary bile acids synthesized in the liver and account for majority of bile acids in the bile acid pool. Upon excretion into intestine, primary bile acids can be converted into secondary bile acids by gut bacteria. Specifically, CA is converted into deoxycholic acid (DCA), while CDCA is converted into lithocholic acid (LCA) or UDCA in the intestine by dehydroxylation [80, 81] or 7β epimerization [82, 83, 84]. Majority of primary and secondary bile acids are conjugated by either glycine or taurine in the liver, generating glycine- or taurine-conjugated bile acids [80, 81]. Under physiological conditions, total bile acid levels, as well as the composition of the bile acid pool, are regulated and maintained. However, under various pathological conditions, especially liver disorders, the bile acid pool size or total bile acids and bile acid pool compositions are altered. A large number of clinical and preclinical studies have revealed that bile acid profiles are altered in patients with NAFLD and rodent NAFLD models.
2.1 Altered bile acid profiles in patients with NAFLD
2.1.1 Serum bile acids
Under the physiological condition, serum bile acid concentrations are much lower than those in the enterohepatic system. However, when the enterohepatic cycling of bile acids is compromised due to hepatic injuries or intestine disorders, bile acids are spilled into the blood circulation system, altering serum bile acid concentrations, as well as compositions. Bile acid profiling in healthy populations has revealed that serum bile acid concentrations and compositions are age dependent [85]. Therefore, the serum bile acid profiles in adult and children with NAFLD are separately described in the following sections.
2.1.1.1 Serum bile acid profiling in adults with NAFLD
Currently, there are total nine clinical studies investigating serum bile acid levels and compositions in adults with NAFLD. In study 1 with 25 healthy subjects, 11 patients with steatosis, and 24 patients with NASH, it was found that serum bile acid profiles after overnight fasting were significantly altered in both steatotic and NASH patients, especially in patients with NASH [86]. The most prominent alteration is the markedly increased conjugated CA concentration. Taurine-conjugated CAs (TCAs) were elevated 4- and 2.2-fold, while glycine-conjugated CAs (GCAs) were increased 4.3- and 3.1-fold in patients with NASH and steatosis, respectively. Similarly, GCDCA levels were also elevated by 2- and 2.4-fold in patients with NASH and steatosis, respectively. Other bile acid species, including CA, GDCA, TDCA, and TCDCA, exhibited a trend of increase but their levels did not reach a statistical significance. It should be noted that patients with steatosis or NASH had significantly elevated insulin levels and exhibited insulin resistance, although the blood glucose levels were within the normal range. The patients, especially those with NASH, also had elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, indicating liver damage in those patients.
In study 2 with 15 healthy controls and 7 NASH patients, both fasting and postprandial bile acids were altered [87]. Total fasting serum bile acid levels were increase by more than twofold. Such increases in total bile acids are mainly due to significantly increased conjugated bile acids with both glycine and taurine, while unconjugated bile acids were not significantly altered. Both primary (CDCA and CA and their conjugated) and secondary (DCA and LCA and their conjugated) bile acids were markedly elevated. Similarly, postprandial serum bile acid levels were also markedly increased in patients with NASH, including total, conjugated and unconjugated, primary, and secondary bile acids. However, the relative ratios or the compositions of the serum bile acid pools were not significantly altered in both fasting and postprandial levels. Significant elevations in individual bile acids including DCA, GCA, GCDCA, and TCA were also noted. Other bile acid species including CA and CDCA were either not altered or slightly increased without reaching a statistical significance. Patients with NASH had significantly elevated alkaline phosphatase (ALP), ALT, insulin, and homeostatic model assessment (HOMA) levels accompanied with significantly higher fast blood glucose levels when compared to the control subjects.
In study 3 with 24 healthy subjects, 25 steatotic, and 37 NASH patients, plasma bile acids after fasting were measured [88]. Total plasma primary bile acids (CA and CDCA) were gradually increased from controls to steatotic to NASH patients. On the contrary, total secondary bile acids (DCA and LCA) were gradually decreased from controls to steatotic to NASH patients. The increases in primary bile acids are mainly resulted from elevation of the conjugated bile acids, while the unconjugated primary bile acids (CA and CDCA) were comparable to those in the control subjects. Comparison between the two NAFLD groups, total conjugated CA and conjugated primary bile acids, was significantly higher in subjects with NASH compared to steatotic subjects. In addition, the compositions of the primary bile acid pools were also changed with significant increase in the ratios of total primary CA to CDCA, regardless of the status of diabetes. Although total secondary bile acids were lower in NASH patients, most of the individual secondary bile acids including GDAC, TDCA, TLCA, and GLCA were comparable among the three groups except for unconjugated DCA, which was significantly higher in NASH patients. Unconjugated UDCA levels were comparable among the three groups, while conjugated UDCA was significantly higher in NASH patients compared to steatotic and control subjects. It should be mentioned that AST and ALT levels were significantly elevated in both steatotic and NASH patients, indicating hepatic injury under the steatotic and NASH conditions. In addition, a large percentage of NASH patients (62.2%) were diabetic, while 20% of steatotic patients were diabetic with only one subject (4.2%) being diabetic in the control group.
In study 4 with 14 healthy controls and 7 patients with NASH, serum total bile acids were significantly elevated by 2.5-fold in patients with NASH compared to healthy control subjects [89]. Individual bile acids including GCA and TCA were markedly increased by 3.1- and 5.7-fold in patients with NASH, respectively. In addition, linear regression analysis revealed a significant association between NAFLD activity scores (NAS) and fasting total serum bile acid, GCA, and TCA concentrations. It should be mentioned that the fasting total bile acids, GCA and TCA serum, concentrations in healthy controls in the study were comparable to those reported previously for healthy adults [90].
In study 5 with 46 healthy control subjects and 13 patients with NAFLD, serum bile acids were dysregulated in patients with NAFLD [38]. Total serum bile acid levels were significantly increased by 4.7-fold from 2.8 μM in control subjects to 13.0 μM in NAFLD patients. Primary and secondary bile acids were elevated by 3.8- and 1.9-fold, respectively, in NAFLD patients. These increases in total, primary, and secondary bile acids are mainly due to much higher concentrations of conjugated bile acids in NAFLD patients (5.0 μM) than in control subjects (1.2 μM). Unconjugated bile acids were also slightly increased from 0.88 μM in control subjects to 1.30 μM in NAFLD patients without reaching a statistical significance.
In contrast to most of the previous studies, a recent study 6 with 32 patients with NASH and 26 non-NASH controls reported that plasma total, primary, secondary, unconjugated, and conjugated bile acids were not significantly different between the two groups [91]. The compositions of the plasma bile acid pools were also not altered either in patients with NASH when compared to non-NASH subjects. However, when the subjects were subcategorized into insulin resistance and insulin sensitive groups, significant changes in bile acid profiles were detected. Total serum CA (CA + GCA and TCA), unconjugated CA, total CDCA (CDCA + GCDCA + TCDCA), unconjugated CDCA, total primary and unconjugated primary, total unconjugated, and non-12α bile acids were all significantly elevated in subjects with insulin resistance compared to insulin sensitive subjects. The authors therefore concluded that bile acid alterations were associated with insulin resistance but not NASH. The study also showed that body mass index (BMI), fasting plasma insulin concentrations, and HOMA values positively correlated with plasma CA and CDCA levels. It should be mentioned that the BMI and HOMA values were matched between the NASH patients and the non-NASH control subjects in this study. The average BMI was 40.2 for NASH and 39.4 for non-Nash subjects, indicating that both groups are severely obese. The average HOMA was 4.05 for NASH patients and 3.25 for non-NASH controls, indicating insulin resistance in both groups.
Consistent with the findings from the sixth study, another clinical study reported that patients with NAFLD exhibited comparable serum total bile acid concentrations to those in healthy control subjects [92]. The study included 16 healthy controls with an average BMI of 24.2, 14 overweight NAFLD patients with BMI of 28.3, and 12 obese NAFLD patients with an average BMI of 35.3. No significant alterations in fasting as well as postprandial serum total bile acid levels were detected between healthy control subjects and overweight or obese NAFLD patients.
In another study with 38 control subjects and 36 NASH patients, limited information about the characteristics of the studied subjects was provided and only data on three individual bile acid species were reported. The plasma concentrations of GCA, TCA, and TCDCA during fasting were significantly elevated in patients with NASH compared to control subjects [93]. Consistent with finding from most of the studies, another clinical study with 10 healthy controls, 39 steatotic, and 59 NASH patients reported that total serum bile acid levels were significantly elevated in patients with NAFLD [94].
The findings from six clinical studies, which provide detailed characteristics of the studied subjects as well as the corresponding bile acid profiles, are summarized in Table 1. The results from studies 1 to 5 are largely consistent. Serum total, primary, and conjugated bile acids were all significantly increased with limited changes for unconjugated bile acids. However, the secondary bile acids were significantly increased in studies 1, 2, and 5 but decreased in study 3. In contrast to the findings from studies 1 to 5, no significant alterations were detected in serum total, primary, secondary, conjugated, and unconjugated bile acids in the study 6.
Dysregulation of bile acids in adults with NAFLD with characteristics of the studied subjects.
N/A, not available.
Compared the characteristics of the control and NAFLD subjects, it is noticed that the control subjects in study 6 were severely obese with BMI 39.4 ± 5.9, while the control subjects in studies 1–5 have normal or close to normal body weights with BMI ranging from 24.5 ± 2.6 to 27.3 ± 5.8. The BMI values were matched between NAFLD patients and control subjects in study 6 but significantly different in studies 1–5. Compared with serum bile acid levels in a healthy population [85], the control subjects in study 6 had markedly increased total, primary, secondary, conjugated, and unconjugated bile acids. The results indicate that obesity or increased BMI is a contributing factor to the dysregulation of serum bile acids. Indeed, several studies have reported that subjects with overweight or obese had increased serum bile acid concentrations [85, 95, 96].
The second characteristic of the studied subjects that is different between study 6 and studies 1–5 is the status of insulin resistance in the control subjects. The serum insulin levels and HOMA values in study 6 are markedly higher than those in the other five studies, suggesting that insulin resistance is a contributing factor for the dysregulation of serum bile acids. Indeed, when all the subjects (NAFLD and control patients) in the study 6 were separated by insulin resistance status, primary bile acids, unconjugated bile acids, and non-12α bile acids, total CA and total CDCA were significantly increased in subjects with insulin resistance compared to insulin sensitive subjects regardless of the status of NAFLD. These data strongly suggest that insulin resistance is a contributing factor to the dysregulation of bile acids, which is supported by the findings from previous studies [95, 96, 97, 98, 99, 100].
The third different characteristic of the NASH patients in study 6 from studies 1 to 5 is the liver injury status. The NASH patients in study 6 exhibited much lower ALT and AST levels than those in the NASH patients in studies 1–5, indicating that the NASH patients in study 6 experienced minimal liver injury, while the NASH patients in other studies exhibited hepatic injury or damage with the ALT and AST levels above the physiological values. As discussed earlier, it is well established that liver injury potentially can cause dysregulation of bile acids [38, 39, 40, 41, 42]. The differing liver injury statuses may provide an explanation for the discrepancy in bile acid alterations between the study 6 and the other five studies. Taken together, the characteristic variations in BMI, insulin resistance, and hepatic injury of the studied subjects may all contribute to the inconsistency in serum bile acid levels reported in those studies.
2.1.1.2 Serum bile acid profiling in children with NAFLD
There are three studies conducted with children from ages 4 to 17 years old. In one study with 11 healthy controls (average age 12.8 years) and 16 patients with NASH (average age 13.7 years), total serum bile acid levels were significantly elevated by threefold in children with NASH compared to healthy controls [101]. More specifically, the absolute concentrations of CA, CDCA, DCA, and UDCA were all markedly increased. The percentages of CA and DCA in the total bile acid pools were significantly increased, while the percentages of CDCA in the pools were decreased with no changes in UDCA. It is noted that both ALT and AST levels in patients with NASH were increased, indicating hepatic injury in those patients. The children with NASH also exhibited insulin resistance with an average HOMA value of 4.3 ± 2.8 and overweight or obese with an average BMI of 33.8 ± 7.7.
In the second study with 105 healthy controls at ages 9.3 ± 2.5 and 92 children with NAFLD, which were further classified into two groups based on the stages of fibrosis: NAFLD-F0 group at ages 10.9 ± 3.7 and F ≥ 1 group at ages 11.5 ± 1.9, total serum bile acids were significantly decreased from 3.6 μM in control subjects to 1.73 μM in nonfibrotic (NAFLD-F0) patients accompanied by decreased glycine-conjugated bile acids and slightly increased taurine-conjugated and unconjugated bile acids [102]. The total serum bile acids in patients with more advanced NAFLD with fibrosis (NAFLD-F ≥ 1) were also decreased to 2.45 μM. Comparison between the two NAFLD groups, the serum bile acid levels increased by 41.9% in the NAFLD-F ≥ 1 group. These data indicate that serum bile acid levels decrease in the early stage of NAFLD, followed by an increase as NAFLD progresses to fibrosis. No significant differences were detected in the compositions of serum total bile acid pools among the groups. It should be mentioned that compared with control subjects (BMI 18.8 ± 4.2), children in the NAFLD groups were overweight (BMI > 26) with significantly elevated glucose and insulin levels. In addition, NAFLD patients had elevated AST and ALT levels, indicating hepatic injury in those patients.
In a most recent third study with 35 control children at ages 12.8 ± 4.2 and 41 NAFLD children at ages 13.7 ± 2.4, which were further divided into mild and moderate/severe NAFLD groups, no significant alternations in serum total, primary, and secondary bile acids were detected in children with NAFLD compared to control subjects [103]. Most of individual bile acid species (CA, CDCA, DCA, and LCA), conjugated and unconjugated bile acids, were comparable among the groups. Significant differences were only detected for unconjugated CDCA and unconjugated primary bile acids (CDCA + CA). Unconjugated CDCA and primary bile acids increased by 1.58-fold and 1.43-fold, respectively, in NAFLD children. After adjusted for age, sex, HOMA and BMI, unconjugated DCA, conjugated DCA (GDCA and TDCA), and total DCA were significantly lower in NAFLD patients than those in the control group. Meanwhile, serum GLCA and total conjugated LCA (GCA + TLCA) were significantly decreased in NAFLD patients compared to control subjects.
The findings from the three clinical studies with detailed characteristics of the studied subjects are summarized in Table 2. The results from the three studies are largely inconsistent. In the second study with a larger size of samples, serum bile acid levels decrease in early stage of NAFLD and then increase during progression to fibrosis, but the levels were still below that in control subjects. In the third study with a medium size of samples, no significant alternations in serum total, primary, and secondary bile acids were detected in children with NAFLD. However, in the first study with smallest size of samples, total serum bile acid levels and compositions were significantly altered in patients with NASH compared to healthy controls.
Dysregulation of bile acids in children with NAFLD with characteristics of the studied subjects.
N/A, not available.
Comparing the characteristics of studied subjects, the trend of bile acid alterations from decrease to no changes to increase correlates with the trend of gradually increased BMI from slightly overweight (26.5 ± 3.59) to severe overweight (29.6 ± 5.2) to obese (33.8 ± 7.7). Such correlation indicates that NAFLD-associated overweight or obesity may play important roles in influencing the bile acid homeostasis in children as well [85, 95, 96]. Another possible factor playing a role in bile acid dysregulation under the NAFLD conditions is the HOMA values, which were increased from 3.0 ± 3.0 in study 1 to 4.1 ± 3.2 in study 2 and 4.3 ± 2.8 in study 3. The differences in sample sizes of the studies certainly also contribute to the variations of bile acid levels among the studies. The sample sizes in the control groups ranged from 105 in study 2 to 35 in study 3 to 11 in study 1. Meanwhile, the sample sizes for NAFLD subjects were decreased from 92 in study 2 to 42 in study 3 to 16 in study 1. Taken together, serum bile acid levels were differentially altered in children with NAFLD. The differences in BMI, insulin resistance, and sample sizes may contribute to the variations of serum bile acids detected among the three studies.
2.1.2 Hepatic bile acids
There are three relevant studies investigating hepatic bile acids in patients with NAFLD. In the first study with 15 NASH patients and 8 control subjects, total hepatic bile acids were significantly increased in patients with NASH compared to control subjects [104]. The concentrations of individual bile acid species including CA, CDCA, and DCA were markedly higher in patients with NASH than those in the controls. It was also found that hepatic total bile acid levels were significantly correlated with hepatic inflammation status. Meanwhile, CDCA concentrations were positively correlated with fibrosis status in patients with NASH.
In a second study with liver tissues from 17 normal control subjects, 4 patients with simple steatosis, and 37 patients with NASH, significant alterations in hepatic bile acids were detected in NASH patients [105]. Hepatic CA and GDCA concentrations were markedly decreased by 69 and 91%, respectively, in patients with NASH compared to the control subjects. In contrast, hepatic TCA, TDCA, and GCDCA were significantly increased by approximately three, five, and twofold in NASH patients, respectively. Overall, hepatic total and conjugated bile acid concentrations were significantly higher in patients with NASH than those in controls. On the other hand, unconjugated bile acids were significantly decreased in patients with NASH. In patients with simple steatosis, total, conjugated, and unconjugated bile acids were all decreased without reaching a statistical significance mainly due to a small sample size of the group.
In a relevant third study with 20 control subjects and 22 diabetic patients, hepatic bile acid concentrations were significantly altered [106]. Among the 22 diabetic patients, 77.7% patients had NAFLD with NAS score of 2 or above. Consistently, majority of patients (68%) were overweight, obese, or severe obese, with hypercholesterolemia being detected in 86.4% of the patients. Total hepatic bile acids were markedly reduced by 53% in diabetic patients compared to control subjects. The significant decrease in total bile acids is largely due to the marked reduction in conjugated bile acids. On the other hand, unconjugated bile acids were slightly increased by 33% without reaching a statistical significance. Among the conjugated bile acids, both glycine and taurine conjugated bile acids were significantly reduced in diabetic patients. However, the reductions were more severe in glycine conjugated than taurine-conjugated bile acids.
In summary, no clear consensus can be reached for hepatic bile acid profiles in patients with NAFLD. Both increases and decreases of hepatic bile acids were reported. Some specific bile acid species were markedly increased, while other species significantly decreased in the same patients. From the limited clinical studies, it can be concluded that hepatic bile acid homeostasis is dysregulated in patients with NAFLD. However, due to the complexity of bile acid regulation, variations in characteristics and stages of NAFLD patients, and lack of high quality clinical studies, it largely remains to be determined by the effects of NAFLD on hepatic bile acid homeostasis.
2.1.3 Fecal and urine bile acids
There are only one study investigating fecal bile acids in patients with NAFLD. The study has 25 healthy controls, 12 patients with steatosis, and 17 patients with NASH [107]. Total fecal bile acid levels were significantly higher in patients with NASH compared to healthy controls. Meanwhile, total fecal bile acids also showed an increased trend in steatotic patients without reaching a statistical significance. Primary, secondary, conjugated, and unconjugated bile acid concentrations all exhibited a gradual increase from healthy controls to steatotic to NASH patients. Unconjugated primary bile acids including CA and CDCA were significantly increased in NASH patients compared to healthy controls, while unconjugated secondary bile acids were not significantly different among the three groups. Patients with NASH had significantly higher concentrations of conjugated LCA compared to patients with steatosis. In addition, a higher ratio of primary to secondary bile acids in patients with NASH was also detected. However, the ratio of total conjugated over unconjugated bile acids was not significantly different among the groups. Correlation analysis revealed that fecal unconjugated primary bile acids positively correlated with steatosis, ballooning, fibrosis, NAS scores, and liver injury (AST and ALT levels). The results from the study demonstrated that fecal disposition of bile acids was enhanced in patients with NASH. However, it remains to be determined that such increase in fecal disposition of bile acids is resulted from impairment of intestine reabsorption of bile acids or enhanced biliary excretion of bile acids or both.
There is only one study with 15 healthy controls and 7 NASH patients to investigate urine bile acid profiles in patients with NAFLD. Urine total, primary, secondary, conjugated, and unconjugated bile acids all exhibited a trend of increase without reaching a statistical significance [87]. However, individual bile acid species including DCA, TCA, GCA, and GCDCA were significantly elevated in patients with NASH compared to control subjects. Consistently, total serum bile acid levels were also significantly increased by more than twofold in NASH patients compared to control subjects.
In summary, the findings from clinical studies to evaluate serum, hepatic, and urine bile acid profiles are inconsistent among the studies. The reasons for those inconsistent or even conflicting results are multiple folds. First, bile acid synthesis and serum concentrations fluctuate during the days and nights [108, 109, 110, 111, 112]. Although most of the samples were collected after fasting, there was no mentioning on exactly when the samples were collected in the studies. Second, NAFLD represents a spectrum of pathological liver conditions from simple steatosis to NASH with or without fibrosis. The severity of bile acid dysregulation appears NAFLD stage dependent. Bile acid alterations gets worsening in patients with advanced stages of NAFLD, such as NASH, compared to the patients with simple steatosis [86, 88, 101, 102, 107]. Some studies differentiate NAFLD patients into simple steatosis and NASH [86, 88, 101, 102, 107], while the others [38, 87, 89, 91, 103] do not, which certainly influences the outcomes of the studies. Third, NAFLD is often associated with various metabolic conditions, especially obesity and insulin resistance/diabetes. It has been reported that obesity and insulin resistance directly impacts bile acid homeostasis [85, 95, 96, 97, 98, 99, 100]. Fourth, selection of the control groups varies from study to study [38, 86, 87, 88, 89, 91], which certainly contributes to the discrepancy of the outcomes among the studies. Finally, the sizes of samples are relatively small in most of the studies with individual variations potentially masking the alterations.
2.2 Altered bile acid profiles in NAFLD animal models
Several rodent models for NAFLD have been developed [113, 114, 115], including high-fat cholesterol (HFC) and methionine- and choline-deficient (MCD) diet-induced or genetic deficient models, including leptin-deficient ob/ob, leptin receptor-deficient db/db mice, and fa/fa rats. Several preclinical studies were conducted to investigate the effects of NAFLD on bile acid homeostasis using NAFLD mouse or rat models. In one study, NAFLD was induced in rats with HFC diet [116]. Total hepatic bile acids were significantly increased in rats on HFC diet for 2 weeks. Primary, secondary, conjugated, and unconjugated bile acid concentrations were all increased after 2 weeks on HFC diet. Most bile acid species remained higher in rats on HFC diet for 8 and 14 weeks than those on regular diet. However, the levels of CA and DCA species declined from their peaks at 2 weeks, while CDCA species persistently increased for the entire treatment. In addition, CDCA species positively correlated with macrovesicular steatosis score, serum ALT levels, and quantified fibrotic area. Among the conjugated bile acids, glycine-conjugated bile acid species (GCA, GCDCA, GDCA, GLCA, and GUDCA) were predominate over taurine-conjugated bile acid species and positively correlated with macrovesicular steatosis score. The finding demonstrated that bile acid homeostasis is severely disrupted in HFC diet-induced NAFLD rats, especially the CDCA and glycine-conjugated bile acid species.
In another study with MCD-induced NASH mouse model, markedly increased serum concentrations of taurine-conjugated CA and β-muricholate (βMCA) were detected in mice on MCD diet for 2 or 8 weeks compared to mice on control diet, indicating dysregulation of serum bile acid in mice with NASH [117]. Similar findings were reported with ob/ob mouse model. Serum total bile acid concentrations were markedly elevated by sevenfold from 1.9 ± 1.0 μM in wt control mice to 14.9 ± 5.4 μM in ob/ob mice [118]. In contrast to the findings from the studies described above, a more recent study showed that total serum bile acid concentrations were not significantly different in HFD-induced NAFLD mice than mice on control diet [119].
Taken together, bile acid homeostasis is disrupted in NAFLD rodent models. Serum bile acid levels were markedly elevated in most of the studies. However, variations in serum bile acid concentrations exist in different NAFLD rodent models, may reflecting species difference between mouse and rat.
3. Alterations in bile acid synthesis in subjects with NAFLD
3.1 Alterations in bile acid synthesis in patients with NAFLD
Primary bile acids CA and CDCA are synthesized in the liver through either the classical or alternative synthesis pathways. In the intestine, CA can be converted into secondary bile acid DCA, while CDCA is converted into secondary bile acids LCA or UDCA (Figure 1). Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the classical pathway, while CYP8B1 is the rate-limiting enzyme for the production of CA. The two rate-limiting enzymes for the alternative pathway are CYP27A1 and CYP7B1 (Figure 1). Alterations in the expression levels of rate-limiting enzymes in the bile acid synthesis pathways result in dysregulation of bile acid homeostasis. A number of clinical studies have conducted to investigate the effects of NAFLD on bile acid synthesis.
Figure 1.
Primary bile acids CDCA and CA are synthesized in the liver through classical (CYP7A1) and alternative (CYP27A1) bile acid synthesis pathways and converted into secondary bile acids LCA, UDCA, and DCA in the intestine.
3.1.1 CYP7A1
There are eight clinical studies investigating the expression of CYP7A1 in patients with NAFLD. Most of the studies revealed that CYP7A1 expression was dysregulated in patients with NAFLD. Among the eight studies, the results from five studies showed that the mRNA expression levels of CYP7A1 were significantly increased in patients with NAFLD [88, 91, 94, 101, 120], indicating that bile acid synthesis through the classical pathway is enhanced in patients with NAFLD. However, in a study with 17 normal control subjects, 4 patients with simple steatosis, and 37 patients with NASH, CYP7A1 expression was not altered in patients with steatosis or NASH [105]. In another study with 6 lean healthy controls, 20 obese normal controls, 20 patients with simple steatosis, and 20 patients with NASH [121], CYP7A1 mRNA expression significantly increased in obese normal control subjects, patients with steatosis, and NASH compared to healthy lean subjects. However, at the protein level, CYP7A1 expression was comparable in obese normal controls compared to healthy lean subjects. More strikingly, CYP7A1 protein expression was markedly decreased in patients with steatosis and especially with NASH, indicating that bile acid synthesis through the classical pathway is reduced in patients with NAFLD. In a study with 78 NAFLD patients, the subjects were divided into three groups based on the NAS scores, NAS 1–2, NAS 3–4, and NAS 5–8. The mRNA expression levels of CYP7A1 were comparable among the three groups, indicating that bile acid synthesis through the classical pathway remains unchanged during the progression of NAFLD [122].
Taken together, CYP7A1 expression was largely upregulated in patients with NAFLD, indicating that bile acid synthesis through the classical pathway is enhanced in patients with NAFLD. Discrepancy in CYP7A1 mRNA and protein levels was noted, indicating the importance of post-transcriptional regulation of CYP7A1 under the NAFLD condition.
3.1.2 CYP27A1
There are three clinical studies evaluating the effects of NAFLD on the expression of CYP27A1. The findings from the three studies are largely inconsistent. In one study, the expression levels of CYP27A1 were significantly induced in patients with NAFLD [101]. In contrast, a second study reported that CYP27A1 expression was significantly decreased in patients with NAFLD compared to control subjects [105]. A third study showed that CYP27A1 expression was not altered in NAFLD subjects [121]. Therefore, it can be concluded that the effects of NAFLD on CYP27A1 expression are inclusive.
3.1.3 Other enzymes
There are a couple of studies investigating other enzymes involved in bile acid synthesis, including CYP8B1 and CYP7B1. One study reported that the expression levels of CYP8B1 were decreased, while CYP7B1 levels were increased in patients with NAFLD [105]. The other study revealed that the expression levels of CYP8B1 were significantly increased in patients with NAFLD compared to control subjects [101]. Therefore, additional studies are required to determine the effects of NAFLD on CYP8B1 and CYP7B1 expression.
3.1.4 C4
7α-Hydroxy-4-cholesten-3-one (C4) is an intermediate of bile acid synthesis (Figure 1) and serves as an indicator for bile acid synthesis in vivo [123]. There are three studies investigating serum C4 levels in patients with NAFLD. In one study with 26 NAFLD patients and 16 healthy controls, the serum concentrations of C4 were not significantly different between the two groups, indicating that de novel bile acid synthesis was not changed in patients with NAFLD [38]. Consistent results were obtained with a second study which includes 26 healthy controls and 32 patients with NASH. The serum C4 concentrations were not significantly altered in patients with NASH compared to the control subjects [90]. However, in the third study with 25 healthy controls, 12 patients with steatosis, and 16 patients with NASH, serum C4 levels were significantly elevated in patients with steatosis and NASH compared to healthy control subjects, suggesting that bile acid synthesis is enhanced in patients with NAFLD. Correlation analysis revealed that the serum C4 concentrations were directly correlated with fecal total bile acid levels in the studied subjects [104]. Taken together, the serum C4 concentrations either increased or did not change in patients with NAFLD.
3.2 Alterations in bile acid synthesis in NAFLD animal models
There are five studies investigating the expression of enzymes involved in bile acid synthesis. In one study with high fat diet (HFD)–induced NAFLD mice, the mRNA expression levels of Cyp7a1 and Cyp8b1 were markedly decreased compared to control mice on regular diet [124], indicating that de novel bile acid synthesis through the classical pathway is reduced in NAFLD mice. Consistent with the finding, a study with ob/ob mice, the expression levels of Cyp7a1 were significantly decreased in ob/ob mice compared to lean wt mice [118]. However, in a study with HFD/streptozotocin (STZ)-induced NAFLD rats, the expression levels of Cyp7a1 were dramatically increased, while the expression levels of Cyp27a1 and Cyp7b1 were also significantly induced in NAFLD rats compared to control rats [125]. The findings indicate that bile acid synthesis through both classical and alternative pathway is increased in HFD/STZ-induced NAFLD rats. On the other hand, in one study with MCD-induced simple steatotic rats, the expression levels of Cyp7a1 were comparable between the steatotic rats and healthy control rats [126]. Consistently, a study with MCD-induced NASH in mice showed that the expression levels of Cyp7a1 were not altered in mice with NASH compared to control mice [117]. In addition, the expression levels of Cyp27a1 and Cyp8b1 were not significantly changed in steatotic mice compared to healthy control mice. The findings indicate that both classical and alternative bile acid synthesis pathways are not impaired in MCD-induced NASH mice. In summary, the effects of NAFLD on Cyp7a1, Cyp27a1, and Cyp8b1 expression are inconclusive in NAFLD rodent models, which are to a large extent different from the findings in patients with NAFLD, especially for CYP7A1.
4. Alterations in bile acid transporters in subjects with NAFLD
The enterohepatic circulation of bile acids is mediated by a series of bile acid transporters in the liver and intestine (Figure 2). After synthesis in the liver, bile acids are excreted into bile through the bile salt export pump (BSEP). Majority of bile acids are actively transported into enterocytes by the apical sodium-dependent bile acid transporter (ASBT). Bile acids exit the enterocytes on the basolateral side via the heterodimeric organic solute transporter α and β (OSTα/β) and then return to the liver through the Na+/taurocholate cotransporting polypeptide (NTCP), completing the circulation. In the liver, other transporters are also capable of transport bile acids, including multidrug resistance associated protein 2 (MRP2) on the canalicular membrane and multidrug resistance-associated protein 3 (MRP3), MRP4, and organic anion-transporting polypeptides (OATP1B1 and OATP1B3) on the basolateral membrane. It should be emphasized that biliary excretion through BSEP is the rate-limiting step in the circulation and bile acid spilling into blood is mediated mainly by MRP3 and MRP4. Alteration in bile acid transporter expression has significant impact on bile acid compartmenting and homeostasis.
Figure 2.
Enterohepatic circulation of bile acids through a series of bile acid transporters, and regulation of bile acid synthesis by the FXR/SHP and FGF19/FGFR4 synthesis pathway.
4.1 Alterations in bile acid transporters in patients with NAFLD
4.1.1 BSEP
As the canalicular bile acid transporter, BSEP expression was dysregulated in patients with NAFLD. Three clinical studies showed that BSEP mRNA expression was decreased in steatotic or NASH patients compared to control subjects [88, 91, 122]. A different study reported that BSEP mRNA expression levels were increased in patients with NASH compared to the patients with simple steatosis [118]. On the other hand, two studies revealed that BSEP mRNA expression was not altered in patients with NAFLD or diabetes compared to healthy control subjects [101, 106]. Finally, another study reported that BSEP mRNA levels were elevated in lean NAFLD patients but reduced in overweight or obese patients with steatosis or NASH [94], indicating that body weight of the patients influences the expression of BSEP under the NAFLD condition. Taken together, it can be cautiously concluded that BSEP expression was largely decreased in patients with NAFLD. The alterations BSEP expression may be influenced by the body weight of the patients.
4.1.2 NTCP
Three clinical studies showed that NTCP mRNA expression levels were significantly upregulated in patients with NAFLD compared to control subjects [88, 101, 94]. However, a different study reported that NTCP mRNA expression was significantly decreased as NAFLD progressed from earlier stage (steatosis) to late stage (NASH) [122]. On the other hand, one study reported that the mRNA levels of NTCP were significantly increased in patients with NASH compared to patients with simple steatosis. However, at the protein level, NTCP expression was significantly reduced in the patients with NASH compared to patients with simple steatosis [127], indicating the dominance of post-transcriptional regulation of NTCP under the NASH condition. Another study with diabetic patients reported that NTCP mRNA expression levels were comparable between diabetic patients and control subjects [106]. In summary, NTCP expression was likely upregulated in NAFLD patients with certain inconsistency.
4.1.3 MRPs
In one study with NAFLD and one study with diabetic patients, MRP2 mRNA expression levels were not significantly altered in NAFLD and diabetic patients compared to control subjects [88, 106]. Another study reported that MRP2 mRNA expression levels were decreased as the NAFLD progressed from steatosis to NASH [122]. Supporting MRP2’s role in NAFLD, it was found that a polymorphism in MRP2 was significantly associated with NAFLD [128]. Currently, there is only one study investigating the expression levels of MRP3 in patients with NAFLD. The MRP3 mRNA expression levels were significantly elevated in patients with NAFLD, especially with NASH, compared to the healthy control subjects [94]. In another study with diabetic patients, MRP3 and MRP4 expression levels were not significantly altered in diabetic patients compared to control subjects [106]. Taken together, the results from limited studies suggest that MRP3 and MRP4 were upregulated in patients with NAFLD, while the effects of NAFLD on MRP2 expression were minimal.
4.1.4 OATPs
There is currently only one study investigating the expression of OATPs in patients with NAFLD. Both OATP1B1 and OATP1B3 mRNA expression levels were significantly upregulated in patients with NAFLD compared to control subjects [101]. In a different study with diabetic patients, the expression levels of OATP1B1 were comparable in diabetic patients compared to control subjects [106]. Therefore, it can be cautiously concluded that OATP1B1 and OATP1b3 expression were largely induced in patients with NAFLD.
4.2 Alterations in bile acid transporters in NAFLD animal models
4.2.1 Bsep
Several studies have investigated the effects of NAFLD on Bsep expression in rodents. In one study with HFD/STZ-induced NAFLD rats, the Bsep mRNA levels were significantly downregulated in NAFLD rats compared to control rats [125], indicating reducing biliary excretion of bile acids in HFD/STZ-induced NAFLD rats. However, in two other studies with MCD-induced NAFLD rats and mice, the mRNA expression levels of Bsep were not altered in NAFLD rats or mice [126, 117]. Consistently, a study with obese zucker rats showed that Bsep expression was not significantly altered in obese ZR rats compared to control rats [129]. In another study with obese ZR rats, the expression levels of Bsep mRNA were significantly decreased in obese ZR rats, while Bsep protein levels detected by Western blot as well as immunohistochemistry were comparable between obese ZR rats and lean control rats [130]. In another study with ob/ob mice, the expression levels of Bsep mRNA were significantly increased in ob/ob mice compared to lean control mice. However, in contrast to the mRNA levels, Bsep protein levels were significantly decreased in ob/ob mice when compared to lean control mice [118]. Consistent with decreased Bsep expression in NAFLD mice, overexpression of Bsep increases hepatobiliary lipid secretion and reduces hepatic steatosis [131]. Taken together, Bsep expression was either not altered or decreased in NAFLD rodent models.
4.2.2 Ntcp
Currently, there are six studies evaluating the effects of NAFLD on Ntcp expression in rodents. In three studies, the expression levels of Ntcp were consistently decreased in animals with NAFLD compared to control animals [117, 125, 132]. Two studies were conducted in rats, while one study was carried out in mice. The common feature among the three studies is that NAFLD was induced by MCD for 8 weeks. In the same study [132], Ntcp expression levels were also significantly decreased when NAFLD was induced by HFD. On the other hand, another two studies with rats showed the Ntcp expression was not altered under the NAFLD condition [126, 130]. Different effects of NAFLD on Ntcp mRNA and protein expression were reported in a study with ob/ob mice [118]. The expression levels of Ntcp mRNA were not changed in ob/ob mice compared to the lean control mice. However, Ntcp protein levels were significantly lower in ob/ob mice than those in lean control mice. Taken together, the effects of NAFLD on Ntcp expression were largely consistent among the six studies, either no significant changes or decreased dependent on the species and methods by which NAFLD was induced.
4.2.3 Mrps
The effects of NAFLD on Mrp expression were extensively investigated mainly due to the fact that Mrps are important transporters for xenobiotics including drugs. Data from eight studies evaluating Mrp2 expression in NAFLD rodents are not consistent. Two studies with obese ZR rats reported consistent results that the expression levels of Mrp2 mRNA and protein were significantly downregulated in obese ZR rats compared to lean control rats [129, 130]. Consistent with downregulation of Mrp2 in obese zucker rats, Mrp2 expression levels were reduced in MCD-induced NAFLD rats compared to control rats on supplemented MCD [126]. On the other hand, other two studies showed that Mrp2 expression levels were not significantly altered in MCD-induced NAFLD rats or HFD/STZ-induced NAFLD mice compared to the control rats or mice [117, 125]. In a study with ob/ob mice, Mrp2 expression levels were significantly increased at the mRNA level but decreased at the protein level [118]. In contrast, the mRNA levels of Mrp2 were decreased but protein levels were increased in MCD-induced NAFLD rats [132]. In a comprehensive study to evaluate various NAFLD models with mice and rats, Mrp2 expression was significantly increased in athrogenic diet and MCD-induced NAFLD rats and all four types of NAFLD mouse models when compared to the corresponding control rats or mice. At the protein level, Mrp2 expression was only increased in MCD-induced NAFLD rats [133]. Compared with Mrp2, the data for the effects of NAFLD on the expression of Mrp3 and Mrp4 are more consistent among the studies. Mrp3 and/or Mrp4 expression were significantly upregulated in five studies with NAFLD rats or mice [117, 124, 126, 118, 133]. On the other hand, another three studies with HFD/STZ-induced NAFLD rats or obese ZR rats reported that the expression levels of Mrp3 and/or Mrp4 were not altered in NAFLD or obese ZR rats compared to the controls [125, 129, 130].
In summary, the effects of NAFLD on Mrp2 expression were inconsistent or even conflicting. The discrepancy between Mrp2 mRNA and protein levels was also noted in the studies, indicating that post-transcriptional regulation plays an important role in regulating Mrp2 expression under the NAFLD condition. On the other hand, the expression of Mrp3 and Mrp4 was largely upregulated in NAFLD rodent models.
4.2.4 Oatps
Currently, there are seven studies evaluating the effects of NAFLD on the expression of Oatps. The expression levels of Oatp1a1 mRNA and/or protein were consistently decreased in six studies [117, 118, 125, 129, 132, 133], while one study showed no changes [126]. There are three studies investigating Oatp1a4. In one study, the expression levels of Oatp1a4 were significantly reduced at both mRNA and protein levels in ob/ob mice compared to lean control mice [118]. In another study, the expression levels of Oatp1a4 mRNA were increased but its protein levels were decreased in various mouse and rat NAFLD models compared to the corresponding control mice or rats [133]. On the other hand, no alterations in Oatp1a4 expression were detected in MCD-induced NAFLD rats [126]. The effects of NAFLD on the expression of Oatp1b2 were very much consistent among the five studies. Oatp1b2 expression was significantly downregulated in four studies [117, 126, 132, 133], while no alterations in Oatp1b2 expression were detected in one study [125]. There are three studies investigating Oatp2b1. One study with ob/ob mice reported that Oatp2b1 mRNA levels were significantly upregulated in ob/ob mice compared to the lean control mice [118]. However, other two studies showed that Oatp2b1 was downregulated in obese ZR rats compared to lean control rats [129, 132]. Taken together, Oatp1a1 and Oatp1b2 were consistently downregulated, while the effects on Oatp1a4 and Oatp2b1 were inconsistent in NAFLD rodents.
5. Alterations in bile acid regulators in subjects with NAFLD
Bile acid synthesis is tightly regulated by multiple signaling pathways, mainly the FXR/SHP [134, 135] and FGF19/FGFR4 [136, 137] negative feedback loops (Figure 2). In the liver, activation of FXR by bile acids induces SHP expression, which in turn represses CYP7A1 expression, leading to reduced bile acid synthesis. In the intestine, activation of FXR by bile acids upregulates FGF19 (FGF15 in rodents). After entering the circulation, FGF19 binds to FGFR4 in the liver to activate the downstream signaling, which subsequently inhibits CYP7A1 expression, resulting in decreased bile acid synthesis. Those two negative feedback regulatory loops play critical roles in regulating bile acid synthesis and maintaining bile acid homeostasis. Impairment or dysregulation of the FXR/SHP and FGF19/FGFR4 signaling pathways interrupts bile acid balance.
5.1 FXR/SHP signaling pathway
5.1.1 In human
Most of the human clinical studies revealed that the FXR/SHP signaling pathway was dysregulated in patients with NAFLD. In one study with 10 healthy controls, 39 steatotic, and 59 NASH patients, both FXR and SHP mRNA levels were significantly downregulated [94]. In two studies with 20 or 11 normal control subjects and 20 NAFLD or 16 NASH patients, the expression levels of FXR were significantly deceased in NAFLD or NASH patients compared to control subjects [101, 138]. However, the expression levels of SHP remain comparable between the control subjects and NAFLD or NASH patients, indicating that the FXR signaling is impaired in NAFLD or NASH patients [101, 138]. In a study with 33 children (19 NAFLD patients and 14 control children), the FXR protein levels were gradually decreased from control subjects to steatotic to NASH patients, indicating the worsening of FXR signaling as NAFLD progresses [139]. Consistently, in a study with 20 simple steatosis and 20 NASH patients, the FXR protein expression levels were significantly decreased in NASH patients compared to the patients with simple steatosis, although at the mRNA level, FXR expression was higher in patients with NASH than those in patients with simple steatosis [127]. On the other hand, in one study with 26 controls and 32 NASH patients, no differences were detected in the expression of both FXR and SHP between control and NASH subjects [91]. Finally, one study showed gender differences in FXR expression. A significant decrease in FXR expression was detected in female but not male NASH patients compared to control subjects, while SHP expression was significantly decreased in both male and female with NASH [122]. In summary, most of the studies revealed a decreased or impaired FXR signaling in patients with NAFLD, and such impairment gets worsening as NAFLD progresses from simple steatosis to NASH.
5.1.2 In rodent NAFLD models
Inconsistent results have been reported regarding the status of FXR signaling in NAFLD rodent models. In two studies with HFD or fructose-induced NAFLD mice, the FXR expression levels were significantly reduced in NAFLD mice compared to control mice [124, 140]. However, SHP expression remained unchanged in fructose-induced NAFLD mice while significantly increased in HFD-induced NAFLD mice. In another two studies with HFD/STZ or MCD-induced NAFLD rats, the FXR expression levels remained comparable between the NAFLD and control rats [125, 126]. Consistent with no changes in FXR expression, SHP expression was comparable between the two groups. In another study with ob/ob mice, FXR mRNA and protein were significantly increased in ob/ob mice compared to lean control mice, while no alterations in SHP expression was detected [118]. Finally, in a study with HFD-induced NAFLD mice, the FXR signaling status was investigated during the progression of NAFLD from simple steatosis to NASH, fibrosis, and hepatocellular carcinoma (HCC) on an HFD [141]. FXR signaling was strongly activated in the early stage of NAFLD (simple steatosis) evidenced by strong upregulation of FXR target genes including Bsep, Mrp2, and ATP-binding cassette subfamily G member 5 (Abcg5)/Abcg8. However, as NAFLD progressed, FXR signaling gradually decreased but was still higher than that in the control mice on regular diet. Taken together, the inconsistent results from the NAFLD rodent models indicate that the effects of NAFLD on the FXR signaling pathway are dependent on the methods by which NAFLD is induced as well as the species (mouse or rat).
5.2 FGF19/FGFR4 signaling pathway
A large number of clinical studies have demonstrated that the FGF19 signaling is dysregulated in patients with NAFLD. Serum FGF19 concentrations were significantly reduced in patients with simple steatosis or NASH compared to control subjects [88, 92, 101, 102, 139, 142, 143, 144]. The decreases in FGF19 concentrations were more severe in patients with NASH than the patients with steatosis, indicating the worsening of FGF19 signaling impairment as the NAFLD progresses from simple steatosis to NASH. On the other hand, there are two clinical studies showing that the fasting serum concentrations of FGF19 were not altered in patients with NAFLD compared to control subjects [107, 145]. Taken together, most of the clinical studies showed that the FGF19 signaling was reduced or impaired in patients with NAFLD.
6. Conclusions
A large body of evidence from clinical as well as preclinical studies has demonstrated that bile acid homeostasis is disrupted in subjects with NAFLD. The dysregulation of bile acids in patients with NAFLD gets worsening as the disease progresses from early stage simple steatosis to late stages NASH and NASH with fibrosis. Risk factors for NAFLD, especially obesity and insulin resistance, contribute to the dysregulation of bile acids in NAFLD patients.
Due to the complexity of bile acid regulation, small sample sizes in most of the clinical studies, variations in control subject selection, inherited differences in various rodent NAFLD models, and discrepancy in mRNA and protein levels of the target genes, inconsistent or even conflicting results, have been reported for serum and hepatic bile acid concentrations and compositions, as well as the expression levels of bile acid synthesis enzymes, transporters, and regulators. However, detailed examination and evaluation of the results from various studies, especially considering the characteristics of the studied subjects and the quality of each study, certain trends on alterations in serum and hepatic bile acid levels, bile acid synthesis, and regulation in patients with NAFLD are emerged.
As depicted in Figure 3, serum total bile acid concentrations are increased in patients with NAFLD, as a result of increased CYP7A1 expression and bile acid synthesis, elevated hepatic bile acids, and augment of MRP3 and MRP4 expression. Increased CYP7A1 expression and bile acid synthesis in patients with NAFLD are mainly due to the impairment of the FXR/SHP and FGF19/FGFR4 signaling pathways. Limited studies on investigating fecal and urine bile acids showed that both fecal and urine bile acid concentrations were elevated in patients with NAFLD, consistent with increased serum and hepatic bile acid levels in those patients.
Figure 3.
Effects of NAFLD on serum, hepatic, and fecal bile acid concentrations as well as on bile acid synthesis (CYP7A1), transporters (MRP3 and MRP4), and regulators (FXR, SHP, FGF19/15).
7. Guidance for future studies
Future studies with high quality and large sample size are needed to solidify the trends depicted in Figure 3. The following points should be considered in the design of the future studies and interpretation of the findings. First, limited studies with children and adolescents revealed a different feature in bile acid dysregulation from adults with NAFLD. In contrast to the findings in adults, serum bile acid levels decrease in the early stage of NAFLD, followed by an increase as NAFLD progresses to fibrosis but the levels remain lower than those in the healthy control children. The effects of NAFLD on bile acid regulation appear different in children from adults. Second, the effects of NAFLD on bile acid homeostasis are stage dependent. No or mild effects of simple steatosis on bile acid regulation were detected, while significant alterations in bile acids are mostly detected in patients with NASH. A large percentage of previous studies did not separate the steatotic and NASH patients in the test groups, which certainly complicates the analysis and interpretation of data. Third, as risk factors for NAFLD, obesity and insulin resistance/diabetes are often associated with NAFLD. It is well documented that obesity and insulin resistance directly cause dysregulation of bile acids. Therefore, those risk factors should be adjusted or matched in the control group in order to reveal the exact effects of NAFLD on bile acid homeostasis. Among the clinical studies reported, only one study was conducted with a matched control group, in which a different conclusion was reached that NASH has no effects on bile acid regulation [93]. Fourth, in future studies using NAFLD rodent models, it should be emphasized that species differences between rodents and human and even between mouse and rat exist, especially in the effects of NAFLD on bile acid transporter expression. Finally, in the investigation of gene expression, both mRNA and protein levels should be detected and quantified for the target genes. Most of the previous studies only evaluated the mRNA levels. However, discrepancy between the mRNA and protein levels is often detected in studies investigating both levels. It appears that under the NAFLD condition, posttranscriptional regulation plays a predominant role in regulating the genes involved in bile acid synthesis, transport, and regulation.
Acknowledgments
This work was supported by the National Institutes of Health (NIH) Grants R01DK087755, R01CA213419 and R01GM061988.
Conflict of interest
The authors have no conflict of interest.
\n',keywords:"NAFLD, steatosis, fatty liver, NASH, bile acids, FXR, bile acid synthesis, enterohepatic circulation, bile acid transporters, FGF19",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/63978.pdf",chapterXML:"https://mts.intechopen.com/source/xml/63978.xml",downloadPdfUrl:"/chapter/pdf-download/63978",previewPdfUrl:"/chapter/pdf-preview/63978",totalDownloads:1430,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 12th 2018",dateReviewed:"September 12th 2018",datePrePublished:"November 5th 2018",datePublished:"November 20th 2019",dateFinished:"October 9th 2018",readingETA:"0",abstract:"Bile acids are synthesized in the liver and tightly regulated through the enterohepatic circulation. Recent studies reveal that bile acids serve as hormone-like signaling molecules to activate nuclear receptors, notably farnesoid X receptor (FXR), regulating metabolic homeostasis of bile acids, cholesterol, lipids, and glucose. A connection between bile acids and nonalcoholic fatty liver disease (NAFLD) has long been recognized. Although inconsistent or even contradictory results are reported, a large body of evidence from clinical as well as preclinical studies demonstrates that bile acid homeostasis is disrupted in patients with NAFLD. The bile acid dysregulation gets worsening as NAFLD progresses from early stage simple steatosis to late stage nonalcoholic steatohepatitis (NASH) and NASH with fibrosis. As the risk factors for NAFLD, obesity and insulin resistance, which are often associated with NAFLD, contribute to the dysregulation of bile acids in patients with NAFLD. Total serum and fecal bile acid concentrations are mostly elevated in patients with NAFLD as a result of increased bile acid synthesis, elevated hepatic bile acids, and upregulation of bile acid transporters. The two negative feedback regulatory pathways for bile acid synthesis, FXR/SHP (small heterodimer partner) and fibroblast growth factor-19 (FGF19)/FGF receptor-4 (FGFR4), are impaired in patients with NAFLD.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/63978",risUrl:"/chapter/ris/63978",signatures:"Xinmu Zhang and Ruitang Deng",book:{id:"8330",type:"book",title:"Nonalcoholic Fatty Liver Disease",subtitle:"An Update",fullTitle:"Nonalcoholic Fatty Liver Disease - An Update",slug:"nonalcoholic-fatty-liver-disease-an-update",publishedDate:"November 20th 2019",bookSignature:"Emad Hamdy Gad",coverURL:"https://cdn.intechopen.com/books/images_new/8330.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83962-870-2",printIsbn:"978-1-83962-869-6",pdfIsbn:"978-1-83962-871-9",isAvailableForWebshopOrdering:!0,editors:[{id:"222727",title:"Associate Prof.",name:"Emad Hamdy",middleName:null,surname:"Gad",slug:"emad-hamdy-gad",fullName:"Emad Hamdy Gad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"262784",title:"Prof.",name:"Ruitang",middleName:null,surname:"Deng",fullName:"Ruitang Deng",slug:"ruitang-deng",email:"dengr@uri.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"271586",title:"Dr.",name:"Xinmu",middleName:null,surname:"Zhang",fullName:"Xinmu Zhang",slug:"xinmu-zhang",email:"xmzhang@uri.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Altered bile acid profiles in subjects with NAFLD",level:"1"},{id:"sec_2_2",title:"2.1 Altered bile acid profiles in patients with NAFLD",level:"2"},{id:"sec_2_3",title:"Table 1.",level:"3"},{id:"sec_2_4",title:"Table 1.",level:"4"},{id:"sec_3_4",title:"Table 2.",level:"4"},{id:"sec_5_3",title:"2.1.2 Hepatic bile acids",level:"3"},{id:"sec_6_3",title:"2.1.3 Fecal and urine bile acids",level:"3"},{id:"sec_8_2",title:"2.2 Altered bile acid profiles in NAFLD animal models",level:"2"},{id:"sec_10",title:"3. Alterations in bile acid synthesis in subjects with NAFLD",level:"1"},{id:"sec_10_2",title:"3.1 Alterations in bile acid synthesis in patients with NAFLD",level:"2"},{id:"sec_10_3",title:"3.1.1 CYP7A1",level:"3"},{id:"sec_11_3",title:"3.1.2 CYP27A1",level:"3"},{id:"sec_12_3",title:"3.1.3 Other enzymes",level:"3"},{id:"sec_13_3",title:"3.1.4 C4",level:"3"},{id:"sec_15_2",title:"3.2 Alterations in bile acid synthesis in NAFLD animal models",level:"2"},{id:"sec_17",title:"4. Alterations in bile acid transporters in subjects with NAFLD",level:"1"},{id:"sec_17_2",title:"4.1 Alterations in bile acid transporters in patients with NAFLD",level:"2"},{id:"sec_17_3",title:"4.1.1 BSEP",level:"3"},{id:"sec_18_3",title:"4.1.2 NTCP",level:"3"},{id:"sec_19_3",title:"4.1.3 MRPs",level:"3"},{id:"sec_20_3",title:"4.1.4 OATPs",level:"3"},{id:"sec_22_2",title:"4.2 Alterations in bile acid transporters in NAFLD animal models",level:"2"},{id:"sec_22_3",title:"4.2.1 Bsep",level:"3"},{id:"sec_23_3",title:"4.2.2 Ntcp",level:"3"},{id:"sec_24_3",title:"4.2.3 Mrps",level:"3"},{id:"sec_25_3",title:"4.2.4 Oatps",level:"3"},{id:"sec_28",title:"5. Alterations in bile acid regulators in subjects with NAFLD",level:"1"},{id:"sec_28_2",title:"5.1 FXR/SHP signaling pathway",level:"2"},{id:"sec_28_3",title:"5.1.1 In human",level:"3"},{id:"sec_29_3",title:"5.1.2 In rodent NAFLD models",level:"3"},{id:"sec_31_2",title:"5.2 FGF19/FGFR4 signaling pathway",level:"2"},{id:"sec_33",title:"6. Conclusions",level:"1"},{id:"sec_34",title:"7. Guidance for future studies",level:"1"},{id:"sec_35",title:"Acknowledgments",level:"1"},{id:"sec_38",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011;140:124-131. DOI: 10.1053/j.gastro.2010.09.038'},{id:"B2",body:'Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. DOI: 10.1002/hep.28431'},{id:"B3",body:'Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388-1393. 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Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
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Nevertheless, in most cases, after a very short useful life, these products become waste material and contribute to environmental degradation. This situation has created an environmental crisis that has reached global proportions. In efforts to combat this issue and to promote sustainable development and reduce environmental pollution, some investigations have focused on recycling using innovative and clean technologies, such as gamma radiation, as an alternative to conventional mechanical and chemical recycling procedures. In this context, the reuse and recycling of waste materials and the use of gamma radiation are useful tools for improving the mechanical properties of concrete; for example, the compressive strength and modulus of elasticity are improved by the addition of waste particles and application of gamma radiation. In this chapter, we propose the use of gamma radiation as a method for modifying waste materials; for instance, polyethylene terephthalate plastic bottles, automotive tire rubber, and the cellulose in Tetra Pak containers, and their reuse to enhance the properties of concrete.",signatures:"Gonzalo Martínez-Barrera, Liliana Ivette Ávila-Córdoba, Miguel\nMartínez-López, Eduardo Sadot Herrera-Sosa, Enrique Vigueras-\nSantiago, Carlos Eduardo Barrera-Díaz, Fernando Ureña-Nuñez and\nNelly González-Rivas",authors:[{id:"102080",title:"Dr.",name:"Gonzalo",surname:"Martínez-Barrera",fullName:"Gonzalo Martínez-Barrera",slug:"gonzalo-martinez-barrera",email:"gonzomartinez02@yahoo.com.mx"},{id:"110214",title:"Dr.",name:"Fernando",surname:"Ureña-Nuñez",fullName:"Fernando Ureña-Nuñez",slug:"fernando-urena-nunez",email:"fernando.urena@inin.gob.mx"},{id:"177864",title:"Dr.",name:"Liliana Ivette",surname:"Ávila-Córdoba",fullName:"Liliana Ivette Ávila-Córdoba",slug:"liliana-ivette-avila-cordoba",email:"liac07@gmail.com"},{id:"177865",title:"Dr.",name:"Miguel",surname:"Martínez-López",fullName:"Miguel Martínez-López",slug:"miguel-martinez-lopez",email:"oroshi_mml@hotmail.com"},{id:"177866",title:"Dr.",name:"Eduardo",surname:"Sadot Herrera-Sosa",fullName:"Eduardo Sadot Herrera-Sosa",slug:"eduardo-sadot-herrera-sosa",email:"sadoths@yahoo.com.mx"},{id:"177867",title:"Dr.",name:"Enrique",surname:"Vigueras-Santiago",fullName:"Enrique Vigueras-Santiago",slug:"enrique-vigueras-santiago",email:"enriquevigueras@yahoo.com.mx"},{id:"177868",title:"Dr.",name:"Carlos Eduardo",surname:"Barrera-Díaz",fullName:"Carlos Eduardo Barrera-Díaz",slug:"carlos-eduardo-barrera-diaz",email:"cbd0044@yahoo.com"},{id:"177869",title:"Dr.",name:"Nelly",surname:"González-Rivas",fullName:"Nelly González-Rivas",slug:"nelly-gonzalez-rivas",email:"nelymagr@gmail.com"}],book:{id:"4604",title:"Evolution of Ionizing Radiation Research",slug:"evolution-of-ionizing-radiation-research",productType:{id:"1",title:"Edited Volume"}}},{id:"56947",title:"Waste and Recycled Textiles as Reinforcements of Building Materials",slug:"waste-and-recycled-textiles-as-reinforcements-of-building-materials",abstract:"Currently, the use of composite materials in the construction areas has had a great impact on the society; mainly, those related with sustainability and environment aspects. Daily proposals aimed at overcoming the properties of traditional materials that arise, which include emergent materials either from waste or recycled products. One of them is related to the textile materials, which include fibers such as wool, hemp, linen, and cotton. In the past decade, special attention has been focused on the used clothes, which represent a source of raw materials environmentally responsible and economically profitable. Textile materials are discarded daily around the world, representing approximately 1.5% of the generated waste. Blue jeans are the most used clothing in the world, and they are elaborated by one of the most commonly used natural textile fibers—cotton. Textile materials have been reused in different applications, for example, in the production of poor-quality wires, crushed to manufacture noise and temperature insulation materials, and as fillers or reinforcements of concrete. In this chapter, different topics are described that include: (a) environmental impact of textile waste—a result of massive consumption of clothing, (b) recycling and reuse of textile waste, and (c) waste and recycled textile materials used as building materials.",signatures:"Patricia Peña Pichardo, Gonzalo Martínez-Barrera, Miguel Martínez-\nLópez, Fernando Ureña-Núñez and Liliana I. 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He received a Ph.D from Kyoto University in 1992 for the study on induced accumulation of polyubiquitin gene transcripts after exposure to ultraviolet light and treatment with 12-O-Tetradecanoylphorbol 13-acetate. In 1991, he stayed at University of Cincinnati College of Medicine, USA as a visiting scientist, and was involved in the study of mechanisms for transcriptional regulation of small heat shock genes of Drosophila. Dr. Nenoi is now a Director, Radiation Risk Reduction Research Program, Research Center for Radiation Protection of NIRS. His research interest is radiation biology, especially on the mechanism for gene regulation after exposure to ionizing radiation.",institutionString:null,institution:{name:"National Institute of Radiological Sciences",institutionURL:null,country:{name:"Japan"}}},{id:"91936",title:"Dr.",name:"Bing",surname:"Wang",slug:"bing-wang",fullName:"Bing Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Institute of Radiological Sciences",institutionURL:null,country:{name:"Japan"}}},{id:"99609",title:"Prof.",name:"Ernesto",surname:"Lamanna",slug:"ernesto-lamanna",fullName:"Ernesto Lamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99609/images/718_n.png",biography:"The teaching and academic activities of Prof. Ernesto Lamanna were carried out: from 1980 to 1998 as Researcher of Nuclear Physics at the Physics Department, University of Rome \\La Sapienza\\ from 1998 to 2003; as Associate Professor of Nuclear Physics at the Department of Physics, University of Calabria; from 2004 as Full Professor of Physics Applied to Medicine in the Faculty of Medicine and Surgery, University Magna Graecia of Catanzaro.\nThe scientific activity of Prof. Ernesto Lamanna was carried out inside the research activities of the \\'Institute of Nuclear Physics’ since 1976 to the study of sub-nuclear particles and their use for the knowledge of the microcosm (experiments at the European Center for Nuclear Research, CERN, and the Stanford Linear Accelerator Center, SLAC), to the knowledge of the macrocosm (astro-particle at the Gran Sasso Laboratories), to diagnostics and therapy in Medical Physics since 1998.\nHe is currently working on:\n• completing a research project under the National Institute of Nuclear Physics (DOSIORT) for the construction of a scintillating fiber dosimeter for the dosimetry of electron beams at high intensity as those produced by accelerators dedicated to IORT;\n• conducting a feasibility study of hadron beams for hadron therapy and for the production of thermal and epithermal beams for BNCT therapy;\n• working on a low radiation tomograph for the study of defects due to the variation of small anatomic components in the inner ear;\n• researching the most effective approaches for teaching the physics applied to the medicine ;\n\nMain technologies used in scientific work in which he has acquired skills:\nDosimetry (Dosimetry internal, external, and characterization of therapeutic beams);\nVisualization detectors (nuclear emulsions, bubble chamber; scintillating microfibers);\nCalorimetry detectors (Uranium calorimeter, plastics scintillator, liquid scintillator, scintillating fibers);\nElectronic tracer detectors (proportional, drift and streamer chambers; drift tubes);\nData Acquisition (Design and production of data acquisition systems, reconstruction and management online of images);\nData analysis (Simulation of hadronic and weak interactions; simulation of experimental apparatus; simulation of drift chambers; spatial reconstruction, offline image reconstruction);\nParticle Accelerators (Experiments in which he participated, except the passive experiment MACRO, were carried out using particle beams).",institutionString:null,institution:{name:"Magna Graecia University",institutionURL:null,country:{name:"Italy"}}},{id:"103129",title:"Ms.",name:"Kaoru",surname:"Tanaka",slug:"kaoru-tanaka",fullName:"Kaoru Tanaka",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"103130",title:"Dr.",name:"Yasuharu",surname:"Ninomiya",slug:"yasuharu-ninomiya",fullName:"Yasuharu Ninomiya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"103131",title:"Dr.",name:"Kouichi",surname:"Maruyama",slug:"kouichi-maruyama",fullName:"Kouichi Maruyama",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"104912",title:"Dr.",name:"Lidia",surname:"Strigari",slug:"lidia-strigari",fullName:"Lidia Strigari",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/104912/images/2892_n.png",biography:null,institutionString:null,institution:{name:"Istituti Fisioterapici Ospitalieri",institutionURL:null,country:{name:"Italy"}}},{id:"173416",title:"Dr.",name:"Takanori",surname:"Katsube",slug:"takanori-katsube",fullName:"Takanori Katsube",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"176144",title:"Prof.",name:"Cataldo",surname:"Bianco",slug:"cataldo-bianco",fullName:"Cataldo Bianco",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"176146",title:"Dr.",name:"Giulia",surname:"Marvaso",slug:"giulia-marvaso",fullName:"Giulia Marvaso",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"compacts",title:"IntechOpen Compacts",intro:"
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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. 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\r\n\tThe Business and Management series topic focuses on the most pressing issues confronting organizations today and in the future. Businesses are trying to figure out how to lead in a time of global uncertainty. In emerging markets, issues such as ill-defined or unstable policies, as well as corrupt practices, can be hugely problematic. Changes in governments can result in new policy, regulations, and interest rates, all of which can be detrimental to foreign businesses and investments. A growing trend towards economic nationalism also makes the current global political landscape potentially hostile towards international businesses.
\r\n
\r\n\tThe demographic shifts are creating interesting challenges. People are living longer, resulting to an aging demographic. We have a large population of older workers and retirees who are living longer lives, combined with a declining birthrate in most parts of the world. Businesses of all types are looking at how technology is affecting their operations. Several questions arise, such as: How is technology changing what we do? How is it transforming us internally, how is it influencing our clients and our business strategy? It is about leveraging technology to improve efficiency, connect with customers more effectively, and drive innovation. The majority of innovative companies are technology-driven businesses. Realizing digital transformation is today’s top issue and will remain so for the next five years. Improving organizational agility, expanding portfolios of products and services, creating, and maintaining a culture of innovation, and developing next -generation leaders were also identified as top challenges in terms of both current and future issues.
\r\n
\r\n\tThe most sustained profitable growth occurs when a company expands its core business into an adjacent space. This has significant implications for management because innovation in business ecosystems differs from traditional, vertically integrated firms. Every organization in the ecosystem must be aware of the bigger picture. Innovation in ecosystems necessitates collaborative action to invent and appraise, efficient, cross-organizational knowledge flows, modular architectures, and good stewardship of legacy systems. It is built on multiple, interconnected platforms. Environmental factors have already had a significant impact in the West and will continue to have an impact globally. Businesses must take into account the environmental impact of their daily operations. The advantage of this market is that it is expected to grow more rapidly than the overall economy. Another significant challenge is preparing the next generation of leaders to elevate this to the number one priority within the next five years. There can be no culture of innovation unless there is diverse leadership or development of the next generation of leaders; and these diverse, next-generation leaders are the ones who will truly understand the digital strategies that will drive digital transformation.
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