Macronutrient concentration of human milk and cow milk.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art novel imaging techniques by focusing on the most important evidence-based developments in this area.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"d9159ce31733bf78cc2a79b18c225994",bookSignature:"Dr. Gabriel Cismaru",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11867.jpg",keywords:"Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy, Restrictive Cardiomyopathy, Transesophageal Echocardiography, Intracardiac Echocardiography, 3-Dimensional Echocardiography, Adult Congenital Heart Disease, Tetralogy of Fallot, Transposition of the Great Vessels, Coronary Artery Disease, Risk Stratification, Revascularization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 21st 2022",dateEndSecondStepPublish:"May 19th 2022",dateEndThirdStepPublish:"July 18th 2022",dateEndFourthStepPublish:"October 6th 2022",dateEndFifthStepPublish:"December 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Cismaru Gabriel is an Assistant Professor at the University of Medicine and Pharmacy Cluj-Napoca, certified in Cardiology. After completing his certification in cardiology, Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu. He has authored or co-authored peer-reviewed articles and book chapters in the field of cardiac pacing, defibrillation, electrophysiological study, and catheter ablation.",coeditorOneBiosketch:"Raluca Tomoaia is an MD, Ph.D. in novel techniques in Echocardiography at the University of Medicine and Pharmacy in Cluj-Napoca, Romania., assistant professor, and a researcher in echocardiography and cardiovascular imaging.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"191888",title:"Dr.",name:"Gabriel",middleName:null,surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru",profilePictureURL:"https://mts.intechopen.com/storage/users/191888/images/system/191888.png",biography:"Dr. Cismaru Gabriel is an assistant professor at the Cluj-Napoca University of Medicine and Pharmacy, Romania, where he has been qualified in cardiology since 2011. He obtained his Ph.D. in medicine with a research thesis on electrophysiology and pro-arrhythmic drugs in 2016. Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, France, after finishing his cardiology certification with stages in Clermont-Ferrand and Dinan, France. He began working at the Rehabilitation Hospital\\'s Electrophysiology Laboratory in Cluj-Napoca in 2011. He is an experienced operator who can implant pacemakers, CRTs, and ICDs, as well as perform catheter ablation of supraventricular and ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation. He has been qualified in pediatric cardiology since 2022, and he regularly performs device implantation and catheter ablation in children. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"58668",title:"Bioactive Components of Human Milk: Similarities and Differences between Human Milk and Infant Formula",doi:"10.5772/intechopen.73074",slug:"bioactive-components-of-human-milk-similarities-and-differences-between-human-milk-and-infant-formul",body:'\nMilk and dairy product are considered a main part of the healthy and balanced diet [1]. In this context, human milk is the most appropriate choice for feeding newborns and provides all the energy and nutrients needed to ensure proper growth and development [2]. Furthermore, human milk provides a large group of functional components which improve the newborn health, increase the immunity, and protect against the gastrointestinal and respiratory infections [3]. So, it was noted that breastfed infants suffer less gastrointestinal disorders and respiratory infections rather than formula-fed infants [4]. The exclusive breastfeeding pattern during the first 6 months of life was recommended by various health and breastfeeding organizations such as the American Academy of Pediatricians (AAP) and the American Academy of Family Physicians (AAFP) [5].
\nIt is scientifically accepted that using the nutritional factors may decrease or prevent the extension of these diseases and its implications to the adult life. Nowadays, researchers and health and breastfeeding organizations are trying to discover the precise substances in human milk that seem to supply physiological benefits beyond its normal nutritional value which contribute earlier in delay, treatment or prevent some diseases [6]. Thus, these functional ingredients hold a great promise for future trends in human nutrition. Additionally, the relationship between milk consumption and human health requires a deeper understanding to uncover the protective role of some bioactive compounds, which naturally present in human milk.
\nAlthough human milk is considered the optimal food and supplies all the nutrient and some bioactive components, it is no longer sufficient to meet all the necessary nutritional requirements after 4–6 months of infant life [7]. In this case, infant formulas play an indispensable role in infant feeding. The formulas should be similar to mature human milk regarding its micronutrient and macronutrient contents. During the evolution of infant formulas, the manufacturers should take into account the necessary nutritional requirements of the newborns and infants and enrich the formulas with the functional ingredients which are naturally present in human milk [8]. The aim of this review is to present current knowledge regarding evidence on the importance of breastfeeding, the functionality of selected human milk ingredients, infant formulas as a human milk alternative, and the similarities and differences between human milk and infant formulas.
\nIt is well established that breastfeeding pattern of newborn provides more benefits for both mothers and their babies. It is well documented that breastfeeding not only provides the optimal nutrition [9] but also has many health benefits for both children and their mothers [10]. Breastfeeding pattern is positively associated with maternal sensitivity and with bonding between mother and infant [11]. It helps to build up a safe and full-of-feeling relationship between the mother and her infant and offers numerous other positive advantages. Breastfeeding mothers suffer less from certain serious diseases: reduced risk of certain cancers, including ovarian and breast cancer, type 2 diabetes, delayed resumption of menses, and more rapid postpartum weight loss. So, breastfeeding mothers are likely to be more health conscious, and, therefore, to promote healthy habits, which are likely to prevent overweight and obesity later in childhood [12].
\nOn the other hand, breastfeeding pattern provides the protection against childhood-related diseases. In this regard, breastfed infants showed higher resistance to infectious disease and stronger immune systems, leading to lower rates of chronic diseases as compared to formula-fed infants. The ideal composition of human milk provides nutritional, growth, and developmental advantages to the child [13]. By the way, lower risk of gastrointestinal infection, otitis media, asthma, allergies, respiratory tract infection, type 1 diabetes, and sudden infant death syndrome are observed in breastfed infants. Other benefits include evidence of protection against childhood obesity, which may persist into adulthood, and less cognitive development and behavioral problems in breastfed children compared with children not breastfed [14]. Based on the abovementioned, breastfeeding should be actively recommended and supported as the most preferred method of infant feeding at both nutritionally and healthy states.
\nIt is well established that infancy is the most important stage of human life where newborns are growing with high rate allowing to duplicate the infant weight in only 4–5 months. So, an adequate supply of nutrients represents paramount importance in this early stage of infant life. The breastfeeding of infants is obviously important to provide the needed nutrients and energy for the synthesis and deposition of new tissues from birth until 4–6 months of infant life.
\nThe high metabolic requirements contrast with the limited ability of young infants to compensate for an inadequate supply of nutrients due to the diminished body reserves of nutrients and the immature homeostatic mechanisms. For example, the activity of some metabolic pathways and the kidney’s ability to concentrate the urine are still low during the first 3–4 months of life. Young children may not be able to synthesize sufficient amounts of certain substrates considered as nonessential or dispensable since the limited capacity of the specific metabolic synthesis is not always sufficient to achieve the high requirements. Some nutrients considered nonessential in adults and older children can become indispensable for young infants that would be supplied in the diet [15].
\nIn addition to the immediate consequences of infant feeding on growth, body composition, health, and wellness, a number of recent studies have also provided indications that the quantity and quality in the supply of nutrients during childhood has important long-term consequences in the development and function of the organs, health, and risk of disease as well as in the cognitive ability [16]. Human milk is nowadays universally recognized as the optimal feeding choice for every infant [17] where it contains many nutritional components that are able to conserve his development.
\nThe nutritional components of human milk are classified into two categories: macronutrients and micronutrients [18]. Macronutrients of human milk include protein, fat, and sugar. The concentration of human milk macronutrients differed during the course of lactation and between the mothers as well as differed between term and preterm milk. The latter has a higher content of protein and fat. Generally, the mean macronutrient composition of term mature human milk is presented in Table 1 as compared with cow milk, the most common milk type used in infant formula manufacturing.
\nComponents | \nContent (mg/100 g) | \n|
---|---|---|
Human milk | \nCow milk | \n|
Protein | \n1.2 | \n3.2 | \n
Fat | \n3.7 | \n3.7 | \n
Sugar | \n7 | \n4.9 | \n
Energy (kcal) | \n65 | \n66 | \n
Proteins provide amino acids for growth as well as are presented in the form of polypeptides that facilitate digestion [19], the defense of the guest [20], and other functions [21]. Fats provide energy, but some have antiviral properties [22]. Carbohydrates provide energy and can also stimulate the absorption of minerals [23], and various human milk oligosaccharides (HMOs) play a pivotal role in the microbial intestinal balance. Energy estimates range from 65 to 70 kcal/dL and are highly correlated with the fat content of human milk. Butte et al. [24] also clearly showed that intakes of energy, protein, fat, and carbohydrate were lower in breastfed than in formula-fed infants at 3 and 6 months. The differences in composition between human milk and infant formulas seem to affect the growth pattern between breastfed infants and formula-fed infants [25]. However, no apparent consequences were associated with the lower intake and slower weight gain of breastfed infants where they do not differ in activity level, and they suffer less gastrointestinal and respiratory infections and have higher cognitive development [26].
\nBecause human milk is considered the optimal and first functional food for infant feeding, nowadays, especially in the USA, pasteurized donor milk represents the suitable alternative provided for an infant that is in high risk [28]. However, infant formulas become necessary for infant feeding when human milk is unavailable or the mother cannot breastfeed her infant. So, special efforts are needed to ensure an adequate diet composition in young infants [25].
\nVarious negative consequences are noted with very low- or very high-specific nutrients [29]. For example, cow’s milk is not an ideal food during the first year of life. The ingestion of protein for the infants fed with cow’s milk is higher than that for those fed with human milk, and this leads to overload renal solutes [30]; in addition, a high-protein intake can cause hypercalciuria [31]. On the other hand, high consumption of cow’s milk below the first year of life is one of the most important risk factors for the development of iron deficiency anemia. Cow’s milk is low in iron, and much of that iron is attached to the casein micelles, which interferes with its absorption. Additionally, its low content in vitamin C does not favor the absorption of the little iron that contains [32].
\nOverall, the breastfeeding pattern is the preferred choice of infant nutrition and human milk provides all the nutritional components during 4–6 months of life. It also provides a large group of bioactive components, which play an indispensable role in protecting the infant health.
\nIncreasing evidence currently shows that short- and long-term benefits of human milk feeding are resulted by its content of various components named functional or bioactive components. These functional components involved a large group of several compounds such as protein (such as lactoferrin (Lf)), carbohydrates (especially human milk oligosaccharides), fats (polyunsaturated fatty acids), vitamins, nucleotides, minerals, and immunoglobulins. In this section, the occurrence, variation, and functionality of selected components of human milk are discussed.
\nLactoferrin (Lf) is the second most abundant protein in human milk belonging to the transferrin family [33]. It is a glycoprotein first isolated from cow’s milk and second from human milk [34]. It is well known as the principal iron-binding protein in mammals’ milk [35] and the first-line defense molecule against infections [33]. The highest content of Lf is found in human colostrum (7 g/L), and this content declined after 2 weeks after birth reaching 2–4 g/L of mature human milk [36]. While Lf content in cow colostrum and milk is 10-fold lower [37]. Structurally, Lf is an iron-binding glycoprotein consisting of a single polypeptide chain distributed to two lobes (N and C lobes). Both human Lf and bovine Lf are sharing a sequence homology of about 70%, and their 3D structures (Figure 1) are very similar but not identical [38]. Each lobe of Lf contains an iron-binding site with a high affinity and a glycan-binding site. N and C lobes have very similar conformations but show slight differences in their affinity for iron [39]. Table 2 presents the differences between human and bovine Lf.
\nProtein structure of human Lf. Source: Ref. [
Characteristics | \nHuman Lf | \nBovine Lf | \n
---|---|---|
Molecular weight (kDa) | \n80 | \n77 | \n
Amino acids | \n711 | \n689 | \n
N lobe | \n1–332 | \n1–233 | \n
C lobe | \n344–703 | \n345–689 | \n
α-Helix | \n333–344 | \n334–344 | \n
Due to its distribution in several parts of the body and its involvement in several physiological processes, Lf is considered as a multifunctional protein. Moreover, numerous studies have been carried out to uncover the wide range of activities of Lf and its peptides [42, 43]. Iron absorption enhancement by Lf is one of the most observed activities especially in breastfed as compared to formula-fed infants. In this context, the high affinity of Lf to bind iron is a key characteristic of this beneficial role. Although iron is the main cation bound by Lf, other metals such as Cu2+, Zn2+, and Mn2+ ion can be bound by Lf [44]. Lf exists in three forms, according to its saturation degree with iron: apo-lactoferrin (iron free), mono-ferric form (one ferric iron), and holo-lactoferrin (binds two Fe3+ ions) [45]. Apo-lactoferrin is the secreted form of Lf in human milk where its saturation degree does not exceed 10%, whereas its saturation degree in cow milk is about 20% [46].
\nThe apo-Lf molecule is an open molecule, whereas the holo-Lf is a closed molecule [47]. Thus, apo-Lf is less stable than holo-Lf against gastrointestinal enzymes [48]. In view of this, the stability of Lf against gut enzymes is determined by its degree of saturation with iron. Interestingly, media pH plays a key role in iron release from Lf. So, bovine Lf retains the metal over a wide range of pH and starts to release its iron below pH 4 and at pH 2 iron is completely released, while it starts to release at pH 3 in human Lf [42].
\nAmong the principal factors that influence the iron bioavailability is its distribution in milk where 20–45% of iron in human milk is mainly bound to Lf, while 24% of iron in cow milk is bound to casein micelles [49]. This distribution resulted in a high iron bioavailability from human milk. Moreover, the high iron absorption from human milk was attributed to its high content of Lf. This hypothesis was supported by the discovery of species-specific receptors with high affinity for Lf (Lf receptors) in the enterocytes. This would explain the high bioavailability of iron from human milk, as only human lactoferrin releases iron to the enterocyte by this mechanism [48]. Additionally, Lf can increase the gene expression of divalent metal transporter 1 (DMT1) receptors that may play a central role in enhancing Fe uptake via proton-coupled mechanism [50]. It was also reported that Lf may be useful as a natural solubilizer of iron for food products, and it was suggested that Lf, orally administered, could solubilize ferric Fe in the intestine [51]. The endocytosis, another possible mechanism, was speculated to explain the role of Lf in iron absorption. The enterocytes catch Lf-iron complex through the endocytosis and then release its iron, through Lf degradation, at the intracellular level [52]. The released iron inside the cell is quickly complexed, forming another protein named ferritin, and then, apo-form of Lf comes back again to mucosa surface to catch another iron to start another transport process [53]. Figure 2 shows the possible mechanisms of iron absorption enhancement by Lf.
\nPossible mechanisms and characteristics of Lf associated with Fe bioavailability enhancement.
Overall, Lf is a multifunctional glycoprotein and has a central role in decreasing the gastrointestinal and respiratory infections and protecting the newborn from anemia.
\nHuman milk oligosaccharides (HMOs), the third most abundant component of human milk, are another multifunctional milk ingredient. Its content is higher in colostrum (15–23 g/L) than mature milk, which contains 8–12 g/L [54]. Structurally, human milk contains more than one hundred oligosaccharides with diverse structure and functions. A wide range of activities were reported for HMOs [55]. The prebiotic activity of HMOs has been observed by various studies [54] where it acts as a bifidogenic molecule that improves the beneficial microflora growth. It also provides functional capacity including anti-adhesive and immunomodulators [56].
\nHMOs are nondigestible substances, and this property is the main key to its physiological role. HMOs can survive against the gastrointestinal conditions, digestive enzymes, and pH and thus reach the colon in an intact form where these serve as fermentable substances, leading to improvement in the beneficial bacteria growth and activity [57], preferably Bifidobacteria [58]. The fermentation of prebiotics is accompanied by organic acid production and pH decrease. Hence, prebiotic fermentation may create an environment in the colon that inhibits the growth and activity of pathogens. In addition, prebiotics fermentation may enhance the beneficial bacteria in the colon that can produce various antibacterial factors, leading to pathogen growth inhibition. Additionally, HMOs possess direct activities resulted in pathogen inhibition where it has anti-adhesive effects that reduce or prevent the pathogen biofilm formation through its ability to reduce pathogens binding to colonocytes [59]. Similarly, HMOs also act as receptor analogues to inhibit the adhesion of pathogens on the epithelial surface, and this evidence is seen as a passive defense of the host [60].
\nHMO’s structure and diversity represent another difference among human milk, cow milk, and infant formulas. As well known that human milk is structurally very complex and has huge diversity [61], identical structures are not available for use in infant formulas [62]. Thus, several researchers proposed using oligosaccharides much simpler such as GOS and FOS or that derived from cow milk [63]. Thus, breastfed infants have less gastrointestinal infections and their stools contain more beneficial bacteria,
Nucleotides, another bioactive ingredient of human milk, are nitrogenous compounds which play a main role in various metabolism processes, such as energy transfer, nucleic acid synthesis (DNA and RNA), and carbohydrates, lipids, and proteins synthesis. Nucleotides are found in human milk in free form as ribonucleotides and ribonucleosides accounting 2–5% of nonprotein nitrogen and participate in protein utilization by breastfed infants [35]. Free nucleotide content is higher in human milk than cow milk. Additionally, some related components such as nucleosides, purine and pyrimidine bases, nucleic acids, and products derived from them (such as uridine diphosphate galactose) have been found in human milk [64]. Human milk contains a higher content of free nucleotides than cow milk. Thus, it is recommended to enrich cow milk-based formulas with the nucleotide level similar to that found in human milk [65]. Recently, legislation allows the addition to infant formulas and follow-on formula, nucleotides in quantities of: 1.5 mg adenosine-5-phosphate/100 kcal, 2.5 cytosine-5-phosphate/100 kcal, 0.5 kcal guanosine-5-phosphate/100 mg, 1.75 mg uridine-5-phosphate/100 kcal, 1 mg inosine-5-phosphate/100 kcal, until a total concentration of 5 mg/100 kcal, which is similar to the amounts of free ribonucleotides in milk (4–6 mg/100 kcal) [25]. Also in this context, Koletzko et al. [15] reported that ESPGHAN supports the optional addition of nucleotides in amounts not to exceed 5 mg/100 kcal as adverse effects have been seen with higher concentrations.
\nAddition of nucleotides to infant formulas have been found to increase the probiotic bacteria counts and reduce the pathogen counts in stool samples in infants fed on nucleotide-supplemented formula as compared to whose fed standard infant formula, but probiotic counts in the stool of breastfed infants were still higher. The intestinal microflora modulation attributed to nucleotides due to that nucleotides serve as an energy source of intestinal microflora. Because probiotic bacteria are characterized by a higher growth rate than pathogenic bacteria, they limit the growth of pathogens. Thus, supplementation with nucleotides able to positively modulate the intestinal microbial balance, leading to increase probiotic growth and limit the growth of the pathogens [66].
\nAlthough human milk contains all nutrients and provides diverse bioactive ingredients and considered the first functional food in infant life, it is not generally attractive, adequate, or acceptable or it is not available; in some cases, the infants cannot be breastfed. Thus, looking for a suitable alternative is of importance.
\nIn these cases, infant formulas play an indispensable role in infant nutrition. All efforts of industry are aimed to resemble human milk composition [67]. The accumulated knowledge about human milk composition highly assists in infant formula development. However, the human milk composition is not stable, since it changes along breastfeeding period [68], as well as depending on different factors such as environment, mother’s diet, and so on. Nowadays, companies and research centers are devoted to prepare these formulas focused on enhancing the quality of infant formulas, not only adapting the concentration of macronutrients and micronutrients but also the composition of bioactive compounds to make it as similar as possible to human milk [69] where the final aim of infant formula development is not necessarily to mimic the composition of human milk in every respect but to achieve physiological effects as in breastfed infants [70].
\nNowadays, there are numerous infant formulas adapted to special physiological state and infant formula based on soy or without lactose, among others. But, in this chapter, we are focused on those formula based on supplemented cow milk with functional ingredients. The current trend of infant formula manufacturing is to enrich it with the functional ingredients that naturally found in human milk. Thus, these ingredients such as probiotics, prebiotics (oligosaccharides), proteins such as lactoferrin and α-lactalbumin, nucleotides,and polyunsaturated fatty acids (mainly docosahexaenoic and arachidonic acids) among others are incorporated in infant formulas to make them more functional [71]. In fact, many studies revealed the higher efficacy of infant formulas supplemented with certain bioactive ingredients than the unsupplemented ones [72].
\nHuman milk must be always selected as the first option for the best infant nutrition. However, when it is impossible, an adequate substitute should be found. Historically, milk from different animals was studied, obtaining the best results for the cow. However, some problems have been found after using cow milk as a substitute, since the high-protein content, the different protein composition, and the sodium content, among others, could induce some metabolic problems to the not fully developed gastrointestinal system of newborns. From last decades until now, the infant formula has been developed trying to mimic to human milk in macronutrients and energy density, but it is in the most recent past when the functional ingredients are included in the infant formulation to simulate the beneficial health effects of breast milk. Table 3 shows the composition of infant formula supplemented or not including legal limits according to the European Commission [73].
\n\n | Standard infant formula | \nSupplemented infant formula | \nSupplemented infant formula | \n|
---|---|---|---|---|
\n | \n | \n | Minimum limit | \nMaximum limit | \n
Energy (kcal) | \n68 | \n67 | \n60 | \n70 | \n
Protein (g) | \n1.3 | \n1.5 | \n1.1 | \n2.1 | \n
Fat (g) | \n3.8 | \n3.5 | \n2.6 | \n4.2 | \n
α-Linoleic (mg) | \n586 | \n500 | \n300 | \n840 | \n
α-Linolenic (mg) | \n55.9 | \n61.5 | \n30 | \n70 | \n
AA (mg) | \n— | \n8.7 | \n— | \n42 | \n
DHA (mg) | \n— | \n8.6 | \n12 | \n35 | \n
Carbohydrate (g) | \n7.2 | \n7.5 | \n5.4 | \n9.8 | \n
FOS (g) | \n— | \n— | \n— | \n0.1 | \n
GOS (g) | \n— | \n0.5 | \n— | \n0.7 | \n
Others | \n\n | \n | \n | \n |
l-Carnitin (mg) | \n— | \n1.1 | \n0.8 | \n— | \n
Taurin (mg) | \n1.0 | \n6.0 | \n— | \n8.4 | \n
Nucleotides (mg) | \n— | \n3.2 | \n\n | 3.5 | \n
The composition of different infant formulas. Values are expressed as grams per 100 mL of reconstituted formula.
Source: Ref. [73].
As can be seen, different compounds are included in supplemented infant formulas in different concentrations. The caloric values have also been considered to establish a minimum or maximum legal limit for each one. Prebiotics (FOS and GOS) are considered as key compounds in human milk in order to promote an adequate intestinal microbiota; for this reason, infant formulas should be adequately supplemented. Beneficial bacteria of human milk should be also included in infant formulas; however, it is very difficult that added bacteria achieve colon as live microorganisms with beneficial effects on health.
\nOne of the functional ingredients added to infant formula is oligosaccharides (fructo- and/or galactooligosaccharides) since they are in human breast milk providing a beneficial effect on newborns due to its prebiotic activity. Furthermore, these compounds show anti-adhesive properties, protecting the intestinal epithelium against pathogens as well as enhancing the immune system that, in infants younger than 6 months, is not still fully developed.
\nPolyunsaturated fatty acids can be produced by newborns using its precursors (linolenic and linoleic acid), but this transformation pathway is not fully developed at this age. For that, most infant formulas are enriched with arachidonic and docosahexaenoic acids (ARA and DHA, respectively), since they play an important role in neuronal function and cognitive and visual development [74].
\nOther important bioactive compounds present in human milk are polyamines that are nitrogen compounds and are present in a very low concentration in cow’s milk. Nowadays, based on different studies, polyamines should be added to infant formula; however, due to the scarce information found in the literature about its specific function and the effect on human health on medium-long term, more studies should be developed. Studies performed show an interesting role of polyamines in the maturation of intestinal and immune systems of infants [75].
\nStudies in infant formula composition must be studied in detail. Related to this, there is no doubt that the proteins in human milk provide an important source of amino acids to rapidly growing breastfed infants. However, this is not the only one role of milk proteins since many of them also play a role in facilitating the digestion and uptake of other nutrients in breast milk. Included in this group of functional proteins are lactoferrin and haptocorrin, which may assist in the absorption of iron and vitamin B12, respectively [76]. Vitamin B12 in human milk is mostly bound to haptocorrin, and these proteins have also been suggested to inhibit pathogenic bacterial growth by tightly binding and withholding vitamins and minerals from the bacteria [77].
\nAnother important human milk protein is alpha-lactalbumin (15% of the total protein content). This protein is responsible, in the mammary gland, for lactose synthesis, but it is also secreted in the milk. This functional protein is easily digested, forming peptides that may provide different bioactivities in the upper gastrointestinal tract (duodenum and jejunum) [78]. Alpha-lactalbumin, after gastrointestinal digestion, serves as a good source of essential amino acids.
\nBreastfeeding during the first 6 months of infant life represents the cornerstone of building his body and maintaining his health status. Feeding of an infant during this critical period of life has several short-term and long-term effects. So, breastfeeding is recommended exclusively after birth till 6 months; then, the complementary food must be included to meet the increasing nutrients needed. As we know, human milk is the optimal food during this early stage of life. In some cases, infant formulas represent the best alternative for infant feeding which must resemble human milk composition not only in its macronutrients but also in its functionality.
\nAge-related macular degeneration (AMD) is a complex, degenerative, progressive, multifactorial disease with multiple genetic and environmental factors contributing to its onset and progression [1].
Age-related macular degeneration (AMD) represents damage of the retinal macula and thus the central visual field and is the leading cause of blindness and visual impairment in people over 60 years of age [2, 3]. Prevalence of an early AMD (the presence of medium-sized drusen or drusen with degeneration or hyperpigmentation of the retinal pigment epithelium (RPE)) is 18% in the elderly population between 65 and 74 years of age and as much as 30% in the population older than 74 years [4].
The initial site of damage, according to most researchers, is the retinal pigment epithelium, although some authors find primary damage in the choriocapillary or extracellular matrix of the sensory retina. Regardless of the location and mechanism of initial damage, there is an opinion that oxidative stress plays an increasingly important role in the genesis of age-related macular degeneration.
The eye is a unique organ, because it is constantly exposed to radiation, atmospheric oxygen, chemicals from the environment, but also to the physical damages [5]. Therefore, oxidative stress is one of the most important mechanisms of the onset of many eye diseases such as cataract, glaucoma, uveitis, retrolental fibroplasia, age-related macular degeneration, as well as various forms of retinopathy [6]. Most free radicals are formed as bioproducts of normal cellular physiology. The most common damage to the eye by free radicals is caused by hydroxyl radical (OH
The objective of this review was to describe the mechanisms of oxidative stress in order to elucidate their significance and association with the pathogenesis of AMD.
Based on the Beckman AMD classification system, the disease is classified into early-stage AMD, intermediate-stage AMD and late-stage AMD [8]. Early-stage AMD encompasses the presence of medium-sized drusen (63–125 μm) without any impairment of visual function. Intermediate-stage AMD is defined by the presence of large drusen (>125 μm) or/and abnormalities in the RPE. Late-stage AMD (advanced AMD) is classified into two clinical entities: central geographic atrophy (GA, dry or nonexudative AMD) and neovascular AMD (wet or exudative AMD) [9]. Irreversible loss of vision occurs in geographic atrophy when there is an irreversible loss of RPE and photoreceptor cells, usually in the perifoveal region of the macula. In the neovascular form of AMD, there is an invasion of new choroidal blood vessels (choroidal neovascularization-CNV), followed by retinal detachment and RPE and vision loss [9].
Oxidative processes participate in almost all pathological processes in the eye. The presence of oxidative stress has also been registered in uveitis, diabetic retinopathy, various forms of glaucoma, cataractogenesis and other degenerative processes [10]. As highly reactive intermediates, free radicals can lead to oxidative tissue damage through a number of mechanisms such as peroxidation of unsaturated fatty acids leading to disturbances in the permeability and fluidity of biological membranes, which is accompanied by increased membrane permeability. Oxidation of thiol groups of enzymes leads to a decrease in their activity and even inactivation of enzymes. Fragmentation of fatty acid chains leads to loss of membrane integrity, while disruption of lysosomal membrane continuity leads to release of hydrolytic enzymes and cell damage [11].
The oxidation of polyunsaturated fatty acids in the phospholipids of the cell membranes could damage the cell integrity and function. In addition to negative and destructive effects, this process may have important physiological functions such as: the lipid metabolism regulation, and changes in their physicochemical properties and permeability. Under controlled conditions, ROS enables the control of synthesis of biologically active prostaglandins and leukotrienes, proliferation and initiation of cell death.
Proteins are also targeted by free radicals’ action that could change their primary, secondary and even tertiary structure. Oxidative modifications of the primary structure of proteins resulting from the modification or loss of some amino acids or aggregation and fragmentation of proteins, which are reflected in changes in solubility and charge, are described [12]. These processes affect the integrity of the cell and its function and lead to oxidative tissue damage.
Oxidation of nucleic acids leads to changes in DNA structure, gene mutations, synthesis of inadequate genes or lack of synthesis of other genes. As a result of such processes, malignant cell transformations occur. Mitochondrial DNA is particularly sensitive to such transformations.
The degree of biomolecule damage depends on their vulnerability and intensity of oxidative stress. The repair of primarily damaged molecules results in structural changes that remain at the molecular, i.e. at the cellular level. At one point, the damage becomes so great that it exceeds the critical mass. At that moment, the symptoms of illness appear [13].
Eye damages caused by these changes as well as the mechanisms of antioxidant protection show certain specifics, not only in the eye as a special organ but also in its highly differentiated and specialised structures. Oxidative stress in epithelial cells occurs mainly as a consequence of a photodynamic process or as a by-product of oxidative phosphorylation in mitochondria.
The retina is very complex in its structure, and it is one of the highest oxygen-consuming tissues that continuously transforms light into vision, generating reactive oxygen species (ROS), such as the superoxide (O2•−), the hydroxyl radical (•OH), hydrogen peroxide (H2O2) and singlet oxygen (1O2) as normal metabolic by-products [14]. Generally, ROS are produced during oxidative metabolism under physiological conditions and participate in normal cellular metabolism [15]. Retinal photoreceptor membranes are rich in polyunsaturated fatty acids.
Photooxidative retinal damage is in the function of duration of intensity and wavelength of light. Changes that occur in the pigment layer of the retina are considered to be initial in the process of genesis of age-related macular degeneration. During ageing, functions of all senses gradually weaken. Degenerative processes in the eye and especially in the lens are the first signs of ageing that are noticed [10].
It is well established that light exposure has the potential to cause detrimental effects in RPE and retina as well as in many other organs and tissues, such as the skin, cornea, conjunctiva and lens [16].
Large quantities of ROS are produced by exposure to ultraviolet light (λ = 100–400 nm) and to blue light (λ = 400–500 nm) [17]. The photoreceptors in the macula absorb parts of the light spectrum through rhodopsin, a photoreceptor molecule in rods [18].
Roehlecke and Schumann [19] suggested that the synthesis of ROS occurred directly in outer segments of photoreceptors in the reaction catalysed by the enzyme nicotinamide adenine dinucleotide phosphate oxidase (NOX) as well as by the mitochondrial activity of the outer segments after absorption of visible blue light (λ = 405 nm) with an output power of 1 mW/cm2 [19]. The authors found that the generation of ROS is highly increased in the photoreceptors of retinal explants after 0.5–1 h of blue light absorption, due to increased NOX activity (especially NOX2 and NOX4). Under these conditions (light exposure of 1 mW/cm2), it is possible to do the following extrapolation to the superoxide anion [20]: 1) One granule of lipofuscin can synthesise 8 x 10−19 mol of superoxide anion/min; 2) since 1 mol contains 6.02 x 1023 molecules, then 1 granule is capable of producing 4.8 x 105 molecules of superoxide/min; and 3) if we take into account that the average cell volume is 2000 μm3 and if up to 19% of that volume is occupied by lipofuscin granules 1 μm in diameter, then each RPE cell has a synthesis capacity of 3.5 x 108 superoxide anions/per cell per minute [21].
This high level of free radical synthesis may explain why RPE cells contain a high concentration of various antioxidants [22]. The spectral dependence of lipofuscin explains the so-called ‘blue light hazard’ on retina. Light with a wavelength of 550 nm or less can cause ‘actin’ or photochemical damage, but is too low to cause thermal effects [23]. These photochemical lesions are expressed at the level of RPE, where the action spectrum of ‘blue light’ is similar to the bandwidth of the absorption spectrum of melanin [24] and lipofuscin [22, 25]. Photoreactivity analysis of blue light in freshly isolated RPE cells shows a high level of oxygen uptake with increasing age of the donor and that this ‘photo-uptake’ is predominantly related to lipofuscin [26]. These observations suggest a different function of lipofuscin in cells that may explain the association between high levels of lipofuscin and AMD. RPE cells are rich in antioxidants which may be enough to detoxify any reactive oxygen species [27]. Conversely, antioxidants may be insufficient to detoxify all radicals throughout life so that oxidative damage can manifest at some point in life (for example, in old age).
It has also been observed that lipofuscin photosensitivity reactions lead to increased intragranular lipid peroxidation, measured through the accumulation of lipid peroxides and malondialdehyde in pigment granules [26, 28]. Moreover, lipofuscin can perform extracellular lipid peroxidation and enzyme inactivation. Freshly isolated lipofuscin granules incubated with visible light induced up to a 30% increase in lipid peroxidation, compared with the control. Granules incubation with catalase (antioxidant) and lysosomal enzymes (acid phosphatase), in the presence of light, causes as much as 30–50% reduction in enzyme activity. Lipid peroxidation and loss of enzyme activity can be prevented by antioxidants which indicate that lipofuscin photodamage is a product of action of free reactive oxygen species. It is generally accepted that RPE cell dysfunction is an early, crucial moment in the pathogenesis of AMD [29, 30].
RPE cells have a variety of functions from metabolic to supportive, and they are vital for photoreceptors including maintenance of the blood-retinal barrier, participation in the visual cycle (uptake, transport and release of vitamin A and its metabolites) as well as in degradation and uptake of apical phagocited parts of the photoreceptor outer segments [31]. One of the leading factors of RPE cell dysfunction is age-related phagocytic and metabolic insufficiency of postmitotic RPE cells, leading to progressive accumulation of lipofuscin granules which are mainly composed of lipids (~50%) and protein (~44%) of phagosomal, lysosomal and photoreceptor origin (including the retinoid transporter-cellular retinaldehyde binding protein/CRALBP). These substances from the lipofuscin composition can be oxidatively modified either as a result of exposure to UV light or high doses of oxygen in the eye [29, 30].
The well-known cytotoxic constituent of lipofuscin is fluorophore bisretinoid which consists of two retinoid chains derived from the pyridinium ring (A2E) which together with other photoreactive molecules is a powerful photoinducible ROS generator with a strong effect on oxidative damage of lipids, proteins and DNA [31]. N-retinyl-N-retinyldiene-ethanolamine 2-(2,6-dimethyl-8-(2,6,6- trimethyl-1-cyclohexene-1-yl) -1E, 3E, 5E, 7E-octyltetraenyl]-1-(2-hydroxyethyl)-4-[4- methyl-6-(2,6,6-trimethyl] or A2E increases the RPE sensitivity to blue light and exhibits several toxic effects on RPE cells [32, 33]. By the action of light of wavelength, λ = 430 nm, A2E is converted to A2E-epoxide by binding to oxygen. The resulting epoxide can destabilise the membranes of mitochondria and lysosomes [34] and can also inhibit cytochrome oxidase, leading to disruption of electron flow in the respiratory chain [35]. This process, in addition to producing more ROS (reactive oxygen species), reduces the efficiency of energy metabolism. An alternative A2E toxic pathway has been described by Finnemann [36], who in a study with A2E-laden RPE cells demonstrated the presence of destabilised lysosomes, resulting in incomplete digestion of phagocited photoreceptors of the outer segments during 24 h. Since phagocytosis is a circadian regulated process, this will constantly increase the non-degraded phospholipids that are a source of ROS. Mitochondrial destabilisation and incomplete digestion of lipids and proteins caused by lysosome destabilisation lead to increased free radical accumulation. In a closed circle, this mechanism destabilises RPE cells, leading to their loss and this process conditions the initiation of drusen formation [37].
Although lipid peroxidation products are considered to be the main substrates for the genesis of lipofuscin and its cytotoxic constituents, other identified lipofuscin proteins also play a significant role in cytotoxicity [30, 31].
The study of King et al. conducted on the human adult RPE cell line-19 (ARPE-19) revealed that the mitochondrial electron transport chain was an important source of ROS which played a critical role in the death of cells exposed to short-wavelength blue light (425 ± 20 nm) [38].
Except lipofuscin, several other retinal pigments, such as rhodopsin and melanin, were shown to be involved in the oxidative stress process [39]. Grimm et al. reported rhodopsin-mediated blue-light-induced damage in the retina, which occurred after short time exposure to the blue light [40].
In the RPE, lipofuscin is derived primarily from phagocytosis of shed photoreceptor outer segments and is considered a heterogeneous waste material that accumulates with age in active postmitotic cells, such as those of the RPE [41]. The RPE cells are able to phagocyte the photoreceptors of outer segments (POSs) that contain a high amounts of unsaturated fatty acids [42]. During phagocytosis, a high quantity of oxygen is consumed and a significant production of ROS occurs (generated by NOX or peroxidase) via the oxidation of fatty acids in the POSs [43]. Mitter et al. in their study have shown that autophagy plays a significant role in protection of the RPE from oxidative stress [44]. Recent evidence showed that dysfunctional autophagy/mitophagy in the RPE may lead to mitochondrial disintegration by affecting the mitochondrial fission/fusion ratio, resulting in excessive amounts of ROS [45].
Excessive synthesis of free radicals in the eye is associated with the production of oxidatively modified compounds and cytotoxic damage of ocular structures. The cell types with relatively high levels of polyunsaturated fatty acids (PUFAs), such as retinal cells, are highly sensitive to lipid peroxidation. Polyunsaturated fatty acids in phospholipids and glycolipids are the basic substrate of oxidative damage to lipids caused by free radicals.
Lipid peroxidation, a complex process involving the interaction of oxygen-derived free radicals with polyunsaturated fatty acids, finally results in a variety of primary compounds: highly reactive compounds (alkyl radicals, conjugated dienes, peroxy and alkoxy/oxyl radicals and lipid hydroperoxide). During further decomposition of primary compounds, a series of secondary products are produced such as: short-chain evaporable hydrocarbons, aldehydes and end products of lipid peroxidation (i.e. isoprostanes, MDA, 4-hydroxy-2,3, trans nonenal and 4,5-dihydroxydecenal) [46, 47].
MDA is a secondary product of peroxidation of unsaturated fatty acids, (particularly arachidonic acid) and is a physiological ketoaldehyde [48]. In a higher concentration, it reacts with free amino groups of proteins (especially with lysine cysteine or histidine residue). Such modified protein structures have immunogenic features. Some studies have shown that an increased titre of these autoantibodies directly correlates with the extent of oxidative damage and may predict the progression of some diseases. It was suggested that reduced ability to protein proteolysis after their oxidative modification with MDA and 4-HNE represents one of the main factors of lipofuscin synthesis during the development of AMD [49].
Lipid peroxidation highly reactive end products, such as 4-hydroxylnonenal (4-HNE), malondialdehyde (MDA), oxidised nucleotides and carboxyethyl pyrrole (CEP), have been demonstrated to be associated with drusen formation and RPE atrophic modifications in both human and animal eye [50].
Recently, Kim et al. [51] found that the injection of hydroperoxy-octadecadienoic acid (HpODE), (a peroxidized lipid) into the subretinal space of a murine AMD model, could initiate an early increase in the expression of markers of oxidative stress and lipid peroxidation, especially high levels of 4-HNE and MDA [51]. Zor et al. [52] documented a significantly increased MDA values (~15%) in patients with neovascular AMD compared with the controls [53].
F2-isoprostane (F2-IsoPs) is another marker of lipid peroxidation which is considered to be an important ‘in vivo’ marker of oxidative damage in AMD [54, 55]. Sabanayagam et al. [56] demonstrated that the presence of F2-IsoPs in urine was positively associated with AMD.
Oxidative DNA damage of both nuclear and mitochondrial genomes can result in strand breaks, base modifications and DNA-protein cross linkages which are all strongly implicated in ageing and age-related diseases [57, 58]. Over 20 base modifications related to ROS attack of DNA are identified, with the following oxidative DNA damage products: 8-oxo-7,8-dihydroadenine, 8-oxo-7,8-dihydroguanine, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 5,6-dihydroxy-5,6-dihydrothymine as well as the ring-opened lesions of 4,6-diamino-5-formamido-pyrimidine and 2,6-diamino-4-hydroxy-5-formamido-pyrimidine [59]. The 8-oxodG, which is formed through the oxidation of guanine at the C8 position in the guanine base, serves as a reliable biomarker of oxidative stress and oxidative modification of DNA, and it is associated with ageing and ageing-related diseases [58].
Age-related increases in lipofuscin, 8-oxoguanine, CEP, 4-HNE and MDA expression have been observed in the ageing retina [60, 61, 62] which have been reported to cause inflammatory responses and AMD features [63].
Age-related macular degeneration is characterised by degenerative changes involving the outer portion of the retina, RPE, Bruch’s membrane and choriocapillaris. Drusen are considered as a hallmark of AMD and as an amorphous deposit that accumulates extracellularly in the zone between the RPE and the inner collagen zone of the Bruch’s membrane [64]. Clinically, they are divided into two main phenotypes: ‘soft and hard’, depending on their relative size and shape. A few smaller hard drusen (<65 μm) can be found in at least 95% of the elderly population, but do not represent AMD. Only the presence of larger drusen (>125 μm), especially soft drusen (> 125–250 μm) in the macula, is considered as a major risk factor for the development of advanced forms of AMD, i.e. exudative-neovascular forms, especially if they are combined with pigmentation disorders [65].
In the later stage of AMD, neovascularization, exudative changes or disciform scars can occur. In the atrophic form of AMD, there is a loss of pigment epithelium or ‘attenuation’ of the choriocapillaris but without neovascularization [66]. Early pathological changes include basal deposits in the Bruch’s membrane which occur exclusively in pathological samples and have two types: a) basal laminar deposits consisting of basement membrane proteins and long collagen filaments located between RPE and basement membrane and b) basal linear deposits that are more specific for early AMD changes and consist mainly of membrane material located in the Bruch membrane, externally from the RPE basement membrane. The combination of these deposits with secondary changes in RPE results in the formation of drusen [67].
Many different molecules have been identified in drusen, including glycoconjugates and other compounds also found in atherosclerotic plaque (hence the link between atherosclerosis and AMD formation by some authors), including vitronectin, apoprotein B and E, α-crystalline, HtrA1 and lipids [68, 69, 70]. Macrophages found in drusen regression suggest a possible hypothesis that macrophages are involved in the process of degradation of deposits within the Bruch membrane [71]. Activated microglias have also been found in AMD degenerative lesions [72]. Discrete nodules or hard drusen deposits consisting of hyaline-like material were found between the RPE and the Bruch membrane. Soft drusen are usually large and occur with detachment of RPE cells and diffuse changes of the Bruch membrane. They can occur in deeper damages of the RPE and choroids and lead to choroidal neovascularization or cell death in the RPE as well as geographical atrophy. Autofluorescent pigments, such as lipofuscin, which are accumulated in RPE cells, reach a size that often leads to decreased cellular function, retinal ageing and degeneration, mostly in the form of geographic atrophy [73].
Lipofuscin in RPE is the most common cause of fundus autofluorescence. These are spherical particles of micrometre size with characteristic yellow fluorescence when exposed to blue light. The main component of lipofuscin is N-retinylidine-N-retinyletanol-amine (A2E), a quaternary amine and retinoid bioproduct of visual cycle [74]. Lipofuscin synthesis is a pathogenic reaction in which the resulting A2E interferes with the function of RPE cells and leads to their apoptosis. Choroidal neovascularization can occur in the macular, peripapillary and peripheral regions. Early choroidal neovascularization occurs below the RPE cells to later break through the RPE layer and develop an exudative, haemorrhagic or disciform form of AMD. In the neovascular form of AMD, lipid accumulation occurs below the RPE or neuroretin. In the haemorrhagic form of AMD, blood penetrates through the RPE into the subretinal space and sometimes through the retina to the vitreous. In the disciform form of AMD, fibrous tissue with neovascularization and changes in RPE cells proliferates and may partially or totally replace neuroretin [75]. Additional pathological lesions include serous exudation, haemorrhage, gliosis and calcification. Macrophages have been proven both morphologically and functionally in the neovascular form of AMD [76]. Activated macrophages and microglias can secrete chemokines and cytokines, causing further cell damage, degradation of the Bruch’s membrane and angiogenesis [77].
Among AMD cases, approximately 10–15% have neovascular AMD characterised by abnormal vascular morphology and growth [8]. Vascular endothelial growth factor (VEGF) upregulation plays a crucial role in the development of neovascular AMD. Yi and assoc. [78] documented an increased VEGF expression in a study using laser to induce choroidal neovascularization (CNV) in rats. This author suggests that the macrophages could be probably the most important source of VEGF in the early phase of AMD [78]. VEGF expression in subfoveal fibrovascular membranes was concentrated in cells resembling fibroblasts, implicating a significant role of fibroblasts in the progression of CNV [79]. The results showed that even temporary overexpression of VEGF in RPE cells was sufficient to induce CNV in the rat eye [80]. Wang et al. reported that IQ protein motif-containing GTPase activating protein 1 (IQGAP1), scaffold protein with a Rac1-binding domain, regulated VEGF activation by binding to Rac1GTP in choroidal endothelial cells, activating their migration [81]. IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein that is involved in multiple cellular functions such as cell survival and trafficking [82].
The vascular endothelial dysfunction is considered as a crucial event in development and progression of choroidal vascular dysfunction [82]. Nitric oxide and nitric oxide synthase enzymes have been shown to be involved in the upregulation of VEGF. Nitric oxide synthases (NOSs) are a family of enzymes that catalyse the conversion of L-arginine into nitric oxide (NO). They are classified into three isoforms: endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) [83]. The eNOS maintains the physiological function of the vascular endothelium [84]. It was demonstrated that eNOS mediated endothelium-dependent vasodilation in retinal arterioles and ophthalmic arteries [85]. NO is considered not only a mediator of vasodilation, but also a regulator of various vascular functions. For example, physiologically, NO can dilate a blood vessel, inducing relaxation of vascular smooth muscle cells (VSMCs), inhibiting cell proliferation and regulating angiogenesis and vascular permeability [86]. Bhutto et al. [87] reported that eNOS and nNOS expression was significantly decreased in the eyes of AMD patients. This author suggested that the decreased expression of eNOS and nNOS might reduce the NO production that could induce hemodynamic changes in CNV [87].
It was documented that excessive amounts of NO can have detrimental effects on cells and tissues, implicated that the production of NO is not always beneficial. In that case, NO can be an important stimulator of CNV. Ando et al. suggested that blockade of nNOS and iNOS could reduce CNV formation [88]. Excessive amounts of nitric oxide can react with the superoxide anion to form peroxynitrite, a very toxic and reactive radical which compromises vascular endothelial function [89].
There is some evidence that ROS and vascular dysfunction may together contribute to the pathology of neovascular AMD. It was demonstrated that NOX was the connection between VEGF and ROS in human choroidal endothelial cells [90]. The family of NOX consists of seven isoforms such as: NOX1, NOX2, NOX3, NOX4, NOX5, dual oxidase (Duox) 1 and Duox2) which are differentially expressed in tissues and cells [91]. NOX1, NOX2 and NOX4 are expressed in choroidal vascular endothelial cells [92]. ROS generated by NOX function as signalling molecule promoting endothelial cell proliferation, migration and tube formation [92]. Some studies documented that ROS generated from NOX2 could activate the transcription factors NF-κB and activator protein 1 (AP-1) and increase the expression of intracellular adhesion molecule (ICAM)-1 and VEGF leading to vascular hyperpermeability and retinal neovascularization [93]. Moreover, NOX4-derived ROS generation is essential for the expression of hypoxia-inducible factor 1-alpha (HIF-1α) which was linked to cell proliferation and migration of vascular smooth muscle cells [94].
One of the risk factors for AMD may be increased collagen synthesis in the choriocapillaris which is then incorporated into the Bruch’s membrane, creating thickenings that precede the appearance of linear deposits [95]. Chromatographic analysis of the drusen showed that they contained more than a hundred different proteins originated from retinal pigment epithelial cells, neuronal retinas and choriocapillaris. However, their composition differs depending on the existence i.e. absence of AMD. It is thought that certain ingredients can promote angiogenesis. The integrity of the RPE cellular structures in a culture that is chronically exposed to oxidative stress is impaired by the action of hydrogen peroxide due to the interruption of intercellular compounds. This is one of the possible mechanisms of breaking the blood-brain barrier in the pathogenesis of AMD [96].
Programmed cell death (apoptosis) is an essential protective mechanism of the organism against the accumulation and spread of damaged or unnecessary cells. An increased degree of apoptosis is observed in most ageing cell populations. A similar thing happens in RPE cells. There is an opinion that mitochondria play a key role in the regulation of apoptosis. Reactive oxygen metabolites that are formed in RPE cells exposed to the blue part of the spectrum originate in mitochondrial processes [97]. Oxidative stress can reduce the sensitivity of senescent cells to apoptosis through defective oxidative phosphorylation. The process of drusen formation is very similar to apoptotic process in the retina and predisposes the development of neovascularization during the progression of AMD [98].
In postmitotic tissues, during ageing, the oxidatively modified and damaged mitochondrial DNA are accumulated in mitochondria. It is believed that their genetic material is the main substrate of oxidative damage in the retinal pigment epithelium. With inefficient damage repair, redox potential of mitochondria in the human RPE retinal cells is compromised over time in photoreceptors as well [99].
It was suggested that other types of regulated cell death (e.g. pyroptosis, necroptosis and autophagy) may contribute to development of AMD [100]. Ferroptosis is a newly discovered, iron-dependent, regulated cell death pathway that is initiated by lipid peroxidation. It is implicated in neurodegeneration, ischemia–reperfusion injury and myocardial infarction [101]. It is characterised by iron-dependent accumulation [102, 103]. In contrast to apoptosis, ferroptosis is a pro-inflammatory condition that arises due to the release of intracellular content after the rupture of plasma membrane [104]. Under normal conditions, ferroptosis is a mechanism that protects cellular integrity, but leads to cell death when cellular integrity is compromised, while apoptosis represents a suicide mechanism that eliminates certain types of cells from the whole organism at specific time points [105].
It was documented that angiotensin II (Ang II) was implicated in the pathology of AMD. It was shown that Ang II can mediate various pathological processes in ocular blood vessels such as proliferation and migration of smooth muscle cells and pericytes, increase of VEGF expression and potentiation of VEGF-dependent angiogenic activity [106, 107]. Receptors for AngII have been identified in retinal and optic nerve blood vessels. Some studies have shown that blocking the renin-angiotensin system may delay the breakdown of the blood-retinal barrier and prevent retinal neovascularization and the development of AMD [108].
In this review, we tried to highlight the pathways of oxidative stress and their implication in the pathogenesis of AMD. Considering the unique structure and function of the retina in the eye, as well as the environment in which it is located, it indicates a significant synthesis of free radicals during normal physiological processes as well as during light absorption. The presence of free fatty acids and their exposure to free radicals make lipid peroxidation processes a daily occurrence in the eye. This was confirmed by many studies that found high concentrations of MDA, 4-HNE and other lipid peroxidation products in the eyes (and blood) of AMD patients. Oxidative damage of mitochondria and nuclear DNA was also observed in AMD patients, as well as increased products of oxidative damage of proteins. An impairment of autophagy and other types of cell death such as pyroptosis, necroptosis and ferroptosis were also described in AMD patients. The upregulation of VEGF and isoforms of NOX with impairment of NO synthesis have significant implications in the development of new blood vessels and the onset of choroidal neovascularization (CNV) in the pathogenesis of advanced-wet AMD. In view of all the above, further research is certainly needed in order to find adequate methods for disease prevention as well as adequate drugs for the treatment of various forms of AMD.
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Rezek",authors:[{id:"107471",title:"Dr.",name:"Egor",middleName:null,surname:"Ukraintsev",slug:"egor-ukraintsev",fullName:"Egor Ukraintsev"}]}],mostDownloadedChaptersLast30Days:[{id:"69731",title:"Isolation and Purification of Sulfate-Reducing Bacteria",slug:"isolation-and-purification-of-sulfate-reducing-bacteria",totalDownloads:1550,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"Sulfate-reducing bacteria (SRB) are a widespread group of microorganisms that are often isolated from the anoxygenic environments (lake depths, soil, or swamps), and they are also present in the human and animal intestines. This group is often detected in patients with inflammatory bowel disease, including ulcerative colitis. That is why new rapid methods for their isolation, purification, and identification are important and necessary. In this chapter, the methods of mesophilic SRB isolation from various environments are described. Particular attention is paid to the purification of mesophilic SRB since they can be in close interaction with other microorganisms (Clostridium, Bacteroides, Pseudomonas, etc.), which are their frequent satellites. Moreover, the main methods of mesophilic SRB identification based on their morphological, physiological, biochemical, and genetical characteristics are presented.",book:{id:"8997",slug:"microorganisms",title:"Microorganisms",fullTitle:"Microorganisms"},signatures:"Ivan Kushkevych",authors:[{id:"252191",title:"Associate Prof.",name:"Ivan",middleName:null,surname:"Kushkevych",slug:"ivan-kushkevych",fullName:"Ivan Kushkevych"}]},{id:"65773",title:"Life Cycle of Trypanosoma cruzi in the Invertebrate and the Vertebrate Hosts",slug:"life-cycle-of-em-trypanosoma-cruzi-em-in-the-invertebrate-and-the-vertebrate-hosts",totalDownloads:1490,totalCrossrefCites:4,totalDimensionsCites:7,abstract:"Trypanosoma cruzi (T. cruzi) is a protozoan parasite that causes Chagas disease, a zoonotic disease that can be transmitted to humans by blood-sucking triatomine bugs. T. cruzi is a single-celled eukaryote with a complex life cycle alternating between reduviid bug invertebrate vectors and vertebrate hosts. This article will look at the developmental stages of T. cruzi in the invertebrate vector and the vertebrate hosts, the different surface membrane proteins involved in different life cycle stages of T. cruzi, roles of different amino acids in the life cycle, carbon and energy sources and gene expression in the life cycle of T. cruzi. The author will also look at extracellular vesicles (EV) and its role in the dissemination and survival of T. cruzi in mammalian host.",book:{id:"8806",slug:"biology-of-em-trypanosoma-cruzi-em-",title:"Biology of Trypanosoma cruzi",fullTitle:"Biology of Trypanosoma cruzi"},signatures:"Kenechukwu C. Onyekwelu",authors:[{id:"245368",title:"Dr.",name:"Kenechukwu C.",middleName:null,surname:"Onyekwelu",slug:"kenechukwu-c.-onyekwelu",fullName:"Kenechukwu C. Onyekwelu"}]},{id:"54154",title:"Staphylococcus aureus: Overview of Bacteriology, Clinical Diseases, Epidemiology, Antibiotic Resistance and Therapeutic Approach",slug:"staphylococcus-aureus-overview-of-bacteriology-clinical-diseases-epidemiology-antibiotic-resistance-",totalDownloads:7214,totalCrossrefCites:14,totalDimensionsCites:26,abstract:"Staphylococcus aureus is an important human pathogen that causes wide range of infectious conditions both in nosocomial and community settings. The Gram-positive pathogen is armed with battery of virulence factors that facilitate to establish infections in the hosts. The organism is well known for its ability to acquire resistance to various antibiotic classes. The emergence and spread of methicillin-resistant S. aureus (MRSA) strains which are often multi-drug resistant in hospitals and subsequently in community resulted in significant mortality and morbidity. 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To overcome some of the major limitations of chemical control methods such as rising resistance, environmental and health risks, and the adverse effect on non‐target organisms, biological control (biocontrol) is now at the forefront of parasite (pests) control. Biocontrol is now a core component of the integrated pest management. Biocontrol is defined as “the study and uses of parasites, predators and pathogens for the regulation of host (pest) densities”. Considerable successes have been achieved in the implementation of biocontrol strategies in the past. This chapter presents a review of the history of biocontrol, its advantages and disadvantages; the different types of biological control agents (BCAs) including predators, parasites (parasitoids) and pathogens (fungi, bacteria, viruses and virus‐like particles, protozoa and nematodes); the effect of biocontrol on native biodiversity; a few case studies of the successful implementation of biocontrol methods and the challenges encountered with the implementation of biocontrol and future perspectives.",book:{id:"5527",slug:"natural-remedies-in-the-fight-against-parasites",title:"Natural Remedies in the Fight Against Parasites",fullTitle:"Natural Remedies in the Fight Against Parasites"},signatures:"Tebit Emmanuel Kwenti",authors:[{id:"191763",title:"Dr.",name:"Tebit Emmanuel",middleName:null,surname:"Kwenti",slug:"tebit-emmanuel-kwenti",fullName:"Tebit Emmanuel Kwenti"}]},{id:"70336",title:"Plastics Polymers Degradation by Fungi",slug:"plastics-polymers-degradation-by-fungi",totalDownloads:1453,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"The studies on plastic degradation are very important for the development of biodegradable plastics, and for reduction of pollution, since plastic waste can remain in the environment for decades or centuries. We have showed the degradation of oxo-biodegradable plastic bags and green polyethylene by Pleurotus ostreatus. This fungus can also produce mushrooms using these plastics. The plastic degradation was possibly by three reasons: (a) presence of pro-oxidant ions or plant polymer, (b) low specificity of the lignocellulolytic enzymes, and (c) the presence of endomycotic nitrogen-fixing microorganisms. In this chapter, the plastic bags’ degradation by abiotic and microbial process using the exposure to sunlight and the use of a white-rot fungus will described. The physical, chemical, and biological alterations of plastic were analyzed after each process of degradation. The degradation of plastic bags was more effective when the abiotic and biotic degradations were combined.",book:{id:"8997",slug:"microorganisms",title:"Microorganisms",fullTitle:"Microorganisms"},signatures:"José Maria Rodrigues da Luz, Marliane de Cássia Soares da Silva, Leonardo Ferreira dos Santos and Maria Catarina Megumi Kasuya",authors:[{id:"217699",title:"Dr.",name:"Jose Maria",middleName:null,surname:"Da Luz",slug:"jose-maria-da-luz",fullName:"Jose Maria Da Luz"}]}],onlineFirstChaptersFilter:{topicId:"151",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). 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He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!0,editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",slug:"tomas-jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",biography:"Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his Ph.D. degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his D.Sc. degree. His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. He is also a reviewer and a member of editorial boards of a number of international journals.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",slug:"katarzyna-garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",biography:"Katarzyna Maria Garbacz, MD, is an Associate Professor at the Medical University of Gdańsk, Poland and she is head of the Department of Oral Microbiology of the Medical University of Gdańsk. She has published more than 50 scientific publications in peer-reviewed journals. She has been a project leader funded by the National Science Centre of Poland. Prof. Garbacz is a microbiologist working on applied and fundamental questions in microbial epidemiology and pathogenesis. Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. 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